Clinical trial NCT00116142
Conditions: Prostate Cancer
Keywords: Prostate Cancer Hormone Refractory Metastatic Localized Locally Advanced Prostate Cancer - High Risk Localized or Locally Advanced
Sponsor: Dana-Farber Cancer Institute
Start date: 2005-06-01; Completion date: 2020-06-29
Enrollment: 350 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized study is looking at the benefits of using docetaxel (chemotherapy) added to one of the standard treatments (radiation and hormones) for men with high-risk prostate cancer.

Detailed description:
Radiation therapy plus six months of hormone therapy is one standard way of treating men with high-risk prostate cancer. In this study, we want to see whether or not adding the chemotherapy drug docetaxel (Taxotere)will make this treatment more effective. Docetaxel has shown a benefit in median survival when given to men who have become resistant to hormonal therapy and in men who have metastatic prostate cancer (spread to other areas of the body).

Arms: arm 1: Androgen Suppression Therapy and Radiation therapy arm 2: Docetaxel plus androgen suppression therapy and radiation therapy
Interventions: intervention 1: Docetaxel intervention 2: Androgen Hormonal Suppression and Radiation intervention 3: Androgen Suppression Therapy and Radiation Therapy
Intervention descriptions: intervention 1: 60 mg/m² q 3 weeks for 3 cycle at the start of treatment followed by weekly Docetaxel at 20 mg/m² per week beginning at week one of radiation therapy and continuing for seven weeks. intervention 2: Total Androgen Ablation and external beam radiation therapy intervention 3: Total Androgen Ablation and External Beam Radiation Therapy

Protocol documents:
Prot_SAP_000.pdf: 
 
Title: Docetaxel (Taxotere®) plus 6-Month Androgen Suppression and 
Radiation Therapy vs. 6-Month Androgen Suppression and Radiation 
Therapy for Patients with High-Risk Localized or Locally Advanced 
Prostate Cancer: A Randomized Controlled Trial 
 
 
 
 
 
NCT Number: 00116142 
 
 
 
 
IRB Approval Date: May 02, 2005 


 
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  CLINICAL PROTOCOL 
TITLE: 
Docetaxel (Taxotere®) plus 6-Month Androgen 
Suppression and Radiation Therapy vs. 6-Month 
Androgen Suppression and Radiation Therapy 
for Patients with High-Risk Localized or Locally 
Advanced Prostate Cancer:  A Randomized 
Controlled Trial 
PROTOCOL NUMBER: 
05-043 
STUDY DRUG: 
Taxotere® 
IND: 
Non-IND 
SPONSOR/CRO 
Dana-Farber Cancer Institute 
   
 
 
MEDICAL MONITOR/ 
Anthony V. D’Amico, M.D. Ph.D. 
                 
                                 
 
 
    
 
 
                                                                              
 
PROJECT MANAGER                     
                                                              
                                                           
 
 
 
 
                                                                
 
DATE OF PROTOCOL: 
 
 29 March 2005                                                       
DATE OF AMENDMENT #1: 
 14 Sept 2005 
DATE OF AMENDMENT #2:          27 Sept 2005                                                     
DATE OF AMENDMENT #3:          22 Nov 2005 
DATE OF AMENDMENT #4:   
  30 Dec 2005  
DATE OF AMENDMENT #5:          12 May 2006 
DATE OF AMENDMENT #6:          02 Oct 2006                                                                                      
DATE OF AMENDMENT #7:          12 Feb 2007 
DATE OF AMENDMENT #8            30 March 2007                                                   
 
 
 
 
 
 


 
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DATE OF AMENDMENT #9             1 August 2007   
DATE OF AMENDMENT #10:         14, November 2007  
DATE OF AMENDMENT # 11:         06, March 2008 
DATE OF AMENDMENT #12:          26, June, 2008    
DATE OF AMENDMENT #13: 
    27, January, 2009 
DATE OF AMENDMENT #14:          05, June, 2009  
DATE OF AMENDMENT #15:          11, August, 2009 
DATE OF AMENDMENT #16:          18, DECEMBER, 2009 
No Protocol Changes to Amendment # 17   
DATE OF AMENDMENT # 18: 
     20, May, 2010   
DATE OF AMENDMENT # 19:       15, February, 2011          
DATE OF AMENDMENT #20:  
     31, October, 2011  
DATE OF AMENDMENT #21             31 January 2012                 
DATE OF AMENDMENT # 22 
       27, June 2012 
DATE OF AMENDMENT # 23 (DFCI# 75)   21, March 2013 
 
DATE OF AMENDMENT # 24 (DFCI# 76) 1 May 2013 
 
DATE OF AMENDMENT #25 (DFCI# 77) 19, JUNE 2013 
 
DATE OF AMENDMENT #26 (DFCI# 86) November 5, 2015 
 
DATE OF AMENDMENT #27 (DFCI#90) August 23, 2016 
 
DATE OF AMENDMENT #28 (DFCI #92) November 14, 2017 
 
DATE OF AMENDMENT #29 (DFCI#94) April 6, 2018 
 
DATE OF AMENDMENT #30 (DFCI#96) August 16, 2019 
 
 
 
 
 
 
 
 


 
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CONFIDENTIAL INFORMATION 
The information contained herein is confidential and the proprietary property 
of the Dana Farber Cancer Institute and any unauthorized use or disclosure 
of such information without the prior written authorization of the Dana 
Farber Cancer Institute is expressly prohibited. 
 
 
 
 
 
 


 
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PROTOCOL SIGNATURE PAGE 
 
05-043:  Docetaxel (Taxotere®) plus 6-Month Androgen Suppression and Radiation 
Therapy   vs. 6-Month Androgen Suppression and Radiation Therapy for Patients 
with High-Risk Localized or Locally Advanced Prostate Cancer:  A Randomized 
Controlled Trial 
By signing below, the Investigator agrees to adhere to the protocol as outlined and 
agrees that any changes to the protocol must be approved by Dana Farber Cancer 
Institute, prior to seeking approval from the Institutional Review Board (IRB) and/or 
Ethics Review Committee (ERC). 
 
 
This study will be conducted in accordance with current US Food and Drug 
Administration (FDA) regulations, good clinical practices (GCPs), the Declaration of 
Helsinki, and local ethical and legal requirements. 
 
Investigator’s Signature:  _______________________________________________ 
Printed Name:  _______________________________________________________ 
Name of Institution/Company:___________________________________________ 
Date:  ______________________________________________________________ 
 
Please submit a signed copy of this page to Dana-Farber Cancer Institute: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS                                                                       PAGE                 
SCHEMA .................................................................................................................... 6 
1.0  INTRODUCTION ................................................................................................. 7 
2.0  STUDY OBJECTIVES......................................................................................... 8 
3.0 PATIENT SELECTION........................................................................................ 9 
4.0  PATIENT ENTRY .............................................................................................. 11 
5.0 TREATMENT PLAN ......................................................................................... 11 
6.0  REQUIRED DATA ............................................................................................ 28 
7.0 MODALITY REVIEW ........................................................................................ 30 
8.0  STATISTICS ..................................................................................................... 31 
9.0  CENTRAL PATHOLOGY REVIEW .................................................................. 25 
REFERENCES ......................................................................................................... 36 
APPENDICES A – C .......................................................................................... 28-33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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SCHEMA 
 
Patient Selection:  Clinical Criteria 
 
Bone Scan (-) 
Pelvic Lymph nodes with a long axis of 1.5 cm or less (CT, or MR) 
 
 
Clinical category T2c, T3a, T3b or T4 as per 2002 AJCC guidelines 
-OR- 
Clinical category T1b to T2b AND any one of the following: 
 
PSA > 10 ng/mL 
-OR- 
Gleason score ≥ (4+3=7) 
-OR- 
Any minor tertiary grade of 5 
-OR- 
Gleason score ≥ (3+4=7) with 50% or more cores positive 
-OR- 
2.0 ng/ml rise in PSA during the year prior to treatment 
or a 2.0 ng/ml average annual rise in PSA based on any PSA values within 3 years 
prior to treatment 
                                                            -OR- 
Biopsy proven or Radiographic (erMRI) Seminal Vesicle Invasion 
 
 
Refer to Section 3.0 for a listing of ALL patient eligibility criteria 
 
Randomize 
 
Group 1 
 
Weeks 1 – 9: 
Total Androgen Suppression# 
 
 
 
Weeks 10 – 17: 
Total Androgen Suppression# + External Beam 
Radiation Therapy* 
Pelvic lymph nodes at the discretion of the 
treating physician 
 
 
 
Weeks 18 – 26: 
Group 2 
 
Weeks 1 – 9: 
Total Androgen Suppression#  
+ Docetaxel 60 mg/m2/q3 weeks x 3 cycles 
 
Weeks 10 - 17 
Total Androgen Suppression# + External Beam 
Radiation Therapy* 
Pelvic lymph nodes at the discretion of the 
treating physician+ Docetaxel 20 mg/m2/week 
beginning at week 10 x 7 cycles and continuing 
through week 16 
 
Weeks 18 - 26 
Total Androgen Suppression# 
Dana arber
 
 
 
 
 


 
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Total Androgen Suppression# 
 
 
Post Therapy Evaluation:  (see section 6.0 Required Data).   
 
# Total Androgen Suppression (AST): Casodex (or Bicalutamide) 50 mg. Po q 24or 
Eulexin  250  mg. PO q 8 hours  with either Eligard - Leuprolide acetate 
(7.5 mg S.C. q 4 weeks or 22.5 mg. S.C. q 12 weeks) or Lupron 7.5 mg IM 
q 4 weeks or 22.5 mg IM q 12 weeks) or Zoladex 3.6 mg S.C. q 4 weeks or 
10.8 mg S.C. q 12 weeks, approximately 2 months prior to, 2 months 
concurrent with, and 2 months after completion of radiation therapy.  
Any LHRH agonist may be used with any dosing schedule (e.g. monthly, 
3 month depot, 6 month depot, etc.) as long as the total on study AST 
treatment does not exceed 26 weeks.   As per Section 5.13 patients with up 
to 4 weeks of AST treatment prior to enrollment will not exceed a total of 
30 weeks of AST treatment.  Patients being registered from sites 
outside of the USA are allowed a 2 week leeway if needed.  
 
