Dose-Reduced Consolidation Radiation Therapy in Patients With Diffuse Large B-cell Lymphoma
Phase: NA
Conditions: Diffuse Large B-cell Lymphoma
Sponsor: Duke University

                                                  
 
Kelsey: Ph II DLBCL  
 
 
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Rev. 02-11-2015 
Phase II study of Dose-Reduced Consolidation Radiation Therapy in Patients with Diffuse Large B-cell 
Lymphoma  
 
 
Principal Investigator 
Chris R. Kelsey, M.D. 
Assistant Professor 
Department of Radiation Oncology 
Duke University Medical Center 
DUMC Box 3085 
Durham, NC 27710 
 
 
Sub-Investigators 
Bridget Koontz, M.D. 
David Yoo, M.D. 
 
 
Statistician 
Bercedis L. Peterson, Ph.D. 
 
 
Collaborators 
Anne Beaven, M.D.  
Louis Diehl, M.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                                                  
 
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1.0  
BACKGROUND AND SIGNIFICANCE 
3 
1.1 CHEMOTHERAPY AND RADIATION THERAPY FOR DIFFUSE LARGE B-CELL LYMPHOMA 
3 
1.2 RITUXIMAB FOR DLBCL 
3 
1.3 PET ASSESSMENT AFTER CHEMOTHERAPY 
3 
1.4 RISK OF IN-FIELD FAILURE AFTER COMBINED MODALITY THERAPY 
4 
1.5 RATIONALE FOR RADIATION THERAPY DOSE REDUCTION 
4 
1.6 RATIONALE FOR RADIATION THERAPY FIELD REDUCTION 
4 
2.0  
PURPOSE 
4 
2.1 HYPOTHESIS 
4 
3.0  
OBJECTIVES 
4 
3.1 PRIMARY OBJECTIVE 
4 
3.2 SECONDARY OBJECTIVES 
5 
4.0  
PATIENT RECRUITMENT 
5 
5.0  
PATIENT SELECTION 
5 
5.1 ELIGIBILITY 
5 
5.2 INELIGIBILITY 
5 
6.0  
PRETREATMENT EVALUATION 
5 
7.0  
REGISTRATION PROCEDURE 
6 
8.0  
TREATMENT 
6 
8.1 RADIATION THERAPY 
6 
9.0  
EVALUATIONS DURING AND AFTER TREATMENT 
7 
9.1 DURING RADIATION THERAPY 
7 
9.2 CRITERIA FOR GOING OFF PROTOCOL 
7 
9.3 FOLLOW-UP 
7 
10.0  CONFIDENTIALITY AND PROTECTION OF RESEARCH SUBJECTS 
7 
11.0  PROTOCOL MANAGEMENT AND DATA COLLECTION 
7 
12.0 RISKS/BENEFIT ASSESSMENT 
7 
13.0  COSTS 
8 
14.0 
STATISTICAL CONSIDERATIONS 
8 
REFERENCES 
8 
 
 

                                                  
 
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1.0  
BACKGROUND AND SIGNIFICANCE 
1.1 Chemotherapy and Radiation Therapy for Diffuse Large B-Cell Lymphoma  
Based on two randomized studies performed in the 1980s and 1990s (1, 2), chemotherapy followed 
by involved-field radiation therapy has become a standard treatment for patients with early-stage diffuse 
large 
B-cell 
lymphoma 
(DLBCL). 
In 
these 
studies, 
chemotherapy 
consisted 
of 
CHOP 
(cyclophosphamide, doxorubicin, vincristine, and prednisone). Radiation therapy (RT) consisted of 30 
Gy in the ECOG study (1) after eight cycles of CHOP and 40-55 Gy in the SWOG study (2) after 3 
cycles of CHOP. Our practice at Duke, which is consistent with guidelines set forth by the National 
Comprehensive Cancer Network, is to treat patients who achieve a complete response after 4 to 6 cycles 
of chemotherapy with radiation therapy, 30 Gy, to originally involved sites. 
 
