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Therapy Adapted for High Risk and Low Risk HIV-Associated Anal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04929028
Recruitment Status : Not yet recruiting
First Posted : June 18, 2021
Last Update Posted : September 14, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies the side effects of chemotherapy and intensity modulated radiation therapy in treating patients with low-risk HIV-associated anal cancer, and nivolumab after standard of care chemotherapy and radiation therapy in treating patients with high-risk HIV-associated anal cancer. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Chemotherapy drugs, 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. Giving chemotherapy with radiation therapy may kill more tumor cells. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab after standard of care chemotherapy and radiation therapy may help reduce the risk of the tumor coming back.

Condition or disease Intervention/treatment Phase
AIDS-Related Anal Carcinoma Anal Basaloid Carcinoma Anal Canal Cloacogenic Carcinoma Anal Squamous Cell Carcinoma HIV Infection Rectal Squamous Cell Carcinoma Stage I Anal Cancer AJCC v8 Stage II Anal Cancer AJCC v8 Stage IIA Anal Cancer AJCC v8 Stage IIB Anal Cancer AJCC v8 Stage III Anal Cancer AJCC v8 Stage IIIA Anal Cancer AJCC v8 Stage IIIB Anal Cancer AJCC v8 Stage IIIC Anal Cancer AJCC v8 Drug: Capecitabine Drug: Fluorouracil Radiation: Intensity-Modulated Radiation Therapy Drug: Mitomycin Biological: Nivolumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 53 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Risk-Adapted Therapy for HIV-Associated Anal Cancer
Estimated Study Start Date : October 29, 2021
Estimated Primary Completion Date : April 30, 2023
Estimated Study Completion Date : April 30, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: High-risk stratum (nivolumab)
Patients receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • CMAB819
  • MDX-1106
  • NIVO
  • Nivolumab Biosimilar CMAB819
  • ONO-4538
  • Opdivo

Experimental: Low-risk stratum (mitomycin
Patients receive mitomycin IV on day 1 and either fluorouracil IV on day 1 or capecitabine PO BID on Monday-Friday until the completion of radiation therapy at the discretion of the treating physician. Patients also undergo IMRT QD for 20-23 treatment sessions over 6 weeks.
Drug: Capecitabine
Given PO
Other Names:
  • Ro 09-1978/000
  • Xeloda

Drug: Fluorouracil
Given IV
Other Names:
  • 5 Fluorouracil
  • 5 Fluorouracilum
  • 5 FU
  • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
  • 5-Fluorouracil
  • 5-Fluracil
  • 5-Fu
  • 5FU
  • AccuSite
  • Carac
  • Fluoro Uracil
  • Fluouracil
  • Flurablastin
  • Fluracedyl
  • Fluracil
  • Fluril
  • Fluroblastin
  • Ribofluor
  • Ro 2-9757
  • Ro-2-9757

Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy
  • Radiation, Intensity-Modulated Radiotherapy

Drug: Mitomycin
Given IV
Other Names:
  • Ametycine
  • Jelmyto
  • MITO
  • Mito-C
  • Mito-Medac
  • Mitocin
  • Mitocin-C
  • Mitolem
  • Mitomycin C
  • Mitomycin-C
  • Mitomycin-X
  • Mitomycine C
  • Mitosol
  • Mitozytrex
  • Mutamycin
  • Mutamycine
  • NCI-C04706




Primary Outcome Measures :
  1. Incidence of adverse events (Low-risk stratum) [ Time Frame: Up to 5 years ]
    Evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The adverse events will be summarized by overall, as well as by grade using frequency (percentage). A two-sided 95% confidence interval will be reported together with percentage estimates. The proportion of participants who experience grade 3-4 toxicities will be estimated using a binomial point estimate and its 95% confidence interval.

  2. Incidence of adverse events (High-risk stratum) [ Time Frame: Up to 5 years ]
    Evaluated by CTCAE version 5.0. The adverse events will be summarized by overall, as well as by grade using frequency (percentage). A two-sided 95% confidence interval will be reported together with percentage estimates. The proportion of participants who experience grade 3-4 toxicities will be estimated using a binomial point estimate and its 95% confidence interval.


Secondary Outcome Measures :
  1. Disease free survival (High-risk stratum) [ Time Frame: Time from enrollment until progression of local disease, distant metastasis, secondary primary cancer or death, assessed at 2 years ]
    Will be estimated using Kaplan-Meier method. The 95% confidence interval will be estimated using Greenwood's formula. The cumulative incidence of pelvic disease relapse will also be estimated from Kaplan-Meier method and the corresponding 90% confidence interval will be estimated using Greenwood's formula. In the analyses above, a two-sided p-value of 0.05 will be used to assess statistical significance.