 
 
*External Beam Radiation Therapy:  45 Gy in 25 1.8 Gy doses of radiation therapy will be 
delivered to the prostate and seminal vesicles using a classic 4-field box technique or any conformal 
technique including IMRT or protons.  An intra-rectal immobilization or localization device may 
be used.  The prostate should be boosted for an additional 25.20 Gy (14 doses of 1.8 Gy) using any 
conformal technique with up to a 1.5 cm margin from the prostate gland to the block edge.  In 
known cases of seminal vesicle invasion by digital rectal examination (Category T3b) or endorectal 
MRI, the involved seminal vesicle(s) will also be treated to a total dose of 70.2 Gy. 
 
Pelvic Lymph Nodes may be treated at the discretion of the physician using the following 
guidelines.    
 
The superior border of the treatment volume for the prostate and seminal vesicle pelvic fields are 
at L5/S1 and the pelvic brim should be covered with up to a 2cm margin laterally to include the 
internal and external iliac nodal chains.   The inferior border of the treatment volume of the pelvic 
field and the posterior border on the treatment volume should have up to a 1.5 cm margin from the 
prostate and seminal vesicles to the block edge using any conformal technique.  The anterior 
border on the treatment volume should extend to the anterior aspect of the pubic symphysis.  The 
posterior boarded should be no more anterior than S2/3 ensuring at least a 1.5 cm margin 
posterior aspect of the SV.   
 
When using IMRT only the total prescribed dose of 70.2 Gy to the clinically involved structures is 
requested.  Normal tissue constraints can be applied at the discretion of the treating physician.   
 
1.0 Introduction 
 
The current standard of practice for patients seeking radiotherapeutic 
management who have a prostate-specific antigen  (PSA) level of at least 
10 ng/ml or biopsy Gleason score of 7 or higher but clinically localized 
adenocarcinoma of the prostate is 70 Gray of 3-dimensional conformal 
external beam radiation (3D CRT) and 6 months of androgen suppression 
therapy (AST).  This practice standard is based on significant 
improvement in overall survival noted from a randomized study of 70 
Gray 3D CRT with or with out 6 months of AST.1  
 
 
 
 
 
 
 


 
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The first documented prolongation in median survival for the use of 
cytotoxic chemotherapy has been reported with the use of Docetaxel for 
patients with hormone refractory and metastatic prostate cancer.2-3 Given 
this benefit in median survival attention has been given to the study of this 
chemotherapy agent in surgically managed patients with clinically 
localized high-risk disease.  Specifically, the Cancer and Leukemia and 
Group B is planning a phase III trial of radical prostatectomy with or with 
out neoadjuvant Docetaxel for these patients. However a randomized trial 
has not been developed to date for patients with high-risk disease managed 
primarily with external beam radiation and AST. 
 
Toxicity data from a phase I/II study of concurrent weekly Docetaxel and 
external beam radiation therapy (EBRT) has been reported.4 This study 
has shown that the maximum tolerated dose of Docetaxel with EBRT was 
20 mg/m2 and that the primary acute side effect was diarrhea, which was 
controlled in all cases with dietary modification and oral agents such as 
Imodium.   
 
Therefore, the rationale exists for the development of a phase III trial of 70 
Gray 3D CRT plus 6 months of AST with or without weekly Docetaxel at 
20 mg/m2. 
 
The rationale for the secondary endpoints listed in 2.2 and 2.3 are:   
 
A PSA DT <3 months has been shown to be a surrogate endpoint amongst 
men treated with RP or RT for PC but not amongst men treated with RT 
and 6 mos of ADT+/-Taxotere.  If a PSA DT <3 mos is also a surrogate 
for death from PC in men undergoing RT and 6 mos of ADT +/- Taxotere, 
it could then be generalized for use in design of future randomized trials 
building upon the RT + 6 mos ADT or RT and 6 mos ADT + Taxotere 
paradigms.  
 
Results of RTOG 0521 show improved overall survival (1-side p-value 
=0.04) to the addition of Taxotere to RT and 2 years of ADT yet this 
survival benefit appeared to be driven to a large extent by other cause 
death.  We are collecting detailed information on cause of death in DFCI 
05-043 (IST 16172) that can enable us to assess the hypothesis as to 
whether the reduced other cause mortality in the Docetaxel arm is from 
reduced cardiac death.  Given that we know about Taxol coated cardiac 
stents and a decreased risk of revascularization, Docetaxel, a sister drug to 
Taxol, may also be cardio protective. 8 
 
2.0 Study Objectives 
 
Primary Objective: 
 
2.1 
To determine if the 5-year estimates of overall survival are increased in 
patients receiving 6 months of AST, radiation therapy (RT), and 16 weeks 
of Docetaxel compared to those patients receiving 6 months of AST and 
radiation therapy in a population of patients known to be at high risk for 
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progression and death following 6 months of AST and radiation therapy. 
 
Secondary Objective: 
 
2.2 
To determine if the proportion of patients with a PSA doubling time of 3 
months or more is increased and PSA failure and cancer specific mortality 
is decreased in patients receiving 6 months of AST, RT, and 16 weeks of 
Docetaxel compared to those patients receiving 6 months of AST and RT 
in a population of patients known to be at high risk for progression and 
death following 6 months of AST and RT. 
2.3    To compare the safety profile between the two arms, including AE/SAE, 
late effect toxicities, and time to onset of cardiovascular events (non-fatal 
or fatal CVE). 
 
Exploratory Objective: 
 
2.4 To compare overall survival and mortality from prostate cancer, 
cardiovascular, or other causes by randomized treatment group within 
subgroups defined by (1) biopsy Gleason score (≤7 versus >7) (2) baseline 
comorbidity groups (3) baseline serum testosterone levels (Low versus 
normal).  
 
3.0 Patient Selection  
 
3.1      Eligibility Criteria 
 
3.1.1     Histologic confirmation of prostate cancer5 
 
3.1.2 
Clinical category T2c, T3a, T3b or T4 as per 2002 AJCC 
guidelines -OR- Clinical category T1b to T2b AND any one of the 
following: PSA > 10 ng/ml -OR- Gleason score ≥ (4+3=7) -OR- Any 
minor tertiary grade of 5 -OR- Gleason score ≥ (3+4=7) with 50% or more 
cores positive -OR- > 2.0 ng/ml rise in PSA during the year prior to 
treatment or a 2.0 ng/ml average annual rise in PSA based on any PSA 
values within 3 years prior to treatment  -OR- Positive radiographic 
findings of Seminal Vesicle Invasion (SVI) by endorectal coil MRI or 
biopsy proven SVI. 
 
PSA rise should be verified after the following criteria have been 
met:  
 
1) Abstinence from sexual activity/ejaculation 1 week prior 
2) No invasive procedures including but not limited to, 
colonoscopy, erMRI, cystsocopy, prostate needle biopsy, 2 
weeks prior. 
3) No horseback or bike riding 1 week prior. 
4) Genitourinary infection/inflammation ruled out 2 weeks 
prior. 
 
PSA should be repeated if any of the above conditions apply. 
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3.1.3 
No evidence of metastatic disease (-) bone scan and (-) lymph 
node   assessment (CT, MR) meaning pelvic lymph nodes with a 
long axis of 1.5 cm or less obtained within 6 months of study 
entry and prior to the initiation of hormonal therapy. 
 
3.1.4    A PSA should be obtained prior to the initiation of hormonal 
therapy and within 3 months of study entry, except when a 
Transurethral Resection of the Prostate (TURP) has been 
performed which has falsely lowered the prostate specific 
antigen (PSA).  In this case, the PSA drawn immediately prior to 
the TURP will be used as the baseline PSA, even if the PSA 
exceeds 3 months prior to entry. 
  
3.1.5      Adequate hematologic function: WBC > 3,000/ mm3, platelet 
count > 105/mm3, Hemoglobin > 8.0 g/dl obtained within 1 
month of study entry. 
 
3.16 
Creatinine <2.0 mg/dl, Total Bilirubin <ULN (except for 
Gilbert’s syndrome); AST and ALT and Alkaline Phosphatase 
obtained within 1 month of study entry within the range allowing 
for eligibility as shown in the table below.  In determining 
eligibility, the value of AST or ALT farthest outside the ULN 
should be used. 
 
 
AST or ALT: 
ALK PHOS: 
 ULN 
>1x but 1.5x  
>1.5x but 5x  
>5x ULN 
 ULN 
Eligible 
Eligible 
Ineligible 
Ineligible 
>1x but 2.5x  
Eligible 
Eligible 
Ineligible 
Ineligible 
>2.5x but 5x  
Eligible 
Ineligible 
Ineligible 
Ineligible 
>5x ULN 
Ineligible 
Ineligible 
Ineligible 
Ineligible 
 
                  
      
              
3.1.7      ECOG performance status of 0 or 1. (Appendix B) Patients with 
an ECOG performance status of 1 will not be excluded if 
wheelchair bound for injury or illness that would not impact his 
life expectancy. 
 
3.1.8      A free and/or total serum testosterone must be obtained within 
3months of patient entry. 
 
3.1.9      Age > 30 year 
 
3.1.10     Peripheral neuropathy: must be < grade 1 
 
3.1.11     Patients must agree to either abstain from sexual intercourse or                                
use a medically acceptable form of contraception while on 
chemotherapy treatment and for one month after completing 
chemotherapy treatment 
 
 
 
 
 
 


 
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3.1.12      Stratification will occur based on the following 2 factors:   
 
                                Gleason Grade <=6 to 7 OR 8 to 10 and PSA <=20 or >20 ng/ml  
 
(See Schema) 
 
3.2 Exclusion Criteria  
 
3.2.1      Prior history of malignancies that are < 5 years disease free 
except for any cancers found to be in-situ or would not likely 
impact a patient’s life expectancy with appropriate medical 
management. 
 
3.2.2 
Prior pelvic radiotherapy 
 
3.2.3 
Prior hormonal therapy (excluding up to 4 weeks prior to 
registration/randomization). 5-Alpha Reductase Inhibitors such 
as Finasteride and Dutasteride to treat Benign Prostatic 
Hypertrophy are allowed.  Patients being registered from sites 
outside of the USA are allowed a 2 week leeway if needed.  
 
 
3.2.4       Prior Radical Prostatectomy 
 
3.2.5       Individuals who are unable to tolerate lying still for a 5 - 10 
minute radiation treatment because of mental illness or other 
physical ailment. 
 
