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Neoplasms, Squamous Cell

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Anal Cancer

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Fluorouracil

Capecitabine

Mitomycins

Mitomycin

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Immunologic Factors

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Enzyme Inhibitors

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 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.

Intensity-Modulated Radiation Therapy

Quality-of-Life Assessment

Questionnaire Administration

Site Public Contact

Alison K. Conlin

Nicholas DiBella

John A. Ellerton

Shahzad Siddique

Jay W. Carlson

James D. Murphy

Jason A. Zell

Tyler Robin

Gregory A. Masters

Anteneh A. Tesfaye

Lorraine Portelance

Michael D. Chuong

Patrick Kelly

Sudha R. Amarnath

John M. Schallenkamp

Daniel H. Barnett

Bryan A. Faller

Sheetal M. Kircher

Thomas Kim

Yolande Chen

Jennifer A Dorth

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.

PRIMARY OBJECTIVES:

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 outcomes (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 image 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 whether an online, interactive educational tool (eContour) may improve the quality of radiation target delineation for anal cancer.

VII. 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.

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.

Lower-Dose Chemoradiation in Treating Patients With Early-Stage Anal Cancer, the DECREASE Study

A Randomized Phase II Study De-Intensified ChemoRadiation for Early-Stage Anal Squamous Cell Carcinoma (DECREASE)

Will be compared between experimental and control arm. Will be estimated for all treatment arms using the Kaplan-Meier method (1958).

An event is local-regional failure, distant metastasis and chemoradiation-related death. Will determine if de-intensified chemoradiation achieves 2-year disease control of 85% or higher while improving anorectal health-related quality of life (HRQL), compared to standard-dose CRT, as measured by the change in the Fecal Incontinence Quality of Life scale (FIQoL) instrument coping/behavior domain from baseline to 1 year. The co-primary endpoints of disease control and FIQoL will be formally assessed in a hierarchical manner with disease control being assessed first. Will be estimated for all treatment arms using the Kaplan-Meier method (1958).

Quality of life analyses, will be compared between arms using a two-sample independent t-tests at a significance level of 0.05 and appropriate longitudinal models will be evaluated to assess the trajectory of HRQL endpoints over time and to evaluate those trajectories between treatment arms. Overall score and change from baseline will be summarized using mean and standard deviation at each time point for each arm.

Will compare changes as per HRQL: Health Related Quality of Life FACT-G (Functional Assessment of Cancer Therapy-General - Scoring: 0 - 32 with higher worse) between the experimental and control arm. Quality of life analyses, will be compared between arms using a two-sample independent t-tests at a significance level of 0.05 and appropriate longitudinal models will be evaluated to assess the trajectory of HRQL endpoints over time and to evaluate those trajectories between treatment arms. Overall score and change from baseline will be summarized using mean and standard deviation at each time point for each arm.

Will compare changes as per Fecal Incontinence Severity Index \[FISI - Scoring: 0 - 61 with lower better\] between the experimental and control arm.

Will compare changes as per International Index of Erectile Function \[IIEF\], Erectile Dysfunction: Scoring 7 - 35 with lower better. Ejaculation Frequency: Scoring 1 - 5 with lower better - between the experimental and control arm.

Will compare changes as per Orgasm ability/pleasure (PROMIS-Brief): scoring 2 - 10 with lower better - between the experimental and control arm.

PROMIS = Patient Reported Outcomes Measurement Information System

Will compare changes as per Anal Discomfort/pain (PROMIS- Full): scoring 3 - 15 with lower better. - between the experimental and control arm.

PROMIS = Patient Reported Outcomes Measurement Information System

Will compare changes as per Satisfaction with sex life (PROMIS-Brief) (scoring 2 - 10 with higher better) between the experimental and control arm.

PROMIS = Patient Reported Outcomes Measurement Information System

Will compare changes as per Therapeutic Aids for Sexual Function - Male (Scoring 6 - 22 with lower better) between the experimental and control arm.

Will compare changes as per Therapeutic Aids for Sexual Function - Female (Scoring 5 - 17 with lower better) between the experimental and control arm.

Will compare changes as per Sexual Function-Vaginal Changes Questionnaire \[SVQ\] (Scoring 5 - 26 with higher better) between the experimental and control arm.

Will compare changes as per Vaginal Assessment Scale \[VAS\]/Vulvar Assessment Scale \[VuAS\] (Scoring:0 - 22 with lower better) between the experimental and control arm.

Will be compared between experimental and control arm. The cumulative incidence method will be used to estimate local-regional and distant failure rates and the failure rates for the experimental treatment will be compared against the control using a failure specific log rank test.

Vaginal dilator use during radiation delivery will be correlated with sexual function.

Will be validated as a prognostic indicator that can identify patients with early-stage anal squamous cell carcinoma for whom treatment with de-intensified CRT is appropriate.

Will determine whether an online, interactive educational tool (eContour) may improve the quality of radiation target delineation for anal cancer.

Rates of grade 3+ adverse events (Common Terminology Criteria for Adverse Events \[CTCAE\], version \[v.\] 5) will be estimated using a binomial distribution along with their associated 95% confidence intervals and compared using Fisher's exact test between arms.

National Cancer Institute (NCI)

ECOG-ACRIN Cancer Research Group

Symptoms and General Pathology

Recurrence

Neoplasm Metastasis

Disease Attributes

Paclitaxel

Albumin-Bound Paclitaxel

Carboplatin

Cisplatin

Tubulin Modulators

Antimitotic Agents

Patients receive cisplatin IV over 1-4 hours on day 1 and fluorouracil IV continuously over 24 hours on days 1-4. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. Patients with complications associated with the central venous access which prevent further infusion of fluorouracil and only after discussion with the Chief Investigator receive capecitabine BID on days 1-4.

Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Cathy Eng

This randomized phase II trial studies how well cisplatin and fluorouracil work compared with carboplatin and paclitaxel in treating patients with anal cancer that cannot be removed by surgery, has come back at or near the same place as the primary tumor, or spread to other places in the body. Drugs used in chemotherapy, such as cisplatin, fluorouracil, carboplatin and paclitaxel, 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. It is not yet known whether cisplatin and fluorouracil are more effective than carboplatin and paclitaxel in treating anal cancer.

PRIMARY OBJECTIVES:

I. To evaluate best overall response rate (ORR).

SECONDARY OBJECTIVES:

I. Overall survival (OS). II. Progression free survival (PFS). III. Disease control rate (DCR) (stable disease \[SD\] or better) at 12 and 24 weeks.

IV. Best ORR of non-irradiated lesions. V. Anti-tumor activity and magnitude of response as captured by waterfall plot analyses.

VI. Toxicity. VII. Quality of life (QOL). VIII. Feasibility of conducting a multicenter international study on squamous cell carcinoma of the anus (SCCA) and recruit within a reasonable time frame.

TERTIARY OBJECTIVES:

I. Explorative biomarker analysis.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive cisplatin intravenously (IV) over 1-4 hours on day 1 and fluorouracil IV continuously over 24 hours on days 1-4. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. Patients with complications associated with the central venous access which prevent further infusion of fluorouracil and only after discussion with the Chief Investigator may receive capecitabine twice daily (BID) on days 1-4.

ARM B: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks.

Cisplatin and Fluorouracil Compared With Carboplatin and Paclitaxel in Treating Patients With Inoperable Locally Recurrent or Metastatic Anal Cancer

InterAACT - An International Multicentre Open Label Randomised Phase II Advanced Anal Cancer Trial Comparing Cisplatin Plus 5-Fluorouracil Versus Carboplatin Plus Weekly Paclitaxel in Patients With Inoperable Locally Recurrent or Metastatic Disease

Multivariate analyses will be performed to evaluate the effect of known prognostic factors and biomarkers on outcomes observed.

The ORR will be summarized as the percentage (including 95% confidence intervals) of responders and presented by treatment group and will be compared (as exploratory endpoint) between treatment groups using a chi-squared test.

Anti-tumor activity and magnitude of response will be captured by waterfall plot analyses. The percentage change in tumor size from baseline to the time of best response will be plotted by patients (ordered from worst to best) and bars colored according to best response.

The ORR of non-irradiated lesions will be summarized as the percentage (including 95% confidence intervals) of responders and presented by treatment group and will be compared (as exploratory endpoint) between treatment groups using a chi-squared test.

QOL will be evaluated using the European Organization for Research and Treatment of Cancer Core Quality of Life and EuroQOL-5 dimension-5 level questionnaires. Differences from baseline will be compared between arms of the study using the two sample t-test or Wilcoxon non-parametric method as appropriate.

DCR will be summarized as the percentage (including 95% confidence intervals) of responders and presented by treatment group and will be compared (as exploratory endpoint) between treatment groups using a chi-squared test.

The proportion of centers engaging will be presented with 95% confidence intervals.

The recruitment rate will be calculated overall centers and by country and center.

The Kaplan Meier estimates of OS over time and median OS with associated 95% confidence intervals will be presented by treatment and (as exploratory endpoint) compared using a log rank test. Cox multivariate regression analysis will be used (as exploratory analysis) to calculate the hazard ratio between treatments along with its 95% confidence interval. The treatment effect will be adjusted for the stratification factors and other identified prognostic factors (e.g. time to disease relapse \& whether pre-treated with platinum) in a multivariate setting.

The Kaplan Meier estimates of PFS over time and median PFS with associated 95% confidence intervals will be presented by treatment and (as exploratory endpoint) compared using a log rank test. Cox multivariate regression analysis will be used (as exploratory analysis) to calculate the hazard ratio between treatments along with its 95% confidence interval. The treatment effect will be adjusted for the stratification factors and other identified prognostic factors (e.g. time to disease relapse \& whether pre-treated with platinum) in a multivariate setting.

The proportion of patients experiencing grade 3-5 toxicity will be compared on a regimen basis using the chi-squared test. Fisher's exact test will be used when expected cell frequencies are \< 5.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Lower-Dose Chemoradiation in Treating Patients With Early-Stage Anal Cancer, the DECREASE Study	NCT04166318	Anal Basaloid C... Anal Canal Cloa... Anal Canal Squa... Anal Margin Squ... Stage I Anal Ca... Stage IIA Anal ...	Capecitabine Fluorouracil Intensity-Modul... Mitomycin Quality-of-Life... Questionnaire A...	18 Years -	Eastern Cooperative Oncology Group
Cisplatin and Fluorouracil Compared With Carboplatin and Paclitaxel in Treating Patients With Inoperable Locally Recurrent or Metastatic Anal Cancer	NCT02560298	Anal Basaloid C... Anal Canal Cloa... Anal Squamous C... Metastatic Anal... Recurrent Anal ... Stage IIIB Anal... Stage IV Anal C...	Capecitabine Carboplatin Cisplatin Fluorouracil Laboratory Biom... Paclitaxel Quality-of-Life...	18 Years -	Eastern Cooperative Oncology Group

Spots Global Cancer Trial Database for anal basaloid carcinoma