Clinical trial NCT01118026
Conditions: Lymphoma
Keywords: stage I adult Hodgkin lymphoma stage II adult Hodgkin lymphoma adult favorable prognosis Hodgkin lymphoma adult lymphocyte depletion Hodgkin lymphoma adult lymphocyte predominant Hodgkin lymphoma adult mixed cellularity Hodgkin lymphoma adult nodular sclerosis Hodgkin lymphoma adult unfavorable prognosis Hodgkin lymphoma
Sponsor: Alliance for Clinical Trials in Oncology
Start date: 2010-09-01; Completion date: 2021-09-29
Enrollment: 101 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research is being done in order to improve treatment outcomes in patients diagnosed with bulky, early stage Hodgkin lymphoma and to reduce the side effects that are associated with use of radiation used in current treatments. The chemotherapy treatment in this study consists of a combination of four drugs approved by the Food and Drug Administration (FDA): doxorubicin, bleomycin, vinblastine, and dacarbazine. This regimen (called ABVD) has been found to be effective in treating patients with Hodgkin lymphoma and is considered the standard of treatment used with radiation therapy in patients with bulky early stage Hodgkin lymphoma. As part of the evaluation of the effectiveness of the chemotherapy treatment, PET scans will be obtained during the course of therapy. The usefulness of this PET scan will be evaluated to determine whether radiation may be left out in the treatment of disease if the PET scan shows that the patient has responded to chemotherapy alone. The plan is to identify a group of patients using early PET scans in order to change to a chemotherapy treatment called BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone). It is one of the most highly effective chemotherapy regimens for Hodgkin lymphoma, but is associated with more side effects than ABVD. Although it has become standard of care in Europe, its use has been more limited in the U.S. because of concerns about toxicity.

Detailed description:
This is single-arm phase II clinical trial of response-adapted therapy based on PET for bulky stage I and stage II Hodgkin lymphoma. A maximum of 123 patients will be entered to the study. The primary outcome of this study is progression-free survival (PFS), defined as the time from study entry to disease progression or death.

Primary Objective:

To determine the progression-free survival (PFS) at 36 months from enrollment for patients with bulky stage I and II Hodgkin lymphoma. All patients will begin treatment with ABVD. Patients who are PET negative after 2 cycles of chemotherapy will receive 6 cycles of ABVD without radiotherapy. Patients who are PET positive after 2 cycles of ABVD will then receive 4 cycles of escalated BEACOPP followed by IFRT. A comparison will be made of the 36-month PFS between patients who are PET positive and those who are PET negative following 2 cycles of ABVD.

Secondary Objectives:

1. To evaluate the complete response (CR) rate of patients diagnosed with bulky stage I and II Hodgkin lymphoma following PET response-adapted chemotherapy with or without radiation therapy.
2. To determine the predictive value of FDG uptake using various semiquantitative approaches, at baseline, after 2 cycles of ABVD and at completion of therapy.
3. To determine the predictive value of volumetric vs. 2 dimensional (2-D) measurement changes on CT between baseline and after 2 cycles, at the end of chemotherapy (PET negative patients only) and after RT (PET positive patients only) and compare with PET parameters.
4. To determine if changes in both qualitative and semiquantitative FDG-PET findings between baseline and after cycle 2, at end of chemotherapy (PET negative patients only) and after RT (PET positive patients only) with combination analyses with incorporating changes obtained from dedicated CT scans, correlate with response and PFS.
5. To compare the predictive value of both qualitative and semiquantitative FDG-PET changes, 2-D and volumetric CT changes, and combinatorial analyses (PET+dedicated CT data) with molecular parameters, and conventional parameters, including IPS.
6. To assess whether elevated baseline serum soluble CD30 (sCD30), IL10, CCL17, and CCL22 correlate with clinical response and PFS.
7. To assess whether persistent or recurrent elevation of serial serum sCD30, IL10, CCL17, or CCL22 correlate with relapse/progression or PET scan results.
8. To confirm independently useful tissue biomarkers (bcl-2, MAL, FOXP3, CD68, GzB) for risk stratification in patients with bulky stage I and II Hodgkin lymphoma treated with this regimen.
9. To compare mediastinal bulk on standing PA and lateral chest x-ray (\> 0.33 maximum chest diameter) with chest CT (mass \> 10 cm).

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 2-3 years, and then once a year for a maximum of ten years from the time of entry on the study.

Arms: arm 1: Patients receive ABVD administered by intravenous (IV) infusion on days 1 and 15 of each cycle. A cycle is considered 28 days. Patients receive a total of two cycles.

Patients undergo a PET scan following two cycles of ABVD. If the PET scan is negative, then the patient will receive four more cycles of ABVD (a total of 6 cycles of ABVD). If the PET scan is positive, then the patient receives four cycles of escalated BEACOPP for 21 days (a total of 4 cycles).

3-6 weeks after BEACOPP therapy, patients receive radiation therapy for 5 days per week (a total of 3.5 weeks).

All patients will be followed for a maximum of ten years.
Interventions: intervention 1: ABVD intervention 2: BEACOPP intervention 3: radiation therapy
Intervention descriptions: intervention 1: doxorubicin 25 mg/m\^2 IV bleomycin 10 units/m\^2 IV vinblastine 6 mg/m\^2 IV dacarbazine 375 mg/m\^2 IV intervention 2: bleomycin 10 units/m\^2 IV on Day 8 etoposide 200 mg/m\^2 IV on Days 1, 2 and 3 doxorubicin 35 mg/m\^2 IV on Day 1 cyclophosphamide 1250 mg/m\^2 IV on Day 1 vincristine 1.4 mg/m\^2 IV on Day 8 procarbazine 100 mg/m\^2 orally on Days 1-7 prednisone 40 mg/m\^2 orally on Days 1-14 intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 






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P H A S E II T RI A L O F R E S P O N S E - AD A P T E D T H E R A P Y B A S E D O N P O SI T R O N E MI S SI O N T O M O G R A P H Y 
( P E T) F O R B U L K Y S T A G E I A N D S T A G E II C L A S SI C A L H O D G KI N L Y M P H O M A  
Sc he m a 
 
Eli gi bilit y Criteri a  
I niti al Re q uire d L a b or at or y V al ues 
Hist ol o gicall y  d oc u me nte d  sta ge  I A,  I B,  II A,  II B  classical 
H o d g ki n l y m p h o ma.  
A N C  
≥ 1 0 0 0/ µ L  
N o d ular  l y m p h oc yte  pre d o mi na nt  H o d g ki n  l y m p h o ma  is 
e xcl u de d. 
Platelet C o u nt  
≥ 1 0 0, 0 0 0/ µ L  
Mass > 1 0 c m or > 0. 3 3 ma xi m u m i ntrat h oracic dia meter (see 
Secti o n 4. 1. 2 ). 
Ser u m Creati ni ne  
≤ 2 m g/ d L  
N o c urre ntl y acti ve sec o n d mali g na nc y ot her t ha n n o n - 
   mela n o ma s ki n  ca ncers.  
Bilir u bi n 1 
≤ 2 x U L N  
A S T  
≤ 2 x U L N  
N o pri or treat me nt f or H o d g ki n l y m p h o ma , a part fr o m o ne 
    c ycle of A B V D (see Secti o n 4. 3 ). 
 
 
E C O G P erf or ma nce Stat us 0 -2.  
 
L V E F b y E C H O or M U G A wit h i n i nstit uti o nal n or mal li mits.2  
D L C O ≥ 6 0 % wit h n o s y m pt o matic p ul m o nar y disease. 2 
 
Patie nts wit h k n o w n HI V m ust ha ve a C D 4 c o u nt >  3 5 0  a n d 
    be o n c o nc urre nt a ntiretr o virals.  
 
 
N o n -pre g na nt a n d n o n -n ursi n g.  
1I n t he a bse nce of Gil bert’s disease 
A ge 1 8 -6 0 years.  
 2U nless t h o u g ht t o be disease relate d  
 
Acc ess t o F D G-P E T/ C T  is a re q uire me nt f or i nstit uti o ns e nr olli n g p atie nts o n t his pr ot oc ol. I nstit uti o ns 
m ust be cre de nti ale d by t he Alli a nce  I m a gi n g C ore L a b at I R O C O hi o pri or t o e nr olli n g p atie nts (see 
Secti o n 8. 1. 1 ). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I F R T (see Secti o n 7. 2)  
P E T/ C T sca n a n d Ce C T sca n  
( Ce C T li mite d t o i n v ol ve d sites at b aseli n e) * 
A B V D x 2 c ycles  
 
A B V D x 4 c ycles  
(t otal of 6 c ycles) 
Escalate d B E A C O P P * * ( x 4 c ycl es) 
 
F oll o w -U p †  
 
R E GI S T R A TI O N  
 
C R, P R, S D: P E T –  
( Secti o n 7. 3. 1 ) 
 
C R, P R, S D: P E T +  
 
 
 
C R, P R, S D: P E T –  
 
C R, P R, S D: P E T +  
 
P E T/ C T sca n,  
C T sca n (li mite d t o i n v ol ve d site at b aseli n e) *  
 
A B V D Tre at me nt  
C ycle = 2 8 d a ys  
Escalate d B E A C O P P 
Treat me nt * *  
C ycle = 2 1 d a ys  
Bi o ps y ‡ 
P ositi ve  
Bi o ps y ‡ 
Ne gati v e  
Bi o ps y 
Deferre d ‡  
See Secti o n 
1 4. 1. 2  
F oll o w -U p †  
 
P E T/ C T 
sca n¥  
 
See Secti o ns 7. 3. 1  a n d 7. 3. 2.  
 


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* 
If t he P E T/ C T sca n was perf or me d pri or t o c o ntrast-e n ha nce d C T ( Ce C T) a n d s h o ws disease c o nfi ne d 
t o a s pecific a nat o mic l ocati o n/s (e. g. nec k, c hest, a b d o me n, pel vis), Ce C T after t w o c ycles of A B V D 
a n d at e n d of treat me nt ca n be li mite d t o t he i n v ol ve d a nat o mic l ocati o n.  
* * F or  HI V  p ositi ve  patie nts,  sta n dar d  B E A C O P P  will  be  use d  i nstea d  of  escalate d  B E A C O P P  (see 
Secti o n 7. 1. 3 ). 
†  F oll o w- u p acc or di n g t o t he p ost- treat me nt sc he d ule i n Secti o n 6. 0 . 
‡ 
Bi o ps y ma y be perf or me d if me dicall y necessar y at t he discreti o n of t he treati n g p h ysicia n. If bi o ps y is 
neit her cli nicall y i n dicate d n or me dicall y a p pr o priate, t he n patie nt s h o ul d u n der g o a re peat P E T/ C T 
t hree m o nt hs l ater as n ote d i n t he f o ot n ote ( ¥) bel o w. 
¥ 
If bi o ps y is neit her cli nicall y feasi ble n or a p pr o priate, t he n re peat P E T/ C T s h o ul d be o btai ne d 3 m o nt hs 
later (see Secti o n  7. 3. 2 ). 
 


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T A B L E O F C O N T E N T S  
 
S E C TI O N  
P A G E  
1. 0  
I N T R O D U C TI O N ........................................................................................................................... 9 
1. 1  
T R E A T M E N T O F B U L K Y E A R L Y  S T A G E H O D G KI N L Y M P H O M A  .................................................... 9 
1. 2  
R O L E O F P E T  S C A N NI N G I N H O D G KI N L Y M P H O M A  ..................................................................... 9 
1. 3  
B E A C O P P  I N H O D G KI N L Y M P H O M A  ......................................................................................... 1 0 
1. 4  
R A TI O N A L E F O R I F R T D O S E  ....................................................................................................... 1 0 
1. 5  
R A TI O N A L E F O R C U R R E N T S T U D Y  .............................................................................................. 1 2 
1. 6  
IN C L U SI O N O F W O M E N &  M I N O RI TI E S ....................................................................................... 1 2 
2. 0  
O B J E C TI V E S  ............................................................................................................................... 1 3 
2. 1  
P RI M A R Y O BJ E C TI V E  .................................................................................................................. 1 3 
2. 2  
S E C O N D A R Y O BJ E C TI V E S  ............................................................................................................ 1 3 
3. 0  
O N -S T U D Y G UI D E LI N E S  .......................................................................................................... 1 4 
4. 0  
E LI GI BI LI T Y C RI T E RI A  .......................................................................................................... 1 4 
4. 1  
D O C U M E N T A TI O N O F D I S E A S E .................................................................................................... 1 4 
4. 2  
S E C O N D M A LI G N A N C Y  ............................................................................................................... 1 4 
4. 3  
P RI O R T H E R A P Y  .......................................................................................................................... 1 4 
4. 4  
E C O G  P E R F O R M A N C E  ................................................................................................................ 1 5 
4. 5  
L V E F  A N D D L C O  ....................................................................................................................... 1 5 
4. 6  
HI V  IN F E C TI O N  ........................................................................................................................... 1 5 
4. 7  
P R E G N A N C Y R E S T RI C TI O N S  ........................................................................................................ 1 5 
4. 8  
A G E R E S T RI CI TI O N S  .................................................................................................................... 1 5 
4. 9  
INI TI A L R E Q UI R E D L A B O R A T O R Y D A T A : ................................................................................... 1 5 
5. 0  
R E GI S T R A TI O N, D A T A S U B MI S SI O N, HI S T O L O GI C R E VI E W, A N D C O R R E L A TI V E 
S CI E N C E S A M P L E P R O C U R E M E N T A N D S U B MI S SI O N ............................................................. 1 6  
5. 1  
R E GI S T R A TI O N  ............................................................................................................................ 1 6 
5. 2  
D A T A S U B MI S SI O N  ...................................................................................................................... 1 9 
5. 3  
H I S T O L O GI C R E VI E W  .................................................................................................................. 2 2 
5. 4  
C O R R E L A TI V E S CI E N C E S A M P L E S U B MI S SI O N ............................................................................ 2 3 
6. 0  
R E Q UI R E D D A T A  ....................................................................................................................... 2 8 
7. 0  
T R E A T M E N T P L A N  ................................................................................................................... 3 0 
7. 1  
C H E M O T H E R A P Y R E GI M E N S  ....................................................................................................... 3 0 
7. 2  
IN V O L V E D - FI E L D R A DI A TI O N T H E R A P Y (I F R T) ......................................................................... 3 1 
7. 3  
T R E A T M E N T D U R A TI O N A N D S T A GI N G ....................................................................................... 3 6 
8. 0  
I M A GI N G ...................................................................................................................................... 3 7 
8. 1  
IN S TI T U TI O N C R E D E N TI A LI N G P R O C E D U R E S F O R F D G -P E T/ C T  IM A GI N G  ................................ 3 7 
8. 2  
P E T/ C T  IM A GI N G T I M E LI N E S ..................................................................................................... 3 9 
8. 3  
C T  D A T A A C Q UI SI TI O N  ............................................................................................................... 4 0 
8. 4  
P E T/ C T  D A T A A C Q UI SI TI O N  ...................................................................................................... 4 0 
8. 5  
E V A L U A TI O N O F P E T/ C T  D A T A  ................................................................................................. 4 2 
8. 6  
P RI M A R Y O BJ E C TI V E / EN D P OI N T : D E FI NI TI O N O F R E S P O N S E B Y M E T A B O LI C C RI T E RI A  ........... 4 3 
8. 7  
S E C O N D A R Y O BJ E C TI V E S / EN D P OI N T S  ........................................................................................ 4 3 
8. 8  
P O S T - TH E R A P Y F O L L O W - UP O F T U M O R S  ................................................................................... 4 4 
8. 9  
P E T  A N D C T  D A T A S U B MI S SI O N  ................................................................................................ 4 4 


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9. 0  
D O S E M O DI FI C A TI O N S A N D M A N A G E M E N T O F T O X I CI T Y ....................................... 4 5 
9. 1  
D O S E M O DI FI C A TI O N S F O R A B V D  ............................................................................................. 4 5 
9. 2  
D O S E M O DI FI C A TI O N S F O R E S C A L A T E D B E A C O P P  .................................................................. 4 7 
9. 3  
D O S E M O DI FI C A TI O N F O R O B E S E P A TI E N T S  ............................................................................... 4 9 
1 0. 0  
C O R R E L A TI V E S CI E N C E C O M P A NI O N S T U DI E S  ............................................................ 4 9 
1 0. 1  
S E R U M M A R K E R S  ........................................................................................................................ 4 9 
1 0. 2  
P L A S M A M A R K E R S  ...................................................................................................................... 5 0 
1 0. 3  
IM M U N O HI S T O C H E MI C A L M A R K E R S  .......................................................................................... 5 1 
1 1. 0  
D R U G F O R M U L A TI O N, A V AI L A BI LI T Y, A N D P R E P A R A TI O N  .................................... 5 2 
1 1. 1  
Q U A LI FI E D P E R S O N N E L ............................................................................................................... 5 2 
1 1. 2  
D I S C A R DI N G U N U S E D A G E N T S  ................................................................................................... 5 2 
1 1. 3  
C A L C U L A T E D D O S E R A N G E  ........................................................................................................ 5 2 
1 1. 4  
D O X O R U BI CI N H C L  .................................................................................................................... 5 2 
1 1. 5  
B L E O M Y CI N  ................................................................................................................................. 5 3 
1 1. 6  
V I N B L A S TIN E S U L F A T E  ............................................................................................................... 5 3 
1 1. 7  
D A C A R B A ZI N E ( D TI C) ................................................................................................................ 5 4 
1 1. 8  
E T O P O SI D E  .................................................................................................................................. 5 5 
1 1. 9  
C Y C L O P H O S P H A MI D E  .................................................................................................................. 5 5 
1 1. 1 0  
V I N C RI S TI N E............................................................................................................................ 5 6 
1 1. 1 1  
P R O C A R B A ZI N E  ....................................................................................................................... 5 7 
1 1. 1 2  
P R E D NI S O N E  ............................................................................................................................ 5 8 
1 2. 0  
A N CI L L A R Y T H E R A P Y  ............................................................................................................ 5 8 
1 2. 1  
S U P P O R TI V E C A R E  ...................................................................................................................... 5 8 
1 2. 2  
C O N DI TI O N S F O R O T H E R T H E R A P Y  ............................................................................................ 5 8 
1 2. 3  
P R O P H Y L A XI S F O R P R E V E N TI O N O F H E M O R R H A GI C C Y S TI TI S  ................................................... 5 8 
1 2. 4  
A N TI E M E TI C T H E R A P Y  ................................................................................................................ 5 8 
1 2. 5  
T R A N S F U SI O N S  ............................................................................................................................ 5 8 
1 3. 0  
C RI T E RI A F O R R E S P O N S E, P R O G R E S SI O N, A N D R E L A P S E  ........................................ 5 9 
1 3. 1  
D E FI NI TI O N S O F R E S P O N S E [ 6 0] .................................................................................................. 5 9 
1 3. 2  
G UI D E LI N E S F O R E V A L U A TI O N O F M E A S U R A B L E D I S E A S E ........................................................ 6 0 
1 3. 3  
R E S P O N S E A S S E S S M E N T T A B L E  .................................................................................................. 6 1 
1 3. 4  
D E FI NI TI O N O F P R O G R E S SI O N - FR E E S U R VI V A L  .......................................................................... 6 1 
1 4. 0  
R E M O V A L O F P A TI E N T S F R O M P R O T O C O L T H E R A P Y ............................................... 6 1  
1 4. 1  
D U R A TI O N O F T R E A T M E N T  ......................................................................................................... 6 1 
1 4. 2  
E X T R A O R DI N A R Y M E DI C A L C I R C U M S T A N C E S: .......................................................................... 6 2 
1 5. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  ........................................................................................ 6 2 
1 5. 1  
S T U D Y D E SI G N  ............................................................................................................................ 6 2 
1 5. 2  
P RI M A R Y E N D P OI N T  .................................................................................................................... 6 2 
1 5. 3  
A C C R U A L A N D F O L L O W - UP  ........................................................................................................ 6 3 
1 5. 4  
S A M P L E S I Z E M O DI FI C A TI O N  ...................................................................................................... 6 3 
1 5. 5  
IN C L U SI O N O F W O M E N &  M I N O RI TI E S ....................................................................................... 6 4 
1 5. 6  
P R E DI C TI V E V A L U E O F F D G -P E T  .............................................................................................. 6 4 
1 5. 7  
S E C O N D A R Y O BJ E C TI V E S  ............................................................................................................ 6 4 
1 5. 8  
C O R R E L A TI V E E N D P OI N T S  .......................................................................................................... 6 5 
1 6. 0  
A D V E R S E E V E N T R E P O R TI N G ( A E R) .................................................................................. 6 6 
1 6. 1  
C A L G B  5 0 8 0 1  A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S  .................................................. 6 6 


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A D DI TI O N A L IN S T R U C TI O N S O R E X C L U SI O N S T O C T E P -A E R S  E X P E DI T E D R E P O R TI N G 
R E Q UI R E M E N T S F O R C A L G B  5 0 8 0 1: ..................................................................................................... 6 7  
1 7. 0  
R E F E R E N C E S  .............................................................................................................................. 6 9 
A P P E N DI X I  
L O N D O N/ D E A U VI L L E C RI T E RI A  ......................................................................... 7 4 
A P P E N DI X II  
I M M U N O HI S T O C H E MI C A L A N A L Y SI S A N D I M A GI N G  P R O C E D U R E S  . 7 5 
A P P E N DI X III  
 S U M M A R Y O F BI O L O GI C  P R O G N O S TI C M A R K E R S I N C L A S SI C A L H L 
( ≥5 0 P T S)   
7 6 
A P P E N DI X I V  
C A L G B 5 0 8 0 1 P E T/ C T I N S T R U M E N T T E C H NI C A L S P E CI FI C A TI O N S 
F O R M   
7 7 
A P P E N DI X V  
C A L G B 5 0 8 0 1 I M A GI N G SI T E P E R S O N N E L F O R M  ....................................... 8 2 
 


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1. 0  I N T R O D U C TI O N  
1. 1  
Tre at me nt of B ul k y E arl y St a ge H o d g ki n L y m p h o m a 
T he maj orit y of patie nts wit h earl y sta ge H o d g ki n l y m p h o ma ( H L) a n d b ul k y me diasti nal 
disease, t y picall y defi ne d as a mass meas uri n g > 1 0 c m or o ne -t hir d t he ma xi mal dia meter 
of t he t h oracic ca vit y, recei ve c o m bi ne d m o dalit y t hera p y wit h 4 -6 c ycles of c he m ot hera p y 
f oll o we d  b y  i n v ol ve d  fiel d  ra diati o n  [ 1,  2].  M ulti ple  retr os pecti ve  st u dies  ha ve 
de m o nstrate d si g nifica nt l o n g -ter m t o xicities ass ociate d wit h me diasti nal ra di ot hera p y. A 
rece nt a nal ysis i n dicates t hat t here is a c u m ulati ve i nci de nce of sec o n dar y mali g na ncies of 
1 4 % at 5 years a n d 2 3 % at 1 0 years [ 3, 4]. S oli d t u m ors pre d o mi nate, wit h breast ca ncer 
a n d l u n g ca ncer bei n g t he m ost c o m m o n sec o n dar y mali g na ncies. I n w o me n, t he relati ve 
ris k of de vel o pi n g breast ca ncer is relate d t o a ge at treat me nt, wit h patie nts y o u n ger t ha n 
1 5  ha vi n g  t he  hi g hest  relati ve  ris k  ( 1 1 1. 8 -ti mes)  a n d  patie nts  u p  t o  a ge  4 0  ha vi n g  a 
persiste ntl y  hi g her  relati ve  ris k  ( 3. 4 -ti mes) [ 3].  Ot her  t o xicities  of  me diasti nal  ra diati o n 
i ncl u de val v ular da ma ge, accelerate d c or o nar y arter y disease a n d pericar dial fi br osis [ 5, 6]. 
T w o ra n d o mize d st u dies a n d o ne p hase 2 st u d y i n patie nts wit h o ut b ul k y disease s u g gest 
t hat A B V D c he m ot hera p y al o ne res ults i n si milar o verall s ur vi val c o m pare d wit h c o m bi ne d 
m o dalit y  t hera p y  or  ra diati o n  al o ne [ 7- 9].  A  rece nt  st u d y  fr o m  Ital y  ra n d o mize d  1 6 0 
patie nts wit h b ul k y disease, defi ne d as a mass greater t ha n 5 c m i n greatest di me nsi o n w h o 
achie ve d a ne gati ve P E T f oll o wi n g 6 c ycles of V E -B E P ( vi n blasti ne, et o p osi de, ble o m yci n, 
e pir u bici n, a n d pre d nis o ne) t o ra di ot hera p y vers us o bser vati o n [ 1 0]. At a me dia n f oll o w-
u p of 4 0 m o nt hs, 1 4 % of patie nts i n t he c he m ot hera p y o nl y ar m rela pse d c o m pare d t o 4 % 
of patie nts w h o recei ve d c he m ot hera p y pl us ra di ot hera p y ( 2 cases of H L a n d o ne carci n o ma 
i n t he ra diati o n fiel d). All of t he rela pses i n t he c he m ot hera p y o nl y ar m occ urre d i n t he 
b ul k y  site  a n d  c o nti g u o us  n o dal  re gi o ns.  P E T  sca ns  were  n ot  o btai ne d  at  mi d -c ycle 
resta gi n g. 
1. 2 
R ole of P E T Sc a n ni n g i n H o d g ki n L y m p h o m a  
Rece nt e vi de nce s u g gests t hat earl y resta gi n g P E T sca ns are hi g hl y pre dicti ve of o utc o me 
i n  H L [ 1 1- 1 3].  H utc hi n gs  a n d  c ollea g ues  eval uate d  t he  pre dicti ve  val ue  of  P E T  i n  7 7 
patie nts wit h sta ges I -I V H L [ 1 3]. F oll o wi n g 2 c ycles of c he m ot hera p y, 6 1 patie nts were 
P E T ne gati ve a n d 1 6 were P E T p ositi ve. At a me dia n f oll o w -u p of 2 3 m o nt hs, t hree of t he 
P E T ne gati ve patie nts, all of w h o m ha d a d va nce d sta ge disease, rela pse d. El e ve n of 1 6 P E T 
p ositi ve patie nts rec urre d. Of 1 6 P E T p ositi ve patie nts, fi ve ha d earl y sta ge disease a n d 
o nl y  o ne  rela pse d.  All  earl y  sta ge  patie nts  recei ve d  i n v ol ve d  fiel d  ra di ot hera p y  (I F R T) 
f oll o wi n g  c he m ot hera p y.  T he  i m pact  of  b ul k y  disease  i n  earl y  sta ge  patie nts  was  n ot 
s pecificall y a d dresse d. T he ma n uscri pt, t heref ore, c o ncl u de d t hat p ositi ve earl y resta gi n g 
P E T sca ns were hi g hl y pre dicti ve of rec urre nt H L i n patie nts wit h a d va nce d sta ge disease.  
A rece nt st u d y b y Galla mi ni e val uate d 2 6 0 patie nts wit h sta ge II B -I V H L w h o u n der we nt 
P E T sca ns after 2 c ycles of c he m ot hera p y [ 1 1]. T he maj orit y of patie nts recei ve d A B V D 
wit h or wit h o ut ra di ot hera p y. Treat me nt was n ot altere d base d o n res ult of t he P E T. Fift y 
of 2 6 0 patie nts ha d a p ositi ve resta gi n g P E T a n d 2 1 0 were P E T ne gati ve. T he defi niti o n of 
P E T p ositi ve was descri be d as “clearl y i ncrease d ac ti vit y relati ve t o t he bac k gr o u n d.” T w o 
ce ntral ra di ol o gists re vie we d P E T sca ns t hat s h o we d “ mi ni mal resi d ual u pta ke,” a n d sca ns 
wit h sta n dar dize d u pta ke val ues ( S U V) of 2 -3. 5 were c o nsi dere d ne gati ve f or t he a nal ysis. 
At  a  me dia n  f oll o w -u p  of  2  years,  t he  pr o gressi o n -free  s ur vi val  ( P F S)  i n  P E T  ne gati ve 
patie nts was 9 5 %, w hereas o nl y 1 2. 8 % of patie nts wit h a p ositi ve P E T sca n were free fr o m 
disease.  A p pr o xi matel y  o ne -t hir d  of  patie nts  ha d  b ul k y  disease,  w hic h  was  n ot  a n 
i n de pe n de nt pre dict or of o utc o me. 