  2. Disease control rate (Low-risk stratum) [ Time Frame: Time from enrollment until first recurrence (locoregional or distant metastasis) or chemo-radiation-related death, assessed up to 5 years ]
    Will be estimated using Kaplan-Meier method. The 95% confidence interval will be estimated using Greenwood's formula. The cumulative incidence of pelvic disease relapse will also be estimated from Kaplan-Meier method and the corresponding 90% confidence interval will be estimated using Greenwood's formula. In the analyses above, a two-sided p-value of 0.05 will be used to assess statistical significance.

  3. Change in CD4+ cell counts (High-risk stratum) [ Time Frame: Baseline up to 5 years ]
    Will be assessed by evaluating the changes from baseline in CD4+ using the Wilcoxon signed rank test to allow for nonnormality.

  4. Change in human immunodeficiency virus (HIV) viral load (Low-risk stratum) [ Time Frame: Baseline up to 5 years ]
    Will be assessed by evaluating the changes from baseline in HIV viral load using the Wilcoxon signed rank test to allow for nonnormality.

  5. Change in combination antiretroviral therapy (cART) adherence [ Time Frame: Baseline up to 5 years ]
    To assess cART adherence before, during, and after treatment with CRT and nivolumab to identify potential barriers to cART adherence when receiving concurrent oncological care.


Other Outcome Measures:
  1. Relationship between specific human papillomavirus (HPV) subtypes and clinical response to reduced intensity chemo-radiation therapy (CRT) or nivolumab [ Time Frame: Up to 5 years ]
    Will be presented using descriptive statistics (with no inferential statistics involved).

  2. Relationship between expression of PD-1 in immune cells and PD-L1 in immune cells or cancer epithelial cells in the primary diagnostic tumor and clinical response to nivolumab or reduced intensity CRT [ Time Frame: Up to 5 years ]
    Will be presented using descriptive statistics (with no inferential statistics involved).

  3. Effect of reduced intensity CRT and nivolumab on viral HIV reservoirs [ Time Frame: Up to 5 years ]
    Will be presented using descriptive statistics (with no inferential statistics involved).

  4. Prevalence of cell-free plasma HPV deoxyribonucleic acid (DNA) before and after reduced intensity CRT and nivolumab [ Time Frame: Up to 5 years ]
    Relationship with clinical response with be explored. Will be presented using descriptive statistics (with no inferential statistics involved).

  5. Impact of reduced intensity CRT on quality of life [ Time Frame: Up to 5 years ]
    Will be presented using descriptive statistics (with no inferential statistics involved).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIGH-RISK STRATUM: Participant is able to understand and willing to sign a written informed consent document
  • HIGH-RISK STRATUM: Participant must have histologically proven stage (T3-T4N0M0 OR T2-4N1M0) invasive squamous cell carcinoma (SCC) of the anus or anorectum as documented before CRT initiation, according to the American Joint Committee on Cancer (AJCC) 8th edition. Participants with squamous cell carcinoma of the anal margin are eligible if there is evidence of extension of the primary tumor into the anal canal. Participants with tumors of non-keratinizing histology such as basaloid, transitional cell or cloacogenic histology are permitted
  • HIGH-RISK STRATUM: HIV-positive. Documentation of HIV-1 infection by means of any one of the following:

    • Documentation of HIV diagnosis in the medical record by a licensed health care provider. If the record contains information that the patient is taking Food and Drug Administration (FDA)-approved combination therapy for HIV infection, then this can be part of the record substantiating the HIV positive diagnosis
    • HIV-1 ribonucleic acid (RNA) detection by a licensed HIV-1 RNA assay demonstrating > 1000 RNA copies/mL
    • Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay such as a HIV-1 Western blot confirmation or HIV rapid multispot antibody differentiation assay.

      • NOTE: The term "licensed" refers to a kit that has been certified or licensed by an oversight body within the participating country and validated internally (e.g., United States [U.S.] FDA)
      • WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test must be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load
  • HIGH-RISK STRATUM: Age >= 18 years

    • Because no dosing or adverse event data are currently available on the use of nivolumab in participants < 18 years of age, children are excluded from this study
  • HIGH-RISK STRATUM: Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)
  • HIGH-RISK STRATUM: Life expectancy of greater than 6 months
  • HIGH-RISK STRATUM: Hemoglobin > 10 g/dL (within 2 weeks before enrollment)
  • HIGH-RISK STRATUM: Absolute neutrophil count: >= 1,500/mm^3 (within 2 weeks before enrollment)
  • HIGH-RISK STRATUM: Platelets: >= 100,000/mm^3 (within 2 weeks before enrollment)
  • HIGH-RISK STRATUM: Total bilirubin: < 2 X upper limit of normal (ULN) (within 2 weeks before enrollment)
  • HIGH-RISK STRATUM: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]): =< 2.5 X institutional ULN (within 2 weeks before enrollment)
  • HIGH-RISK STRATUM: Albumin >= 3.0 g/dL (within 2 weeks before enrollment)
  • HIGH-RISK STRATUM: Creatinine levels =< 1.5 X normal institutional limits; or calculated creatinine clearance must be > 50 ml/min (within 2 weeks before enrollment)
  • HIGH-RISK STRATUM: Females of childbearing potential (FOCBP) must agree to follow contraception requirements:

    • The effects of nivolumab on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, FOCBP must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) before study entry, for the duration of study participation and 5 months after completion of nivolumab administration. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately

      • NOTE: 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)
  • HIGH-RISK STRATUM: Participant must have a CD4 count of >= 100 cells/uL at least 2 weeks prior to enrollment OR >= 100 cells/uL before receiving prior CRT, as CD4 may be low due to the effects of CRT
  • HIGH-RISK STRATUM: Participant must be on a stable antiretroviral therapy (ART) regimen for at least 2 weeks prior to enrollment with no intention to change the regimen within 12 weeks after enrollment
  • HIGH-RISK STRATUM: Participant must have an HIV RNA viral load of < 200 copies/mL
  • HIGH-RISK STRATUM: Participant must have received at least 54 Gy of radiation to the PTVp (primary) and 45 Gy to PTVn (elective nodal region) for the treatment of the anal cancer within 9 weeks before enrollment
  • HIGH-RISK STRATUM: Participant must have =< grade 2 diarrhea

    • Participants with grade 1 or grade 2 diarrhea are eligible provided stool for ova/parasites and stool cryptosporidium studies are negative
  • HIGH-RISK STRATUM: Purified protein derivative (PPD) negative. Alternatively, the QuantiFERON-tuberculosis (TB) Gold In-Tube (QFT-GIT) assay (Cellestis Limited, Carnegie, Australia) can be used. An individual is considered positive for M. tuberculosis infection if the interferon (IFN)-gamma response to TB antigens is above the test cut-off (after subtracting the background IFN-gamma response in the negative control). The result must be obtained within 20 weeks prior to enrollment. PPD positive (or QuantiFERON assay positive) participants are permitted if prophylaxis has been completed prior to enrollment
  • HIGH-RISK STRATUM: Participants with impaired decision-making capacity (IDMC) may be eligible for the study provided all other eligibility criteria are satisfied:

    • The participant's legally authorized representative (LAR) is able and willing to sign consent in addition to the study candidate
    • Both participant and LAR agree to follow study parameters per protocol
  • HIGH-RISK STRATUM: The participant, in the opinion of the treating investigator, is able to receive IV contrast injections:

    • All participants in the High-risk Stratum must have an oral contrast (rectal contrast optional) and IV iodine contrast abdomen and pelvis computed tomography (CT) (A/P C+CT) at baseline and for all clinical follow up time points. Imaging centers should follow their local routine guidelines for determination of patient eligibility for IV contrast injection and appropriate post contrast follow up renal function determinations
  • SCREENING ELIGIBILITY LOW-RISK STRATUM: Participant is able to understand and willing to sign a written informed consent document
  • SCREENING ELIGIBILITY LOW-RISK STRATUM: Age >= 18 years

    • Because no dosing or adverse event data are currently available on the use of low-dose radiation concurrent with mitomycin-C/fluorouracil (5-FU) or mitomycin-C/capecitabine in participants < 18 years of age, children are excluded from this study
  • SCREENING ELIGIBILITY LOW-RISK STRATUM: Participant must have histologically proven T1-2N0M0 invasive anal canal or anal margin squamous cell carcinoma with tumors measuring =< 4 cm within 6 weeks before pre-registration. Measurable disease is not required. Participants with tumors of non-keratinizing histology such as basaloid, transitional cell, or cloacogenic histology are permitted. Participants 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 participants 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 Baseline imaging including, fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/CT and A/P C+CT must be submitted for central review for confirmation of no lymph node involvement. Results of central review (including discrepancies between local read and central review) will be returned to the site within 5 business days of submission, allowing participants with imaging suspicious for lymph node (LN) involvement determined by central review to undergo a fine needle aspirate (FNA) or core biopsy at their local center confirming no lymph node involvement (N0) for eligibility
  • SCREENING ELIGIBILITY LOW-RISK STRATUM: HIV positive. Documentation of HIV-1 infection by means of any one of the following:

    • Documentation of HIV diagnosis in the medical record by a licensed health care provider. If the record contains information that the patient is taking FDA-approved combination therapy for HIV infection, then this can be part of the record substantiating the HIV positive diagnosis
    • HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating > 1000 RNA copies/mL
    • Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay such as a HIV-1 Western blot confirmation or HIV rapid multispot antibody differentiation assay.

