June 2004 9811-1 RTOG Protocol No: 9811 Protocol Status: ECOG Protocol No: R9811 Opened October 31, 1998 CALGB Protocol No: 89808 NCCTG Protocol No: R9811 SWOG Protocol No: R9811 Title: A Phase III Randomized Study of 5-Flourouracil, Mitomycin-C, and Radiotherapy Versus 5-Flourouracil, Cisplatin

and Radiotherapy in Carcinoma of the Anal Canal. Patient Population:

All patients must have primary T2-T4 squamous, baseloid, or eloacogenic carcinoma of the anal canal. Patients must be at least 18 years of age with a Karnofsky performance score of at least 60. Patients are not allowed to have had prior chemotherapy or radiotherapy, unless it was completed more than 5 years prior to registration. Patients are not permitted to have had prior surgery for cancer of the anus, except a biopsy. Patients must have eligible laboratory values as follows: creatinine ≤ 1.5 mg/dl, bilirubin < 1.4 mg/dl, WBC ≥ 4000, ANC ≥ 100,000. A study-specific consent form must be signed by all patients prior to randomization.

Objectives:

Primary• To compare disease-free survival in patients treated with 5-FU plus Mitomycin-C concurrently with radiation

therapy to patients treated with distant metastases induction 5-FU plus cisplatin followed by 5-FU plus cisplatin concurrently with radiation therapy.

Secondary• To identify any differences in local control to patients treated with distant metastases and colostomy rates. • To identify any differences in colostomy-free, and overall survival. • To compare the toxicity profiles between the two treatment arms. • To evaluate the prognostic effects of tumor markers p53 overexpression, human papilloma virus status, and enzyme

HAP1. Schema:

S

T

R

A

T

I

F

Y

Gender 1. Male 2. Female Clinical Nodal Status1. Positive 2. Negative Primary Size1. > 2 cm to 5 cm 2. > 5 cm

R

A

N

D

O

M

I

Z

E

Arm 1:5-FU + Mitomycin-C and Radiotherapy (Concurrent with EBRT) Arm 2:5-FU + Cisplatin and Radiotherapy (Induction and Concurrent)

Chemotherapy (Note: In Arm 1, both courses of chemotherapy will be administered during radiotherapy. In arm 2,

patients will receive two courses of induction chemotherapy in addition to 2 courses during radiotherapy.)

5-FU + Mitomycin-C: Mitomycin-C 10 mg/m2 i.v. bolus on days 1 and 29 (not to exceed 20 mg per course). 5-FU 1000 mg/m2/day by continuous infusion on days 1-4 and 29-32.

5-FU + Cisplatin: Cisplatin 75 mg/m2 i.v. over 60 min. on days 1 and 29, and also repeated on days 57 and 85

(days 57 and 85 should correspond to days 1 and 29 of radiotherapy). 5-FU 1000 mg/m2/day by continuous infusion on days 1-4 and 29-32, and also repeated on days 57-60 and 85-88 (days 57 and 85 should correspond to days 1 and 29 of radiotherapy).

Continued on next page

June 2004 9811-2

External Beam Irradiation (EBRT): (Note treatment break of < 10 days will be optional for severe local skin reactions)

Note: Large pelvic field (to 30.6 Gy) and reduction field #1 (to 45 Gy) will be used in all patients; reduced field #2 is to be used for all patients with T3, T4, or N + lesions and for those patients with T2 lesions that have residual disease after 45 Gy.

1) Initial Field: 30.6 Gy in 17 Fx (1.8 Gy/fx) to large pelvic field with superior border at L5-S1. 2) Field reduction #1: Reduce superior border to inferior level of S1 joints.

a) Deliver 14.4 Gy in 8 Fx (1.8 Gy/fx) for a total of 45 Gy. b) For N0 patients, reduce off inguinal nodes after 36 Gy.

