Anal Cancer
Conditions
Keywords
stage II anal cancer, stage IIIA anal cancer, stage IIIB anal cancer, basaloid carcinoma of the anus, cloacogenic carcinoma of the anus, squamous cell carcinoma of the anus
Brief summary
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.
Detailed description
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.
Interventions
DRUGfluorouracil
1000 mg/m\^2/day 96-hour continous infusion (M-F) starting on day 1 and again on day 29 of radiation therapy.
DRUGmitomycin C
10 mg/m\^2 intravenous therapy on day 1 and day 29 of radiation therapy.
RADIATIONIntensity-modulated radiation therapy
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.
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed carcinoma of the anal canal, including any of the following subtypes: * Squamous cell * Basaloid * Cloacogenic * Primary invasive disease * T2-4, N0-3 disease * Clinically positive small inguinal nodes (i.e., \< 1 cm in size) must be confirmed by biopsy (preferably fine-needle aspiration) within the past 6 weeks * Biopsy is not required for enlarged inguinal, perirectal, or pelvic nodes on exam or CT scan that are found to be ≥ 1.0 cm and are considered to be clinically positive PATIENT CHARACTERISTICS: * Zubrod performance status 0-1 * Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention allowed) * ALT and AST \< 3 times upper limit of normal * Absolute neutrophil count ≥ 1,800/mm³ * Serum creatinine ≤ 1.5 mg/dL * Platelet count ≥ 100,000/mm³ * Bilirubin \< 1.4 mg/dL * WBC ≥ 3,000/mm³ * INR ≤ 1.5 * No known AIDS * HIV-positive patients without AIDS are eligible * HIV test required for patients with clinical suspicion of AIDS * No other invasive malignancy within the past 3 years except for nonmelanomatous skin cancer * No severe, active comorbidity, defined as any of the following: * Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months * Transmural myocardial infarction within the past 6 months * Acute bacterial or fungal infection requiring IV antibiotics * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study treatment * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects * Uncontrolled diabetes mellitus, uncompensated heart disease, and/or uncontrolled high blood pressure, that in the opinion of the patient's treating physician, requires an immediate change in management * Patients may be eligible if appropriate changes in management have resulted in adequate control of the above mentioned conditions * Other immunocompromised status (e.g., organ transplantation or chronic glucocorticoid use) * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No prior radiation therapy to the pelvis that would result in overlap of radiation therapy fields * No prior systemic chemotherapy for cancer of the anus * No prior surgery for cancer of the anus that removed all macroscopic anal cancer * No concurrent sargramostim (GM-CSF) * No concurrent amifostine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | From the start of treatment to 90 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Acute Adverse Events (AE) | From the start of treatment to 90 days | 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. |
| Percentage of Subjects With Late Adverse Events (AE) | From 91 days after start of study treatment to the end of follow-up. Maximum follow-up at time of analysis was 9.2 years. | 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. |
| Clinical Complete Response Rate | 8 and 12 weeks after treatment completion (corresponding to 14 and 18 weeks from registration) | 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. |
| Duration of Radiotherapy Treatment | From start to end of radiation therapy (6 weeks) | Number of days from radiotherapy treatment start to radiotherapy treatment end |
| Five-year Rate of Overall Survival | From registration to 5 years | 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. |
| Number of Patients With Major Radiation Planning Deviations | Planning occurred prior to radiation therapy | Deviations in intensity-modulated radiation therapy technique (IMRT) planning were determined by central review by the radiation oncology co-chairs of the study. |
| Five-Year Cumulative Incidence Rate of Local-regional Failure | From registration to 5 years | 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. |
| Five-Year Cumulative Incidence Rate of Distant Failure | From registration to 5 years | 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. |
| Five-Year Cumulative Incidence Rate of Colostomy Failure | From registration to 5 years | 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. |
| Five-Year Rate of Colostomy-free Survival | From registration to 5 years | 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. |
| Five-year Rate of Disease-free Survival | From registration to 5 years | 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. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 5-FU + Mitomycin + IMRT 5-FU + Mitomycin + IMRT | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible / No protocol treatment | 11 |
Baseline characteristics
| Characteristic | 5-FU + Mitomycin + IMRT |
|---|---|
| Age, Continuous | 58 years |
| Sex: Female, Male Female | 42 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 52 / 52 |
| serious Total, serious adverse events | 6 / 52 |
Outcome results
Primary
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)
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.
Time frame: From the start of treatment to 90 days
Population: Eligible patients with adverse event information.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5-FU + Mitomycin + IMRT | 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) | 77 percentage of participants |
Comparison: 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%.)p-value: 0.5Chi-squared
Secondary
Clinical Complete Response Rate
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.