Chemotherapy is the cornerstone of treatment for patients with stage III-IV DLBCL, and the role of 
consolidation RT is not well defined. Retrospective studies evaluating the role of RT are conflicting (3, 
4). The only randomized phase III trial is the one carried out by Aviles et al. This study demonstrated 
improved event-free survival and overall survival for patients with stage IV DLBCL who received 
radiation therapy to original sites of bulky disease after achieving a complete response to chemotherapy 
(5). Currently, we do consolidate with radiation therapy selected patients with advanced DLBCL with 
radiation therapy who achieve CR with chemotherapy. These patients are generally treated to all sites of 
original disease if practical (as opposed to just bulky sites).  
While CHOP is the most common regimen used for DLBCL, other regimens have been found to be 
equally effective (6). At Duke, the vast majority of patients are treated with rituximab and CHOP (R-
CHOP), though other regimens are occasionally employed based on medical comorbidities and side 
effect profile. 
 
1.2 Rituximab for DLBCL 
 
Since the initial studies of radiation therapy in early stage DLBCL were performed, the standard 
therapy for DLBCL has been significantly improved with the addition of rituximab to the standard 
CHOP regimen. Several randomized studies have evaluated CHOP versus R-CHOP showing a 
significant improvement in both progression-free survival and overall survival with the addition of 
rituximab (7, 8). As a result of more effective chemotherapy regimens, a lower dose of consolidation 
radiation therapy than has previously been studied may be effective. 
 
1.3 PET Assessment after Chemotherapy 
 
Positron emission tomography (PET) scans have become standard in lymphoma management to both 
assess disease extent at diagnosis as well as evaluate response to therapy. Patients treated with 
chemotherapy alone who have not achieved a complete response by PET are at substantially higher risk 
of relapse compared with patients who have a negative post-chemotherapy PET(9-11). A positive PET is 
also associated with an increased risk of local failure after chemotherapy and consolidation RT. In a 
study from Duke, patients with a positive post-chemotherapy PET were at higher risk of in-field failure 
compared with patients with a negative post-chemotherapy PET after administration of consolidation 
RT(12). Four-year in-field control was 97% with a negative PET versus 81% with a positive PET 
(p<0.01). The median RT dose was 30 Gy. Thus, PET scans help discriminate patients who have not had 
an optimal response to chemotherapy and are at increased incidence of disease relapse after a combined 
modality regimen. These patients may require a higher dose of consolidation radiation therapy and 
would not be candidates for this study. PET interpretations be standardized based on the Deauville 
Criteria. In the setting of combined modality therapy, a Deauville score of 1-3 is currently considered 
negative and a Deauville score of 4-5 is currently considered positive. 
 

                                                  
 
Kelsey: Ph II DLBCL  
 
 
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1.4 Risk of In-field Failure after Combined Modality Therapy 
 
In-field failure (disease recurrence within the radiation field) is rare after combined modality 
therapy. In three large randomized trials, crude in-field failure rates after CHOP and radiation therapy 
(30 to 40 Gy) ranged between 4% and 7% (1, 13, 14). In these studies, rituximab was not administered 
and PET scans were not used to assess response to chemotherapy prior to consolidation RT.  
 
1.5 Rationale for Radiation Therapy Dose Reduction 
 
There are no prospective studies in DLBCL guiding the appropriate dose that should be used after 
effective chemotherapy. In Hodgkins lymphoma, the German Hodgkin Study Group HD10 recently 
demonstrated that 20 Gy was as effective as 30 Gy after 2-4 cycles of ABVD in patients with early-
stage, favorable disease (ASH 2009).  The risk of complications related to radiation therapy, including 
cardiac disease and secondary cancers, appear to be related to both dose (15) and volume (15, 16). If the 
dose and volume of radiation therapy can be reduced, while maintaining high rates of disease control, 
this would undoubtedly decrease the risk of side effects and long-term risks. 
 
1.6 Rationale for Radiation Therapy Field Reduction 
 
There is no consensus as to the optimal RT field size for patients with DLBCL. Many institutions 
follow the pattern used for Hodgkins lymphoma, namely treating an involved field (i.e., a region as 
opposed to true anatomic extent of disease) (17).  However, several cooperative groups and institutions 
currently treat only originally involved sites (as opposed to regions). For example, in a retrospective 
analysis from the University of British Columbia of patients treated with combined modality therapy for 
DLBCL (3 cycles of CHOP +/- rituximab), the local control rate was equivalent between involved field 
and involved node treatment volumes (18). Only 2% of patients developed a marginal recurrence, 
defined as a recurrence outside the involved nodal field but within what would have been encompassed 
with an involved field. The same group has recently reported similar findings for Hodgkin’s Disease 
(19). In this study, we will treat the original anatomical extent of disease and not attempt to treat sites 
which were not clinically involved at diagnosis. The hypothesis being, that chemotherapy can 
successfully eradicate microscopic disease, and consolidation RT will be utilized to help control gross 
disease. 
 