3) Reduction #2 (for all T3, T4, or N+lesions and T2 lesions with residual cancer after 45 Gy). Deliver 10-14 Gy (2 Gy/fx) to gross primary or nodal disease plus a 2.0 to 2.5 cm margin for a total dose of 55-59 Gy within boost field #2.

Surgery: a) Biopsy of palpable inguinal lymph nodes prior to treatment. b) (Optional) Full thickness biopsy to be performed 8 weeks after completion of radiation and

chemotherapy if any palpable residual abnormality is present. Study Chairs: Jaffer Ajani, M.D. (Medical Oncology) Patients entered through: John Pedersen, M.D. (Radiation Oncology) 4/16/04 537 Leonard Gunderson, M.D. (Radiation Oncology) John Skibber, M.D. (Surgical Oncology) Asif Rashid (Pathology) Al Benson, III, M.D. (ECOG, Medical Oncology) James Martenson, M.D. (ECOG, Radiation Oncology) Robert J. Mayer, M.D. (CALGB, Medical Oncology) Joel Tepper, M.D. (CALGB, Radiation Oncology) Steven R. Alberts, M.D. (NCCTG, Medical Oncology) Michael G. Haddock, M.D. (NCCTG, Radiation Oncology) Heidi Nelson, M.D. (NCCTG, Surgical Oncology) Charles R. Thomas, Jr., M.D. (SWOG, Radiation Oncology) Kevin Billingsley, M.D. (SWOG, Surgical Oncology) Statistician: Kathryn Winter, M.S. (RTOG) Reyna Hochstedler, B.S. (RTOG) Research Associate: Wendy Bergantz, R.N. (RTOG) Debora Grant, R.N., M.S.N. (RTOG) Dosimetrist: Lorraine Quarles, R.T.T. (RTOG) Protocol Associate: Marian Bellus, B.A. (RTOG) I. Summary:

This is an intergroup study which RTOG coordinates and in which NCCTG, ECOG, CALGB and SWOG participate. The study opened October 31, 1998. The targeted accrual is 650 patients. As of April 16, 2004, 537 patients had entered the study. Of those, 524 are analyzable for toxicities. Table 3.1 shows the pretreatment characteristics of the two arms. Tables 4.1 and 4.3 show acute and late toxicities by arm. On the mitomycin arm, 31% of the patients had grade 4 chemotherapy and acute radiotherapy toxicity as compared to 22% on the cisplatin arm. In Tables 5.1 and 5.2 the status of radiotherapy and chemotherapy reviews are shown. On the mitromycin arm 71% of cases have had a radiotherapy review and 67% of cases on the cisplatin arm have had a review. For chemotherapy reviews, 10% of cases on the mitromycin arm have been reviewed and 9% of cases on the cisplatin arm have been reviewed.

June 2004 9811-3 II. Administrative Information:

Table 2.1 Patient Accrual

Estimated number of patients required 650

Total patients entered through 4/16/04 537

Average monthly accrual for study 8.2

Average monthly accrual for last 6 months 7.8

Projected completion date based on last 6 months June 2005

Table 2.2 Institutional Accrual

(See Appendix A)

Table 2.3a Case Status

RT + 5-FU & Mitomycin-C

RT + 5-FU & Cisplatin

Total

Patients entered 268 269 537 Ineligible/Cancelled* 6 7 13 Eligible/Pending† 262 262 524 With on-study information 251 258 509 With toxicity information 239 233 472

Table 2.3b *Reasons for Exclusion

CN RX Status Reason 21 RT+5-FU & Mitomycin-C Ineligible Prior surgery of the anus other than biopsy

236 RT+5-FU & Mitomycin-C Ineligible Patient is T1 249 RT+5-FU & Mitomycin-C Ineligible HGB < 10 at on-study 264 RT+5-FU & Mitomycin-C Ineligible Concurrent colon cancer 299 RT+5-FU & Mitomycin-C Ineligible Patient underwent potentially curative resection 454 RT+5-FU & Mitomycin-C Ineligible Patient has prior malignancy

