Lower-Dose Chemoradiation in Treating Patients With Early-Stage Anal Cancer, the DECREASE Study
Purpose
This phase II trial studies how well lower-dose chemotherapy plus radiation (chemoradiation) therapy works in comparison to standard-dose chemoradiation in treating patients with early-stage anal cancer. Drugs used in chemotherapy, such as mitomycin, fluorouracil, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving chemotherapy with radiation therapy may kill more tumor cells. This study may help doctors find out if lower-dose chemoradiation is as effective and has fewer side effects than standard-dose chemoradiation, which is the usual approach for treatment of this cancer type.
Conditions
- Anal Basaloid Carcinoma
- Anal Canal Cloacogenic Carcinoma
- Anal Canal Squamous Cell Carcinoma
- Anal Margin Squamous Cell Carcinoma
- Stage I Anal Cancer AJCC v8
- Stage IIA Anal Cancer AJCC v8
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Criteria
Inclusion Criteria:
- STEP 0 (PRE-REGISTRATION)
- Patient must be ≥ 18 years of age
- Patients must be English speaking to participate in the trial. (Please note that
this requirement is due to the fact that the quality-of-life studies are mandatory
and we currently do not have full translated versions of the questionnaires into
other languages)
- Patient must have histologically proven T1-2N0M0 invasive anal canal or anal margin
squamous cell carcinoma with tumors measuring =< 4 cm. This may include tumors of
non-keratinizing histology such as basaloid, transitional cell or cloacogenic
histology. Measurable disease is not required
- Patients who are status/post local excision or excisional biopsy procedure are
eligible provided there was tumor involvement of the anal canal and/or anal verge
prior to the reaction, if the margins were positive, and/or if the stage is T2N0
based on tumor size before the procedure. This means that patients with T1N0M0 anal
margin squamous cell carcinoma who underwent surgical excision with negative margins
and no involvement of the anal verge and/or anal canal are not eligible
- Tumor size must be documented based on physical examination including digital rectal
exam and/or anoscopy/proctoscopy within 4 weeks prior to Step 0 pre-registration
- Patient's human immunodeficiency virus (HIV) status must be known and documented at
baseline
- NOTE: For patients without a history of HIV infection, it is recommended (but
not required) that updated HIV testing be performed within one year of study
enrollment
- Patients who are HIV-negative will be registered to Arm R. They must not have lymph
nodes that are radiographically-concerning for cancer involvement using computed
tomography (CT) and fludeoxyglucose F-18 (FDG) - positron emission tomography
(PET)/CT-based criteria
- NOTE: Patients who are HIV-negative and meet the below criteria may proceed
directly to Step 1 Randomization
- Patients will be considered to be lymph node (LN) positive and thereby not
eligible in this study if the lymph nodes meet any of the following criteria:
- Mesorectal, presacral, internal iliac or obturator LN with:
- Short axis measuring > 5 mm based on CT/magnetic resonance imaging
(MRI) OR
- Morphologic features of irregular border or central necrosis if
assessed on MRI and LN measures > 3 mm OR
- FDG uptake > blood pool (Deauville 3-5) based on FDG-PET/CT or
PET/MRI
- Internal Iliac and obturator LN with:
- Short-axis measuring > 7 mm based on CT/MRI OR
- Morphologic features of irregular border or central necrosis based on
CT/MRI OR
- FDG uptake > blood pool (Deauville 3-5) based on FDG-PET/CT or
PET/MRI
- External Iliac and common Iliac:
- Short-axis measuring > 10 mm based on CT/MRI OR
- Morphologic features of irregular border or central necrosis based on
CT/MRI OR
- FDG uptake > blood pool (Deauville 3-5) based on FDG-PET/CT or
PET/MRI
- Inguinal LN (superficial and deep) meeting any of the following criteria will
be ineligible unless an fine needle aspiration (FNA) is performed and resulting
cytology is negative.
- Morphologic features of irregular border or central necrosis based on
CT/MRI
- FDG uptake > liver (Deauville 4) based on FDG-PET/CT.