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C A L G B 5 0 2 0 3 e val uate d earl y resta gi n g P E T sca ns i n patie nts wit h n o n -b ul k y sta ge I a n d 
II H L treate d wit h 6 c ycles of A V G ( A dria m yci n, vi n blasti ne a n d ge mcita bi ne) wit h o ut 
I F R T. T he c o m plete res p o nse rate ( C R/ C R u) was 6 7 % a n d esti mate d 1 a n d 2 year P F S 
rates were  8 1 %  a n d  7 1 %,  res pecti vel y.  T he  st u d y  di d  n ot  meet  its  pri mar y  e n d p oi nt. 
Alt h o u g h  t he  ne gati ve  pre dicti ve  val ue  of  a  p ositi ve  P E T  sca n  after  t w o  c ycles  was 
c o m para ble t o ot her st u dies at 9 1 %, t he p ositi ve pre dicti ve val ue was 4 8 %. It is u nclear 
w het her t his differe nce is relate d t o t he i ncl usi o n of e xcl usi vel y earl y sta ge patie nts, t he 
n o vel c he m ot hera p y re gi me n or p ossi bl y differe nces i n t he defi niti o n of a p ositi ve P E T 
sca n. Earlier st u dies use d less stri n ge nt defi niti o ns, a n d relie d o n S U V’s. C A L G B 50 2 0 3 
was  c o nsiste nt  wit h  rece ntl y  p u blis he d  g ui deli nes  w here  a  ne gati ve  P E T  is  defi ne d  as 
u pta ke l o wer t ha n t hat of me diasti nal bl o o d p o ol str uct ures f or resi d ual n o des ≥ 2 c m. F or 
n o des less t ha n 2 c m, p ositi vit y is defi ne d as u pta ke greater t ha n s urr o u n di n g bac k gr o u n d 
n o dal str uct ures [ 1 4]. 
1. 3 
B E A C O P P i n H o d g ki n L y m p h o m a  
B E A C O P P  ( ble o m yci n,  et o p osi de,  a dria m yci n,  c ycl o p h os p ha mi de,  vi ncristi ne, 
pr ocar bazi ne  a n d  pre d nis o ne)  is  a n  i nte nsi ve  c he m ot hera p y  re gi me n  de vel o pe d  b y  t he 
Ger ma n H o d g ki n L y m p h o ma St u d y Gr o u p ( G H S G).  T he re gi me n, w hic h is gi ve n e ver y 
t hree  wee ks,  s u bstit utes  et o p osi de  f or  dacar bazi ne  a n d  vi ncristi ne  f or  vi n blasti ne  a n d 
i nc or p orates  i ncrease d  d ose  c ycl o p h os p ha mi de.  A  lar ge  ra n d o mize d  st u d y  c o m pare d 
sta n dar d  d ose  B E A C O P P,  d ose  escalate d  B E A C O P P  a n d  C O PP- A B V D [ 1 5].  1, 2 0 1 
patie nts  wit h  sta ge  II B -I V  were  ra n d o mize d.  T he  st u d y  was  cl ose d  earl y  after  i nteri m 
a nal ysis re veale d t he C O P P-A B V D ar m was i nferi or wit h res pect t o P F S a n d O S, c o m pare d 
t o t he ot her t w o ar ms. Wit h l o n g ter m f oll o w-u p of 1 0 years, free d o m fr o m treat me nt fail ure 
rates were 6 4 %, 7 0 %, a n d 8 2 % a n d o verall s ur vi val rates were 7 5 %, 8 0 %, a n d 8 6 % f or 
C O P P -A B V D , sta n dar d B E A C O P P, a n d escalate d B E A C O P P, res pecti vel y ( p < 0. 0 0 1) 
[ 1 6]. He mat ol o gic t o xicit y of escalate d B E A C O P P was si g nifica nt wit h 9 0 % a n d 4 7 % of 
patie nts  de vel o pi n g  gra de  4  le u k o pe nia  a n d  t hr o m b oc yt o pe nia  res pecti vel y. 
M ye l o d ys plasia or sec o n dar y ac ute m yel oi d le u ke mia was see n i n o ne of 2 6 0 e val ua ble 
patie nts  treate d  wit h  C O P P -A B V D  c o m pare d  wit h  4  of  4 6 9  treate d  wit h  sta n dar d 
B E A C O P P  a n d  9  of  4 6 6  wit h  escalate d  B E A C O P P.  I nfertilit y  was  nearl y  u ni versal  i n 
patie nts recei vi n g escalate d B E A C O P P.  
A n  Israeli  st u d y  treate d  6 9  patie nts  wit h  earl y  u nfa v ora ble  sta ge  H L  ( defi ne d  as  B 
s y m pt o ms,  b ul k y  disease,  > 4  i n v ol ve d  n o dal  re gi o ns,  E S R  > 5 0,  l y m p h oc yte  de plete d 
hist ol o g y or e xtra n o dal disease) or a d va nce d sta ge disease wit h a n I nter nati o nal Pr o g n ostic 
I n de x of less t ha n or e q ual t o 2 wit h t w o c ycles of sta n dar d d ose B E A C O P P. 2 7 patie nts 
ha d b ul k y  me diasti nal disease. T h ose w h o were P E T or 6 7 Ga ne gati ve after t w o c ycles 
were c o nti n ue d o n sta n dar d B E A C O P P, w hile t h ose w h o were P E T or 6 7 Ga p ositi ve were 
s witc he d t o escalate d B E A C O P P. T he 5-year P F S a n d O S were si milar f or b ot h gr o u ps at 
8 4 %,  a n d  9 0 %  res pecti vel y. [ 1 7].  I n  a d diti o n,  t he  G H S G  rece ntl y  prese nte d  a n  i nteri m 
a nal ysis of t heir st u d y i n earl y u nfa v ora ble H L. Patie nts were ra n d o mize d t o 2 c ycles of 
escalate d B E A C O P P  f oll o we d b y 2 c ycles of A B V D pl us I F R T c o m pare d t o 4 c ycles of 
A B V D pl us I F R T. 1 1 2 7 of a t otal 1 6 0 0 pla n ne d patie nts were e val ua ble.  Wit h a me dia n 
f oll o w-u p of 3 2 m o nt hs, t he C R rates were 9 3. 7 % a n d 9 5 % a n d O S 9 1 % a n d 9 5 % f or t he 
A B V D a n d escalate d B E A C O P P ar ms, res pecti vel y.  
1. 4 
R ati o n ale f or I F R T D ose  
M ulti ple ra n d o mize d st u dies ha ve s h o w n t hat c o m bi ne d m o dalit y t hera p y pr o vi des s u peri or 
disease c o ntr ol c o m pare d t o ra diati o n t hera p y al o ne [ 2, 1 8, 1 9] or c he m ot hera p y al o ne [ 7, 
2 0, 2 1]  i n earl y sta ge H o d g ki n l y m p h o ma ( H L). H o we ver, t he o pti mal d ose of i n v ol ve d-


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fiel d  ra diati o n  t hera p y  (I F R T)  i n  c o m bi ne d  m o dalit y  treat me nt  pr o gra ms  is  u n k n o w n. 
P ote ntial car diac a n d p ul m o nar y c o m plicati o ns relate d t o me diasti nal irra diati o n, as well 
as i n d ucti o n of sec o n dar y mali g na ncies, ha ve le d t o trials e xa mi ni n g l o wer I F R T d oses.  
O ne of t he first s uc h  trials was fr o m t he Ger ma n H o d g ki n L y m p h o ma St u d y Gr o u p ( H D 1) 
[ 2 2]. T his trial e nr olle d 1 4 6 patie nts wit h sta ge I-IIIa H L wit h a d verse pr o g n ostic fact ors 
i ncl u di n g lar ge me diasti nal a de n o pat h y ( L M A), massi ve s ple nic i n v ol ve me nt, m ore t ha n 
fi ve  lesi o ns,  a n d/ or  e xtra n o dal i n v ol ve me nt.  All  patie nts  res p o n di n g  t o  4  c ycles  of 
c o m bi nati o n c he m ot hera p y ( C O P P/ A B V D) were ra n d o mize d t o 2 0 G y vers us 4 0 G y I F R T. 
H o we ver,  all  patie nts  wit h  L M A  recei ve d  4 0  G y.  T he  4 -year  free d o m  fr o m  treat me nt 
fail ure di d n ot differ bet wee n t he treat me nt ar ms ( 7 9 % a n d 8 0 %, res pecti vel y). 
T he C hil dre n’s Ca ncer Gr o u p 5 9 4 2 st u d y ra n d o mize d c hil dre n a n d a d olesce nts y o u n ger 
t ha n  2 1  years  of  a ge  t o  I F R T  or  o bser vati o n  after  ac hie vi n g  a  c o m plete  res p o nse  t o 
c he m ot hera p y ( C O P P -A B V) [ 2 1]. L M A was prese nt i n a mi n orit y of patie nts ( 2 5 %). All 
patie nts ra n d o mize d t o I F R T, re gar dless of disease b ul k, recei ve d 2 1 G y. T he 3 -ye ar e ve nt -
free  s ur vi val  was  8 5 %  f or  patie nts  ra n d o mize d  t o o bser vati o n  a n d  9 3 %  f or  patie nts 
recei vi n g I F R T ( p = 0. 0 5 7). O utc o mes f or patie nts wit h L M A were n ot s pecificall y re p orte d. 
F or  patie nts  wit h  fa v ora ble  disease  prese ntati o ns,  preli mi nar y  res ults  fr o m  m ore  rece nt 
st u dies als o s u p p ort a l o wer R T d ose. T he E O R TC H 9 -F c o m pare d 3 6 G y, 2 0 G y, a n d 0 
G y I F R T after 6 c ycles of E B V P [ 2 3]. T he 4-year e ve nt -free s ur vi val was 8 7 %, 8 4 %, a n d 
7 0 %,  res pecti vel y.  T he  o bser vati o n  ar m  was  dr o p pe d  after  a n  i nteri m  re p ort  s h o we d 
i nferi or o utc o mes. T he Ger ma n H o d g ki n L y m p h o ma St u d y Gr o u p trial H D 1 0 ra n d o mize d 
patie nts wit h earl y sta ge, fa v ora ble H L t o 2 vers us 4 c ycles of A B V D wit h a se c o n dar y 
ra n d o mizati o n  t o  2 0  G y  vers us  3 0  G y  of  I F R T [ 2 4].  Preli mi nar y  res ults  s h o we d  n o 
differe nce i n free d o m fr o m treat me nt fail ure bet wee n 3 0 G y a n d 2 0 G y. L o n ger f oll o w- u p 
will be necessar y t o c o nfir m t he fi n di n gs fr o m t hese t w o trials.  
T here are n o p u blis he d ra n d o mize d trials e val uati n g t he o pti mal I F R T d ose f or patie nts 
wit h L M A. A retr os pecti ve a nal ysis fr o m D u ke a n d Yale e xa mi ni n g 8 3 patie nts wit h H L 
wit h L M A  treate d wit h c o m bi ne d m o dalit y t hera p y s u g geste d t hat l o w d ose I F R T ma y be 
a de q uate [ 2 5]. Rela pse-free s ur vi val was 1 0 0 % i n patie nts recei vi n g < 2 0 G y ( n = 1 2), 7 1 % 
after 2 0-2 5 G y ( n = 2 4), 8 3 % after 2 5 -3 0 G y ( n = 3 0) a n d 7 5 % after > 3 0 G y ( n = 1 2). A s maller 
st u d y fr o m t he U ni versit y of Mic hi ga n als o f o u n d e q ui vale nt fail ure rates after l o w d oses 
( 1 9. 8-2 5. 2 G y) c o m pare d wit h hi g her d oses ( 3 0 -4 4 G y) [ 2 6]. H o we ver, fir m c o ncl usi o ns 
ca n n ot be dra w n gi ve n t he retr os pecti ve nat ure of t he a nal yses a n d s mall patie nt n u m bers.  
C o nsi derati o n of treat me nt-relate d t o xicities m ust be ta ke n i nt o acc o u nt w he n f or m ulati n g 
treat me nt  pr o gra ms  f or  patie nts  wit h  H L.  T here  is  i ncreasi n g  data  s u g gesti n g  t hat  R T-
i n d uce d  t o xicities,  i n  partic ular  car diac  c o m plicati o ns  a n d  sec o n dar y  mali g na ncies,  are 
d ose relat e d. I n a retr os pecti ve st u d y fr o m D u ke, t here was a si g nifica nt differe nce i n t he 
i nci de nce of sec o n dar y mali g na ncies bet wee n patie nts treate d wit h R T al o ne ( mea n d ose 
3 7. 9 G y), c o m pare d wit h patie nts treate d wit h c o m bi ne d m o dalit y t hera p y wit h l o w d ose 
I FR T ( mea n d ose 2 5. 5 G y) [ 2 7]. T he 2 0-year act uarial ris k of sec o n dar y mali g na ncies was 
1 6 % wit h R T al o ne c o m pare d wit h 0 % wit h c o m bi ne d m o dalit y utilizi n g l o w d ose I F R T. 
T he R T fiel ds were als o s maller i n t he c o m bi ne d m o dalit y t hera p y gr o u p, w hic h als o li kel y 
c o ntri b ute d  t o  t he  decre ase  i n  sec o n dar y  mali g na ncies.  I n  a  retr os pecti ve  st u d y  fr o m 
Sta nf or d, t he ris k of deat h fr o m heart disease a p peare d t o be d ose relate d. D oses a b o ve 3 0 
G y were ass ociate d wit h a relati ve ris k of 3. 5, w hile d oses less t ha n 3 0 G y c o nferre d n o 
e xcess ris k [ 2 8]. 
I n t he prese nt st u d y of patie nts wit h b ul k y s u pra dia p hra g matic H L, t he use of I F R T will be 
base d  o n  res p o nse  t o  c he m ot hera p y.  Patie nts  w h o  ac hie ve  a  P E T  C R  after  2  c ycles  of 
c he m ot hera p y  will  n ot  recei ve  I F R T.  Patie nts  w h o  res p o n d  sl o wl y  t o  c he m ot hera p y,  or 




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O B J E C TI V E S  
2. 1 
P ri m ar y O bjecti ve  
2. 1. 1 
T o deter mi ne t he pr o gressi o n -free s ur vi val ( P F S) at 3 6 m o nt hs fr o m e nr oll me nt 
f or patie nts wit h b ul k y sta ge I a n d II H o d g ki n l y m p h o ma. All patie nts will be gi n 
treat me nt  wit h  A B V D.  Patie nts  w h o  are  P E T  ne gati ve  after  2  c ycles  of 
c he m ot hera p y will recei ve 6 c ycles of A B V D wit h o ut ra di ot hera p y.  Patie nts w h o 
are P E T p ositi ve after 2 c ycles of A B V D will t he n recei ve 4 c ycles of escalate d 
B E A C O P P f oll o we d b y I F R T.  A c o m paris o n will be ma de of t he 3 6-m o nt h P F S 
bet wee n patie nts w h o are P E T p ositi ve a n d t h ose w h o are P E T ne gati ve f oll o wi n g 
2 c ycles of A B V D.  
2. 2 
Sec o n d ar y O bjecti ves  
2. 2. 1 
T o e val uate t he c o m plete res p o nse ( C R) rate of patie nts dia g n os e d wit h b ul k y sta ge 
I a n d II H o d g ki n l y m p h o ma f oll o wi n g P E T res p o nse-a da pte d c he m ot hera p y wit h 
or wit h o ut ra diati o n t hera p y. 
2. 2. 2 
T o deter mi ne t he pre dicti ve val ue of F D G u pta ke usi n g vari o us se mi q ua ntitati ve 
a p pr oac hes, at baseli ne, after 2 c ycles of AB V D a n d at c o m pleti o n of t hera p y. 
2. 2. 3 
T o  deter mi ne  t he  pre dicti ve  val ue  of  v ol u metric  vs.  2  di me nsi o nal  ( 2 -D) 
meas ure me nt c ha n ges o n C T bet wee n baseli ne a n d after 2 c ycles, at t he e n d of 
c he m ot hera p y ( P E T ne gati ve patie nts o nl y) a n d after R T ( P E T p ositi ve patie nts 
o nl y) a n d c o m pare wit h P E T para meters.  
2. 2. 4 
T o  deter mi ne  if  c ha n ges  i n  b ot h  q ualitati ve  a n d  se mi q ua ntitati ve  F D G -P E T 
fi n di n gs bet wee n baseli ne a n d after c ycle 2, at e n d of c he m ot hera p y ( P E T ne gati ve 
patie nts o nl y)  a n d after R T ( P E T p ositi ve patients o nl y) wit h c o m bi nati o n a nal yses 
wit h  i nc or p orati n g  c ha n ges  o btai ne d  fr o m  de dicate d  C T  sca ns,  c orrelate  wit h 
res p o nse a n d P F S. 
2. 2. 5 
T o c o m pare t he pre dicti ve  val ue  of  b ot h  q ualitati ve a n d  se mi q ua ntitati ve  F D G -
P E T  c ha n ges,  2 -D  a n d  v ol u metric  C T  c ha n ges,  a n d  c o m bi nat orial  a nal yses 
( P E T + de dicate d  C T  data)  wit h  m olec ular  para meters,  a n d  c o n ve nti o nal 
para meters, i ncl u di n g I P S.  
2. 2. 6 
T o assess w het her ele vate d baseli ne ser u m s ol u ble C D 3 0 (s C D 3 0), I L 1 0, C C L 1 7, 
a n d C C L 2 2 c orrelate wit h cli nical res p o nse a n d P F S . 
2. 2. 7 
T o assess w het her persiste nt or rec urre nt ele vati o n of serial ser u m s C D 3 0, I L 1 0, 
C C L 1 7, or C C L 2 2 c orrelate wit h rela pse/ pr o gressi o n or P E T sca n res ults.  
2. 2. 8 
T o c o nfir m i n de pe n de ntl y usef ul tiss ue bi o mar kers ( bcl -2, M A L, F O X P 3, C D 6 8, 
Gz B) f or ris k  stratificati o n i n patie nts wit h b ul k y sta ge I a n d II H o d g ki n l y m p h o ma 
treate d wit h t his re gi me n. 
2. 2. 9 
T o  c o m pare  me diasti nal  b ul k  o n  sta n di n g  P A  a n d  lateral  c hest  x -ra y  ( >  0. 3 3 
ma xi m u m c hest dia meter) wit h c hest C T ( mass > 1 0 c m) . 


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O N - ST U D Y  G UI D E LI N E S  
T his cli nic al tri al c a n f ulfill its o bjecti ves o nl y if p atie nts a p pr o pri ate f or t he tri al are e nr olle d.  
All rele va nt me dical a n d ot her c o nsi derati o ns s h o ul d be ta ke n i nt o acc o u nt w he n deci di n g w het her 
t his pr ot oc ol is a p pr o priate f or a partic ular patie nt. T o ma xi mi ze patie nt safet y, patie nts s h o ul d be 
treate d o n t his pr ot oc ol o nl y at ce nters ha vi n g rea d y access t o bl o o d pr o d uct s u p p ort a n d a de q uate 
staff t o care f or t he se verel y ne utr o pe nic patie nt. P h ysicia ns s h o ul d c o nsi der t he ris ks a n d be nef its of 
a n y  t hera p y  a n d  t heref ore  o nl y  e nr oll  patie nts  f or  w h o m  t he  a ge nts  a d mi nistere d  are  a p pr o priate. 
Alt h o u g h t he y will  n ot  be  c o nsi dere d  as f or m al  eli gi bilit y  (e xcl usi o n)  criteri a,  as  p art  of  t he 
decisi o n -m a ki n g pr ocess p h ysici a ns s h o ul d rec o g nize t h at  t he f oll o wi n g m a y i ncre ase t he ris k 
t o t he p atie nt e nteri n g t his pr ot oc ol: 
• 
Seri o us me dical ill ness or ps yc hiatric c o n diti o n t hat c o ul d pre ve nt c o m plia nce wit h treat me nt or 
i nf or me d c o nse nt. 
• 
U nc o ntr olle d  or  se vere  car di o vasc ular  disease  i ncl u di n g  rece n t  ( <  6  m o nt hs)  m y ocar dial 
i nfarcti o n.  Patie nts  wit h  car diac  arr h yt h mias  re q uiri n g  treat me nt  ma y  be  e ntere d  at  t heir 
p h ysicia n’s discreti o n. 
4. 0  
E LI GI BI LI T Y C RI T E RI A  
All q uesti o ns re gar di n g eli gi bilit y criteria s h o ul d be directe d t o t he St u d y C hair. Please n ote t hat t he 
St u d y C hair ca n n ot gra nt wai vers t o eli gi bilit y re q uire me nts.  
I nstit uti o ns m ust be cre de ntiale d b y t he Allia nce  I ma gi n g C ore La b at I R O C O hi o pri or t o e nr olli n g 
patie nts (see Secti o n 8. 1. 1 ). 
4. 1  
D oc u me nt ati o n of Di se ase 
4. 1. 1 
Hist ol o gicall y  d oc u me nte d  H o d g ki n  l y m p h o ma  s u bclassifie d  acc or di n g  t o  t he 
W H O m o dificati o n of t he R ye Classificati o n a n d sta ge d acc or di n g t o t he m o difie d 
A n n Ar b or Sta gi n g Classificati o n s yste m. Patie nts m ust ha ve cli nical sta ge I A, I B, 
II A or II B. Patie nts wit h “ E” e xte nsi o ns will be eli gi ble if all ot her criteria ha ve 
bee n met. N o d ular l y m p h oc yte pre d o mi na nt H o d g ki n l y m p h o ma is e xcl u de d.  
C ore  nee dle  bi o psies  are  acce pta ble  if  t he y  c o ntai n  a de q uate  tiss ue  f or  pri mar y 
dia g n osis  a n d  i m m u n o p he n ot y pi n g.  Fi ne  nee dle  as pirates  are  n ot  acce pta ble.  If 
m ulti ple s peci me ns are a vaila ble, please s u b mit t he m ost rece nt. F ail ure t o s u b mit 
p at h ol o g y m ateri als wit hi n 6 0 d a ys of p atie nt re gistr ati o n will be c o nsi dere d 
a m aj or pr ot oc ol vi ol ati o n (see Secti o n 5. 3 ). 
4. 1. 2 
Patie nts m ust ha ve a me diasti nal mass > 0. 3 3 ma xi m u m i ntrat h oracic dia meter o n 
sta n di n g  p oster o-a nteri or  c hest  x -ra y  or mass meas uri n g  >  1 0  c m  i n  its  lar gest 
dia meter.  
4. 2 
Sec o n d M ali g n a nc y  
N o “c urre ntl y acti ve” sec o n d mali g na nc y ot her t ha n n o n -mela n o ma s ki n ca ncers. Patie nts 
are n ot c o nsi dere d t o ha ve a “c urre ntl y acti ve” mali g na nc y if t he y ha ve c o m plete d t hera p y 
a n d are c o nsi dere d b y t heir p h ysicia n t o be at less t ha n 3 0 % ris k of rela pse. 
4. 3 
P ri or T her a p y  
Patie nt s ma y  ha ve ha d o ne c ycle o nl y of A B V D pri or t o e nr olli n g o n st u d y. N o ot her pri or 
treat me nt (c he m ot hera p y or ra diati o n t hera p y) f or H o d g ki n l y m p h o ma is all o we d. 
If patie nt has ha d o ne c ycle of A B V D, i n or der t o be eli gi ble t o e nr oll o n C A L G B 5 0 8 0 1, 
t he patie nt m ust ha ve ha d all of t he f oll o wi n g tests pri or  t o starti n g t he first c ycle of A B V D: 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
1 5  
U p date # 1 3  
•  
L V E F b y E C H O or M U G A  
•  
P F Ts (i ncl u di n g D L C O/ F V C)  
•  
C T sca n ( nec k *, c hest, a b d o me n, pel vis) 
•  
F D G -P E T/ C T sca n  
•  
C hest X -ra y, P A & Lateral  
•  
C B C, differe ntial, platelets 
•  
E S R  
•  
Ser u m crea ti ni ne  
•  
Gl uc ose 
•  
A S T  
•  
Al kali ne p h os p hatase  
•  
Bilir u bi n  
•  
L D H  
* Patie nts wit h a ne gati ve F D G -P E T/ C T sca n d o n ot nee d t o ha ve ha d a de dicate d nec k C T 
sca n pri or t o starti n g t he pre vi o us c ycle of A B V D. 
4. 4 
E C O G P erf or m a nce  
E C O G p erf or ma nce stat us 0 - 2. 
4. 5 
L V E F a n d D L C O  
L V E F b y E C H O or M U G A wit hi n i nstit uti o nal n or mal li mits u nless t h o u g ht t o be disease 
relate d. D L C O ≥ 6 0 % wit h n o s y m pt o matic p ul m o nar y disease u nless t h o u g ht t o be disease 
relate d. 
4. 6 
HI V I nfecti o n  
Patie nts wit h k n o w n  HI V m ust ha ve a C D 4 c o u nt > 3 5 0  an d be o n c o nc urre nt a ntiretr o virals 
( See Secti o n  1 2. 1 ).  Patie nts  wit h  a  hist or y  of  i ntra ve n o us  dr u g  a b use  or  a n y  be ha vi or 
ass ociate d wit h a n i ncrease d ris k of HI V i nfecti o n s h o ul d be teste d f or e x p os ure t o t he HI V 
vir us. A n HI V t est is n ot re q uire d f or e ntr y o n t his pr ot oc ol, b ut is re q uire d if t he patie nt is 
percei ve d t o be at ris k.  
4. 7 
P re g n a nc y Restricti o ns  
N o n -pre g na nt a n d n o n - n ursi n g. D ue t o t he terat o ge nic p ote ntial of t he a ge nts use d i n t his 
st u d y, pre g na nt or n ursi n g w o me n ma y n ot be e nr olle d. W o me n a n d me n of re pr o d ucti ve 
p ote ntial s h o ul d a gree t o use a n effecti ve mea ns of birt h c o ntr ol.  
4. 8 
A ge Restriciti o ns  
A ge 1 8 – 6 0 years.  
4. 9 
I niti al Re q uire d L a b or at or y D at a: 
A N C  
≥ 1 0 0 0/ µ L  
Platelet c o u nt  
≥ 1 0 0, 0 0 0/ µ L  
Ser u m Creati ni ne  
≤ 2 m g/ d L  
Bilir u bi n *  
≤ 2 x u p per li mit of n or mal  
A S T  
≤ 2 x u p per li mit of n or mal  
* I n t he a bse nce of Gil bert’s disease  










C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
2 0  
U p date # 1 3  
r ole,  t he  user  m ust  h ol d  a  mi ni mu m  of  a n  A P  re gistrati o n  t y pe. T o  h ol d  t he  Ra ve  Site 
I n vesti gat or r ole, t he i n di vi d ual m ust be re gistere d as a n N PI V R or I V R. Ass ociates ca n 
h ol d  rea d -o nl y  r oles  i n  Ra ve.  T he  Ra ve  s yste m  ca n  be  accesse d  t hr o u g h  t he i Me di data 
p ortal at 
. F or a d diti o nal i nf or mati o n re gar di n g acc o u nt set u p 
or  trai ni n g,  please  visit  t he  trai ni n g  secti o n  of  t he  Allia nce  we bsite.  F or ms  s h o ul d  be 
s u b mitte d i n c o m plia nce wit h t he ta ble bel o w, a n d a c o p y of t he All F or ms Pac ket ca n be 
d o w nl oa de d fr o m t he Allia nce we bsite. 
U p o n i nitial site re gistrati o n a p pr o val f or t he st u d y i n R S S, site pers o n nel wit h Ra ve r oles 
assi g ne d o n t he a p pr o priate r oster ma y recei ve a st u d y i n vitati o n e -mail fr o m i Me di data. 
T o  acce pt  t he  i n vitati o n,  site  users  
m ust  l o g  i nt o  t he  Select  
L o gi n 
 usi n g t heir C T E P-I A M user na me a n d pass w or d, 
a n d clic k o n t he “acce pt” li n k i n t he u p per ri g ht -c or ner of t he i Me di data pa ge. Please n ote, 
site users will n ot be a ble t o access t he st u d y i n Ra ve u ntil all re q uire d Me di data a n d st u d y 
s pecific  trai ni n gs  are  c o m plete d.  Trai ni n gs  will  be  i n  t he  f or m  of  electr o nic  lear ni n gs 
(e Lear ni n gs), a n d ca n be accesse d b y clic ki n g o n t he li n k i n t he u p per ri g ht pa ne of t he 
i Me di data scree n. Pers o n nel w h o di d n ot recei ve a n i n vitati o n s h o ul d c o ntact t he Allia nce 
Ser vice Ce nter.  
Users w h o ha ve n ot pre vi o usl y acti vate d t heir i Me di data/ Ra ve acc o u nt at t he ti me of a n 
i nitial site re gistrati o n a p pr o val f or a st u d y i n R S S will als o recei ve a se parate i n vitati o n 
fr o m i Me di data t o acti vate t heir acc o u nt. Acc o u nt acti vati o n i nstr ucti o ns are l ocate d o n t he 
C T S U we bsite’s Ra ve ta b u n der t he Ra ve Res o urce Materials hea di n g ( Me di data Acc o u nt 
Acti vati o n a n d St u d y I n vitati o n Acce pta nce). A d diti o nal i nf or mati o n o n i Me di data/ Ra ve 
is a vaila ble o n t he C T S U me m bers’ we bsite u n der t he Ra ve ta b at w w w.cts u. or g/ R A V E/ 
or  b y  c o ntacti n g  t he  C T S U  Hel p  Des k  at 
  or  b y  e-mail  at 
. 
 
 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
2 1  
U p date # 1 3  
F or m *  
S u b missi o n Sc he d ule  
B aseli ne  
 
5 0 8 0 1 Re gistrati o n W or ks heet  
Wit hi n o ne m o nt h of re gistrati o n  
 
5 0 8 0 1 Eli gi bilit y C hec klist  
C -1 8 7 7  
5 0 8 0 1 O n -St u d y F or m  
L Y -4  
L y m p h o ma Pre -St u d y Fl o w S heet  
C -1 8 7 8  
5 0 8 0 1 P E T a n d C T Meas ure me nt F or m  
C -1 8 8 3  
5 0 8 0 1 F D G -P E T A dj u ncti ve Data S heet  
Re p ort  
Baseli ne P E T, C T, a n d Pat h ol o g y re p orts  
 
Tre at me nt * * *  
C -1 8 8 0  
5 0 8 0 1 Treat me nt S u m mar y F or m  
S u b mit  after  eac h  c ycle  of  A B V D, 
B E A C O P P, or I F R T  
S -0 6 8  
5 0 8 0 1 Me dicati o n Cale n dar † †  
C -1 8 8 1  
5 0 8 0 1 A d verse E ve nt F or m * *  
L Y -5  
L y m p h o ma Fl o w S heet  
 
 
 
C -1 8 8 2  
5 0 8 0 1 F oll o w -u p F or m  
P E T ne gati ve: S u b mit after c ycle 2 a n d 
c ycle 6 of A B V D 
 
P E T  p ositi ve:  S u b mit  after  c ycle  2  of 
A B V D,  c ycle  6  of  B E A C O P P  ( C - 1 8 8 2 
o nl y), a n d f oll o wi n g I F R T  
C -1 8 7 8  
5 0 8 0 1 P E T a n d C T Meas ure me nt F or m  
C -1 8 8 3  
5 0 8 0 1 F D G -P E T A dj u ncti ve Data S heet  
Re p ort 
C o pies of P E T/ C T sca ns a n d pat h ol o g y re p orts 
 
F oll o w -u p ( P ost -tre at me nt)  
C -1 8 8 2  
5 0 8 0 1 F oll o w -u p F or m  
S u b mit e ver y 3 m o nt hs f or t he first year 
p ost treat me nt, e ver y 6 m o nt hs f or years 
2 a n d 3, a n d a n n uall y at years 4 a n d 5 
C -1 8 7 8  
5 0 8 0 1 P E T a n d C T Meas ure me nt F or m  
C -1 8 8 3  
5 0 8 0 1 F D G -P E T A dj u ncti ve Data S heet †  
Re p ort  
C o pies of P E T/ C T sca ns a n d pat h ol o g y re p orts  
 
 
 
C -4 0 0  
L o n g T er m F oll o w -u p F or m  
S u b mit a n n uall y years 6 -1 0  
 
 
 
Ot her  
R T -1  
Ra diati o n D osi metr y S u m mar y F or m  
S u b mit per Secti o n 7. 2. 1 3  
R T -2  
Ra diati o n T otal D ose Rec or d  
 
C -3 0 0  
Off Treat me nt F or m  
At e n d of all pr ot oc ol treat me nt  
C -1 1 3  
N otificati o n of Deat h  
At ti me of deat h  
C -1 0 0 1  
Ne w Mali g na nc y F or m  
At ti me of dia g n osis of ne w mali g na nc y  
C- 1 8 2 0 
A d verse E ve nts A d de n d u m F or m 
C o m plete if a d diti o nal s pace is nee de d t o 
re p ort  ot her  a d verse  e ve nts.    See  f or m 
f or i nstr ucti o ns.  
C -1 7 4 2  
C A L G B C o nfir mati o n of L ost t o F oll o w U p  
See f or m f or s u b missi o n i nstr ucti o ns  
* 
Use C A L G B Re mar ks  A d de n da ( C -2 6 0) if a d diti o nal c o m me nts are necessar y or a d diti o nal  writi n g  s pace is 
nee de d.   
* *  
S u b mit A E f or m u ntil all pr ot oc ol treat me nt relate d e ve nts ha ve res ol ve d or u ntil n o n -pr ot oc ol treat me nt be gi ns. 
If patie nt deat h is re p orte d vi a C T E P -A E R S , re p ort Gra de 5 e ve nt of A E f or m e ve n if p atie nt is off pr ot oc ol 
treat me nt.   
* * *  If patie nt ne ver starts treat me nt, s u b mit all baseli ne data a n d t he C-3 0 0 Off -Treat me nt F or m.  N o ot her f oll o w -
u p f or ms are re q uire d f or s u b missi o n.  
† 
O nl y s u b mit t hr o u g h year 3.  
† †  
S u b missi o n o nl y f or t h ose pati e nts recei vi n g escalate d B E A C O P P.  




C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
2 3  
U p date # 1 3  
If patie nt has c o nse nte d t o all o w t heir tiss ue t o be use d f or c urre nt researc h descri be d i n 
Secti o n  1 0. 3  ( m o del  c o nse nt  q uesti o n  # 1)  or  ke pt  f or  f ut ure  researc h  ( m o del  c o nse nt 
q uesti o ns  # 2  a n d  # 3,  o nl y  o ne  tiss ue  bl oc k  nee d  be  s u b mitte d  t o  acc o m m o date  b ot h 
hist ol o gic c o nfir mati o n of dia g n osis a n d c orrelati ve scie nce st u dies (see Secti o n 5. 4. 2 ). 
T he Allia nce/ C A L G B  has  i nstit ute d  s pecial  c o nsi derati o ns  f or  t he  s mall  perce nta ge  of 
i nstit uti o ns w h ose p olicies pr o hi bit release of a n y bl oc ks. If, d ue t o i nstit uti o nal p olic y, a 
bl oc k  ca n n ot  be  se nt,  please  call 
  t o  o btai n  a  pr ot oc ol  f or  s u b missi o n  of 
re prese ntati ve tiss ue fr o m y o ur i nstit uti o n. 
5. 4 
C orrel ati ve Scie nce S a m ple S u b missi o n  
All  partici pati n g  i nstit uti o ns  m ust  as k  patie nts  f or  t heir  c o nse nt  t o  partici pate  i n  t he 
c o m p o ne nts of t he c orrelati ve s u bst u d y ( C A L G B 1 5 0 9 0 3) , alt h o u g h patie nt partici pati o n 
is o pti o nal. Rati o nale a n d met h o ds f or t hese st u dies are descri be d i n Secti o n 1 0. 0 . 
S peci me ns f or patie nts re gistere d o n t his st u d y m ust be l o g ge d a n d s hi p pe d usi n g t he o nli ne 
Allia nce Bi os peci me n M a na ge me nt S yste m ( Bi o M S).  
U S E  O F  T H E  A L LI A N C E  BI O S P E CI M E N  M A N A G E M E N T  S Y S T E M  ( Bi o M S)  I S 
M A N D A T O R Y  A N D  A L L  S P E CI M E N S  M U S T  B E  L O G G E D  A N D  S HI P P E D  VI A 
T HI S S Y S T E M.  
Bi o M S  is  a  we b -base d  s yste m  f or  l o g gi n g  a n d  trac ki n g  all  bi os peci me ns  c ollecte d  o n 
Allia nce / C A L G B trials. A ut h orize d i n di vi d uals ma y access Bi o M S at t he f oll o wi n g U R L: 
, usi n g m ost sta n dar d we b br o wsers ( Safari, Firef o x, I nter net 
E x pl orer).  F or i nf or mati o n o n usi n g t he Bi o M S s yste m, please refer t o t he ‘ Hel p’ li n ks o n 
t he Bi o M S we b pa ge t o access t he o n -li ne user ma n ual, F A Qs, a n d trai ni n g vi de os.  T o 
re p ort tec h nical pr o ble ms, s uc h as l o gi n iss ues or a p plicati o n err ors, please c o ntact: 
  F or  assista nce  i n  usi n g  t he  a p plicati o n  or  q uesti o ns  or  pr o ble ms  rela te d  t o 
s pecific s peci me n l o g gi n g, please c o ntact: 
 
After l o g gi n g c ollecte d s peci me ns i n Bi o M S, t he s yste m will create a s hi p pi n g ma nifest. 
T his  s hi p pi n g  ma nifest  m ust  be  pri nte d  a n d  place d  i n  t he  s hi p me nt  c o ntai ner  wit h  t he 
s peci me ns. 
 
