Multimodality Management of Head and Neck Cancer: A Phase II Trial of Induction Chemotherapy, Organ Preservation Surgery, and Concurrent Chemoradiotherapy
Phase: PHASE2
Conditions: Head and Neck Cancer
Sponsor: City of Hope Medical Center

IRB #98147 
 
 
 
 
 
 
 
 
 
06/06/2012 
Packet: 08 
 
CITY OF HOPE 
 
1500 E. DUARTE ROAD 
 
DUARTE, CA 91010 
 
 
 
 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
 
TITLE:  
Multimodality Management of Head and Neck Cancer:  A Phase II Trial of Induction 
Chemotherapy, Organ Preservation Surgery, and Concurrent Chemoradiotherapy 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION:  IRB # 98147          PROTOCOL DATE: 06/06/2012  
 
DATE(S) OF AMENDMENT(S)/REVISION(S): 
          
 
COH A-1 
( Revision, 6/13/01) 
1999.01 
COH A-2 
(Revision, 7/9/01) 
1999.02 
COH A 
(IC Rev, 6/3/02) 
COH 
(Amend 4/26/07) 
 
 1999.03 
COH 
(Amend 09/13/10) 
 
 1999.04 
COH 
 
 
 
 
(PI Change 06/06/2012)                                    
 
  1999.05 
COH 
 
 
 
 
(Personnel Change 07/30/13)                              
  1999.06 
COH 
 
 
 
 
(Personnel Change 02/14/17)                              
  1999.07 
COH Amendment 08 at Continuation 
Protocol Dated 06/06/2012 (TP)  
 
            Packet: 08 
 
 
SITE: 
Head and Neck 
 
HISTOLOGY: 
Resectable Squamous Cell Carcinoma 
  
STAGE (If applicable): 
III - IV 
 
MODALITY: 
Neoadjuvant Chemotherapy, Surgery/Chemoradiation 
 
TYPE: 
Phase II  
 
PRINCIPAL INVESTIGATOR: 
Dean Lim, M.D. 
 
COLLABORATING INVESTIGATORS: 
George Somlo, M.D., Nayana Vora, M.D. 
 
 
Biostatistics:  Jeffrey Longmate, Ph.D. 
 
PARTICIPATING CLINICIANS: 
Medical Oncology: 
 
Stephen Koehler, M.D.,Dean Lim, M.D., Przemyslaw 
Twardowski, M.D.  
 
 
Radiation Oncology: 
 
Jeffrey Wong, M.D. 
 
PARTICIPATING INSTITUTIONS: 
City of Hope 

 
 
 
Multimodality Management of Head and Neck Cancer: 
 
A Phase II Trial of Induction Chemotherapy, Organ 
 
Preservation Surgery, and Concurrent Chemoradiotherapy 
 
 
City of Hope National Medical Center 
 
1500 E. Duarte Road 
 
Duarte, CA  91010 
 
 
Principal Investigator 
 
Dean Lim, M.D. 
 
 
Co-Principal Investigators 
 
 
George Somlo, M.D. 
 
Nayana Vora, M.D. 
Sharon Wilczynski, M.D., Ph.D. 
 
 
 
 
 
 
 
Associate Investigators 
 
 
Department of Medical Oncology 
 
Warren Chow, M.D. 
 
Lucille Leong, M.D. 
 
Robert Morgan, Jr., M.D. 
 
Przemyslaw Twardowski, M.D. 
Yun Yen, M.D. Ph.D. 
 
 
Department of Radiation Oncology 
 
Richard Pezner, M.D. 
 
Jeffrey Wong, M.D. 
 
Paul Pagnini, M.D. 
 
 
Department of General Oncologic Surgery 
 
Lawrence Wagman, M.D. 
 
David Chu, M.D. 
 
Roderich Schwarz, M.D. 
 
 
 
Department of Biostatistics 
 
Jeffrey Longmate, Ph.D. 

 
IRB #98147 
 
June 6. 2012 
2 
 
SCHEMA 
 
 
Neoadjuvant Chemotherapy 
 
1) 
Docetaxel 60 mg/m2 i.v. over one hour, followed by 
2) 
Cisplatin 25 mg/m2 i.v. over 24 hours.  Repeat q day x 4 for a total of 100mg/m2. 
3) 
Leucovorin 500 mg/m2 over 24 hours.  Repeat qday for 4 days. 
4) 
5-fluorouracil 700 mg/m2 over 24 hours. Repeat q day for a total of 4 days. 
5) 
Tumor biopsy before chemotherapy and after day 1 of treatment. 
 
Day 28 Repeat chemotherapy 
 
Day 55 Clinical Evaluation of Response 
 
Day 56 Repeat chemotherapy 
 
 
Concurrent Chemoradiotherapy 
 
Gemcitabine 25mg/m2 intravenously over 30 minutes 
 
Cisplatin 25mg/m2 intravenously over 60 minutes. Hydrate with 500 ccs D5NS with 10 Meq 
KCL/liter and 8 Meq MgSO4.  Give 500cc of same IV after cisplatin after.  Premedications 
at the discretion of the treating physician. 
 
Chemotherapy to be given on day 1 of each week of radiation. 

 
IRB #98147 
 
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Concurrent Chemoradiation
(patients in CR after neoadjuvant therapy will recieve radiation therapy alone)
Medical Oncology, Surgery, & Radiation Therapy Follow-up
     Quality of life, speech, and swallowing evaluation
     Examination under anesthesia three months after
Saliva and oral rinse samples for cytology every 3 months
Surgery for the
Primary and/or Neck
No
Yes
Surgery required will
cause more than four
weeks of radiation delay
or significant functional deficit
Primary Complete Response or
Primary Partial Response < T1
and N0 or N1 neck
Yes
Surgery for the
Primary and/or Neck
No
Surgery required will include
a total laryngectomy or a
total glossectomy
Primary Partial Response > T1
and N0 or N1 neck
Day 90
Quality of life, speech, swallowing, and dental evaluation
Pathological staging, biopsies for gene and protein expression
Saliva and oral rinse samples for cytology
Day 56: Repeat Chemotherapy
Partial Response at the Primary
and  N0 or N1 Neck
Medical Oncology, Surgery, & Radiation Therapy Follow-up
Quality of life, speech, and swallowing evaluation
Examination under anesthesia three months after
Saliva and oral rinse samples for cytology every 3 months
Concurrent
Chemoradiation
Surgery for the
Primary and/or Neck
Stable Disease or Progression at the Primary
and/or N2 or more Neck
Day 55: Clinical Response Evaluation
Day 28: Repeat Chemotherapy
Day 2: Biopsies for gene and protein expression
Dexamethasone 8 mg PO b.i.d. x 3 days, Docetaxel Premedication
Docetaxel 60mg/m² over one hour, Cisplatin 25mg/m²/ IV, after Docetaxel X 4 days
Leucovorin 500 mg/m²/d CIV & 5-Fluorouracil 700 mg/m² CIV, after Docetaxel, X 4 days
Medical Oncology, Surgery, & Radiation Therapy Consults
Quality of life, speech, swallowing, and dental evaluation
Pathological staging, biopsies for gene and protein expression
Saliva and oral rinse samples for cytology
Stage III-IV Resectable SCC
of the Head and Neck

 
IRB #98147 
 
June 6. 2012 
4 
TABLE OF CONTENTS 
 
SCHEMA 
 
1.0 
OBJECTIVES 
 
2.0 
BACKGROUND 
 
3.0 
DRUG INFORMATION 
 
4.0 
STAGING 
 
5.0 
ELIGIBILITY CRITERIA 
 
6.0 
DESCRIPTIVE FACTORS 
 
7.0 
TREATMENT PLAN 
 
8.0 
TOXICITIES MONITORED AND DOSAGE MODIFICATIONS 
 
9.0 
STUDY PARAMETERS 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
11.0 
TISSUE HANDLING AND QUANTITATIVE POLYMERASE CHAIN REACTION 
TECHNIQUE 
 
12.0 STATISTICAL CONSIDERATIONS 
 
13.0 REGISTRATION GUIDELINES 
 
14.0 RECORDS TO BE KEPT/DATA SUBMISSION SCHEDULE 
 
15.0 MINORITIES AND GENDER STATEMENT 
 
16.0 ETHICAL AND REGULATORY CONSIDERATIONS 
 
17.0 REFERENCES 
 
APPENDICES 
 
1. 
Common Toxicity Criteria 
2. 
Karnofsky Performance Status Scale 
3. 
Quality of Life Evaluation (FACT-H&N) 
4. 
RTOG/EORTC Morbidity Criteria 
5. 
NCI ADR Reporting guidelines (1/01) 
6. 
Tumor tissue sampling guidelines 
6/13/01 

 
IRB #98147 
 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 
To assess the complete and overall response rate of neoadjuvant 
docetaxel/cisplatin/5-fluorouracil/leucovorin in previously untreated patients 
with local-regionally advanced head and neck cancer. 
 
1.1.2 
To evaluate the feasibility of a multimodality treatment approach with the 
goal of reducing long-term sequelae. 
 
1.1.3 
To evaluate prospectively the impact of neoadjuvant chemotherapy, 
concurrent chemoradiotherapy, and organ preservation surgery on overall 
survival, time to progression, and pattern of disease recurrence in patients 
with locally advanced head and neck cancer. 
 
1.1.4 
To evaluate prospectively biochemical correlates of response and prognosis. 
Markers will include, among potentially others, thymidylate synthetase, 
ribonucleotide reductase, and ERCC1 which will be measured by 
quantitative PCR.  P53 will be evaluated by immunohistochemistry.  The 
HPV status and apoptosis (TUNEL assay) will also be assessed. 
 
1.2 
Secondary Objectives 
 
1.2.1 
To evaluate treatment-associated morbidity with the use of a quality of life 
assessment tool. 
 
1.2.2 
To compare the results of diagnostic salivary cytology with those of 
histopathology at initial diagnosis as well as follow-up in head and neck 
cancer patients.  
 
1.2.3 
To evaluate the tolerability of combined chemoradiation using gemcitabine 
and cisplatin after definitive surgery for SCC of the Head and Neck. 
 
2.0 
BACKGROUND  
 
2.1 
Neoadjuvant Chemotherapy 
 
2.1.1 
Introduction 
 
Worldwide, carcinoma of the head and neck is a relatively common 
malignancy: in developing countries alone, an estimated 300,000 new cases 
of oral cancer occurred in 1985 [1].  The comparable figure for the United 
States in 1996 is greater than 29,000 cases of oral cancer and additional 
11,600 cases of laryngeal cancer [2].  The great majority of patients have 
squamous cell carcinoma.  

 
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Most patients present with local or regionally advanced disease (stage III or 
IV), fewer than 30 percent of such patients are cured with standard surgery 
and radiation therapy [3]. 
 
The clinical evaluation of the addition of chemotherapy to surgery and 
radiation therapy has been ongoing for nearly two decades.  In patients with 
local-regionally advanced head and neck cancer, the strategy of neoadjuvant 
chemotherapy has been the most studied.  The goals of primary 
chemotherapy include enhancement of survival and organ-function 
preservation. 
 
The promising rates of complete response have been reported for the 
combination of cisplatin and infusional fluorouracil [3],[4].  Rapid tumor 
response occurs in 70-90% of patients after 2 to 3 cycles of this combination. 
 Although consistently high response rates are observed, no randomized trial 
to date has demonstrated improved survival [3], [5], [6].  Three randomized 
trials of [7],[8],[9] and two randomized trials testing adjuvant chemotherapy 
[10],[11] have demonstrated reduced rates of distant metastases; however, a 
favorable impact on local-regional disease control has yet to be demonstrated 
in a randomized trial.  The potential for induction chemotherapy to allow for 
larynx preservation for patients with locally advanced squamous cell 
carcinoma of the larynx [7] or pyriform sinus [8] has been demonstrated.   
 
2.1.2 
Docetaxel 
 
The clinical investigation of new active agents appears essential if improved 
outcome is to be achieved for advanced head and neck cancer patients.  The 
taxoid family includes a group of compounds that share the taxane skeleton.  
These include paclitaxel and docetaxel, agents that share a unique 
mechanism of action as promoters of microtubule assembly and inhibitors of 
microtubule disassembly.  Both paclitaxel [12] and docetaxel [13],[14] have 
demonstrated consistent significant activity in a variety of cancers.  In vitro 
studies of paclitaxel in concentrations as low as 0.001 g/ml resulted in 
cytotoxic activity in a squamous cell cancer of the tongue cell line [15].  
Braakhuis and colleagues observed significant growth inhibition in the two 
tested human tumor xenografts derived from head and neck squamous cell 
carcinoma when docetaxel was administered intravenously at a dose of 20 
mg/kg [16].  Both head and neck tumor xenograft lines were less sensitive to 
treatment with cisplatin, suggesting absence of cross-resistance between the 
two drugs.   
 
