Neoplasms

All Conditions

Digestive System Diseases

Rare Diseases

Carcinoma

Carcinoma, Squamous Cell

Anus Neoplasms

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Anus Diseases

Rectal Diseases

Acute Graft Versus Host Disease

Anal Cancer

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Fluorouracil

Mitomycins

Mitomycin

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Alkylating Agents

Enzyme Inhibitors

1000 mg/m\^2/day 96-hour continous infusion (M-F) starting on day 1 and again on day 29 of radiation therapy.

fluorouracil

10 mg/m\^2 intravenous therapy on day 1 and day 29 of radiation therapy.

mitomycin C

Prescription dose depends on tumor staging.

T2N0: The primary tumor PTV (planning target volume) (PTVA) receives 50.4 Gy in 28 fractions (fx) at 1.8 Gy/fx. The nodal PTVs receive 42 Gy in 28 fx at 1.5 Gy/fx. PTVA receive 50.4 Gy in 28 fractions at 1.8 Gy/fx. PTV42 receive 42 Gy in 28 fx at 1.5 Gy/fx and will include all nodal regions.

T3N0 or T4N0: The primary tumor PTV (PTVA) will receive 54 Gy in 30 fx at 1.8 Gy/fx. The nodal PTVs will receive 45 Gy in 30 fx at 1.5 Gy/fx. PTVA will receive 54 Gy in 30 fx at 1.80 Gy/fx. PTV45 will receive 45 Gy in 30 fx electively at 1.5 Gy/fx and will include all nodal regions.

For N+ disease: The primary tumor PTV (PTVA) will receive 54 Gy in 30 fx at 1.8 Gy/fx. For involved nodes ≤ 3 cm in maximum dimension, the involved nodal PTV will receive 50.4 Gy in 30 fx at 1.68 Gy/fx. For involved nodes \> 3 cm in maximum dimension, the involved nodal PTV will receive 54 Gy in 30 fx at 1.80 Gy/fx.

Intensity-modulated radiation therapy

Lisa A. Kachnic, MD

RATIONALE: Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as fluorouracil and mitomycin C, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with 5-fluorouracil (5-FU) and mitomycin C may kill more tumor cells.

PURPOSE: This phase II trial is studying the side effects and how well giving intensity-modulated radiation therapy together with fluorouracil and mitomycin C works in treating patients with invasive anal cancer.

OBJECTIVES:

Primary

* Determine if dose-painted, intensity-modulated radiation therapy (IMRT), fluorouracil, and mitomycin C decreases the combined rate of gastrointestinal and genitourinary adverse events (grade II or greater) by at least 15% in the first 90 days after the start of treatment in patients with primary invasive carcinoma of the anal canal compared to patients treated on the radiotherapy, fluorouracil, and mitomycin C arm on clinical trial RTOG 98-11.

Secondary

* Determine the feasibility of performing IMRT in these patients in a cooperative group setting.
* Evaluate adverse events experienced by patients treated with this 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 radiotherapy and mitomycin C arm of RTOG 98-11.
* Evaluate the total duration of radiotherapy.
* Evaluate the efficacy of this regimen, in terms of locoregional failure, disease-free survival, time to colostomy, colostomy-free survival, and overall survival of these patients.
* Determine clinical complete response at 8 weeks after completion of study treatment.

OUTLINE: This is a multicenter study.

Patients receive mitomycin C IV over 10-30 minutes on days 1 and 29 and fluorouracil IV continuously over 96 hours on days 1-4 and 29-32. Patients also undergo dose-painted intensity-modulated radiation therapy once daily, 5 days a week, for 5½ to 6 weeks beginning on day 1. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 59 patients will be accrued for this study.

Intensity-Modulated Radiation Therapy, Fluorouracil, and Mitomycin C in Treating Patients With Invasive Anal Cancer

A Phase II Evaluation of Dose-Painted Intensity-Modulated Radiation Therapy (IMRT) in Combination With 5-Fluorouracil (5-FU) and Mitomycin-C for Reduction of Acute Morbidity in Carcinoma of the Anal Canal

Highest grade adverse event per subject were counted. Adverse events were graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Acute toxicities occur within 90 days of the start of treatment.

Deviations in intensity-modulated radiation therapy technique (IMRT) planning were determined by central review by the radiation oncology co-chairs of the study.