85 RT+5-FU & Cisplatin Cancelled Case cancelled—patient withdrew consent

171 RT+5-FU & Cisplatin Ineligible Tumor measurements are too small; proctoscopy/sigmoidoscopy not done

207 RT+5-FU & Cisplatin Ineligible Prior surgery of the anus other than biopsy 210 RT+5-FU & Cisplatin Ineligible HGB < 10 at on-study 271 RT+5-FU & Cisplatin Ineligible Patient has evidence of metastases 360 RT+5-FU & Cisplatin Ineligible Ineligible baseline HGB at on-study 379 RT+5-FU & Cisplatin Ineligible Ineligible baseline HGB at on-study

June 2004 9811-4

Table 2.3c †Eligibility Pending

CN RX Reason 75 RT + 5 - FU + Mitomycin - C Tumor size ≤ 2.0

203 RT + 5 - FU + Mitomycin - C Tumor dimensions are too small, t-stage is unclear 344 RT + 5 - FU + Mitomycin - C Colonoscopy results were negative for cancer 375 RT + 5 - FU + Mitomycin - C Tumor size ≤ 2.0 415 RT + 5 - FU + Mitomycin - C Tumor size ≤ 2.0 450 RT + 5 - FU + Mitomycin - C Tumor size ≤ 2.0 500 RT + 5 - FU + Mitomycin - C Tumor size ≤ 2.0 515 RT + 5 - FU + Mitomycin - C Unclear t-stage 517 RT + 5 - FU + Mitomycin - C Tumor size ≤ 2.0

15 RT + 5 – FU + Cisplatin Tumor size ≤ 2.0

129 RT + 5 – FU + Cisplatin Unclear tumor measurements 223 RT + 5 – FU + Cisplatin Tumor size ≤ 2.0 341 RT + 5 - FU + Cisplatin Prior surgery of the anus other than biopsy 355 RT + 5 - FU + Cisplatin Tumor size ≤ 2.0 389 RT + 5 - FU + Cisplatin Unclear t-stage 393 RT + 5 - FU + Cisplatin Tumor measurements are too small, unclear t-stage 425 RT + 5 - FU + Cisplatin Tumor size ≤ 2.0 484 RT + 5 - FU + Cisplatin Tumor size ≤ 2.0 503 RT + 5 - FU + Cisplatin Tumor size ≤ 2.0 508 RT + 5 - FU + Cisplatin Prior malignancy within 5 years 511 RT + 5 - FU + Cisplatin Tumor size ≤ 2.0

June 2004 9811-5 III. Pretreatment Characteristics:

Table 3.1 Pretreatment Characteristics

RT + 5-FU & Mitomycin-C

(n=251) RT + 5-FU & Cisplatin

(n=258) Age Median 56 54 Range 25-83 31-88 Gender Male 80 (32%) 83 (32%) Female 171 (68%) 175 (68%) KPS 60 3 ( 1%) 2 ( 1%) 70 8 ( 3%) 9 ( 3%) 80 33 (13%) 33 (13%) 90 106 (42%) 111 (43%) 100 100 (40%) 103 (40%) Pending 1(<1%) 0 Tumor location Above dentate line 32 (13%) 34 (13%) Anal canal 171 (68%) 158 (61%) Perianal skin 9 ( 4%) 4 ( 2%) Anal canal and perianal skin 38 (15%) 62 (24%) Pending 1 (<1%) 0 Largest tumor dimension 2-5cm 172 (69%) 176 (68%) >5cm 71 (28%) 74 (29%) Pending 8 ( 3%) 8 ( 3%) Histology Squamous cell 209 (83%) 223 (86%) Baseloid 17 ( 7%) 16 ( 6%) Cloacogenic 22 ( 9%) 15 ( 6%) Other 3 ( 1%) 4 ( 2%) T-Stage (clinical) T2 157 (63%) 167 (65%) T3 67 (27%) 70 (27%) T4 26 (10%) 21 ( 8%) Pending 1 (<1%) 0 N-Stage (clinical) N0 177 (71%) 176 (68%) N1 31 (12%) 19 ( 7%) N2 25 (10%) 38 (15%) N3 8 ( 3%) 10 ( 4%) NX 10 ( 4%) 15 ( 6%)

June 2004 9811-6 IV. Toxicities:

Table 4.1 Chemotherapy and Acute Radiotherapy Toxicities

RT +

5-FU & Mitomycin-C (n=239)

RT + 5-FU & Cisplatin

(n=233) Grade Grade 1 2 3 4 1 2 3 4 Allergy/immunology 5 1 0 0 5 2 0 0 Auditory/hearing 2 1 0 0 7 19 1 0 Blood/bone marrow 26 43 78 58 39 64 51 38 Cardiovascular (arrhythmia) 3 1 3 0 1 0 1 0 Cardiovascular (general) 16 18 6 0 16 11 19 1 Coagulation 2 0 0 0 0 1 3 0 Constitutional symptoms 64 66 19 1 61 67 30 1 Dermatology/skin 25 83 93 10 21 86 86 6 Endocrine 3 2 0 0 2 3 1 0 Gastrointestinal 44 80 72 9 29 81 88 9 Hemorrhage 20 3 1 0 23 7 0 0 Hepatic 28 9 3 0 23 2 4 0 Infection/febrile neutropenia 6 27 32 4 5 35 19 3 Metabolic/laboratory 37 12 15 2 42 17 16 3 Musculoskeletal 1 2 3 0 0 1 0 0 Neurology 20 14 9 1 44 28 10 0 Ocular/visual 0 1 1 0 4 0 0 0 Pain 18 53 51 1 28 58 36 2 Pulmonary 11 7 6 1 15 11 2 2 Renal/genitourinary 36 43 5 1 39 43 7 2 Sexual reproductive function 2 1 2 0 1 6 1 0 Worst non-hematologic 8

(3%) 55

(23%)137 (57%)

27 (11%)

6 (3%)

50 (21%)

141 (59%)

22 (9%)

Worse overall 4 (2%)

29 (12%)

121 (51%)

75 (31%)

3 (1%)

36 (15%)

128 (55%)

52 (22%)

June 2004 9811-7

Table 4.2 All Grade 4+ Acute Toxicities

RX CN Group Toxicity Grade RT+5-FU&Mitromycin-C 10 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 11 Gastrointestinal Stomatitis 4 28 Blood/bone marrow Leukopenia NOS 4 33 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 37 Blood/bone marrow Neutropenia 4 38 Gastrointestinal Stomatitis 4 Diarrhea NOS 4 45 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 51 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 Infection/febrile neutropenia Infection with grade 3 or 4 neutropenia 4 52 Blood/bone marrow Neutropenia 4 57 Blood/bone marrow Neutropenia 4 58 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 Dermatology/skin Toxicoderma 4 Pain Pain-other 4 60 Blood/bone marrow Neutropenia 4 77 Gastrointestinal Duodenal ulcer 4 Esophagitis NOS 4 Neurology Cerebral ischaemia 4 80 Blood/bone marrow Neutropenia 4 89 Blood/bone marrow Leukopenia NOS 4 Infection/febrile neutropenia Febrile neutropenia 4 99 Renal/genitourinary Urogenital fistula 4 111 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 112 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 117 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 118 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 123 Dermatology/skin Dermatitis radiation NOS 4 Pulmonary Adult respiratory distress syndrome 4 126 Constitutional symptoms Fatigue 4 135 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 Dermatology/skin Dermatitis radiation NOS 4 138 Blood/bone marrow Neutropenia 4 145 Dermatology/skin Dermatitis radiation NOS 4 147 Blood/bone marrow Neutropenia 4 161 Blood/bone marrow Neutropenia 4 166 Gastrointestinal Colitis NOS 4 174 Dermatology/skin Dermatitis radiation NOS 4 182 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 193 Blood/bone marrow Neutropenia 4 Platelet count decreased 4

