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2010 RTOG Protocol No: 0529

0529-1 Protocol Status: Opened: December 21, 2006 Closed: March 21, 2008

Title: A Phase II Evaluation of Dose-Painted IMRT in Combination with 5-Fluorouracil and Mitomycin-C for Reduction of Acute Morbidity in Carcinoma of the Anal Canal Patient Population: Histologically proven, invasive primary squamous, basaloid, or cloacogenic carcinoma of the anal canal. T stage 2-4 and N0-N3 stage. ANC ≥ 1,800 cells/mm3, platelets ≥ 100,000 cells/mm3, hemoglobin ≥ 8.0 g/dl, serum creatinine ≤ 1.5 mg/dl, bilirubin < 1.4 mg/dl, WBC ≥ 3,000/µl, ALT/AST < 3 x ULN and INR ≤ 1.5. All patients must be ≥ 18 and not pregnant or nursing. Women of child bearing potential and male participants must agree to use medically effective birth control. HIV-positive patients without AIDS are eligible. Objectives: Primary: To determine if the combined rate of ≥ grade 2 GI and GU adverse events from IMRT + 5-FU & mitomycin-C is decreased by at least 15% in the first 90 days following the start of treatment, as compared to the RT+ 5-FU & mitomycin-C arm from RTOG 9811 Secondary: • To determine the feasibility of performing IMRT in a cooperative group setting for the treatment of anal carcinoma • To evaluate adverse events associated with this treatment regimen and to decrease the grade 2 and higher and grade 3 and higher overall adverse event rates by 15% or 20% as compared to the RT and mitomycin-C arm of RTOG 9811 • To estimate clinical complete response at 8 weeks following treatment completion • To evaluate total duration of radiotherapy treatment time • To estimate the following efficacy endpoints: local-regional failure, disease-free survival, time to colostomy, colostomy-free survival and overall survival Schema: 5-FU + Mitomycin-C and IMRT R E G I S T E R 5-FU + Mitomycin-C • Mitomycin-C on days 1 and 29 • 5-FU by 96-hour continuous infusion (M-F) beginning on day 1 and again on day 29 Note: Days 1 and 29 are based on calendar days. Lisa Kachnic, M.D. Robert Myerson, M.D. Michael Goodyear, M.D. John Willins, Ph.D. Jacqueline Esthappan, Ph.D. Kathryn Winter, M.S. Jennifer Moughan, M.S. Wendy Bergantz, R.N. Debora Grant, R.N., M.S.N. Denise Manfredi, R.T.(T.) Courtney Conroy, B.A., C.C.R.P. IMRT The prescription dose scheme will depend on staging as follows: (see Section 6.0 for complete details) • T2N0: 28 fractions over 5.5 weeks • T3N0 or T4N0: 30 fractions over 6 weeks • N+: 30 fractions over 6 weeks Total patients entered: 63

Study Chairs:

(Radiation Oncology) (Radiation Oncology) (Medical Oncology) (Medical Physics) (Medical Physics)

Statisticians: Research Associates:

Dosimetrist: Protocol Associate:

Administrative Information: Table 2.000/ul Ineligible – Patient was a T1 Ineligible – Registered in error. Adverse event information is provided in Section IV. Adverse events were graded using CTCAE version 3.2 Case Status Total patients entered Ineligible/no protocol RX Eligible With on-study information With adverse event information Table 2. Summary: 0529-2 RTOG 0529 opened December 21.0.1%) (9.1%) (9.3 Cases Excluded (n=11) Reason No protocol treatment Ineligible – H & P performed > 14 days prior to registration Ineligible – Biopsy performed > 42 days prior to registration Ineligible – WBC < 3. wanted RTOG 0522 not 0529 1 6 1 1 1 1 (9.2010 I.1%) (54.1 Patient Accrual Study sample size Total patients entered Average monthly accrual for the study 59 63 4. 2008. Administrative information can be found in Section II and pretreatment characteristics can be found in Section III. The data provided in this report are as of August 2010. 2006 and closed March 21.1%) 63 11 52 52 52 .1%) (9.2 Table 2.5%) (9. after accruing a total of 63 patients. II.