Time frame: 8 and 12 weeks after treatment completion (corresponding to 14 and 18 weeks from registration)
Population: Eligible patients who started study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 5-FU + Mitomycin + IMRT | Clinical Complete Response Rate | 12 weeks after treatment | 81 percentage of participants |
| 5-FU + Mitomycin + IMRT | Clinical Complete Response Rate | 8 weeks after treatment | 64 percentage of participants |
Secondary
Duration of Radiotherapy Treatment
Number of days from radiotherapy treatment start to radiotherapy treatment end
Time frame: From start to end of radiation therapy (6 weeks)
Population: Eligible patients who started IMRT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 5-FU + Mitomycin + IMRT | Duration of Radiotherapy Treatment | 43 Days |
Secondary
Five-Year Cumulative Incidence Rate of Colostomy Failure
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.
Time frame: From registration to 5 years
Population: Eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5-FU + Mitomycin + IMRT | Five-Year Cumulative Incidence Rate of Colostomy Failure | 10 percentage of participants |
Secondary
Five-Year Cumulative Incidence Rate of Distant Failure
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.
Time frame: From registration to 5 years
Population: Eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5-FU + Mitomycin + IMRT | Five-Year Cumulative Incidence Rate of Distant Failure | 16 percentage of participants |
Secondary
Five-Year Cumulative Incidence Rate of Local-regional Failure
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.
Time frame: From registration to 5 years
Population: Eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5-FU + Mitomycin + IMRT | Five-Year Cumulative Incidence Rate of Local-regional Failure | 16 percentage of participants |
Secondary
Five-Year Rate of Colostomy-free Survival
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.
Time frame: From registration to 5 years
Population: Eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5-FU + Mitomycin + IMRT | Five-Year Rate of Colostomy-free Survival | 74 percentage of participants |
Secondary
Five-year Rate of Disease-free Survival
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.
Time frame: From registration to 5 years
Population: Eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5-FU + Mitomycin + IMRT | Five-year Rate of Disease-free Survival | 70 percentage of participants |
Secondary
Five-year Rate of Overall Survival
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.
Time frame: From registration to 5 years
Population: Eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5-FU + Mitomycin + IMRT | Five-year Rate of Overall Survival | 76 percentage of participants |
Secondary
Number of Patients With Major Radiation Planning Deviations
Deviations in intensity-modulated radiation therapy technique (IMRT) planning were determined by central review by the radiation oncology co-chairs of the study.
Time frame: Planning occurred prior to radiation therapy
Population: All eligible patients who started IMRT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 5-FU + Mitomycin + IMRT | Number of Patients With Major Radiation Planning Deviations | 0 Participants |
Secondary
Percentage of Subjects With Acute Adverse Events (AE)
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.
Time frame: From the start of treatment to 90 days
Population: Eligible patients who started protocol treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 5-FU + Mitomycin + IMRT | Percentage of Subjects With Acute Adverse Events (AE) | GI Grade 2+ | 73 percentage of participants |
| 5-FU + Mitomycin + IMRT | Percentage of Subjects With Acute Adverse Events (AE) | GU Grade 2+ | 15 percentage of participants |
| 5-FU + Mitomycin + IMRT | Percentage of Subjects With Acute Adverse Events (AE) | Hematologic Grade 2+ | 73 percentage of participants |
| 5-FU + Mitomycin + IMRT | Percentage of Subjects With Acute Adverse Events (AE) | Skin Grade 2+ | 75 percentage of participants |
| 5-FU + Mitomycin + IMRT | Percentage of Subjects With Acute Adverse Events (AE) | Any Grade 2+ | 94 percentage of participants |
| 5-FU + Mitomycin + IMRT | Percentage of Subjects With Acute Adverse Events (AE) | Any Grade 3+ | 83 percentage of participants |
Comparison: 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.p-value: 0.5Chi-squared
Comparison: 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.p-value: 0.18Chi-squared
Comparison: 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.p-value: 0.032Chi-squared
Comparison: 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.p-value: 0.1Chi-squared
Comparison: 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.p-value: 0.12Chi-squared
Comparison: 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.p-value: 0.23Chi-squared
Secondary
Percentage of Subjects With Late Adverse Events (AE)
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.
Time frame: From 91 days after start of study treatment to the end of follow-up. Maximum follow-up at time of analysis was 9.2 years.
Population: 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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 5-FU + Mitomycin + IMRT | Percentage of Subjects With Late Adverse Events (AE) | GI/GU Grade 2+ | 35 percentage of participants |
| 5-FU + Mitomycin + IMRT | Percentage of Subjects With Late Adverse Events (AE) | Non-Hematologic Grade 2+ | 67 percentage of participants |
| 5-FU + Mitomycin + IMRT | Percentage of Subjects With Late Adverse Events (AE) | Any Grade 2+ | 75 percentage of participants |
| 5-FU + Mitomycin + IMRT | Percentage of Subjects With Late Adverse Events (AE) | Any Grade 3+ | 20 percentage of participants |