INTRODUCTION
Squamous cell carcinoma of the anal canal is a rare malignancy and accounts for 2% of gastrointestinal (GI) cancers.[ 1 ] In the past three decades, the incidence of anal canal malignancy has slowly increased.[ 2–4 ] This may be due to a higher detection rate resulting from more sophisticated diagnostic tests or from the increasing trend in the incidence of all cancers. As per the Surveillance, Epidemiology, and End Result data, the estimated number of new cases of carcinoma of the anal canal was 9,440 and the number of deaths was 1,679 in 2022 in the United States.[ 5 ] As per Global Cancer Observatory (GLOBOCAN) 2020 data, there were 5,452 new cases and 2,776 deaths due to carcinoma of the anal canal in India.[ 6 ] The etiology of anal canal cancer is similar to that of other genital malignancies including infection with the human papillomavirus, human immune deficiency virus, the number of sexual partners, receptive anal intercourse, genital warts, and smoking.[ 7 ] Among the cancers of the anal canal, squamous cell carcinoma (80%) is the most common malignancy.[ 8 ] Other histologies may occur in the anal canal including adenocarcinoma, melanoma, and neuroendocrine carcinoma.[ 9 ]
As per the National Comprehensive Cancer Network guidelines, chemoradiation is the treatment of choice for squamous cell carcinoma of the anal canal, both in India and the rest of the world.[ 10 ] Owing to the rarity of the disease, it is challenging to study the factors affecting the long-term outcomes of anal cancer.[ 11 ] There are limited data from India on squamous cell carcinoma of the anal canal. The primary purpose of this study was, therefore, to assess the survival and prognostic factors influencing the outcome of squamous cell carcinoma of the anal canal in a cohort of patients in India.
MATERIALS AND METHODS
General study details
This retrospective observational study was conducted at the Cancer Institute, Chennai, India, from January 2000 to December 2015. The study was approved by the Institute Ethics Committee of the Cancer Institute (IEC/2022/June 13) on June 22, 2022 [Supplementary Appendix 1 ]. The requirement to obtain informed consent was waived as this study was retrospective. The study was conducted in accordance with the ethical guidelines set by the Declaration of Helsinki and other guidelines such as Good Clinical Practice guidelines and those set by the Indian Council of Medical Research. No funding was received for this study. The study was not registered in a publicly accessible clinical trials registry, as it was a retrospective study.
Supplementary Appendix 1
Participants
We included patients aged more than 18 years with biopsy-proven squamous cell carcinoma of the anal canal who had been treated with chemoradiation or radiation alone. Exclusion criteria included the presence of metastatic disease, prior radiation, non-squamous cell carcinoma histology, incomplete treatment, and untreated patients with very advanced disease.
Aims/objectives
The primary objective of this study was to assess the survival of patients with squamous cell carcinoma of the anal canal, both overall survival (OS) and progression-free survival (PFS). The secondary objective was to evaluate the impact of prognostic factors such as age, sex, stage, treatment, radiation dose, radiation treatment technique (conventional or conformal method), radiation treatment interruption (total radiation treatment interruption of more than 10 days or less than 10 days other than usual breaks [Saturday/Sunday]), and chemotherapy.