S a m ple T y pe  
S a m ple C ollecti o n Ti me P oi nts 1 
W h ole Bl o o d 
( Ser u m) * 
W h ole Bl o o d 
( Plas ma) * * 
F F P E Tiss ue  
Pri or t o i nitiati o n of t hera p y ( B aseli ne) 
X 
X 
X * * *  
Ti me of 2 n d P E T/ C T sca n ( p ost -c ycle 2)  
X 
X 
 
Ti me of 3r d P E T/ C T sca n  
At c he m o c o m pleti o n f or P E T ne gati ve patie nts  
P ost I F R T c o m pleti o n f or P E T p ositi ve patie nts  
X 
X 
 
D uri n g year 1 f oll o w -u p  
(at 3, 6, 9, a n d 1 2 m o nt hs p ost-t x) 
X 
X 
 
D uri n g year 2 f oll o w -u p  
(at 1 8 a n d 2 4 m o nt hs p ost-t x) 
X 
X 
 
D uri n g year 3 f oll o w -u p  
(at 3 0 a n d 3 6 m o nt hs p ost -t x) 
X 
X 
 
Pr o gressi o n or Rela pse  
 
 
X 2 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
2 4  
U p date # 1 3  
 
(Sec ti o n 5. 4. 3 ) 
* 
W h ole bl o o d f or ser u m ( 1 0 m L) is c ollecte d at t he ti me of eac h P E T/ C T sca n a n d at 
t he ti me of eac h C T sca n d uri n g t he first 3 years of f oll o w- u p. 
* * 
W h ole bl o o d f or plas ma ( 1 0 m L) is c ollecte d at t he ti me of eac h P E T/ C T sca n a n d at 
t he ti me of eac h C T sca n d uri n g t he first 3 years of f oll o w- u p. 
* * * A n F F P E tiss ue bl oc k is ma n dat or y f or hist ol o gic c o nfir mati o n of dia g n osis a n d if 
patie nt has c o nse nte d t o all o w tiss ue t o be ke pt f or c urre nt a n d/ or f ut ure researc h, o nl y 
o ne bl oc k nee ds t o be s u b mitte d. 
1  
Patie nts w h o a ns were d, “ yes” t o m o del c o nse nt q uesti o n # 1. 
2  
Patie nts w h o a ns were d, “ yes” t o m o del c o nse nt q uesti o n # 2 a n d # 3. 
5. 4. 1 
Ser u m a n d Pl as m a S u b missi o n f or t he C orrel ati ve S u bst u d y ( 1 5 0 9 0 3)  
F or patie nts w h o c o nse nt t o partici pate ( m o del c o nse nt q uesti o n # 1), b ot h ser u m 
a n d plas ma will be use d f or t he bi o mar ker a nal yses descri be d i n Secti o n s 1 0. 1 a n d 
1 0. 2 . S u b missi o n of b ot h s peci me n t y pes is re q uire d. 
W h ole bl o o d ( 2 0 m L) will be c ollecte d at baseli ne ( pri or t o i nitiati o n of t hera p y), 
at eac h of t he first t w o P E T/ C T sca ns, a n d at t he ti me of eac h P E T/ C T sca n d uri n g 
t he first 3 years of p ost- treat me nt f oll o w-u p. T hat is, bl o o d will be c ollecte d at t he 
f oll o wi n g 1 1 or 1 2 ti me p oi nts: 
1.  Pri or t o i nitiati o n of t hera p y  
2.  At t he ti me of t he sec o n d P E T/ C T sca n ( p ost c ycle 2)  
3.  At  t he  ti me  of  t he  t hir d  P E T/ C T  sca n  (at  c he m o  c o m pleti o n  f or  P E T 
ne gati ve  patie nts; at p ost I F R T c o m pleti o n f or P E T p ositi ve patie nts)  
4.  3 m o nt hs p ost- treat me nt 
5.  6 m o nt hs p ost- treat me nt 
6.  9 m o nt hs p ost- treat me nt 
7.  1 2 m o nt hs p ost- treat me nt 
8.  1 8 m o nt hs p ost- treat me nt 
9.  2 4 m o nt hs p ost- treat me nt 
1 0.  3 0 m o nt hs p ost- treat me nt 
1 1.  3 6 m o nt hs p ost- treat ment 
5. 4. 1. 1 
Ser u m C ollecti o n Pr oce d ures  
F or patie nts w h o c o nse nt t o partici pate ( m o del c o nse nt q uesti o n # 1), ser u m 
sa m ples will be use d f or t he st u dies descri be d i n Secti o n 1 0. 1 .  
1. 
C ollect  bl o o d  i n  1 0  m L  Re d  T o p  T u be.  After  c ollecti o n,  t u bes 
(“ vac utai ners”)  s h o ul d  sit  u pri g ht  after  t he  bl o o d  is  dra w n  at  r o o m 
te m perat ure f or a mi ni m u m of 3 0 t o a ma xi m u m of 6 0 mi n utes t o all o w 
t he cl ot t o f or m. N ote: Use re d t o p (ser u m) t u bes (silic o n-c oate d) — n o 
a d diti ves a n d n ot S S T (ser u m se parat or t u bes).  
2. 
Ce ntrif u ge  t he  bl o o d  sa m ple  at  t he  e n d  of  t he  cl otti n g  ti me  ( 3 0 - 6 0 
mi n utes) i n a h oriz o ntal r ot or (s wi n g -o ut hea d) f or 2 0 mi n utes at 1 1 0 0 -
1 3 0 0 g at r o o m te m perat ure.   
3. 
Use  a  pi pette  t o  tra nsfer  t he  ser u m  ( Rec o m me n dati o n:  d o  n ot  p o ur). 
Pi p ette ser u m i nt o t he la bele d cr y o vials (rec o m me n de d cr y o vials are 


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descri be d i n Secti o n 5. 4. 1. 3 ). Ali q u ot v ol u me is t o be 5 0 0 µ L. Cl ose 
t he ca ps o n t he vials ti g htl y. T his pr ocess s h o ul d be c o m plete d wit hi n 
1 h o ur of ce ntrif u gati o n. N ote: Be ver y caref ul n ot t o pic k u p re d bl o o d 
cells w he n ali q u oti n g. T his ca n be d o ne b y kee pi n g t he pi pet a b o ve t he 
re d bl o o d cell la yer a n d lea vi n g a s mall a m o u nt of ser u m i n t he t u be.  
4. 
C hec k t hat all ali q u ot vial ca ps are sec ure a n d t hat all vi als are la bele d.  
5. 
Place  all  ali q u ots  u pri g ht  i n  a  s peci me n  b o x  or  rac k  i n  a n -8 0° C  or 
c ol der freezer. All s peci me ns s h o ul d re mai n at -8 0° C or c ol der pri or t o 
s hi p pi n g. T he C A L G B 5 0 8 0 1 sa m ples s h o ul d n ot be t ha we d pri or t o 
s hi p pi n g. Ser u m s h o ul d be s hi p pe d o n dr y ice acc or di n g t o t he s hi p pi n g 
pr oce d ures i n Secti o n 5. 4. 1. 3 . 
5. 4. 1. 2 
Pl as m a C ollecti o n P r oce d ures  
F or patie nts w h o c o nse nt t o partici pate ( m o del c o nse nt q uesti o n # 1), plas ma 
sa m ples will be use d f or t he st u dies descri be d i n Secti o n 1 0. 2 .  
1. 
C ollect bl o o d i n 1 0 m L P ur ple T o p T u be. After c ollecti o n, ge ntl y mi x 
t he bl o o d b y i n verti n g t he t u be 8 t o 1 0 ti mes. St ore vac utai ner t u bes 
u pri g ht  at  4° C  u ntil  ce ntrif u gati o n.  Bl o o d  sa m ples  s h o ul d  be 
ce ntrif u ge d wit hi n f o ur h o urs of bl o o d c ollecti o n.   
2.  
Ce ntrif u ge bl o o d sa m ples i n a h oriz o ntal r ot or (s wi n g- o ut hea d) f or 1 0 
t o 2 0 mi n utes at 1 1 0 0-1 3 0 0 g at r o o m te m perat ure. War ni n g: E xcessi ve 
ce ntrif u ge s pee d ( o ver 2 0 0 0 g) ma y ca use t u be brea ka ge a n d e x p os ure 
t o bl o o d a n d p ossi ble i nj ur y.  If nee de d, R C F f or a ce ntrif u ge ca n be 
calc ulate d.  F or  a n  o n -li ne  calc ulat or  t o ol,  please  refer  t o: 
  
3. 
After  ce ntrif u gati o n,  plas ma  la yer  will  be  at  t he  t o p  of  t he  t u be. 
M o n o n uclear cells a n d platelets will be i n a w hitis h la yer, calle d t he 
“ b uff y c oat”, j ust u n der t he plas ma a n d a b o ve t he re d bl o o d cells.  
4. 
Caref ull y c ollect t he plas ma la yer wit h a n a p pr o priate tra nsfer pi pette 
wit h o ut  dist ur bi n g  t he  b uff y  c oat  la yer.  Pi pette  t he  plas ma  i nt o  t he 
la bele d  cr y o vials  (rec o m me n de d cr y o vials  are  descri be d  i n Secti o n 
5. 4. 1. 3 ). Ali q u ot v ol u me is t o be 5 0 0 µ L. Cl ose t he ca ps ti g htl y a n d 
place  o n  ice.  T his  pr ocess  s h o ul d  be  c o m plete d  wit hi n  1  h o ur  of 
ce ntrif u gati o n.   
5. 
C hec k t hat all ali q u ot vial ca ps are  sec ure an d t hat all vials are la bele d.  
6. 
Place  all  ali q u ots  u pri g ht  i n  a  s peci me n  b o x  or  rac k  i n  a n -8 0° C  or 
c ol der freezer. All s peci me ns s h o ul d re mai n at -8 0° C or c ol der pri or t o 
s hi p pi n g. T he sa m ples s h o ul d n ot be t ha we d pri or t o s hi p pi n g. Plas ma 
s h o ul d be s hi p pe d o n dr y ice acc or di n g t o t he s hi p pi n g pr oce d ures i n 
Secti o n 5. 4. 1. 3 . 






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6. 0  
R E Q UI R E D D A T A  
G ui deli nes F or Pre- St u d y Testi n g 
T o be c o m plete d wit hi n 1 6 D A Y S bef ore re gistrati o n: 
-  All bl o o d w or k 
- Hist or y a n d p h ysical e xa mi nati o n 
T o be c o m plete d wit hi n 2 8 D A Y S bef ore re gistrati o n: 
-  A n y sca n of a n y t y pe (e. g., P E T, C T, or M RI) t hat is utilize d f or t u m or meas ure me nt 
T o be c o m plete d wit hi n 4 2 D A Y S bef ore re gistrati o n: 
- A n y baseli ne e xa ms use d f or scree ni n g (i.e., M U G A, P F Ts)  
- A n y sca n of a n y t y pe, or ultras o u n d of u ni n v ol ve d or ga ns t hat is n ot utilize d f or t u m or meas ure me nt  
Tests & O bser vati o ns  
Pri or  
t o St u d y  
D a y 1 of  
E ac h 
C y cle *  
D a y 1 5 of  
E ac h 
C y cle * *  
Ti me of 
Rest a gi n g  
 
P ost Tre at me nt F oll o w -u p  
( after c y cle 2 of A B V D a n d 
f oll o wi n g eit her c y cle 6 of 
A B V D or I F R T) * * *  
Hist or y a n d Pr o gress N otes  
X  
X  
 
 
X  
P h ysical E xa mi n ati o n  
X  
X  
 
 
X  
Hei g ht/ Wei g ht/ B S A  
X  
 
 
 
 
P erf or ma nce Stat us  
X  
X  
 
 
 
T u m or Meas ure me nts  
X  
A  
 
X  
X  
Dr u g T o xicit y Ass ess me nt  
 
X  
X  
X  
X  
L a b or at or y St u dies  
 
 
 
 
 
C B C, Differe ntial, Platelets  
G  
X  
X * *  
X  
 
E S R  
G  
 
 
X  
 
Ser u m Creati ni n e  
G  
X  
 
X  
 
Gl uc ose  
G  
 
 
X  
 
A S T, Al kali ne P h os p h atase, Bilir u bi n  
G  
X  
 
X  
 
Ser u m or uri ne β H C G  
X 
 
 
 
 
L D H  
G 
 
 
 
 
L V E F b y E C H O or M U G A  
F  
 
 
 
P R N  
P F Ts (i ncl u di n g D L C O/ F V C)  
F 
 
 
 
P R N 
HI V (if re q uire d, see secti o n 4. 5) 
B 
 
 
 
 
St a gi n g  
 
 
 
 
 
C T sca n ( nec k, c h est, a b d o me n/ p el vis)  
F , H  
 
 
X  
D  
F D G -P E T/ C T sc a n †  
E , F 
 
 
C 1 -3  
 
C hest X -ra y, P A & Lateral  
F 
 
 
 
 
Hist ol o gic Re vie w (s ee S ecti o n 5. 3 ) 
X 
 
 
 
 
C A L G B 1 5 0 9 0 3 (c o nse nti n g p atie nts)  
F F P E tiss ue  
At b aseli n e a n d at t h e ti me of pr o gressi o n / rela pse.  
W h ole bl o o d f or mar ker a n al ysis  
Pri or  t o  re gistrati o n;  at  t h e  ti me  of  t h e  p ost -c ycle  2  P E T/ C T  sca n,  c he m o 
c o m pleti o n P E T/ C T sca n; p ost I F R T P E T/ C T sc a n (if p ost -c ycle 2 P E T/ C T sc a n 
is p ositi ve); at 3, 6, 9, 1 2, 1 8, 2 4, 3 0 a n d 3 6 m o nt hs p ost-treat me nt f oll o w-u p.  
†  I nstit uti o ns m ust be cre de ntiale d b y t he Allia nce  I ma gi n g C ore La b at I R O C O hi o  pri or t o e nr olli n g 
patie nts (see  Secti o n 8. 1. 1 ). It is critical t hat all F D G-P E T/ C T sca ns be perf or me d i n a n i de ntical wa y 


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t o t he baseli ne sca n, wit h t he sa me sca n ner, sa me sca n directi o n, a n d c o nsiste nt ar m p ositi o ni n g. T he 
i nter val bet wee n F D G i njecti o n a n d i nitiati o n of e missi o n sca n ni n g s h o ul d be t he sa me or si milar t o 
t he baseli ne sca n. 
* Wit hi n 4 8 h o urs pri or t o da y 1 of A B V D or B E A C O P P. 
* *  
Wit hi n 4 8 h o urs pri or t o da y 1 5 of eac h treat me nt c ycle of A B V D. 
* * * 
E ver y 3 m o nt hs  f or o ne year fr o m t he res p o nse assess me nt at t he c o m pleti o n of t hera p y, 
t he n e ver y 6 m o nt hs f or years 2 a n d 3, a n d t he n a n n uall y f or a ma xi m u m of te n years fr o m st u d y 
e ntr y.  
A If accessi ble t o p h ysical e xa mi nati o n, rec or d meas ure me nts o n da y 1 of eac h c ycle. 
B A n HI V test is n ot re q uire d f or e ntr y o n t his pr ot oc ol, b ut is re q uire d if t he patie nt is percei ve d t o 
be at ris k.  
C 1 
P ost -c ycle 2 F D G-P E T/ C T sca ns m ust be perf or me d 8 -1 0 da ys after t he Da y -1 5 d ose of 
A B V D  d uri n g  c ycle  2. (i.e. o n  da y  2 3,  2 4 or 2 5  o f  c ycle  2, see Secti o n  8. 2  f or  acce pta ble  F D G-
P E T/ C T sca n c o m pleti o n da ys).   
C 2 
F or  patie nts  w h o  are  P E T ne gati ve  after  2  c ycles  of  A B V D,  p ost -treat me nt  c o m pleti o n 
F D G -P E T/ C T will be perf or me d ≥ 3 a n d ≤ 8 wee ks after c o m pleti o n o f c he m ot hera p y. 
C 3 
F or patie nts w h o are P E T p ositi ve after 2 c ycles of A B V D, p ost -I F R T F D G-P E T/ C T sca ns 
m ust be perf or me d ≥1 2 wee ks a n d ≤1 6 wee ks after c o m pleti o n of I F R T. 
D C o ntrast- e n ha nce d helical/s piral C T sca ns of t he c hest, a b d o me n, a n d pel vis will be o btai ne d e ver y 
3 m o nt hs f or year o ne a n d e ver y 6 m o nt hs f or years 2 -3 a n d a n n uall y f or years 4 - 5. F oll o w-u p r o uti ne 
C Ts of t he nec k will n ot us uall y be necessar y, si nce m ost rec urre nces i n t he nec k will be f o u n d b y 
p h ysical e xa mi nati o n. 
E Baseli ne F D G - P E T/ C T will be o btai ne d ≤ 2 8 da ys pri or t o re gistrati o n. See S ecti o n 5. 1. 2  i n t he 
case of a patie nt w h o has alrea d y ha d a baseli ne sca n at a n ot her facilit y.  
F If a patie nt has ha d o ne pre vi o us c ycle of A B V D pri or t o e nr olli n g o n st u d y, t he patie nt m ust ha ve 
ha d t he f oll o wi n g tests pri or t o starti n g t he pre vi o us c ycle of A B V D: L V E F, P F Ts, C T sca n, F D G -
P E T/ C T sca n, a n d c hest x -ra y. T hese tests d o n ot nee d t o be re peate d pri or t o st u d y i n t h ose patie nts 
wit h a pre vi o us c ycle of A B V D.  
G If a patie nt has ha d o ne pre vi o us c ycle of A B V D pri or t o e nr olli n g o n st u d y, t he patie nt m ust ha ve 
ha d t he f oll o wi n g tests pri or t o starti n g t he pre vi o us c ycle of A B V D: C B C, differe ntial, platelets; 
E S R; ser u m creati ni ne; gl uc ose; A S T, al kali ne p h os p hatase, bilir u bi n; a n d L D H. T hese tests d o n ot 
nee d t o be re peate d pri or t o st u d y i n t h ose patie nts wit h a pre vi o us c ycle of A B V D.  
H Patie nts wit h a ne gati ve F D G - P E T/ C T sca n d o n ot nee d t o ha ve a de dicate d nec k C T sca n pri or t o 
st u d y. 
P R N As cli nicall y i n dicate d.  


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7. 0  
T R E A T M E N T P L A N  
I nstit uti o ns m ust be cre de ntiale d b y t he Allia nce  I ma gi n g C ore La b at I R O C Ohi o pri or t o e nr olli n g 
patie nts (see Secti o n 8. 1. 1 ). 
Patie nts m ust be gi n treat me nt wit hi n 7 da ys of re gistrati o n. Q uesti o ns re gar di n g treat me nt ma y be 
directe d t o t he St u d y C hair. 
A misse d or v o mite d d ose of oral a ge nt s h o ul d n ot be ma de u p.  
7. 1 
C he m ot her a p y Re gi me ns  
M o n da ys  a n d  T ues da ys  are  rec o m me n de d  as  t hera p y  i nitiati o n  da ys  t o  ass ure  a  ti mel y 
ce ntral P E T rea di n g.  
7. 1. 1 
A B V D  
T hera p y will c o nsist of d o x or u bici n, ble o m yci n, vi n blasti ne, a n d dacar bazi ne o n 
Da ys 1 a n d 1 5 of eac h c ycle. A c ycle will be c o nsi dere d 2 8 da ys. 
D o x or u bici n 2 5 m g/ m 2 I V o n Da ys 1 a n d 1 5 of eac h c ycle 
Ble o m yci n 1 0 u nits/ m 2 I V o n Da ys 1 a n d 1 5 of eac h c ycle 
Vi n blasti ne 6 m g/ m 2 I V o n Da ys 1 a n d 1 5 of eac h c ycle 
Dacar bazi ne 3 7 5 m g/ m 2 I V i nf usi o n o n Da ys 1 a n d 1 5 of eac h c ycle 
All  patie nts  will  recei ve  2  c ycles  of  A B V D. F or  patie nts  w h o  ha ve  ha d  o ne 
pre vi o us c ycle of A B V D pri or t o re gistrati o n, t he pre vi o us c ycle will be c o nsi dere d 
c ycle 1. Patie nts w h o ac hie ve a C R, P R, or S D a n d w h ose P E T sca ns are ne g ati v e 
after  t w o  c ycles  of  A B V D  (see Secti o n  8. 2  f or  ti mi n g  of  i ma gi n g  st u dies)  will 
recei ve f o ur m ore c ycles of A B V D (a t otal of si x c ycles). 
See Secti o n 9. 0  f or d ose m o dificati o ns a n d ma na ge me nt of t o xicit y. See Secti o n 
1 2. 0  f or a ncillar y t hera p y. 
7. 1. 2 
Esc al ate d B E A C O P P  
Patie nts w h o ac hie ve a C R, P R, or S D a n d w h ose P E T sca ns are p ositi ve  after t w o 
c ycles  of  A B V D  will  recei ve  f o ur  c ycles  of  escalate d  B E A C O P P  f oll o we d  b y 
i n v ol ve d-fiel d ra di ot hera p y (see secti o n 7. 2): 
Ble o m yci n 1 0 u nits/ m 2 I V o n Da y 8 of eac h c ycle 
Et o p osi de 2 0 0 m g/ m 2 I V o ver 6 0 mi n utes o n Da ys 1, 2 a n d 3 of eac h c ycle 
D o x or u bici n 3 5 m g/ m 2 I V o n Da y 1 of eac h c ycle 
C ycl o p h os p ha mi de 1 2 5 0 m g/ m 2 I V o ver 6 0 mi n utes o n Da y 1 of eac h c ycle 
Vi ncristi ne 1. 4 m g/ m 2 ( ma xi m u m 2 m g) I V o n Da y 8 of eac h c ycle 
Pr ocar bazi ne *  1 0 0 m g/ m 2 (r o u n de d t o nearest 5 0 m g) orall y o n Da ys 1-7 of eac h 
c ycle 
Pre d nis o ne *  4 0 m g/ m 2 (r o u n de d t o nearest 5 m g) orall y o n Da ys 1- 1 4 of eac h c ycle  
Re peat escalate d B E A C O P P treat me nt e ver y 2 1 da ys f or f o ur c ycles.  
Fil grasti m ( G -C S F) *  5 mc g/ k g s u bc uta ne o usl y o n Da ys 8 -1 4 of eac h c ycle. G -
C S F ma y be disc o nti n ue d w he n, after reac hi n g t he na dir, t he ne utr o p hil c o u nt has 
re mai ne d o ver 1, 0 0 0/ m m3 o n 3 s uccessi ve da ys. D o n ot gi ve escalate d B E A C O P P 
wit hi n 4 8 h o urs of fil grasti m. 


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A nti bi otic pr o p h yla xis * wit h c otri m o xaz ole, o ne d o u ble stre n gt h ta blet t wice dail y 
is  re q uire d  o n  da ys  8-1 5  of  eac h  c ycle.  Da ps o ne  ( 5 0  m g  orall y  t wice  dail y)  or 
pe nta mi di ne ma y be s u bstit ute d f or P ne u m oc ystis pr o p h yla xis i n s u bjects aller gic 
t o c otri m o xaz ole. 
See Secti o n 9. 0  f or d ose m o dificati o ns a n d ma na ge me nt of t o xicit y. See Secti o n 
1 2. 0  f or a ncillar y t hera p y. 
* Patie nts s h o ul d rec or d t he d oses of pr ocar bazi ne, pre d nis o ne a n d a nti bi otic ta ke n, 
as well as t he da y i n w hic h G -C S F i nj ecti o n is gi ve n o n t he C A L G B f or m S - 0 6 8 
( 5 0 8 0 1 Me dicati o n Cale n dar). ( See Secti o n 5. 2 ) 
7. 1. 3 
St a n d ar d B E A C O P P  
Patie nts w h o are HI V -p ositi ve a n d w h ose P E T sca ns are p ositi ve  after t w o c ycles 
of A B V D will recei ve f o ur c ycles of sta n dar d B E A C O P P f oll o we d b y i n v ol ve d -
fiel d ra di ot hera p y (see secti o n 7. 2). 
Ble o m yci n 1 0 u nits/ m 2 I V o n Da y 8 of e ac h c ycle 
Et o p osi de 1 0 0 m g/ m 2 I V o ver 6 0 mi n utes o n Da ys 1, 2 a n d 3 of eac h c ycle 
D o x or u bici n 2 5 m g/ m 2 b y I V o n Da y 1 of eac h c ycle 
C ycl o p h os p ha mi de 6 5 0 m g/ m 2 I V o ver 6 0 mi n utes o n Da y 1 of eac h c ycle 
Vi ncristi ne 1. 4 m g/ m 2 ( ma xi m u m 2 m g) I V o n Da y 8 of eac h c ycle  
Pr ocar bazi ne * 1 0 0 m g/ m 2 (r o u n de d t o nearest 5 0 m g) orall y o n Da ys 1 -7 of eac h 
c ycle 
Pre d nis o ne * 4 0 m g/ m 2 (r o u n de d t o nearest 5 m g) orall y o n Da ys 1 -1 4 of eac h c ycle
  
 
Re peat sta n dar d B E A C O P P treat me nt e ver y 2 1 da ys f or f o ur c ycles.  
Fil grasti m ( G -C S F ) * 5 mc g/ k g s u bc uta ne o usl y o n Da ys 8 -1 4 of eac h c ycle. G -
C S F ma y be disc o nti n ue d w he n, after reac hi n g t he na dir, t he ne utr o p hil c o u nt has 
re mai ne d o ver 1, 0 0 0/ m m 3 o n 3 s uccessi ve da ys. D o n ot gi ve sta n dar d B E A C O P P 
wit hi n 4 8 h o urs of fil grasti m. 
A nti bi otic pr o p h yla xis * wit h c otri m o xaz ole, o ne d o u ble stre n gt h ta blet t wice dail y 
is  re q uire d  o n  da ys  8-1 5  of  eac h  c ycle.  Da ps o ne  ( 5 0  m g  orall y  t wice  dail y)  or 
pe nta mi di ne ma y be s u bstit ute d f or P ne u m oc ystis pr o p h yla xis i n s u bjects aller gic 
t o c otri m o xaz ole. 
See Secti o n 9. 0  f or d ose m o dificati o ns a n d ma na ge me nt of t o xicit y. See Secti o n 
1 2. 0  f or a ncillar y t hera p y. 
* Patie nts s h o ul d rec or d t he d oses of pr ocar bazi ne, pre d nis o ne a n d a nti bi otic ta ke n, 
as well as t he da y i n w hic h G-C S F i nj ecti o n is gi ve n o n t he C A L G B f or m S - 0 6 8 
( 5 0 8 0 1 Me dicati o n Cale n dar). ( See Secti o n 5. 2 ) 
7. 2  
I n v ol ve d- Fiel d R a di ati o n T her a p y (I F R T)  
7. 2. 1 
A d mi nistr ati o n of I F R T  
A d mi nistrati o n  of  i n v ol ve d -fiel d  ra diati o n  t hera p y (I F R T)  will  de pe n d  o n  P E T 
res p o nse (see Secti o n 8. 0 ) after 2 c ycles of A B V D as f oll o ws: 
1.  Patie nts w h o are P E T ne gati ve after 2 c ycles of A B V D will n ot  recei ve 
I F R T. 


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3 2  
U p date # 1 3  
2.  Patie nts w h o are P E T p ositi ve after 2 c ycles of A B V D, will  recei ve I F R T 
f oll o wi n g  4  c ycles  of  escalate d  B E A C O P P.  T hese  patie nts  will  recei ve 
3 0. 6 G y I F R T. 
A  peri o d  of  3 -6  wee ks  will  ela pse  bet wee n  t he  be gi n ni n g  of  t he  last  d ose  of 
c he m ot hera p y a n d t he be gi n ni n g of ra diati o n t hera p y, I F R T ma y n ot be gi n u ntil 
t he W B C is > 2, 0 0 0/ micr oliter a n d t he platelet c o u nt is > 1 0 0, 0 0 0/ micr oliter. 
7. 2. 2 
E q ui p me nt  
E ner g y :  4-1 0  M V  p h ot o ns  are  re q uire d  f or  all  disease  sites.  C o balt -6 0  is n ot 
all o we d. I M R T is n ot all o we d. Pr ot o n t hera p y is n ot all o we d. 
Ge o metr y : I n ge neral, parallel o p p ose d e q uall y wei g hte d fiel ds ( A P/ P A) are m ost 
a p pr o priate. Is oce ntric tec h ni q ue wit h S A D ≥ 8 0 c m is prefera ble, wit h t he patie nt 
s u pi ne i n t he sa me p ositi o n f or b ot h t he A P a n d P A treat me nts. F or lar ge fiel d sizes 
(e. g., nec k pl us me diasti n u m), e xte n de d dista nce a n d S S D tec h ni q ue are all o we d, 
wit h t he S S D i n t he 1 1 0 -1 2 0 c m ra n ge. I n t his setti n g, S S D tec h ni q ue w here t he 
patie nt t ur ns fr o m s u pi ne t o pr o ne is acce pta ble.  
Si m ul ati o n : C T base d treat me nt pla n ni n g is re q uire d f or all patie nts.  
C ali br ati o n:  All  t hera p y  u nits  use d  f or  t his  pr ot oc ol  s hall  ha ve  cali brati o ns 
verifie d b y t he Ra di ol o gical P h ysics Ce nter. 
7. 2. 3 
Re q uire d Be nc h m ar ks  
Ce nters partici pati n g i n t his pr ot oc ol usi n g 3 D -C R T are re q uire d t o c o m plete t he 
3 D Be nc h mar k. Be nc h mar k materials ma y be o btai ne d fr o m t he Q ualit y Ass ura nce 
Re vie w  Ce nter  ( w w w. qarc. or g )  a n d  m ust  be  s u b mitte d  bef ore  patie nts  o n  t his 
pr ot oc ol ca n be e val uate d.  
7. 2. 4 
Pl a n ni n g T ar get V ol u me  
G ui deli nes f or deli neati n g t he i n v ol ve d fiel d ha ve  bee n pre vi o usl y p u blis he d [ 2 9]. 
Briefl y,  a  re gi o n,  n ot  i n di vi d ual  l y m p h  n o des,  is  treate d.  I n  ge neral,  pre -
c he m ot hera p y v ol u mes are utilize d, wit h t he e xce pti o n of t he tra ns verse dia meter 
of  me diasti nal  disease.  T o  s pare  n or mal  tiss ue,  p ost -c he m ot hera p y  vol u mes  are 
treate d i n t his circ u msta nce. All sites i n v ol ve d at prese ntati o n nee d t o be i ncl u de d 
i n t he  treat me nt  fiel ds. Treat me nt  will  i ncl u de t he  v ol u mes  as  descri be d  bel o w. 
Ori gi nal e xte nt of disease pl us 2. 0 c m mar gi n m ust be i ncl u de d; t his s u perse des all 
ot her  re q uire me nts. T he  o nl y  e xce pti o n  is  f or fiel ds  near critical  or ga ns  (l u n gs) 
w he n a 1- 1. 5 c m mar gi n ma y be acce pta ble (see bel o w).  
T he Gr oss T u m or V ol u me  ( G T V) is defi ne d as t he v ol u me occ u pie d b y visi ble 
or  pal pa ble  disease,  a n d  will  be  li mite d  t o  areas  of  disease  as  defi ne d  at 
prese ntati o n  a n d  i ncl u des  resi d ual  disease  prese nt  after  t he  c o m pleti o n  of 
c he m ot hera p y.  T he Cli nic al  T ar get  V ol u me  ( C T V)  is  t he  a nat o mical 
c o m part me nt(s)  i n  w hic h  t he  G T V  is  l ocate d.  T he Pl a n ni n g  T ar get  V ol u me  
( P T V) is defi ne d as t he mar gi n ar o u n d t he C T V t o acc o u nt f or patie nt m oti o n a n d 
set- u p varia bilit y. T he P T V fiel ds are o utli ne d bel o w. 
•  
U nil ater al Cer vic al/ S u pr acl a vic ul ar Re gi o n:  I n v ol ve me nt at a n y u nilateral 
cer vical  le vel  wit h  or  wit h o ut  i n v ol ve me nt  of  t he  i psilater al  s u pracla vic ular 
( S C L) n o des. Ar ms a ki m b o or at si des. 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
3 3  
U p date # 1 3  
U p per B or der:  1-2 c m a b o ve t he l o wer ti p of t he mast oi d pr ocess a n d mi d p oi nt 
t hr o u g h  t he  c hi n.  If  o nl y  t he  S C L  n o des  are  i n v ol ve d  ( n o  cer vical  n o dal 
i n v ol ve me nt), t he u p per b or der s h o ul d be place d at t he t o p of t he lar y n x. 
L o wer B or der:  2 c m bel o w t he b ott o m of t he cla vicle. 
L ater al B or der:  T o i ncl u de t he me dial 2/ 3 of t he cla vicle. 
Me di al B or der:  
( a) If t he s u pracla vic ular n o des are n ot i n v ol ve d, place t he b or der at t he 
i psilateral tra ns verse pr ocesses e xce pt w he n me dial n o des cl ose t o t he 
verte bral b o dies are prese nt o n i nitial sta gi n g, i n w hic h case t he b or der 
s h o ul d all o w 2 c m mar gi n or i ncl u de t he e ntire verte bral b o d y. 
( b) W he n  t he  i psilateral  s u pracla vic ular  n o des  are  i n v ol ve d,  t he  b or der  
s h o ul d be place d at t he c o ntralateral tra ns verse pr ocesses. 
Bl oc ks: 
( a) Mi d -nec k calc ulati o ns s h o ul d be perf or me d t o deter mi ne t he ma xi m u m 
s pi nal c or d d ose. 
( b) A s mall a nteri or lar y n x bl oc k ma y be use d t hr o u g h o ut treat me nt u nless 
t his bl oc k w o ul d s hiel d disease.  
•  
Bil ater al  Cer vic al/ S u pr acl a vic ul ar  Re gi o n:  Treat  b ot h  cer vical  a n d 
s u pracla vic ular re gi o ns as descri be d a b o ve. Use a p osteri or m o ut h bl oc k o n t he 
p osteri or- a nteri or fiel d t o bl oc k t he u p per fiel d di ver gi n g t hr o u g h t he m o ut h. 
Bl oc ks ma y be use d as descri be d a b o ve.  
•  
Me di asti n u m:  I n v ol ve me nt of t he me diasti n u m a n d/ or t he hilar n o des. T he 
fiel d  i ncl u des  als o  t he  bilateral  me dial  S C L  n o des  e ve n  if  n ot  cli nicall y 
i n v ol ve d. Ar ms a ki m b o, at si des, or u p. 
U p per  B or der:  C 5 -C 6  i nters pace  if  t he  S C L  n o des  were  n ot  ori gi nall y 
i n v ol ve d. If S C L n o des were i n v ol ve d, t he u p per b or der s h o ul d be place d at 
t he t o p of t he lar y n x a n d t he lateral b or der s h o ul d be a dj uste d as descri be d i n 
t he secti o n o n treati n g nec k n o des. 
L o wer B or der : 5 c m bel o w t he cari na or 2 c m bel o w t he pre -c he m ot hera p y 
i nferi or b or der, w hic he ver is l o wer. 
L ater al B or der:  P ost -c he m ot hera p y G T V wit h 1. 5 c m mar gi n. 
Hil ar Are a:  T o be i ncl u de d wit h 1 c m mar gi n (e xce pt w here G T V re q uires 1. 5 
c m mar gi n).  
He art:  Treat me nt of t he e ntire pericar di u m s h o ul d be li mite d t o patie nts wit h 
e xte nsi ve pericar dial i n v ol ve me nt; i n t his case, t he w h ole heart ca n be treate d 
t o  1 4. 4  G y.  Selecte d  pericar dial  treat me nt  is  reas o na ble  i n  ot her  cli nical 
sit uati o ns, s uc h as e xte nsi o n of a n i nter nal ma m mar y n o de t o t he pericar di u m, 
or ri g ht -si de d pericar dial fat pa d i n v ol ve me nt a butti n g t he pericar di u m wit h o ut 
eff usi o n. 
•  
Me di asti n u m wit h i n v ol ve me nt of t he cer vic al n o des:  W he n b ot h cer vical 
re gi o ns are i n v ol ve d, t he fiel d is a ma ntle wit h o ut a xillae usi n g t he g ui deli nes 
descri be d a b o ve. If o nl y o ne cer vical c hai n is i n v ol ve d, t he verte bral b o dies, 
c o ntralateral u p per nec k, a n d lar y n x ca n be bl oc ke d as pre vi o usl y descri be d.  