3.2.6.  
Patients with a history of severe hypersensitivity reaction to 
Docetaxel or other drugs formulated with polysorbate 80. 
 
4.0 Patient Entry 
 
            4.1 
Confirm eligibility; obtain confirmatory Central Pathology Report from 
Dr. Renshaw, a requirement for patient registration (See Section 9.0) 
 
4.2 
Baseline studies will be obtained (see Section 6.0)  
 
4.3        At the time of patient entry a Patient Registration Form and documents 
confirming eligibility (PSA/PSA Rise, Gleason sum, clinical stage, (-) 
bone scan, (-) lymph node by CT or MRI, CBC and differential, LFT’s, 
creatinine, ECOG, free and/or total serum testosterone, original 
pathology report, central pathology report, and the signed consent form 
should be faxed to the Project Staff at Dana-Farber Cancer Institute (fax) 
617-355-6115 (phone) 617-355-7264 for Evenings or sites outside of the 
USA (fax) (401)293-5681 Phone (401)-293-5680  
 
  
5.0 Treatment Plan 
 
 
 
 
 
 
 


 
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5.1 Total Androgen Suppression (AST) 
 
5.1.1 LHRH agonist will consist of either Eligard (Leuprolide 
Acetate) that will be given SC 7.5 mg q 4 weeks or 22.5 mg 
every 12 weeks or Lupron that will be given (7.5 mg IM. q 4 
weeks or 22.5 mg. IM. q 12weeks) or Zoladex 3.6 mg S.C. q 4 
weeks or 10.8 mg S.C. q 12 weeks. These medications will begin 
9 weeks prior to the start of radiation therapy (see section 5.3) for 
a total of 6 injections or 1 injection every 12 weeks for a total of 
2 injections, and will continue for a total of 26 weeks.  Any 
LHRH agonist may be used with any dosing schedule (e.g. 
monthly, 3 month depot, 6 month depot, etc.) as long as the total 
on study AST treatment does not exceed 26 weeks or 180 days.  
As per Section 5.13patients with up to 4 weeks of AST treatment 
prior to enrollment will not exceed a total of 30 weeks of AST 
treatment.  Patients being registered from sites outside of the 
USA are allowed a 2 week leeway if needed.  
 
 
 
 
5.1.2  Casodex will be administered 50 mg by mouth or Eulexin 250 mg. 
PO q 8 hours each day starting at least 2 days before the first Eligard, 
Lupron, or Zoladex injection and will continue for a total of 26 weeks (6 
months).  No missed or skipped doses will be made up after the 26 
weeks of therapy.  The generic form of Casodex (Bicalutamide) may be 
used if available. 
 
Up to 4 weeks of AST with either an LHRH agonist with or without a 
non-steroidal anti-androgen is permitted prior to patient 
enrollment as long as all eligibility criteria have been met, 
including labs and staging. The PSA and radiographic studies 
(bone scan, CT, MRI) must all be obtained prior to the start of 
AST and within the designated time frames (PSA within 3 
months of study entry and radiographic studies within 6 months 
of study entry) as outlined in Sections 3.103 and 3.104. This will  
not be counted as part of the 9 weeks of total AST to be 
administered prior to the start of radiation therapy as outlined in 
Section 5.1.1..  Patients being registered from sites outside of the 
USA are allowed a 2 week leeway if needed.  
 
5.1.3  
 
 
 
             Hormonal Therapy, per the above guidelines, may be administered by 
treating physicians at outside facilities as it is part of the standard of care.  It is the 
responsibility of the consenting physician’s study team to oversee and ensure that the 
hormonal therapy is administered according to study guidelines.  The consenting 
physician’s study team will also be responsible for entering all hormonal therapy data 
into the Electronic Data Capture System (eDC).   
 
 
 
 
 
 
 


 
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Time Zero is the date of randomization for men who began up to 4 
weeks of AST prior to randomization. Otherwise, Time Zero will 
be the date of initiation of hormonal therapy (LHRH agonist or 
anti-androgen, which ever started sooner).  It is conceivable and 
is permitted that due to unforeseen scheduling issues with the 
patient or physician that up to a 2 week allowance will be 
permitted without a violation for deviation from the protocol 
guideline for beginning chemotherapy and hormonal treatment 
after randomization.  Regardless of the definition of Time Zero, 
the study’s primary endpoint will be calculated from the date of 
randomization  
 
 
5.1.4 External beam radiation will begin at week 10 (+/- 5 days), and 
continue for 8 weeks through week 17.    
  
 
5.2 Chemotherapy (Group 2) 
 
5.2 1 Treatment with Docetaxel at 60mg/m2 q 3 weeks (1 hour infusion) 
for 3 cycles will begin with the initiation of the LHRH agonist and 
be followed by weekly Docetaxel at 20 mg/m2/week (1 hour 
infusion) beginning at week 1 of radiation therapy and continuing 
for 7 weeks. Although the recommended infusion time is 1 hour, 
this time period may be extended as per institution protocol.  If 
there is disease progression or unacceptable toxicities occur while 
on treatment, dose modifications may be made but Docetaxel will 
not exceed the recommended dose and will be completed on week 
16. 
 
5.2.2 Patients should receive weekly Docetaxel starting at week 10 or at 
the start of the first week of radiation therapy, but this may vary 
+/- 5 days due to uncontrolled circumstances (e.g., holidays or 
patients’ personal conflicts). 
 
5.2.3 Dexamethasone: All patients should undergo pre-medication and 
post-medication.  The following guidelines may be used or the 
standard of care for your institution may be followed:: 
 
The day before Docetaxel infusion:  8 mg p.o. in the morning and 8 mg 
p.o. in the evening. 
 
          The day of Docetaxel infusion:  8 mg p.o. 2 hours before Docetaxel              
          infusion and 8 mg p.o. that same evening.  
 
 
 
Note:  The dexamethasone dose may be modified at the physician’s 
discretion.  The physician may use IV corticosteroid as an alternative 
route of administration or in addition to by mouth corticosteroids. 
 
 
 
 
 
 
 


 
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The Docetaxel must be administered by an authorized study physician and at 
an authorized facility that has full IRB approval to enroll and treat patients on this 
protocol. 
 
5.3 External Beam Radiation Therapy 
 
5.3.1 
A PSA will be obtained prior to the start of radiation therapy 
(and approximately 2 months after the initiation of hormonal 
therapy). 
 
5.3.2 
Megavoltage linear accelerators (> 6 MV) with dose rates  
=/>200  cGy/min will be used.. 
 
5.3.3 
Diagnostic or treatment planning CT scans can be used to 
determine the position of the prostate and seminal vesicles. 
 
5.3.4 
External beam radiation therapy will commence within 4 weeks 
(+/- 5 days) after simulation and will not start on a Friday. 
5.3.5       45 Gy in 25 1.8 Gy doses of radiation therapy will be delivered 
to the prostate and seminal vesicles using a classic 4-field box 
technique or any conformal technique including IMRT or 
protons.  An intra-rectal immobilization or localization device 
may be used.  The prostate should be boosted for an additional 
25.20 Gy (14 doses of 1.8 Gy) using any conformal technique 
with up to a 1.5 cm margin from the prostate gland to the block 
edge.  In known cases of seminal vesicle invasion by digital 
rectal examination (Category T3b) or endorectal MRI, the 
involved seminal vesicle(s) will also be treated to a total dose of 
70.2 Gy 
Pelvic Lymph Nodes may be treated at the discretion of the 
physician using the following guidelines.    
 
The superior border of the treatment volume for the prostate and 
seminal vesicle pelvic fields are at L5/S1 and the pelvic brim 
should be covered with up to a 2cm margin laterally to include 
the internal and external iliac nodal chains.   The inferior border 
of the treatment volume of the pelvic field and the posterior 
border on the treatment volume should have up to a 1.5 cm 
margin from the prostate and seminal vesicles to the block edge 
using any conformal technique.  The anterior border on the 
treatment volume should extend to the anterior aspect of the 
pubic symphysis.  The posterior boarded should be no more 
anterior than S2/3 ensuring at least a 1.5 cm margin posterior 
aspect of the SV.   
 
When using IMRT only the total prescribed dose of 70.2 Gy to 
the clinically involved structures is requested.  Normal tissue 
constraints can be applied at the discretion of the treating 
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physician.  
 
5.3.6     Radiation therapy will be delivered once daily (Monday through    
Friday, holidays and machine maintenance excluded)  In the 
event that a patient needs to miss a radiation treatment due to 
weather conditions, illness, or personal reason(s), the physician 
needs to be notified.  If the physician approves with the missed 
day of radiation therapy, a violation will not need to be filed.  
Any missed days of radiation will be made up at the end of 
treatment and will be entered into the Electronic Data Capture 
System (eDC). 
 
 
5.3.7 
Dose should be prescribed to no less than a 95% isodose.  If 
prescribing 70.2 Gy to the 95% isodose line please note that 
100% isodose is receiving 73.7 Gy. 
 
 
5.3.8 
Per the physician’s discretion, the cone down may be done 
before or after the prostate and seminal vesicles field.  If during 
the prostate and seminal vesicles radiation a patient needs to stop 
because of acute radiation induced enteritis, the physician may 
proceed to the cone down field.  Once the cone down course is 
completed, the physician may decide to reintroduce the prostate 
and seminal vesicles field if tolerated or complete the radiation 
using the cone down field.  
 
 
The following guidelines have been recommended to maximize the 
radiation therapy dose to the critical tumor containing volume while 
still adhering to the protocol guidelines and while still protecting 
normal structures (particularly the rectum): 
 
 
Prescribe 70.2 Gray in 1.8 Gray fractions with the option to have 
dosimetry  
 
(a) Keep the Planning Treatment Volume (PTV) minimum dose 
at 105% of prescription 
 
(b) Place the hot spots (typically 3 to 5%) in the posterior and 
lateral aspect of the PTV 
 
(c) Suggest to maintain the rectal V70 less than 20% as per 
QUANTEC guidelines 
 
This enables 8 to 10% more dose than prescription to the critical 
tumor containing volume (i.e. peripheral zone) of the PTV to a 
dose range of 75.8 to 77.2 Gray. 
 
 
 
 
 
 
 
 


 
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             External Beam Radiation Therapy, per the above guidelines, may be 
administered by treating physicians at outside facilities as it is part of the standard of 
care.  It is the responsibility of the consenting physician’s study team to oversee and 
ensure that the radiation therapy is administered according to study guidelines.  The 
consenting physician’s study team will also be responsible for entering all radiation 
therapy data into the Electronic Data Capture System (eDC).   
 