Study methodology
Patients were identified from the Cancer Institute’s hospital-based cancer registry. The search criterion used was “anal canal.” Data were collected from the electronic medical records of patients treated for squamous cell carcinoma of the anal canal from January 2000 to December 2015. The diagnosis of anal canal carcinoma was established by biopsy of the anal canal mass, contrast-enhanced computerized tomography of the abdomen and pelvis, and chest X-ray. All the patients underwent routine investigations like complete blood count, renal function test, liver function test, electrocardiography, and echocardiogram. Patients were treated either with radiation alone or chemoradiation , depending on the treating physician’s discretion. Radiation consisted of 180-200 cGy per day to a total dose of 50 to 60 Gy over 6 to 8 weeks. The chemotherapy regimen consisted of bolus 5-fluorouracil (825 mg/m2 /day on days 1-4 and 29-32) and mitomycin C (10 mg/m2 on day 1) administered concurrently with radiation. Response assessment was done 6-8 weeks after the completion of either chemoradiation or radiation with clinical examination and sigmoidoscopy. The response was categorized as either complete response, partial response, stable disease, or progressive disease as per the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1; 2000). Contrast-enhanced computerized tomography/magnetic resonance imaging and biopsy were done in case of suspected residual disease. After treatment, patients were evaluated every month for the first six months, once every two months for two years, once every three months in the third year, and then every six months after that. Salvage surgery was performed if there was a recurrence or residual disease. Patients underwent annual colonoscopy, chest X-ray, and ultrasound of the abdomen and pelvis. If the patient developed metastatic disease at follow-up, palliative therapy and symptomatic supportive treatment were given.
Statistics
This was a retrospective study and hence a formal sample size was not calculated. Statistical analysis was performed using the Statistical Program for the Social Sciences (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). Median follow-up was calculated as a simple median. PFS was calculated from the date of diagnosis to the date of progression or date of death without progression. OS was calculated from the date of diagnosis to the date of death or the date of the last follow-up. Survival was estimated by the Kaplan-Meier method.[ 12 ] A Cox regression model was used to evaluate prognostic factors.[ 13 ] Prognostic factors were divided into categories like age <65 years vs. ≥65 years. A P value ≤ 0.05 was considered significant.
RESULTS
General study-related and patient-related details
Between January 2000 and December 2015, 151 patients reported to the Cancer Institute, Chennai, with carcinoma of the anal canal, of which 86 patients were included in this study [Figure 1 ]. The baseline clinicodemographic features are provided in Table 1 . The median age was 55 years (range, 26-80).
Figure 1: The flow chart of patient enrollment and analysis in the study on patients with squamous cell carcinoma of the anal canal
Outcomes Table 1: Baseline clinicodemographic features
Complete responses were noted in 60 (70%) patients and partial responses in 26 (30%) patients following chemoradiation or radiation alone. At a median follow-up of 61 months (range, 2-190), 34 patients (39.5%) were alive, 38 (44.2%) had died (29 deaths due to cancer, 9 deaths due to other causes), and 4 (4.7%) were lost to follow-up. The 5-year PFS in patients who received chemoradiation was 54.7% as compared to only 28.9% in those who received radiation alone (hazard ratio [HR], 1.85; 95% confidence interval [CI], 1.00-3.41; P = 0.48). There were 11/18 (61%) patients who underwent salvage surgery (abdominoperineal resection) for residual/recurrent cancer. The 5-year OS in patients who were treated with chemoradiation was 60.4% vs. 44.4% in those who received radiation alone (HR, 1.79; 95% CI, 096-3.31, P = 0.059).
Factors affecting outcomes
Factors included in the univariate analysis [Table 2 ] were age, sex, grade, primary tumor size, nodal involvement, radiation treatment method, radiation dose, and the number of days of treatment interruption during radiation. Univariate analysis showed that the following factors were associated with an improved OS: primary tumor size less than 5 cm (HR, 3.02; 95% CI, 1.57-5.81; P = 0.001), early stage (stages I and II) (HR, 2.19; 95% CI, 1.25-3.83; P =0 .004), and fewer radiation treatment interruptions (less than 10 total days cumulatively) (HR, 3.02; 95% CI, 1.70-5.35, P = 0.001). The comparison between the patients who had received concurrent chemoradiation versus those who received radiation alone was not significant; however, only 20 patients received radiation alone (HR, 1.79; 95% CI, 0.96-3.31; P =0.059).
Table 2: Univariate analysis evaluating the factors that affected the overall survival in patients with squamous cell carcinoma of the anal canal
On performing a multivariate analysis [Table 3 ], we found that the factors significantly associated with poor OS were primary tumors of size 5 cm or more (HR, 2.23; 95% CI, 1.12-4.44; P = 0.022) and radiation treatment interruption for 10 or more days (HR, 2.20; 95% CI, 1.21-4.02; P = 0.009). Figures 2 and 3 show the Kaplan-Meier survival curves based on the treatment modalities (chemoradiation /radiation) and radiation treatment interruption, respectively.