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
3 4  
U p date # 1 3  
•  
A xill ar y Re gi o n:  T he i psilateral a xillar y, i nfracla vic ular, a n d s u pracla vic ular 
areas are treate d w he n t he a xilla is i n v ol ve d. W he ne ver p ossi ble use C T -base d 
pla n ni n g f or t his re gi o n.  
U p per B or der : C 5 -C 6 i nters pace or i nferi or b or der of t he lar y n x (if n o S C L 
i n v ol ve me nt; ot her wise m o dif y fiel d as n ote d a b o ve). 
L o wer B or der:  T he ti p of t he sca p ula or 2 c m bel o w t he l o west a xillar y n o de, 
w hic he ver is l o wer.  
Me di al B or der : I psilateral cer vical tra ns verse pr ocess. I ncl u de t he verte bral 
b o dies o nl y if t he S C L is i n v ol ve d. 
L ater al B or der:  Flas h a xilla.  
•  
U n us u al Sites ( W al de yer’s Ri n g):  T o be disc usse d wit h t he C A L G B 5 0 8 0 1 
Ra diati o n O nc ol o g y C o -C h air.  
7. 2. 5 
T ar get D ose  
All fiel ds will be treate d t o a t otal d ose of 3, 0 6 0 c G y, calc ulate d at t he is oce nter or 
at t he ce ntral a xis at mi d pla ne. Eac h dail y fracti o n will be 1 8 0 c G y. 
7. 2. 6 
Ti me -D ose C o nsi der ati o ns  
Prescri be 1 8 0 c G y per fracti o n t o t he prescri pti o n p oi nt. Treat wit h 1 fracti o n/ da y, 
5 fracti o ns/ wee k. Treat all fiel ds eac h da y. N o d ose a dj ust me nts will be ma de  f or 
treat me nt i nterr u pti o ns.  
7. 2. 7 
D ose U nif or mit y a n d Refere nce P oi nts  
E ver y  eff ort  s hall  be  ma de  t o  ma ke  t he  d ose  u nif or m  t hr o u g h o ut  t he  treat me nt 
v ol u me. T he d ose s h o ul d be 3, 0 6 0 c G y ± 7. 5 % t hr o u g h o ut t he treat me nt v ol u me. 
D oses s h o ul d be carrie d at t he ce ntral a xis, 2 c m a b o ve t he i nferi or fiel d e d ge a n d 
2  c m  bel o w  t he  s u peri or  fiel d  e d ge.  Off -a xis  refere nce  p oi nts  s h o ul d  als o  be 
carrie d,  as  a p pr o priate  f or  t he  fiel d  (e. g.,  mi d -nec k,  mi d -a xilla,  S C L). 
C o m pe nsat ors/ b o osti n g/ bl oc ki n g  is  all o we d  w he n  nec essar y  t o  ac hie ve  t he  
± 7. 5 % h o m o ge neit y. 
7. 2. 8 
Heter o ge neit y C orrecti o ns  
Calc ulati o ns t hat ta ke i nt o acc o u nt tiss ue heter o ge neities s hall be use d.  
7. 2. 9 
Tre at me nt Tec h ni q ues  
P atie nt  P ositi o n : S u pi ne  t hr o u g h o ut  is  prefera ble.  Ge nerall y  treat  wit h  ar ms 
a ki mb o ( ha n ds o n hi ps). If a xillar y l y m p h n o des are i n v ol ve d, p ositi o ni n g wit h t he 
ar ms u p is als o acce pta ble. Ot her s pecific p ositi o ni n g rec o m me n dati o ns are n ote d 
a b o ve. A p pr o priate i m m o bilizati o n de vices are hi g hl y rec o m me n de d. 
Fiel d S h a pi n g : Use c ust o m s hie l di n g wit h di ver ge nt a n d i n di vi d uall y c ut bl oc ks 
or m ultileaf c olli mat ors. Treat me nt will be verifie d wit h wee kl y p ortal fil ms.  
7. 2. 1 0 N or m al Tiss ue S p ari n g  
T he ma xi m u m d ose t o a n y p oi nt i n t he s pi nal c or d will be ≤ 4, 0 0 0 c G y. 
T he v ol u me of l u n g recei vi n g o ver 2 0 G y ( V 2 0) will be ≤ 3 5 %. 






C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
3 7  
U p date # 1 3  
P D  at  a n y  ti me  will  be  re m o ve d  fr o m  pr ot oc ol  t hera p y.  Patie nts  will  be  e val uate d  f or 
res p o nse after c ycle 2 a n d after c o m pleti o n of treat me nt c he m ot hera p y. P ost c o m pleti o n of 
treat me nt P E T/ C T sca ns m ust be o btai ne d ≥ 3 wee ks b ut ≤ 8 wee ks fr o m c o m pl eti o n of 
last  c ycle  of  c he m ot hera p y f or  P E T  ne gati ve  patie nts  o nl y.  Patie nts  recei vi n g  escalate d 
B E A C O P P + I F R T will als o u n der g o a P E T/ C T sca n ≥ 1 2 wee ks a n d ≤ 1 6 wee ks after 
c o m pleti o n I F R T. 
7. 3. 1  
C R, P R, or S D a n d P E T Ne g ati ve after C o m pleti o n of Tre at me nt  
Patie nts w h o ac hie ve a C R, P R, or S D a n d w h o are P E T ne gati ve after c o m pleti o n 
of treat me nt will be f oll o we d acc or di n g t o t he p ost -treat me nt f oll o w-u p sc he d ule 
i n Secti o n 6. 0 . 
7. 3. 2  
C R, P R, or S D a n d P E T P osi ti ve after C o m pleti o n of Tre at me nt 
F or patie nts w h o ac hie ve a C R, P R, S D a n d w h o are P E T p ositi ve after c o m pleti o n 
of treat me nt, a bi o ps y ma y be perf or me d at t he discreti o n of t he treati n g p h ysicia n. 
If  bi o ps y  ne gati ve,  t he n  t he  patie nt  s h o ul d  be  f oll o we d acc or di n g  t o  t he  p ost -
treat me nt f oll o w-u p sc he d ule i n Secti o n 6. 0 . If bi o ps y p ositi ve, t he n t he patie nt 
s h o ul d be f oll o we d per Secti o n 1 4. 1. 2 . If a bi o ps y is neit her cli nicall y i n dicate d 
n or  me dicall y  feasi ble,  t he n  t he  patie nt  s h o ul d  u n der g o  re peat  P E T/ C T  a n d  C T 
sca ns t hree m o nt hs later. 
If P E T ne gati ve after t hree m o nt hs, t he n t he patie nt will be f oll o we d acc or di n g t o 
t he p ost-treat me nt f oll o w- u p sc he d ule i n Secti o n 6. 0 . 
If PE T p ositi ve after t hree m o nt hs, t he n at t he discreti o n of t he treati n g p h ysicia n 
t he patie nt ma y u n der g o a bi o ps y if cli nicall y feasi ble a n d a p pr o priate.  
If, at t hree m o nt hs, bi o ps y is neit her cli nicall y a p pr o priate n or me dicall y feasi ble, 
t he n  t he  patie nt  s h o ul d  be  f oll o we d  acc or di n g  t o  t he  p ost-treat me nt  f oll o w- u p 
sc he d ule i n Secti o n 6. 0 . 
8. 0  I M A GI N G  
F D G - P E T I ma gi n g, I nter pretati o n, P E T a n d C T Data S u b missi o n, a n d Se mi q ua ntitati ve A nal ysis. 
8. 1 
I nstit uti o n Cre de nti ali n g P r oce d ures f or F D G-P E T/ C T I m a gi n g  
Pri or t o e nr oll me nt of patie nts, i nstit uti o ns m ust be cre de ntiale d t o partici pate i n t he trial 
b y t he Allia nce  Ima gi n g C ore La b or at or y (I C L) at I R O C O hi o if t he y ha ve n ot pre vi o usl y 
bee n cre de ntiale d f or a n y ot her C A L G B trials (see Secti o n 8. 1. 1 ). T he I ma gi n g C ore La b 
has de vel o pe d a n d will pr o vi de a site ma n ual t hat o utli nes all of t he details as t he y re late t o 
t he i ma ge ac q uisiti o n a n d rec o nstr ucti o n.  
8. 1. 1 
F D G -P E T/ C T Re q uire me nts f or P artici p ati o n  
T he partici pati n g ce nter m ust ha ve, or ha ve access t o, a facilit y wit h a n i nte grate d 
p ositr o n-e missi o n t o m o gra p h y a n d c o m p ute d t o m o gra p h y ( P E T/ C T) sca n ner.  
T he  partici pati n g  ce nter  m ust  ha ve  t he  a bilit y  t o  s u b mit  P E T  a n d  C T  st u dies 
electr o nicall y t o t he I C L i n di gital DI C O M f or mat ( ot her f or mats: BI T M A P, J P G, 
har dc o p y  or  sca n ne d  files  are  n ot  acce pta ble).  See Secti o n  8. 9  f or  s u b missio n 
pr oce d ures. 
Partici pati n g  sites  m ust  be  cre de ntiale d  b y  t he  I C L  s o  t hat  t he  perf or ma nce 
c haracteristics a n d i nfrastr uct ure re q uire me nts are met:  


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
3 8  
U p date # 1 3  
If  a  site  has  bee n  cre de ntiale d  b y  t he  I C L  f or  partici pati n g  i n  C A L G B  5 0 3 0 3 
P E T/ C T  i ma gi n g  st u d y,  a  pr ot oc ol  refres h me nt  o nl y  will  be  nee de d f or 
partici pati n g i n C A L G B 5 0 8 0 1. 
If a site has ne ver bee n cre de ntiale d b y t he I C L, h o we ver t he site partici pate d or is 
partici pati n g i n a n y ot her Allia nce/ C A L G B  P E T or C T i ma gi n g trials, a pr ot oc ol 
refres h me nt  (a n d  a  Virt ual  Site  Visit,  if  necessar y)  is  re q uir e d  f or  partici pati n g 
C A L G B 5 0 8 0 1. 
If  a  site  has  neit her  bee n  cre de ntiale d  b y  t he  I C L  n or  partici pate d  i n  a n y 
Allia nce/ C A L G B P E T or C T i ma gi n g trials, t he Allia nce / C A L G B I C L will a d here 
t o t he A C RI N criteria f or P E T i ma gi n g a p pr o val pr oce d ures. C o nsiste nc y i n t he 
ac q uisiti o n  pr ot oc ol  b ot h  fr o m  a  ti me  a n d  a n  ac q uisiti o n  m o de  is  re q uire d.  I n 
a d diti o n, data ma na ge me nt m ust be d o ne i n a sta n dar dize d pr ocess. I n or der f or a n 
instit uti o n t o be a p pr o ve d t o partici pate i n t his st u d y, t he y are re q uire d t o s u b mit 
t he f oll o wi n g f or tec h nical a n d q ualit y re vie w b y t he Allia nce  I ma gi n g C ore La b 
at I R O C O hi o : 
1)  T w o test patie nt st u dies ( F O R A L L P E T/ C T i nstr u me nts utilize d)  
I ma ges of tw o u ni de ntifie d patie nts s hall c o nsist of t hree v ol u me or m ultislice files 
as  f oll o ws:  a)  W h ole  b o d y  C T  fr o m  P E T/ C T  sca n ner;  b)  W h ole  b o d y  (t ors o) 
e missi o n wit h atte n uati o n c orrecti o n ( A/ C); a n d c) W h ole b o d y (t ors o) e missi o n 
wit h o ut A/ C. 4  
2)  U nif or m p ha nt o m data wit h t he S U V meas ure me nt of t he p ha nt o m ( F O R A L L 
P E T/ C T i nstr u me nts utilize d)  
Water -filla ble  u nif or m  p ha nt o m:  T he  p ha nt o m  m ust  be  fille d  wit h  water, a n d a 
k n o w n a m o u nt of F -1 8 (eit her as fl u ori de or as F D G) s h o ul d be i njecte d i nt o t he 
p ha nt o m.  T he acti vit y  i njecte d  s h o ul d  be  deter mi ne d  b y  meas ure me nt  of  t he 
s yri n ge bef ore a n d after t he i njecti o n i n a pr o perl y cali brate d d ose cali brat or. T he 
i njecte d acti vit y s h o ul d be c h ose n t o res ult i n a n acti vit y c o nce ntrati o n si milar t o 
t hat e nc o u ntere d i n cli nical F D G i ma gi n g (i.e., 1-1. 5 m Ci of F -1 8 s h o ul d be a d de d 
t o t he 6, 2 8 3 m L p ha nt o m: 2 m Ci f or t he 9. 2 9 3 m L p ha nt o m). After t h or o u g hl y 
mi xi n g t he p ha nt o m, t he p ha nt o m m ust be sca n ne d wit h t he sa me pr ot oc ol use d 
f or  t he  patie nt  i ma gi n g.  T he  i ma ges  als o  m ust  be rec o nstr ucte d  wit h  t he  sa me 
al g orit h m  a n d  filters use d f or  patie nt  i ma gi n g.  A  circ ular or  elli ptical re gi o n  of 
i nterest ( R OI) c o veri n g m ost of t he i nteri or of t he p ha nt o m m ust be dra w n o ver all 
slices, a n d t he a vera ge S U V a n d sta n dar d de viati o n m ust be meas ure d a n d re p orte d 
i n  t he  P E T/ C T  I nstr u me nt  T ec h nical  S pecificati o ns  F or m  (A p pe n di x  I V ).  T he 
e x pecte d S U V f or t he u nif or m p ha nt o m is 1. 0 a n d t he acce pta ble ra n ge is 0. 9 t o 
1. 1. 
( Alter nati vel y)  Ge- 6 8/ Ga-6 8  cali brati o n  p ha nt o m:  T his  p ha nt o m  ca n  rea dil y  be 
sca n ne d  wit h  t he  sa me  pr ot oc ol  use d  f or  patie nt  i ma gi n g.  T he  assa y  date  a n d 
acti vit y fr o m t he cali brati o n certificate of t his p ha nt o m m ust be re p orte d o n t he 
P E T/ C T  I nstr u me nt  T ec h nical  S pecificati o ns  F or m  ( A p pe n di x  I V ).  T he  i ma ges 
m ust be rec o nstr ucte d wit h t he sa me al g orit h m a n d filters use d f or patie nt i ma gi n g. 
A circ ular or elli ptical R OI c o veri n g m ost of t he i nteri or of t he p ha nt o m m ust be 
dra w n  o ver  all  slices,  a n d  t he  a vera ge  S U V  a n d  sta n dar d  de viati o n  m ust  be 
meas ure d a n d re p orte d i n t he P E T I nstr u me nt T ec h nical S pecificati o n f or m. T he 
e x pecte d S U V f or t he u nif or m p ha nt o m is 1. 0 a n d t he acce pta ble ra n ge is 0. 9 t o 
1. 1. 




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All  p ost -t hera p y  P E T/ C T  a n d  I V  c o ntrast  C T  sca ns  s h o ul d  be  perf or me d  o n  t he  sa me 
sca n ner wit h t he sa me s pecificati o ns as t h ose perf or me d at baseli ne. I deall y, t he I V c o ntrast 
C T sca n s h o ul d be d o ne o n t he sa me da y f oll o wi n g t he P E T/ C T sca n. H o we ver, if t he I V 
c o ntrast C T is o btai ne d o n a se parate da y, t he ti me differe nce bet wee n P E T/ C T a n d I V 
c o ntrast C T s h o ul d n ot e xcee d 1 5 da ys at baseli ne a n d s h o ul d n ot e xcee d 5 da ys after a n y 
c ycle of t hera p y. I n t he case of a p atie nt w h o  has alrea d y ha d a baseli ne F D G -P E T/ C T sca n 
at a n o utsi de facilit y, t he sca n m ust be s u b mitte d t o t he Allia nce I ma gi n g C ore La b at I R O C 
O hi o wit hi n 3 0 da ys of patie nt re gistrati o n . F urt her m ore, t hese patie nts will n ot be i ncl u de d 
i n t he q ua ntitati ve e val uati o ns. 
F or re pr o d uci ble a n d acc urate res ults, p ost -t hera p y P E T/ C T sca ns s h o ul d be ac q uire d usi n g 
t he sa me F D G u pta ke ti me ( p ost-i njecti o n i nter val) as t he pre-t hera p y sca n. T he differe nce 
i n waiti n g peri o d after i njecti o n of F D G bet wee n t he baseli ne a n d p ost-t hera p y (after c ycle 
2 of A B V D a n d f oll o wi n g eit her c ycle 6 of A B V D f or P E T ne gati ve patie nts, or I F R T f or 
P E T  p ositi ve  patie nts )  P E T/ C T  sca ns  s h o ul d  n ot  e xcee d  1 0  mi n utes  f or  mai ntai ni n g 
c o nsiste nc y a n d e ns uri n g acc urac y f or q ua ntitati ve st u dies.  
8. 3 
C T D at a Ac q uisiti o n  
C o ntrast e n ha nce d helical/s piral C T sca ns of t he  c hest, a b d o me n, a n d pel vis ( nec k will be 
i ncl u de d if baseli ne C T d oc u me nts prese nce of disease i n t he nec k) s h o ul d be o btai ne d o n 
all patie nts acc or di n g t o pr ot oc ol re q uire me nts at baseli ne. T he sa me C T sca ns s h o ul d als o 
be perf or me d after 2 c ycles a n d 4 c ycles, eit her c oi nci di n g wit h t he date of t he P E T/ C T or 
wit hi n 5 da ys of t he P E T/ C T.  
D uri n g f urt her f oll o w -u p, c o ntrast e n ha nce d helical/s piral C T sca ns of t he c hest, a b d o me n, 
pel vis, a n d nec k (if i n v ol ve d at baseli ne) e ver y 3 m o nt hs f or t he first year f r o m t he res p o nse 
assess me nt at c o m pleti o n of t hera p y, e ver y 6 m o nt hs f or years 2 a n d 3, a n d t he n a n n uall y 
f or years 4 a n d 5 acc or di n g t o t he p ost-treat me nt f oll o w-u p sc he d ule i n Secti o n 6. 0 . 
Patie nt C T sca ns s h o ul d f oll o w i nstit ut i o nal sta n dar ds wit h f oll o wi n g mi ni m u m criteria: 
•  
Sc a n m o de:  M ulti -detect or a n d/ or helical  
•  
E n h a nce me nt:  I V a n d oral c o ntrast u nless c o ntrai n dicate d  
•  
Secti o n t hic k ness: ma xi m u m 5 m m, prefera ble 2. 5 m m or less  
•  
I ncre me nt: c o nti n u o us or o verla p pi n g secti o ns; n o ga ps  
•  
M atri x size: 5 1 2 × 5 1 2 or better  
•  
Rec o nstr ucti o n ：I nstit uti o nal sta n dar d 
C T sca ns s h o ul d be perf or me d i n a c o nsiste nt ma n ner f or f oll o w -u p fr o m t he baseli ne, wit h 
t he sa me secti o n or slice t hic k ness, i ncre me nt, rec o nstr ucti o n pr ot oc ol a n d i ma ge matri x 
size as well as patie nt p ositi o ni n g. 
8. 4 
P E T/ C T D at a Ac q uisiti o n  
All  data  ac q uisiti o ns  a n d  rec o nstr ucti o ns  will  be  perf or me d  o n  a  P E T/ C T  s yste m.  A 
p ha nt o m st u d y will be perf or me d t o sta n dar dize all P E T/ C T s yste ms pri or t o t he i nitiati o n 
of t he pr ot oc ol. 
8. 4. 1 
P ri or t o F D G I njecti o n a n d D uri n g U pt a ke P eri o d  
Patie nts m ust fast f or at least f o ur h o urs bef ore t he P E T/ C T sca n. Oral h y drati o n 
is str o n gl y e nc o ura ge d pri or t o a n d d uri n g i nj ecti o n of 1 8F- F D G ( 2 5 0 -5 0 0 m L water 
ca n  be  gi ve n  P O  d uri n g  t he  u pta ke  peri o d )  a n d  d uri n g  t he  u pta ke  peri o d  after 
a d mi nistrati o n of 1 8F- F D G. I V f ur ose mi de ( 1 0 m g) ma y be a d mi nistere d ( b ut is 


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n ot ma n dat or y) t o i ncrease uri nar y eli mi nati o n of t he tracer a n d mi ni mize i ma ge 
artifacts  ca use d  b y  uri nar y  stasis  i n  t he  a b d o me n  a n d  pel vis. I ntra ve n o us  fl ui ds 
c o ntai ni n g de xtr ose or pare nteral fee di n g s h o ul d be wit h hel d f or at least 6 h o urs 
pri or t o t he i njecti o n of 1 8F- F D G. N o ster oi d a d mi nistr ati o n is all o we d f or at 
le ast 7 d a ys pri or t o F D G-P E T i m a gi n g.  Acti ve e xercise s h o ul d be disc o ura ge d  
f or  at  least  2 4  h o urs  pri or  t o  t he  st u d y.  M uscle  stress,  te nsi o n,  c he wi n g,  a n d 
m o ve me nt  d uri n g  t he  u pta ke  peri o d  s h o ul d  be  mi ni mize d  t o  decrease  m uscle 
u pta ke.  Patie nts  s h o ul d  n ot  s pea k  d uri n g  t he  i njecti o n  a n d  u pta ke  peri o d. 
I nter vie ws  wit h  t he  patie nt  sh o ul d  be  wit h hel d  u ntil  after  c o m pleti o n  of  t he 
i ma gi n g st u d y. 
T he bl o o d gl uc ose le vel s h o ul d be c hec ke d bef ore 1 8F- F D G i njecti o n. Bl o o d s u gar 
( meas ure d b y gl uc o meter) m ust be less t ha n 2 0 0 m g/ d L at t he ti me of t he F D G-
P E T/ C T st u d y.  If  t he  bl o o d  gl uc ose le vel is  greater t ha n  2 0 0  m g/ d L,  t he  F D G -
P E T/ C T i ma gi n g s h o ul d be resc he d ule d. If t he bl o o d gl uc ose le vel still e xcee ds 
2 0 0 m g/ d L o n t he f oll o wi n g sc he d ule d da y f or P E T sca n ni n g, t he patie nt will n ot 
be  i ncl u de d  i n  t he  trial.  I ns uli n  a d mi nistrati o n  i m me diate l y  bef ore  t he  P E T/ C T 
st u d y  t o  re d uce t he  gl uc ose  le vels is  n ot  all o we d.  Patie nts  wit h  dia betes s h o ul d 
c o nti n ue  t o  a d here  t o  t heir  oral  a ge nts  or  i ns uli n  r o uti nes.  T hese  me dicati o ns 
s h o ul d n ot be a d mi nistere d near t he 1 8F- F D G i nj ecti o n ti me. I n i ns uli n - de pe n de nt 
patie nts,  i ns uli n  s h o ul d  be  a d mi nistere d  at  least  5  h o urs  pri or  t o  t he 1 8F- F D G 
i njecti o n. Patie nts wit h dia betes w h o are o n dia betic me dicati o n s h o ul d ta ke t heir 
me dicati o n 4 -5 h o urs pri or t o t he test. If bl o o d s u gar e xcee ds 1 5 0 m g/ d L ( b ut less 
t ha n 2 0 0 m g/ d L), a n ote s h o ul d be ma de i n o n t he case re p ort f or m. 
Metallic o bjects s h o ul d be re m o ve d fr o m t he patie nts w he ne ver p ossi ble. Patie nts 
s h o ul d be ke pt i n a war m waiti n g r o o m pri or t o 1 8F- F D G i njecti o n t o a v oi d br o w n 
a di p ose tiss ue  u pta ke.  I n  a n xi o us  a n d cla ustr o p h o bic patie nts,  a d mi nistrati o n of 
oral  diaze pa m  ( 0. 0 6 -0. 1 0  m g/ k g)  is  rec o m me n de d  3 0 -4 0  mi n utes  pri or  t o  t he 
i nitiati o n of t he i ma gi n g st u d y. 
Wei g ht  ( k g),  hei g ht  (c m),  bl o o d  gl uc ose  ( m g/ d L),  a n d  t he  date  a n d  ti me  of 
c he m ot hera p y a n d c ol o n y sti m ulati n g a d mi nistrati o n (e. g., G C S F, G M C S F) will 
be rec or de d pri or t o t he i njecti o n of 1 8F- F D G.  
1 0- 2 0 m Ci of 1 8F- F D G will be a d mi nistere d I V, de pe n di n g o n t he ma n ufact urer’s 
rec o m me n dati o n. A 1 0-2 0 m L sali ne fl us h is rec o m me n de d i n re d uci n g t he ve n o us 
retenti o n of 1 8F- F D G. T he patie nt m ust wait f or at least 6 0 mi n utes pri or t o t he 
i nitiati o n  of  t he  P E T/ C T  ac q uisiti o n  f or  all  P E T/ C T  sca ns  ( b ot h  pre-a n d  p ost -
t hera p y sca ns). T he wait peri o d s h o ul d be ke pt wit hi n a ma xi m u m of 1 0 mi n utes  
a m o n g patie nts. T he wait peri o d m ust n ot e xcee d 8 0  mi n utes at baseli ne. It is N O T 
acce pt a ble  t o  st art  i m a gi n g  wit h  w ait  peri o ds  of  less  t h a n  6 0  mi n utes  a n d 
l o n ger  t h a n  8 0 mi n utes  f or  b ot h  pre- a n d  p ost -t her a p y  P E T/ C T  sc a ns. T he 
ti me differe nce bet wee n baseli ne a n d ot her P E T st u dies (after c ycle 2 of A B V D, 
a n d f oll o wi n g eit her c ycle 6 of A B V D f or P E T ne gati ve patie nts, or I F R T f or P E T 
p ositi ve patie nts ) s h o ul d n ot  be > 1 0 mi n utes. A ti me differe nce of > 1 5 mi n utes 
bet wee n P E T/ C T st u dies is N O T  acce pta ble. 
T he i ma gi n g will start aft er v oi di n g t he bla d der. 1 5 0 -2 0 0 m L of water m ust be 
gi ve n  t o  t he  patie nt  i m me diatel y  pri or  t o  t he  st u d y  ac q uisiti o n  bef ore  t he y  are 
p ositi o ne d o n t he ta ble t o diste n d st o mac h a n d a v oi d p h ysi ol o gic st o mac h u pta ke. 


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8. 4. 2 
P E T/ C T I m a ge Ac q uisiti o n  
Patie nts wil l be p ositi o ne d o n t he ta ble i n a hea dfirst, s u pi ne p ositi o n wit h ar ms 
ele vate d a b o ve t he hea d  t o re d uce bea m-har de ni n g artifacts at t he le vel of t he li ver. 
A se parate hea d a n d nec k i ma gi n g will be p urs ue d f or t h ose w h ose pri mar y disease 
site is i n t he neck wit h t he ar ms p ositi o ne d al o n g t he si de. T he use of oral c o ntrast 
is at t he discreti o n of eac h facilit y. H o we ver, I V-c o ntrast de dicate d C T ac q uisiti o n 
s h o ul d f oll o w P E T i ma gi n g wit h n o n-c o ntrast l o w d ose C T t o a v oi d variati o ns i n 
F D G u pta ke i n t he bl o o d p o ol a n d t he t u m or t hat is ca use d b y t he I V c o ntrast a ge nt. 
T he l o w d ose C T ass ociate d wit h P E T s h o ul d be ac q uire d usi n g a c urre nt of n ot 
less t ha n 8 0 m A/sec o n d. 
It is critical t hat all p ost-t hera p y P E T/ C T sca ns be perf or me d i n a n i de ntical wa y 
t o t he baseli ne sca n wit h t he sa me sca n ner, sa me sca n ni n g directi o n (s k ull t o t hi g hs 
or t hi g hs t o s k ull) a n d c o nsiste nt ar m p ositi o ni n g. 
F or P E T i ma gi n g, si x t o se ve n c o nti g u o us v ol u mes will be c h ose n, de pe n di n g o n 
t he patie nt’s hei g ht, t o e ns ure data ac q uisiti o n of t he e ntire re gi o n of i nterest ( R OI), 
t he le vel of t he s k ull base t o t he 1/ 3 pr o xi mal fe m urs. T he ti me/ be d p ositi o n s h o ul d 
be i n acc or da nce wit h t he ma n ufact urer’s rec o m me n dati o ns f or o pti mal i ma gi n g. 
A djace nt fiel ds of vie w s h o ul d s hare o verla p pi n g slices.  
8. 4. 3 
P E T/ C T I m a ge P r ocessi n g  
F oll o w  t he  ma n ufact urer’s  rec o m me n dati o n  f or  i ma ge  rec o nstr ucti o n.  T he 
e missi o n data will be c orrecte d f or scatter, ra n d o m c oi nci de nce e ve nts, a n d s yste m 
dea d -ti me usi n g pr o vi de d s oft ware. A n iterati ve rec o nstr ucti o n ( or dere d s u bsets 
e x pectati o n ma xi mizati o n) a n d C T -base d atte n uati o n c orrecti o n will be use d f or 
t he  P E T  i ma ges.  Rec o nstr ucti o ns  s h o ul d  be  arc hi ve d  b ot h  wit h  a n d  wit h o ut 
atte n uati o n c orrecti o n t o res ol ve iss ues arisi n g fr o m p ote ntial artifacts ge nerate d 
b y t he C T- base d atte n uati o n c orrecti o n pr oce d ure. 
8. 5 
E v al u ati o n of P E T/ C T D at a  
All i ma ges will be rea d ce ntrall y b y t he Allia nce  I ma gi n g C ore La b orat or y at I R O C O hi o . 
T o e ns ure t he hi g hest sta n dar ds a n d c o nsiste nc y bet wee n differe nt ce nters, all F D G -P E T 
sca ns ( baseli ne, i nteri m, a n d e n d of treat me nt P E T sca ns) m ust be s u b mitte d t o t he Allia nce  
I ma gi n g  C ore  La b  at I R O C  O hi o f or  ce ntralize d  re vie w ( See Secti o n  8. 9 ).  Res p o nse 
deter mi nati o ns  a n d  treat me nt  decisi o ns  (e. g.  c o nti n uati o n  of  A B V D  or s witc h  t o 
B E A C O P P) m ust be base d o n t he ce ntralize d re vie w of t he F D G -P E T sca n a n d N O T o n 
sca n assess me nts b y l ocal p h ysicia ns. The cr ucial F D G -P E T sca n c o n d ucte d after t he 2 n d 
c ycle of A B V D will be 8 -1 0 da ys after t he Da y -1 5 d ose of A B V D d uri n g C ycle 2 (i .e. o n 
da y 2 3 or 2 4 or 2 5 of c ycle 2, see  Secti o n 8. 2  f or acce pta ble F D G-P E T/ C T sca n c o m pleti o n 
da ys). T he sec o n d P E T sca n s h o ul d be sc he d ule d at t he start of C ycle 2 of treat me nt t o 
e ns ure a p pr o priate ti mi n g of res p o nse sca ns.  
Ce ntralize d re vie w will be perf or me d b y a me m ber of a tea m of P E T/ C T rea ders. T here 
will be a n a dj u dicat or fr o m t he sa me p o ol of re vie wers i n t he case of disa gree me nt. T here 
will be o ne re vie wer, Dr. Nat ha n Hall, w h o will pr o vi de bac k -u p P E T/ C T re vie wer ser v ices 
wit hi n t he Allia nce  Ima gi n g C ore La b at I R O C O hi o . T he Allia nce  I ma gi n g C ore La b at 
I R O C O hi o will tra ns mit t he sca ns t o t he e x pert re vie wers f or res p o nse deter mi nati o n a n d 
t he n  will  tra ns mit  t he  res ults t o  t he Allia nce  Statistic s a n d  Data Ce nter  a n d t o  t he  sites 
pri mar y c o ntact wit h 7 2 h o urs of i ma ge recei pt ( n ot i ncl u di n g wee ke n ds).   