To date, three clinical trials evaluating docetaxel in patients with head and 
neck cancer have been reported.  Catimel and colleagues reported the results 
of a multicenter trial of docetaxel in patients with recurrent or advanced 
disease [17].  An overall response rate of 32% was observed, with two CRs 

 
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and 10 PRs in 37 assessable patients.  Dreyfuss et al. reported a major 
response rate of 42% (four CRs and nine PRs in 29 assessable patients) in 
patients with advanced or metastatic squamous cell cancer of the head and 
neck [18].  Premedication with dexamethasone, cimetidine, and 
diphenhydramine was associated with a reduced incidence of edema, 
hypersensitivity reactions, and dermatologic toxicities.  A preliminary report 
of a phase II study of docetaxel in patients with metastatic or unresectable 
squamous cell carcinoma of the head and neck was reported by Couteau and 
colleagues [19].  Patients with a single site of local relapse in a previously 
irradiated field were ineligible.  Three PRs (one in a patient with a previously 
untreated hypopharynx cancer) were recorded in the 11 patients evaluable 
for response.   
 
The studies above may be compared to the 40% response rate reported by 
Forastiere et al [20] in patients with recurrent disease after surgery or 
radiotherapy or previously untreated, advanced, incurable or distant 
metastatic disease treated with high-dose paclitaxel, 250 mg/m² by 24-hour 
continuous IV infusion every 3 weeks with granulocyte colony-stimulating 
factor (G-CSF).  The same dose and schedule of paclitaxel was investigated 
in 23 previously treated and untreated patients with squamous cell cancer of 
the oral cavity, oropharynx, hypopharynx, or larynx [21]. Two complete 
(12%) and four partial responses (24%) were recorded in 17 evaluable 
patients. 
 
2.1.3 
Taxane/cisplatin combination chemotherapy  
 
The Eastern Cooperative Oncology Group has completed a randomized 
comparison of high- versus low-dose paclitaxel in combination with 
cisplatin.  The high-dose arm uses paclitaxel 200 mg/m² by 24-hour infusion 
plus cisplatin 75 mg/m² plus G-CSF.  The low dose arm consists of 
paclitaxel 135 mg/m² by the same infusion schedule plus cisplatin 75 mg/m² 
without G-CSF.  The study completed accrual in June 1995 and is still 
undergoing analysis.  As of March 1, 1995, there did not appear to be any 
difference in response rate, toxicity, or survival.  A direct comparison of the 
low dose arm with the combination of cisplatin and 5-FU is planned. 
 
The Early Clinical Trials Group of the European Organization for Research 
and Treatment of Cancer reported the results of a multicenter phase II study 
of the combination of docetaxel and cisplatin in patients with locally 
advanced, recurrent, or metastatic squamous cell carcinoma of the head and 
neck [22].  The feasibility and potential efficacy of this chemotherapy 
combination had previously been demonstrated in a phase I study [23].  One 
cycle of treatment consisted of docetaxel, 100mg/m², as an intravenous (IV) 
infusion over 1 hour, followed after 3 hours by cisplatin, 75 mg/m², as an IV 
infusion over 3 hours; cycles were repeated every 3 weeks.  Twelve patients 
had received prior radiation therapy and four had recurrent disease after 

 
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neoadjuvant chemotherapy.  All patients received a five-day course of 
methylprednisolone beginning one day prior to the day of infusion.  Dose 
reduction and chemotherapy delay were required in three and 12 
chemotherapy cycles, respectively.  Major toxicities included neutropenia 
(grade 3-4 in 72% of 57 cycles), asthenia (grade 3-4 in 12% of administered 
cycles), sensory neurotoxicity (grade 1-2 in 23% of cycles with no grade 3-4 
neurotoxicity noted), and dermatologic toxicity (grade 3-4 in 2%).  The 
incidence of edema was 9% (all grade 1-2) and febrile neutropenia occurred 
in 3% of chemotherapy cycles.  Two CRs and 12 PRs were observed 
yielding an overall major response rate of 78%, indicating high activity in 
this patient population.  
 
2.1.4 
Docetaxol combinations with other chemotherapeutic agents 
 
Docetaxol has also been combined with other chemotherapeutic agents. 5-
fluorouacil has been combined with docetaxol with synergistic results in 
preclinical studies [24].   Phase I studies have shown the feasibility of 
combining 60mg/m2 of docetaxol with 300mg/m2 if 5-FU as a continuous 
infusion over 5 days [25]. Primary toxicities were neutropenia and mucositis. 
 
Docetaxol has also been combined with cisplatin, 5-fluorouracil, and 
leucovorin. A recently published report notes that this is a feasible 
combination with high response rates [26]. The treatment consisted of 
docetaxol 60mg/m2 given over one hour, followed by continuous infusions 
of cisplatin (125 mg/m2 over 5 day), 5-FU ( 700 mg/m2/24 hr x 4 day), and 
leucovorin (500mg/m2/24 hr x 5 day). This treatment was supported with G-
CSF and prophylactic antibiotics. Significant toxicities included neutropenia, 
mucositis, diarrhea and salt-wasting nephropathy. Response rates were a 
61% clinical complete response with a 39% clinical partial response for a 
100% total response rate.  At the primary site, 91% of patients had a 
pathologic complete response. 
 
Although this regimen was felt to be feasible, toxicity was significant, and 
may not be tolerable in patients with less than optimal performance status. In 
light of this, a modification of this protocol has been piloted [27]. This 
involves the same drugs in the same doses as the regimen described above. 
However, the daily dose of cisplatin is changed to 31.25 mg/m2/day and 5-
fluorouracil and leucovorin are started together at the same time as cisplatin. 
The rationale for the change has been to shorten the time of delivery and 
thereby allow earlier institution of G-CSF. Preliminary results show response 
rates similar to those reported by the original regimen.  However, patients 
continued to require a significant level of support with 14% of the cycles 
requiring hospitalizations for post chemotherapy support. 
 

 
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9 
2.1.5 Neoadjuvant chemotherapy protocol 
 
Based on the above background, we propose to test a combination of 
docetaxel, cisplatin, 5-fluororuacil and leucovorin in the neoadjuvant setting 
in patients with local-regionally advanced squamous cell carcinoma of the 
head and neck.   In an attempt to improve tolerability, the cisplatin dose will 
be fixed at 25 mg/m2 per day x four days, combined with docetaxol at 60 
mg/m2, and a continuous infusion of 5-fluorouracil  (700 mg/m2 per day x 4) 
and leucovorin (500 mg/m2 per day x 4). 
 
2.1.6 
P53 and chemotherapeutic agent sensitivity 
 
2.1.6.1 
General Background  
 
Approximately one half of human tumors have deleted or 
mutated p53 [28]. Individuals with heterozygous p53 germline 
mutations such as in the Li-Fraumeni syndrome show an 
increased susceptibility to the development of multiple 
malignancies including breast cancer, brain tumors, leukemias, 
and sarcomas [29], [30],[31].  P53 protein is a regulator of cell 
cycle control, via direct control of the G1 + G2  checkpoints.  
After DNA damage p53 levels increase and mediate multiple 
cellular responses including cell cycle arrest via the 
transcriptional induction of the CDK inhibitor p21 [32], DNA 
damage repair mediated via the transcriptional induction of 
Gadd45 [33], and activation of a p53 dependent apoptotic 
pathway [34], [35]. In addition to p53 genetic alterations, viral 
oncogenes such as the human papilloma virus (HPV) E6 
protein can cause direct degradation of the p53 protein via a 
ubiquitin dependent pathway [36], [37].  MDM2, a cellular 
oncogene has also been shown to down regulate p53 in several 
types of cancers (Momand et al. 1998).  It is unclear what 
effect the loss of p53 function has on the efficacy of 
chemotherapeutic agents in-vivo. Loss of p53 function by 
mutation is associated with chemotherapy resistance and short 
overall survival in hematologic malignancies [38], and to 
decreased chemotherapy and radiation sensitivity in lymphoma 
cell lines [39],[40].  These findings are supported by cell 
culture studies of mouse embryonic fibroblasts (MEF) derived 
from p53 (-/-) knock-out mice, showing resistance to 
chemotherapy and [41], as well as in vivo studies in nude mice 
with transplanted fibrosarcomas derived from adenovirus early 
region (E1A) and ras oncogene transformed fibroblasts [42]. 
The correlation between p53 mutations and increased 
chemotherapy resistance has been reported in colorectal cancer 

 
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[43], in non-small cell lung cancer [44], in ovarian primary 
tumors [45], and in breast cancer [46].  
 
Interestingly in some situations, p53 mutations may also lead to 
enhanced chemosensitivity, as was reported in ovarian cancer 
cell lines [47].  Increased sensitivity to chemotherapeutic 
agents has also been shown in cultured human foreskin 
fibroblasts (HFF) transformed with a retrovirus vector 
containing the HPV 16 gene for E6 to abolish p53 protein 
function.  In this study, HFF transfected with the HPV 16/E6 
vector were 6-9 times more sensitive to cisplatin when 
compared to the controls, and 8-12 times more sensitive to 
paclitaxel [48].  When levels of p53 and p21 were measured by 
Western blotting, HFF transfected with a control vector 
showed increased levels of p53 and p21 following exposure to 
1 g/ml of cisplatin for 6 hours, whereas HFF transfected with 
a vector containing the HPV 16/E6 gene showed almost non 
detectable levels of p53 and p21 even after the exposure to 25 
g/ml of cisplatin for one hour.  These studies suggest that the 
mechanism of p53 function abrogation, and the response of its 
downstream effectors are critical in understanding p53-
dependent chemosensitivity.  
 
Analysis of pre-chemotherapy and in post-chemotherapy tumor 
and normal tissue biopsies following the first cycle of 
chemotherapy will help to establish the function of the p53 axis 
in response to chemotherapy.  Among the most critical 
functions of p53 after DNA damage are the induction of cell 
cycle arrest (mediated through p21) and initiation of the 
apoptotic pathway.  This study should allow a better 
understanding of the mechanism of p53-dependent 
chemosensitivity in patients with SCC of the head and neck 
treated with a platinum-taxane containing regimen, and may 
provide insight into the possible p53 downstream pathways that 
determine this sensitivity. 
 
 
2.1.6.2 
P53 expression and Head and Neck Cancer response to therapy 
 
In a study of 22 patients with squamous cell carcinomas of the 
head and heck (SCCHN), histocultures were established from 
surgical specimens [49].  Following 24 hr continuous exposure 
of the cells to paclitaxel, response was measured by DNA 
synthesis inhibition and apoptosis. DNA synthesis inhibition 
measured by bromodeoxyuridine (BrdUrd) DNA incorporation 
was not complete, and apoptosis measured by TUNEL assay 

 
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and by nucleosomal DNA fragmentation in agarose gels was 
present in all tumors.  P53 and Bcl-2 protein expression were 
determined by immunohistochemistry and did not correlate 
with  paclitaxel-induced inhibition of DNA synthesis or 
apoptosis.  These data suggest that paclitaxel-induced apoptosis 
may occur via a p53-independent pathway as observed in other 
cell lines [47].  However, since immunohistochemistry is not 
always a reliable method to determine p53 mutations, these 
data do not rule out the possibility that paclitaxel-induced 
apoptosis is mediated through a p53-dependent mechanism.  
Furthermore, clonal selection of the most resistant cells might 
have occurred during the establishment of the histocultures, 
making these data difficult to apply to the clinical setting. 
 
In another study, 73 patients with unresectable SCCHN were 
treated with cisplatin (CDDP) 80 mg/m2 or with carboplatinum 
(CBDCA) 375 mg/m2 with concomitant radiation.  P53 and 
Bcl-2 expression were determined by immunohistochemistry.  
One third of the tumors showed a strong diffuse staining for 
bcl-2 protein; this expression was not associated with any 
specific clinico-pathological feature nor with any other 
biological marker studied.  P53 immunostaining was present in 
56% of the tumors, and the increase of p53 expression 
correlated with a decrease in disease free survival by 
multivariate analysis[50].  The p53 expression did not correlate 
with Bcl-2 expression, and these proteins were not independent 
predictors of chemoradiation response.  Although p53 
expression did not reach statistical significance in this study as 
a predictor of chemoradiation response, the odds ratio for p53 
(-) vs. p53(+) tumors was 0.61 (C.I. 0.22-1.67), suggesting that 
p53(-) (perhaps with a wild type p53 gene) tumors were more 
sensitive to the treatment.  Analysis of p53 in tumor samples 
immediately following treatment, might clarify the role of p53 
in this setting. 
 