8%) 40 ( 76.8%) 47 ( 90. Pretreatment Characteristics: Table 3.8%) 13 ( 25.5%) 16 ( 30.Max Q1 .6%) 42.2%) 42 ( 80.6%) 9.64 10 ( 19.2010 III.0%) 9.6%) 84.9%) 12 ( 23.8%) 3 ( 5.1%) 48 ( 92.6%) 28 ( 53.8%) 25.0%) 11 ( 21.3%) 4 ( 7.6%) 3.8%) 4 ( 7.8%) 1 5 44 2 ( ( ( ( 1.7%) 29 13 5 5 ( ( ( ( 55.2%) .4%) 2 ( 3.3%) 26.2%) 32 ( 61.1 Pretreatment Characteristics (n=52) Age (years) Median Min .9%) 21.9%) 9. Q3 = third quartile 0529-3 58 34 .Q3 Gender Male Female Race American Indian or Alaskan Native Black or African American White Unknown Ethnicity Hispanic or Latino Not Hispanic or Latino Unknown Zubrod Performance Status 0 1 Histology Squamous cell Basaloid Differentiation Low grade Intermediate High grade Unknown T stage (clinical) T2 T3 T4 N stage (clinical) N0 N1 N2 N3 AJCC Stage (6th Edition) Stage II Stage IIIA Stage IIIB Q1 = first quartile.7%) 5 22 14 11 ( ( ( ( 9.82 50 .

2010 Table 3.9%) 3 (5.5%) 5 (9.6%) 2 (3.9%) 2 (3. or Possibly Adverse Event Worst non-hematologic Grade 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 3 (5.8%) 2 (3.8%) 1 (1.8%) 16 (30.2%) 32 (61.1 Summary of Worst Adverse Event per Patient (n=52) Relationship to Treatment Definitely.4%) 3 (5.8%) 5 (9.8%) 11 (21.2 Gender/Ethnicity/Race Distributions Sex/Gender Females Males 3 0 37 10 2 0 42 10 1 4 35 2 42 0 1 9 0 10 0529-4 Ethnic Category Hispanic or Latino Not Hispanic or Latino Unknown (Individuals not reporting ethnicity) Ethnic Category: Total of All Subjects Racial Category American Indian/Alaska Native Black or African American White Unknown or not reported Racial Category: Total of All Subjects IV.6%) 25 (48. Adverse Events: Total 3 47 2 52 1 5 44 2 52 Table 4.1%) 18 (34.2%) 34 (65.8%) Worst overall Any Worst non-hematologic Worst overall .8%) 5 (9.8%) 1 (1.6%) 28 (53.6%) 2 (3.8%) 10 (19. Probably.

or Possibly Related to Protocol Treatment (n=52) Category Term ALLERGY/IMMUNOLOGY Hypersensitivity NOS BLOOD/BONE MARROW Blood/bone marrow . Probably. Term.Other Dry skin Erythema multiforme Flushing Pruritus Radiation recall syndrome Skin atrophy Grade 3 0 0 16 0 1 5 17 2 15 5 1 1 0 0 1 0 0 0 0 6 0 6 1 0 0 0 0 12 0 0 1 0 0 10 0 0 0 0 0 2 0 1 1 1 4 1 0 17 3 1 5 12 0 0 0 0 0 0 0 0 0 7 1 5 0 4 1 1 7 5 10 0 0 0 1 3 0 4 0 1 3 2 1 2 1 1 8 0 0 11 9 0 4 9 1 0 1 0 0 1 1 0 0 21 0 18 0 0 0 0 4 29 2 1 0 1 8 17 1 0 1 0 0 5 0 4 0 0 14 0 0 1 4 3 9 6 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0 5 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .2010 0529-5 Table 4. and Grade Definitely.Other Fatigue Insomnia Pyrexia Rigors Sweating increased Weight decreased DERMATOLOGY/SKIN Alopecia Burn Culture wound negative Decubitus ulcer Dermatitis exfoliative NOS Dermatitis radiation NOS Dermatology/skin .Other CD4 lymphocytes decreased Hemoglobin Leukopenia NOS Lymphopenia Neutrophil count Platelet count decreased CARDIAC ARRHYTHMIA Atrial fibrillation Atrial tachycardia Sinus bradycardia Sinus tachycardia CARDIAC GENERAL Hypertension NOS COAGULATION Disseminated intravascular coagulation CONSTITUTIONAL SYMPTOMS Constitutional Symptoms .2 Number of Patients with an Adverse Event by Category.