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T he ce ntral P E T/ C T e x pert re vie w will o nl y f oc us o n t he assess me nt of H o d g ki n l y m p h o ma 
disease sites. T his ce ntral e x pert re vie w will N O T pr o vi de a c o m pre he nsi ve assess me nt of 
t he e ntire P E T/ C T st u d y a n d will t h us N O T rec or d i nci de ntal fi n di n gs a n d a b n or malities 
u nrelate d t o H o d g ki n l y m p h o ma.  Ce ntralize d P E T/ C T is d o ne f or t he p ur p ose of t his trial; 
it d oes N O T relie ve l ocal P E T/ C T rea ders of t heir res p o nsi bilit y t o issue a c o m pre he nsi ve 
P E T/ C T re p ort.  
C ycle 3 of c he m ot hera p y m ust n ot be a d mi nistere d u ntil t he res ults of t he sec o n d P E T sca n 
are a vaila ble. Deter mi nati o n of F D G -P E T p ositi vit y or ne gati vit y will be perf or me d usi n g 
a 5 p oi nt sc ori n g s yste m o n g ui deli nes esta blis he d b y a n i nter nati o nal P E T har m o nizati o n 
c o nfere nce  c o n ve ne d  i n  L o n d o n  i n  Ma y  2 0 0 7  ( See A p pe n di x  I ). Acc or di n g  t o  t hese 
g ui deli nes, sca ns will be j u d ge d t o be p ositi ve if lesi o ns are m ore h y per meta b olic t ha n t he 
li ver b y vis ual, q ualitati ve i ns pecti o n.  B or derli ne meta b olis m i n a lesi o n will be c o nsi dere d 
ne gati ve  i n  c o nc or da nce  wit h  t he  p olicies  of  Galla mi ni  a n d  H utc hi n gs  w h ose  st u dies 
esta blis he d t he val ue of earl y i nteri m F D G -P E T i ma gi n g. [ 1 1- 1 3, 3 0]  
8. 6 
P ri m ar y O bjecti ve/ E n d p oi nt: Defi niti o n of Res p o nse b y Met a b olic Criteri a  
T he pri mar y e n d p oi nt is pr o gressi o n free s ur vi val ( P F S) at 3 6 m o nt hs fr o m e nr oll me nt f or 
patie nts  wit h  b ul k y  sta ge  I  a n d  II  H o d g ki n  l y m p h o ma.  T he  t otal  n u m ber  of  c ycles  of 
c he m ot hera p y ( ±  I F R T) will be deter mi ne d b y meta b olic res p o nse as vis uall y assesse d b y 
P E T/ C T i ma gi n g after 2 c ycles usi n g criteria pr o vi de d  i n A p pe n di x I.   
8. 6. 1 
Ne g ati ve P E T Sc a n ( Met a b olic Res p o n ders)  
All  P E T/ C T  i nter pretati o ns  will  be  perf or me d  o n  b ot h  a xial  a n d  c or o nal  slices. 
Mai nl y, fi n di n gs o n a xial slices s h o ul d be c o nfir me d b y fi n di n gs o n c or o nal slices, 
as c o m paris o n wit h t he li ver is us uall y easier a n d m ore acc urate o n c or o nal slices.  
U p o n q ualitati ve e val uati o n, t u m or F D G u pta ke t hat is less t ha n or e q ual t o t he 
li ver i n tar get or n o n -tar get t u m ors, re gar dless of t heir l ocati o n, a n d a bse nce of 
ne w lesi o ns t hat are dee me d t o be t u m or a n d a bse nce of n o n -tar get t u m ors will be 
c o nsi dere d ne gati ve f or t he prese nce of resi d ual l y m p h o ma  ( A p pe n di x I). 
8. 6. 2 
P ositi ve P E T Sc a n  
U p o n q ualitat i ve e val uati o n, diff use or f ocal u pta ke e xcee di n g t hat see n i n t he li ver 
i n tar get  or  n o n-tar get  t u m ors,  re gar dless  of  t heir  l ocati o n, will  be  c o nsi dere d 
p ositi ve f or resi d ual t u m or.  
8. 7 
Sec o n d ar y O bjecti ves/ E n d p oi nts  
8. 7. 1 
Se mi q u a ntit ati ve A n al ysis: I n patie nts wit h m ulti ple t u m or sites, t he si x sites wit h 
t he hi g hest u pta ke will be desi g nate d as t he tar get sites. F or t hese lesi o ns, S U V 
meas ure me nts  will  be  deter mi ne d  at  baseli ne,  after  c ycle  2,  at  c o m pleti o n  of 
c he m ot hera p y, a n d after I F R T i n res pecti ve patie nt gr o u ps, as o utli ne d bel o w. 
At baseli ne, a 3 D v ol u me of i nterest ( V OI) wil l be ta ke n o ver t he t u m or o n a xial, 
sa gittal, a n d c or o nal m ulti-pla nar ref or matti n g ( M P R) vie ws t hat vis uall y s h o w t he 
m ost  pr o mi ne nt  u pta ke. M a xi m u m  S U V  b o d y  wei g ht  ( S U V b w) , S U V pea k  a n d 
S U V lea n b o d y mass ( S U Vl b m) will be o btai ne d o ver t he lesi o n .  
A si milar V OI will be o btai ne d i n t he:  
1) a dj ace nt  bac k gr o u n d  t hat  d oes  n ot  c orres p o n d  t o  p h ysi ol o gicall y  or 
pat h ol o gicall y acti ve sites a wa y fr o m t he F D G a vi d sites;  


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2) Me diasti nal  bl o o d p o ol ( M B P) ta ke n i n t he mi d -a ortic le vel  or  wit hi n  2 
slices of t he a ortic arc h; 
3) a p pr o xi matel y mi d -li ver re gi o n or i n secti o ns t hat are wit hi n 3 slices of t he 
p orta he patis re gi o ns .   
I n or der t o ta ke meta b olic varia bilit y i nt o c o nsi derati o n, t w o S U V meas ure me nts 
o n t w o differe nt a xial slices will be o btai ne d f or ite ms 1 -3 a b o ve a n d t he a vera ge 
S U Vs will be use d ( mea n S U V b w a n d mea n S U Vl b m of t w o a xial slices).  
After c ycle  2 of A B V D a n d f oll o wi n g eit her c ycle 6 of A B V D (f or P E T ne gati ve 
patie nts) o r I F R T (f or P E T p ositi ve patie nts), i n patie nts wit h meta b olicall y acti ve 
resi d ual t u m ors, as well as i n t h ose wit h meta b olicall y n o nacti ve C T masses, t he 
sa me ste ps as descri be d a b o ve will be re peate d. 
8. 7. 2 
Usi n g recei ver o perat or c ur ves ( R O C), m ost o pti mal c ut off f or a bs ol ute decrease 
i n ma xi m u m S U V b w, S U V pea k a n d S U Vl b m, a bs ol ute u pta ke i n t he t u m or/s a n d 
relati ve  u pta ke  i n  t u m or/s  vers us  vari o us  refere nce  a nat o mic  sites  (li ver, 
me diasti nal  bl o o d  p o ol,  a n d  bac k gr o u n d),  as  well  as  vari o us  c ut offs  f or  p os t-
t hera p y  ma xi m u m  S U V b w,  S U V pea k  a n d  S U Vl b m,  will  be  deter mi ne d  an d 
c o m pare d after c ycle 2 of A B V D a n d f oll o wi n g eit her c ycle 6 of A B V D (f or P E T 
ne gati ve patie nts) or I F R T (f or P E T p ositi ve patie nts) . 
8. 7. 3 
I n patie nts wit h m ulti ple t u m or sites, t he si x sites c orrelati n g wit h t he P E T tar get 
lesi o ns will be desi g nate d as t he tar get sites.  I n eac h l y m p h n o de re gi o n t he lesi o ns 
wit h  t he  hi g hest  u pta ke  will  be  c h ose n. If  t here  is  a n y  lesi o n  t hat  de m o nstrates 
u pta k e after t hera p y ot her t ha n t he desi g nate d tar get  lesi o ns, t he y will be n o n-tar get 
lesi o ns  a n d  will  be  e val uate d  i n  t he  sa me  fas hi o n  as  tar get  lesi o ns. F or  t hese 
lesi o ns,  v ol u metric  vs.  2  di me nsi o nal  ( 2-D)  meas ure me nt  c ha n ges  bet wee n 
baseli ne  a n d  after c ycle  2  of  A B V D  a n d  f oll o wi n g  eit her  c ycle  6  of  A B V D  or 
I F R T, will be deter mi ne d fr o m de dicate d C T sca ns. Usi n g recei ver o perat or c ur ves 
( R O C), t he m ost o pti mal c ut off f or a bs ol ute decrease a n d perce nt decrease will be 
deter mi ne d. A c o m bi nat orial a nal ysis will be perf or me d i nc or p orati n g t he c ha n ges 
fr o m P E T data a n d de dicate d C T data t o deter mi ne if t his a p pr oac h i ncreases t he 
pre dicti ve val ue of b ot h tests c o m bi ne d c o m pare d t o eac h test al o ne.  
8. 7. 4. 
Q ualitati ve a n d se mi q ua ntitati ve F D G -P E T fi n di n gs/c ha n ges, 2 -D a n d v ol u metric 
C T  c ha n ges,  a n d  c o m bi nat orial  a nal yses  ( P E T + de dicate d  C T  data)  will  be 
c o m pare d wit h m olec ular para meters, a n d c o n ve nti o nal para meters, i ncl u di n g I P S 
i n t he pre dicti o n of res p o nse a n d P F S. 
8. 8 
P ost -T her a p y F oll o w -U p of T u m ors  
At a n y p oi nt after t hera p y, t he decisi o n f or bi o ps y of a n y lesi o n is at t he discreti o n of t he 
treati n g p h ysicia n. After c o m pleti o n of treat me nt, f or t h ose patie nts w h o ac hie ve a C R or 
P R w h o are P E T ne gati ve, C T sca ns will be o btai ne d e ver y 3 m o nt hs f or t he first year, t he n 
e ver y 6 m o nt hs f or years 2 a n d 3, a n d a n n uall y years 4 a n d 5 acc or di n g t o t he p ost -treat me nt 
f oll o w- u p sc he d ule i n Secti o n 6. 0 . 
8. 9 
P E T a n d C T D at a S u b missi o n  
T he c o m plete P E T a n d C T st u dies m ust be electr o nicall y s u b mitte d t o t he Allia nce I ma gi n g 
C ore La b  at I R O C O hi o  i n di gital DI C O M f or mat, a n y ot her f or mats s uc h as Bit ma p, J P G, 
har dc o p y  files  or  sca n ne d  fil ms  are  u nacce pta ble.  De -i de ntif y  t he  patie nt  data  usi n g 
i nstit uti o nal  pr oce d ures  t o  re m o ve  patie nt  na me  a n d  me dical  rec or d  n u m ber  w hile 
preser vi n g t he C A L G B patie nt I D n u m ber a n d C A L G B pr ot oc ol n u m ber se paratel y. 




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vi n blasti ne a n d d o x or u bici n t o 7 5 % of t he last d ose recei ve d f or t he ne xt c ycle (i n 
a d diti o n t o a b o ve a nti bi otic a n d G -C S F s u p p orti ve care meas ures).    Re -escalati o n 
is at t he discreti o n of t he treati n g p h ysicia n. 
9. 1. 2  
T hr o m b oc yt o pe ni a  
F or  platelets  ≥  7 5, 0 0 0  – 1 0 0, 0 0 0  o n  t he  da y  of  treat me nt  ( or  wit hi n  4 8  h o urs), 
c o nti n ue  A B V D  wit h a  decrease i n t he d oses  of  vi n blasti ne  a n d  d o x or u bici n t o 
7 5 % of t he last d ose recei ve d f or t he ne xt c ycle.  Re -escalati o n is at t he discreti o n 
of t he treati n g p h ysicia n. F or platelets < 7 5, 0 0 0 o n t he da y of treat me nt ( or wit hi n 
4 8  h o urs),  dela y  treat me nt  u ntil  platelets  ≥  7 5, 0 0 0,  t he n  res u me  A B V D  wit h  a 
decrease  i n  t he  d oses  of  vi n blasti ne  a n d  d o x or u bici n  t o  7 5 %  of  t he  last  d ose 
recei ve d f or t he ne xt c ycle. 
9. 1. 3 
He p atic D ysf u ncti o n  
All patie nts wit h bilir u bi n ≤ 2 x t he u p per li mit of n or mal ( U L N) will recei ve a f ull 
i nitial d ose of d o x or u bici n a n d vi n blasti ne.  If t he bilir u bi n i ncreases t o > 2 x U L N 
a n d is < 5 x U L N, t he d o x or u bici n a n d vi n blasti ne d oses s h o ul d be re d uce d b y 5 0 % 
of t he last d ose.  F ull d oses s h o ul d be a d mi nistere d if t he bilir u bi n rec o vers t o ≤ 2 
x U L N.  If t he bilir u bi n e xcee ds 5 x U L N, d o x or u bici n a n d vi n blasti ne s h o ul d be 
o mitte d f or t hat c ycle.  If t he bilir u bi n ha s n ot rec o vere d t o ≤ 2 x U L N b y t he ti me 
t he ne xt c ycle is d ue, t he n re m o ve t he patie nt fr o m pr ot oc ol treat me nt.  I n cases of 
biliar y o bstr ucti o n b y a t u m or mass, a biliar y drai na ge ste nt s h o ul d be place d pri or 
t o c he m ot hera p y. 
Bilir u bi n  
D o x or u bici n d ose  
Vi n bl asti ne d ose  
≤ 2 x U L N  
1 0 0 %  
1 0 0 %  
> 2 -5 x U L N  
5 0 % ( of last d ose recei ve d)  
5 0 % ( of last d ose recei ve d)  
> 5 x U L N  
0 %  
0 %  
9. 1. 4  
C ar di ot o xicit y 
F or persiste nt arr h yt h mia (i ncl u di n g si n us tac h ycar dia wit h se vere s y m pt o ms a n d 
wit h n o  de m o nstra ble  ca use); c o n gesti ve  heart  fail ure;  or  a  decrease  i n  ejecti o n 
fracti o n b y ≥ 1 5 % (a bs ol ute perce nta ge p oi nts) fr o m baseli ne or t o less t ha n 4 5 %, 
disc o nti n ue pr ot oc ol t hera p y.  
9. 1. 5 
S ki n T o xicit y  
Vi n blasti ne  a n d  d o x or u bici n  are  vesica nts;  st o p  i nf usi o n  i m me diatel y  if 
e xtra vasati o n  is  s us pecte d  a n d  a d mi nister  t he  dr u g  at  a n ot her  site.  I nstit uti o nal 
sta n dar d meas ures f or treat me nt of e xtra vasati o n s h o ul d be e m pl o ye d. 
9. 1. 6  
Ne ur ot o xicit y 
F or gra de 3 se ns or y ne ur o pat h y, or f or se vere c o nsti pati o n wit h ile us, re d uce d ose 
of vi n blasti ne b y 5 0 % f or all s u bse q ue nt d oses. 
F or gra de 4 se ns or y ne ur o pat h y, vi n blasti ne will be o mitte d fr o m all f ut ure d oses. 
9. 1. 7  
P ul m o n ar y T o xicit y 
Ble o m yci n i n d uce d p ne u m o nitis ma y be diffic ult t o dia g n ose cli nicall y.  A hi g h 
res ol uti o n C T sca n of t he c hest a n d p ul m o nar y f u ncti o n tests s h o ul d be perf or me d 
at  t he  sli g htest  s us pici o n.    As  t here  are  n o  re pr o d uci ble  cli nical  or  hist ol o gic 


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fi n di n gs  f or  ble o m yci n -i n d uce d  p ne u m o nitis,  t he  dia g n osis  m ust  be  ma de  o n 
cli nical, ra di ol o gic, a n d/ or hist ol o gic fi n di n gs after e xcl u di n g ot her eti ol o gies.  If 
t hese st u dies s u g gest ble o m yci n t o xicit y, ble o m yci n s h o ul d be disc o nti n ue d.  Later 
res u m pti o n  s h o ul d  o nl y  be  c o nsi dere d  if  t he  s us pici o n  f or  ble o m yci n-i n d uce d 
t o xicit y has pr o ve d u nf o u n de d. 
9. 2 
D ose M o dific ati o ns f or esc al ate d B E A C O P P  
9. 2. 1 
A c ycle of B E A C O P P s h o ul d n ot be gi n u ntil le u k oc ytes > 2, 5 0 0 a n d platelets > 
8 0, 0 0 0.  If  le u k oc ytes  <  2, 5 0 0  or  platelets  <  8 0 , 0 0 0  o n  da y  1  of  a  c ycle  of 
B E A C O P P, dela y treat me nt u ntil le u k oc ytes ≥ 2, 5 0 0 a n d platelets ≥ 8 0, 0 0 0. C B C 
s h o ul d be rec hec ke d after 3, 7, 1 0 a n d 1 4 da ys. T he first c ycle  of B E A C O P P  ma y 
be gi n t w o wee ks after c ycle 2 of A B V D i n patie nts wit h a p ositi ve i nteri m P E T 
sca n, re gar dless of le u k oc yte c o u nt. 
9. 2. 2 
D ose re d ucti o ns f or escalate d B E A C O P P f oll o w a defi ne d de -escalati o n sc he me 
base d o n t he occ urre nce of t o xic e ve nts i n t he pre vi o us c ycle. T here are n o d ose 
re-escalati o ns. 
9. 2. 3  
T he f oll o wi n g are c o nsi dere d d ose re d ucti o n e ve nts o n B E A C O P P:  
Decrease d w hile bl o o d cells/ Le u k o pe nia: gra de 4 (le u k oc ytes < 1 0 0 0) f or > 4 da ys.  
Platelet c o u nt decrease/ T hr o m b oc yt o pe nia: gra de 4 ( platelets < 2 5, 0 0 0) o n o ne or 
m ore da ys.  
I nfecti o n: gra de 4. 
Ot her t o xicit y: gra de 4 (e . g. m uc ositis);(see bel o w f or d ose re d ucti o ns f or bilir u bi n 
a n d p ul m o n dar y). 
P ost p o ne me nt of treat me nt f or m ore t ha n 2 wee ks d ue t o i na de q uate rec o ver y of 
bl o o d val ues. 
9. 2. 4 
S h o ul d o ne or m ore d ose -re d ucti o n e ve nts occ ur i n a gi ve n c ycle, t he d ose i n all 
f oll o wi n g c ycles will be re d uce d b y o ne d ose le vel.  If a n y t o xic e ve nt occ urs i n 2 
s uccessi ve  c ycles,  t he  f oll o wi n g  c ycle  is  a d mi nistere d  at  sta n dar d  B E A C O P P 
d oses.  N o re d ucti o n is ma de f or treat me nt p ost p o ne me nt of u p t o 2 wee ks.   
9. 2. 5 
All patie nts wit h bilir u bi n ≤ 2 x t he u p per li mit of n or mal ( U L N) will recei ve a f ull 
i nitial d ose of d o x or u bici n a n d vi ncristi ne . If t he bilir u bi n i ncreases t o > 2 x U L N 
a n d is < 5 x U L N, t he d o x or u bici n a n d vi ncristi ne d oses s h o ul d be re d uce d b y 5 0 % 
of  t he  last  d ose.  If  t he  bilir u bi n  e xcee ds  5  x  U L N,  d o x or u bici n  a n d vi ncristi ne 
s h o ul d be o mitte d f or t hat c ycle.  If t he bilir u bi n has n ot rec o vere d t o ≤ 2 x U L N 
b y t he ti me t he ne xt c ycle is d ue, t he n re m o ve t he patie nt fr o m pr ot oc ol treat me nt.  
I n cases of biliar y o bstr ucti o n b y a t u m or mass, a biliar y drai na ge ste nt s h o ul d be 
place d pri or t o c he m ot hera p y.  
Bilir u bi n  
D o x or u bici n d ose  
Vi ncristi ne d ose  
≤ 2 x U L N  
1 0 0 %  
1 0 0 %  
> 2 -5 x U L N  
5 0 % ( of last d ose recei ve d)  
5 0 % ( of last d ose recei ve d)  
> 5 x U L N  
0 %  
0 %  


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9. 2. 6  
P ul m o n ar y T o xicit y  
Ble o m yci n i n d uce d p ne u m o nitis ma y be diffic ult t o dia g n ose cli nicall y.  A hi g h 
res ol uti o n C T sca n of t he c hest a n d p ul m o nar y f u ncti o n tests s h o ul d be perf or me d 
at  t he  sli g htest  s us pici o n.    As  t here  are  n o  re pr o d uci ble  cli nical  or  hist ol o gic 
fi n di ngs  f or  ble o m yci n -i n d uce d  p ne u m o nitis,  t he  dia g n osis  m ust  be  ma de  o n 
cli nical, ra di ol o gic, a n d/ or hist ol o gic fi n di n gs after e xcl u di n g ot her eti ol o gies.  If 
t hese st u dies s u g gest ble o m yci n t o xicit y, ble o m yci n s h o ul d be disc o nti n ue d.  Later 
res u m pti o n  s h o ul d  o nl y  be  c o nsi dere d  if  t he  s us pici o n  f or  ble o m yci n-i n d uce d 
t o xicit y has pr o ve d u nf o u n de d 
9. 2. 7 
I nt oler a nce n ot q u alif yi n g as a d ose re d ucti o n e ve nt 
I n  case  of  dr u g  s pecific  i nt olera nce  (e. g.  vi ncristi ne  ne ur o pat h y,  pr ocar bazi ne 
aller g y), si n gle dr u gs ma y be  dr o p pe d fr o m t he re gi me n wit h o ut s u bstit uti o n.  T he 
reas o n f or a de viati o n s h o ul d al wa ys be rec or de d o n t he c orres p o n di n g treat me nt 
f or ms. 
9. 2. 8 
D ose Le vels of Esc al ate d B E A C O P P  
Treat me nt  al wa ys  be gi ns  wit h  D ose  Le vel  0. D oses  of  ble o m yci n,  vi ncristi ne, 
pr ocar bazi ne a n d pre d nis o ne are n ot re d uce d. 
D ose Le vel 0  
D ose  
R o ute  
Sc he d ule  
C ycl o p h os p ha mi de  
1 2 5 0 m g/ m 2 
I V 
Da y 1  
D o x or u bici n  
3 5 m g/ m 2 
I V 
Da y 1  
Et o p osi de  
2 0 0 m g/ m 2 
I V 
Da ys 1 -3  
 
D ose Le vel -1  
D ose  
R o ute  
Sc he d ule  
C ycl o p h os p ha mi de  
1 1 5 0 m g/ m 2 
I V 
Da y 1  
D o x or u bici n  
3 5 m g/ m 2 
I V 
Da y 1  
Et o p osi de  
1 7 5 m g/ m 2 
I V 
Da ys 1 -3  
 
D ose Le vel -2  
D ose  
R o ute  
Sc he d ule  
C ycl o p h os p ha mi de  
9 5 0 m g/ m 2 
I V 
Da y 1  
D o x or u bici n  
3 5 m g/ m 2 
I V 
Da y 1  
Et o p osi de  
1 5 0 m g/ m 2 
I V 
Da ys 1 -3  
 
D ose Le vel -3  
D ose  
R o ute  
Sc he d ule  
C ycl o p h os p ha mi de  
8 0 0 m g/ m 2 
I V 
Da y 1  
D o x or u bici n  
3 5 m g/ m 2 
I V 
Da y 1  
Et o p osi de  
1 2 5 m g/ m 2 
I V 
Da ys 1 -3  
 
St a n d ar d B E A C O P P  
D ose  
R o ute  
Sc he d ule  
C ycl o p h os p ha mi de  
6 5 0 m g/ m 2 
I V 
Da y 1  
D o x or u bici n  
2 5 m g/ m 2 
I V 
Da y 1  
Et o p osi de  
1 0 0 m g/ m 2 
I V 
Da ys 1 -3  