2.1.6.3 
Apoptosis and chemotherapy response.  
 
Resistance to apoptosis is a new mechanism for multiple drug 
resistance [51].  The most traditional pathways for drug 
resistance are: (1) elevation of P-glycoprotein, encoded by the 
mdr-1 gene that acts at the level of the plasma membrane 
pumping the drug out of the cell; (2) increased gluthathione 
redox detoxification and p450 hepatic activity decreasing the 
amount of drug-induced DNA damage; (3) modification of the 
drug target as in the amplification of the dihydrofolate 
reductase gene following exposure to methotrexate, and 

 
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mutations in topoisomerase 2, a target for multiple drugs; and 
(4) increased repair rates of drug-induced DNA damage 
[52],[53] 
 
Apoptotic response is regulated by the bcl-2 gene family, with 
the expression of Bcl-2 acting as a negative apoptosis 
regulator, and Bax expression sensitizing cells to programmed 
cell death [51], [54].  The role of the bcl-x gene with its two 
alternative splice forms with opposing functions, bcl-xL 
(promotes survival) and bcl-xS (promotes cell death), is not 
fully understood [55], but their differential expression seem to 
be important in the apoptosis regulation of hematopoietic cells 
progenitors and the central nervous system.   Based on the 
experimental evidence available to date, Reed et al. proposes 
that Bax promotes apoptosis through the formation of Bax-Bax 
homodimers, and this activity is inhibited when Bax 
heterodimerize with Bcl-2 homologues (Bcl-2, Bcl-XL, Mcl-1) 
that have anti-death activity [53].  Other apoptosis promoters 
such as Bcl-XS and Bad promote cell death through the binding 
and sequestration to Bcl-2 homologues, thus preventing them 
from heterodimerizing with Bax [53].   
 
Following cell exposure to chemotherapy or radiation, there is 
an increase in p53 that mediates a decrease in Bcl-2 and an 
increase in Bax expression, promoting the homodimerization of 
Bax and the activation of programmed cell death.  This p53 
mediated apoptosis is independent of cell cycle regulation [56], 
and can also be activated through a p53 independent pathway 
[57].   The study of the Bcl-2/Bax expression in leukemic cells 
obtained from 24 patients with chronic lymphocytic leukemia 
(CLL) was a predictor of apoptosis following the in-vitro 
treatment with glucocorticoids (methylprednisolone), or with 
chemotherapy (fludarabine and mitoxantrone) [58].  In these 
patients both the apoptosis-resistant and sensitive cells showed 
a down-regulation of Bcl-2 expression following treatment, but 
Bax down-regulation occurred only in the apoptosis resistant 
cells.  A similar study, in samples obtained from 21 patients 
with B-cell CLL treated in-vitro with a purine analogue  
(fludarabine) or a camptothecin analogue (9-amino-209s0-
camptothecin), showed that none of the samples with low Bcl-
2/Bax ratios were drug-sensitive, and that B-CLL cells with 
intermediate or high ratios were drug-resistant, independently 
of p53 mutations [59].  In an in-vitro study of testicular tumors 
and bladder cancer, etoposide-induced apoptosis was also 
dependent on the Bcl-2/Bax ratio [60]. Etoposide-induced 
apoptosis in testicular tumor cell lines was 40% with high 

 
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13 
levels of Bax and low levels of Bcl-2 expression, while 
treatment-induced apoptosis in bladder cancer cell lines was 
9% with high levels of Bcl-2 and low levels of Bax expression. 
This evidence suggests that the Bcl-2/Bax ratio measurement, 
rather than the levels of functional p53 may be a better 
predictor of the apoptotic response to chemotherapy-induced 
damage. 
 
2.1.6.4 
Intratumoral levels of  mRNAs  
 
Intratumoral levels of mjRNA for the enzymes targeted by 
several different chemotherapeutic agents have correlated with 
clinical outcome in a variety of tumors (61,62).  These results 
are important because they suggest that pre-treatment mRNA 
levels of critical target enzymes may predict responsiveness to 
treatment.  It would be useful to distinguish patients with a 
high chance of benefiting from those that may be better served 
by an alternate therapy.   
 
It is proposed in this study to use relative quantitation PCR to 
determine mRNA levels of the M2 subunit of ribonucleotide 
reductase (RR), ERCC1, and thymidylate synthase (TS) and 
potentially others .  These enzymes are involved in the activity of 
5-fluorouracil and gemcitabine.  Gemcitabine (63) is an inhibitor 
of RR.  Gemcitabine requires phosphorylation by DCK as part of 
its activation (63). TS, which is inhibited by 5-fluorouracil, is 
involved in the formation of thymidylate from dUMP and as such 
influences DNA precursor pools and potentially DNA repair.  It 
is postulated that measurement of the expression of the genes 
coding for these enzymes may allow prediction of response to 
treatment and also possible prognostic information.  As tumor is 
usually accessible in head and neck cancer, it is expected that a 
high percentage of patients entered on this trial can be safely 
biopsied.  
 
2.2 
Concurrent Chemotherapy and Radiotherapy 
 
2.2.1 
Introduction  
 
The rationale and clinical experience with concurrent administration of 
chemotherapy and radiation therapy in patients with solid tumors has been 
reviewed 
[64],[65],[66]. 
 
Although 
the 
terms, 
"enhancement," 
"sensitization," or "potentiation" are commonly used to describe the potential 
for increased antitumor activity within the radiation field as a direct result of 
the interaction of chemotherapy with radiation, other types of interaction 
have been[67]"  The use of thymidine analogs, fluoropyrimidines, 

 
IRB #98147 
 
June 6. 2012 
14 
hydroxyurea, as well as newer agents such as gemcitabine and fludarabine as 
radiosensitizer has been recently reviewed [68], [69], [70], [71].   
 
The investigation of the combined use of chemotherapy and radiation 
therapy in head and neck cancer patients has been long pursued with the 
goals of increasing overall survival and organ-function preservation as 
endpoints [5], [72].  Because 40-60% of advanced head and neck cancer 
patients die of persistent or recurrent local-regional disease (while 20-30% of 
deaths are due to distant metastases), it is clear that improvement in local-
regional control will be necessary in order to improve survival [5], [73]. 
 
Trials of concurrent chemotherapy and radiation therapy in head and cancer 
have been performed primarily in those patients with unresectable disease.  
Randomized trials have demonstrated improvement in disease-free survival 
with the addition of bleomycin [5], [74]; [75] or mitomycin-C [76].  
Improved overall survival has been noted when 5-FU is used with 
concomitant radiotherapy [77].  Until recently, however, radiation as a single 
agent has remained standard therapy because the acute toxicity of combined 
modality therapy (predominantly mucositis) is invariably greater and the 
differences in survival have been small. 
 
Cisplatin has major single agent activity in this disease and may also act as a 
radiosensitizer [77], [65]. Myelosuppression is modest, making it possible to 
use in full-dose during radiation therapy without compromise of either 
modality.  The possible mechanisms of cisplatin radiosensitization include 
inhibition of repair of sublethal or potentially lethal radiation-induced DNA 
damage, selective radiosensitization of hypoxic cells, and direct results of 
cisplatin at the time of irradiation.  The latter "preradiation enhancement" is 
postulated to involve the intracellular formation of free radicals or altered 
binding of platinum complexes to DNA during radiation [78], [79]. 
 
Single agent cisplatin and radiation therapy has been evaluated in several 
trials.  The Eastern Cooperative Oncology Group performed a pilot study 
evaluating weekly cisplatin 10-30 mg/m² during radiation therapy, 1.8 
Gy/day for 5 days/week to a total of 68-76 Gy [80].  A cisplatin dose of 20 
mg/m²/week was identified for further evaluation.  A randomized trial in 371 
patients with unresectable disease compared radiation therapy alone to 
radiation therapy plus cisplatin 20 mg/m²/week [81].  The overall response 
rate was significantly greater for patients receiving cisplatin, 73% vs. 59%, 
p=.007, but there was no difference in complete response rate (34% vs. 30%) 
or survival.  The doses used can be considered suboptimal, as the maximum 
total cisplatin dose was only 160 mg/m²/patient. 
 
An alternative dose and schedule of cisplatin administration, 100 mg/m² 
every 3 weeks for three doses during concurrent radiotherapy, was 
investigated by the Radiation Therapy Oncology Group (RTOG) [82].  

 
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15 
Eighteen and 82% of patients, had stage III and IV disease, respectively.  
The clinical complete response rate in 124 patients was 71%.  The most 
common severe (grade 3) toxicity was stomatitis occurring in 28% of 
patients.  Leukopenia was severe in 11% and moderate in 36% (resulting in 
dose reduction), but chemotherapy-related toxicity did not interfere with 
delivery of radiotherapy.  Eighty-six percent of patients received at least 64.5 
Gy.  The administration of three doses of cisplatin was possible in only 61% 
of patients: severe toxicities and patient refusal were the principal reasons for 
non-compliance.  The estimated 4-year survival rate excluding 
nasopharyngeal primaries was 28%, compared with 12% (all patients) and 
22% (performance status greater than or equal to 90%) from the RTOG data 
base.  The 4-year local-regional control rate was 34%, compared with 18% 
(all patients) and 29% (performance status greater than or equal to 90%). 
 
Patients with advanced but clinically resectable disease may be most likely 
to attain benefit (improved local-regional control) from combined modality 
treatment strategies [83].  A feasibility study of cisplatin and postoperative 
radiotherapy in 51 patients was conducted by the RTOG [84]. Treatment 
consisted of cisplatin 100 mg/m² every 3 weeks for three doses with 60 Gy 
radiotherapy.  Seventy-one percent of patients had Stage IV disease and 53% 
had positive margins.  Ninety percent of patients received within 10% of the 
intended radiotherapy dose and 61% received all three doses of 
chemotherapy.  Acute radiotherapy related toxicity was graded severe in 
27% of patients and was predominantly mucocutaneous.  Chemotherapy-
related toxicity was graded severe in 33% of patients and was mainly 
leukopenia.  The 12-month actuarial survival rate was 74.9% (61.8-88.0%) 
and the local-regional failure rate was 11.7% (2.0-21.5) in a preliminary 
analysis.  A significant improvement in local-regional control was evident 
when compared with a group of matched resected patients treated with post-
operative radiotherapy alone.  Again, the need to investigate measures to 
reduce the incidence of therapy-related toxicity (mucositis and leukopenia) is 
evident.  
 
Bachaud et al conducted a randomized trial of postoperative cisplatin and 
radiotherapy compared with radiotherapy alone in a group of "high risk" 
patients with histologic evidence of lymph node metastases with extra-
capsular spread [85].  Eighty-eight patients were randomized to receive 
radiotherapy alone or with cisplatin 50 mg/week for a total of 7 to 9 cycles.  
The incidence of severe mucositis, nausea and vomiting, and neutropenia 
was greater in the patients treated with cisplatin, but interruptions in 
radiation therapy were required in only three patients.  Fifty-nine percent of 
patients received all scheduled chemotherapy.  Local-regional failure was 
lower in the cisplatin-treated group, 21% vs. 41% (p<.05).  Both 2-year 
disease specific survival and disease-free survival were significantly greater 
in the combined modality group, 75% vs. 44% (p<.05) and 65% vs. 41% 
(p<.01), compared with the radiotherapy alone group. 

 
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16 
 
This positive trial is of interest because of the high risk group under study; 
the report of the Head and Neck Intergroup Study by Laramore and 
colleagues also suggested the potential benefit of adjuvant chemotherapy 
(cisplatin and 5-FU) may be limited to specific high risk subsets [11].  In the 
study by Bachaud et al and in each of the other cited studies, only about 60% 
of patients were able to receive the entire intended treatment.  A recently 
completed 
randomized 
trial 
(Intergroup 
0099) 
in 
patients 
with 
nasopharyngeal cancer and two ongoing randomized trials (Intergroup 0126 
for patients with unresectable locally advanced head and neck cancer 
excluding nasopharynx, paranasal sinus, and parotid gland primaries and 
RTOG 91-11 for patients with laryngeal cancer) will add substantially to the 
smaller studies of concurrent cisplatin and radiation therapy reviewed above.  
 