2 Number of Patients with an Adverse Event by Category.Other Lower gastrointestinal hemorrhage Rectal hemorrhage Urethral hemorrhage Urogenital hemorrhage Vaginal hemorrhage INFECTION Bladder infection NOS Grade 3 0 0 0 0 0 0 11 0 0 0 5 0 0 5 3 0 0 0 2 0 0 0 0 0 0 1 0 0 0 1 3 1 0 0 0 0 0 0 0 0 0 0 11 1 0529-6 1 1 11 3 1 1 1 10 0 0 0 6 0 9 0 20 3 1 1 0 5 2 4 3 0 0 16 7 4 1 0 4 4 19 4 2 2 1 1 11 1 1 2 0 0 2 2 1 0 1 1 1 28 1 1 2 6 1 3 6 16 2 0 0 2 2 0 1 2 1 1 7 7 7 0 0 8 6 1 1 0 0 0 0 0 0 0 0 6 1 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .2010 Table 4. and Grade Definitely.Other Hemorrhoids Ileus paralytic Mucositis/stomatitis (functional/symptomatic): Esophagus Nausea Proctitis NOS Radiation mucositis Rectal ulcer Small intestinal stricture NOS Stomatitis Vomiting NOS HEMORRHAGE/BLEEDING Anal hemorrhage Colonic hemorrhage Epistaxis Hemorrhage/bleeding . or Possibly Related to Protocol Treatment (n=52) Category Term Skin fibrosis Skin hyperpigmentation Skin hypopigmentation Telangiectasia ENDOCRINE Hot flushes NOS GASTROINTESTINAL Abdominal distention Anal fistula Anal stenosis Anorexia Colitis NOS Constipation Dehydration Diarrhea NOS Dysgeusia Dyspepsia Dysphagia Enteritis Fecal incontinence Flatulence Gastrointestinal . Probably. Term.

Other Soft tissue necrosis: Pelvic NEUROLOGY Agitation Anxiety Confusional state Depression Dizziness Peripheral motor neuropathy Peripheral sensory neuropathy PAIN Grade 3 0 7 1 0 1 1 0 0 0 0 0 0 11 2 0 0 1 0 0 0 0 0 1 0 5 5 0 1 1 0 1 2 0 0 1 0 0 0 1 12 0529-7 1 0 0 0 0 0 0 0 0 0 5 4 1 8 2 4 2 0 0 1 1 4 1 7 5 8 8 1 4 0 0 0 7 2 1 0 1 3 2 5 7 2 1 0 0 0 0 3 1 1 1 2 2 0 8 0 2 1 1 2 1 0 2 1 7 5 0 0 0 1 1 1 0 7 0 4 0 3 1 1 1 17 4 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 . and Grade Definitely.0 x 10e9/L): Blood Infection with Grade 3 or 4 neutrophils (ANC <1. or Possibly Related to Protocol Treatment (n=52) Category Term Clostridial infection NOS Febrile neutropenia Infection with Grade 3 or 4 neutrophils (ANC <1. Probably. Term.2010 Table 4.0 x 10e9/L): Lung (pneumonia) Infection with Grade 3 or 4 neutrophils (ANC <1.2 Number of Patients with an Adverse Event by Category.0 x 10e9/L): Urinary tract NOS Infection with unknown ANC: Lung (pneumonia) Skin infection Urinary tract infection NOS LYMPHATICS Edema: limb Edema: trunk/genital METABOLIC/LABORATORY Alanine aminotransferase increased Aspartate aminotransferase increased Blood alkaline phosphatase increased Blood bilirubin increased Blood creatinine increased Hypercalcemia Hypercholesterolemia Hyperglycemia NOS Hyperkalemia Hypoalbuminemia Hypocalcemia Hypokalemia Hyponatremia Hypophosphatemia Metabolic/laboratory .Other MUSCULOSKELETAL/SOFT TISSUE Musculoskeletal/soft tissue .0 x 10e9/L): Appendix Infection with Grade 3 or 4 neutrophils (ANC <1.