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9. 2. 9 
Tre at me nt P ost p o ne me nt a n d D ose M o dific ati o ns f or st a n d ar d B E A C O P P  
A c ycle of B E A C O P P s h o ul d n ot be gi n u ntil le u k oc ytes  > 2, 5 0 0 a n d platelets > 
8 0, 0 0 0.  If  le u k oc ytes  <  2, 5 0 0  or  platelets  <  8 0, 0 0 0  o n  da y  1  of  a  c ycle  of 
B E A C O P P, dela y treat me nt u ntil le u k oc ytes ≥ 2, 5 0 0 a n d platelets ≥ 8 0, 0 0 0. C B C 
s h o ul d be rec hec ke d after 3, 7, 1 0 a n d 1 4 da ys. T he first c ycle of B E A C O P P ma y 
be gi n t w o wee ks after c ycle 2 of A B V D i n patie nts wit h a p ositi ve i nteri m P E T 
sca n, re gar dless of le u k oc yte c o u nt. 
Tre at me nt Del a y  
D ose M o dific ati o n  
< 1 wee k *  
N o d ose re d ucti o n  
1- 2 wee ks  
2 5 % d ose re d ucti o n f or c ycl o p h os p ha mi de, d o x or u bici n , 
pr ocar bazi ne a n d et o p osi de  
> 2 wee ks  
5 0 % d ose re d ucti o n f or c ycl o p h os p ha mi de, d o x or u bici n , 
pr ocar bazi ne a n d et o p osi de  
* N o d ose re d ucti o ns will be perf or me d if dela ys of le u k oc yte or platelet rec o ver y 
are  less  t ha n  o ne  wee k.  Ot her wise  d ose  re d ucti o ns  will  f oll o w  t he  sc he ma 
descri be d b y t he Ger ma n H o d g ki n Disease St u d y Gr o u p. [ 3 1] 
9. 3 
D ose M o dific ati o n f or O bese P atie nts  
T here is n o clearl y d oc u me nte d a d verse i m pact of treat me nt of o bese patie nts w he n d osi n g 
is perf or me d acc or di n g t o act ual b o d y wei g ht. T heref ore, all d osi n g is t o be deter mi ne d 
s olel y b y ( 1) t he p atie nt’s B S A as c alc ul ate d fr o m act u al wei g ht or ( 2) act u al wei g ht 
wit h o ut  a n y  m o dific ati o n  ( wit h  t he  e xce pti o n  of  t he  c a p  o n  vi ncristi n e  d oses  i n 
B E A C O P P as n ot e d i n S ecti o n 7. 1). T his will eli mi nate t he ris k of calc ulati o n err or a n d 
t he p ossi ble i ntr o d ucti o n of varia bilit y i n d ose a d mi nistrati o n. F ail ure t o use act u al b o d y 
wei g ht  i n  t he  c alc ul ati o n  of  dr u g  d os a ges  will  be  c o nsi dere d  a  m aj or  pr ot oc ol 
de vi ati o n.  P h ysicia ns w h o are u nc o mf orta ble wit h a d mi nisteri n g c he m ot hera p y d ose base d 
o n act ual b o d y wei g ht s h o ul d n ot e nr oll o bese patie nts o n C A L G B pr ot oc ols.  
1 0. 0  C O R R E L A TI V E S CI E N C E C O M P A NI O N S T U DI E S  
T here  is  o ne  c orrelati ve  scie nce  c o m pa ni o n  c o m prise d  of  t w o  st u d y  c o m p o ne nts  t hat  m ust  be 
prese nte d t o all patie nts, t h o u g h patie nts ma y o pt n ot t o partici pate. T he first c o m p o ne nt will be t o 
e val uate ser u m a n d plas ma mar kers a n d t o c orrelate wit h cli nical o utc o mes. T he sec o n d c o m p o ne nt 
will  be t o e val uate i m m u n o hist oc he mical mar kers f or pr o g n osis. B ot h c o m p o ne nts will c o m prise t he 
c o m pa ni o n st u d y C A L G B 1 5 0 9 0 3 . 
1 0. 1 
Ser u m M ar kers  
1 0. 1. 1  B ac k gr o u n d 
Se veral ser u m mar kers ha ve bee n s u g geste d t o be of pre dicti ve val ue wit h re gar d 
t o  pr o gressi o n-free  a n d  o verall  s ur vi val.  A m o n g  t he  m ost  pr o misi n g  are  I L 1 0, 
s ol u ble  C D 3 0  (s C D 3 0),  C C L 1 7,  a n d  C C L 2 2 [ 3 2].  Ele vate d  s C D 3 0  has  bee n 
ass ociate d  wit h  p o or  e ve nt -free  s ur vi val [ 3 3- 3 5] a n d  ele vate d  I L 1 0  has  bee n 
ass ociate d  wit h  p o or  fail ure -free  s ur vi val  i n  m ulti varia ble  a nal yses [ 3 6,  3 7].  I n 
a d diti o n,  c he m o ki nes  C C L 1 7  ( T A R C)  a n d  C C L 2 2  ( M D C)  are  ele vate d  i n 
a p pr o xi matel y 7 5 % of patie nts wit h H o d g ki n l y m p h o ma a n d ha ve bee n s h o w n t o 
fall wit h s uccessf ul treat me nt [ 3 8- 4 0]. F urt her m ore, ele vate d T A R C at dia g n osis 
has bee n s h o w n t o c orrelate wit h p o or o verall s ur vi val [ 4 0]. T hese ha ve n ot bee n 
well st u die d pr os pecti vel y a n d t heir c orrelati o n wit h P E T sca n res ults a n d a bilit y 
t o pre dict rela pse after re missi o n i n d ucti o n are u n k n o w n. T heref ore, we pr o p ose 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
5 0  
U p date # 1 3  
t o assess t hese pr o misi n g bi ol o gic ser u m mar kers b y E LI S A t o pre dict o utc o me at 
dia g n osis a n d t o f oll o w serial le vels at t he ti me of i ma gi n g st u dies i n or der t o assess 
w het her t hese mar kers ca n pre dict rela pse.  
1 0. 1. 2 O bjecti ves  
1 0. 1. 2. 1 
T o  assess  w het her  ele vate d  baseli ne  ser u m  s ol u ble  C D 3 0  (s C D 3 0), 
I L 1 0, C C L 1 7, a n d C C L 2 2 c orrelate wit h cli nical res p o nse a n d P F S.  
1 0. 1. 2. 2 
T o assess w het her lac k of n or malizati o n or rec urre nt ele vati o n of serial 
ser u m  s C D 3 0,  I L 1 0,  
C C L 1 7,  or  
C C L 2 2  c orrelate  
wit h 
rela pse/ pr o gressi o n or P E T sca n res ults. 
1 0. 1. 3 Met h o ds  
S a m ple C ollecti o n a n d L a b or at or y Met h o ds: I n patie nts w h o c o nse nt, 1 0 m L 
peri p heral ve n o us bl o o d f or plas ma a n d ser u m will be c ollecte d at baseli ne ( pri or 
t o i nitiati o n of t hera p y), after c ycle 2 of A B V D a n d f oll o wi n g eit her c ycle 6 of 
A B V D (f or P E T ne gati ve patie nts) or I F R T (f or P E T p ositi ve patie nts) , a n d at 3, 
6, 9, 1 2, 1 8, 2 4, 3 0 a n d 3 6 m o nt hs d uri n g p ost -treat me nt f oll o w-u p. E LI S A assa ys 
will  be  perf or me d  acc or di n g  t o  ma n ufact ure  pr ot oc ol  at  Cle vela n d  Cli nic 
Refere nce La b orat or y usi n g c o m merciall y a vaila ble E LI S A kits ( R & D s yste ms). 
Res ults will be re p orte d t o t he Allia nce  Statistics a n d Data  Ce nter i n pic o gra ms/ m L 
via a c o de d e xcel s prea ds heet f or mat. N or mal ra n ges ha ve bee n esta blis he d b y t he 
ma n ufact urer.  
1 0. 2 
Pl as m a M ar kers  
1 0. 2. 1 B ac k gr o u n d  
O ne  of  t he  stri ki n g  his t ol o gic  feat ures  of  c H L  is  t he  d o mi na nt  i nfla m mat or y 
bac k gr o u n d prese nt i n m ost cases. We are n o w be gi n ni n g t o rec o g nize t hat t hese 
cells  pr o vi de  a  c o m ple x  net w or k  of  c yt o ki nes  a n d  c he m o ki nes  t hat  pr o vi de  a 
per missi ve  micr oe n vir o n me nt.  T he  T -cell  hea v y  i nfiltrate  of  c H L  is  hea vil y 
s ke we d  t o war ds  a T h 2  a n d  re g ulat or y  T-cell ( Tre g)  c o m p ositi o n [ 4 1,  4 2].  H R S 
cells secrete n u mer o us c yt o ki nes a n d c he m o ki nes s uc h as  I L-5, I L -6, I L -8, I L - 9, 
I L- 1 0, I L-1 3,  T G F ß ,  A P RI L,  B A F F,  C C L 2 8, I P 1 0/ C X C L 1 0,  R A N T E S/ C C L 5), 
M C P 4 ( C C L 1 3), T A R C/ C C L 1 7, a n d M D C/ C C L 2 2 [ 4 1- 4 5]. W hile s o me ma y act 
as a ut ocri ne gr o wt h fact ors f or H R S cells t he msel ves (I L -1 3, A P RI L, B A F F ) [ 4 3, 
4 6] ,  ot hers  a p pear  t o  attract  a n d  s ha pe  t he  i m m u n e  micr oe n vir o n me nt.    F or 
e xa m ple,  I L -5  a n d  C C L 2 8  ser ve  t o  attract  e osi n o p hils,  w hile  I L -6  a n d  C C L 2 8 
attract  plas ma  cells [ 4 1,  4 2,  4 4,  4 5].  I L-1 0  pr o m otes  a  T h 2  res p o nse  a n d  a n 
i m m u n os u p presse d micr oe n vir o n me nt [ 4 5]. T A R C a n d M D C pr o d ucti o n b y H R S 
cells  als o  pr o m ote  a  T h 2  e n vir o n me nt [ 4 2].  Li ke wise,  galecti n  1  secreti o n 
pr o m otes a n i m m u ne pri vile ge d micr oe n vir o n me nt b y pr o m oti n g a T h 2 res p o nse 
a n d  e x pa nsi o n  of  Tre gs [ 4 7].  T hese  s ol u ble  fact ors  ha ve  bee n  e xa mi ne d  as 
pr o g n ostic  fact ors  i n  H L.  Se veral  of  t hese  fact ors  ha ve  bee n  s h o w n  t o  be  of 
p ote ntial pr o g n ostic si g nifica nce i n H L. I n partic ular s ol u ble C D 3 0 (s C D 3 0) a n d 
I L 1 0  ha ve  bee n  s h o w n  i n  se veral  st u dies  t o  be  of  pr o g n ostic  si g nifica nce  at 
baseli ne ( A p pe n di x III ). T A R C a n d M D C, hi g hl y e x presse d i n H R S cells, are als o 
ele vate d  i n  ser u m  of  H L  patie nts [ 3 9,  4 8,  4 9].  T h us,  t hese  mar kers  ma y  be 
i n dicati ve of t u m or b ur de n a n d, i n t he case of T A R C, ma y als o be of pr o g n ostic 
si g nifica nce.    I m p orta ntl y,  t hese  mar kers,  c haracteristicall y  pr o d uce d  b y  H R S 
cells, ma y als o be i n dicati ve of rela pse. We pr o p ose st u d yi n g plas ma le vels of t hese 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
5 1  
U p date # 1 3  
I L 1 0, s C D 3 0, T A R C, a n d M D C i n patie nts at baseli ne, at ti me of P E T sca ns a n d 
selecte d ti me p oi nts d uri n g f oll o w-u p i n or der t o deter mi ne w het her t hese mar kers 
ha ve pr o g n ostic val ue i n t he c o o perati ve gr o u ps setti n g.  
1 0. 2. 2 O bjecti ves  
1 0. 2. 2. 1 
T o  assess  w het her  ele vate d  baseli n e  plas ma  s ol u ble  C D 3 0  (s C D 3 0), 
I L 1 0, C C L 1 7, a n d C C L 2 2 c orrelate wit h cli nical res p o nse a n d E F S. 
1 0. 2. 2. 2 
T o  assess  w het her  lac k  of  n or malizati o n  or  rec urre nt  ele vate d  serial 
plas ma  s C D 3 0,  I L 1 0,  
C C L 1 7,  or  
C C L 2 2  c orrelate  
wit h 
rela pse/ pr o gressi o n. 
1 0. 2. 2. 3 
T o  assess w het her  ele vate d  plas ma  bi o mar ker  le vels  c orrelate  wit h 
a b n or mal P E T sca n res ults.  
1 0. 2. 3 Met h o ds  
S a m ple C ollecti o n a n d L a b or at or y Met h o ds: I n patie nts w h o c o nse nt, 1 0 m L 
peri p heral ve n o us bl o o d f or plas ma will be c ollecte d at baseli ne ( pri or t o i nitiati o n  
of t hera p y), after c ycle 2 of A B V D, a n d f oll o wi n g eit her c ycle 6 (f or P E T ne gati ve 
patie nts) or I F R T (f or P E T p ositi ve patie nts), a n d  at 3, 6, 9, 1 2, 1 8, 2 4, 3 0 a n d 3 6 
m o nt hs  d uri n g  p ost -treat me nt  f oll o w-u p.  E LI S A  assa ys  will  be  perf or me d 
acc or di n g t o ma n ufact ure pr ot oc ol at Cle vela n d Cli nic Refere nce La b orat or y usi n g 
c o m merciall y  a vaila ble  E LI S A  kits  ( T A R C,  M D C,  I L 1 0  fr o m  R & D  s yste ms, 
Mi n nea p olis,  M N  a n d  s C D 3 0  Ale xis  Bi oc he micals,  Pl y m o ut h  Meeti n g,  P A).   
Sa m ples will be r u n i n d u plicate a n d c orrelate d wi t h cli nical o utc o mes. 
1 0. 3 
I m m u n o hist oc he mic al M ar kers 
1 0. 3. 1  B ac k gr o u n d 
Rece nt  data  s u g gest  t hat  t here  are  bi ol o gic  pre dict ors  of  o utc o me  i n  H o d g ki n 
l y m p h o ma.  Pre dict ors  of  p o or  o utc o me  i n  si n gle  i nstit uti o n  series  i n 
heter o ge ne o usl y  treate d  patie nts  i ncl u de  Bcl -2  a n d  M A L  e x pressi o n  i n  t he 
H o d g ki n  l y m p h o ma  cells [ 5 0- 5 3].  I n  a d diti o n,  F O X P 3 +  cells  (as  a  mar ker  of 
re g ulat or y T-cells wit hi n t he n o n -ne o plastic l y m p h oc ytes) ha ve bee n re p orte d t o 
be a mar ker of fa v ora b le o utc o me [ 5 4]. M A L a n d F O X P 3 ha ve n ot bee n vali date d 
i n ot her series a n d n o ne of t hese mar kers ha ve bee n teste d s pecificall y i n patie nts 
wit h earl y sta ge H L or i n p atie nts treate d wit h t his re gi me n. I n a d diti o n t o F O X P 3, 
mar kers of effect or T -cells, s uc h as gra nz y me B ( Gz B; acti vate d c yt ot o xic T -cells) 
[ 5 5, 5 6] a n d mast cells (tr y ptase/ C D 1 1 7) [ 5 7] will be assesse d as a c o m ple me nt t o 
t he s u p pressi ve re g ulat or y T- cells. B ot h Gz B + T -cells a n d mast cells ha ve bee n 
ass ociate d  wit h  p o or  o utc o me  i n  H L [ 5 5- 5 8]. C D 6 8 +  macr o p ha ges  ha ve  als o 
e mer ge d as a n i m p orta nt micr oe n v ir on me ntal fact or  wit h cases s h o wi n g less t ha n 
5 % C D 6 8 + cells ha vi n g a fa v ora ble pr o g n osis c o m pare d t o t h ose wit h ≥ 5 %. 
1 0. 3. 2 O bjecti ve  
T o deter mi ne w het her t hese tiss ue bi o mar kers c orrelate wit h cli nical o utc o me i n 
patie nts wit h b ul k y sta ge I a n d II H o d g ki n l y m p h o ma treate d wit h t his re gi me n. 
1 0. 3. 3 Met h o ds  
S a m ple C ollecti o n a n d L a b or at or y Met h o ds: I n patie nts w h o c o nse nt, T M As 
will be c o nstr ucte d fr o m f or mali n -fi xe d, paraffi n-e m b e d de d tiss ue c ollecte d pri or 
t o i nitiati o n of t hera p y. M o n ocl o nal a nti b o dies t o Gz B ( Ve nta na), F O X P 3 ( A bca m, 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
5 2  
U p date # 1 3  
Ca m bri d ge,  U K),  C D 1 1 7  ( Ve nta na),  C D 6 8  ( K P 1,  D A K O), a n d  M A L  ( Dr.  M. 
Al o ns o, C NI O) will be use d t o perf or m a ut o mate d i m m u n o hist oc he mistr y at t he 
Allia nce Bi ore p osit or y at O hi o State  acc or di n g t o sta n dar d pr ot oc ols. N u m bers of 
Gz B, F O X P 3, a n d C D 1 1 7 will be sc ore d as n u m ber of p ositi ve cells/ 5 h pf. M A L 
will be c o nsi dere d p ositi ve if > 2 0 % of H R S cells e x press t his mar ker [ 5 1]. Bcl- 2 
will be c o nsi dere d p ositi ve if > 1 0 % of H R S cells s h o w str o n g Bcl -2 e x pressi o n 
c o m pare d t o a n i nter nal T -cell c o ntr ol  ( A p pe n di x II). C D 6 8 will b e assesse d b y 
ma n ual c o u nti n g as < 5 %, 5- 2 5 %, 2 6- 5 0 %, a n d > 5 0 % [ 5 9]. 
1 1. 0  D R U G F O R M U L A TI O N , A V AI L A BI LI T Y , A N D P R E P A R A TI O N  
1 1. 1 
Q u alifie d Pers o n nel  
Q ualifie d  pers o n nel  w h o  are  fa miliar  wit h  pr oce d ures  t hat  mi ni mize  u n d ue  e x p os ure  t o 
t he msel ves a n d t o t he e n vir o n me nt s h o ul d u n derta ke t he pre parati o n, ha n dli n g, a n d safe 
dis p osal of c he m ot hera pe utic a ge nts i n a self -c o ntai ne d, pr otecti ve e n vir o n me nt. 
1 1. 2 
Disc ar di n g U n use d A ge nts  
Discar d  u n use d  p orti o ns  of  i njecta ble  c he m ot hera pe utic  a ge nts  t hat  d o  n ot  c o ntai n  a 
bacteri ostatic  a ge nt  or  are  pre pare d  wit h  u n preser ve d  dil ue nts  (i.e.,  Sterile  Water  f or 
I nj ecti o n U S P or 0. 9 % S o di u m C hl ori de f or I nj ecti o n U S P) wit hi n ei g ht h o urs of vial e ntr y 
t o mi ni mize t he ris k of bacterial c o nta mi nati o n. 
1 1. 3 
C alc ul ate d D ose R a n ge  
T he t otal a d mi ni stere d d ose of c he m ot hera p y ma y be r o u n de d u p or d o w n wit hi n a ra n ge 
of 5 % of t he act ual calc ulate d d ose. 
1 1. 4 
D o x or u bici n H C L  
Please refer t o t he F D A -a p pr o ve d pac ka ge i nsert f or d o x or u bici n f or pr o d uct i nf or mati o n, 
e xte nsi ve pre parati o n i nstr ucti o ns, a n d  a c o m pre he nsi ve list of a d verse e ve nts.  
A V AI L A BI LI T Y  
D o x or u bici n is c o m merciall y a vaila ble as a l y o p hilize d p o w der f or rec o nstit uti o n i n 1 0, 2 0, 
5 0, a n d 1 5 0 m g vials. Als o a vaila ble are 2 m g/ m L s ol uti o n f or i njecti o n i n 1 0, 2 0, 5 0, 7 5, 
a n d 2 0 0 m g vials of d o x or u bici n i n s ol uti o n. 
S T O R A G E &  S T A BI LI T Y  
I ntact  vials  of  d o x or u bici n  s ol uti o n  s h o ul d  be  st ore d  i n  t he  refri gerat or.  I ntact  vials  of 
p o w der f or rec o nstit uti o n s h o ul d be st ore d at r o o m te m perat ure. Rec o nstit ute d s ol uti o ns 
are sta ble f or 7 da ys at r o o m t e m perat ure a n d 1 5 da ys u n der refri gerati o n w he n pr otecte d 
fr o m li g ht. C o m merciall y a vaila ble s ol uti o ns la bele d as s uc h are i nte n de d t o be m ulti d ose 
vials.  
P R E P A R A TI O N  
Rec o nstit ute  t he  vials  wit h  5,  1 0,  2 5,  or  5 0  m L,  res pecti vel y,  of  s o di u m  c hl ori de  f or 
i njecti o n, U S P, res ulti n g i n a c o nce ntrati o n of 2 m g/ m L. 
A D MI NI S T R A TI O N  
D o x or u bici n  is  a d mi nistere d  i ntra ve n o usl y  o ver  3 -5  mi n utes.  A v oi d  e xtra vasati o n,  as 
se vere l ocal tiss ue necr osis ma y res ult. 
T O XI CI TI E S  
He mat ol o gic:  le u k o pe nia ( d ose-li miti n g), t hr o m b oc yto pe nia, a ne mia. Na dir i n 1 0 -1 4 da ys 
wit h rec o ver y us uall y i n 2 1 da ys.  


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
5 3  
U p date # 1 3  
Der mat ol o gic:  al o pecia ( us uall y c o m plete; re versi ble) ra diati o n recall reacti o ns; i ncrease d 
se nsiti vit y t o s u nli g ht. 
Gastr oi ntesti nal:  na usea a n d v o miti n g ( d o x or u bici n is ge nerall y c o nsi dere d m o deratel y t o 
hi g hl y e met o ge nic), a n ore xia, diarr hea, m uc ositis (st o matitis, es o p ha gitis).  
Car di o vasc ular:  car di o m y o pat h y ma y occ ur a n d is relate d t o t otal c u m ulati ve lifeti me d ose. 
T he ris k f or car di o m y o pat h y i ncreases wit h t otal d oses > 4 5 0 m g/ m 2. E C G c ha n ges a n d 
less ofte n, arr h yt h mias, are see n. Rarel y, s u d de n deat h has occ urre d. 
Ot her:  re d disc ol orati o n of uri ne f or 2 4- 4 8 h o urs after dr u g a d mi nistrati o n. D o x or u bici n is 
a vesica nt a n d ca n ca use tiss ue necr osis if e xtra vasate d.  
1 1. 5 
Ble o m yci n  
Pleas e refer t o t he F D A -a p pr o ve d pac ka ge i nsert f or ble o m yci n f or pr o d uct i nf or mati o n, 
e xte nsi ve pre parati o n i nstr ucti o ns, a n d a c o m pre he nsi ve list of a d verse e ve nts.  
A V AI L A BI LI T Y  
Ble o m yci n  is  c o m merciall y  a vaila ble  i n  vials  c o ntai ni n g  1 5  or  3 0  u nits  of l y o p hilize d 
p o w der f or rec o nstit uti o n. ( 1 u nit = 1 m g) 
S T O R A G E &  S T A BI LI T Y  
I ntact  vials  s h o ul d  be  st ore d  i n  t he  refri gerat or.  Rec o nstit ute d  s ol uti o ns  pre pare d  wit h 
bacteri ostatic dil ue nts are sta ble f or 2 8 da ys at r o o m te m perat ure or u n der refri gerati o n.  
P R E P A R A TI O N  
Rec o nstit ute  t he  vial  wit h  1 -5  m L  of  water  f or  i njecti o n  or  0. 9 %  s o di u m  c hl ori de  wit h 
bacteri ostat res ulti n g i n a c o nce ntrati o n of 3 -1 5 u nits/ ml ( 1 5 u nit vial) or 6 -3 0 u nits/ ml ( 3 0 
u nit vial).  
A D MI NI S T R A TI O N  
Ble o m yci n is a d mi nistere d I V.  
T O XI CI TI E S  
Der mat ol o gic :  s ki n  reacti o ns  are  c o m m o n  ( 5 0 %)  a n d  ma y  i ncl u de,  h y per pi g me ntati o n, 
e de ma, er yt he ma, t hic ke ni n g of nail be ds, a n d al o pecia. Ble o m yci n is n ot a vesica nt a n d 
has bee n a d mi nistere d b y S Q or I M i nj ecti o n. 
P ul m o nar y :  i nterstitial  p ne u m o nitis, p ul m o nar y  fi br osis.  P ne u m o nitis  is  relate d  t o  t otal 
c u m ulati ve  d ose  (e. g.,  it  is  m ore  li kel y  t o  occ ur  wit h  c u m ulati ve  d oses  >  4 0 0  u nits). 
H o we ver,  t he  occ urre nce  i n  i n di vi d ual  patie nts  is  s o me w hat  u n pre dicta ble.  Si g ns  a n d 
s y m pt o ms  i ncl u de  d ys p nea,  c o u g h,  fi ne  rales,  ra di o gra p hic  fi n di n gs  rese m bli n g 
p ne u m o nia, a n d altere d p ul m o nar y f u ncti o n stat us. 
H y perse nsiti vit y : a na p h ylact oi d reacti o ns are re p orte d t o occ ur i n a b o ut 1 % of l y m p h o ma 
patie nts.  T he  reacti o n  is  c haracterize d  b y  se vere  h y per p yre xia,  wit h  s u bse q ue nt 
car di o vasc ular c olla pse. 
Ot her :  Fe ver  wit h  or  wit h o ut  c hills  is  ofte n  see n  ( u p  t o  5 0 %  of  patie nts)  s o o n  after 
a d mi nistrati o n  a n d  ma y  last  f or  4 -1 2  h o urs.  Pre  treat me nt  wit h  aceta mi n o p he n  ma y 
decrease t he li keli h o o d or se verit y of fe ver  
1 1. 6 
Vi n bl asti ne S ulf ate  
Please refer t o t he F D A -a p pr o ve d pac ka ge i nsert f or vi n blasti ne f or pr o d uct i nf or mati o n, 
pre parati o n i nstr ucti o ns, a n d a c o m pre he nsi ve list of a d verse e ve nts.  


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
5 4  
U p date # 1 3  
A V AI L A BI LI T Y  
Vi n blasti ne is c o m merciall y a vaila ble i n vials of 1 0 m g as a p o w der f or rec o nstit uti o n.  
S T O R A G E &  S T A BI LI T Y  
St ore  i ntact  vials  u n der  refri gerati o n.  O nce  rec o nstit ute d  wit h  bacteri ostatic  dil ue nt, 
s ol uti o ns are sta ble f or 2 1 da ys at r o o m te m perat ure or u n der refri gerati o n. 
P R E P A R A TI O N  
Rec o nstit ute wit h 1 0 m L bacteri ostatic H 2O or 0. 9 % Na Cl, or 0. 9 % Na Cl or sterile H 20 f or 
i njecti o n, t o yiel d a c o nce ntrati o n of 1 m g/ m L. Bacteri ostatic dil ue nt s h o ul d be use d w he n 
vials will be st ore d as descri be d i n “ St ora ge & Sta bilit y.”  
A D MI NI S T R A TI O N  
I V o ver 3-5 mi n utes.  
T O XI CI TI E S  
He mat ol o gic : m yel os u p pressi o n is a m o n g t he m ost c o m m o n si de effects, a n d ma y be d ose 
li miti n g. 
Gastr oi ntesti nal:  na usea a n d v o miti n g ma y occ ur, b ut vi n blasti ne is ge nerall y c o nsi dere d 
mil dl y e met o ge nic w he n use d as a si n gle a ge nt.  
Ne ur ot o xicit y: vi n blasti ne is ass oc iate d wit h q ualitati vel y t he sa me ne ur ot o xicit y as is see n 
wit h  vi ncristi ne  (e. g.,  peri p heral  ne ur o pat h y,  a ut o n o mic  d ysf u ncti o n,  e ve n  ile us),  b ut 
q ua ntitati vel y, vi n blasti ne is m uc h less ne ur ot o xic t ha n vi ncristi ne. Hi g her d oses are m ore 
li kel y t o ca use neur ot o xicit y.  
Vesica nt : vi n blasti ne is a vesica nt a n d ma y ca use tiss ue da ma ge u p o n e xtra vasati o n. 
Ot her:  al o pecia; vi n blasti ne has bee n ass ociate d wit h Ra y na u d’s p he n o me n o n.  
1 1. 7 
D ac ar b azi ne ( D TI C)  
Please refer t o t he F D A -a p pr o ve d pac ka ge i nsert f or dacar bazi ne f or pr o d uct i nf or mati o n, 
e xte nsi ve pre parati o n i nstr ucti o ns, a n d a c o m pre he nsi ve list of a d verse e ve nts.  
A V AI L A BI LI T Y  
Dacar bazi ne is c o m merciall y a vaila ble i n vials c o ntai ni n g 1 0 0 m g, 2 0 0 m g, or 5 0 0 m g of 
l y o p hilize d p o w der f or rec o nstit uti o n. 
S T O R A G E &  S T A BI LI T Y  
I ntact vials s h o ul d be u n der refri gerati o n a n d pr otecte d fr o m li g ht. T he y are re p orte d t o be 
sta ble f or 4 wee ks at r o o m te m perat ure. O nce rec o nstit ute d, vials are sta ble f or 4 h o urs at 
r o o m te m perat ure or 9 6 h o urs u n der refri gerati o n. F urt her dil ute d s ol uti o ns f or i nf usi o ns 
are sta ble f or 2 4 h o urs at r o o m te m perat ure a n d pr otecte d fr o m li g ht. 
N ote : A c ha n ge i n c ol or of s ol uti o n fr o m pale yell o w t o pi n k is i n dicati ve of dec o m p ositi o n 
of t he dr u g. 
P R E P A R A TI O N  
T he 1 0 0 m g, 2 0 0 m g, a n d 5 0 0 m g  vials s h o ul d be rec o nstit ute d wit h 9. 9 m L, 1 9. 7 m L, a n d 
4 9. 5  m L  of  sterile  water,  res pecti vel y,  res ulti n g  i n  a  c o nce ntrati o n  of  1 0  m g/ m L.  M ore 
c o nce ntrate d s ol uti o ns (e. g. 2 0 m g/ m L) ma y als o be use d. T he desire d v ol u me s h o ul d t he n 
be wit h dra w n a n d i njecte d i nt o 1 5 0 - 1 0 0 0 m L D 5 W or 0. 9 % Na C L, f or I V i nf usi o n. 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
5 5  
U p date # 1 3  
A D MI NI S T R A TI O N  
Dacar bazi ne s h o ul d be a d mi nistere d b y I V i nf usi o n o ver 3 0 mi n utes or l o n ger. Dacar bazi ne 
a d mi nistrati o n ma y be ass ociate d wit h pai n/irritati o n. Pai nf ul a d mi nistrati o n is mi ni mize d 
wit h t h e use of sl o w a n d dil ute i nf usi o ns. 
T O XI CI TI E S  
He mat ol o gic :  m yel os u p pressi o n;  na dir  of  W B C  a n d  platelet  de pressi o n  occ urs 
a p pr o xi matel y 7-1 0 da ys after treat me nt.  
Der mat ol o gic :  al o pecia,  p h ot ose nsiti vit y.  Dacar bazi ne  is  c o nsi dere d  a n  irrita nt. 
E xtra vasati o n ma y res ult i n pai n, b ut is n ot ass ociate d wit h tiss ue da ma ge.  
Gastr oi ntesti nal : na usea a n d v o miti n g. Dacar bazi ne is c o nsi dere d hi g hl y e met o ge nic. 
Ot her :  fl u-li ke  s y n dr o me  ( wit h  fe ver,  malaise,  m yal gia)  ma y  occ ur  wit hi n  7  da ys  of 
treat me nt. 
1 1. 8 
Et o p osi de   
Please refer t o t he F D A -a p pr o ve d pac ka ge i nsert f or et o p osi de f or pr o d uct i nf or mati o n, 
e xte nsi ve pre parati o n i nstr ucti o ns, a n d a c o m pre he nsi ve list of a d verse e ve nts.  
A V AI L A BI LI T Y  
Et o p osi de  is  c o m merciall y  a vaila ble  i n  5  m L,  2 5  m L,  a n d  5 0  m L  vials  c o ntai ni n g  2 0 
m g/ m L. S ol uti o ns c o ntai n p ol ys or bate 8 0.  
S T O R A G E &  S T A BI LI T Y  
U n o pe ne d vials s h o ul d be st ore d at r o o m te m perat ure a n d pr otecte d fr o m li g ht. S ol uti o ns 
dil ute d t o a c o nce ntrati o n of 0. 2 a n d 0. 4 m g/ m L (i n D 5 W or N S) are sta ble f or 9 6 a n d 4 8 
h o urs, res p ecti vel y, at r o o m te m perat ure u n der n or mal li g ht. 
P R E P A R A TI O N  
T he d ose of et o p osi de s h o ul d be f urt her dil ute d wit h D 5 W or n or mal sali ne f or i njecti o n t o 
a fi nal c o nce ntrati o n of less t ha n or e q ual t o 0. 4 m g/ m L. 
A D MI NI S T R A TI O N  
Et o p osi de is deli vere d b y I V i nf usi o n o ver at least 4 5 -6 0 mi n utes; a d mi nistrati o n t hat is t o o 
ra pi d ma y be ass ociate d wit h h y p ote nsi o n. 
T O XI CI TI E S  
He mat ol o gic : m yel os u p pressi o n. 
Gastr oi ntesti nal :  a n ore xia,  na usea  a n d  v o miti n g  (et o p osi de  is  c o nsi dere d  mil dl y 
e met o ge nic). 
Der mat ol o gic: al o pecia. 
Ot her :  h y perse nsiti vit y  reacti o ns  i ncl u di n g  c hills,  fe ver,  tac h ycar dia,  br o nc h os pas m, 
d ys p nea a n d h y p ote nsi o n are re p orte d rarel y.  
1 1. 9 
C ycl o p h os p h a mi de  
Please  refer  t o  t he  F D A -a p pr o ve d  pac ka ge  i nsert  f or  c ycl o p h os p ha mi de  f or  pr o d uct 
i nf or mati o n, e xte nsi ve pre parati o n i nstr ucti o ns, a n d a c o m pre he nsi ve list of a d verse e ve nts. 
A V AI L A BI LI T Y  
C o m merciall y a vaila ble as a p o w der f or rec o nstit uti o n i n vials c o ntai ni n g 1 0 0, 2 0 0, 5 0 0, 
1 0 0 0, a n d 2 0 0 0 m g. 
St ora ge & Sta bilit y  