Intergroup 0099 randomized patients with Stages III and IV nasopharyngeal 
cancer to radiation therapy with or without chemotherapy [86].  
Chemotherapy consisted of cisplatin 100 mg/m² on days 1, 22, and 43 during 
radiation therapy, followed by cisplatin 80 mg/m² with 5-FU 1000 mg/m²/d 
on days 1-4 every 3 weeks for three courses after completion of radiation.  In 
October 1995, during the first planned interim analysis, highly statistically 
significant differences in favor of the combined modality group were found 
leading to early closure of the trial.  Nausea, vomiting and myelosuppression 
occurred more often in the combined therapy group.  Local toxicities were 
similar in both treatment groups.  Median progression-free survival and 2 
year overall survival were both superior in the combined treatment group: 52 
months vs. 13 months and 80% vs. 55%, respectively.  The concurrent 
chemotherapy and radiotherapy arm has been accepted as a new standard of 
care in patients with advanced nasopharyngeal cancer; however, this study 
does not allow conclusions to be drawn regarding the relative contributions 
of the concurrent and adjuvant therapies to the overall study results. 
 
Ongoing randomized trials evaluating concurrent cisplatin chemotherapy and 
radiation therapy include INT 0126 and RTOG 91-11 [73].  The Intergroup 
study is a three-arm trial for patients with unresectable Stage III and IV 
squamous cell carcinoma of the head and neck.  The control arm is standard 
radiotherapy, 2 Gy/day, 5 days/week for 7 weeks, total dose 70 Gy.  The 
second arm tests cisplatin 100 mg/m² every 3 weeks for three doses with 
concurrent radiation therapy; this is the regimen piloted by RTOG [82].  The 
third arm utilizes a regimen piloted by Adelstein et al: split course radiation 
therapy, 30 Gy, is given with 2 cycles of cisplatin and 5-FU, followed by 
resection of residual disease and split course radiation therapy, 20 Gy, with 2 
additional cycles of cisplatin and 5-FU [87]. 
 
RTOG 91-11 is a larynx preservation study in patients with Stage III and IV 
resectable squamous cell carcinoma of the glottis and supraglottis.  The first 
treatment arm tests 2 cycles of induction cisplatin and 5-FU followed by 

 
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17 
definitive radiotherapy in responding patients; non-responders undergo 
resection followed by the same radiotherapy.  This arm is identical to that 
published by the Department of Veterans Affairs Laryngeal Study Group [7]. 
 The second arm consists of concurrent cisplatin, 100 mg/m² every three 
weeks for three doses, with radiotherapy.  The third arm evaluates 
radiotherapy alone.  This study differs from the Department of Veterans 
Administration Trial in two ways: T4 patients are excluded and an elective 
neck dissection will be performed on all patients with multiple neck nodes or 
any single lymph node 3 cm or greater.  These study modifications should 
allow the three treatments to be tested in a prognostically more favorable 
group of patients than previously studied in randomized trials of combined 
modality therapy. 
 
The recently completed Intergroup Trial demonstrating improved survival 
with combined cisplatin and radiotherapy compared with radiotherapy alone 
has resulted in a new standard of care for patients with advanced 
nasopharyngeal cancer.  The two randomized trials in progress involving 
other head and neck primary sites build on the results of pilot studies and 
small randomized trials that suggest better local-regional control and survival 
with combined modality therapy.   
 
2.2.2 
Gemcitabine as a radiation sensitizer 
 
Gemcitabine, which inhibits ribonucleotide reductase and causes chain 
termination of DNA, is an excellent radiation sensitizer [71].  It has been 
used clinically in a phase I trial of head and neck patients where severe 
mucositis has been dose limiting [88].  Currently doses in the range of 100 – 
150 mg/ m2 are being tested [89].  It is possible that given the strong 
radiosensitizing attributes of gemcitabine that a combination of a modest 
dose of gemcitabine in combination with another active agent, may provide 
enhanced radiation sensitization with manageable toxicity. Cisplatin would 
be an agent that would be a candidate for this approach. It has demonstrated 
radiosensitizing effects as noted in section 2.2.1. It also has possible 
synergistic effects in combination with gemcitabine as suggested by 
preclinical studies [90]. 
 
2.2.3 
Proposed chemoradiation 
 
Based on the information presented, it is proposed to study the combination 
of gemcitabine 25mg/m2 and cisplatin 25mg/m2 on day 1 of each week of 
radiation.  Patients will be followed for tolerance, and for duration of local 
control. There will be no planned dose escalations.  Treatment will be held if 
radiation is held due to excessive mucositis or other radiation related 
toxicity.  Treatment will also be held for hematologic toxicity.  If > 3 patients 
are unable to adequately complete therapy, this part of treatment will be 

 
IRB #98147 
 
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18 
placed on hold and be reevaluated (see section 8.7).  If this occurs, protocol 
treatment will continue, but patients will receive radiation alone.   
 
2.3 
Quality of life, functional assessment, and performance status of the Head and Neck 
cancer patient. 
 
For the quality of life and functional assessment we will use the FACT-H&N 
instrument developed at Rush University.  This instrument in its most recent version 
3 contains 34 general and 11 head and neck specific self-reported questions rated on 
a 0 to 4 Likert type scale.  These items assess and describe patient functioning in six 
areas: physical well-being, social and family well-being, relationship with doctor, 
emotional well-being, functional well-being, and head and neck related symptoms.  
The validity of this instrument in the evaluation of head and neck patients has been 
tested and shown to be discriminatory between good and poor performance patients, 
with a coefficient  of internal consistency of 0.89 for the general section and 0.7 for 
the Head and Neck subscale.  To assess the performance status we will use the scale 
developed by List for head and neck cancer patients (PSS-HN).  The PSS-HN scale 
is a physician-rated instrument consisting of three subscales: normalcy of diet, 
understandability of speech, and eating in public (patient input is incorporated in this 
category).  Each item is scored from 0-to 100, with higher scores indicating better 
performance.  This scale was tested and confirmed to be more sensitive to the unique 
problems of head and neck cancer patients when compared to the Karnofsky status, 
providing independent and additional information.  The complete FACT-H&N 
version 3 and the PSS-HN with the revised normalcy of diet scale are included in the 
Appendix section. 
 
3.0 
DRUG INFORMATION 
 
3.1 
Docetaxel 
 
3.1.1 
Mode of Action: Docetaxel binds to free tubulin and promotes the assembly 
of tubulin into stable microtubules, while simultaneously inhibiting their 
disassembly, thereby resulting in inhibition of mitosis. 
  
3.1.2 
Supply, Reconstitution, and Administration: Docetaxel is a white to almost-
white powder, which is highly lipophilic and almost insoluble in water.  
Taxotere® (docetaxel) for Injection Concentrate is a clear yellow to 
brownish-yellow viscous solution.  Taxotere® is available in single-dose 
vials containing 20 mg (0.5 ml) or 80 mg (2.0 ml) anhydrous docetaxel.  
Each ml contains 40 mg docetaxel (anhydrous) and 1040 mg polysorbate 80. 
Taxotere® should be stored at 4 C away from light.  Taxotere® for Injection 
Concentrate requires dilution prior to use.  The diluent for Taxotere® 
contains 13% ethanol in Water for Injection, and is supplied in 1.5mL and 
6.0 ml vials, to be used with 20 mg and 80 mg Taxotere® for Injection 
Concentrate, respectively.  Prior to administration, Taxotere® is first diluted 
to prepare a premix solution at a concentration of 10 mg/ml.  Further dilution 

 
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19 
is then made in either 5% dextrose or 0.9% sodium chloride for injection to 
achieve a final Taxotere® concentration </= 1 mg/ml.  The drug is stable for 
up to 8 hours from the time the premix solution is prepared.  In order to 
minimize 
patient 
exposure 
to 
the 
plasticizer 
DEHP 
(di-(2-
ethylhexyl)phthalate) which may be leached from polyvinylchloride (PVC), 
Taxotere® for infusion should be prepared in non-PVC bags and 
administered through non-PVC containing administration sets.  In this study, 
docetaxel will be administered by IV infusion over 1 hour.  
 
3.1.3 
Toxicity: myelosuppression (dose-limiting neutropenia), nausea, vomiting, 
dermatologic toxicity, asthenia, fluid retention (including pleural effusion, 
cardiac tamponade, and ascites), mucositis, neuropathy, diarrhea, fever, 
myalgia, alopecia, hypersensitivity reactions, and nail changes. 
 
3.2 
Cisplatin (CDDP) 
 
3.2.1 
Mode of Action: The dominant mode of action of cisplatin is by formation of 
DNA cross-links. 
 
3.2.2 
Supply, Reconstitution, and Administration: Cisplatin is available as 10mg 
and 50 mg vials of dry powder which are reconstituted with 10 ml and 50 ml 
of sterile water for injection USP, respectively.  Due to a lack of 
preservatives, the solution should be used within eight hours of  
reconstitution.  The solution may be further diluted in a chloride containing 
vehicle such as D5NS or NS (precipitation occurs in D5W).  Cisplatin can 
react with aluminum needles, producing a black precipitate within 30 
minutes.  In this study, cisplatin will be administered by IV infusion over 3 
hours. 
 
3.2.3 
Toxicity: myelosuppression, nausea, vomiting, nephrotoxicity, hypokalemia, 
hypomagnesemia, hypocalcemia, allergic reactions, hearing loss, tinnitus, 
loss of muscle or nerve function, and loss of taste. 
 
3.3 
5 Fluorouracil 
 
3.3.1 
Mode of Action: 5-fluorouacil is an inhibitor of thymidylate synthetase and 
thereby limits the supply of thymidylate available for cell growth and DNA 
repair. 5-flourouracil may also be incorporated into DNA leading to 
potentially damaging cycles of insertion, excision, and reexcision. It may 
also be incorporated into RNA with potentially damaging effects. 
 
3.3.2 
Supply, Reconstitution and Administration: 5-fluorouracil is commercially 
available in 500mg vials consisting of 10cc of aqueous solution with pH 
adjusted to 9.2 with sodium hydroxide. No dilution is necessary. The drug is 
given intravenously. The solution should be inspected for particulate matter 
or discoloration. Normally, the solution is colorless, to faintly yellow. If a 

 
IRB #98147 
 
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20 
precipitate occurs due to low temperature, the drug may be resolubilized by  
heating to 140 degrees with shaking. Solution may be administered when it 
cools to body temperature. 
 
3.3.3 
Toxicity: Mucositis, diarrhea, and neutropenia are common toxicities. 
Nausea, vomiting, thrombocytopenia, anemia, photosensitivity, rash, 
alopecia, and neurologic symptoms ( i.e. a cerebellar syndrome) may result. 
Increased pigmentation of the skin, hand-foot syndrome, and tear duct 
stenosis may occur. Myocardial ischemia has been associated with 5-FU on 
occasion. 
 
3.4 
Calcium Leucovorin:  
 
3.4.1 
Mode of Action: Calcium leucovorin is a mixture of diastereomers of the 5- 
formyl derivative of folic acid. It is able to bind in addition to 5-fluorouracil 
to thymidylate synthetase to form a stable  complex  thereby enhancing the 
activity of 5-fluorouracil. 
 
3.4.2 
Supply, Reconstitution, and Administration: Calcium leucovorin is supplied 
in vials of 50, 100, and 350 mg. It is reconstituted with a sterile diluent and 
should be used immediately. If it is reconstituted with Bacteriostatic Water, it 
may be used within 7 days. 
 
3.4.3 
Toxicity: Allergic sensitization has been noted including anaphylactoid 
reactions and uticaria 
 
3.5 
Gemcitabine 
 
3.5.1 
Mode of Action: The cytotoxic effect of gemcitabine is due to a combination 
of the actions of the diphosphate (dFdCDP) and the triphosphate (dFdCTP) 
nucleoside analogs that lead to inhibition of DNA synthesis. Gemcitabine 
diphosphate inhibits ribonucleotide reductase. Gemcitabine triphosphate is 
incorporated into DNA, ultimately resulting in chain termination. 
 
3.5.2 
Supply, Reconstitution, and Administration: Gemcitabine is supplied in vials 
containing either 200mg or 1000mg of gemcitabine HCl formulated with 
mannitol (200 or 1000mg respectively) and sodium acetate (12.5 or 62.5 mg 
respectively) as a sterile lyophilized powder. To reconstitute,  5 ml or 25 ml 
respectively of 0.9% sodium chloride is add. These dilutions each yield a 
gemcitabine concentration of 40mg/ml. The appropriate amount of drug may 
be administered as prepared or further diluted to a concentration as low as 
0.1 mg/ml. Gemcitabine solutions are stable for 24 hours at room 
temperature. 
 