2010 Table 4. and Grade Definitely. Term.Other Ureteric obstruction Urinary incontinence Urinary retention SEXUAL/REPRODUCTIVE FUNCTION Erectile dysfunction NOS Libido decreased Menstruation irregular Sexual/reproductive function .Other Pain NOS Pain in extremity Pain of skin Pain: Peritoneum Pelvic pain NOS Penile pain Perineal pain NOS Pharyngolaryngeal pain Proctalgia Renal pain Scrotal pain Stomach discomfort Urethral pain Vaginal pain PULMONARY/UPPER RESPIRATORY Cough Dyspnea Hypoxia Pleural effusion Pneumonitis NOS RENAL/GENITOURINARY Cystitis NOS Pollakiuria Renal/genitourinary .Other Vaginal atresia Grade 3 4 2 0 1 0 0 0 1 0 0 0 0 1 1 0 1 1 0 4 0 4 0 1 0 0 1 3 0 1 1 0 1 1 0 0 0 1 0 0 3 0 0 1 1 0 0529-8 1 0 4 0 0 1 1 1 2 3 1 0 0 1 0 1 1 0 0 2 3 1 1 0 2 1 2 5 5 2 0 1 0 8 1 11 5 0 0 3 3 0 2 1 2 2 2 4 7 1 1 0 1 0 0 0 2 1 3 0 2 1 0 1 1 4 1 4 0 1 0 2 1 0 0 0 1 0 0 12 7 5 0 0 2 0 6 1 0 0 1 3 4 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 . or Possibly Related to Protocol Treatment (n=52) Category Term Abdominal pain NOS Anal discomfort Arthralgia Back pain Bladder pain Bone pain Buttock pain Chest pain Headache Myalgia Oral pain Pain . Probably.2 Number of Patients with an Adverse Event by Category.

3 Number of Patients with an Adverse Event by Category. or Possibly Related to Protocol Treatment (n=52) Category Term Vaginal discharge Vaginal mucositis Vaginitis Vulvovaginal dryness VASCULAR Vascular access NOS complication PENDING CLARIFICATION OF TERM Grade 3 0 1 0 0 0 0 0 0529-9 1 1 0 0 2 0 0 0 2 1 1 1 4 1 1 1 4 0 0 0 0 0 0 0 5 0 0 0 0 0 0 0 Includes adverse events where relationship to protocol treatment is missing. . Probably. Term.2010 Table 4.0. Adverse events were graded with CTCAE version 3.2 Number of Patients with an Adverse Event by Category. Table 4. and Grade Any Relationship to Protocol Treatment (n=52) Grade 3 0 17 1 1 0 7 0 12 0 12 1 0 11 0 13 2 4 12 4 2 3 1 0 Category Allergy/immunology Blood/bone marrow Cardiac arrhythmia Cardiac general Coagulation Constitutional symptoms Death Dermatology/skin Endocrine Gastrointestinal Hemorrhage/bleeding Hepatobiliary/pancreas Infection Lymphatics Metabolic/laboratory Musculoskeletal/soft tissue Neurology Pain Pulmonary/upper respiratory Renal/genitourinary Sexual/reproductive function Vascular Pending clarification of term 1 1 4 0 0 0 7 0 5 3 11 20 1 0 5 9 0 8 9 7 11 3 0 0 2 1 7 2 1 0 21 0 29 1 27 1 1 7 3 7 1 7 19 0 12 6 2 1 4 0 14 0 0 1 0 0 1 0 0 0 0 1 0 0 0 0 3 1 0 0 0 0 5 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Includes adverse events where relationship to protocol treatment is missing. Adverse events were graded with CTCAE version 3. Term.0. and Grade Definitely.

2010 Table 4. .4 Grade 5 Adverse Events Case Number Category 22 52 Death Cardiac arrhythmia 0529-10 Term Disease progression NOS Sinus bradycardia Days from Days from Relationship Start of End of to Treatment Treatment Treatment Unrelated Possible 483 208 441 163 Adverse events were graded with CTCAE version 3.0.