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ORIGINAL ARTICLE
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Definitive chemoradiation in nonmetastatic squamous cell carcinoma anal canal: A single-institution experience


1 Department of Radiation Oncology, Cancer Research Institute, SRHU, Dehradun, Uttarakhand, India
2 Department of Surgical Oncology, Cancer Research Institute, SRHU, Dehradun, Uttarakhand, India

Date of Submission23-Jul-2020
Date of Decision09-Sep-2020
Date of Acceptance21-Dec-2020
Date of Web Publication15-Oct-2021

Correspondence Address:
Saurabh Bansal,
Department of Radiation Oncology, Cancer Research Institute, SRHU, Dehradun, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_979_20

 > Abstract 


Purpose: The purpose of the study was to analyze the survival outcomes and toxicities in squamous cell carcinoma anal canal treated with definitive chemoradiotherapy.
Materials and Methods: Retrospective analysis of 51 patients with squamous cell carcinoma anal canal treated with chemoradiotherapy was done. Data were collected and analyzed for disease-free survival (DFS), colostomy-free survival (CFS), overall survival (OS), and acute/late toxicities.
Results: Out of total 51 patients, only 44 patients had a follow-up of more than 36 months and were analyzed. After a median follow-up of 46 months (range 10–68 months), the 3-year DFS was 73.9%. Three patients developed locoregional recurrence, while one patient developed distant metastasis. At 3-year OS rate was 77%. Out of 44 patients, six patients lost to follow–up, while two patients died due to progressive disease and two due to noncancer causes. 3-year CFS rate was 59%. Most common grade >3 acute toxicities were skin reactions in nine (18%), followed by hematological in eight (16%) patients.
Conclusion: Definitive chemoradiotherapy in anal canal results in good oncological outcomes with sphincter preservation. No severe treatment-related toxicities were observed.

Keywords: Anal canal, chemoradiation, squamous cell carcinoma



How to cite this URL:
Kumar V, Bansal S, Badola A, Nautiyal V, Gupta M, Ahmad M, Saini S. Definitive chemoradiation in nonmetastatic squamous cell carcinoma anal canal: A single-institution experience. J Can Res Ther [Epub ahead of print] [cited 2021 Nov 28]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=328265




 > Introduction Top


Carcinoma anal canal is a relatively rare malignancy, and it accounts for 4% of lower gastrointestinal malignancies.[1] However, in the past few decades, incidence of anal cancer has increased worldwide, especially in high-income countries.[2] In past chronic irritation resulting from fissures, hemorrhoids were thought to be associated with anal cancer, but several studies found other risk factors including human papillomavirus infection, low CD4 count, anal intercourse cigarette smoking, Crohn's disease, and immunosuppressant therapy.[3]

Majority of patients of carcinoma anal canal present with rectal bleeding (fresh bright red) and pain in perianal region. Large tumor involving anal sphincter can present with fecal incontinence.[4]

Surgery (abdominoperineal resection) with permanent colostomy was the standard treatment option for carcinoma anal canal, but morbidity related to colostomy, has led to an active search for an alternative approaches. After introduction of chemoradiation in anal carcinoma by Nigro et al. in 1974, it has emerged as a primary modality of treatment in these patients.[5] Local control rates of 70%–85% and 5-year overall survival (OS) rate of 66%–92% can be achieved by chemoradiation which are comparable to that achieved by surgery. Patients treated with definitive chemoradiotherapy have better quality of life and colostomy-free survival (CFS) rate.[6] Nowa days, surgery is reserved for salvage of residual/recurrent tumors.[7]

Carcinoma anal canal being rare malignancy, sparse data procured pertaining to treatment modalities, and outcomes in India, limited to individual center experiences. The aim of the present study was to analyze the clinical profile, outcomes, and tolerance of definitive chemoradiotherapy in patients with carcinoma anal canal.