 
IRB #98147 
 
June 6. 2012 
21 
3.5.3 
Toxicity: Myelosuppression, nausea, vomiting, diarrhea, and stomatitis are 
noted. Also, increased liver function tests, rash, alopecia, fever, flu-like 
symptoms, edema and paresthesias have been noted. A syndrome of dyspnea 
has been reported. 
 
4.0 
STAGING 
 
All patients will be staged according to American Joint Committee on Cancer, 1993, 
criteria. 
 
5.0 
ELIGIBILITY CRITERIA 
 
5.1 
Patients must have histologically proven squamous cell carcinoma of the oral cavity, 
oropharynx, hypopharynx, or larynx. 
 
5.2 
Patients with clinical stage III or IV squamous cell carcinoma of the oral cavity, 
oropharynx, hypopharynx, or larynx are study eligible.  Patients with Stage II 
squamous cell carcinoma of the larynx, hypopharynx, or base of tongue will also be 
eligible for treatment on this protocol.  Measurable disease is required. 
 
5.3 
Patients must have resectable tumors (as determined by the attending surgeon) 
which are potentially curable with surgery and radiation therapy. 
 
5.4 
No prior chemotherapy or radiation therapy for head and neck cancer is allowed. 
 
5.5 
Patient Karnofsky performance status must be  60%. 
 
5.6 
Patients must have an absolute neutrophil count (ANC)  1500/ L and platelet count 
 100,000/ L. 
 
5.7 
Serum creatinine  1.5 mg/dl or the 24-hour creatinine clearance must exceed 60 
cc/hr. 
 
5.8 
Serum bilirubin  1.5 mg/dl. 
 
5.9 
Transaminases (ALT or AST) may be up to 2.5 x institutional upper limits of normal 
(ULN) if alkaline phosphatase is < ULN, or alkaline phosphatase may be up to 4 x 
ULN if transaminases are < ULN.  However, patients who have both transaminase 
elevation > 1.5 x ULN and alkaline phosphatase > 2.5 x ULN are not eligible for this 
study (due to decreased clearance of docetaxel and increased risk of toxicity) 
 
5.10 
Patients must be free of serious infection. 
 
5.11 
Women of child-bearing potential should have a negative pregnancy test and use 
effective birth control. 
 

 
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22 
5.12 
Written informed consent must be obtained. 
 
5.13 
EXCLUSION CRITERIA 
 
5.13.1 Patients with unresectable disease (as determined by the attending surgeon) 
are ineligible. 
 
5.13.2 No prior malignancy is allowed for purposes of determining disease free or 
overall survival except for adequately treated basal cell or squamous cell 
skin cancer, in situ cervical cancer, or other cancer for which the patient has 
been disease-free for five years.  Patients with other prior malignancies or 
with concurrent curable malignancies may be enrolled for determination of 
response and tolerance of treatment if they otherwise are eligible. 
 
 
5.13.3 Patients with unstable angina, history of congestive heart failure, or an acute 
myocardial infarction within 6 months prior to study entry are ineligible. 
 
5.13.4 No current symptomatic, Grade 2 or greater neurosensory or neuromotor 
toxicity or other significant medical or psychiatric condition incompatible 
with the protocol. 
 
6.0 
DESCRIPTIVE FACTORS 
 
6.1 
Patients will be described according to: 
 
6.1.1 
Primary site: oral cavity vs. oropharynx vs. hypopharynx vs. larynx. 
 
6.1.2 
T & N staging: T1 and T2 vs. T3 vs. T4; N0 vs. N1 vs. N2 vs. N3  
 
6.1.3 
Karnofsky performance status 
 
7.0 
TREATMENT PLAN 
 
7.1 
All study candidates will undergo consultation by a member of the Department of 
Radiation Oncology, Surgical Oncology, and Medical Oncology prior to initiation of 
treatment on this protocol.  Complete dental evaluation will also be performed prior 
to initiation of radiation therapy. 
 
7.2 
Pretreatment studies 
 
7.2.1 
All pretreatment studies specified in the study calendar will be performed 
prior to initiation of chemotherapy. 
 
7.2.2 
At diagnosis, staging will include examination under anesthesia with 
laryngoscopy, bronchoscopy and esophagoscopy (triple endoscopy); biopsy 
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of any abnormal-appearing areas will be performed (these procedures are 
optional and to be done at the discretion of the treating physicians).  Biopsy 
or cytologic aspiration of neck masses sufficient to determine nodal stage is 
optional.   
 
7.3 
Clinical response evaluation will be performed following the second course of 
chemotherapy.  Patients with less than a partial response at the primary site or with 
N2 or greater disease at the neck will immediately proceed to surgery according to 
established guidelines; all other patients will proceed with a 3rd cycle of protocol 
chemotherapy.  Response evaluation (examination under anesthesia with biopsy) 
will be performed within three weeks of completion of the neoadjuvant 
chemotherapy.  Patients in complete response after neoadjuvant chemotherapy will 
proceed to concurrent chemoradiotherapy which will commence within three weeks 
of biopsies, given ANC > 1500/uL, and platelets > 100,000/uL.  Patients with a 
partial response at the primary site may undergo surgery prior to the 
chemoradiotherapy if in the judgment of the surgeon this will not result in a major 
functional deficit and there will not be a delay in the initiation of the 
chemoradiotherapy.  In patients with N1 disease a lymph node neck dissection will 
be performed before chemoradiotherapy in patients who require surgery for the 
primary.  In all other patients neck lymph node dissection will be performed 
following chemoradiotherapy only for persistent disease. 
 
7.4 
The choice of antiemetics will be left to the attending physician. 
 
7.5 
Neoadjuvant chemotherapy 
 
7.5.1 
Chemotherapy schema 
 
Day 0  
Begin dexamethasone 8 mg po b.i.d. to continue for a total of 
3 days (docetaxel premedication). 
 
Day 1  
1) 
Docetaxel 60 mg/m² IV over one hour  
2) 
Cisplatin 25 mg/m²/day IV, to begin after completion 
of docetaxel. To continue q day x 4 for a total dose of 
100 mg/m2. 
3) 
Leucovorin 500mg/m2/day as a continuous infusion 
for 4 days. 
4) 
5-fluorouracil 700mg/m2/day as a continuous infusion 
for 4 days. 
 
Day 2 –4 
Continuing therapy with cisplatin, 5-fluorouracil, and 
leucovorin 
 
Day 27  
Begin docetaxel premedication. 
 
Day 28  
Repeat  chemotherapy 
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Day 55  
Begin docetaxel premedication. 
 
Day 56  
Repeat chemotherapy. 
 
7.5.2 
After day 1, subsequent chemotherapy courses will be administered provided 
the patient has an ANC 
 1500/uL and platelet count 
 100,000, and 
recovery from prior toxicity to Grade 1 or less has occurred.  If blood counts 
have not sufficiently recovered by the scheduled day of chemotherapy 
administration, blood counts will be obtained weekly, and treatment initiated 
when counts satisfy the above criteria.  A maximum chemotherapy delay of 
14 days will be allowed.  If the ANC and platelet count do not meet the 
above criteria after 14 days delay, the patient will be removed from protocol 
therapy. 
 
7.6 
Surgical Guidelines 
 
7.6.1 Surgical Evaluation of extent of disease 
 
7.6.1.1 
Evaluation of the primary disease 
 
The diagnosis and extent of the primary disease will be 
determined with an examination under general anesthesia using 
direct laryngoscopy , bronchoscopy, and esophagoscopy 
whenever indicated.  Multiple biopsies of the primary site will 
be obtained as well as biopsies of the normal mucosa for 
histologic diagnosis and molecular studies (see appendix).  
Biopsy specimens will be sent for routine pathological studies 
as well as for molecular studies.  Samples obtained for 
molecular studies will be snap frozen in liquid nitrogen, and 
kept in appropriately labeled containers at -80 C  until the 
studies are performed.  Accurate description of the primary site 
as well as of the extent of the tumor will be documented in the 
operative report and in the ad hoc protocol form (see 
appendix).  An examination (under anesthesia if required) will 
be repeated on the last day of the first course of chemotherapy 
and within three weeks after the completion of the neoadjuvant 
chemotherapy.  Tumor and normal mucosa samples will be 
obtained at that time; tissue samples will be processed as 
described above.  Following the second course of 
chemotherapy, clinical response will be determined and 
documented by the surgeon and medical oncologist. Three 
months after the completion of all treatment dictated by the 
protocol or sooner if persistent disease is suspected, a new 
examination under anesthesia will be performed to document 
complete histologic response, tissue biopsies will be obtained 

 
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25 
and processed as described above. 
 
7.6.1.2 
Saliva sample and oral rinse 
 
Prior to the initial diagnosis and at six months intervals for the 
first three years a sample of saliva and an oral rinse with 20 cc 
of normal saline will be collected (these studies will be 
optional).  Cells will be pelleted immediately by centrifugation, 
and slides for cytological diagnosis will be prepared. 
Supernatant will be frozen, aliquoted, and kept at - 80 C  for 
future studies. 
 
7.6.1.3 
Surgical evaluation of the Neck disease 
At the time of the initial diagnosis needle biopsy or surgical 
biopsy of palpable lymph node(s) should be performed to 
document pathologically tumor stage (this procedure is optional 
and to be done at the discretion of the treating physicians). 
 
7.6.2 Resection of the primary tumor 
 
7.6.2.1 
General Guidelines 
 
Following the completion of neoadjuvant chemotherapy the 
primary tumor will be treated according to treatment response 
and location of the primary site.  Radical resection that 
includes all sites of initial tumor involvement will be reserved 
for patients with stable disease or disease progression 
following the second cycle of chemotherapy.  In all other 
patients a functional resection will be performed in an attempt 
to preserve organ function (speech, swallowing, mastication, 
cosmesis).  The presence of a final positive microscopic margin 
will not be cause for protocol exclusion, and patients should 
complete chemoradiation prior to being considered for further 
surgical resection. 
 
7.6.2.2 
Stable disease or disease progression following the second 
cycle of chemotherapy 
 
Radical surgical resection will be performed according to 
standard surgical guidelines followed by chemoradiation. 
 
7.6.2.3 
Complete clinical response or partial clinical response to a 
tumor size of T1 or less according to AJCC criteria following 
the completion of all chemotherapy 
 
Patients with no residual disease at the primary site, or with 
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26 
clinical response equal to T1 or less according to the AJCC 
will not require primary surgery, unless in the judgment of the 
primary surgeon the surgery can be performed without 
significant functional deficit and without delaying subsequent 
treatment more than 4 weeks.  These patients will be treated 
with chemoradiation, reserving surgery for salvage. 
 
7.6.2.4 
Partial clinical response to tumor size larger than T1 according 
to AJCC criteria, but to less than 50% of the initial tumor size 
following the completion of all chemotherapy 
 
Patients with a partial response, but to a size larger than T1 
should have a radical resection of the primary followed by 
chemoradiation according to protocol guidelines.  If in the 
judgment of the surgeon adequate surgical resection of the 
primary will include a total laryngectomy or a total 
glossectomy, chemoradiation will be administered according to 
protocol and surgery will be reserved for salvage. 
 
7.6.3 Surgical  Management of the Neck 
 
7.6.3.1 
General Guidelines 
 
Management of the neck will be determined by the initial 
tumor stage and by the response of the primary and the neck to 
neoadjuvant chemotherapy.  Radical Neck Dissection shall 
include neck nodes from levels 1-5, internal jugular vein, 
sternocleidomastoid and spinal nerve.  All other dissections 
will be considered Modified Neck Dissections, and the 
operative report and the ad-hoc surgical protocol form (see 
appendix) should accurately state the extent of the resection.  
In patients with palpable node(s) at least one level above and 
below the palpable node(s) should be dissected.  In patients 
with bilateral nodes, staged or simultaneous neck lymph node 
dissections may be performed. 
 
7.6.3.2 
N2 or N3 Neck following the completion of the second course 
of chemotherapy 
 
Patients will not receive course #3 of chemotherapy.  A radical 
lymph node dissection will be performed according to standard 
surgical guidelines followed by chemoradiation according to 
protocol. 
 
7.6.3.3 
N0 Neck at diagnosis  
 

 
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27 
There will be no lymph node neck dissection in patients with 
no palpable enlarged lymph nodes and without evidence of 
enlarged (>1 cm) lymph nodes by CT scan.  Patient may 
proceed to chemo-radiation if there is no indication for surgical 
treatment of the primary. 
 