The Radiation Therapy dose should be checked by two individuals to ensure that the 
prescription is written within the protocol guidelines.  These individuals may be from 
nursing, the physician’s group or physics. 
 
 
5.4 Adverse Events and their Management 
 
5.4.1   Anticipated Toxicity: 
 
5.4.1.1 RADIATION THERAPY:  
 
All patients are seen weekly by their radiation oncologist during 
radiation therapy. The related morbidity is discussed with the 
patient using a separate radiation therapy consent form.  
Common immediate side effects include fatigue, skin redness 
and irritation in the peri-anal and gluteal folds as well as bowel 
or bladder irritability.  When radiation therapy is delivered in 
conjunction with Docetaxel chemotherapy, there is an increased 
risk of diarrhea, which can be successfully managed with dietary 
modification and oral agents such as Imodium.  Late effects (> 6 
months following treatment) of radiation therapy include 
permanent impotence or rectal bleeding.  There is a small 
probability (< 5%) of injury to the bladder, urethra, bowel and 
other tissues in the pelvis.   
 
5.4.1.2 ANDROGEN SUPPRESSION THERAPY (AST) 
 
The related morbidity is discussed with the patient using a 
separate medical oncology consent form.  Common immediate 
side effects include fatigue, hot flashes, loss of muscle mass, 
mild anemia, decreased sexual desire and impotence. Less 
frequent toxicities are gynecomastia, diarrhea, and pain at the 
injection site.  Cardiovascular or cerebrovascular accidents and 
skin rashes have rarely been reported. 
 
5.4.1.3 DOCETAXEL 
The following adverse events have been identified from clinical 
trials and/or post-marketing surveillance. Because they are 
reported from a population of unknown size, precise estimates of 
frequency cannot be made.  
 
 
 
 
 
 


 
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Taxotere has been reported to be associated with diffuse body 
ache, chest pain, radiation recall phenomenon, some abnormal 
heart rhythms (atrial fibrillation) and blood clots in the legs or 
lungs, ECG abnormalities, rapid heart rate, heart attack, skin 
rashes, allergic reactions, abdominal pain, decreased appetite, 
constipation, ulcers, esophagitis, inflammation of the colon, 
infections in the colon, dehydration, bleeding, confusion, 
conjunctivitis, tearing of the eyes, shortness of breath, fluid in the 
lungs, pneumonia,  kidney malfunction and neuropathy.  Very 
rarely liver inflammation, seizures, fainting, visual disturbances 
(flashing lights), scarring of the lungs have been reported 
typically occurring during drug infusion and in association with 
an allergic reaction.  These were reversible upon discontinuation 
of the infusion. 
Hematologic and other toxicity is increased in patients with 
elevated baseline liver function tests (LFTs) and therefore our 
eligibility criteria exclude patients with a total serum bilirubin 
above the upper limit of normal  (except in known congenital 
abnormality) or an AST, ALT, or ALK phos greater than 1.5 
times the upper limit of normal.   
 
5.4.2 Toxicity Management 
 
We expect that all side effects associated with radiation therapy, 
total androgen suppression and Docetaxel to be controllable.  
The use of routine skin care and a low residue diet will be 
employed routinely and will temporize most of the acute side 
effects.  Liver function tests will be obtained at the time of study 
entry for baseline purposes and every 3 weeks thereafter until the 
6-month drug course is completed.  LFTs should continue to be 
monitored until they are within normal limits.  It will be up to the 
discretion of the physician to continue obtaining liver function 
tests after the 6-month drug course is completed.     
 
Patient 
treatment(s) 
(including 
hormonal, 
radiation 
or 
chemotherapy) may be held, discontinued, and/or restarted at the 
physician’s 
discretion 
using 
the 
recommended 
dose 
modifications outlined below when applicable.   
 
Any event requiring a dose modification to any of the 
aforementioned treatments should be reported on the case report 
Treatment/Toxicity form and, if applicable, a serious adverse 
event (see Section 5.4.2.4). 
 
5.4.2.1 LHRH Agonist   
 
Mechanism of action of LHRH Agonists 
 
Eligard (Leuprolide acetate) is a synthetic decapeptide analogue 
a a 
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of Luteinizing Hormone Releasing Hormone (LHRH).  It acts 
as a potent inhibitor of pituitary gonadotropin secretion when 
administered in the biodegradable formulation.  Chronic 
administration of the drug leads to sustained suppression of the 
pituitary gonadotropins.  Consequently serum levels of 
testosterone fall to castrate levels 2 - 4 weeks after the initiation 
of therapy.  During routine screening of Eligard, no significant 
pharmacological activity was apparent in the cardiovascular 
system, 
respiratory, 
central 
nervous, 
renal, 
metabolic, 
coagulation, or gastric acid secretory systems.  The acute toxicity 
of Eligard has been found to be very low in relation to its 
pharmacologic potency.  Studies have shown that serum levels of 
testosterone can be reduced and maintained within the castrate 
level resulting in objective evidence of tumor regression.  Other 
than the occasional transient worsening of cancer symptoms 
(tumor flare in 1% - 5% of patients) due to an initial temporary 
rise in testosterone levels on initiating therapy, no significant 
toxicity apart from that attributed to castration (hot flashes, 
decreased erections, impotence) has been reported.  Reports 
show that the incidence of localized or generalized rash with 
patients receiving Eligard is 6%.  There have been no reports of 
bronchospasm in the United States Clinical Trials Program.  In 
general, allergic reactions have been extremely uncommon with 
Eligard therapy.  There have been isolated reports of urethral 
obstruction, uriticaria, or spinal cord compression.  Shortness of 
breath, cardiac arrhythmia, hyperglycemia, back pain, acute 
kidney failure, pneumonia, confusion, and weakness were 
reported in three men.  No episodes of anaphylaxis as result of 
Eligard therapy have occurred in the past. 
 
Lupron and Zoladex have similar toxicities. 
 
5.4.2.2 Casodex 
 
Mechanism of Action of Casodex 
 
Casodex exerts its antiandrogenic action by inhibiting androgen 
uptake and/or inhibiting nuclear binding of androgen in target 
tissues such as the prostate. 
 
The reported side effects of Casodex include diarrhea, abdominal 
cramping or pain, anemia, and mild elevation of liver functions 
without clinical manifestations, gynecomastia, and decrease in 
libido and/or impotence. Refer to the package insert for 
additional information. 
 
    Dose Modification Schedule Related to Casodex/Eulexin 
 
If a patient experiences any intolerable side effects, Casodex or 
Eulexin will be withheld until the side effects resolve.  Casodex 
an  
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may be restarted at 50 mg per day.  Alternatively, Casodex 
may be discontinued at the discretion of the physician.   If patient 
is experiencing gastrointestinal discomfort (cramps, diarrhea), 
Eulexin will be withheld until the side effects subside and then 
reintroduce at a tolerated dose not to exceed 750 mg daily.  
If a patient experiences a rise in the SGOT or SGPT that is 
greater than two times the upper limit of normal, then Casodex or 
Eulexin will be withheld until the liver function tests return to the 
patient’s baseline value or within normal limits. Once 
normalization occurs Casodex can be restarted at 50 mg per day. 
Eulexin can be restarted at a decreased dose and increased as 
tolerated per the physician’s discretion.  If the liver function tests 
become elevated again above two times the upper limit of normal 
then Casodex or Eulexin will be permanently discontinued.  
Once elevation of the liver function tests has been documented 
the liver function tests should be obtained every 3 weeks until 
two consecutive sets of normal LFT's are obtained.  Once the 6-
month course of hormonal therapy is completed, LFTs will be 
drawn at the discretion of the treating physician. Skipped or 
missed doses of Casodex or Eulexin will not be made up. 
 
5.4.2.3 Docetaxel 
 
Mechanism of Action of Docetaxel 
 
Docetaxel is an antineoplastic agent that acts by disrupting the 
microtubular network in cells that is essential for mitotic and 
interphase cellular functions. Docetaxel binds to free tubulin and 
promotes the assembly of tubulin into stable microtubules while 
simultaneously inhibiting their disassembly. This leads to the 
production of microtubule bundles without normal function and to 
the stabilization of microtubules, which results in the inhibition of 
mitosis in cells. Docetaxel's binding to microtubules does not alter 
the number of protofilaments in the bound microtubules, a feature 
that differs from most spindle poisons currently in clinical use. 
 
   
Dose Modification Schedule Related to Docetaxel  
 
Dose Level 
Docetaxel 
Every 3 week 
Chemotherapy 
Weekly 
Chemoradiation 
Level 0 
60mg/m2 
 20mg/m2 
Level -1 
54mg/m2 
16mg/m2 
Level -2 
48mg/m2 
12mg/m2 
  
 
 
 
 Dose adjustments should be based on clinical assessments done 
on the day before or the day of each treatment cycle.  During the 
every 3 week chemotherapy treatment, the docetaxel will not be 
escalated once reduced.  No matter what dose reductions occur 
during the every 3 week chemotherapy treatment, once the 
Dan  Farber
 
 
 
 
 


 
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patient starts the weekly chemoradiation treatment, the patient 
should start at 20mg/m2.  If the weekly chemoradiation dose is 
reduced, it will not be re-escalated.   
If the patient is unable to tolerate the level -2 dose reduction 
during the weekly chemoradiation treatments, the docetaxel 
should be discontinued.  
 
Up to 4 dose reductions are allowed: 2 in the every 3 week 
chemotherapy and 2 in the weekly chemoradiation therapy. 
(Excluding Neurotoxicity and Erythema desquamation). 
 
 
*There are two exceptions to this rule: 
 
Neurotoxicity:   For patients who are experiencing neurotoxicity, 
if the disability persists after 2 reductions, on either the every 3 
weeks chemotherapy treatments or on the weekly chemoradiation 
treatments, all docetaxel should be discontinued.  If during the 
every 3 week chemotherapy treatments the disability resolves to 
grade 2 or less (after 2 reductions) the patient may continue on 
the full dose of the weekly chemoradiation treatment. 
 