2.0  
PURPOSE 
This phase II study will evaluate whether a reduction in the RT dose, concomitant with a decrease in 
the RT field size, in patients that achieve CR and have a negative post-chemotherapy PET scan 
following 4 to 6 cycles of rituximab containing chemotherapy,  will be associated with a low risk of in-
field failure. The goal of this approach is to maintain excellent control rates while minimizing the risk of 
acute and late toxicity. 
 
 
2.1 Hypothesis 
Hypothesis- After more effective systemic therapy (employing rituximab), with confirmation of optimal 
response to chemotherapy(Deauville score of 1-3 on post-chemotherapy (or interim) PET scan), the RT 
dose and treatment volume can be safely reduced from 30 Gy to 20 Gy while maintaining high rates of 
local control. 
 
3.0  
OBJECTIVES 
3.1 Primary Objective 

                                                  
 
Kelsey: Ph II DLBCL  
 
 
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To determine if high rates of local control can be maintained after a reduction in the RT dose and 
volume after 4 to 6 cycles of rituximab containing chemotherapy. 
 
3.2 Secondary Objectives 
3.2.1 To determine the progression-free survival and overall survival after chemotherapy and low-dose 
(20 Gy) consolidation radiation therapy. 
3.2.2 To identify patterns of failure after low-dose, reduced volume consolidation radiation therapy. 
 
4.0  
PATIENT RECRUITMENT 
This is a prospective, phase II, single arm study. Ascertainment of eligibility will be determined by 
review of the records of patients with DLBCL seen by radiation oncology PI, co-investigator or other 
clinical faculty of radiation oncology. The subject population (with no gender or minority restrictions) 
will include adult patients meeting the eligibility criteria.  Inclusion of women and minorities is 
encouraged. All patients must sign an IRB-approved informed consent prior to enrollment. Eligibility of 
patients will be ascertained by reviewing necessary portions of the medical record. 
 
5.0  
PATIENT SELECTION 
5.1 Eligibility 
1. Histologic documentation of diffuse large B-cell lymphoma, or any of its variants as defined in the 
WHO classification, including but not limited to any of the following: 
a. DLBCL NOS 
b. Primary mediastinal DLBCL 
c. T cell/histiocyte-rich large B-cell lymphoma 
2. Completion of at least 4 cycles of a rituximab-containing, anthracycline-based combination 
chemotherapy regimen no sooner than 3 weeks and no longer than 8 weeks prior to the start of radiation 
therapy 
3.  Deauville score of 1-3 on post-chemotherapy (or interim) PET scan 
4. ANC ≥ 1000 and platelet count ≥ 40,000 
5. ≥ 18 years of age. 
6. For females of childbearing potential, a serum pregnancy test within 2 weeks prior to registration; 
Note: if pelvic irradiation is to be given, the serum pregnancy test must be repeated within 48 hours 
prior to registration. 
7. Signed study-specific informed consent. 
8. For patients with HIV/AIDS, the following must be true: 
• The patient is compliant on combination anti-retroviral therapy (CART) 
• The patient has CD4 count ≥ 200 at time of diagnosis 
 
5.2 Ineligibility 
1. Any contraindications to irradiation. 
2. Primary CNS lymphoma 
 
6.0  
PRETREATMENT EVALUATION  
1. A complete history and physical within 4 weeks of consent  
2. Routine laboratory work including complete blood count (CBC) at least 3 weeks after chemotherapy 
and less than 4 weeks before beginning radiation therapy. 
3. PET/CT (interim or post-chemotherapy), available for review 
4. Negative serum pregnancy test for women of child-bearing potential 

                                                  
 
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7.0  
REGISTRATION PROCEDURE 
The patients will be recruited from the clinics by the radiation oncologist from his/her practice.  Only 
radiation oncologists listed as Key Personnel for this study and who have completed the required ethics 
training may enroll patients on this study. The patient’s primary medical oncologist will be apprised of 
the patient’s intent to participate in the study. Following verification of eligibility the patient will be 
assigned a sequential study ID number.  
 