- Patients who are HIV-negative and have inguinal lymph nodes that do not
meet the above criteria must undergo fine needle aspiration and have
negative histology to be eligible
- Patients who are HIV-positive will be registered to Arm S. They must meet the
eligibility criteria below:
- A CD4 count >= 200
- Imaging submitted to ECOG-ACRIN for central review for confirmation of no lymph
node involvement
- No history of acquired immunodeficiency syndrome (AIDS)-related complications
within past year other than a history of low CD4+ T-cell count (> 200/mm^3)
prior to initiation of combination antiretroviral therapy
- Patient must be healthy on the basis of HIV disease with high likelihood of
near normal life span were it not for the anal cancer
- Patient MUST receive appropriate care and treatment for HIV infection,
including antiretroviral medications when clinically indicated, and should be
under the care of a physician experienced in HIV management. Patients will be
eligible regardless of antiretroviral medication provided the regimen has been
stable for at least 4 weeks
- STEP 1 RANDOMIZATION
- Patient must have met the eligibility criteria as outlined Step 0 Pre-registration
- Patient must have Eastern Cooperative Oncology Group (ECOG) - American College of
Radiology Imaging Network (ACRIN) performance status of 0-2
- Patient must have no history of prior chemotherapy for this malignancy
- Patients must not have undergone previous radiation to the pelvis such that
overlapping radiation fields would be expected
- Patient must not have had prior potentially curative surgery (i.e.
abdominal-perineal resection) for carcinoma of the anus. However, patients who
undergo local excision or excisional biopsy are eligible provided they meet
inclusion criteria
- Patients with T1N0M0 anal margin squamous cell carcinoma must not have undergone
surgical excision with negative margins and no involvement of the anal verge and/or
anal canal
- Patient must not be receiving any other standard anti-cancer therapy or experimental
agent concurrently with the study drugs
- Patient must not have intercurrent illness including, but not limited to, ongoing or
active infection or psychiatric/social situations that, in the judgement of the
investigator, would limit compliance with study requirements
- Patient must not have had significant cardiovascular disease including myocardial
infarction, unstable angina, stroke, transient ischemic attack, symptomatic coronary
artery disease, symptomatic congestive heart failure, or uncontrolled cardiac
arrhythmia within 6 months of Step 1 randomization
- Patient must not have a history of a different malignancy unless they have been
disease-free for at least 2 years and are deemed by the investigator to be at low
risk of recurrence
- Exceptions to this rule are individuals with cervical cancer in situ,
non-melanoma skin cancers, and colon polyps
- Patient must not have active inflammatory bowel disease (patients requiring current
medical interventions or who are symptomatic)
- Patients must not have an active autoimmune or connective tissue disease that has
required systemic treatment in the past two years (i.e., with the use of modifying
agents, corticosteroids, or immunosuppressive drugs) Replacement therapy (e.g.,
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency, etc.) is not considered a form of systemic treatment
- Patients who are on anti-coagulation with warfarin within 2 weeks prior to Step 1
randomization and are considering the use of capecitabine, must use an alternative
anti-coagulant
- NOTE: Low molecular weight heparin is permitted provided the patient's
prothrombin time (PT)/international normalized ratio (INR) is < 1.5
- Patients who will receive capecitabine and are on Dilantin for a seizure disorder
must have Dilantin levels checked weekly
- Hemoglobin > 10 g/dL (within 2 weeks prior to Step 1 Randomization)
- Platelets >= 100,000/mm^3 (within 2 weeks prior to Step 1 Randomization)
- Absolute neutrophil count >= 1500/mm^3 (within 2 weeks prior to Step 1
Randomization)
- Serum creatinine must be < 1.5 X upper limit of normal (ULN), or calculated
creatinine clearance must be > 50 ml/min (within 2 weeks prior to Step 1
Randomization)
- Total bilirubin must be < 2 X ULN (within 2 weeks prior to Step 1 Randomization)
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 X
institutional ULN (within 2 weeks prior to Step 1 Randomization)
- Albumin >= 3.0 g/dL (within 2 weeks prior to Step 1 Randomization)
- Women must not be pregnant or breast-feeding because the study treatment
administered may cause harm to an unborn fetus or breastfeeding child. All females
of childbearing potential must have a blood test or urine study within 2 weeks prior