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
5 6  
U p date # 1 3  
I ntact vials s h o ul d be st ore d at r o o m te m perat ure. Rec o nstit ute d s ol uti o ns are sta ble f or 2 4 
h o urs at r o o m te m perat ure a n d 6 da ys i n a refri gerat or. F urt her dil ute d s ol uti o ns are als o 
sta ble f or 2 4 h o urs at r o o m te m perat ure a n d 6 da ys u n der refri gerati o n. 
P R E P A R A TI O N  
Rec o nstit ute 1 0 0 m g, 2 0 0 m g, 5 0 0 m g, 1 g a n d 2 g vi als wit h 5, 1 0, 2 5, 5 0, or 1 0 0 m L of 
S WI or N S t o gi ve a fi nal c o nce ntrati o n of 2 0 m g/ m L. Vi g or o us s ha ki n g ma y be n ecessar y 
f or n o n-l y o p h ylize d pre parati o ns. Bacteri ostatic water f or i njecti o n ( para be n pre parati o ns 
o nl y) ma y b e use d; be nz yl alc o h ol deri vati ves ma y N O T be use d. S ol uti o ns ma y b e f urt her 
dil ute d i n D 5 W or N S f or I V i nf usi o n. 
A D MI NI S T R A TI O N  
C ycl o p h os p ha mi de ma y be a d mi nistere d as a n I V b ol us or I V i nf usi o n. 
T O XI CI T Y  
He mat ol o gic : m yel os u p pressi o n; e x pecte d na dir f or ne utr o pe nia is a p pr o xi matel y 1 0 da ys.  
Gastr oi ntesti nal :  na usea  a n d  v o miti n g;  t he  d ose  of  c ycl o p h os p ha mi de  i n  escalate d  d ose 
B E A C O P P is c o nsi dere d hi g hl y e met o ge nic. T he c ycl o p h os p ha mi de d ose i n sta n dar d d ose 
B E A C O P P is c o nsi dere d m o deratel y e met o ge nic ( w h e n a d mi nistere d as a si n gle a ge nt).  
Der mat ol o gic: al o pecia.  
Ge nit o uri nar y :  he m orr ha gic  c ystitis  is  t h o u g ht  t o  be  d ue  t o  t he  prese nce  of  t he 
c ycl o p h os p ha mi de  meta b olite,  acr olei n,  i n  t he  bla d der.  H y drati o n  a n d  fre q ue nt  v oi di n g 
hel p t o mi ni mize t he occ urre nce of he m orr ha gic c ystitis. I n a d diti o n, i n t his st u d y, mes na 
ma y  be  a d mi nistere d  wit h  c ycl o p h os p ha mi de.  SI A D H  is  see n  less  fre q ue ntl y  t ha n 
he m orr ha gic c ystitis. SI A D H ge nerall y res ol ves wit hi n 2 4 h o urs wit h fl ui d restricti o n.  
Ot her : heart fail ure a n d cardiac necr osis occ ur rarel y after hi g h d ose c ycl o p h os p ha mi de. 
( d oses hi g her t ha n t h ose use d i n t his st u d y) 
1 1. 1 0 Vi ncristi ne  
Please refer t o t he F D A -a p pr o ve d pac ka ge i nsert f or vi ncristi ne f or pr o d uct i nf or mati o n, 
e xte nsi ve pre parati o n i nstr ucti o ns, a n d a c o m pre he nsi ve list of a d verse e ve nts.  
A V AI L A BI LI T Y  
Vi ncristi ne is c o m merciall y a vaila ble as a s ol uti o n 1 a n d 2 m g vials at a c o nce ntrati o n of 1 
m g/ m L.  
S T O R A G E &  S T A BI LI T Y  
I ntact vials s h o ul d be st ore d u n der refri gerati o n. T he y are re p orte d t o be sta ble f or u p t o 3 0 
da ys at r o o m te m perat ure. M ost vials are i nte n de d t o be m ulti -d ose vials. S ol uti o ns f urt her 
dil ute d f or I V i nf usi o n i n D 5 W or N S are sta ble f or 7 da ys or u n der refri gerati o n or 2 da ys 
at r o o m te m perat ure. 
A D MI NI S T R A TI O N  
Vi ncristi ne  is  a d mi nistere d  i ntra ve n o usl y.  N u mer o us  re p orts  of  fatalities  f oll o wi n g 
i na d verte nt  i ntrat hecal  a d mi nistrati o n  of  vi ncristi ne  u n derlie  t he  rec o m me n dati o n  f or 
a d mi nistrati o n as a s h ort I V i nf usi o n rat her t ha n a b ol us I V i nj ecti o n. 
T O XI CI T Y  
T he  d ose  li miti n g  t o xicit y  of  vi ncristi ne  is  ne ur ot o xicit y.  B ot h  se ns or y  a n d  m ot or 
ne ur o pat hies  are  c o m m o n.  Ot her  ma nifestati o ns  of  ne ur ot o xicit y  i ncl u de  cra nial  ner ve 
palsies,  c o nsti pati o n  a n d  ile us,  a n d  ort h ostatic  h y p ote nsi o n.  Al o pecia  is  als o  c o m m o n. 
F atalities ha ve bee n re p orte d f oll o wi n g i na d verte nt i ntrat hecal a d mi nistrati o n of vi ncristi ne 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
5 7  
U p date # 1 3  
a n d  care  s h o ul d  be  ta ke n  t o  a v oi d  t his  err or.  Vi ncristi ne  is  c o nsi dere d  a  vesica nt  a n d 
ulcerati o n ca n occ ur u p o n e xtra vasati o n. 
1 1. 1 1 P r oc ar b azi ne  
Please refer t o t he F D A-a p pr o ve d pac ka ge i nsert f or pr ocar bazi ne f or pr o d uct i nf or mati o n, 
e xte nsi ve pre parati o n i nstr ucti o ns, a n d a c o m pre he nsi ve list of a d verse e ve nts.  
A V AI L A BI LI T Y  
Pr ocar bazi ne is c o m merciall y a vaila ble as 5 0 m g ca ps ules f or oral a d mi nistrati o n.  
S T O R A G E  &  S T A BI LI T Y  
Pr ocar bazi ne ca ps ules s h o ul d be st ore d at r o o m te m perat ure a n d sta bilit y is as n ote d b y t he 
ma n ufact urer(s).  
A D MI NI S T R A TI O N  
Pr ocar bazi ne  s h o ul d  be  a d mi nistere d  orall y,  o nce  dail y.  A d mi nistrati o n  at  be dti me  ma y 
hel p t o mi ni mize na usea. 
T O XI CI T Y  
Ce ntral ner v o us s yste m : ne ur ot o xicit y i ncl u di n g m o o d dis or ders a n d C N S de pressi o n is 
c o m m o nl y  s u g geste d  t o  occ ur  wit h  pr ocar bazi ne,  alt h o u g h  t he  i nci de nce  is  n ot  well 
d oc u me nte d.  I n  t he  Ger ma n  H o d g ki n’s  L y m p h o ma  St u d y  Gr o u p  st u d y  ( N EJ M  2 0 0 3; 
3 4 8: 2 3 8 6) t he  fre q ue nc y of gra de 3 or 4 ne ur ol o gic a d verse e ve nts was 5 % wit h sta n dar d 
d ose  B E A C O P P,  4 %  wit h  escalate d  d ose  B E A C O P P  a n d  4 %  wit h  C O P P -A B V D.  All 
re gi me ns als o i ncl u de d vi ncristi ne a n d t he details of ne ur ot o xicit y are n ot descri be d. 
He mat ol o gic : m yel os u p pressi o n, he m ol ysis i n patie nts wit h G- 6-P D deficie nc y.  
Gastr oi ntesti nal :  na usea  a n d  v o miti n g  ( pr ocar bazi ne  is  c o nsi dere d  m o deratel y 
e met o ge nic); i ncreasi n g t he d ose i n a ste p wise fas hi o n o ver se veral da ys ma y  mi ni mize 
t his, as ma y a d mi nistrati o n of e ntire d ose at be dti me. 
Ge nit o uri nar y: re pr o d ucti ve d ysf u ncti o n > 1 0 %. 
Ot her :  sec o n d  mali g na ncies  (c u m ulati ve  i nci de nce  2 %  t o  1 5 %  re p orte d  wit h  M O P P 
c o m bi nati o n t hera p y). 
IN T E R A C TI O N S  
Pr ocar bazi ne  is  a  wea k  m o n oa mi ne  o xi dase  ( M A O)  i n hi bit or.  Us ual  ca uti o ns  re gar di n g 
a v oi da nce of t yra mi ne -c o ntai ni n g f o o ds are c o m m o nl y e xercise d t o a v oi d t he p ossi bilit y 
of  h y perte nsi ve  crisis.  F o o ds  wit h  t he  hi g hest  a m o u nts  of  t yra mi ne  i ncl u de  b o ursa ult, 
ca me m bert, c he d dar, e m me nt haler, a n d stilt o n c heese; ca viar; pic kle d herri n g; fer me nte d 
sa usa ges ( b ol o g na, pe p per o ni, sala mi, s u m mer sa usa ge); C hia nti wi ne; fa va bea ns (c o ntai n 
d o pa mi ne); yeast e xtract ( ba ke d g o o ds, h o we ver, d o n ot c o ntai n hi g h a m o u nts of t yra mi ne). 
T here  are  n o  re p orts  i n  h u ma ns  of  h y perte nsi ve  crisis  f oll o wi n g  i n gest i o n  of  t yra mi ne-
c o ntai ni n g  f o o ds  i n  w hic h  pr ocar bazi ne  was  t he  M A O  i n hi bit or.  T he  sa me  ca uti o n  is 
a p plie d f or tric yclic a nti de pressa nts a n d s y m pat h o mi metic a ge nts.  
Pr ocar bazi ne is c o m m o nl y sai d t o res ult i n a dis ulfira m reacti o n w he n ta ke n wit h alc o h ol. 
T h e re p orte d reacti o n c o nsiste d of facial fl us hi n g (re d, h ot).  
C N S  de pressi o n:  See  disc ussi o n  of  ner v o us  s yste m  t o xicit y  a b o ve.  Pr ocar bazi ne  is 
s u g geste d t o a d d t o t he effects of ot her C N S de pressa nts. 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
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U p date # 1 3  
1 1. 1 2 P re d nis o ne  
Please refer t o t he F D A -a p pr o ve d pac ka ge i nsert f or pre d nis o ne f or pr o d uct i nf or mati o n, 
e xte nsi ve pre parati o n i nstr ucti o ns, a n d a c o m pre he nsi ve list of a d verse e ve nts.  
A V AI L A BI LI T Y  
Pre d nis o ne is c o m merciall y a vaila ble i n 1, 2. 5, 5, 1 0, 2 0, a n d 5 0 m g ta blets a n d i n a n oral 
s ol uti o n (c o ntai ni n g alc o h ol) i n c o nce ntrati o ns of 1 m g or 5 m g of pre d nis o ne/ m L. 
S T O R A G E &  S T A BI LI T Y  
Pre d nis o ne s h o ul d be st ore d at r o o m te m perat ure. 
A D MI NI S T R A TI O N  
Pre d nis o ne is a d mi nistere d orall y.  
T O XI CI T Y  
S h ort- ter m use of pre d nis o ne (e. g., ≤ 4 wee ks) ma y be ass ociate d wit h gastr oi ntesti nal si de 
effects  ( d ys pe psia,  ulcerati o n); i ns o m nia,  ner v o us ness,  a n d  occasi o nall y,  ps yc h osis;  a n d 
h y per gl yce mia. I m m u n os u p pressi o n wit h a n i ncreasi n g ris k of i nfecti o n is als o see n. 
1 2. 0  A N CI L L A R Y T H E R A P Y  
1 2. 1 
S u p p orti ve C are  
Patie nts  s h o ul d  recei ve  f ull  s u p p orti ve  care,  i ncl u di n g  tra nsf usi o ns  of  bl o o d  a n d  bl o o d 
pr o d ucts,  a nti bi otics,  a ntie metics,  etc.,  w he n  a p pr o priate.  T he  reas o n(s)  f or  treat me nt, 
d osa ge, a n d t he dates of treat me nt s h o ul d be rec or de d o n t he fl o w s heets. HI V p ositi ve 
pati e nt s h o ul d be ma na ge d acc or di n g t o i nstit uti o nal g ui deli nes. Zi d o v u di ne a n d sta v u di ne 
ma y n ot be a d mi nistere d as part of t he a ntiretr o viral t hera p y f or HI V p ositi ve patie nts. See 
S ecti o ns 7. 1. 2 , 7. 1. 3  a n d 9. 1. 1 . 
1 2. 2 
C o n diti o ns f or Ot her T her a p y  
Treat me nt  wit h  h or m o nes  or  ot her  c he m ot hera pe utic  a ge nts  ma y  n ot  be  a d mi nistere d 
e xce pt i n t he f oll o wi n g circ u msta nces: Ster oi ds ma y be a d mi nistere d f or a dre nal fail ure. 
H or m o nes  ma y  be  a d mi nistere d  f or  n o n -disease -relate d  c o n diti o ns  (e. g.,  i ns uli n  f or 
dia betes). De xa met has o ne ma y be a d mi nistere d o n t he da y of c he m ot hera p y f or (ac ute) 
c he m ot hera p y-i n d uce d na usea or v o miti n g. 
1 2. 3 
P r o p h yl a xis f or Pre ve nti o n of He m orr h a gic C ystitis  
Mes n a  ma y  be  a d mi nistere d  f or patie nts  getti n g  c ycl o p h os p ha mi de  t o  pre ve nt/ mi ni mize 
t he  occ urre nce  of  he m orr ha gic  c ystitis.  If  use d,  mes na  s h o ul d  be  gi ve n  acc or di n g  t o 
i nstit uti o nal g ui deli nes. 
1 2. 4 
A ntie metic T her a p y  
A ntie metic  t hera p y  s h o ul d  i ncl u de  5 -H T 3  re ce pt or  a nta g o nists  (e. g.  o n da nsetr o n, 
gra nisetr o n).  
1 2. 5 
Tr a nsf usi o ns  
Er yt hr oc yte a n d platelet tra nsf usi o ns ma y be a d mi nistere d as necessar y at t he discreti o n of 
t he treati n g p h ysicia n. 
 


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U p date # 1 3  
1 3. 0  C RI T E RI A F O R R E S P O N S E , P R O G R E S SI O N , A N D R E L A P S E  
F or t he p ur p oses  of t his st u d y, patie nts will be re -e val uate d after t w o ( 2) c ycles of A B V D t hera p y. 
Patie nts  wit h  a  ne gati ve  P E T  sca n  will  be  re -e val uate d  after  6  c ycles  of  A B V D.  Patie nts  wit h  a 
p ositi ve P E T sca n will be re -e val uate d f oll o wi n g I F R T. Res p o nse assess me nts must be perf or me d 
usi n g t he sa me i ma gi n g m o dalit y ( P E T) as use d at t he ti me of pre -st u d y e val uati o n. 
1 3. 1 
Defi niti o ns of Res p o nse [ 6 0] 
1 3. 1. 1 C o m plete Res p o nse ( C R)  
C o m plete disa p peara nce of all detecta ble cli nical e vi de nce of disease a n d disease -
relate d s y m pt o ms if prese nt bef ore t hera p y. 
T he s plee n a n d/ or li ver, if c o nsi dere d e nlar ge d pri or t o t hera p y o n t he basis of a 
p h ysical e xa mi nati o n or C T sca n, s h o ul d n ot be pal pa ble o n p h ysical e xa mi nati o n 
a n d s h o ul d be c o nsi dere d n or mal size b y i ma gi n g st u dies, a n d n o d ules relate d t o 
l y m p h oma  s h o ul d  disa p pear.  H o we ver,  deter mi nati o n  of  s ple nic  i n v ol ve me nt  is 
n ot al wa ys relia ble beca use a s plee n c o nsi dere d n or mal i n size ma y still c o ntai n 
l y m p h o ma, w hereas a n e nlar ge d s plee n ma y reflect variati o ns i n a nat o m y, bl o o d 
v ol u me, t he use of he mat o p oietic gr o wt h fact ors, or ca uses ot her t ha n l y m p h o ma. 
1 3. 1. 2 P arti al Res p o nse ( P R)  
At least a 5 0 % decrease i n t he s u m of t he pr o d uct of t he dia meters ( S P D) of u p t o 
si x of t he lar gest d o mi na nt n o des or n o dal masses. T hese n o des or masses s h o ul d 
be selecte d  acc or di n g t o all of t he f oll o wi n g: a) t he y s h o ul d be clearl y meas ura ble 
i n  at  least  t w o  per pe n dic ular  di me nsi o ns;  b)  if  p ossi ble,  t he y  s h o ul d  be  fr o m 
dis parate  re gi o ns  of  t he  b o d y;  a n d  c)  t he y  s h o ul d  i ncl u de  me diasti nal  a n d 
retr o perit o neal areas of disease w he ne ver t hese sites are i n v ol ve d. 
N o i ncrease s h o ul d be o bser ve d i n t he size of ot her n o des, li ver, or s plee n. 
S ple nic n o d ules m ust re gress b y ≥ 5 0 % i n t heir S P D, or, f or si n gle n o d ules, i n t he 
greatest tra ns verse dia meter.  
Wit h  t he  e xce pti o n  of  s ple nic  n o d ules,  i n v ol ve me nt  of  ot her  or ga ns  is  us uall y 
assessa ble a n d n o meas ura ble disease s h o ul d be prese nt.  
N o ne w sites of disease s h o ul d be o bser ve d.  
If  t he  P E T  sca n  was  p ositi ve  bef ore  t hera p y,  t he  p ost-treat me nt  P E T  s h o ul d  be 
p ositi ve i n at least o ne pre vi o usl y i n v ol ve d site.  
1 3. 1. 3 St a ble Dise ase ( S D): P atie nt f ails t o att ai n t he criteri a nee de d f or a C R or P R, 
b ut d oes n ot f ulfill t h ose f or pr o gressi ve dise ase (see bel o w). T he P E T s h o ul d 
be p ositi ve at pri or sites of dise ase, wit h n o ne w are as of i n v ol ve me nt o n t he 
p ost -tre at me nt C T or P E T. 
1 3. 1. 4 P r o gressi o n ( P D) or Rel a pse  
L y m p h  n o des  s h o ul d  be  c o nsi dere d  a b n or mal  if  t he  l o n g  a xis  is  >  1. 5  c m, 
re gar dless of t he s h ort a xis. If a l y m p h n o de has a l o n g a xis of 1. 1 t o 1. 5 c m, it 
s h o ul d o nl y be c o nsi dere d a b n or mal if its s h ort a xis is > 1. 0. L y m p h n o des ≤ 1. 0 
c m  b y  ≤  1. 0  c m  will  n ot  be  c o nsi dere d  as  a b n or mal  f or  rela pse  or  pr o gressi ve 
disease.  
A p peara nce of a n y ne w lesi o n > 1. 5 c m i n a n y a xis d uri n g or at t he e n d of t hera p y, 
e ve n if ot her lesi o ns are decreasi n g i n size. I ncrease d F D G u pta ke i n a pre vi o usl y 


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u naffecte d  site  s h o ul d  o nl y  be  c o nsi dere d  rela pse d  or  pr o gressi ve  disease  after 
c o nfir mati o n wit h ot her m o dalities. I n patie nts wit h n o pri or hist or y of p ul m o nar y 
l y m p h o ma,  ne w  l u n g  n o d ules  i de ntifie d b y  C T  are  m ostl y  be ni g n.  T h us,  a 
t hera pe utic decisi o n s h o ul d n ot be ma de s olel y o n t he basis of t he P E T wit h o ut 
hist ol o gic c o nfir mati o n.  
At least a 5 0 % i ncrease fr o m na dir i n t he S P D of a n y pre vi o usl y i n v ol ve d n o des, 
or i n a si n gle i n v ol ve d n o de, or t he size of ot her lesi o ns (e. g., s ple nic or he patic 
n o d ules). T o be c o nsi dere d pr o gressi ve disease, a l y m p h n o de wit h a dia meter of 
t he s h ort a xis of < 1. 0 c m m ust i ncrease b y ≥ 5 0 % a n d t o a size of 1. 5 x 1. 5 c m, or 
> 1. 5 c m i n t he l o n g a xis. 
At least a 5 0 % i nc rease i n t he l o n gest dia meter of a n y si n gle pre vi o usl y i de ntifie d 
n o de > 1. 0 c m i n its s h ort a xis. 
Lesi o ns s h o ul d be P E T -p ositi ve if a t y pical F D G -a vi d l y m p h o ma or t he lesi o n was 
P E T -p ositi ve  pri or  t o  t hera p y  u nless  t he  lesi o n  is  t o o  s mall  t o  be  detecte d  w it h 
c urre nt P E T s yste ms ( < 1. 5 c m i n its l o n g a xis b y C T).  
1 3. 2 
G ui deli nes f or E v al u ati o n of Me as ur a ble Dise ase  
Meas ura ble  e xtra n o dal  disease  s h o ul d be assesse d i n  a  ma n ner si milar t o t hat f or  n o dal 
disease. F or t hese rec o m me n dati o ns, t he s plee n is c o nsi dere d n o dal disease. Disease t hat is 
o nl y assessa ble (e. g., ple ural eff usi o ns, b o ne lesi o ns) will be rec or de d as prese nt or a bse nt 
o nl y, u nless, w hile a n a b n or malit y is still n ote d b y i ma gi n g st u dies or p h ysical e xa mi nati o n, 
it is f o u n d t o be hist ol o gicall y ne gati ve.  
1 3. 2. 1 Cli nical  Lesi o ns  will  o nl y  be  c o nsi dere d  meas ura ble  w he n  t he y  are  s u perficial 
(e. g., s ki n n o d ules, pal pa ble l y m p h n o des). 
1 3. 2. 2 C hest X -ra y: Lesi o ns o n c hest X-ra y are acce pta ble as meas ura ble lesi o ns w he n 
t he y  are  clearl y  defi ne d  a n d  s urr o u n de d  b y  aerate d  l u n g.  H o we ver,  C T  is 
prefera ble.  
1 3. 2. 3 C o n ve nti o nal C T a n d M RI s h o ul d be perf or me d wit h c uts of 1 0 m m or less i n slice 
t hic k ness c o nti g u o usl y. S piral C T s h o ul d be perf or me d usi n g a 5 m m c o nti g u o us 
rec o nstr ucti o n al g orit h m. T his a p plies t o t he c hest, a b d o me n, a n d pel vis. Hea d & 
nec k a n d e xtre mities us uall y re q uire s pecific pr ot oc ols.  
1 3. 2. 4 Ultras o u n d ( U S) s h o ul d n ot be use d t o meas ure t u m or lesi o ns t hat are cli nicall y 
n ot easil y accessi ble w he n t he pri mar y e n d p oi nt of t he st u d y is o bject i ve res p o nse 
e val uati o n.  It  is  a  p ossi ble  alter nati ve  t o  cli nical  meas ure me nts  of  s u perficial 
pal pa ble  n o des,  s u bc uta ne o us  lesi o ns,  a n d  t h yr oi d  n o d ules.  U S  mi g ht  als o  be 
usef ul  t o  c o nfir m  t he  c o m plete  disa p peara nce  of  s u perficial  lesi o ns  us uall y 
assesse d b y cli nical e xa mi nati o n.  


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1 3. 3 
Res p o nse Assess me nt T a ble  
Res p o nse Cate g or y  
Defi niti o n  
N o dal Masses  
S plee n  
C R  
Disa p peara nce of 
all e vi de nce of 
disease  
a) P E T p ositi ve at baseli ne; mass of a n y size 
per mitte d if P E T ne gati ve  
b) Varia bl y P E T ne gati ve at baseli ne; 
re gressi o n t o n or mal size C T 
N ot pal pa ble, 
n o d ules disa p peare d  
P R  
Re gressi o n of 
meas ura ble 
disease, n o ne w 
sites 
≥ 5 0 % decrease i n S P D of u p t o 6 lar gest 
d o mi na nt masses; n o i ncrease i n size of ot her 
n o des  
a) P E T p ositi ve at baseli ne; o ne or m or e P E T 
p ositi ve at pre vi o usl y i n v ol ve d site  
b) Varia bl y P E T ne gati ve at baseli ne; 
re gressi o n o n C T 
≥ 5 0 % decrease i n 
S P D of n o d ules (f or 
si n gle n o d ule i n 
greatest tra ns verse 
dia meter); n o 
i ncrease i n size of 
s plee n 
S D  
Fail ure t o attai n 
C R, P R, or P D  
a) P E T  p ositi ve at baseli ne; P E T p ositi ve at 
pri or sites of disease a n d n o ne w sites o n  C T 
or P E T  
b) Varia bl y P E T ne gati ve at baseli ne; n o 
c ha n ge i n size of pre vi o us lesi o ns o n C T  
 
P D  
A n y ne w lesi o n 
i ncrease b y ≥ 5 0 % 
of pre vi o usl y 
i n v ol ve d disease 
sites 
A p peara nce of a ne w lesi o n(s) > 1. 5 c m i n 
a n y a xis, ≥5 0 % i ncrease i n S P D of m ore t ha n 
o ne n o de, or ≥5 0 % i ncrease i n l o n gest 
dia meter of a pre vi o usl y i de ntifie d n o de > 1 
c m i n s h ort a xis. Lesi o ns P E T p ositi ve if 
F D G -a vi d l y m p h o ma or P E T p ositi ve pri or 
t hera p y. 
≥ 5 0 % i ncrease 
fr o m na dir i n t he 
S P D of a n y pre vi o us 
lesi o ns 
1 3. 4 
Defi niti o n of P r o gressi o n -F ree S ur vi v al  
Pr o gressi o n- free  s ur vi val  ( P F S)  is  meas ure d  as  t he  ti me  fr o m  st u d y  e ntr y  t o  disease 
pr o gressi o n or deat h. 
1 4. 0  R E M O V A L O F P A TI E N T S F R O M P R O T O C O L T H E R A P Y  
1 4. 1  D ur ati o n of Tre at me nt 
1 4. 1. 1 C o nti n ue treat me nt at t he hi g hest t olera ble d ose f or a t otal of 6 c ycles +/ - I F R T or 
u ntil t he a p peara nce of disease pr o gressi o n or u nacce pta ble t o xicit y. Re m o ve fr o m 
pr ot oc ol t hera p y a n y patie nt wit h ra pi d or d oc u me nte d disease pr o gressi o n.  
1 4. 1. 2 P ost -Tre at me nt P atie nt F oll o w -U p: After c ycle 6 wit h or wit h o ut I F R T, patie nts 
will be m o nit ore d de pe n di n g o n res p o nse ac hie ve d, P E T sca ns, a n d, if perf or me d, 
bi o ps y res ults as f oll o ws:  
C R,  P R  a n d  P E T  ne g ati ve:  Patie nts  wil l  be  f oll o we d  acc or di n g  t o  t he  p ost-
treat me nt f oll o w- u p sc he d ule i n Secti o n 6. 0 . 
C R,  P R,  P E T  p ositi ve,  a n d  bi o ps y  p ositi ve:  Patie nts  ma y  be  treate d  at 
i n vesti gat or  discreti o n  a n d  will  be  f oll o we d  f or  s ur vi val  a n d  sec o n dar y 
mali g na ncies or ne w pri maries.  
C R,  P R,  or  S D, P E T  p ositi ve,  a n d  bi o ps y  n ot  perf or me d:  Patie nts  will  ha ve 
re peat P E T/ C T a n d C T sca ns perf or me d t hree m o nt hs later. If P E T sca n bec o mes 
ne gati ve,  patie nts  will  be  f oll o we d  acc or di n g  t o  t he  p ost -treat me nt  f oll o w- u p 
sc he d ule i n Secti o n 6. 0 . If P E T re mai ns p ositi ve, t he n a bi o ps y ma y be perf or me d 
if  me dicall y  a p pr o priate  or  cli nicall y  feasi ble  at  t he  discreti o n  of  t he  treati n g 
p h ysicia n.  If  bi o ps y  is  p ositi ve,  patie nts  will  be  f oll o we d  f or  s ur vi v al  a n d 


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sec o n dar y mali g na ncies or ne w pri maries. If bi o ps y is ne gati ve, patie nts will be 
f oll o we d acc or di n g t o t he p ost-treat me nt f oll o w- u p sc he d ule i n Secti o n 6. 0 . 
1 4. 2 
E xtr a or di n ar y Me dic al Circ u mst a nces :  
If, at a n y ti me t he c o nstrai nts of t his pr ot oc ol are detri me ntal t o t he patie nt’s healt h a n d/ or 
t he  patie nt  n o  l o n ger  wis hes  t o  c o nti n ue  pr ot oc ol  t hera p y,  pr ot oc ol  t hera p y  s hall  be 
disc o nti n ue d. I n t his e ve nt: 
•  
N otif y t he St u d y C hair. 
•  
D oc u me nt t he reas o n(s) f or disc o nti n uati o n  of t hera p y o n fl o w s heets. 
•  
F oll o w  t he  patie nt  f or  rela pse,  pr o gressi o n,  a n d  sec o n dar y  mali g na nc y  or  ne w 
pri maries.  
1 5. 0  S T A TI S TI C A L C O N SI D E R A TI O N S  
1 5. 1 
St u d y Desi g n  
T his  is  si n gle -ar m  p hase  II  cli nical  trial  of  res p o nse -a da pte d  t hera p y  base d  o n  P E T  f or 
b ul k y sta ge I a n d sta ge II H o d g ki n l y m p h o ma. A ma xi m u m of 1 2 3 patie nts will be e ntere d 
t o t he st u d y. 
1 5. 2 
P ri m ar y E n d p oi nt  
T he pri mar y o utc o me of t his st u d y is pr o gressi o n -free s ur vi val ( P F S), defi ne d as t he ti me 
fr o m st u d y e ntr y t o disease pr o gressi o n or deat h.  
1 5. 2. 1 A n al ysis Pl a n  
T he p atie nts w h o ha ve C R, P R or S D after 2 c ycles of A B V D  will u n der g o t he first 
P E T/ C T sca n . We wa nt t o s h o w t hat  b y recei vi n g 4 c ycles of escalate d B E A C O P P 
a n d I F R T, t he P F S of P E T + patie nts will ha ve a P F S t hat is  cl ose t o t hat of P E T - 
patie nts recei vi n g 4 a d diti o nal A B V D. Let λ +  a n d λ - de n ote t he a n n ual hazar d rates 
of P F S f or P E T + a n d P E T - patie nt gr o u ps, res pecti vel y, a n d ∆= λ + / λ- t heir hazar d 
rati o. Base d o n t he pr ojecte d hazar d rates f or P E T + a n d P E T - patie nt gr o u ps as 
di sc usse d  i n Secti o n  1 5. 2. 2 ,  we  wa nt  t o  test H 0:  ∆= 4. 1  vs.  H1:  ∆< 4. 1  usi n g 
u ni variate C o x re gressi o n met h o d wit h o ne -si de d α = 0. 1 5 [ 6 1]. T he fi nal a nal ysis 
will be c o n d ucte d w he n 4 4 e ve nts ( pr o gressi o ns or deat hs) are o bser ve d, w hic h is 
e x pecte d t o occ ur a b o ut 3 years after t he c o m pleti o n of patie nt accr ual.  Ka pla n -
Meier c ur ves of P F S will be esti mate d f or t he t w o patie nt gr o u ps.   
T he u ni variate C o x re gressi o n tests o n t he hazar d rati o bet wee n t w o patie nt gr o u ps, 
s o t hat it d oes n ot re q uire s pecificati o n of t he P F S f or eac h gr o u p. Let S + ( 3) a n d S- 
( 3) de n ote t he 3 year P F S f or P E T + a n d P E T- patie nt gr o u ps, res pecti vel y. F or 
vari o us P F S le vels a n d b y ass u mi n g e x p o ne ntial P F S m o dels, t he 3 year P F S f or 
t w o patie nt gr o u ps u n der H0: ∆= 4. 1 a n d H1: ∆= 2. 2 9 are re prese nte d as f oll o ws:  
S -( 3) 
7 5 %  
8 0 %  
8 5 %  
9 0 %  
S + ( 3) u n der H 0 
3 1 %  
4 0 %  
5 1 %  
6 5 %  
S + ( 3) u n der  H 1 
5 2 %  
6 0 %  
6 9 %  
7 9 %  
As a sec o n dar y a nal ysis, we will test H 0: S+ ( 3)= 4 0 % vs. H 1: S+ ( 3) > 4 0 % usi n g t he 
as y m pt otic res ult of t he Ka pla n -Meier esti mat or of S + ( 3) wit h o ne-si de d α = 0. 1 5  


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1 5. 2. 2 S a m ple Size C alc ul ati o n  
Picar di  et  al. [ 1 0],  usi n g  a  s maller  size  li mit  t o  defi ne  b ul k y  disease  ( >  5  c m 
c o m pare d t o > 1 0 c m i n t his st u d y), o bser ve d a 3 year P F S of a b o ut 8 6 % i n patie nts 
recei vi n g c he m ot hera p y o nl y. Base d o n literat ure i ncl u di n g t his data, we e x pect 
t hat, f oll o wi n g 6 c ycles of A B V D wit h o ut ra di ot hera p y, t he 3-year P F S f or P E T - 
a n d  P E T+ patie nts  (after  2  c ycles  of  A B V D)  will  be  a b o ut  8 0 %  a n d  4 0 %, 
res pecti vel y. We  e x pect 
t hat f or  P E T +  patie nts,  t he  a g gressi ve  treat me nt  b y 4 
c ycles of escalate d B E A C O P P f oll o we d b y ra di ot hera p y f or P E T + patie nts  will 
i ncrease t he 3- year P F S pr o ba bilit y fr o m 4 0 % t o 6 0 %. 
Ass u mi n g e x p o ne ntial distri b uti o ns f or P F S, t hese h y p ot heses i m pl y H 0: ∆= 4. 1 a n d 
H 1: ∆< 4. 1. Ass u mi n g a n a n n ual accr ual of 2 5 patie nts, 3 years of a d diti o nal f oll o w -
u p a n d 3 0 % of P E T p ositi vit y after t w o c ycles of A B V D, a sa m ple size of N = 1 1 0 
eli gi ble patie nts (a b o ut 3 4 P E T + a n d 7 6 P E T - patie nts) g uara ntees 8 0 % of p o wer 
b y t he l o g -ra n k test statistic f or n o n -u nit y hazar d rati o u n der H 0 [ 6 1] wit h o ne -si de d 
α = 0. 1 5 a n d H 0: ∆= 4. 1 ( base d o n S-( 3) = 0. 8, S+ ( 3) = 0. 4) a gai nst H1: ∆= 2. 2 9 ( base d 
o n S -( 3) = 0. 8, S+ ( 3) = 0. 6). 
U n der  t hese  ass u m pti o ns,  wit h  t he  e x pecte d  3 4  P E T +  patie nts,  t he  sec o n dar y 
a nal ysis  f or  testi n g H 0:  S+ ( 3)= 4 0 %  vs. H 1:  S+ ( 3) > 4 0 % usi n g  t he  Ka pla n -Meier 
esti mat or of S + ( 3) wit h o ne -si de d α = 0. 1 5  will ha ve a b o ut 9 0 % p o wer  t o detect H 1: 
S + ( 3) = 6 0 %. 
1 5. 3 
Accr u al a n d F oll o w -U p  
Ass u mi n g  u p  t o  1 0 % of dr o p o ut,  i neli gi b ilit y, or  pr o gressi ve  disease  after  2  c ycles  of 
A B V D (t he latter e x pecte d t o be less t ha n 5 %), we will accr ue  a ma xi m u m of  1 2 3 patie nts.  
T he e x pecte d accr ual is a p pr o xi matel y 2 5 patie nts per year, s o t hat  it will ta ke a b o ut 6 0 
m o nt hs f or patie nt accr ual .  Patie nts will be f oll o we d f or u p t o 1 0 years f or s ur vi val data . 
1 5. 4 
S a m ple Size M o dific ati o n  
D ue t o t he l o wer accr ual rate t ha n e x pecte d, t he accr ual g oal is l o were d fr o m 1 2 3 t o 1 0 0 i n 
A pril  2 0 1 7, w he n a b o ut 9 5 patie nts ha ve re gistere d a n d t he real accr ual rate has bee n o nl y 
a b o ut 1 4 patie nts per year, c o m pare d t o 2 5 patie nts per year e x pecte d at t he de vel o p me nt 
of t his st u d y. I n t his sa m ple size recalc ulati o n, w e ass u me (i) a n a n n ual accr ual rate of 1 4 
patie nts a n d (ii) 7 % of attriti o n d ue t o dr o p o ut, i neli gi bilit y, or pr o gressi ve disease after 2 
c ycles of A B V D, w hile ass u mi n g ot her desi g n para meters t he sa me as bef ore (as i n  secti o n 
1 5. 2. 2 ). Wit h n = 9 3 ( = 1 0 0 x 0. 9 3) eli gi ble a n d e val ua ble patie nts, (a b o ut 2 8 P E T + a n d 6 5 
P E T - patie nts), we ha ve 8 0 % of p o wer b y t he l o g -ra n k test statistic f or n o n-u nit y hazar d 
rati o u n der H0 [ 6 1] wit h o ne-si de d α = 0. 1 5 a n d H0: ∆= 4. 1 ( base d o n S-( 3) = 0. 8, S+ ( 3) = 0. 4) 
a gai nst H 1: ∆= 2. 2 9 ( base d o n S-( 3) = 0. 8, S+ ( 3) = 0. 6). 
U n der t hese ass u m pti o ns, wit h t he e x pecte d 2 8 P E T + patie nts, t he sec o n dar y a nal ysis f or 
testi n g H0: S+ ( 3) = 4 0 % vs. H1: S+ ( 3) > 4 0 % usi n g t he Ka pla n-Meier esti mat or of S
+ ( 3) wit h 
o ne- si de d α = 0. 1 5 will ha ve a b o ut 9 0 % p o wer t o detect H 1: S+ ( 3) = 6 0 %. 
T he  fi nal  a nal ysis  will  be  c o n d ucte d  w he n  D = 4 2  e ve nts  ( pr o gressi o ns  or  deat hs)  are 
o bser ve d, w hic h is e x pecte d t o occ ur after a p pr o xi matel y 3 years of a d diti o nal f oll o w - u p.  
T he st u d y will ta ke a b o ut 1 2 2 m o nt hs  ( 8 6 m o nt hs f or patie nt accr ual a n d 3 6 m o nt hs f or 
a d diti o nal f oll o w- u p). 
T he p o wer a nal ysis f or t he sec o n dar y o bjecti ves a n d c orrelati ve e n d p oi nts is u nc ha n ge d 
(i.e. base d o n n = 1 1 0 eli gi ble a n d e val ua ble patie nts).  