Highest grade adverse event per subject were counted. Adverse events were graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Late toxicities occur greater than 90 days from the start of treatment.

A complete clinical response was defined as complete resolution of all palpable tumor determined by digital rectal exam and proctosigmoidoscopy supplemented with pelvic axial imaging.

Number of days from radiotherapy treatment start to radiotherapy treatment end

Overall survival time is defined as time from registration/randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.

Disease-free survival time is defined as time from registration to the date of local-regional failure, the appearance of distant metastases, the appearance of a second primary failure, or date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive without failure are censored at the date of last contact. Local failure is defined as any measurable disease after 12 weeks from the completion of chemoradiation therapy. Local failure is defined as: a) For patients with no disease in pelvic and/or groin nodes, the appearance of disease in pelvic or groin nodes; b) For patients with disease in pelvic and/or groin nodes at study entry, nodal recurrence following clearance or persistent nodal disease for more than 12 weeks after completion of treatment.

Local-regional failure time is defined as time from registration to date of failure and is estimated by the cumulative incidence method. Patients last known to be alive without failure are censored at the date of last contact. Local-regional failure is defined as a local or regional failure. Local failure is defined as any measurable disease after 12 weeks from the completion of chemoradiation therapy. Regional failure is defined as: a) For patients with no disease in pelvic and/or groin nodes, the appearance of disease in pelvic or groin nodes; b) For patients with disease in pelvic and/or groin nodes at study entry, nodal recurrence following clearance or persistent nodal disease for more than 12 weeks after completion of treatment.

Distant failure time is defined as time from registration to the appearance of distant metastases and is estimated by the cumulative incidence method. Patients last known to be alive without failure are censored at the date of last contact.

Colostomy failure time is defined as time from registration to the date of colostomy or abdominoperineal (A-P) resection and is estimated by the cumulative incidence method. Patients last known to be alive without failure are censored at the date of last contact.

Colostomy-free survival time is defined as time from registration to date of colostomy or abdominoperineal (A-P) resection, or date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive without failure are censored at the date of last contact.

National Cancer Institute (NCI)

NRG Oncology

Radiation Therapy Oncology Group

Eligible patients with adverse event data are included. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.

5-FU + Mitomycin + IMRT

Age, Continuous

Sex: Female, Male

Wendy Seiferheld

The RT+ 5-FU + Mitomycin-C arm on previous Radiation Therapy Oncology Group (RTOG) study 9811 \[NCT00003596\] had a 77% rate of \>= grade 2 GI and GU adverse events. The null hypothesis for this study design was a 15% reduction for that rate. Fifty-four evaluable patients provides 80% power to detect a 15% reduction, using a one-sided chi-squared test with a type I error rate of 0.05. (With 52 patients, the power is reduced to 78%.)

Eligible patients with adverse event information.

Percentage of Subjects With Acute Gastrointestinal (GI) and Genitourinary (GU) Adverse Events (AE) ≥ Grade 2 as Defined by CTCAE v3.0 (Common Terminology Criteria for Adverse Events)

Number of Patients With Major Radiation Planning Deviations

Percentage of patients with GI grade 2+ adverse events were compared to the historical rate of 73%. Null hypothesis: same or greater than historical rate. Alternative hypothesis: less than historical rate.

Percentage of patients with GU grade 2+ adverse events were compared to the historical rate of 20%. Null hypothesis: same or greater than historical rate. Alternative hypothesis: less than historical rate.

Percentage of patients with hematologic grade 2+ adverse events were compared to the historical rate of 85%. Null hypothesis: same or greater than historical rate. Alternative hypothesis: less than historical rate.

Percentage of patients with skin grade 2+ adverse events were compared to the historical rate of 83%. Null hypothesis: same or greater than historical rate. Alternative hypothesis: less than historical rate.

Percentage of patients with any grade 2+ adverse events were compared to the historical rate of 98%. Null hypothesis: same or greater than historical rate. Alternative hypothesis: less than historical rate.

Percentage of patients with any grade 3+ adverse events were compared to the historical rate of 87%. Null hypothesis: same or greater than historical rate. Alternative hypothesis: less than historical rate.

GI Grade 2+

GU Grade 2+

Hematologic Grade 2+

Skin Grade 2+

Any Grade 2+

Any Grade 3+

Eligible patients who started protocol treatment

Percentage of Subjects With Acute Adverse Events (AE)

GI/GU Grade 2+

Non-Hematologic Grade 2+

Eligible patients who started IMRT and were on-study \> 90 days from the start of treatment (or did not withdraw consent until after 90 days).

Percentage of Subjects With Late Adverse Events (AE)

8 weeks after treatment

12 weeks after treatment

Eligible patients who started study treatment

Clinical Complete Response Rate

Duration of Radiotherapy Treatment

Five-year Rate of Overall Survival

Five-year Rate of Disease-free Survival

Five-Year Cumulative Incidence Rate of Local-regional Failure

Five-Year Cumulative Incidence Rate of Distant Failure

Five-Year Cumulative Incidence Rate of Colostomy Failure

Five-Year Rate of Colostomy-free Survival

Overall Study

Infections

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Immune System Diseases

Acquired Immunodeficiency Syndrome

HIV Infections

Cetuximab

Cisplatin

Antineoplastic Agents, Immunological

All patients will receive combined modality therapy (CMT) with 2 cycles of cisplatin and 5-FU chemotherapy, given concurrently with radiation therapy. CMT consists of:

* Cetuximab 400 mg/m2 IV Day -7 (1 week before the cycle 1, Day 1 cisplatin/5-FU and RT), then 250 mg/m2 IV Days 1, 8, 15, 22, 29, 36 and 43 (a minimum of 6 and a maximum of 8 doses of cetuximab will be administered, including the loading dose).
* Cisplatin 75 mg/m2 IV on Day 1 (cycle 1) and Day 29 (cycle 2)
* 5-FU 1000 mg/m2/day by continuous intravenous infusion on Days 1-4 (cycle 1) and Days 29-32 (cycle 2)

400 mg/m2 IV Day -7 (1 week before the cycle 1, Day 1 cisplatin/5-FU and RT), then 250 mg/m2 IV Days 1, 8, 15, 22, 29, 36 and 43 (a minimum of 6 and a maximum of 8 doses of cetuximab will be administered, including the loading dose)

cetuximab

75 mg/m2 IV on Day 1 (cycle 1) and Day 29 (cycle 2)

cisplatin

1000 mg/m2/day by continuous intravenous infusion on Days 1-4 (cycle 1) and Days 29-32 (cycle 2)

Irradiation to tumor site and inguinal nodes beginning on cycle 1, Day 1 cisplatin/5-FU (minimum 45.0 Gy \[5 weeks if given on schedule and without interruption\], maximum 54.0 Gy \[6 weeks if given on schedule and without interruption). IMRT may be used at the discretion of the treating physician.

radiation therapy

Joseph A. Sparano, MD

David M. Aboulafia, MD

RATIONALE: Drugs used in chemotherapy, such as cisplatin and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving cisplatin, fluorouracil, and cetuximab together with radiation therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving cisplatin, fluorouracil, and cetuximab together with radiation therapy works in treating patients with HIV and stage I, stage II, or stage III anal cancer.

OBJECTIVES:

Primary

* Determine the 2-year local failure rate in patients with HIV-associated stage I-IIIB anal carcinoma treated with cisplatin, fluorouracil, cetuximab, and radiotherapy.
* Determine the objective response rate (complete and partial), progression-free survival, relapse-free survival, colostomy-free survival, overall survival, quality of life, and overall toxicity in patients treated with this regimen.

Secondary

* Characterize the effect of this regimen on the underlying HIV condition by describing changes in viral load, CD4 counts, and the incidence of opportunistic illnesses, including the development of AIDS during and in the first year after treatment.
* Evaluate the effect of this regimen on anogenital human papilloma virus (HPV) infection and anal cytology.

OUTLINE: This is an open-label, multicenter study.

Patients receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, and 35\*, fluorouracil IV continuously on days 1-4 and 29-32, and cisplatin IV over 1 hour on days 1 and 29. Beginning on day 1, patients undergo concurrent radiotherapy to the primary tumor 5 days a week for 5-7 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

NOTE: \*Patients receiving 7 weeks of radiotherapy also receive cetuximab on days 42 and 49.

Quality of life is assessed at baseline, at the completion of study treatment, and then at months 3, 6, 12, 24, and 36.

After completion of study treatment, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 47 patients will be accrued for this study.

Combined Modality Therapy for Patients With With HIV and Stage I, Stage II, or Stage III Anal Cancer

Phase II Trial of Combined Modality Therapy Plus Cetuximab in HIV-Associated Anal Carcinoma

Patients will be classified into two groups for purposes of primary endpoint analysis: failure or no failure at 3 years (in the primary analysis, patients lost to follow-up prior to 3 years will be considered failures). For the secondary endpoint of objective response, patients will be classified as responders

Progression-free survival at 1 year is the percentage of patients who are alive and have not experienced progressive disease, defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started, or the appearance of one or more new lesions.

Percentage of participants who are alive and have not experienced progressive disease and have not relapsed

Percentage of participants who are alive and have not had a colostomy

Percentage of participants who are alive at one year

EORTC QLQ-C30 Global Score at 1 year. The EORTC QLQ-C30 is a validated questionnaire that evaluates quality of life. The global score is an overall score for quality of life that ranges from 0 to 100. Higher scores indicate between quality of life

Delayed toxicities are defined as toxicities that occur over 90 days following treatment completion

Change in absolute CD4 counts from start of treatment to 1 year after completion of study treatment

Incidence of opportunistic illnesses, including the development of AIDS during and for 1 year after completion of study treatment

Number of participants with complete and partial responses based on the RECIST criteria

The Emmes Company, LLC

AIDS Malignancy Consortium

cisplatin, 5-flourouruacil, and irradiation plus cetuximab

Combined Modality Therapy

cisplatin, 5-flourouruacil, and irradiation plus cetuximab.

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Director, AMC Statistical Center

Local Failure Rate at 3 Years

Progression-free Survival

Relapse-free Survival

Colostomy-free Survival at 1 Year

Overall Survival

The number of participants analyzed is the number of participants for whom quality of life questionnaires were completed at one year.

Quality of Life

Toxicity

The number of participants analyzed is the number for whom absolute CD4 count data were available at baseline at at 1 year after study completion

Changes in CD4 Counts During and for 1 Year After Completion of Study Treatment

Incidence of Opportunistic Illnesses

Anogenital Human Papilloma Virus (HPV) Infection and Anal Cytology

Objective Response Rate (Complete and Partial)

Combined modality therapy consists of cisplatin, 5-flourouracil, and irradiation plus cetuximab

neoadjuvant therapy

Didier Peiffert, MD

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining chemotherapy with radiation therapy may kill more tumor cells.

PURPOSE: This randomized phase III trial is studying different regimens of giving combination chemotherapy together with radiation therapy and comparing how well they work in treating patients with stage II or stage III anal cancer.

OBJECTIVES:

* Compare the efficacy of concurrent chemotherapy and radiotherapy with or without neoadjuvant chemotherapy with fluorouracil and cisplatin in patients with stage II or III anal canal cancer.
* Compare the efficacy of two levels of radiation dose in patients with stage II or III anal canal cancer.
* Compare the sphincter conservation of the anus by these regimens.
* Compare the effect of these regimens on survival and quality of life of these patients.

OUTLINE: This is a randomized, multicenter study.

Patients are randomized to one of four treatment arms.

* Arm I: Patients receive induction chemotherapy consisting of fluorouracil IV over 24 hours on days 1-4 and cisplatin IV over 1 hour on day 1 or 2 every 4 weeks for 2 courses. Beginning 4 weeks later, patients receive chemoradiotherapy. This regimen consists of fluorouracil IV over 24 hours on days 1-4 and cisplatin IV over 1 hour on day 1 or 2 and repeated 4 weeks later, plus pelvic radiotherapy beginning on day 1 and continuing for 5 weeks (once a day, 5 days/week). Patients receive low dose radiotherapy directly to the tumor beginning 3 weeks later and continuing for 2 weeks.
* Arm II: Patients receive induction chemotherapy and chemoradiotherapy as in arm I, plus high dose radiotherapy directly to the tumor.
* Arm III (control arm): Patients receive chemoradiotherapy and low dose radiotherapy to the tumor as in arm I.
* Arm IV: Patients receive chemoradiotherapy and high dose radiotherapy to the tumor as in arm II.

After study treatment is completed, patients with nonfixed inguinal tumors may undergo surgical resection followed by radiotherapy or radiotherapy alone. Patients with fixed inguinal tumors may receive further radiotherapy alone.

Quality of life is assessed before treatment, at 2 months after completion of treatment, and at 5 years.

Patients are followed every 4 months for 2 years, every 6 months for 3 years, then annually thereafter.

PROJECTED ACCRUAL: A total of 350 patients will be accrued for this study within 4 years.

Combination Chemotherapy Plus Radiation Therapy in Treating Patients With Stage II or Stage III Anal Cancer

Intensification Therapy for Locally Advanced Epidermoid Cancer of the Anal Canal - Phase III Intergroup Study

UNICANCER

Jaffer A. Ajani, MD

Al B. Benson, MD, FACP

Joel E. Tepper, MD

John S. MacDonald, MD

Michael G. Haddock, MD

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug or combining radiation therapy with chemotherapy may kill more tumor cells. It is not yet known whether fluorouracil and mitomycin plus radiation therapy is more effective than fluorouracil and cisplatin plus radiation therapy for anal cancer.

PURPOSE: This randomized phase III trial is studying fluorouracil and mitomycin plus radiation therapy to see how well it works compared to fluorouracil and cisplatin plus radiation therapy in treating patients with stage II or stage III anal cancer.

OBJECTIVES:

* Compare the initial and total local and distant failure rates in patients with anal canal cancer treated with either fluorouracil (5-FU) plus mitomycin concurrently with radiotherapy or 5-FU plus cisplatin followed by 5-FU plus cisplatin concurrently with radiotherapy.
* Identify any differences in local control and colostomy rates at 2 years in patients treated with these regimens.
* Determine any difference in colostomy free, disease free, or overall survival in patients treated with these regimens.
* Compare the toxic effects of these regimens in these patients.
* Evaluate the prognostic effects of tumor markers P53 overexpression, human papilloma virus status, and enzyme HAP1 in patients treated with these regimens.

OUTLINE: This is a randomized study. Patients are stratified according to gender, nodal status (positive vs negative), and primary tumor size (greater than 2 cm to 5 cm vs greater than 5 cm). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive fluorouracil (5-FU) IV continuously over 96 hours beginning on days 1 and 29 and mitomycin IV on days 1 and 29 with concurrent radiotherapy.
* Arm II: Patients receive induction chemotherapy comprising 5-FU IV continuously over 96 hours beginning on days 1, 29, 57, and 85 and cisplatin IV over 1 hour on days 1, 29, 57, and 85. Beginning on day 57, patients receive concurrent radiotherapy.

In both arms, radiotherapy is administered daily, 5 days a week, for 5-6.5 weeks. Patients with T3, T4, or N+ lesions or T2 lesions with residual disease receive additional radiotherapy to a reduced field.

Patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 650 patients will be accrued for this study within 5 years.

Chemotherapy Plus Radiation Therapy in Treating Patients With Stage II or Stage III Anal Cancer

A Phase III Randomized Study of 5-Fluorouracil, Mitomycin-C, and Radiotherapy Versus 5-Fluorouracil, Cisplatin, and Radiotherapy in Carcinoma of the Anal Canal

Eastern Cooperative Oncology Group

Cancer and Leukemia Group B

SWOG Cancer Research Network

North Central Cancer Treatment Group

Patients receive cisplatin IV over 60 minutes on days 1, 29, 57, and 85 and fluorouracil IV continuously over 96 hours on days 1-4, 29-32, 57-60, and 85-88. Patients also receive cetuximab IV over 120 minutes on day 50 and then IV over 60 minutes on days 57, 64, 71, 78, 85, 92, and 99 and undergo radiotherapy once daily 5 days a week for 5 weeks, beginning on day 57. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients receive cetuximab IV over 120 minutes on day 1 and then IV over 60 minutes on days 8, 15, 22, 29, 36, 43, and 50. Patients also receive cisplatin IV over 60 minutes on days 1 and 36, fluorouracil IV continuously over 96 hours on days 8-11 and 36-39, and undergo radiotherapy once daily 5 days a week for 5 weeks beginning on day 8. Treatment continues in the absence of disease progression or unacceptable toxicity.