Table 3: Multivariate analysis evaluating the factors affecting the overall survival in patients with squamous cell carcinoma of the anal canal
Figure 2: Kaplan-Meier curve for treatment modalities
Figure 3: Kaplan-Meier curve for radiation treatment interruption
DISCUSSION
We found that the 5-year OS of patients treated with chemoradiation was 60.4%; colostomy was successfully avoided in these patients and the anal sphincter was preserved, which probably led to an improved quality of life of the patients, who would have been able to carry out every day routine life.
Surgery was the mainstay of treatment for squamous cell carcinoma of the anal canal in the first half of the last century.[ 14 ] Norman Nigro then showed that chemoradiation could achieve the same local control as surgery with the elimination of surgical morbidity by helping to preserve the anal sphincter.[ 15 ] In 1976, Beahrs and Wilson observed that the 5-year OS of patients with squamous cell carcinoma of the anal canal treated with abdominoperineal resection was 58%.[ 16 ] The first United Kingdom Coordinating Committee on Clinical Research anal cancer randomized trial demonstrated that after 12 years of follow-up, there was an improvement in local disease control, disease-free survival , and colostomy-free survival in the patients treated with chemoradiation . Despite this, the leading cause of treatment failure was locoregional relapse. Adding chemotherapy to radiation led to a 46% reduction in the risk of local failure (P < 0.001) and a 29% reduction in the risk of death from anal cancer (P = 0.02). The 5-year OS was 56% for the whole group.[ 17 , 18 ] The results of the phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative groups revealed that patients treated with chemoradiation had a significant improvement in locoregional control and colostomy-free interval (P = 0.02 and P = 0.002, respectively).[ 19 ] The locoregional control rate improved by 18% at 5 years, while the colostomy-free rate increased by 32% by adding chemotherapy to radiation; no difference in survival was noted between the arms. In our study, the 5-year OS of the patients who underwent treatment with chemoradiation (60.4%) was numerically but not statistically higher compared to that of those who received radiation alone (44.4%) (HR,1.79; 95% CI-0.96-3.31; P = 0.059).
A 2023 French nationwide cohort study reported that at a median follow-up of 35.5 months, disease-free survival , colostomy-free survival , and OS at 3 years were 84.3%, 85.6%, and 91.7%, respectively, in the early-stage group compared to 64.4%, 66.9%, and 78.2%, respectively, in the locally advanced group.[ 20 ] As per previous studies, age ≥ 65 years, tumor size, nodal status (involvement of inguinal node), grade (poorly differentiated grade), and the treatment modality (surgery vs. chemoradiation ) were significant predictors of the OS of squamous cell carcinoma of the anal canal.[ 21–23 ] Similarly, in our present study, we found that larger tumor size, higher stage, and radiation treatment interruption were significantly associated with poorer OS. Bilimoria et al. ,[ 23 ] in a national cancer database study from Chicago, observed that male sex, node-positive disease, and age ≥65 years were predictors for poor survival . However, we found that only male sex and node-positive disease were significant predictors of poor outcomes in our patient cohorts.
A study by Lim et al .[ 24 ] from South Korea that explored various factors associated with recurrence reported that in a univariate analysis, larger tumors (>5 cm; P = 0.006), presence of nodal metastasis (P = 0.001), and older age (>55 years, P = 0.031) were significant, while in the multivariate analysis, only nodal involvement retained significance (P < 0.05). In our study, of the factors reported by Lim et al. , we found that only tumor size (≥5 cm, P < 0.001) significantly influenced outcomes. Discrepancy between the results of our study and those of other groups may be attributed to the retrospective nature of our study, small sample size, and the rarity of the disease.