 > Materials and Methods Top


Type and design

This single-center-based retrospective study was conducted at the Cancer Research Institute Swami Rama Himalayan University Dehradun. We collected data of 51 patients of carcinoma anal canal who were treated with definitive chemoradiotherapy from January 2011 to December 2018. Analysis of data was made by studying the patient's files, electronic data (maintained by Uttarakhand State Council for Science and Technology), and records available.

Institutional ethical committee clearance was taken beforehand. Records with incomplete information regarding histology or treatment were excluded. The outcomes were assessed by electronic record of last visits and telephonic confirmation of survival or demise”.

Patients

Patients 18 years of age or older, ECOG performance 0–2, histologically proven squamous cell carcinoma anal canal, adequate bone marrow function, and no prior chemotherapy or radiotherapy were included for analysis. Patients with metastatic disease, poor nutritional status, any comorbid conditions which preclude the use of radiotherapy, and major medical or psychiatric illness were excluded from the study. Pretreatment workup include digital rectal examination, proctoscopy, tissue biopsy, computed tomography (CT) of abdomen and pelvis or magnetic resonance imaging of pelvis, and chest X-ray. Clinical tumor staging was done as per 7th ed.ition of American joint Committee on Cancer staging system”.

Treatment

All patients received definitive chemo-radiotherapy with 3D CRT technique. CT simulation was done in supine position with full bladder. Gross tumor volume includes primary tumor and involved lymph nodes. Clinical target volume includes gross tumor volume plus area at risk of microscopic spread from tumor and at risk nodal areas. Radiation was delivered with shrinking field technique. After a dose of 45 Gy/25# over 5 weeks to whole pelvis, the field was reduced to GTV + 2 cm margin (including the mesorectum and positive lymph nodes) to deliver a boost of 9–14.4 Gy (total dose 54–59.4 Gy) at 1.8 Gy per fraction.” Electively inguinal Lymph nodes were treated with 36 Gy/20# over 4 weeks. Patients received concurrent chemotherapy with mitomycin 10 mg/m2 administered on D1 and D29 and 5-FU 1000 mg/m2 infusion given on D1-D4 and D29 to D32. In place of 5 FU infusion, some patients received oral tablet capecitabine 625 mg/m2 twice daily on the days of external beam radiation therapy.

Response assessment

After treatment completion, patients were initially assessed at 6 weeks, 12 weeks, and at 24 weeks with locoregional examination and/or with radiological imaging. Thereafter, patients were closely followed up every 3 months for 2 years and every 6 months for another 3 years.

Tumor response assessment was done according to the Response Evaluation Criteria in Solid Tumors, version 1.1 at protocol-defined intervals. Acute toxicities were recorded according to National Cancer Institute's Common Toxicity Criteria version 3. The late side effects recorded were proctitis, rectal stenosis, skin ulceration, fibrosis, and urinary incontinence.

Statistical analysis

Statistical analysis was performed using SPSS version 20 (IBM Corp., Armonk, N. Y., USA). Quantitative variables were expressed as mean with standard deviation.

Disease-free survival was defined as the first event of recurrent disease or death in the patients who had complete response posttreatment. OS was calculated from treatment onset to date of death irrespective of the cause of death, with censoring at the date of last contact for the patient alive. CFS was based on date of colostomy or death by any cause. Patients who underwent colostomy before chemoradiation were excluded from analysis. Actuarial survival rates were calculated using the Kaplan–Meier method. Secondary end points were Grade 3 or more acute and late toxicity.


 > Results Top


A total of 51 patients of carcinoma anal canal from January 2011 to December 2018 were enrolled in this study. Median age at the time of diagnosis was 50 years (range 30–76 years) with male: female ratio 3.6:1. Most common symptom at presentation was pain during defecation (86%), followed by bleeding P/R (73%), constipation (63%), anal discharge (29%), and groin swelling (22%). At presentation, 37 patients were in Stage III and 14 patients were in Stage II. Patient's characteristics in study population are summarized in [Table 1].
Table 1: Patient characteristics of study population

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All the patients completed protocol-defined treatment. Radiotherapy was temporarily interrupted in seven patients because of skin reactions. Median days of RT interruption were 10 days (range: 4–15 days). Mild reductions in chemotherapy doses were done because of comorbidities and chemotherapy-related toxicity during treatment.

At 3-month posttreatment, 18 patients (35%) had complete response, while 28 patients (55%) were having partial response and 5 patients had progressive disease [Figure 1]. Out of these patients who had progression, two underwent surgery, two received palliative chemotherapy, and one was put on palliative care. “At 6-month follow-up, 9 out of 28 patients who were having partial response at 3 month achieved complete response. Thus, at 6 months, complete response was seen in 27 patients (53%) and partial response was seen in 19 patients (37%) [Figure 2]. Out of 19 patients who had partial response were advised salvage surgery but only 11 patients underwent abdominoperineal resection (APR) surgery, three underwent diversion colostomy, three patients were put on palliative chemotherapy, and two patients did not turned up of further treatment.
Figure 1: “Patients having complete response, partial response, and progressive disease” at 3 months

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Figure 2: Patients having complete response, partial response at 6 months

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Survival analysis

Out of total 51 patients, only 44 patients had a follow-up of more than 36 months and were included in survival analysis. Median follow-up was 46 months (10–68 months). At 3 years, OS rate was 77% [Figure 3]. Out of 44 patients, six patients lost to follow–up, whereas two patients died due to progressive disease and two due to noncancer causes. The 3-year disease-free survival (DFS) was 73.9% [Figure 4]. Three patients developed locoregional recurrence, whereas one patient developed distant metastasis (lung) and two patients lost to follow-up. 3-year CFS rate was 59% [Figure 5]. Total 18 out of 44 patients underwent colostomy either as palliative diversion or as a part of APR surgery.
Figure 3: Kaplan–Meier curve showing 3-year overall survival

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Figure 4: Kaplan–Meier curve showing 3-year disease-free survival

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Figure 5: Kaplan–Meier curve showing 3-year colostomy-free survival

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Toxicity

Most common grade >3 acute toxicities were skin reactions in nine (18%), followed by hematological in eight (16%) and diarrhea in one (2%) patient. Six patients had grade >3 neutropenia and were given growth colony-stimulating factors. There was no treatment-related death. One patient developed mild infusion reaction to injection mitomycin which was managed symptomatically. Acute toxicities are summarized in [Table 2].
Table 2: Acute toxicities in patients treated with definitive chemoradiation

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There were no grade 3 or 4 late toxicities in any patient when scored independently. Grade 2 late toxicities included proctitis in 3, skin fibrosis in 2, and urinary incontinence in one patient.


 > Discussion Top


Before 1980, APR was the standard treatment for carcinoma anal canal. Treatment of carcinoma anal canal had a paradigm shift in 1980s from radical surgery to definitive chemoradiotherapy with almost similar oncological outcomes and improved quality of life. Squamous cell carcinomas are radiosensitive and chemoradiation in anal canal was first attempted by Nigro et al. in 1974. They observed complete remission of the primary tumor in three patients with squamous cell carcinoma of the anal canal at the time of surgery, who had received preoperative chemoradiation.[8] Since then, various trials have shown that local control and survival are similar to those reported with radical surgery and chemoradiotherapy has now been widely accepted as a definitive treatment for the patient with nonmetastatic carcinoma anal canal.

In the present study, median age at the time of diagnosis was 50 years which is a decade earlier as compare to Western data. Most of the patients presented with pain during defecation and bleeding P/R. Unlike western data, most patients in our study presented with locally advanced disease.

”The global standard of care for” squamous cell carcinoma of the anal canal is radiation therapy with concurrent 5-fluorouracil/capecitabine and mitomycin-C.[9] A wide variety of treatment schedules, radiation techniques, and doses have been used in the past, reflecting variability in individual patient factors and tumor biology. Results from a trial by the European Organisation for the Research and Treatment of Cancer” showed a significant improvement in both locoregional control and colostomy-free survival with definitive chemoradiation with no increase in late complications.[10] The “UKCCCR trial” demonstrated that the addition of 5-fluorouracil and mitomycin to radical radiation therapy substantially reduced local failure rate and colostomy rates and can be considered as standard of care for anal canal carcinoma.[11] Dose escalation has been considered to improve the local failure rates. Study conducted in “M. D Anderson Cancer Centre showed that local control rate of 31%, 71%, and 80% for doses of 45–49 Gy, 50–55 Gy, and 55–60 Gy, respectively.[12] In the present study, the median dose of radiation was 54 Gy (range 45–59.4 Gy) in 30 fractions over 6 weeks.

All patients in the present study completed their treatment in accord with the protocol with some dose reductions due to apparent toxicities. The complete response and survival rates in the present study are inferior to the results in documented literature, likely due to advanced presentation of disease in most patients. At 6-month follow–up, 27 (53%) patients in our study had a complete response as compared to 80%–95% in the previously documented studies.[13],[14]

The estimated 3-year DFS and OS in the present study were 73.9% and 77%, respectively. Total 18 patients had colostomy and estimated 3-year CFS in the present study was 59%. A retrospective analysis of definitive chemoradiation in anal cancers by Lim et al. demonstrated 5-year DFS and OS of 63.4% and 83.6%, respectively.[14] In US Gastrointestinal Intergroup trial RTOG 98–11, 5-year DFS and OS were 60% and 75%, respectively, in patients treated with mitomycin-based chemoradiation.[15] Kim et al. in their analysis of 38 patients of carcinoma anal canal treated with definitive chemoradiotherapy showed a 3-year CFS and 3-year OS of 79.4% and 84.5%.[16]

Most common grade >3 acute toxicities were skin reaction in 18%, followed by hematological in 16% of patients. All the toxicities were managed symptomatically with treatment breaks and chemotherapy dose reductions. In study by Thind et al., 19% of patients experienced Grade 2–4 acute toxicities with protocol specified dose reductions in 8% of patients.[17] In a European study in patients treated with chemoradiation, >3 grade acute toxicities in the form of diarrhea and skin reactions were seen in 20% and 57% of patients, respectively.[10] In an analysis by Kim et al., the most frequent “grade 3 or 4 toxicity was radiation dermatitis seen in 26% followed by hematological in 23.6% patients. Other Grade 3 or 4 toxicities included diarrhea, anorexia, anal pain and fatigue, each in one patient.[16]

Our study was plagued by some limitations including retrospective design and sample size. As this study analyzed population of hilly terrain, many of our patients were lost to follow-up due to various logistical issues. Second, quality of life is a major variable in management of any malignancy; however, our study could not take into consideration the quality of life of patient after completion of chemoradiation.


 > Conclusion Top


Based on above findings and review of literature, we believe that definitive chemoradiotherapy achieves good local control, OS, and CFS with acceptable toxicity and can be recommended as standard treatment in patients with carcinoma anal canal.

Acknowledgment

Authors are highly thankful to SRH University for permitting this research study and Uttarakhand State Council for Science and Technology assistance in data management and compiling.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Heer E, Hackl M, Ferlitsch M, Waldhoer T, Yang L. Trends in incidence of anal cancer in Austria, 1983–2016. Wiener Klinische Wochenschrift 20204:1-6.  Back to cited text no. 1
    
2.
Guren MG, Aagnes B, Nygård M, Dahl O, Møller B. Rising incidence and improved survival of anal squamous cell carcinoma in Norway, 1987-2016. Clinical Colorectal Cancer 2019;18:e96-103.  Back to cited text no. 2
    