8.0  
TREATMENT  
8.1 Radiation Therapy 
 
Radiation therapy is to be initiated no sooner than 3 weeks after completion of chemotherapy. It is 
strongly recommended that radiation therapy start within 8 weeks of the final cycle of chemotherapy. 
 
Equipment 
All patients will be treated using conventional or three-dimensional techniques (preferred) or intensity-
modulated radiation therapy via a linear accelerator using photon energies of 6 and/or 15 MV.  
 
Treatment Planning 
An immobilization device, such as a styrofoam mold or thermoplastic head mask, will be designed for 
each patient. Intravenous and oral contrast will be administered if necessary to optimally design the 
radiation fields in the absence of medical contraindications, such as an allergy to iodinated contrast.  
 
Target Volume 
Stage I-II disease- The clinical target volume (CTV) will include the original extent of disease plus a 
margin of 0-5 cm to account for uncertainties in defining this volume in the post-chemotherapy setting. 
Within the lung and abdomen, the pre-chemotherapy length but the post-chemotherapy width will be 
contoured as target (to protect critical structures such as lung and kidney). The CTV will be expanded by 
5-10 mm to account for daily set-up error and/or target motion (such as the respiratory-induced 
movement of the hilum). The PTV will be expanded by 5-8 mm to account for beam penumbra when 
three-dimensional techniques are utilized. 
 
Stage III-IV- Treatment volumes for patients with advanced DLBCL will be individualized based on the 
clinical presentation. When feasible, consolidation of all sites originally involved is encouraged. 
However, consolidation of only certain sites (such as sites of bulky disease) will be acceptable. 
 
Treatment 
Patients will be set up daily using on-board imaging or weekly/biweekly MV portal films. Radiation will 
be given with 5 fractions per week. Patients will be treated with 1.5 to 2 Gy fractions to a total dose of 
18 to 20 Gy. Treatment to subportions of the target volume can be reduced if critical normal structures 
are in close proximity (i.e. limiting the dose to 18 Gy to the kidneys). 
 
Treatment Interruptions during RT 
Treatment breaks due to RT-induced toxicity are expected to be rare. To be eligible for study 
participation, subjects must have a baseline ANC ≥ 1000. It is very rare for patients who 
initiate radiation therapy with an ANC > 800 to become neutropenic during the course of treatment. The 
standard of care for lymphoma patients receiving chemotherapy is to continue all cycles of 
chemotherapy despite episodes of neutropenia unless the patients experiences an episode of febrile 
neutropenia (temperature greater than 100.5 degrees with an ANC <500). This study will follow the 

                                                  
 
Kelsey: Ph II DLBCL  
 
 
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medical oncology model and radiation treatment will continue during episodes of neutropenia, unless 
febrile neutropenia occurs. However, treatment breaks will be provided for thrombocytopenia, which is 
defined as platelets < 25,000.  
 
9.0  
EVALUATIONS DURING AND AFTER TREATMENT 
9.1 During Radiation Therapy 
1. All patients will be evaluated by a radiation oncologist weekly during RT or more frequently as 
indicated.  
2. An interim history and directed physical examination will be performed during the weekly treatment 
check with documentation of treatment-related acute toxicity  
3. A CBC will be obtained  during the course of radiation treatment. 
 
9.2 Criteria for Going off Protocol   
1. Non compliance with protocol requirements. 
2. Patient request or withdrawal of consent. 
 
9.3 Follow-up 
Patients will be encouraged to return every 6 months for the first two years to Radiation Oncology and 
annually thereafter for follow-up. The medical oncologist will also evaluate the patient routinely per 
standard evaluation practices. This usually involves a CT or PET/CT every 6 months for 2 years 
following the completion of radiation treatment.  All follow-up examinations, including laboratory work 
and imaging studies will be performed at the discretion of the treating physicians. However, if a patient 
relapses, either CT or PET imaging is highly recommended to ascertain sites of disease recurrence in 
relation to the radiation treatment fields. 
 
