Anal Cancer
Conditions
Keywords
stage I anal cancer, stage II anal cancer, stage IIIA anal cancer, stage IIIB anal cancer, squamous cell carcinoma of the anus, basaloid carcinoma of the anus, cloacogenic carcinoma of the anus
Brief summary
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.
Detailed description
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.
Interventions
BIOLOGICALcetuximab
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)
DRUGcisplatin
75 mg/m2 IV on Day 1 (cycle 1) and Day 29 (cycle 2)
DRUGfluorouracil
1000 mg/m2/day by continuous intravenous infusion on Days 1-4 (cycle 1) and Days 29-32 (cycle 2)
RADIATIONradiation therapy
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.
Sponsors
National Cancer Institute (NCI)
The Emmes Company, LLC
AIDS Malignancy Consortium
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 stage I-IIIB invasive anal canal or perianal (anal margin) squamous cell carcinoma, including tumors with any of the following nonkeratinizing histologies: * Basaloid * Transitional cell * Cloacogenic * Documented HIV infection by 1 of the following: * Antibody detection * Culture * Quantitative assay of plasma HIV RNA PATIENT CHARACTERISTICS: * Karnofsky performance status 60-100% * Absolute neutrophil count ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Hemoglobin ≥ 10 g/dL (transfusions, epoetin alfa, or myeloid growth factor support allowed provided blood counts are stable for ≥ 2 weeks prior to study entry) * Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance \> 60 mL/min * AST and ALT ≤ 3 times ULN * Bilirubin ≤ 2 times ULN * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No acute active, serious, uncontrolled opportunistic infection * No other prior invasive malignancy diagnosed within the past 24 months, excluding in situ cervical cancer, anal dysplasia or carcinoma in situ, nonmelanoma skin carcinoma, or Kaposi's sarcoma that has not required systemic chemotherapy within the past 24 months * No peripheral neuropathy \> grade 1 * No severe or poorly controlled diarrhea * No medical or psychiatric illness that would preclude study requirements PRIOR CONCURRENT THERAPY: * No prior chemotherapy or radiotherapy for this malignancy * Prior radiotherapy for another condition (e.g., Kaposi's sarcoma) allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Locoregional Failure Rate at 3 Years | 3 years following completion of therapy | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 1 year | 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. |
| Relapse-free Survival | 1 year | Percentage of participants who are alive and have not experienced progressive disease and have not relapsed |
| Colostomy-free Survival at 1 Year | 1 year | Percentage of participants who are alive and have not had a colostomy |
| Overall Survival | 1 year | Percentage of participants who are alive at one year |
| Number of Delayed Toxicities | 90 days following treatment discontinuation | Delayed toxicities are defined as toxicities that occur over 90 days following treatment completion |
| Changes in CD4 Counts During and for 1 Year After Completion of Study Treatment | 1 year following treatment discontinuation | Change in absolute CD4 counts from start of treatment to 1 year after completion of study treatment |
| Incidence of Opportunistic Illnesses | 1 year following treatment discontinuation | Incidence of opportunistic illnesses, including the development of AIDS during and for 1 year after completion of study treatment |
| Objective Response Rate (Complete and Partial) | 3 years following treatment discontinuation | Number of participants with complete and partial responses based on the RECIST criteria |
| Quality of Life EORTC Global Score at 1 Year | 1 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Count of Participants by Type of HPV at Baseline | baseline | Descriptive statistics will be used to describe the types of HPV found in baseline anal swabs and tissue biopsies. Proportion of cases with each type will be summarized |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Combined Modality Therapy cisplatin, 5-flourouruacil, and irradiation plus cetuximab. | 45 |
| Total | 45 |
Baseline characteristics
| Characteristic | Combined Modality Therapy |
|---|---|
| Age, Continuous | 48.4 years STANDARD_DEVIATION 6.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Region of Enrollment United States | 45 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 41 / 45 |
| serious Total, serious adverse events | 27 / 45 |
Outcome results
Primary
Locoregional Failure Rate at 3 Years
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
Time frame: 3 years following completion of therapy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Combined Modality Therapy | Locoregional Failure Rate at 3 Years | LRF rate by including censored patients treated as failures | 42 percentage of participants |
| Combined Modality Therapy | Locoregional Failure Rate at 3 Years | LRF rate as per Kaplan-Meier estimate | 20 percentage of participants |
Secondary
Changes in CD4 Counts During and for 1 Year After Completion of Study Treatment
Change in absolute CD4 counts from start of treatment to 1 year after completion of study treatment
Time frame: 1 year following treatment discontinuation
Population: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Modality Therapy | Changes in CD4 Counts During and for 1 Year After Completion of Study Treatment | 102 cells/mm3 |
Secondary
Colostomy-free Survival at 1 Year
Percentage of participants who are alive and have not had a colostomy
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combined Modality Therapy | Colostomy-free Survival at 1 Year | 92.4 percentage of participants |
Secondary
Incidence of Opportunistic Illnesses
Incidence of opportunistic illnesses, including the development of AIDS during and for 1 year after completion of study treatment
Time frame: 1 year following treatment discontinuation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combined Modality Therapy | Incidence of Opportunistic Illnesses | 4 participants |
Secondary
Number of Delayed Toxicities
Delayed toxicities are defined as toxicities that occur over 90 days following treatment completion
Time frame: 90 days following treatment discontinuation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combined Modality Therapy | Number of Delayed Toxicities | 5 events |
Secondary
Objective Response Rate (Complete and Partial)
Number of participants with complete and partial responses based on the RECIST criteria
Time frame: 3 years following treatment discontinuation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combined Modality Therapy | Objective Response Rate (Complete and Partial) | 30 participants |
Secondary
Overall Survival
Percentage of participants who are alive at one year
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combined Modality Therapy | Overall Survival | 92.8 percentage of participants |
Secondary
Progression-free Survival
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.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combined Modality Therapy | Progression-free Survival | 87.3 percentage of participants |
Secondary
Quality of Life EORTC Global Score at 1 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
Time frame: 1 year
Population: The number of participants analyzed is the number of participants for whom quality of life questionnaires were completed at one year.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Modality Therapy | Quality of Life EORTC Global Score at 1 Year | 78.9 units on a scale | Standard Deviation 24 |
Secondary
Relapse-free Survival
Percentage of participants who are alive and have not experienced progressive disease and have not relapsed
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combined Modality Therapy | Relapse-free Survival | 83.1 percentage of participants |
Other Pre-specified
Count of Participants by Type of HPV at Baseline
Descriptive statistics will be used to describe the types of HPV found in baseline anal swabs and tissue biopsies. Proportion of cases with each type will be summarized
Time frame: baseline
Population: Participants with available HPV status data
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 54 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 16 | 16 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 6 | 9 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 11 | 9 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 18 | 5 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 31 | 5 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 33 | 3 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 82 | 3 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 68 | 3 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 51 | 2 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 52 | 2 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 26 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 30 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 32 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 35 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 45 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 53 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 56 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 58 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 69 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 72 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 73 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 86 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 87 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | HPV 97 | 1 Participants |
| Combined Modality Therapy | Count of Participants by Type of HPV at Baseline | Mixed | 1 Participants |