7.6.3.4 
N1 Neck following the completion of chemotherapy 
 
Following the completion of the neoadjuvant chemotherapy if 
there is clinical N1 disease, or evidence of enlarged lymph 
nodes by CT scan (>1 cm), patients will be evaluated for 
surgical treatment of the neck.  Patients who initially presented 
with clinically positive neck nodes, will also be evaluated for 
surgery even if they obtain a complete or near complete 
response. 
 
7.7 
Concurrent Chemotherapy and Radiation Therapy 
 
7.7.1 
Chemotherapy 
 
7.7.1.1 
Patients with persistent disease at the primary or neck will 
receive chemoradiation. 
 
7.7.1.2 
Drug cycle schema: On day 1, cisplatin 25 mg/m² IV over 1 hour 
will be administered (to commence with radiation therapy). It 
will be followed with gemcitabine 25mg/m2 over 30 minutes.  
Cisplatin and gemcitabine will be repeated on a weekly basis 
during radiation for a total of 7 planned doses.  
 
7.7.1.3 
Chemotherapy will be administered weekly provided the patient 
has an ANC  1500/ L and platelet count  100,000/ L.  If 
blood counts have not sufficiently recovered by the scheduled 
day of chemotherapy administration, blood counts will be 
obtained weekly, and gemcitabine/cisplatin will be administered 
when counts satisfy the above criteria.  If the ANC and platelet 
count do not meet these criteria within 21 days of scheduled 
chemotherapy 
administration, 
chemotherapy 
will 
be 
discontinued.  
 
7.7.1.4 
Chemotherapy will be held if radiation is held due to toxicity. It 
will also be held if grade III mucositis or oropharyngeal toxicity 
occur.  
 
7.7.2 
Radiation Therapy Parameters   
 
7.7.2.1 
Radiation Dose 

 
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28 
Treatment to the primary tumor and upper neck will be given at 
1.8-2.0 Gy per fraction, once a day, five days a week to a total 
dose of 70 Gy in 35 to 39 fractions in seven to eight weeks.  
Fields must be reduced to exclude the spinal cord at 40-44 Gy at 
the midplane.  However, the entire neck must be irradiated to a 
dose of at least 44 Gy (even in N0 stage) at anatomical levels of 
lymph nodes usually 2-4 cm below the skin surface.  Patients 
with multiple nodes, extracapsular extension, lymph node(s) 
greater than 3 cm, or positive lymph nodes on surgical dissection 
should receive a minimum dose of 60 Gy to the ipsilateral neck 
postoperatively.  Electrons will be used to supplement the dose to 
the posterior neck.  The anterior lower neck field will be treated 
at 1.8-2.0 Gy per fraction once a day, to a total dose of at least 44 
Gy.  The total dose to the primary tumor and clinically positive 
nodes will be 70 Gy in 35 to 39 fractions in 7 to 8 weeks. 
 
An isodose plan must be performed to document close 
homogeneity at multiple levels.  Dose inhomogeneity my not 
exceed 110%. 
 
7.7.2.2 
Physical Factors 
 
7.7.2.2.1 
Equipment: linear accelerators with appropriate 
photon (6 MV to 18 MV) and electron energies (6 
MeV to 20 MeV) for supplemental boosting to the 
nodes. 
 
7.7.2.2.2 
Patients will be treated with treatment distance at 100 
cm SAD for upper neck fields and 100 cm SSD for 
the anterior lower neck field. 
 
7.7.2.3 
Localization Requirements  
 
7.7.2.3.1 
Simulation of all fields is mandatory.  Patients must 
be reproducibly immobilized using Aquaplast 
headmask or equivalent technique.  The use of 
customized blocks to shape the treatment fields is 
recommended. 
 
7.7.2.3.2 
Beam verification (port) films must be obtained for 
each field prior to the first radiation treatment and 
every 1-2 weeks thereafter. 
 
7.7.2.3.3 
Either portal verification, simulation or Polaroid films 
must verify electron fields utilized for supplemental 
nodal boosting. 

 
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IRB #98147 
 
June 6. 2012 
30 
7.7.2.4 
Target Volume Irradiation Portals 
 
A combination of lateral opposing fields, anterior and lateral 
wedged fields, or several beam-directed fields will be used for 
the primary tumor site at the discretion of the attending radiation 
oncologist.  A single anterior field will be used to treat the neck 
below the fields for the primary tumor.  When there are positive 
nodes in the lower neck, an additional posterior field may be 
necessary to deliver a supplemental dose to the positive node(s).  
The lower neck and supraclavicular field should abut the primary 
field at the skin.  Independent jaw technique for the field junction 
with junction shift every 15 Gy is recommended.  For oral cavity 
and oropharynx primaries, a midline block 2 cm wide and at least 
2 cm in length on the skin surface may be placed in the anterior 
lower neck field to shield the larynx and the spinal cord in the 
junction region.  For larynx and hypopharynx primaries, a lower 
lateral block, 2 cm in height could be placed in the lateral upper 
neck fields to shield the areas of potential overlap of diverging 
beams over the spinal cord. The primary treatment fields should 
encompass the pre-chemotherapy tumor volume with adequate 
margins (minimum 1.5 cm) along with sites of known and/or 
suspected lymph node disease in the upper neck.  At least field 
two reductions are recommended.  The first field reduction off 
the spinal cord occurs at 40-44 Gy, and the second field 
reduction at 50-60 Gy encompassing tumor volume with 1.0-1.5 
cm margins depending on the dose delivered to the regional 
lymph nodes (see 7.9.2.1).  The primary treatment fields by 
tumor site and the lower neck field are as follows: 
 
7.7.2.5 
Oral tongue and floor of mouth 
 
The lateral fields should include the primary tumor bed, the 
submandibular and upper jugular nodes.  Boost irradiation of the 
posterior chain is not indicated unless there are clinically positive 
cervical nodes. 
 
7.7.2.6 
Anterior tonsillar pillar and retromolar trigone 
 
Both ipsilateral and contralateral posteriorcervical nodes must be 
irradiated to a minimum of 50 Gy if the primary tumor is T2-T4 
or if there are clinically positive nodes in the anterior chain. 
 
7.7.2.7 
Oropharynx 
 
Both the ipsilateral and contralateral posterior cervical nodes 
must be irradiated to a minimum of 50 Gy if the primary tumor 

 
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31 
is T2-T4 or if there are clinically positive nodes in the anterior 
chain. 
 
7.7.2.8 
Larynx 
 
7.7.2.8.1 
The upper border of the field includes the upper 
jugular nodes.  Two cm. of the mandible is to be 
included to obtain adequate coverage for N0 neck, or 
one cm. above the tip of the mastoid process when 
N+, or involvement of the pyriform sinus and/or 
lateral 
hypopharyngeal 
wall, 
to 
include 
the 
retropharyngeal nodes. 
 
7.7.2.8.2 
The lower border of the field encompasses the larynx 
usually at the inferior border of the cricoid cartilage. 
 
7.7.2.8.3 
If there is subglottic extension, the inferior border 
should extend to the upper trachea (2 cm. below 
disease). 
 
7.7.2.8.4 
Both ipsilateral and contralateral posterior nodes 
should be treated to a minimum of 50 Gy if there are 
T2-T4 or clinically positive nodes in the anterior 
chain. 
 
7.7.2.9 
Hypopharynx 
 
7.7.2.9.1 
The superior border is placed at the base of the skull 
(above C1) to include the retropharyngeal nodes.  
Nodes in the upper jugular region and posterior 
triangle are included.  Two cm. of the mandible is to 
be included to obtain adequate coverage. 
 
7.7.2.9.2 
The lower border of the field encompasses the 
primary lesion with margin (as low as possible 
without treating shoulders). 
 
7.7.2.10 
Lower neck 
 
7.7.2.10.1 A single anterior lower neck field will be used to treat 
the neck and the supraclavicular fossa below the 
fields for the primary tumor.  When there is (are) 
positive node(s) in the lower neck, an additional 
posterior field may be necessary to deliver a 
supplemental dose to the positive node(s). 
 

 
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32 
7.7.2.10.2 For all patients with clinically positive nodes greater 
than 6 cm, positive supraclavicular nodes, or 
pyriform sinus tumors that are T3 or T4 or have 
clinically positive nodes, a mediastinal T field may be 
used.  The lateral limbs of the T extend to 1 cm below 
the clavicle and the central portion of the field 
extends 5 cm more inferiorly to include the upper 
mediastinum.  
 
7.7.2.11 
Photon beam portal arrangements 
 
7.7.2.11.1 The following portal arrangements require dose 
specifications as follows: 
 
For two opposed coaxial equally weighted 
beams: on the central ray at mid-separation of 
beams. 
 
For arrangement of two or more intersecting 
beams: at the intersection of the central ray of 
the beams. 
 
7.7.2.12 
Electron beam dose specifications: 
 
The energy and field size shall be chosen so that the target 
volume is encompassed within 90% (or other appropriate 
minimum dose) of the prescribed dose. 
 
7.7.2.13 
Dose calculations 
 
7.7.2.13.1 Doses are specified as mid-depth at central axis when 
parallel opposed techniques are used or at the 
intersection of the central axis for other techniques.  
Dose to the supraclavicular field is calculated at 3 cm 
depth.  Complete isodose curves are required. 
7.7.2.13.2 Variation within the target volume is not to exceed 
+/- 10% of the target dose. 
 
7.7.2.13.3 Fields must encompass the primary tumor and its 
suspected projections with a minimum 1.5 cm margin 
in all directions.  This tumor (target) volume should 
receive 90% or greater of the central axis mid-depth 
dose. 
 
Fields must be reduced to exclude the spinal cord at a 
dose of 40-44 Gy at the mid-saggital plane.  To 

 
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33 
supplement the dose to gross adenopathy in the neck, 
boost techniques may include electrons, wedge pairs, 
oblique fields, or interstitial implants. 
 
7.7.2.14 
Time and dose modifications 
 
Treatment interruptions are strongly discouraged and should be 
allowed only for healing of severe normal tissue reactions.  
Treatment interruptions, and the reason for these must be clearly 
indicated in the treatment record. 
 
7.7.2.15 
Anticipated side effects and toxicities  
 
7.7.2.15.1 Reversible mucositis, epilation and various degrees of 
skin reaction in the treatment area are expected.  Side 
effects within 90 days of the start of treatment should 
be graded according to the Acute Radiation Morbidity 
Scoring Scale.  Radiation effects persisting beyond or 
appearing after the first 90 days are measured on the 
Late Effects Scale (see Appendix). 
 
7.7.2.15.2 Other expected acute reactions include xerostomia, 
hypogeusia, and dysphagia.  Unusual severity of any 
of these reactions should be noted. 
 
7.7.2.15.3 Late effects include permanent xerostomia in almost 
all patients and occasionally persistent dysphagia.  
Mandibular osteoradionecrosis will occur in 5 % or 
less of the patients, but can be reduced by thorough 
dental evaluation before irradiation, which is 
mandatory.  Pretherapy extraction of badly diseased 
teeth should be carried out with conservation of 
restorable teeth where possible.  Teeth extractions 
should be done at least 2 weeks prior to the start of 
irradiation. 
 
7.7.2.15.4 Radiation-induced myelopathy can occur in less than 
1% of patients providing cervical spinal cord dose 
remains below 40-44 Gy in 20 fractions in 4 weeks.  
Transient radiation effects, manifested by L'Hermittes 
sign, may be more frequent and should be fully 
documented. 
 
7.8 
Criteria for Removal from Protocol Treatment 
 
7.8.1 
Disease progression. 

 
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34 
 
7.8.2 
Delay in treatment of > 2 weeks for chemotherapy or radiation therapy. 
 
7.8.3 
Unacceptable toxicity. 
 
7.8.4 
Patients may withdraw from the study at any time for any reason. 
 
7.9 
All patients will be followed until death. 
 
8.0 
TOXICITIES MONITORED AND DOSAGE MODIFICATIONS 
 
8.1 
Patients will be examined and toxicity graded on the first day of each chemotherapy 
cycle.  Chemotherapy-associated toxicities will be monitored according to the NIH 
Common Toxicity Criteria, Version 2.0 (see Appendix). 
 
8.2 
Acute and chronic radiation morbidity will be graded according to RTOG/EORTC 
criteria (see Appendix). 
 
8.3 
Dose Modifications: Neoadjuvant Chemotherapy 
 
8.3.1 
Hematologic toxicity 
 
8.3.1.1 
At Day 28 and 56: Chemotherapy will be postponed for seven 
days for ANC < 1500/uL or platelet count < 100,000/uL.  The 
patient will be removed from protocol therapy if the ANC and 
platelet count do not satisfy these criteria within 14 days of 
scheduled administration (see Section 7.7.2). 
 