Erythema, desquamation:  For patients who are experiencing 
erythema, desquamation Grade 3-4: Hold Docetaxel until 
resolution to < grade 2, and then decrease one dose level for next 
cycle of therapy. If toxicity resolves to < grade 2 during the 
every 3 week chemotherapy dose the patient can continue with 
the full 20 mg/m2 weekly chemoradiation dose as planned .  If 
toxicity recurs, docetaxel should be permanently discontinued. 
 
If the Neurotoxicity and Erythema Desquamation does not 
resolve within 21 days, the docetaxel should be permanently 
discontinued.    
 
 
Preparation and administration of Docetaxel (see Appendix C) 
 
5.4.2.3.1 Hematologic toxicities 
 
Weekly blood counts will be obtained throughout Docetaxel 
treatment including on the day before or the day of each cycle 
(weeks 1-17).  If granulocytes are <1,000/microliter or platelets are 
<100,000/microliter, hold Docetaxel.  If Docetaxel is held, repeat 
counts weekly and reinstitute therapy when granulocytes > 
1,000/µL and platelets > 100,000/µL; if greater than 1 week delay, 
reinstitute therapy at one lower dose level (i.e., level -1 for first 
granulocytopenia\thrombocytopenia or level -2 for second episode 
of granulocytopenia\thrombocytopenia) for Docetaxel. 
 
Dose adjustments for Febrile Neutropenia 
 
 
 
 
 
 


 
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For febrile neutropenia on any day of any cycle, defined as ANC < 
500 and T > 38.2°C (100.8°F), Docetaxel should be decreased one 
dose level in all subsequent cycles.  
 
5.4.2.3.2 Hepatic Dysfunction 
 
 
 
Dose Modifications for Abnormal Liver Function (Docetaxel) 
*Both AST and ALT should be drawn.  The more abnormal of the 
two values (AST or ALT) should be used in determining the dose.  
 
 
AST or ALT: 
ALK PHOS: 
 ULN 
>1x but 1.5x  
>1.5x but 5x  
>5x ULN 
 ULN  
Full Dose 
Full Dose 
Hold* 
Hold* 
>1x but  2.5x  
Full Dose 
Full Dose 
Hold* 
Hold* 
>2.5x but  5x  
Full Dose 
Reduce Dose 
Hold* 
Hold* 
>5x ULN 
Hold* 
Hold* 
Hold* 
Hold* 
 
For q3 week Docetaxel therapy or weekly Docetaxel therapy with 
 
radiation: 
 
*Hold until recovered and then re-treat at a reduced dose (see 
section 5.4.2.3). “Recovered” is defined as meeting the study 
baseline eligibility criteria. 
 
Bilirubin: Docetaxel should not be administered to patients with 
serum total bilirubin >ULN unless they have Gilbert’s syndrome as 
discussed below..  If serum total bilirubin is >ULN on treatment 
day, hold Docetaxel until serum total bilirubin is  ULN 
(maximum 21 days), then re-treat at a reduced dose (see section 
5.4.2.3). For patients with an elevated bilirubin due to Gilbert’s 
syndrome (and AST, ALT, ALK phos within normal limits), 
Docetaxel dose modifications will be based solely on AST, ALT 
and Alkaline Phosphatase values.   
 
5.4.2.3.3 Neurotoxicity 
 
Docetaxel dose modifications for neurotoxicity Grade 3 sensory 
loss or paresthesia interfering with activities of daily living or 
Grade 4 permanent sensory loss that interferes with function hold 
until the toxicity resolves to grade 2 or less and then reinstitute 
Docetaxel at dose level -1. If during the every 3 week 
chemotherapy treatments the disability resolves to grade 2 or less 
(after 2 reductions) the patient may continue on the full dose of 
the weekly chemoradiation treatment.  If disability persists after 
2 dose reductions, on either the every 3 weeks chemotherapy 
treatments or on the weekly chemoradiation treatments, all 
docetaxel should be discontinued.  . 
 
 
 
 
 
 


 
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.Up to 2 dose reductions are allowed. 
 
5.4.2.3.4 Gastrointestinal toxicity 
 
For > grade 2 oral ulceration, dysphagia, diarrhea, nausea or 
vomiting, hold Docetaxel therapy. Once symptoms resolve to 
grade 1 or less, Docetaxel treatment should be resumed at -1 dose 
level. 
 
5.4.2.3.5 Fluid retention 
 
There are no dose reductions for fluid retention and treatment for    
patients with fluid retention is at the discretion of the treating 
physician.  Below are some general guidelines that may be 
followed:   
 
Patients developing new onset edema, progression of existing 
edema, or another sign of fluid retention (eg. 2 pound weight gain) 
are to be treated with oral diuretics.  Regimens found to be 
effective in the management of fluid retention due to Taxotere are 
listed below. 
 
• Triamterene/hydrochlorothiazide one capsule po qd up to tid. 
• Furosemide 40 mg po daily if edema progresses despite 
Triamterene/hydrochlorothiazide therapy.  Potassium 
supplementation should be given as needed. 
• If after a two-week trial, furosemide 40 mg po qd is ineffective, the 
patient may be treated with furosemide 20 mg po daily plus 
metolazone 2.5 mg po daily with potassium supplementation as 
needed. 
• Further therapy should be customized depending upon the clinical 
situation.  The clinical tolerance of the patient, the overall tumor 
response and the medical judgment of the investigator will 
determine if it is in the patient’s best interest to continue or 
discontinue treatment. 
 
5.4.2.3.6 Erythema, desquamation  
 
Grade 3-4: Hold Docetaxel until resolution to < grade 2, and then 
decrease one dose level for next cycle of therapy    If toxicity 
resolves to < grade 2 during the every 3 week chemotherapy dose 
the patient can continue with the full 20mg/m2 weekly 
chemoradiation dose as planned .  If toxicity recurs, docetaxel 
should be permanently discontinued.   Up to one dose reduction is 
allowed. 
 
5.4.2.3.7 Hypersensitivity Reactions 
 
 
 
 
 
 
 


 
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Hypersensitivity Reactions 
There are no dose reductions for anaphylaxis; patient should be 
taken off protocol.  For all other hypersensitivity reactions, please 
use the guidelines below or follow the Standard of Care for your 
institution:                                                                                                                              
MANAGEMENT OF ACUTE HYPERSENSITIVITY 
 
 
 
 
 
Severity of Symptoms 
Treatment Guidelines 
Mild symptoms: localized cutaneous 
reactions such as mild pruritus, flushing, 
rash 
· 
consider decreasing the rate of infusion until recovery 
from symptoms, stay at bedside and monitor patient 
· 
then, complete Taxotere infusion at the initial planned rate 
Moderate symptoms: any symptom that 
is not listed above (mild symptoms) or 
below (severe symptoms) such as 
generalized pruritus, flushing, rash, 
dyspnea, hypotension with systolic  
BP > 80 mm Hg  
 
· 
interrupt Taxotere infusion 
· 
give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV; monitor patient until resolution 
of symptoms  
· 
resume Taxotere infusion after recovery of symptoms; 
depending on the physician’s assessment of the patient, 
Taxotere infusion should be resumed at a slower rate, 
then increased incrementally to the initial planned rate, 
(eg. infuse at an 8 hour rate for 5 minutes, then at a 4-h 
rate for 5 minutes, then at a 2-h rate for 5 minutes, then 
finally, resume at the initial planned rate. 
· 
depending on the intensity of the reaction observed, 
additional oral or IV premedication with an antihistamine 
should also be given for the next cycle of treatment, and 
the rate of infusion should be decreased initially and then 
increased back to initial planned rate, (eg. infuse at an 8 
hour rate for 5 minutes, then at a 4-h rate for 5 minutes, 
then at a 2-h rate for 5 minutes, and finally, administer at 
the initial planned rate.) 
Severe symptoms: any reaction such as 
bronchospasm, generalized urticaria, 
systolic BP  80mm Hg, angioedema 
· 
immediately discontinue Taxotere infusion  
· 
give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV and/or epinephrine as needed; 
monitor patient until resolution of symptoms. 
· 
he same treatment guidelines outlined under moderate 
symptoms (i.e. the third and fourth bullets) should be 
followed. 
Anaphylaxis (NCI grade 4 reaction) 
· 
NO FURTHER STUDY DRUG THERAPY 
 
Patient 
treatment(s) 
(including 
hormonal, 
radiation 
or 
chemotherapy) may be held, discontinued, and/or restarted at the 
physician’s 
discretion 
using 
the 
recommended 
dose 
modifications when applicable. 
 
 
5.4.2.3.8 Dose Modification for Obese Patients 
 
There is no clearly documented adverse impact of treatment of obese 
patients when dosing is performed according to actual body weight. 
D
a a b r
 
 
 
 
 


 
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Therefore, all dosing is to be determined solely by the patient’s 
actual weight without any modification unless explicitly described in 
the protocol. This will eliminate the risk of calculation error and the 
possible introduction of variability in dose administration. Failure to 
use actual body weight in the calculation of drug dosages will be 
considered a major protocol deviation. 
 
 
5.4.2.4 Adverse Event Reporting: 
 
 
Definitions: 
 
 
An adverse event (AE) is any untoward medical occurrence in a patient 
 
or clinical investigation subject administered a pharmaceutical product 
 
and which does not necessarily have a causal relationship with this 
 
treatment.    
 
 
 
An AE can therefore be any unintended and unfavorable sign 
 
(including a clinically significant abnormal laboratory finding, for 
 
example), symptom or disease temporally associated with the use of a 
 
medicinal product, whether or not considered related to the medicinal 
 
product. 
 
 
An AE includes: 
• An exacerbation of a pre-existing illness or symptom 
• Post-treatment events that occur as a result of protocol-
mandated procedures 
• A condition detected or diagnosed after study drug 
administration 
 
 
An AE does not include: 
• The disease or disorder being studied or signs and symptoms 
associated with the disease/disorder unless there is an 
unexpected worsening of the subject’s condition 
• A pre-existing disease or condition present at the start of the 
study that did not worsen 
• Elective medical or surgical procedures unless resulting from 
a serious adverse event (see SAE definition below) 
• An overdose of the study drug or concurrent medication 
without any clinical sign or symptom 
 
 
 
Adverse events will be recorded from the start of study  
treatment 
through completion of study treatment.  AEs not resolved at the end of 
study treatment will be recorded as ongoing. 
 
 
 
Please note that adverse events should be documented in the source records of 
each facility but only Serious Adverse Events will be recorded in the electronic 
Data Capture System (eDC) after being reported to the DFCI IRB and IRB or 
Ethics Committee of record 
 
 
 
 
 
 


 
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A serious adverse event (SAE) is any adverse event occurring during 
study treatment or within 30 days of the last dose of study drug that:  
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing 
hospitalization 
• results in persistent or significant disability/incapacity 
• a congenital anomaly / birth defect 
 
 
The definition of serious adverse event (experience) also includes 
important medical event.  Medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes 
listed in the definition above.  These should also usually be considered 
serious. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
 
In addition, the Dana-Farber Cancer Institute IRB requires SAE reporting 
of any Grade 2 (moderate) and Grade 3 (serious) Events that are 
Unexpected and Possibly, Probably or Definitely Related/Asssociated with 
the Intervention.  Grade 4 neutropenia is an expected toxicity from the 
Docetaxel.  Only Grade 4 neutropenia with infection will require reporting 
as an SAE.  Please note that the Common Toxicity Criteria Volume 3.0 
(CTCAE) is used for this study. 
 
 
The definition of “related” is that there is a reasonable possibility that the 
drug caused the adverse experience. 
All SAEs should be immediately documented using the Dana-Farber 
Cancer Institute (DFCI) SAE Reporting form.  Please refer to the 
Investigator Study Notebook Vol II for the SAE reporting form...  The 
Medical Monitor(s) at the DFCI will determine if a MedWatch 3500A 
form needs to be filed and will file one if applicable.  SAE should be 
forwarded to: 
 
 
Anthony V. D’Amico, M.D. Ph.D.  
 
   
  
 
 
 
 
 
 
 
 
 
 
 
Evenings and sites outside of USA 
 
 
 
 
 
 


 
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Office: 401-293-5680 
 
 
 
Any questions pertaining to serious adverse events (SAEs) should be forwarded to the 
Project Manager, 
. 
 
  
The Principal Investigator must be informed by the site of an SAE within 24 hours of 
becoming aware of any SAE that occurs during the course of the clinical study. All 
serious adverse events must be reported, whether or not they are considered causally 
related to the study drug. Appropriate clinical, diagnostic, and laboratory measures 
must be performed to delineate the cause of the SAE in question and the results 
reported. All tests that reveal an abnormality considered drug related should be repeated 
at appropriate intervals until:  
• The cause is determined 
• A return to baseline value occurs 
• Stable results over 2 to 3 consecutive readings that are clinically acceptable and 
safe for the patient 
The Principal Investigator is required to assess the causal relationship to the study 
drug(s) for each SAE to determine if the event is associated with the use of the 
drug.  Events should be classified as associated with the use of the drug if there 
is a reasonable probability that the experience may have been caused by the 
drug.  The investigator is also responsible for informing the IRB and/or the 
Regulatory Authority of the SAE as per local requirements. 
 
and 
 
  
Sanofi - Aventis Pharmaceuticals Global Pharmacovigilance and Epidemiology 
 
          
 
 
 
 
 
and 
 
Attention: Casodex Investigator Sponsored Study (ISS) Safety Representative, 
 
 
 
 
5.4.3 Criteria for removal from study:  
 
• Patient decision to withdraw from the study 
• Patient noncompliance with the requirements of the protocol 
• A patient may be removed from the study if it is believed that  
            the constraints of the protocol are detrimental to the patient health  
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• Inability to deliver the planned radiation, LHRH agonist or  
   Docetaxel treatment  
 
A patient may be removed for an expected CTC Grade 3 or greater toxicity, any unexpected 
CTC grade 3 or greater toxicity that is definitely or probably related to study drug, or with 
disease progression during the first 6 months of treatment. 
 
Common Toxicity Criteria http://ctep.cancer.gov/reporting/ctc.html 
 
 
 
 
 
 




 
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not be required for any missing data as long as survival information has been 
obtained and entered. 
 
Every effort will be made to obtain survival information on all patients.  This may 
include patients who have been previously lost to follow up.  
 
Survival information will be obtained on all patients except for those who 
specifically requested that no further information be collected.   
 
 
 
Second malignancies/new primary malignancies need to be recorded for all patients once identified. 
 
  1 The Medical History and Physical Exam must be completed within 4 weeks prior to or within 2 weeks after study entry and prior to the start of 
chemotherapy.  Assessment and documentation of any of the following should be included in the Medical History at baseline, follow-up, and survival:  (These 
should be recorded if they are present before treatment begins or anytime after (during follow up and survival visits). 
   
Diabetes – If yes IDDM or NIDDM 
 
 
 
 
Hypertension 
Hypercholesterolemia 
 
 
 
 
 
Pulmonary Embolism 
Coronary Artery Disease 
 
 
 
 
 
Arrhythmias 
Congestive Heart Failure 
 
 
 
 
 
Heart Attack (MI) 
Peripheral Vascular Disease   
 
 
 
 
Stroke or TIA 
Cardiomyopathy   
 
 
 
 
 
 
Please include any Medical Management or Surgical Procedures for the treatment of Coronary Artery Disease for example CABG, Stents, Angioplasty and 
Medications. 
 
 
     
 
  2 A Gleason pattern score of prostate tumor histology is requested.  Central Pathology Review of all original prostate biopsy material is required and will be 
performed by Dr. Andrew Renshaw at the Baptist Hospital of Miami (Section 9.0) 
 
3 PSAs may be drawn more frequently than the required six month and annual time points during the follow-up period; however, the interim PSA 
values will not be used to determine PSA failure and/or progression unless there is a significant rise and the physician decides to initiate or add a 
new salvage therapy.  Salvage therapy is defined as medical or surgical hormonal ablation. In these situations the PSA on which the physician 
based his decision to initiate salvage therapy will be considered the time of PSA failure. 
 
   4 Bone scans will be obtained within 6 months of study entry.  Bone scans or PET scans will be obtained for PSA Failure and Progression at the discretion 
of the treating physician.  Record all bone scans and results in the Edc system.  .   
 
   5Lymph node assessment, obtained within 6 months prior to study entry, can be a CT or MRI of the pelvis and is considered negative if the long axis of the 
pelvic lymph node is 1.5 cm or less. 
 
  6 After completion of the 26 weeks of study treatment, CBCs will be done according to the follow-up schedule of every 6 months for 5 years and then 
annually thereafter and may be eliminated once they have normalized or returned to patient’s baseline or at the discretion of the treating physician. 
 
    7 Liver function tests will be obtained within 1 month prior to study entry for baseline purposes and every 3 weeks after study entry for the 26 weeks of 
study treatment.    
 
    8Baseline erectile function should be recorded prior to the initiation of hormone therapy for accurate assessment. 
 
   9 Free and/or total serum testosterone (preferably total) will be obtained at baseline (within 3 months prior to study entry).  After radiation therapy +/- 60 
days at: 6 months, 18 months, 36 months, at time of PSA failure (see section 7.1), at time of progression (see section 7.2), and when the patient is taken off 
study (annually) if obtainable. 
 
10 Survival status is required for all randomized patients regardless of whether they complete the study treatment unless they have withdrawn 
consent to be followed.  For patients who are off study, every effort should be made to obtain annual survival status.  If available, enter PSA and 
Testosterone levels, late effects, all salvage therapies and radiographic findings.  This may be obtained via telephone assessment or from 
documented office visits.   
 
11 Late effects will be focused on GU/GI including Urinary/Fecal Incontinence; Hematuria; Diarrhea; Rectal Bleeding; and other.  Please note if 
GU/GI late effects are not reported in source documentation, they will be recorded in the Electronic Data Capture as negative.  This information 
may be obtained via telephone assessment. 
 
 
 
 
 
For baseline studies the following time intervals will be accepted prior to 
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registration: 
 
 
1 month: CBC and Diff, LFT's, and Creatinine 
 
 
3 months: PSA and Free and/or Total Serum Testosterone 
 
 
6 months: (Lymph node assessment) CT or MRI of the pelvis, bone scan  
 
 
No time limit: Diagnostic Biopsy 
 
Once a patient is taken “off study” for any reason including additional salvage therapy, 
long-term follow-up will continue annually to assess PSA, second malignancies and 
survival. 
 
 
6.1 Data Collection  
 
For each patient enrolled, an On-Study Visit must be completed in the Electronic 
Data Capture (eDC) system. This does not apply to those patients who fail 
screening.  For patients who sign consent but fail screening they should be 
recorded on the Patient Screening Log.   For patients who are randomized but do 
not receive study treatment or are “off study”, a Survival Form will be 
completed annually, unless the patient withdraws consent to be followed. If a 
patient is withdrawn from the study because of a treatment-limiting adverse 
event, thorough efforts should be made to clearly document the outcome.  
 
All forms are to be entered electronically via the Electronic Data Capture System 
(eDC).   The data from the On-Study visit should be completed within 2 weeks 
of patient registration.  The data from the Follow-up visit should be submitted 
within one month of patient visits or assessments.   
 
7.0 Modality Review 
 
7.1 PSA failure 
 
A secondary endpoint of this study is freedom from PSA failure and PSA 
Doubling Time.   PSAs may be drawn more frequently than the required six 
month or annual time points during the follow-up period; however, the interim 
PSA values will not be used to determine PSA failure unless there is a 
significant rise and the physician decides to initiate salvage therapy. Salvage 
therapy is defined as a medical or surgical hormonal ablation.  This may include, 
but is not limited to, standard marketed antineoplastic therapies including 
antiandrogens, other hormonal agents, cytotoxic chemotherapy agents, and 
biologic response modifiers.  In these situations the PSA on which the physician 
based his decision to initiate salvage therapy will be considered the time of PSA 
failure. 
 
PSA failure is defined as any single PSA value that exceeds the Nadir PSA level 
+ 2 ng/ml.  The patient is considered to have sustained PSA failure on the date of 
that single PSA.  At the time of PSA failure a bone scan or PET scan should be 
obtained at the discretion of the treating physician.   (See section 6.0 footnote4). 
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Salvage medical or surgical hormonal ablation is recommended to be 
delivered no later than a PSA level of 10 ng/ml or at the time of a positive bone 
or PET scan whichever comes first.  However, the discussion of salvage therapy 
is to provide guidance to the investigator regarding treatment at the time of 
progression; this is not a protocol requirement.  Treatment at the time of 
progression is at the discretion of the physician and patient; however, PSAs are 
required every 6 months or at annual time points following PSA failure as 
defined in Section 7.1.   
 
7.2 Progression (2nd PSA failure after salvage therapy) 
 
Progression is two consecutive PSA rises of at least 0.2 ng/ml above the PSA 
nadir following salvage therapy or once a new salvage therapeutic intervention 
(including an antiandrogen withdrawal) has been introduced because of concern 
regarding progression.   At the time of progression, the bone scan or PET scan 
should be obtained every year until the bone scan or PET scan is positive at the 
discretion of the treating physician.  (See section 6.0 footnote4). Once the bone 
scan or PET scan is positive subsequent bone scans or PET scans can be 
obtained at the discretion of the treating physician.   
 
7.3 Distant Failure 
       
The time to distant failure will be defined as the time from randomization until 
the documentation of a positive bone scan/PET scan or other biopsy proven 
metastatic disease.  
 
7.4 Survival 
       
The primary end point of this study is overall survival.  Prostate cancer-specific 
survival is a secondary endpoint.  Upon the death of a patient, the cause will be 
determined by the treating physician with all deaths being attributed to prostate 
cancer if the patient had evidence of a rising PSA on salvage hormonal therapy 
and/or a previously documented positive bone scan or PET scan.  The survival 
time will be measured from the date of randomization. For patients who are off 
study, every effort should be made to obtain annual survival status.  If available, 
enter PSA and Testosterone levels, late effects, all salvage therapies and 
radiographic findings.  This may be obtained via telephone assessment or 
documentation from office visits.   
 
8.0 Statistics 
 
8.1 General Study Design 
 
The primary endpoint of the study is overall survival, defined as time from 
randomization to death from any cause.  Important secondary endpoints include 
prostate cancer-specific survival and PSA progression-free survival.  Toxicity will 
also be examined. Patients will be stratified for balancing purposes based on 
Gleason Grade and PSA.  Treatments will be assigned using permuted blocks within 
strata with dynamic balancing within institutions.  An intent-to-treat analysis is 
planned for the study as its primary analysis, including all patients as randomized. 
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8.2 Sample Size Determination 
 
8.2.1 Original Design 
Patients who are randomized to RT + AST are expected to have overall survival at 5 
years of 84% based on the results of two randomized studies.1,7 Assuming an 
exponential distribution, this is equivalent to median overall survival of 19.9 years.   
It is hypothesized that patients randomized to RT + AST + Chemotherapy would 
have overall survival at 5 years of 92%, or median survival of 41.6 years.  We 
assume that the distribution is exponential with a constant failure (hazard) rate and 
that accrual is uniform during the accrual period.  With accrual of 70 eligible 
patients per year for 5 years and 4 years of additional follow-up, the study will have 
power of 80% using a one-sided log rank test with significance level of 5%.  Full 
information will be achieved when approximately 53 patients have died. 
 
Two interim analysis of overall survival are planned at 33% (17 deaths) and 66% 
(35 deaths) of information.  The final analysis will be conducted when 53 deaths 
have been observed. Early stopping for efficacy will be monitored using O’Brien 
Fleming use function boundaries.  The O’Brien Fleming boundary at 33%, 66% and 
100% information are 3.2181, 2.1546, and 1.6937 with corresponding one-sided 
normal significance levels of 0.0006, 0.0156 and 0.0452.  Monitoring for early 
stopping in favor of the null hypothesis (lack of difference in overall survival) will 
be done using repeated confidence interval methodology similar to that described by 
Jennison and Turnbull (1989).  At each interim analysis a nominal (1-2*alpha) % 
confidence interval on the hazard ratio will be computed, where alpha is the nominal 
significance level of the O’Brien Fleming use function boundary (for an overall one-
sided 5% level test) at that analysis time.  If the confidence interval does not contain 
the alternative of interest, in particular the target alternative of 92% 5-year survival 
(hazard ratio of 2.1), then the Data Safety Monitoring Committee may consider 
stopping the study early for lack of effect. 
 
 
PSA progression-free survival is defined as the time from randomization to the 
earliest of PSA failure or death from any cause.  PSA failure is defined in Section 
7.1 of the protocol.  Based on previous studies, 1,7 we assume that patients 
randomized to RT + AST will have 5-year progression-free rates of 79% and those 
randomized to RT + AST + Chemotherapy will have 5-year progression-free rates of 
89%.  Adequate power (88%) for this endpoint using a one-sided 5% test will be 
available after 5 years of accrual and 4 years of follow-up.  Full information will be 
available when 70 patients have progressed or died.  The study does not have 
statistical power to examine treatment effects within racial and ethnic subgroups; 
however, these will be described in the study report.   
 
 
8.2.2 Study Status and Design Change in Feb, 2018 
 
The study completed enrollment in January, 2015, with 350 patients randomized 
over 9.5 years. Two interim analyses have been conducted at 34% information (18 
deaths) and 64% information (34 deaths), respectively, according to the original 
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design. Full information was reached in August 2017 when 53 patients have died. 
As of January 2018, 59 deaths were reported.  
 
The study was initially designed with 80% power to detect an hazard ratio of 0.48 
(i.e. 5-year OS rate of 0.84 for the AST+RT arm versus 5-year OS rate of 0.92 for 
the AST+RT+Chemotherapy arm under the exponential distribution) using the one-
sided alpha of 0.05. With this amendment, we will extend follow-up until 86 deaths 
occur, which increases the study power to 90% based on one-sided alpha level of 
0.025. The new design is based on the actual accrual rate and accounts for two 
interim analyses that have been conducted. The targeted difference (hazard 
ratio=0.48) and sample size (N=350) stay the same. The table below provides the 
expected number of events and associated statistical power with the extended 
follow-up times.  
 
Design parameters (unchanged): 
• RT + AST arm: 5-year OS rate of 0.84 (hazard=0.0349 per year under 
exponential distribution) 
• RT + AST + Chemotherapy arm: 5-year OS rate of 0.92 (hazard=0.0167 per 
year under exponential distribution) 
• Targeted difference: Hazard ratio =0.48 
• Total N=350 
 
Design parameters (changed): 
• Accrual period: 350 patients were uniformly enrolled over 9.5 years (Sep 
2005-Jan 2015) 
• Overall Type I error (one-sided): 0.025  
Total study duration, years 
12(current) 13 
14 
15 
16 
Expected numbers of deaths 
58 
65 
73 
79 
86 
Statistical Power 
75.6% 
80.5% 
84.5% 
87.6% 
90.1% 
Approximate calendar times 
2018/1 
2019/1 
2020/1 
2021/1 
2022/1 
 
8.3 Final Analysis and Reporting 
 
Final analysis of overall survival will be performed after the full information (86 
deaths) is achieved.  Survival distribution will be estimated using the method of 
Kaplan-Meier; 5 year survival rate and 95% two-sided confidence interval (CI) 
will be provided by treatment arm.  Overall survival between the two arms will 
be compared using a stratified log-rank test, which includes the stratification 
factors defined at randomization.  A one-sided p-value (from stratified log-rank 
test) less than 0.024 (or two-sided p-value less than 0.048, accounting for two 
interim analyses conducted at 21% and 40% information under the new design) 
will indicate that the experimental arm is superior to the control arm. 
 
Prostate cancer-specific survival will be analyzed using a competing risk model, 
where cumulative incidence of prostate cancer mortality, cardiovascular (CV) 
mortality and deaths from other causes will be estimated and compared between 
treatment arms using Gray’s test with adjustment of stratification factors of 
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randomization.  
 
Analysis of other secondary endpoints, including PSA progression-free survival, 
time to metastasis, metastasis-free survival will be similar to those described for 
the OS analysis.  A nominal p-value ≤ 0.05 (two-sided) is considered as 
statistically significant. 
 
Time to onset of cardiovascular events (non-fatal or fatal CVE) will be analyzed 
under a competing risk model.  Cumulative incidence function for risk of CVE 
will be estimated accounting for competing risk of inter-current deaths from non-
CV cause.  Comparison between treatment groups will be conducted using 
Gray’s test adjusted for baseline stratification factors and history of prior 
heart/coronary artery disease status.    
 
To compare overall survival and mortality from prostate cancer, cardiovascular, 
or other causes by randomized treatment group, we will conduct subgroup 
analysis defined by:  
(1) biopsy Gleason score (≤7 versus >7), 
(2) baseline comorbidity groups (patients will be classified to “none or minimal” 
versus “moderate or severe” comorbidity using the established Adult 
Comorbidity Metric),  
(3) baseline serum testosterone levels (Low versus normal). 
(4) pre treatment PSA velocity > 2ng/ml/year versus < 2 ng/ml/year 
 
Cox regression and Fine and Gray method will be used to explore whether a 
significant interaction exists between treatment and subgroup variables on 
overall mortality and prostate cancer, cardiac, and other-cause mortality, 
adjusting for the stratification factors defined at randomization. These analyses 
would be considered exploratory with limited statistical power unless large 
difference exists between  groups regarding treatment effect on these outcomes. 
 
This study will be monitored by the DF/HCC Data and Safety Monitoring 
Committee (DSMC).  The DSMC meets twice each year.  For each meeting, all 
monitored studies are reviewed for safety and progress toward completion.  
When appropriate, the DSMC will also review interim analyses of outcome data.  
Safety data may be shared in a blinded fashion (combined across treatment arms) 
with the study team.  Reports regarding outcome will remain blinded to the study 
team until full information is achieved or as directed by the DSMC. 
  
 
9.0 Central Pathology Review 
 
9.1 Central pathology review of diagnostic biopsies are required for this study.  
  
9.2 The clinical investigator will mail hematoxylin and eosin (H & E) stained 
slides, and the pathology report to 
 at the address below An 
attempt should be made to include all the H&E slides including those that 
may not show cancer for central review.  It is mandatory for all slides to be 
reviewed if the patient is being randomized using the Gleason =/>3+4=7 
with =/> 50% cores positive for eligibility criteria: For sites who are only 
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allowed to send one slide for central review, the slide that represents the 
highest Gleason score should be sent. 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
      
   
 
  
 
 
 
 
 
 


 
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References 
 
1. D’Amico AV, Manola J, Loffredo M, Renshaw AA, Della Croce A, Kantoff, 
Philip. 6-Month Androgen Suppression Plus Radiation Therapy Versus Radiation 
Therapy Alone For Patients With Clinically Localized Prostate Cancer: A 
Randomized Controlled Trial. Journal of the American Medical Association 2004; 
292:821-7. 
 