Given once daily 5 days a week for 5 weeks

radiotherapy

Madhur K. Garg, MD

RATIONALE: Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cisplatin and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Cetuximab may help cisplatin and fluorouracil work better by making tumor cells more sensitive to the drugs. It may also make tumor cells more sensitive to radiation therapy. Giving cetuximab together with chemotherapy and radiation therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving cetuximab together with cisplatin, fluorouracil, and radiation therapy works in treating immunocompetent patients with stage I (closed to accrual as of 11/3/2008), stage II, (some stage II closed to accrual as of 11/3/2008) or stage III anal cancer.

OBJECTIVES:

Primary Objective:

* Determine whether the addition of cetuximab to combined modality therapy (CMT) comprising cisplatin, fluorouracil, and radiotherapy reduces the local failure rate by ≥ 50% at 3 years (compared with historical data) in immunocompetent patients with stage I-III invasive anal carcinoma.

Secondary Objectives:

* Determine objective response rate (complete and partial), progression-free survival, colostomy-free survival, and overall survival.
* Determine the overall toxicity of concurrent cisplatin, fluorouracil, and radiation therapy combined with cetuximab.

Exploratory Objectives:

* Evaluate the effect of cetuximab and CMT on anogenital herpes papilloma virus (HPV) infection and anal cytology.
* Evaluate whether moderate to strong expression of epidermal growth factor receptor, Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and P-Akt (as determined by immunohistochemistry) is associated with an increased risk of local failure.

OUTLINE: This is a multicenter study with two sequential arms. Arm I was closed to accrual as of 11/3/2008, and arm II opened to accrual on 8/18/2009. Patients are assigned to 1 of the 2 treatment arms.

* Arm I (closed to accrual as of 11/3/2008): Patients receive cisplatin intravenously (IV) over 60 minutes on days 1, 29, 57, and 85 and fluorouracil IV continuously over 96 hours on days 1-4, 29-32, 57-60, and 85-88. Patients also receive cetuximab IV over 120 minutes on day 50 and then IV over 60 minutes on days 57, 64, 71, 78, 85, 92, and 99 and undergo radiotherapy once daily 5 days a week for 5 weeks, beginning on day 57.
* Arm II (open to accrual on 8/18/2009): Patients receive cetuximab IV over 120 minutes on day 1 and then IV over 60 minutes on days 8, 15, 22, 29, 36, 43, and 50. Patients also receive cisplatin IV over 60 minutes on days 8 and 36, fluorouracil IV continuously over 96 hours on days 8-11 and 36-39, and undergo radiotherapy once daily 5 days a week for 5 weeks beginning on day 8.

After completion of study treatment, patients are followed periodically for up to 10 years.

PROJECTED ACCRUAL: A total of 62 patients will be accrued for this study.

Cetuximab, Cisplatin, Fluorouracil, and Radiation Therapy in Treating Patients With Anal Cancer

Phase II Trial of Cetuximab Plus Cisplatin, 5- Fluorouracil and Radiation in Immunocompetent Patients With Anal Carcinoma

Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.

Local failure was defined as progression/relapse of disease in the anal canal and/or regional organs and/or regional lymph nodes after completion of protocol therapy, or progression during protocol therapy. Lost to follow-up and death (regardless of cause of death) prior to 3 years were also considered as local failures. For the calculation of local failure rate at 3 years, patients were classified into two groups (ie, coded as binary variable): failure (patients with local failure events prior to 3 years) vs. no failure (patients who still alive and had no local failure at 3 years). The binomial proportion and its exact two-sided 80% confidence interval (CI) were used to estimate it.

Overall survival (OS) is defined as time from registration to death from any cause. Patients alive are censored at the last contact date. Kaplan-Meier method was used to estimate the 3-year OS rate.

Progression-free survival (PFS) was defined as time from registration to disease progression, relapse or death (whichever occurred first), censoring cases without PFS events at the date of last disease assessment documenting the patient was free of progression/relapse. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Kaplan-Meier method was used to estimate the 3-year PFS rate.

Objective response rate is defined as number of patients with complete response (CR) or partial response (PR) divided by all eligible and treated patients. Responses are evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline. CR is defined as disappearance of all target and non-target lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameters), and/or persistence of one or more non-target lesion(s).