      • NOTE: The term "licensed" refers to a kit that has been certified or licensed by an oversight body within the participating country and validated internally (e.g., U.S. FDA)
      • WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test must be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load
  • SCREENING ELIGIBILITY LOW-RISK STRATUM: Tumor size must be documented by digital rectal exam and anoscopy/proctoscopy within 6 weeks prior to pre-registration
  • SCREENING ELIGIBILITY LOW-RISK STRATUM: Life expectancy of greater than 6 months
  • LOW-RISK STRATUM: Participant satisfies all criteria in Eligibility for Screening Low-Risk Stratum. Participants with imaging suspicious for LN involvement determined by central review must undergo a fine needle aspirate (FNA) or core biopsy confirming no lymph node involvement (N0)
  • LOW-RISK STRATUM: ECOG performance status =< 2 (Karnofsky >= 50%)
  • LOW-RISK STRATUM: Hemoglobin > 10 g/dL (within 2 weeks before enrollment)
  • LOW-RISK STRATUM: Absolute neutrophil count: >= 1,500/mm^3 (within 2 weeks before enrollment)
  • LOW-RISK STRATUM: Platelets: >= 100,000/mm^3 (within 2 weeks before enrollment)
  • LOW-RISK STRATUM: Total bilirubin: < 2 X ULN (within 2 weeks before enrollment)
  • LOW-RISK STRATUM: AST (SGOT) / ALT (SGPT): =< 2.5 X institutional ULN (within 2 weeks before enrollment)
  • LOW-RISK STRATUM: Albumin >= 3.0 g/dL (within 2 weeks before enrollment)
  • LOW-RISK STRATUM: Serum creatinine levels =< 1.5 X ULN or calculated creatinine clearance must be > 50 ml/min (within 2 weeks before enrollment)
  • LOW-RISK STRATUM: Participant must agree to follow contraception requirements:

    • Females of childbearing potential (FOCBP) 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
    • NOTE: FOCBP is defined as a sexually mature woman, regardless of sexual orientation or whether they have undergone tubal ligation who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months, i.e., has had menses at any time in the preceding 24 consecutive months
  • LOW-RISK STRATUM: Participant must have a CD4 count of >= 100 cells/uL at least 2 weeks before enrollment
  • LOW-RISK STRATUM: Participant must on a stable ART regimen for at least 2 weeks before enrollment and receive appropriate care and treatment for HIV infection under the care of a physician experienced in HIV management
  • LOW-RISK STRATUM: Participant has a HIV RNA viral load of < 200 copies/mL
  • LOW-RISK STRATUM: Participant has started an alternative anti-coagulant regimen within 2 weeks prior to enrollment if taking warfarin and considering capecitabine

    • NOTE: Low molecular weight heparin is permitted provided the participants prothrombin time (PT)/international normalized ratio (INR) is < 1.5
  • LOW-RISK STRATUM: Participant must agree to having phenytoin levels checked weekly if planning to receive capecitabine while taking phenytoin for a seizure disorder
  • LOW-RISK STRATUM: Participants with IDMC may be eligible for the study provided all other eligibility criteria are satisfied:

    • The participant's legally authorized representative (LAR) is able and willing to sign consent in addition to the study candidate
    • Both participant and LAR agree to follow study parameters
  • LOW-RISK STRATUM: The participant, in the opinion of the treating investigator, is able to receive IV contrast injections:

All participants in the Low-risk Stratum must have an oral contrast (rectal contrast optional) and IV iodine contrast CT (A/P C+CT and chest C+CT) at baseline and for all clinical follow up time points. Imaging centers should follow their local routine guidelines for determination of patient eligibility for IV contrast injection and appropriate post contrast follow up renal function determinations

Exclusion Criteria:

  • HIGH-RISK STRATUM: Any live vaccines within 30 days prior to enrollment

    • Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines and are not allowed
    • NOTE: No live vaccines may be administered while participating in the trial.
  • HIGH-RISK STRATUM: Participant has known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
  • HIGH-RISK STRATUM: Prior treatment with an immune checkpoint inhibitor (anti-PD-1, ant

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04929028


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Rafi Kabarriti AIDS Malignancy Consortium
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04929028    
Other Study ID Numbers: NCI-2021-06041
NCI-2021-06041 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AMC-110 ( Other Identifier: AIDS Malignancy Consortium )
AMC-110 ( Other Identifier: CTEP )
UM1CA121947 ( U.S. NIH Grant/Contract )
First Posted: June 18, 2021    Key Record Dates
Last Update Posted: September 14, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Anus Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Anus Diseases
Carcinoma
Carcinoma, Squamous Cell
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Fluorouracil
Capecitabine
Nivolumab
Mitomycins
Mitomycin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs