Treatment of Stage I-III Squamous Cell Carcinoma (SCC) of the Anal Canal

KQ1: What is the comparative effectiveness of different modalities of initial treatment for stages I-III squamous cell anal cancer?

KQ2: What is the comparative effectiveness of different radiation therapy doses and fractionation schemes for initial treatment of stage I-III squamous cell anal cancer?

KQ3: What is the comparative effectiveness of different radiation therapy types for initial treatment of stages I-III squamous cell anal cancer?

KQ4: What is the comparative effectiveness of different chemotherapy types or combinations of chemotherapy types and dose de-escalation for initial treatment of stages I-III squamous cell anal cancer?

KQ5: What is the effectiveness of immunotherapy for initial treatment of stages I-III squamous cell anal cancer?

a. How do outcomes vary based on the conditions surrounding immunotherapy (e.g., other treatments given, patient characteristics, tumor characteristics)? What is the effectiveness and what are the harms of radiation therapy in the palliative treatment of bone metastases?

Anal cancer is a disease in which malignant cells form in the tissues of the anus and at the end of the large intestine, below the rectum. Based on data from 2017 to 2019, roughly 0.2 percent of people will be diagnosed with anal cancer at some point in their lifetime, and the five-year survival rate is approximately 70 percent. While the condition is relatively uncommon, age-adjusted death rates have been rising an average of 3.5 percent each year over the last decade.¹ An analysis conducted in 2019 found that the average lifetime cost of anal cancer was estimated to be approximately $50,000 for patients, and the disease-related lifetime economic burden for Medicare patients in the United States was approximately $112 million.²

Major risk factors for anal carcinoma include human papillomavirus (HPV)-16 and HPV-18, two strains of HPV with genes that can cause healthy cell to act abnormally. Conditions with lowered immunity also increase the risk of anal carcinoma. This would include things like acquired immune deficiency syndrome (AIDS), which is advanced HIV infection without current suppressive treatments); taking medications that cause immunosuppression for organ transplants; and smoking.³ The treatment of anal cancer is dependent upon the stage of an individual’s carcinoma, their overall health, and their personal preferences.⁴ Treatment may include chemotherapy, radiation, and/or surgery.

The Patient-Centered Outcomes Research Institute (PCORI) is partnering with the Agency for Healthcare Research and Quality (AHRQ) to develop a systematic evidence review on Treatment of Stage I-III Squamous Cell Carcinoma (SCC) of the Anal Canal. The American Society for Clinical Oncology (ASCO) and the American Society for Radiation Oncology (ASTRO) plan to use this systematic evidence review to develop related clinical guidelines.

Figure 1. Draft analytic framework

$Figure 1: This figure depicts key questions 1 to 5 within the context of the PICO Framework described in Table 1. In general, the figure illustrates how interventions such as chemoradiation, radiation therapy [with consideration of different doses, fractionation schemes and types (including IMRT, proton radiation therapy, brachytherapy, 3-D CRT, photon radiation therapy, electron therapy boost)], induction or maintenance chemotherapy (with consideration of types, combinations, and dose de-escalation), and immunotherapy may result in health outcomes such as overall survival, disease-free survival, colostomy-free survival, local control, pathologic complete response, salvage rate, sphincter preservation, acute and late toxicity, health-related quality of life, and harms of treatment among adults with stages I-III squamous cell anal cancer. Also, adverse events may occur after the intervention is received. The relationship between intervention and outcomes may be different among subgroups of patients based on stage, patient and tumor characteristics, and other treatments.$

Table 1. Questions and PICOs (population, intervention, comparator, outcome) for KQ1 & KQ2

Questions	Comparative effectiveness of initial treatment modalities	Comparative effectiveness of radiation therapy doses and fractionation schemes of initial treatment
Population	Adults with stages I-III squamous cell anal cancer Subgroup: stage, age, tumor characteristics, etc.	Adults with stages I-III squamous cell anal cancer
Interventions	Chemoradiation Induction or maintenance chemotherapy Surgery	Radiation therapy: Doses Fractionation schemes
Comparators	Radiation Therapy Chemoradiation Other treatment	Other: Doses Fractionation schemes
Outcomes	Overall survival Disease-free survival Colostomy-free survival Local control Pathologic complete response Salvage rate Sphincter preservation Acute and late toxicity Health-related quality of life Harms of treatment	Overall survival Disease-free survival Local control Pathologic complete response Salvage rate Sphincter preservation Acute and late toxicity Health-related quality of life Harms of treatment

Table 2. Questions and PICOs (population, intervention, comparator, outcome) for KQ3 & KQ4

Questions	Comparative effectiveness of radiation therapy types for initial treatment	Comparative effectiveness of different chemotherapy types or combinations of chemotherapy types and dose de-escalation for initial treatment
Population	Adults with stages I-III squamous cell anal cancer	Adults with stages I-III squamous cell anal cancer
Interventions	IMRT Proton radiation therapy Brachytherapy	Chemotherapy types/combinations (e.g., fluorouracil, mitomycin, cisplatin) Dose de-escalation
Comparators	3-D CRT Photon radiation therapy Electron therapy boost	Chemotherapy types/combinations (e.g., fluorouracil, mitomycin, cisplatin) Other dose de-escalation
Outcomes	Overall survival Disease-free survival Colostomy-free survival Local control Pathologic complete response Salvage rate Sphincter preservation Acute and late toxicity Health-related quality of life Harms of treatment	Overall survival Disease-free survival Local control Pathologic complete response Salvage rate Sphincter preservation Acute and late toxicity Health-related quality of life Harms of treatment

Abbreviations: IMRT=intensity-modulated radiation therapy; 3-D CRT= three-dimensional conformal radiation therapy.

Table 3. Questions and PICOs (population, intervention, comparator, outcome) for KQ5

Questions	Effectiveness of immunotherapy for initial treatment of stages I-III anal carcinoma How do outcomes vary based on the conditions surrounding immunotherapy
Population	Adults with stages I-III squamous cell anal cancer Subgroup: other treatments, patient characteristics, tumor characteristics, stage
Interventions	Immunotherapy (e.g., pembrolizumab, nivolumab)
Comparators	Other treatment (e.g., chemotherapy, radiation, chemotherapy + radiation)
Outcomes	Overall survival Disease-free survival Colostomy-free survival Local control Pathologic complete response Salvage rate Sphincter preservation Acute and late toxicity Health-related quality of life Harms of treatment

Cancer Stat Facts: Anal Cancer. NIH National Cancer Institute. doi: https://seer.cancer.gov/statfacts/html/anus.html#:~:text=Rate%20of%20New%20Cases%20and%20
Deaths%20per%20100%2C000%3A,age-adjusted%20and%20based%20on%202015%E2%80%932019%20cases%20and%20deaths.
Deshmukh AA, Zhao H, Franzini L, et al. Total Lifetime and Cancer-related Costs for Elderly Patients Diagnosed With Anal Cancer in the United States. Am J Clin Oncol. 2018 Feb;41(2):121-7. doi: 10.1097/coc.0000000000000238. PMID: 26523440.
About Anal Cancer. American Cancer Society. doi: https://www.cancer.org/cancer/anal-cancer/about.html.
Anal Cancer. Mayo Clinic. doi: https://www.mayoclinic.org/diseases-conditions/anal-cancer/diagnosis-treatment/drc-20354146.1. Metastatic Cancer: When Cancer Spreads. National Institutes of Health, National Cancer Institute. doi: https://www.cancer.gov/types/metastatic-cancer.

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Treatment of Stage I-III Squamous Cell Carcinoma (SCC) of the Anal Canal

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