Colostomy-free survival was defined as time from registration until time of colostomy or death without colostomy, censoring cases without colostomy at the data of last disease assessment documenting the patient was free of colostomy. Kaplan-Meier method was used to estimate the 3-year colostomy-free survival rate.

ECOG-ACRIN Cancer Research Group

Patients receive cisplatin IV over 60 minutes on days 1, 29, 57, and 85 and fluorouracil IV continuously over 96 hours on days 1-4, 29-32, 57-60, and 85-88. Patients also receive cetuximab IV over 120 minutes on day 50 and then IV over 60 minutes on days 57, 64, 71, 78, 85, 92, and 99 and undergo radiotherapy once daily 5 days a week for 5 weeks, beginning on day 57. Treatment continues in the absence of disease progression or unacceptable toxicity.

cetuximab: Given IV

cisplatin: Given IV

fluorouracil: Given IV

radiation therapy: Given once daily 5 days a week for 5 weeks

Arm I (Closed to Accrual as of 11/3/2008)

Patients receive cetuximab IV over 120 minutes on day 1 and then IV over 60 minutes on days 8, 15, 22, 29, 36, 43, and 50. Patients also receive cisplatin IV over 60 minutes on days 1 and 36, fluorouracil IV continuously over 96 hours on days 8-11 and 36-39, and undergo radiotherapy once daily 5 days a week for 5 weeks beginning on day 8. Treatment continues in the absence of disease progression or unacceptable toxicity.

cetuximab: Given IV

cisplatin: Given IV

fluorouracil: Given IV

radiation therapy: Given once daily 5 days a week for 5 weeks

Arm II (Open to Accrual on 8/18/2009)

Total

ECOG-ACRIN statistician

Null hypothesis is that the local failure rate at 3 years is no more than 35%.

The null hypothesis is that the local failure rate at 3 years is no more than 35%.

3-year Overall Survival Rate

3-year Progression-free Survival Rate

Objective Response Rate

eligible and treated patients who did not have permanent colostomy at study entry

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Intensity-Modulated Radiation Therapy, Fluorouracil, and Mitomycin C in Treating Patients With Invasive Anal Cancer	NCT00423293	Anal Cancer	fluorouracil mitomycin C Intensity-modul...	18 Years - 120 Years	Radiation Therapy Oncology Group
Combined Modality Therapy for Patients With With HIV and Stage I, Stage II, or Stage III Anal Cancer	NCT00324415	Anal Cancer	cetuximab cisplatin fluorouracil radiation thera...	18 Years - 120 Years	AIDS Malignancy Consortium
Combination Chemotherapy Plus Radiation Therapy in Treating Patients With Stage II or Stage III Anal Cancer	NCT00003652	Anal Cancer	cisplatin fluorouracil neoadjuvant the... radiation thera...	0 Years - 80 Years	UNICANCER
Chemotherapy Plus Radiation Therapy in Treating Patients With Stage II or Stage III Anal Cancer	NCT00003596	Anal Cancer	cisplatin fluorouracil mitomycin C radiation thera...	18 Years - 120 Years	Radiation Therapy Oncology Group
Combined Modality Therapy for Patients With With HIV and Stage I, Stage II, or Stage III Anal Cancer	NCT00324415	Anal Cancer	cetuximab cisplatin fluorouracil radiation thera...	18 Years - 120 Years	AIDS Malignancy Consortium
Chemotherapy Plus Radiation Therapy in Treating Patients With Stage II or Stage III Anal Cancer	NCT00003596	Anal Cancer	cisplatin fluorouracil mitomycin C radiation thera...	18 Years - 120 Years	Radiation Therapy Oncology Group
Cetuximab, Cisplatin, Fluorouracil, and Radiation Therapy in Treating Patients With Anal Cancer	NCT00316888	Anal Cancer	cetuximab cisplatin fluorouracil radiotherapy	18 Years -	Eastern Cooperative Oncology Group
Intensity-Modulated Radiation Therapy, Fluorouracil, and Mitomycin C in Treating Patients With Invasive Anal Cancer	NCT00423293	Anal Cancer	fluorouracil mitomycin C Intensity-modul...	18 Years - 120 Years	Radiation Therapy Oncology Group

Spots Global Cancer Trial Database for basaloid carcinoma of the anus