2. Eisenberger MA, De Wit R, Berry W, Bodrogi I, Pluzanska A, Chi K, Oudard S, 
Christine T, James N, Tannock I.  A multicenter phase III comparison of Docetaxel 
(D) + prednisone (P) and mitoxantrone (MTZ) + P in patients with hormone-
refractory prostate cancer.  Proceedings of the American Society of Clinical 
Oncology 2004; 23:2 (Abstract # 4). 
 
3. Petrylak DP, Tangen C, Hussain M, Lara PN, Jones J, Taplin ME, Burch P, Greene 
G, Small E, Crawford ED. SWOG 99-16: Randomized phase III trial of Docetaxel 
(D)/estramustine (E) versus mitoxantrone(M)/prednisone (p) in men with 
androgen-independent prostate cancer (AIPCA).  Proceedings of the American 
Society of Clinical Oncology 2004; 23:2 (Abstract # 3). 
 
4. Kumar P, Perrotti M, Weiss R, Todd M, Goodin S, Cummins K, DiPaola RS. Phase 
I trial of weekly Docetaxel with concurrent three-dimensional conformal radiation 
therapy in the treatment of unfavorable localized adenocarcinoma of the prostate.  J 
Clin Oncol 2004; 15:1909-15. 
 
5. Gleason DF and the Veterans Administration Cooperative Urological Research 
Group: Histologic grading and staging of prostatic carcinoma. In: Tannenbaum M, 
ed. Urologic pathology. Philadelphia, PA: Lea & Febiger; 1977, pp 171-87. 
 
6. Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG, Morrow M. 
American Joint Committee on Cancer, Manual for staging cancer, 6th edition, New 
York, NY Philadelphia, Pa.,Springer-Verlag, 2002, p337-46. 
 
7. Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, 
Kuten A, Sternberg C, Gil T, Collette L, Pierart M. Improved survival in patients 
with locally advanced prostate cancer treated with radiotherapy and goserelin. N 
Engl J Med. 1997 Jul 31; 337(5):295-300. 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix A 
 
 
 
 
 
 
 


 
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Appendix B 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
 
 
 
 
 
 
 


 
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Appendix C 
 
PREPARATION AND ADMINISTRATION OF DOCETAXEL 
 
 
Please note that in June 2013 the 2 vial Taxotere will no longer be available in the 
USA 
 
Please note that in August, 2013 the 2 vial Taxotere will no longer be available in 
Australia and New Zealand 
 
 
Below please find administration and preparation for the one vial Taxotere with 
correspondence from Sanofi 
 
The 2 vial Taxotere can continue to be used until it has expired 
 
 
 
 
 
 
 
 


 
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STUDY MEDICATIONS  
 
PREPARATION AND ADMINISTRATION FOR 2 VIAL TAXOTERE 
 
TAXOTERE is a cytotoxic anticancer drug and, as with other potentially toxic compounds, 
caution should be exercised when handling and preparing TAXOTERE solutions. The use 
of gloves is recommended. Please refer to Handling and Disposal section. 
 
If TAXOTERE Injection Concentrate, initial diluted solution, or final dilution for infusion 
should come into contact with the skin, immediately and thoroughly wash with soap and 
water. If TAXOTERE Injection Concentrate, initial diluted solution, or final dilution for 
infusion should come into contact with mucosa, immediately and thoroughly wash with 
water. 
 
Contact of the TAXOTERE concentrate with plasticized PVC equipment or devices used 
to prepare solutions for infusion is not recommended. In order to minimize patient 
exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from 
PVC infusion bags or sets, the final TAXOTERE dilution for infusion should be stored in 
bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered 
through polyethylene-lined administration sets. 
 
TAXOTERE Injection Concentrate requires two dilutions prior to administration. Please 
follow the preparation instructions provided below. Note: Both the TAXOTERE Injection 
Concentrate and the diluent vials contain an overfill to compensate for liquid loss during 
preparation.  This overfill ensures that after dilution with the entire contents of the 
accompanying diluent, there is an initial diluted solution containing 10 mg/mL Docetaxel. 
 
The table below provides the fill range of the diluent, the approximate extractable volume 
of diluent when the entire contents of the diluent vial are withdrawn, and the concentration 
of the initial diluted solution for TAXOTERE 20 mg and TAXOTERE 80 mg. 
 
      Product 
Diluent  
13% (w/w) ethanol 
 in water for injection 
Fill Range 
(mL) 
Approximate 
extractable volume of 
diluent when entire 
contents are withdrawn  
(mL) 
Concentration of 
the initial diluted 
solution 
 
(mg/mL Docetaxel) 
 
 
 
 
Taxotere®  
20 mg/0.5 mL 
1.88 – 2.08  mL 
1.8 mL 
10 mg/mL 
Taxotere®  
80 mg/2 mL 
6.96 - 7.70 mL 
7.1 mL 
10 mg/mL 
 
 
 
 
Preparation and Administration 
 
 
 
 
 
 


 
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A. Initial Diluted Solution 
 
1.  TAXOTERE vials should be stored between 2 and 25°C (36 and 77°F). If the vials are 
stored under refrigeration, allow the appropriate number of vials of TAXOTERE 
Injection Concentrate and diluent (13% ethanol in water for injection) vials to stand at 
room temperature for approximately 5 minutes. 
 
2.  Aseptically withdraw the entire contents of the appropriate diluent vial (approximately 
1.8 mL for TAXOTERE 20 mg and approximately 7.1 mL for TAXOTERE 80 mg) 
into a syringe by partially inverting the vial, and transfer it to the appropriate vial of 
TAXOTERE Injection Concentrate. If the procedure is followed as described, an 
initial diluted solution of 10mg docetaxel/mL will result. 
 
3.  Mix the initial diluted solution by repeated inversions for at least 45 seconds to assure 
full mixture of the concentrate and diluent. Do not shake. 
 
4. The initial diluted TAXOTERE solution (10 mg docetaxel/mL) should be clear; 
however, there may be some foam on top of the solution due to the polysorbate 80. 
Allow the solution to stand for a few minutes to allow any foam to dissipate. It is not 
required that all foam dissipate prior to continuing the preparation process. 
 
5.  The initial diluted solution may be used immediately or stored either in the refrigerator 
or at room temperature for a maximum of 8 hours. 
  
B. Final Dilution for Infusion 
 
1.  Aseptically withdraw the required amount of initial diluted TAXOTERE solution (10 
mg docetaxel/mL) with a calibrated syringe and inject into a 250 mL infusion bag or 
bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a 
final concentration of 0.3 to 0.74 mg/mL.  If a dose greater than 200 mg of 
TAXOTERE is required, use a larger volume of the infusion vehicle so that a 
concentration of 0.74 mg/mL TAXOTERE is not exceeded. 
 
2. Thoroughly mix the infusion by manual rotation. 
 
3. As with all parenteral products, TAXOTERE should be inspected visually for 
particulate matter or discoloration prior to administration whenever the solution and 
container permit. If the TAXOTERE initial diluted solution or final dilution for 
infusion is not clear or appears to have precipitation, these should be discarded. 
 
4. The final TAXOTERE dilution for infusion should be administered intravenously as a 
1-hour infusion under ambient room temperature and lighting conditions. 
 
 
 
 
 
 
 
 


 
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Stability: TAXOTERE infusion solution, if stored between 2 and 25°C (36 and 77°F) is 
stable for 4 hours. Fully prepared TAXOTERE infusion solution (in either 0.9% Sodium 
Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 1 
hour i.v. administration). 
 
HOW SUPPLIED 
TAXOTERE Injection Concentrate is supplied in a single-dose vial as a sterile, pyrogen-
free, non-aqueous, viscous solution with an accompanying sterile, non-pyrogenic, Diluent 
(13% ethanol in water for injection) vial. The following strengths are available: 
 
TAXOTERE 80 MG/2 ML  
(NDC 0075-8001-80) 
TAXOTERE (Docetaxel) Injection Concentrate 80 mg/2 mL: 80 mg Docetaxel in 2 mL 
polysorbate 80 and Diluent for TAXOTERE 80 mg (13% (w/w) ethanol in water for 
injection). Both items are in a blister pack in one carton. 
 
TAXOTERE 20 MG/0.5 ML 
(NDC 0075-8001-20) 
TAXOTERE (Docetaxel)) Injection Concentrate 20 mg/0.5 mL: 20 mg Docetaxel in 0.5 
mL polysorbate 80 and diluent for TAXOTERE 20 mg (13% (w/w) ethanol in water for 
injection). Both items are in a blister pack in one carton. 
 
Storage: Store between 2 and 25°C (36 and 77°F). Retain in the original package to 
protect from bright light. Freezing does not adversely affect the product. 
 
Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs 
should be considered. Several guidelines on this subject have been published1-7. There is 
no general agreement that all of the procedures recommended in the guidelines are 
necessary or appropriate. 
 
 
 
 
 
 


 
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REFERENCES 
 
1. OSHA Work-Practice Guidelines for Controlling Occupational Exposure to 
Hazardous Drugs. Am J Health-Syst Pharm. 1996; 53: 1669-1685. 
 
2. American Society of Hospital Pharmacists Technical Assistance Bulletin on 
Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47(95): 1033-
1049. 
 
3. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA. 
1985; 253 (11): 1590-1592. 
 
4. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH 
Publication   No. 83-2621. For sale by the Superintendent of Documents, US 
Government Printing    Office,    Washington, DC 20402. 
 
5. National Study Commission on Cytotoxic Exposure - Recommendations for 
Handling Cytotoxic Agents. Available from Louis P. Jeffry, Chairman, National 
Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy 
and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. 
 
6. Clinical Oncological Society of Australia. Guidelines and Recommendations for 
Safe Handling of Antineoplastic Agents. Med J Austr. 1983; 426-428. 
 
7. Jones, RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from the 
Mt. Sinai Medical Center. CA-A Cancer Journal for Clinicians. 1983; Sept/Oct: 
258-263. 
 
8. Sandler HM, Rosenthal SA, Sartor O, et al.. A phase III protocol of 
androgen suppression (AS) and 3DCRT/IMRT versus AS and 
3DCRT/IMRT followed by chemotherapy (CT) with docetaxel and 
prednisone for localized, high-risk prostate cancer (RTOG 0521). 2015 
ASCO Annual Meeting J Clin Oncol 33, 2015 (suppl; abstr LBA5002) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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