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
6 4  
U p date # 1 3  
As of pr ot oc ol U p d ate # 1 3, t he f oll o wi n g  c h a n ge h as bee n m a de:  
Re vise d fi n al a n al ysis ti mi n g d ue t o l o w e ve nt r ate:  
T his st u d y cl ose d t o accr ual i n Se pte m ber 2 0 1 7, ha vi n g re gistere d 1 0 1 patie nts. A t otal of 
9 4 patie nts were eli gi ble, ha d a P E T/ C T sca n after c ycle 2, a n d will be i ncl u de d i n t he 
p ri mar y e n d p oi nt a nal ysis ( 2 5 P E T + a n d 6 9 P E T-). As of Se pte m ber 2 0 1 9, t he p o ole d e ve nt 
rate was m uc h l o wer t ha n t hat s pecifie d b y t he st u d y desi g n. Wit h a me dia n f oll o w-u p of 
3. 6 years (I Q R 2. 5 t o 5. 5), t he o bser ve d n u m ber of e ve nts at t his ti me was 9 ( bas e d  o n 
pr ot oc ol  ass u m pti o ns,  we  w o ul d  ha ve  e x pecte d  a p pr o xi matel y  3 3  e ve nts).  I n  or der  t o 
pr o vi de a ti mel y fi nal a nal ysis, t he fi nal a nal ysis will be perf or me d w he n all patie nts ha ve 
bee n f oll o we d f or at least 3 years, w hic h is e x pecte d i n Se pte m ber 2 0 2 0.  
1 5. 5 
I ncl usi o n of W o me n & Mi n orities 
Alt h o u g h t here is n o e vi de nce t o s u g gest t hat t he o utc o me will differ b y ge n der or et h nicit y 
a n d t here is i ns ufficie nt p o wer t o detect s mall or m o derate effects, we will, i n a sec o n dar y 
a nal ysis, re p ort t he res ults b y g e n der a n d et h nicit y. 
1 5. 6 
P re dicti ve V al ue of F D G -P E T  
I n a nal ysis, t he rati o bet wee n t he S U V ma x after t w o c ycles a n d t he S U V ma x at baseli ne 
will be use d as t he o bser vati o n f or eac h patie nt. ( A rati o s maller t ha n 1 mea ns decrease i n 
p ost- t hera p y S U V ma x fr o m t he baseli ne.) We e x pect t hat a b o ut 3 0 % of patie nts will be 
P E T p ositi ve after c ycle 2 . 
1 5. 7 
Sec o n d ar y O bjecti ves  
P F S a n d C R rate will be esti mate d f or P E T p ositi ve a n d ne gati ve patie nt  gr o u ps after 2 
c ycles  of  A B V D.  P F S f or  eac h  gr o u p will be esti mated b y  Ka pla n -Meier  met h o d.  T he 
c o nfi de nce i nter val ( CI) f or C R rate will be base d o n e xact bi n o mial distri b uti o n. T he p oi nt -
wise CI’s f or P F S will be esti mate d base d o n t he n or mal distri b uti o n a p pr o xi mati o ns. 
Pre dicti ve val ues, se nsiti vit y a n d s pecificit y of  se mi q ua ntitati ve e val uati o n of F D G u pta ke 
will be esti mate d wit h res pect t o P F S a n d C R usi n g vari o us a p pr oac hes, i ncl u di n g recei ver 
o perati n g c haracteristic ( R O C) c ur ves f or differe nt c ut off val ues, perce nt decrease i n S U V, 
a n d  a bs ol ute  S U Vs  after  2  a n d  6  c ycles  i n P E T - patie nt  gr o u p  a n d after  2 c ycles  of 
c he m ot hera p y a n d I F R T i n P E T +  patie nt  gr o u p.  F or P F S,  ti me -de pe n de nt R O C met h o d 
(Hea gert y  et  al.  2 0 0 4)  will  be  use d  i n  t he  prese nce  of  ce ns ori n g  wit hi n  3  years.  T he 
e x pecte d sa m ple size is 1 1 0 f or b ot h c ycle 2 data a nal ysis a n d c ycle 6  (f or P E T- gr o u p) or 
p ost I F R T (f or P E T + gr o u p)  data a nal ysis. Ass u mi n g 8 0 % O R rate ( or 8 0 % e ve nt free at 
year  3),  t he  esti mate d  se nsiti vit y  ( N = 1 1 0 x 0. 2 = 2 2)  will  ha ve  a  sta n dar d  err or  ( S E)  of 
ma xi m u m  0. 1 0 7  a n d  t he  esti mate d  s pecificit y  ( N = 1 1 0 x 0. 8 = 8 8)  will  ha ve  a  varia nce  of 
ma xi m u m  0. 0 5 3.  F urt her,  ass u mi n g  3 0 %  of  P E T  p ositi vit y  after  c ycle  2,  t he  esti mate d 
p ositi ve  pre dicti ve  val ue  ( N = 1 1 0 x 0. 3 = 3 3)  will  ha ve  a  sta n dar d  err or  ( S E)  of  ma xi m u m 
0. 0 8 7 a n d t he esti mate d ne gati ve pre dic ti ve val ue ( N = 1 1 0 x 0. 7 = 7 7) will ha ve a varia nce of 
ma xi m u m a b o ut 0. 0 5 7. Si milar a nal ysis will be c o n d ucte d f or P E T data after R T fr o m t he 
patie nts wit h p ositi ve P E T o utc o me after 2 c ycles of c he m ot hera p y.  
Pre dicti ve val ues, se nsiti vit y a n d s pecificit y of v ol u metric c ha n ges o n C T will be esti mate d 
wit h res pect t o P F S a n d C R after 2 a n d 6 c ycles (f or P E T- gr o u p) or p ost I F R T (f or P E T + 
gr o u p) i n res pecti ve patie nt gr o u ps. F or P F S, ti me- de pe n de nt R O C met h o d will be use d i n 
t he prese nce of ce ns ori n g wit hi n 3 year s [ 6 2]. Si milar a nal ysis will be c o n d ucte d f or P E T 
data after R T fr o m t he patie nts wit h p ositi ve P E T o utc o me after 2 c ycles of c h e m ot hera p y. 
Pre dicti ve val ues, se nsiti vit y a n d s pecificit y of F D G -P E T i ma gi n g will be esti mate d usi n g 
a m ore li beral q ualitati ve rea di n g scale b y usi n g t he li ver as a refere nce bac k gr o u n d. T he 


C A L G B 5 0 8 0 1  
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U p date # 1 3  
sa me  a nal yses  as  i n Secti o n  1 5. 6  wil l  be  c o n d ucte d  usi n g  li ver-base d  P E T  data. F or 
se mi q ua ntitati ve  P E T  data,  t he  c ha n ge  bet wee n  baseli ne  a n d  after  c ycle  2,  a n d  after 
c he m ot hera p y (f or P E T - gr o u p) or after I F R T (f or P E T + gr o u p) will be c orrelate d wit h O R 
a n d P F S. Si milar a nal ysis will be c o n d ucte d f or t he c ha n ge bet wee n baseli ne a n d after R T 
f or t he patie nts wit h p ositi ve P E T o utc o me after 2 c ycles of c he m ot hera p y. 
Pre dicti ve  val ue  will  be  c o m pare d  a m o n g  meta b olic  para meters  ( b ot h  vis ual  a n d 
q ua ntitati ve  c ha n ges),  v ol u metric  C T  c ha n ges,  a n d  m olec ular  para meters.  R O C  c ur ves 
fr o m c orrelate d mar kers will be c o m pare d usi n g t he met h o d b y Del o n g et al [ 6 3]. 
1 5. 8 
C orrel ati v e E n d p oi nts 
All  eli gi ble  patie nts  w h o  c o nse nt  t o  t he  c orrelati ve  scie nce  sa m ple  c ollecti o n  will  be 
i ncl u de d  i n  t he  c orrelati ve  st u dies.  Base d  o n  o ur  e x perie nce  fr o m  pre vi o us  st u dies,  we 
ass u me 7 0 % of patie nts will c o nse nt ( 7 0 % of 1 1 0 eli gi ble patie nts, n = 7 7 ) t o t he c orrelati ve 
scie nce sa m ple c ollecti o n. 
1 5. 8. 1 Ser u m a n d Pl as m a M ar kers  
Ser u m  mar kers  will  be  a nal yze d  as  a  c o nti n u o us  varia ble  as  well  as  a  bi nar y 
(ele vate d vers us n ot ele vate d) varia ble. 
Baseli ne ser u m mar ker val ues will be c orrelate d wit h res p o nse ( o verall res p o nse 
vs.  n o  res p o nse)  at  t he  e n d  of  treat me nt.  Ass u mi n g  8 0 %  of  o verall  res p o nse 
( O R = C R + P R), a t w o-sa m ple t-test wit h t w o-si de d α= 0. 0 5 has 8 0 % p o wer t o detect 
a  sta n dar dize d  effect  size  of  0. 8 usi n g  c o nti n u o us  ser u m  mar ker  val ues.  F or  a 
dic h ot o m o us ser u m mar ker, we ass u me t hat t he baseli ne ser u m mar ker val ue will 
be  ele vate d  f or  a b o ut  6 0 %  of  patie nts.  T he n,  a  c hi -s q uare d  test  wit h  t w o-si de d 
α = 0. 0 5 has 8 9 % p o wer w he n t he pr o ba bilities of ele vati o n i n ser u m mar ker are 
5 0 % f or O R a n d 9 0 % f or n o n- O R.  
Baseli ne ser u m mar ker val ues will be c orrelate d wit h P F S usi n g C o x re gressi o n 
met h o d.  S u p p ose t hat t he 3 -year  P F S  is  8 5 %  f or t he  w h ole  p o p ulati o n,  a n d  we 
ass u me 4 years of accr ual a n d 3 years of a d diti o nal f oll o w- u p after c o m pleti o n of 
accr ual. Usi n g a c o nti n u o us ser u m mar ker, a C o x re gressi o n wit h t w o -si de d α= 0. 0 5 
has 8 4 % p o wer t o detect a l o g hazar d rati o (l o g -H R) of 0. 7 bet wee n t w o patie nt 
gr o u ps  wit h  mar ker  val ues  o ne  sta n dar d  de viati o n  a wa y.  We  ass u me  t hat  t he 
mar ker  val ue  ( or  its  tra nsf or mati o n)  f oll o ws  a  n or mal  distri b uti o n.  F or  a 
dic h ot o m o us  ser u m  mar ker,  t he  l o g -ra n k  test  wit h  t w o-si de d  α= 0. 0 5  has  8 7 % 
p o wer w he n t he pr o ba bilit y of ele vate d ser u m mar ker is a b o ut 6 0 % a n d t he 3 -year 
P F S is 7 5 % f or t he patie nt gr o u p wit h a n ele vate d ser u m mar ker a n d 9 3 % f or t he 
ot her gr o u p. 
We will c o n d uct m ulti variate re gressi o n a nal yses (l o gistic re gressi o n f or res p o nse 
a n d C o x re gressi o n f or P F S), i ncl u di n g treat me nt i n dicat or, differe nt mar kers, a n d 
k n o w n  pre dict o rs.  T hese  m ulti variate  a nal yses  are  t o  test  if  a  baseli ne  ser u m 
mar ker  is  a n  i n de pe n de nt  pre dict or  after  a dj usti n g  f or  ot her  pre dict ors,  or  a 
s urr o gate mar ker wit h res pect t o res p o nse or P F S. 
T he  ser u m  mar ker  val ues  at  eac h  P E T  sca n  will  be  c orrelate d  wit h  t he  P E T 
o utc o me usi n g a n R O C met h o d. We will c o m pare t he areas u n der t he R O C c ur ves 
a m o n g differe nt ser u m mar kers b y c o m bi ni n g t he data fr o m t w o P E T sca ns usi n g 
E mir et al. [ 6 4]. Pr o ba bilit y of p ositi ve P E T o utc o me will be c o m pare d a m o n g t he 
gr o u ps defi ne d b y t he tre n d of mar ker val ues ar o u n d eac h P E T sca n.  
Si milar a nal yses will be c o n d ucte d f or plas ma mar ker data.  






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6 8  
U p date # 1 3  
•  
T he re p orti n g of a d verse e ve nts descri be d i n t he ta ble a b o ve is i n a d diti o n t o a n d 
d oes n ot s u p pla nt t he re p orti n g of a d verse e ve nts as part of t he re p ort of t he res ults 
of t he cli nical trial, e. g., st u d y s u m mar y f or ms or c o o perati ve gr o u p data re p orti n g 
f or ms (see Secti o n 5. 2  f or re q uire d C A L G B f or ms). 
•  
Sec o n d ar y m ali g n a nc y:  A sec o n dar y mali g na nc y is a ca ncer ca use d b y treat me nt 
f or  a  pre vi o us  mali g na nc y  (e. g.,  treat me nt  wit h i n vesti gati o nal  a ge nt/i nter ve nti o n, 
ra diati o n or c he m ot hera p y). A sec o n dar y mali g na nc y is n ot c o nsi dere d a metastasis 
of t he i nitial ne o plas m.  
C T E P re q uires all sec o n dar y mali g na ncies t hat occ ur f oll o wi n g treat me nt wit h a n 
a ge nt u n der a n N CI I N D/I D E be re p orte d via C T E P -A E R S. I n C T C A E versi o n 5. 0, 
t hree o pti o ns are a vaila ble t o descri be t he e ve nt:  
-Le u ke mia sec o n dar y t o o nc ol o g y c he m ot hera p y (e. g., ac ute m yel oc ytic le u ke mia 
[ A M L])  
- M yel o d ys plastic s y n dr o me ( M D S)  
-Treat me nt -relate d sec o n dar y mali g na nc y  
A n y mali g na nc y p ossi bl y relate d t o ca ncer treat me nt (i ncl u di n g A M L/ M D S) s h o ul d 
als o be re p orte d via t he r o uti ne re p orti n g mec ha nis ms o utli ne d i n eac h pr ot oc ol. 
Sec o n d m ali g n a nc y:  A sec o n d mali g na nc y is o ne u nrelate d t o t he treat me nt of a 
pri or  mali g na nc y  (a n d  is  N O T  a metastasis  fr o m  t he  i nitial  mali g na nc y).  Sec o n d 
mali g na ncies re q uire O N L Y r o uti ne re p orti n g u nless ot her wise s pecifie d.  
•  
P re g na nc y  l oss is  defi ne d as  “ Deat h  i n  uter o,” a n d  a n y  pre g na nc y  l oss  s h o ul d be 
re p orte d  e x pe diti o usl y  as  Gra de  4  “ Pre g na nc y  l oss”  u n der  t he  Pre g na nc y, 
p uer peri u m a n d peri natal c o n diti o ns S O C. A pre g na nc y l oss s h o ul d N O T be re p orte d 
as a Gra de 5 e ve nt u n der  t he Pre g na nc y, p uer peri u m a n d peri natal c o n diti o ns S O C 
as c urre ntl y C T E P -A E R S r ec o g nizes t his e ve nt as a patie nt deat h.  
A  ne o natal  deat h  s h o ul d  be  re p orte d  e x pe diti o usl y  as  Gra de  4,  “ Deat h  ne o natal” 
u n der t he Ge neral dis or ders a n d a d mi nistrati o n S O C. 
•  
Dea t h  d ue  t o  pr o gressi ve  disease  s h o ul d  be  re p orte d  as  Gra de  5  “ Disease 
pr o gressi o n” i n t he s yste m or ga n class ( S O C) “ Ge neral dis or ders a n d a d mi nistrati o n 
site c o n diti o ns.” E vi de nce t hat t he deat h was a ma nifestati o n of u n derl yi n g disease 
(e. g., ra di ol o gical c ha n ges  s u g gesti n g  t u m or  gr o wt h  or  pr o gressi o n:  cli nical 
deteri orati o n ass ociate d wit h a disease pr ocess) s h o ul d be s u b mitte d.  
 
 
 


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Versi o n date: 0 5 /1 1 / 2 02 0  
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U p date # 1 3  
1 7. 0  R E F E R E N C E S  
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C A L G B 5 0 8 0 1  
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7 3  
U p date # 1 3  
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U p date # 1 3  
 
A P P E N DI X  I  LO N D O N / DE A U VI L L E C RI T E RI A  
 
Ne g ati ve Sc a n 
•  
Sc ore 1   
 n o u pta ke 
•  
Sc ore 2   
 u pta ke ≤ me diasti n u m 
•  
Sc ore 3   
 u p date > me diasti n u m a n d ≤ li ver 
 
P ositi ve Sc a n 
•  
Sc ore 4   
 m o deratel y  > li ver  
•  
Sc ore 5  
mar ke dl y  u pta ke > > li ver  
 
Sc ore X:  
Ne w are as of u p d ate u nlikely t o be rel ate d t o ly m p h o m a. 
 
 
 


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7 5  
U p date # 1 3  
A P P E N DI X  II  IM M U N O HI S T O C H E MI C A L A N A L Y SI S A N D IM A GI N G P R O C E D U R E S  
 
I m m u n o hist oc he mical stai ns will be perf or me d usi n g a ut o mate d i m m u n ostai ns f or B C L 2, F O X P 3, Gz B, 
t yr ptase,  a n d  M A L  o n  a  Ve nta na  Be nc h mar k  stai ner  ( Ve nta na,  T ucs o n  A Z)  wit h  I VI E WT M   
dia mi n o be nza di ne  detecti o n  i n  t he  C LI A -certifie d  la b orat or y  of  t he  Cle vela n d  Cli nic  Pat h ol o g y  a n d 
La b orat or y Me dici ne I nstit ute.  Stai ni n g c o n diti o ns are s u m marize d i n T a ble A 1 .   
 
Stai ns  will  be  q ua ntitate d  b y  ma n ual  c o u nti n g  per  5/ hi g h  p o wer  oil  o bjecti ve  fiel ds.    T he  wit hi n  r u n 
re pr o d uci bilit y  of  ma n ual  T M A  i m m u n ostai ni n g  c o u nti n g  b y  Dr  Hsi  (ra n d o m  rec o u nti n g)  f or  m ulti ple 
mar kers  is  e xcel le nt  wit h  Pears o n  c orrelati o n  c oefficie nts  of  0. 8 2  or  greater  ( P <. 0 0 1).    S pecific  assa y 
precisi o n acr oss i m m u n ostai ni n g r u ns has bee n c haracterize d b y re petiti ve c o nsec uti ve r u ns of c o ntr ol tiss ue 
wit h  q ua ntitati o n  of serial secti o ns.  T he  c oefficie nt of  v ariati o n  ta ki n g  i nt o acc o u nt  b ot h tec h nical  a n d 
c o u nti n g varia bilit y f or B C L 2, F O X P 3, Gz B a n d tr y pase is 5 %, 7 %, 8 %, a n d 5 % res pecti vel y.  Precisi o n 
f or M A L has n ot yet bee n c haracterize d b ut will be perf or me d pri or t o st u d y a n d is a ntici pate d t o be less 
t ha n 1 0 %. 
T a ble A 1:  I m m u n o hist oc he mistr y  
A nti b o d y  
Cl o ne  
Ve n d or  
A nti ge n retrie v al  
B C L 2 cl o ne  
1 2 4  
Ve nta na  
HI E R *  
M A L  
6 D 9  
M. Al o ns o  
HI E R  
F O X P 3  
2 2 5 1 0  
A bca m  
Pr otease 2  
Gz B  
Gr B -7  
Acc urate  
HI E R  
Tr y ptase  
A A 1  
D A K O  
Pr otease 2  
* hea d i n d uce d e pit o pe retrie val, C C 1 sta n dar d 
 
I m a gi n g: 
I ma ge a nal ysis of t he i m m u n ostai ns will als o be perf or me d f or c o m paris o n t o t he ma n ual met h o ds.  Sli des 
will a nal yze d usi n g t he Ari ol S L -5 0 a ut o mate d sli de sca n ner ( A p plie d I ma gi n g, Sa n J ose, C A) t o q ua ntitate 
t he a m o u nt of p ositi ve stai ni n g f or eac h area of i nterest. T hres h ol ds f or eac h i ma ge are a p plie d base d o n 
m ulti ple para meters: R G B al g orit h m, s ha pe, a n d size. P ositi ve stai ni n g is calc ulate d b y a p pl yi n g t w o c ol or 
t hres h ol ds,  wit h  o ne  rec o g nizi n g  bl ue  bac k gr o u n d  c o u nterstai n  ( he mat o x yli n)  a n d  a n ot her  rec o g nizi n g 
br o w n i m m u n ostai n p ositi ve cells. I n di vi d ual cells were discri mi nate d b y i nc or p orati n g t he s ha pe a n d size 
t hres h ol ds, pr o vi di n g, wit h t he c ol or t hres h ol ds, a n d act ual cell c o u nts. F or n uclear a nti ge ns t he perce nta ge 
of p ositi vit y is t he cell n u m ber detecte d b y t he br o w n t hres h ol d di vi de d b y t he t otal cell n u m ber, detecte d 
b y t he br o w n a n d bl ue t hres h ol ds. T otal tiss ue area a nal yze d ma y als o be i ncl u de d i n t he fi nal a nal ysis. 
 
 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
7 6  
U p date # 1 3  
A P P E N DI X  III  
SU M M A R Y O F B I O L O GI C P R O G N O S TI C M A R K E R S I N C L A S SI C A L H L  ( ≥5 0  P T S) 
 
Ser u m M ar kers  
N  
I m p act 
E n d p oi nt  
Si g nific a nt  o n  M ulti v ari a ble 
A n al ysis  
s C D 3 0 
 
 
 
 
Cassa n o vas 2 0 0 7 [ 3 3] 
5 1 9  
a d verse 
E F S  
Y E S  
Ga use 1 9 9 1 [ 6 5] 
9 0  
a d verse 
T T F  
N O  
Na dali 1 9 9 4 [ 3 4] 
1 1 7  
a d verse 
E F S  
Y E S  
Visc o 2 0 0 6 [ 3 5] 
3 2 1  
a d verse 
F F S  
Y E S  
Za n otti 2 0 0 2 [ 6 6] 
1 0 1  
a d verse 
F F S  
Y E S  
A x d or p h 2 0 0 0 [ 6 7] 
9 3  
a d verse 
C S S  
Y E S  
 
 
 
 
 
I L-1 0  
 
 
 
 
Cassa n o vas 2 0 0 7  [ 3 3] 
5 1 9  
a d verse 
E F S  
N O  
A x d or p h 2 0 0 0 [ 6 7] 
1 2 3  
a d verse 
C S S  
Y E S  
B o hle n 2 0 0 0 [ 6 8] 
6 4  
a d verse 
F F T F  
Y E S  
Sarris 1 9 9 9 [ 3 6] 
1 0 1  
a d verse 
F F S  
Y E S  
Vassila k o p o ul os 2 0 0 1 [ 3 7] 
1 2 2  
a d verse 
F F S  
Y E S  
Visc o 2 0 0 4  [ 6 9] 
6 9  
a d verse 
P F S  
Y E S  
Vi via ni 2 0 0 0  [ 7 0] 
7 3  
a d verse 
F F P  
Y E S  
 
 
 
 
 
T A R C  
 
 
 
 
Wei hra uc h 2 0 0 5  [ 4 0] 
6 3  
a d verse 
O S  
N O  
 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
7 7  
U p date # 1 3  
A P P E N DI X  I V C A L G B  5 0 8 0 1  P E T/ C T  IN S T R U M E N T T E C H NI C A L S P E CI FI C A TI O N S F O R M  
 
C A L G B 5 0 8 0 1 P E T/ C T I N S T R U M E N T T E C H NI C A L S P E CI FI C A TI O N S F O R M  
(Fr o m A C RI N  Cre de ntiali n g A p plicati o n, 2 0 0 5) 
 
P a ge 1 of 5 
 
I nstit uti o n:  
  
  
  
  
  
 
D ate:  
 
I nstit uti o n A d dress: 
 
 
I nstit uti o n C o nt act N a me a n d Tele p h o ne N u m ber: 
 
E- m ail:   
  
  
  
  
 
F a x:  
 
P E T Ce nter N a me:   
  
  
  
  
 
D ate:  
 
P E T Ce nter A d dress:  
 
 
 
P E T Ce nter C o nt act N a me a n d Tele p h o ne N u m ber:  
 
E- m ail:   
  
  
  
  
 
F a x:  
 
T y pe of Sc a n ner:   
(e. g., G E Disc overy S T, Sie me ns Bi o gr a p h, P hili ps Ge mi ni, G E A dv a nce, Sie me ns/ C TI E C A T, etc.) 
 
 
Tr a ns missi o n S o urce:  
(e. g., 6 8G E -r o ds, 1 3 7Cs - p oi nt, C T) 
 
 
Met h o d of Atte n u ati o n C orrecti o n:  
(e. g., se g me nt ati o n, s u btr acti o n of e missi o n c o ntri b uti o n t o tr a ns missi o n sc a n, C T A C) 
 
 
R o ut i ne Q C Testi n g P erf or me d 
 
D ail y:  
 
M o nt hl y: 
 
Q u arterl y:  
 
Ye arl y:  
 
Ot her:  
 
 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
7 8  
U p date # 1 3  
C A L G B 5 0 8 0 1 P E T/ C T I N S T R U M E N T T E C H NI C A L S P E CI FI C A TI O N S F O R M  
(Fr o m A C RI N  Cre de ntiali n g A p plicati o n, 2 0 0 5) 
 
P a ge 2 of 5  
 
U NI F O R M P H A N T O M S C A N  I N F O R M A TI O N 
 
P h a nt o m Le n gt h:  
  
  
  
P h a nt o m Di a meter:  
 
P h a nt o m V ol u me: 
 
R a di o n ucli de:  
 
F or W ater- Fill a ble P h a nt o ms, Pr o vi de t he F oll o wi n g Data : 
 
Ass a ye d Acti vit y i n S yri n ge bef ore  i njecti o n: 
m Ci   
 
Ti me:  
 
Ass a ye d Acti vit y i n S yri n ge after  i njecti o n: 
m Ci   
 
Ti me:  
 
 
F or Ge -6 8/ G a -6 8 C ali br ati o n P h a nt o ms, Pr o vi de t he F oll o wi n g Data : 
 
C ali br ati o n D ate:  
  
  
 
Ti me:  
 
C ali br ati o n Acti vit y:  
m Ci    
Ti me:  
 
  
  
  
  
  
  
  
  
  
  
 
St d De v of S U V  
N u m ber of Pi xels i n  
Slice #  
A ver a ge S U V i n R OI 1    
  (if a v ail a ble) 
R OI:  
  
 
1    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
2    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
3    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
4    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
5    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
6    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
7    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
8    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
Re p ort i nf o f or E V E R Y   
9    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
slice of t he p ha nt o m 
1 0    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
1 1    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
1 2    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
1 3    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
1 4    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
1 5    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
1 6    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
1 7    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
1 8    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
1 9    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
  
 
2 0    
  
_ _ _ _ _ _ _ _  
  
     _ _ _ _ _ _ _ _ 
1 A circ ular or elli ptical re gi o n of i nterest ( R OI) c o veri n g m ost of t he i nteri or of t he p ha nt o m.  


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
7 9  
U p date # 1 3  
C A L G B 5 0 8 0 1 P E T/ C T I N S T R U M E N T T E C H NI C A L  S P E CI FI C A TI O N S F O R M  
(Fr o m A C RI N  Cre de ntiali n g A p plicati o n, 2 0 0 5) 
 
P a ge 3 of 5  
 
 
F O R I M A GI N G C O R E L A B O R T O R Y U S E O N L Y:  
 
P h a nt o m I m a ges Re vie w: 
 
D ate:  
C o m me nts:  
 
 
 
 
 
 
        A p pr o ve d  
 
        Dis a p pr o ve d 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _        _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 Si g nat ure                                                            Date  
 
 
 
 
 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
8 0  
U p date # 1 3  
C A L G B 5 0 8 0 1 P E T/ C T I N S T R U M E N T T E C H NI C A L S P E CI FI C A TI O N S F O R M  
(Fr o m A C RI N  Cre de ntiali n g A p plicati o n, 2 0 0 5) 
 
P a ge 4 of 5  
 
W H O L E B O D Y F D G -P E T T E S T P A TI E N T # 1 : 
 
File N a me:   
  
  
 
P atie nt Hei g ht:  
P atie nt Wei g ht:  
 
F D G D ose ( m Ci):   
  
 
D ose Ass a y Ti me:  
 
Bl o o d gl uc ose pri or t o F D G a d mi nistr ati o n ( m g/ d L):  
 
I njecti o n Ti me:  
  
 
St art Ti me of E missi o n Sc a n:  
 
A C Q UI SI TI O N  N o. of B e d P ositi o ns: 
 
 
E MI S SI O N TI M E ( MI N/ B E D):   
 
T R A N S MI S SI O N TI M E ( MI N/ B E D):  
 
 
R E C O N S T R U C TI O N A L G O RI T H M:  
(e. g., 2 D F B P, 2 D O S E M, 3 D F O R E/ O S E M, 
3 D R A M L A)  
PI X E L SI Z E ( m m)  
X -Y:  
 
Z:  
 
Sc atter C orrecti o n A p plie d:    
Yes   
 
N o  
 
(Incl u de al g orit h m t y pe, e. g., m o del - b ase d, t ail-fit, B er gstr o m): 
 
R a n d o ms C orrecti o n A p plie d:   
O nli ne    
S m o ot he d R a n d o ms ( offli ne)    
N o ne  
 
 
F O R I M A GI N G C O R E L A B O R T O R Y U S E O N L Y:  
 
Test P atie nt # 1  Re vie w:  
 
D ate:  
C o m me nts:  
 
 
 
        A p pr o ve d  
 
        Dis a p pr o ve d 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _        _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 Si g nat ure                                                            Date  
 


C A L G B 5 0 8 0 1  
Versi o n date: 0 5 /1 1 / 2 02 0  
8 1  
U p date # 1 3  
C A L G B 5 0 8 0 1 P E T/ C T I N S T R U M E N T T E C H NI C A L S P E CI FI C A TI O N S F O R M  
(Fr o m A C RI N  Cre de ntiali n g A p plicati o n, 2 0 0 5) 
 
P a ge 5 of 5  
 
W H O L E B O D Y F D G -P E T T E S T P A TI E N T # 2 : 
 
File N a me:   
  
  
 
P atie nt Hei g ht:  
P atie nt Wei g ht:  
 
F D G D ose ( m Ci):   
  
 
D ose Ass a y Ti me:  
 
Bl o o d gl uc ose pri or t o F D G a d mi nistr ati o n ( m g/ d L):  
 
I njecti o n Ti me:  
  
 
St art Ti me of E missi o n Sc a n:  
 
A C Q UI SI TI O N  N o. of B e d P ositi o ns: 
 
 
E MI S SI O N TI M E ( MI N/ B E D):   
 
T R A N S MI S SI O N TI M E ( MI N/ B E D):  
 
R E C O N S T R U C TI O N A L G O RI T H M:  
(e. g., 2 D F B P, 2 D O S E M, 3 D F O R E/ O S E M, 
3 D R A M L A)  
PI X E L SI Z E ( m m)  
X -Y:  
 
Z:  
 
 
Sc atter C orrecti o n A p plie d:     
  Yes    
N o  
 
(Incl u de al g orit h m t y pe, e. g., m o del - b ase d, t ail-fit, B er gstr o m): 
 
R a n d o ms C orrecti o n A p plie d:   
O nli ne    
S m o ot he d R a n d o ms ( offli ne)    
N o ne  
 
 
F O R I M A GI N G C O R E L A B O R T O R Y U S E O N L Y:  
 
Test P atie nt # 2  Re vie w:  
 
D ate:  
C o m me nts:  
 
 
 
        A p pr o ve d  
 
        Dis a p pr o ve d 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _        _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 Si g nat ure                                                            Date