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Wells JS, Flowers L, Paul S, Nguyen ML, Sharma A, Holstad M, et al. Knowledge of anal cancer, anal cancer screening, and HPV in HIV-positive and high-risk HIV-negative women. J Cancer Educ 2020;35:606-15.  Back to cited text no. 3
    
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Ryan DP, Mayer RJ. Anal carcinoma: Histology, staging, epidemiology, treatment. Curr Opin Oncol 2000;12:345-52.  Back to cited text no. 4
    
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Deniaud-Alexandre E, Touboul E, Tiret E, Sezeur A, Hannoun L, Houry S, et al. [Epidermoid carcinomas of anal canal treated with radiation therapy and concomitant chemotherapy (5-fluorouracil and cisplatin)]. Cancer Radiother 2006;10:572-82.  Back to cited text no. 5
    
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Zampino MG, Magni E, Leonardi MC, Santoro L, Petazzi E, Fodor C, et al. Concurrent cisplatin, continuous infusion fluorouracil and radiotherapy followed by tailored consolidation treatment in non metastatic anal squamous cell carcinoma. BMC Cancer 2011;11:55.  Back to cited text no. 6
    
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Ghosn M, Kourie HR, Abdayem P, Antoun J, Nasr D. Anal cancer treatment: Current status and future perspectives. World J Gastroenterol 2015;21:2294-302.  Back to cited text no. 7
    
8.
Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: A preliminary report. Dis Colon Rectum 1974;17:354-6.  Back to cited text no. 8
    
9.
British Columbia Cancer Agency Protocol Summary for Curative Combined Modality Therapy for Carcinoma of the Anal Canal Using Mitomycin, Capecitabine and Radiation Therapy (GICART). In Edited by 2013. Available From: http://www.bccancer.bc.ca/NR/rdonlyres/C0A8933B-3AAD-4EBAA95C- 4552A0A060C9/63672/GICART_Protocol_1May2013.pdf. [Last accessed on 2013 May 30].  Back to cited text no. 9
    
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Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase III randomized trial of the european organization for research and treatment of cancer radiotherapy and gastrointestinal cooperative groups. J Clin Oncol 1997;15:2040-9.  Back to cited text no. 10
    
11.
UKCCCR Anal Canal Cancer Trial Working Party. Epidermoid anal cancer results from the UKCCCR randomized trial of radiotherapy alone versus radiotherapy, 5flurouracil and mitomycin. Lancet 1996; 348:1049-54.  Back to cited text no. 11
    
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Hughes LL, Rich TA, Delclos L, Ajani JA, Martin RG. Radiotherapy for anal cancer: Experience from 1979-1987. Int J Radiat Oncol Biol Phys 1989;17:1153-60.  Back to cited text no. 12
    
13.
James RD, Glynne-Jones R, Meadows HM, Cunningham D, Myint AS, Saunders MP, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial. Lancet Oncol 2013;14:516-24.  Back to cited text no. 13
    
14.
Lim DR, Hur H, Min BS, Baik SH, Lee KY, Kim NK. Oncologic outcomes of squamous cell carcinoma of the anal canal after chemoradiation therapy. Korean Journal of Clinical Oncology 2016;12:41-7.  Back to cited text no. 14
    
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Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB 3rd, Thomas CR Jr, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: A randomized controlled trial. JAMA 2008;299:1914-21.  Back to cited text no. 15
    
16.
Kim KH, Chang JS, Keum KC, Ahn JB, Lee CG, Koom WS, et al. Chemoradiotherapy in squamous cell carcinoma of the anal canal: A single institution experience. Radiat Oncol J 2013;31:25-33.  Back to cited text no. 16
    
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Thind G, Johal B, Follwell M, Kennecke HF. Chemoradiation with capecitabine and mitomycin-C for stage I-III anal squamous cell carcinoma. Radiat Oncol 2014;9:124.  Back to cited text no. 17
    


    Figures

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