June 2004 9811-8

Table 4.2 All Grade 4+ Acute Toxicities

(continued) RX CN Group Toxicity Grade RT+5-FU&Mitromycin-C 198 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 209 Metabolic/laboratory Hypokalemia 4 215 Blood/bone marrow Neutropenia 4 216 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 219 Blood/bone marrow Leukopenia NOS 4 234 Blood/bone marrow Leukopenia NOS 4 Platelet count decreased 4 253 Blood/bone marrow Neutropenia 4 255 Blood/bone marrow Neutropenia 4 256 Blood/bone marrow Neutropenia 4 258 Blood/bone marrow Leukopenia NOS 4 Platelet count decreased 4 268 Blood/bone marrow Neutropenia 4 Gastrointestinal Anorexia 4 270 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 277 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 283 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 287 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 288 Blood/bone marrow Neutropenia 4 290 Blood/bone marrow Neutropenia 4 Dermatology/skin Dermatitis radiation NOS 4 293 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 Gastrointestinal Radiation mucositis 4 302 Dermatology/skin Dermatitis radiation NOS 4 308 Blood/bone marrow Neutropenia 4 319 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 329 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 330 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 335 Blood/bone marrow Platelet count decreased 4 339 Blood/bone marrow Neutropenia 4 344 Blood/bone marrow Neutropenia 4 345 Blood/bone marrow Leukopenia NOS 4 346 Blood/bone marrow Leukopenia NOS 4 349 Blood/bone marrow Leukopenia NOS 4 351 Gastrointestinal Diarrhea NOS 4 363 Blood/bone marrow Neutropenia 4 Dermatology/skin Toxicoderma 4 371 Blood/bone marrow Neutropenia 4 Dermatology/skin Dermatitis radiation NOS 4 372 Blood/bone marrow Neutropenia 4

June 2004 9811-9

Table 4.2 All Grade 4+ Acute Toxicities

(continued) RX CN Group Toxicity Grade RT+5-FU&Mitromycin-C 373 Blood/bone marrow Neutropenia 4 383 Metabolic/laboratory Hypophosphatemia 4 384 Gastrointestinal Anorexia 4 412 Dermatology/skin Dermatitis radiation NOS 4 444 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 461 Blood/bone marrow Neutropenia 4 463 Blood/bone marrow Neutropenia 4 478 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 Infection/febrile neutropenia Infection, Other 4 482 Gastrointestinal Anal fistula 4 492 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 Platelet count decreased 4 515 Infection/febrile neutropenia Ferbrile neutropenia 4 RT+5-FU&Cisplatin 9 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 13 Blood/bone marrow Neutropenia 4 25 Blood/bone marrow Neutropenia 4 39 Blood/bone marrow Neutropenia 4 41 Blood/bone marrow Neutropenia 4 48 Metabolic/laboratory Hypokalemia 4 67 Metabolic/laboratory Hyperglycemia NOS 4 73 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 78 Blood/bone marrow Neutropenia 4 87 Blood/bone marrow Neutropenia 4 Gastrointestinal Stomatitis 4 Pulmonary Dyspnea NOS 4 Pneumonitis NOS 4 Hypoxia 4 88 Blood/bone marrow Neutropenia 4 96 Dermatology/skin Toxicoderma 4 98 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 Gastrointestinal Anorexia 4 Stomatitis 4 Dehydration 4 Diarrhea NOS 4 Infection/febrile neutropenia Ferbrile neutropenia 4 100 Blood/bone marrow Neutropenia 4 106 Blood/bone marrow Neutropenia 4 Infection/febrile neutropenia Infection with grade 3 or 4 neutropenia 4 119 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 122 Blood/bone marrow Neutropenia 4 Gastrointestinal Anorexia 4 Pulmonary Adult respiratory distress syndrome 4

June 2004 9811-10

Table 4.2 All Grade 4+ Acute Toxicities

(continued) RX CN Group Toxicity Grade RT+5-FU&Cisplatin 125 Gastrointestinal Radiation mucositis 4 159 Blood/bone marrow Neutropenia 4 176 Cardiovascular (general) Thrombosis NOS 4 183 Blood/bone marrow Neutropenia 4 195 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 211 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 213 Blood/bone marrow Neutropenia 4 218 Blood/bone marrow Neutropenia 4 222 Blood/bone marrow Neutropenia 4 225 Blood/bone marrow Neutropenia 4 233 Blood/bone marrow Neutropenia 4 243 Blood/bone marrow Neutropenia 4 251 Blood/bone marrow Neutropenia 4 Gastrointestinal Esophagitis NOS 4 254 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 Dermatology/skin Dermatitis radiation NOS 4 260 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 Platelet count decreased 4 Gastrointestinal Radiation mucositis 4 261 Dermatology/skin Dermatitis radiation NOS 4 263 Metabolic/laboratory Hypokalemia 4 280 Blood/bone marrow Neutropenia 4 284 Blood/bone marrow Neutropenia 4 294 Blood/bone marrow Leukopenia NOS 4 297 Blood/bone marrow Neutropenia 4 301 Blood/bone marrow Neutropenia 4 304 Blood/bone marrow Platelet count decreased 4 Constitutional symptoms Fatigue 4 Dermatology/skin Dermatitis radiation NOS 4 314 Gastrointestinal Stomatitis 4 355 Dermatology/skin Toxicoderma 4 Gastrointestinal Vomiting NOS 4 Pain Pain due to radiation 4 Renal/genitourinary Dysuria 4 358 Blood/bone marrow Neutropenia 4 389 Gastrointestinal Stomatitis 4 396 Pain Pain due to radiation 4 398 Renal/genitourinary Blood creatinine increased 4 414 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 439 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 448 Dermatology/skin Dermatitis radiation NOS 4 462 Blood/bone marrow Neutropenia 4 Leukopenia NOS 4 480 Infection/febrile neutropenia Infection NOS 4 485 Blood/bone marrow Neutropenia 4

June 2004 9811-11

Table 4.3 Late Radiotherapy Toxicities

RT +

5-FU & Mitomycin-C (n=213)

RT + 5-FU & Cisplatin

(n=209)

Grade Grade 1 2 3 4 1 2 3 4 Bladder 9 6 2 0 12 7 0 0 Skin (within treatment field) 35 7 4 3 24 5 1 3 Small/Large Intestine 43 17 2 2 23 12 3 1 Subcutaneous 6 6 3 0 8 4 0 2 Other 25 21 5 1 17 19 7 3 Worst per patient 48

(23%) 41

(19%) 13 (6%)

6 (3%)

32 (15%)

32 (15%)

10 (5%)

8 (4%)

* Late radiotherapy toxicities are those that occurred greater than 90 days from the start of RT.

Table 4.4 Grade 3+ Late RT Toxicities

RX CN Toxicity Grade RT+5-FU & Mitomycin-C 2 Small/large intestine Telangiectasis 3 14 Skin Radiation necrosis 4 62 Small/large intestine Radiation enteritis 3 Bladder Radiation enteritis 3 99 Skin Erythema 3 101 Other Rectal pain 3 128 Skin Pending 3 Subcutaneous Tissue Pending 3 193 Other Decreased hemoglobin 3 203 Other Vaginal stenosis 3 206 Skin Proctalgia 4 Other Ulceration 3 268 Skin Telangiectasis 3 279 Skin Abcess 3 303 Other Necrosis/non-healing wound 4 312 Subcutaneous Tissue Necrosis 3 353 Small/large intestine Bowel obstruction 4 387 Small/large intestine Ulcer 4 404 Skin Erythema 4 444 Subcutaneous Tissue Ectasia 3 461 Other Anal fissure 3 RT+5-FU & Cisplatin 9 Other Hearing 3 15 Small/large intestine Diarrhea 3 36 Small/large intestine Diarrhea 3 39 Other Mucus membrane 3 61 Subcutaneous tissue Radiation atrophy 4 Other Ulcer 3 73 Other Ulcerative lesion 4 125 Other Mucus membrane 4 136 Small/large intestine Bowel obstruction 3 159 Skin Enterosis 3 162 Other Neutropenia 3

June 2004 9811-12

Table 4.4 Grade 3+ Late RT Toxicities

(continued)

RX CN Toxicity Grade RT+5-FU & Cisplatin 200 Other Stenosis 3 201 Other Lymphadema 3 222 Other Bone 3 228 Small/large intestine Enteritis 4 246 Skin Ulcer 4 292 Other Anal fistula 4 307 Skin Abcess 4 376 Skin Open draining wound 4 Subcutaneous tissue Open draining wound 4

Table 4.5 Worst Toxicity At Any Time

Grade 3 4 RT + 5-FU & Mitomycin-C (n=239) 117 (49%) 81 (34%) RT + 5-FU & Cisplatin (n=233) 123 (52%) 58 (24%)

V. Study Chair Review:

Table 5.1 Radiotherapy Review

RT + 5-FU & Mitomycin-C RT + 5-FU & Cisplatin (n=262) (n=262) Not Reviewed 76 (29%) 87 (33%) Reviewed 186 (71%) 175 (67%)

Per Protocol 139 (75%) 126 (72%) Variation – Acceptable 34 (18%) 30 (17%) Deviation – Unacceptable 7 ( 4%) 9 ( 5%) Incomplete RT -- death during RT 2 ( 1%) 3 ( 2%) Incomplete RT – progression 0 1 ( 1%) Incomplete RT – refusal 2 ( 1%) 2 ( 1%) No RT given 2 ( 1%) 3 ( 2%) Not evaluable 0 1 ( 1%)

Table 5.2 Chemotherapy

CT+5-FU & Mitromycin-C (n=262)

RT+5 FU & Cisplatin (n=262)

Not Reviewed 237 (90%) 239 (91%) Reviewed 25 (10%) 23 ( 9%)

Per protocol 17 (68%) 17 (74%) Variation acceptable – minor 5 (20%) 6 (26%) Variation acceptable – NOS 1 ( 4%) 0 Cancelled 1 ( 4%) 0 Incomplete chemo 1 ( 4%) 0

June 2004 9811-13

Appendix A Institutional Accrual

(Affiliates Included in Full Member Totals) RTOG (394) Fox Chase Cancer Center 29McMaster University, Hamilton 23Thomas Jefferson University Hospital 20Wayne State University 20Washington University 18LDS Hospital 14Univ. of Texas-MD Anderson Can. Ctr. 12Radiological Associates of Sacramento 11Columbus Comm. Clinical Oncology Prog. 10Dartmouth Hitchcock Medical Center 10SE Cancer Control Consortium, Inc., CCOP 10University of Kentucky Hospital 10University of Texas Medical Branch 10Akron City Hospital 8Mayo Clinic 8Michigan Cancer Res. Consortium CCOP 8Partners/Dana Farber Cancer Institute 8SUNY Health Science Center/Brooklyn 8University of California San Francisco 8Greenville S.C. CCOP 7Johns Hopkins Hospital 7Mt. Sinai Comprehensive Can. Ctr. CCOP 7Toledo Comm. Hosp. Oncology Prog. CCOP 7Cross Cancer Institute - Univ. of Alberta 6Medical College of Wisconsin 6Metro-MN CCOP 6Northern Indiana Can. Res. Consortium 6University of Miami 6Albert Einstein Medical Center 5Cancer Research for the Ozarks 5

Natalie Warren Bryant Can. Ctr. at St. Francis Hosp. 5Univ. of Alabama at Birmingham Med. Ctr. 5Univ. of California Davis Med. Ctr. 5University of Western Ontario 5Virginia Mason Medical Center 5

Atlanta Regional CCOP 4Christiana Care Health Services, Inc. 4McGill University 4University of Rochester 4Cleveland Clinic Foundation 3Columbia River CCOP 3Dayton CCOP 3Southern Nevada Cancer Res. Found. CCOP 3St. Vincent Regional Can. Ctr. CCOP 3University of Michigan Med. Ctr. 3Bay Area Tumor Institute CCOP 2Beaumont CCOP 2Benefis Healthcare CCOP 2Gulf Coast MBCCOP 2Kansas City CCOP 2Santa Rosa Memorial Hospital CCOP 2Univ. of Pennsylvania Medical Center 2University of South Florida 2Baptist Cancer Institute CCOP 1Central Illinois CCOP 1Foundation for Cancer Res. and Edu. 1Main Line Health CCOP 1New York University Hospital 1Scott and White Memorial Hospital 1

June 2004 9811-14

Appendix A Institutional Accrual

(Affiliates Included in Full Member Totals) (continued)

ECOG (60) S Africa, Verwoerd Hosp (SAFR) 9Carle Clinic Association 4Pennsylvania Hospital 4Swedish Medical Center 3Archbishop Bergan Mercy Hospital 2Fairview University Medical Center 2Hackensack Hospital 2Illinois Onc. Assoc. (MAYO) 2Maplewood Cancer Center 2Memorial Hospital Association 2Metro Health Medical Center 2St Paul-Ramsey Hospital 2Toledo Clinic (MAYO) 2University of Wisconsin Hospital 2St Joseph Hospital 1Chester County Hospital 1Delaware County Memorial Hospital 1

Duluth Clinic (MAYO) 1Evanston Hospital Corp 1Hem Onc Associates-Chicago 1Lawrence Memorial (TUFT) 1Lehigh Valley Hospital 1Mary Imogene Bassett Hospital 1McFarland Clinic (WISC) 1Medical Center Aurora Health One 1Memorial Hospital 1Mercy Hospital 1New Britain General Hospital(Tuft) 1Pottstown Memorial Medical Center 1Sewickley Valley Hospital 1St Mary Regional Cancer Center 1St Mary's Hospital 1St Vincent Mercy Medical Center 1West Michigan Cancer Center 1

NCCTG (30) Bismarck 4Des Moines 4Mayo Clinic Scottsdale 4St Joseph Hospital 4Wichita CCOP 4Grand Forks Clinic 3

Rapid City Regional Hospital 2St Cloud Hospital 2Cedar Rapids 1Rochester Methodist Hospital 1Sioux Falls 1

SWOG (28) St. Louis CCOP 5Brooke Army Medical Center 3Tumor Institute at Swedish Hospital 3Louisiana State Univ Hospital 2Multicare - Tacoma General Hospital 2Univ. of So. California-Los Angeles 2University of Arkansas Medical Center 2University of Texas Medical Branch 2

L A County-USC Medical Center 1Northwest CCOP 1Oregon Health Sciences Center 1Poudre Valley Hospital 1St Anthony Hospital 1University of Michigan Med. Ctr. 1Valley Care Health System 1

CALGB (25) Univ. of Texas Southwestern Med. Sch. 5SUNY Health Science Center/Syracuse 3Virginia Oncology Associate 3Lakeland Medical Center 2Rhode Island Hospital 2Eastern Maine Medical Center 1Lenoir Memorial Hospital 1New York Hospital/Cornell MC 1

Northeast Alabama Regional Med. Ctr. 1Ohio State University 1Southwestern Vermont Med. Ctr. 1University of Illinois at Chicago 1University of Iowa Hospital 1University of Minnesota 1Vermont Regional Cancer Center 1