In a study from India, Engineer et al .[ 25 ] reported that locoregional control of carcinoma of the anal canal was significantly affected by disease stage (I, II vs. III, P = 0.007) and higher radiation dose (>60 vs. <60Gy, P = 0.01; higher radiation dose associated with better locoregional control). The study suggested that to achieve better local control, disease-free survival , and OS, a radiation dose of 56-60 Gy for T1 and T2 tumors and 65 Gy for T3 and T4 tumors, along with concurrent chemotherapy were required. We also observed that locoregional control was worse with higher stages (I, II vs. III, P = 0.004) but was not influenced by the radiation dose (≥60 Gy vs. <60 Gy, P = 0.562).
We found that a cumulative radiation treatment interruption of more than 10 days was a statistically significant factor in predicting a poor OS (P = 0.009; HR, 2.20; 95% CI, 1.21-4.02). Kim et al .[ 26 ] also reported a lower 3-year OS when treatment was interrupted for more than 10 days. The poor results were mainly due to the accelerated repopulation of clonogenic cells surviving the radiation. Withers et al .[ 27 ] reported that an accelerated repopulation phenomenon was observed approximately 4 weeks after conventional radiotherapy at 2 Gy per fraction. Weber et al .[ 28 ] evaluated the impact of the radiation gap duration on local control. A significant decrease in locoregional control due to longer overall treatment time and a prolonged gap was an independent poor prognostic factor in the multivariate analysis for local control. With the use of the latest radiotherapy methods like intensity-modulated radiotherapy (IMRT)/volumetric modulated radiotherapy and the use of capecitabine instead of 5FU, we could avoid unnecessary delays in radiation. Glynne-Jones et al. ,[ 29 ] in a multicenter phase II study, revealed that 5 days of capecitabine and 1 day of intravenous mitomycin C regimen was well tolerated; at a median follow-up of 14 months, there were 77% clinical complete responses and 16% partial responses. Several small retrospective studies have reported on the use of IMRT with chemoradiation with a median follow-up of 16-24 months, 2-year to 3-year locoregional control, colostomy-free survival , and OS ranged from 77% to 95%, 81% to 93%, and 87% to 100%, respectively.[ 30–33 ] IMRT with capecitabine and mitomycin C has become the standard of care for treating squamous cell carcinoma of the anal canal.[ 34 , 35 ]
Our study is one of the first studies from south India that has reported the outcomes and prognostic factors for squamous cell carcinoma of the anal canal and confirms the findings reported in the literature. The limitations of this study were that it was retrospective, non-randomized, had a small sample size, and the management decision was at the treating physician’s discretion.
CONCLUSION
In addition to prognostic factors such as tumor staging and grading, treatment factors like radiation interruptions also play an essential role in predicting the outcome of squamous cell carcinoma of the anal canal on treatment with chemoradiation .
Author contributions
Conception or design of the work: AK; Data collection: AK; Data analysis and interpretation: AK, AJ; Drafting the article: AK, AJ; Critical revision of the article: AAK, AJ, VR, GS; Final approval of the version to be published and accountability for all aspects of the work: all authors.
Data sharing statement
Data collected as part of the study will be shared on request made to the corresponding author by qualified researchers with permission from the head of the Cancer Institute. The study protocol has already been shared as a supplementary document with the manuscript. The data will be accessible on request, starting 9 months after publication for up to 24 months. Extensions to this deadline will be considered on a case-by-case basis. Access to the data can be requested by qualified researchers engaging in independent scientific research. The data will be provided following the review and approval of a research proposal and statistical analysis plan and the execution of a data-sharing agreement.
Institutional review board
Approved.
Financial support and sponsorship
Nil.
Conflicts of interest
Venkatraman Radhakrishnan is a member of the editorial board of Cancer Research, Statistics and Treatment. As such, he may have had access to information and/or participated in decisions that could be perceived as influencing the publication of this manuscript. However, he had recused himself from the peer review, editorial, and decision-making process for this manuscript, to ensure that the content is objective and unbiased.
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