to Step 1 Randomization to rule out pregnancy. A female of childbearing potential is
any woman, regardless of sexual orientation or whether they have undergone tubal
ligation, who meets the following criteria: 1) has achieved menarche at some point,
2) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been
naturally postmenopausal (amenorrhea following cancer therapy does not rule out
childbearing potential) for at least 24 consecutive months (i.e., has had menses at
any time in the preceding 24 consecutive months)
- Women of childbearing potential and sexually active males must be strongly advised
to use accepted and effective method(s) of contraception or to abstain from sexual
intercourse for the duration of their participation in the study and for at least 6
months after the completion of treatment
Study Design
- Phase
- Phase 2
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Active Comparator Arm A (standard-dose chemoradiation) |
Patients undergo 28 fractions of intensity-modulated radiation therapy (IMRT). Within 24 hours, patients also receive mitomycin IV over 30 minutes or less on day 1 and either fluorouracil IV over 24 hours on days 1-4 and 29-32 or capecitabine PO BID 5 days per week (Monday - Friday) until completion of IMRT in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial. |
|
|
Experimental Arm B (de-intensified chemoradiation) |
Patients undergo 20 or 23 fractions of IMRT. Within 24 hours, patients also receive mitomycin IV over 30 minutes or less on day 1 and either fluorouracil IV over 24 hours on days 1-4 or capecitabine PO BID 5 days per week (Monday - Friday) until completion of IMRT in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial. |
|
More Details
- Status
- Active, not recruiting
- Sponsor
- ECOG-ACRIN Cancer Research Group
Study Contact
Detailed Description
PRIMARY OBJECTIVE: I. To determine whether de-intensified chemoradiation for early stage squamous cell carcinoma of the anal canal (SCCA) is able to maintain excellent 2-year disease control of 85% or higher while improving anorectal health-related quality of life (HRQL), compared to standard-dose chemoradiation therapy (CRT), as measured by the change in the Fecal Incontinence Quality of Life scale (FIQoL) instrument coping/behavior domain from baseline to 1 year. SECONDARY OBJECTIVES: I. To compare changes in patient-reported HRQL (as per Fecal Incontinence Severity Index [FISI], Patient Reported Outcomes Measurement Information System [PROMIS], International Index of Erectile Function [IIEF], Sexual Function-Vaginal Changes Questionnaire [SVQ], and Vaginal Assessment Scale [VAS]/Vulvar Assessment Scale [VuAS] instruments) between the experimental and control arm. II. To compare patterns of failure (local and regional relapse versus distant; in-field versus out-of-field of radiation), disease control, and overall survival between experimental and control arm. III. To correlate vaginal dilator use during radiation delivery with sexual function. IV. To measure changes in serum total testosterone from baseline to up to 12 months after radiation. V. To validate the utility of imaging features of inguinal and pelvic lymph nodes obtained prior to treatment as a prognostic indicator that can identify patients with early-stage anal squamous cell carcinoma for whom treatment with de-intensified chemoradiation is appropriate. VI. To determine the incidence of and predictors for cardiovascular toxicity in patients receiving fluorouracil (5-FU) or capecitabine. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A (STANDARD-DOSE CHEMORADIATION): Patients undergo 28 fractions of intensity-modulated radiation therapy (IMRT). Within 24 hours, patients also receive mitomycin intravenously (IV) over 30 minutes or less on day 1 and either fluorouracil IV over 24 hours on days 1-4 and 29-32 or capecitabine orally (PO) twice daily (BID) 5 days per week (Monday - Friday) until completion of IMRT in the absence of disease progression or unacceptable toxicity. ARM B (DE-INTENSIFIED CHEMORADIATION): Patients undergo 20 or 23 fractions of IMRT. Within 24 hours, patients also receive mitomycin IV over 30 minutes or less on day 1 and either fluorouracil IV over 24 hours on days 1-4 or capecitabine PO BID 5 days per week (Monday - Friday) until completion of IMRT in the absence of disease progression or unacceptable toxicity. All patients receive fludeoxyglucose F-18 (FDG) and undergo positron emission tomography (PET)/magnetic resonance imaging (MRI) or receive FDG and undergo PET/computed tomography (CT) during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial. After completion of study treatment, patients are followed up at 6 weeks, every 3 months for years 1-2, every 6 months for year 3, then annually for years 4-5.