8.3.1.2 
Should febrile neutropenia occur after the first cycle of 
neoadjuvant chemotherapy, there will be a 20% reduction in the 
dose of docetaxol.  Support with G-CSF may be considered in 
place of a dose reduction if the episode of neutropenic fever was 
uncomplicated, and if there were no other significant toxicities 
(i.e. no other toxicities greater than grade 2). 
 
8.3.2 
Hypersensitivity reactions 
 
Docetaxel infusion should be stopped immediately if a patient develops 
anaphylaxis manifested by bronchospasm or hypotension sufficient to 
require parenteral therapy.  Acute anaphylaxis should be treated with 
standard emergency medical regimens.  Patients who develop anaphylaxis 
or grade 3 hypersensitivity reaction will be removed from the protocol. 
Any hypersensitivity reaction should be recorded as an adverse event.  In 
case of late-occurring hypersensitivity symptoms (e.g., appearance within 
1 week after treatment of a localized or generalized pruritis), symptomatic 
treatment may be given (e.g., oral antihistamine).  Additional oral or 

 
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parenteral premedication with antihistamine may also be given for the next 
cycle of treatment, depending on the intensity of the reaction observed.  
No dose reductions will be made in any case. 
 
8.3.2.1 
MANAGEMENT OF SUBSEQUENT CYCLES 
 
Patients with hypersensitivity reactions to Taxotere® are at risk 
for recurrent reactions.  These patients must be informed of the 
potential risk of recurrent allergic reactions and must be 
carefully monitored. 
 

 
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36 
Management of Hypersensitivity Reactions (Taxotere®) 
Management of Hypersensitivity Reactions 
 
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 
1-h infusion 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 the recommended 1-hour 
infusion, (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 1-h infusion 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 
 
the 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 
 

 
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37 
8.3.3 Renal toxicity 
 
The dose of cisplatin during neoadjuvant therapy will be based on serum 
creatinine and calculated creatinine clearance values on the scheduled 
treatment days: 
 
Serum Creatinine 
Creatinine Cl(calculated) 
% Cisplatin Dose    
 
 1.5 mg/dl and 
 
> 50 cc/hr 
 
 
100% 
 
1.6-2.0  or 
 
 
30-50 cc/hr 
 
 
50% 
 
> 2.0 or 
 
 
< 30 cc/hr 
 
 
No cisplatin 
 
8.3.4 
Mucositis, diarrhea, dermatitis 
 
Grade 3 mucositis, diarrhea, or dermatitis occurring during the previous 
cycle will result in a 10% reduction in docetaxel dose as well as a 10% 
reduction in 5-fluorouracil. 
 
Grade 4 mucositis, diarrhea, or dermatitis during the previous cycle will 
require a 20% reduction in docetaxel dose and a 20% reduction of the 5-
fluorouracil dose 
 
8.3.5 
Neurotoxicity 
 
Doses of docetaxel and cisplatin will be modified based on the most severe 
neurotoxicity during the previous cycle: 
 
Neurotoxicity Grade  
Dose Adjustment 
 
0 - 2 
 
 
None 
3 
 
 
Hold chemotherapy until recovery to  Grade 
1, then decrease docetaxel and cisplatin by 
25% 
4 
 
 
Patient removed from study 
 
If neurotoxicity does not improve to  Grade 1 after a 2 week delay, the 
patient will be removed from protocol treatment. 
 
8.3.6 
Fluid retention 
 
No dose reduction is planned.  Patients developing new onset or 
symptomatic edema, or other signs of fluid retention, should be treated with 

 
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38 
oral diuretics.  The choice of diuretics will be at the discretion of the 
attending physician.   
 
8.3.7 
Abnormal liver function tests  
 
Patients who develop abnormal liver function tests while on the study, for 
any reason, will have the following docetaxel dose reductions: 
 
 
 
 
Bilirubin 
Alkaline phosphatase ALT/AST 
Action 
  
 
 
 
1) > ULN     or >5 x ULN      or 
         >5 x ULN      Wait  2 weeks.    
 
 
 
 
If recovered, reduce dose by 25%.  If not, off study. 
 
 
 
 
2)  ULN 
 5 x ULN        and 
          <  5x ULN 
       Dose reduce 25%. 
 
 
8.4 
Dose Modifications: Concurrent Chemotherapy (and radiation therapy)  
 
8.4.1 
Hematologic toxicity 
 
At the beginning of each week of radiation therapy, gemcitabine and CDDP 
will be held if ANC < 1500, or PLT < 100,000. 
 
8.4.2 
Renal toxicity 
 
The dose of cisplatin will be based on serum creatinine and calculated 
creatinine clearance values on the scheduled treatment days: 
 
Serum Creatinine 
Creatinine Cl(calculated) 
% Cisplatin Dose 
 1.5 mg/dl 
 
and 
> 50 cc/hr 
 
100% 
1.6-2.0  
 
or 
30-50 cc/hr 
 
50% 
> 2.0   
 
or  
< 30 cc/hr 
 
No cisplatin 
 
If renal function declines to the point that cisplatin is placed on hold, 
gemcitabine with also be held. 
 
8.4.3 
Neurotoxicity 
 
In the event of a grade 3 or greater neurotoxicity, CDDP will be held until 
recovery to toxicity level  Grade 1, then subsequent cisplatin doses will be 
reduced by 25%.  Therapy with gemcitabine alone may continue. 
 

 
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8.5 
Ototoxicity 
 
Audiograms will be performed if subjective hearing loss develops.  Significant (>40 
dB) loss in the speech frequency range is an indication to discontinue cisplatin. 
 
8.6 
Radiation Therapy Treatment Interruption 
 
Skin reaction, mucositis, ulceration, edema or other acute radiotherapy complication 
may necessitate interruptions in radiotherapy.  The interruption should not exceed 
two weeks. 
 
8.7 
If > 3 patients are unable to receive at least 4 of the planned 7 weekly chemotherapy 
treatments, or if >3 patients require radiation interruptions of more than 2 weeks, then 
this part of the protocol will be reevaluated  for feasibility. Accrual to the protocol 
will continue, but patients will be treated with radiation alone. 
 
8.8 
ADVERSE EVENT REPORTING 
 
Adverse events will be reported as outlined in appendix .  In addition, Rhône-
Poulenc Rorer, the manufacturers of Taxotere, has requested the following 
guidelines included as additional information.  
 
8.8.1 Definitions  
 
A serious adverse event (experience) or reaction is any untoward medical 
occurrence that at any dose: results in death, is life-threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results 
in persistent or significant disability/incapacity, or is 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. 
 

 
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40 
8.8.2 Reporting 
 
In IND studies, all docetaxel serious, related, unlabeled, (unexpected) 
adverse events will be reported to the FDA, by the investigator, as 
required by 21 CFR 312.32.   
 
In IND studies, Rhône-Poulenc Rorer Pharmaceuticals, Inc., will be 
provided with a copy of all docetaxel serious, related adverse event 
reports.  These reports should be filed utilizing the Form FDA 3500A 
(MedWatch Form).  This includes serious, related, labeled (expected) and 
serious, related, unlabeled (unexpected) adverse experiences. These 
reports must be sent by FAX to Rhône-Poulenc Rorer Drug Product Safety 
(610-454-2190), within 24 hours of receipt by investigator / sponsor 
 
For Comparator Drugs / Secondary Suspects (Concomitant Medications), 
all serious adverse experiences will be forwarded to the product 
manufacturer, by the investigator. 
 
In IND-exempt studies, Rhône-Poulenc Rorer Pharmaceuticals, Inc., will 
be provided with a copy of all docetaxel serious, related adverse event 
reports.  These reports  should be filed utilizing the Form FDA 3500A 
(MedWatch Form).   This includes serious, related, labeled (expected) and 
serious, related, unlabeled (unexpected) adverse experiences. These 
reports must be sent by FAX to Rhône-Poulenc Rorer Drug Product Safety 
(610-454-2190), within 24 hours of receipt by investigator / sponsor. 
 
For Comparator Drugs / Secondary Suspects (Concomitant Medications), 
all serious adverse experiences will be forwarded to the product 
manufacturer, by the investigator. 

 
IRB #98147 
 
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41 
9.0 
STUDY PARAMETERS 
 
 
 
 
Prestudy 
Before each 
Chemotherapy Cycle 
During 
Chemoradiation 
After 2nd 
Chemotherapy/After all 
Chemotherapy/After 
Radiotherapy 
History & Physical 
Examination 
X 
X 
q2wk 
0/X/X 
Tumor Measurements 
X 
0 
0 
X/X/X 
Performance Status 
X 
X 
q2wk 
0/X/X 
CBC, platelet count and 
differential AФ 
X 
X 
qwk 
0/X/X 
Chem 18, MagnesiumФ 
X 
X 
qwk 
0/X/X 
Creatinine Clearance 
(actual) 
X 
0 
0 
0/X/X 
Creatinine Clearance 
(calculated) 
X 
X 
qwk 
0/0/0 
Triple Endoscopy* 
X* 
0 
0 
0/0/0 
Tumor Biopsy *(when 
feasible) 
X* 
0 
0 
X*/X*/X* 
Oral Rinses* 
X* 
0 
0 
0/X*/X* 
Serum Specimen 
*(peripheral blood) 
X* 
0 
0 
0/0/X* 
CT or MRI of Neck 
*(optional) 
X* 
0 
0 
0/X*/X* 
Chest X-ray 
X 
0 
0 
0/0/X 
Quality of Life 
Assessment 
X 
0 
0 
0/X/X 
Audiogram 
X 
0 
0 
0/0/X 
 
 
- labs should be repeated on day 8 –12 to determine nadir and electrolyte status, and 
should be drawn otherwise as clinically indicated. 
* - tests are optional. 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1 
Disease status 
 
10.1.1 Measurable disease:  Bidimensionally measurable lesions with clearly 
defined margins by 1) medical photograph (skin or oral lesions) or plain 
7/9/01 

 
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42 
x-ray, with at least one diameter .5 cm or greater (bone lesions not 
included) or 2) CT, MRI, or other imaging scan, with both diameters 
greater than the distance between cuts of the imaging study or 3) 
palpation, with both diameters 1 cm or greater. 
 
10.1.2 Evaluable disease:  Unidimensionally measurable lesions, masses with 
margins not clearly defined, lesions with both diameters less than 0.5 cm, 
lesions on scan with either diameter smaller than the distance between 
cuts, palpable lesions with either diameter less than 2 cm, bone disease.  
Markers that have been shown to be highly correlated with extent of 
disease are also considered to be evaluable. 
 
10.2 
Objective status 
 
If an organ has too many measurable lesions at each evaluation, choose three to 
be followed before the patient is entered on study.  The remaining measurable 
lesions in that organ will be considered evaluable for the purpose of objective 
status determination.    
 
10.2.1 Complete response (CR):  Complete disappearance of all measurable and 
evaluable disease.  No new lesions.  No disease-related symptoms.  No 
evidence of non-evaluable disease, including normalization of markers 
and other abnormal lab values.  All measurable, evaluable, and non-
evaluable lesions and sites must be assessed using the same technique as 
baseline.  Refers to clinical CR.  (When restaging surgery is required, a 
separate pathologic response variable is incorporated in the response 
data). 
 
10.2.2 Partial response (PR):  Applies only to patients with at least one 
measurable lesion.  Greater than or equal to 50% decrease under baseline 
in the sum of products of perpendicular diameters of all measurable 
lesions.  No progression of evaluable disease.  No new lesions.  All 
measurable and evaluable lesions and sites must be assessed using the 
same techniques as baseline. 
 
10.2.3 Stable/No response:  Does not qualify for CR, PR, or progression,  All 
measurable and evaluable sites must be assessed using the same 
techniques as baseline. 
 
10.2.4 Progression:  50% increase OR an increase of 10 cm2 (whichever is 
smaller) in the sum of products of all measurable lesions over smallest 
sum observed (over baseline if no decrease) using the same techniques as 
baseline, OR clear worsening of any evaluable disease, OR reappearance 
of any lesion that had disappeared, OR appearance of any new 
lesion/site, OR failure to return for evaluation due to death OR 
deteriorating condition (unless clearly unrelated to this cancer).  For 

 
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43 
scan-only bone disease, increased uptake does not constitute clear 
worsening.  Worsening of existing non-evaluable disease does not 
constitute progression. 
 