9.4 Adverse Event Capture 
Adverse event information will be collected for up to five years following completion of study 
treatment. Only adverse events that are related, probably related, or possibly related to study treatment 
will be captured. 
 
10.0  CONFIDENTIALITY and PROTECTION of RESEARCH SUBJECTS 
All study-related materials will be stored electronically on password-protected DUHS maintained 
servers. All personnel involved in the conduct and analysis of data from the study will have ethics 
training in the protection of research subjects. 
 
11.0  PROTOCOL MANAGEMENT and DATA COLLECTION   
This study will be conducted in accordance with applicable Federal regulations and radiation therapy 
standards. Data will be entered in the study specific database within a timely manner.  
 
12.0 RISKS/BENEFIT ASSESSMENT  
Radiation therapy is a standard treatment modality for patients with DLBCL. The risks of treatment are 
expected to be less since a lower dose of RT will be employed. It is possible that 20 Gy is insufficient 
which may increase the risk of disease recurrence which may necessitate further treatment. With smaller 
RT doses, it is expected that both acute and long-term toxicity will be less. 
 
 
 

                                                  
 
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13.0  COSTS 
Since chemotherapy and radiation therapy are standard of care for DLBCL, all costs of the treatment as 
well as follow-up examinations will be billed to the patient or their insurance carrier.  
 
14.0 
STATISTICAL CONSIDERATIONS 
Statistical Analysis of Primary Objective 
This trial will accrue 62 patients over a time period of approximately 5-6 years. The primary objective is 
to determine whether the observed 5-year LC rate, estimated from the Kaplan-Meier curve of time-to-
local failure, is as high as that observed in historical controls, i.e., 0.90. Time -to-local-failure is defined 
as time from on-study to time of local failure; deaths are censored; distant failures are ignored (i.e., we 
will continue to follow for local failure after observing a distant failure). The lower 90% confidence 
bound of the 5-year LC rate will be calculated, and if the lower 90% bound is ≥ 0.84, the study will be 
considered a success. This decision rule is equivalent to requiring that the observed 5-year LC rate be ≥ 
0.90. If the true 5-year LC rate is 0.84 (0.94), there is 7% (87%) probability that the lower bound will be 
≥ 0.84. These probabilities (7% and 87%) are the alpha (one-sided) and power, respectively, for the null 
hypothesis that the 5-year LC rate is ≤ 0.84 and the alternative hypothesis that the 5-year LC rate is ≥ 
0.94.  The expected number of events in this study assuming each of these distributions is 15.0 and 5.4, 
respectively. 
 
The operating characteristics of the design above take into account two interim analyses designed to stop 
the study early when there is evidence that the null hypothesis is true. The first analysis will be done 
after 45 person-years (PY) of follow-up have accumulated (at about year 3). We will also perform a 
second interim analysis if the trial is accruing slower than anticipated, after 185 person-years of follow-
up. These interim analyses will assess whether the cumulative incidence of LC (i.e., the number of 
events divided by the total PY of follow-up) exceeds the values shown in the table below. If the 
cumulative incidence is “too high,” the trial will stop. The probabilities of stopping early are also shown 
in the table. 
 
     
Stage 
                  
Analysis time 
Minimum cumulative 
incidence needed to stop the 
trial and accept the null 
Probability of accepting the 
null when the null is true 
(when the alternative is true) 
1 
~3 years (45 PY) 
0.044 (2/45) 
0.35 (0.06) 
2 
~6 years (185 PY) 
0.032 (6/185) 
0.32 (0.01) 
3 
(Final)  
11 years 
NA 
0.26 (0.05) 
 
 
Statistical Analysis of Secondary Objective 1 
 Progression-free survival (PFS) will be defined as the time from on-study to disease progression or 
death due to any cause, whichever comes first.  Overall survival will be defined as the time from on-
study to death due to any case.  Both distributions will be estimated with the Kaplan-Meier method.  The 
5-year PFS rate and the 5-year overall survival rate will be give with their 80% confidence intervals.  
 
Statistical Analysis of Secondary Objective 2 
To examine the patterns of failure, we will tabulate the various ways that patients failed up until the time 
of the analysis.  For example, these ways will include local only, local + distant, and distant only. 
REFERENCES 

                                                  
 
Kelsey: Ph II DLBCL  
 
 
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