10.2.4.1 
Exceptions: 
 
10.2.4.1.1 In cases for which initial tumor flare reaction is 
possible (hypercalcemia, increased bone pain, 
erythema of skin lesions), either symptoms must 
persist beyond 4 weeks or there must be additional 
evidence of progression. 
 
10.2.4.1.2 Lesions that appear to increase in size due to 
presence of necrotic tissue will not be considered 
to have progressed. 
 
10.2.5 Clinically Significant Response (CSR): patients achieving a complete 
response (as defined in section 10.2.1) of the primary tumor, or a partial 
response of the primary tumor less than or equal to T1 by AJCC staging  
and neck metastases staged as NO or N1.  A clinically non-significant 
response would include patients achieving a partial response at the primary 
tumor greater than T1, stable disease, progression or metastatic disease in 
the neck greater than N1. 
 
10.3 
Best Response: Best response is determined from the sequence of objective 
statuses. 
 
10.3.1 Disease assessment every 4 weeks.  Two objective status determinations 
of CR before progression are required for a best response of CR.  Two 
determinations of PR or better before progression, but not qualifying for 
a CR, are required for a best response of PR.  Two determinations of 
PRNM or better before progression, but not qualifying for CR, are 
required for PRNM.  Two determinations of stable/no response or better 
before progression, but not qualifying as CR, PR or PRNM, are required 
for a best response of stable/no response; if the first objective status is 
unknown, only one such determination is required.  Patients with an 
objective status of progression on or before the second evaluation 
(second AFTER the prestudy evaluation) will have a best response of 
increasing disease.  Best response is unknown if the patient does not 
qualify for a best response of increasing disease and if all objective 
statuses after the first determination and before progression are 
unknown. 
 
Use of the definition is illustrated in Table 1 with several sequences of 
objective statuses and the corresponding best response. 
 

 
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Table 1.  Sequences of objective statuses with corresponding best response 
1st objective status 
2nd objective status 
3rd objective status 
Best response 
3-6 week assessment interval 
Progression 
 
 
Progression 
Stable, PR, CR, unk 
Progression 
 
Progression 
Stablea 
Stable 
Progression 
Stable 
Stable, unka 
PR, CR 
Progression 
Stablee 
Stable, unk 
Unknownd 
Progression 
Unknown 
PRb 
PR 
Progression 
PR 
PRb 
CR 
Progression 
PR 
PR, CR 
Unknownd 
Progression 
PR (Unconfirmed) 
CRc 
CR 
Progression 
CR 
Unknowna 
Stable 
Progression 
Stable 
 
aBest response is the same if these sequences are preceded by the objective statuses of unknown 
or stable, or if unknowns separate the first objective status from the second. 
bBest response is the same if these sequences are preceded by the objective statuses of 
unknown, stable or PR, or if unknowns separate the first objective status from the second. 
cBest response is the same if these sequences are preceded by the objective statuses of 
unknown, stable, PR or CR, or if unknowns separate the first CR from the second. 
dBest response is the same if followed by additional unknowns. 
eEvaluation codes allow identification of these patients with best response of stable or unknown 
who had unconfirmed PR or CR. 
 
10.4 
ENDPOINT DEFINITIONS 
 
10.4.1 Overall Survival.  Defined as the time from first day of treatment to time 
of death due to any cause.  If a patient is still alive, survival time is 
censored at the time of last follow-up. 
 
10.4.2 Disease-Free Survival.  Defined as the time from first day of treatment to 
the first observation of disease recurrence or progression or death due to 
any cause.  If a patient has not progressed or died, disease-free survival 
is censored at the time of last follow-up. 
 
10.4.3 Disease-Free Interval.  Defined as the time from first day of treatment to 
the first observation of disease recurrence or progression or death due to 
disease.  If failure has not occurred, failure time is censored at the time 
of last follow-up. 
 
10.4.4 Duration of response.  Defined as the time from first objective status 
assessment of response to the first time or progression or death due to 
any cause.  If a responding patient has not progressed or died, duration is 
censored at the time of last follow-up. 

 
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45 
 
11.0 
TISSUE HANDLING  
 
11.1 
Tumor Tissue Procurement 
 
Tumor tissue specimens and normal mucosa will be obtained by the surgical service 
via biopsy (or excision) of primary tumors or regional lymph nodes at diagnosis, on 
day 2 of the first chemotherapy cycle, at the completion of the neoadjuvant 
chemotherapy, and at the time of the definitive surgical resection if indicated.  All 
tissue obtained will be transported in an iced container to anatomic pathology for 
immediate processing.  A surgical pathologist will review portions of all specimens 
to confirm malignant histology.   Dr. Sharon Wilczynski, from the Division of 
Pathology at COH, will supervise the handling of the tissues obtained.  Using 
standard methods, each biopsy will be divided longitudinally: half of the tissue will 
be placed in buffered formalin for routine histology and for immunohistochemical 
evaluation.  Half of the tissue will be immediately frozen and sent to Dr. 
Doroshow’s laboratory for DNA and protein extraction for future molecular studies. 
 Specimens obtained at the time of surgical resection and future staging procedures 
will be processed under the same conditions. 
 
In cases where tissue is not available at City of Hope, a request will be made for 
access to an outside paraffin block.  In addition, a request will be made for a 
blood sample to further as correlate with tissue parameters. 
 
Samples will be submitted to: 
 
Clinical and Molecular Pharmacology Laboratory 
 
Kaplan Clinical Research Building 
 
City of Hope National Medical Center 
 
1500 E. Duarte Rd. 
 
Duarte, CA 91010 
 
 
12.0 
STATISTICAL CONSIDERATIONS 
 
This is a Phase II study.  The first objective of this trial is to obtain preliminary estimates of 
the anti-tumor efficacy of three cycles of a preoperative combination of platinum-taxane-5-
FU-LV chemotherapy in patients with stage III-IV resectable squamous cell carcinoma 
(SCC) of the head and neck (assessment of response at day 55).  Patients will be considered 
evaluable for response and evaluable for toxicity as outlined in section 10.0.  The second 
objective of the trial is to determine the tolerability and feasibility of a multimodality 
approach including  combined chemoradiation after initial neoadjuvant chemotherapy and 
surgery.  A further purpose is to explore whether biochemical parameters of tumor tissue 
correlate with response and outcome.  
 
A maximum of 30 patients will be accrued to the trial.  Justification of the samples size is 
provided below.  

 
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46 
 
12.1 
STUDY DESIGN AND JUSTIFICATION OF SAMPLE SIZE 
 
A two stage design will be used to evaluate the anti-tumor efficacy (CR or PR) of 
the induction chemotherapy.  It is assumed that a true response rate less than 50% 
would not warrant further study of this regimen and a response rate of 70% would 
be considered promising for further studies in these patients.  In the first stage, 20 
evaluable patients will be entered.  If nine or less responses are observed, the 
accrual will stop with the conclusion that the regimen is not promising for further 
study.  If ten or more responses are observed in the first 20 patients, an additional 
10 patients will be accrued during the second stage of the study.  Nineteen or more 
responses out of 30 patients will be considered as evidence warranting further study 
of the regimen providing other factors, such as toxicity and survival, also appear 
favorable.  If less than 19 responses out of 30 patients are observed, further study of 
the regimen would not be warranted.   The probability of falsely declaring an agent 
with a 50% response probability as warranting further study is 0.10 (alpha) and the 
probability of correctly declaring an agent with a 70% response probability as 
warranting further study is 0.84 (power). With 30 patients the true probability of 
response can be estimated with a maximum standard error equal to 9%. 
 
Statistics on biochemical studies performed on biopsy specimens are planned to be 
exploratory.  Trends noted on this study will be used to guide studies in future 
trials. 
 
Based on current projections of patients evaluated in the Department of Medical 
Oncology and the Division of Surgery, it is estimated that accrual of 30 patients 
should be completed within a maximum of two years.   
 
12.2 
ANALYSIS OF RESULTS 
 
12.2.1 Analysis of Anti-tumor Activity 
 
The response rate is defined as the percent of evaluable patients who 
experience a CR or PR.  Binomial confidence intervals (95%) will be [91].  
Duration of response will be estimated using the product-limit method of 
Kaplan and Meier [92]. 
 
12.2.2 Summary of Toxicities and Side Effects 
 
All observed toxicities and side effects will be recorded on flow sheets and 
the data collection forms.  Toxicity information including the type, severity, 
time of onset and time of resolution, and probable association with the drugs 
will be recorded.  Tables will be constructed to summarize the observed 
incidence by severity and type of toxicity. 
 
12.2.3 Analysis of Survival and Disease-Free Survival 

 
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Overall and disease-free survival will be estimated using the product limit 
method of Kaplan and Meier. 
 
12.2.4 Analysis of functional outcome 
 
Data collected using the FACT-H&N quality of life questionnaire and the 
PSS-HN performance status scale for head and neck patients will be used. 
These instruments have been validated and used at other institutions for 
assessing quality of life in patients with head and neck cancer.  Data will be 
analyzed using the psychometric and correlation analysis recommended by 
the developers of the instrument. 
 
13.0 
REGRISTRATION GUIDELINES 
 
To register a patient, the treating physician should contact the responsible Clinical 
Research Associate (CRA) in Biostatistics or the protocol nurse to determine whether the 
patient meets all of the eligibility criteria, and to confirm the a Patient Informed Consent 
has been signed.  After verifying the eligibility and receiving the signed informed consent, 
the CRA will register the patient on study. 
 
14.0 
RECORDS TO BE KEPT AND DATA SUBMISSION SCHEDULE 
 
14.1 
Confidentiality of Records: The original data collection forms will be stored in 
secure cabinets in the Department of Biostatistics. 
 
14.2 
Patient Consent Form: At the time of registration, three signed and dated copies of 
the patient Informed Consent form with the Human Rights must be available (for 
patient, patient's medical chart and one for the Biostatistics Office).  
 
14.3 
Registration Eligibility Worksheet:  At the time of registration, the information 
requested on the On-Study/Eligibility Form will be submitted to Data Manager.  
 
14.4 
Data Collection Forms and Submission Schedule 
 
All data will be collected using COH Biostatistics Information Tracking System 
(BITS) data collection forms.  Copies of the completed forms will be submitted to 
City of Hope Department of Biostatistics for data entry and stored in a secure 
location.  The original data collection forms will reside at the originating 
institution in secure location. 
 
14.4.1 The data manager will complete the Eligibility Checklist Worksheet at the 
time of registration: 
 
14.4.2 Within two weeks of registration, the data manager will complete the On-
Study Form (Form OS). 

 
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48 
 
14.4.3 Within four weeks of completion of each course of treatment, the data 
manager must complete the following: 
 
14.4.3.1 
Treatment and Adverse Event Form  
14.4.3.2 
Supplemental Data Form (if applicable) 
14.4.3.3 
Flow Sheets  (These are to be submitted along with each 
treatment form.) 
 
14.4.4 Each time a patient is evaluated for response and/or new follow-up 
information is obtained the data manager will complete the Response/Off-
Study/Follow- Up Form. 
 
15.0 
MINORITIES AND GENDER STATEMENT 
 
Recruitment is open to all minorities and both genders.  Our recruitment procedures have 
been developed to enroll patients who are representative of the respective target 
population.  The ethnic and gender distribution of cancer patients in the COH catchment 
area is given in Table 2.  These neoplasms are more frequent in the male population in a 
ratio 4:1, so we expect a disproportionate accrual of male subjects, consistent with this 
frequency. 
 
Table 2 
Gender and Minority Breakdowns for COH Catchment Area1 
 
Gender 
 
Caucasian 
 
Hispanic 
African 
American 
 
Asian 
 
Other 
 
Total 
Males 
18% 
16% 
2.5% 
5.0% 
8.5% 
50.0% 
Females 
18% 
16% 
2.5% 
5.0% 
8.5% 
50.0% 
Total 
36% 
32% 
5.0% 
10.0% 
17.0% 
100.0% 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
All patients will have signed an informed consent for participation in research activities 
in accord with all institutional, NCI and Federal regulations, and will have been given a 
copy of the Experimental Subject's Bill of Rights. 
 
When the results of this study are reported in medical journals or meetings, identification of 
those taking part will be withheld.  Medical records of patients will be maintained in strictest 
confidence according to current legal requirements.  However, they will be made available 
for review, as required by the FDA or other authorized users such as the National Cancer 
Institute, under the guidelines established by the Federal Privacy Act. Record may also be 
made available for review to Rhône-Poulenc Rorer, the manufacturers of Taxotere. 

 
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