Clinicopathological Characteristics and Outcomes of Anal Squamous Cell Carcinoma Patients With and Without HIV Infection in Sub-Saharan Africa

Abstract

PURPOSE

In the past 20 years, the burden of anal cancer (AC) increased by 60% in the United States and over three-fold in Africa. Rates of AC have increased by 20× in people living with HIV and the highest (50×) in men with HIV who have sex with men. However, in sub-Saharan Africa (SSA) where HIV is endemic, data on clinicopathological characteristics and outcomes of patients with AC are lacking. To address this, we have investigated AC disease presentation, treatment outcomes, and its predictors in a cohort of patients who were either HIV-infected or HIV-uninfected in SSA.

METHODS

We conducted a retrospective cohort study of patients with anal squamous cell carcinoma (SCC) treated at Ocean Road Cancer Institute in Dar es Salaam, Tanzania from January 2014 to December 2019. Associations between the study outcomes and their predictors were analyzed using univariate and multivariate analysis models.

RESULTS

A total of 59 patients with anal SCC were retrieved and had at least 2-year follow-up. The mean age was 53.9 (standard deviation ±10.5) years. While none of the patients presented with stage I disease, 64.4% had locally advanced disease. HIV infection was the major comorbidity (64.4%). The rate of complete remission at the end of treatment was at 49% while the 2-year overall survival (OS) and local recurrence-free survival were 86.4% and 91.3%, respectively. Despite high HIV coinfection in the cohort, AC treatment outcomes were not significantly associated with HIV status. Disease stage (P = .012) and grade (P = .030) were significantly associated with 2-year OS.

CONCLUSION

Patients with anal SCC in Tanzania present mainly with locally advanced disease associated with high HIV prevalence. In this cohort, the SCC grade was independently associated with treatment outcomes unlike other factors such as HIV coinfection.

INTRODUCTION

In the past 20 years, the burden of anal cancer (AC) increased by 60% in the United States and over three-fold in Africa.^1-3 Rates of AC have increased by 20× in people living with HIV and the highest (50×) in men who are HIV-infected and have sex with men.¹ The estimated number of new AC cases in the United States for the year 2021 was 9,090 accounting for 0.5% of all cancer new cases, and the fatality rate was approximated to be 1,430 which accounted for 0.2% of all cancer deaths.² Outcome data for AC in Africa are limited. Globocan 2020 reported 669 new AC cases in Tanzania with an incidence of 1.7% and 5-year prevalence of 2.12 per 100,000 persons.⁴ The fatality rate was approximated at 481 cases, accounting for 1.8% of cancer deaths.⁴ In Tanzania, where the HIV prevalence in the general population is approximately 5%,⁵ the prevalence of cancer among patients who are HIV-infected is estimated at 9% with an increasing trend over time.⁶ The incidence is high for non–AIDS-defining cancer (72%) in comparison with AIDS-defining cancer (28%).⁶ However, data on the burden of HIV among patients with AC in Tanzania are lacking.

CONTEXT

• Key Objective

• In Tanzania, HIV is endemic and anal cancer (AC) incidence is rising, so the main objective was to determine clinicopathological presentation and predictors of treatment outcomes in patients with anal squamous cell carcinoma (SCC) with and without HIV infection.

• Knowledge Generated

• In 59 patients with anal SCC recruited, HIV prevalence was high (64.4%) and the majority presented with locally advanced disease (64.4%). While the overall survival at the end of 2 years was high (86.4%) and associated with disease stage, HIV infection was not significantly associated with treatment outcomes in this cohort of patients with anal SCC.

• Relevance

• While our findings highlight the need for early detection of anal precancerous lesions and cancer to reduce the advanced disease presentation particularly in people living with HIV infection, additional research is needed to fully characterize patients with AC and establish long-term outcomes and associated predictors.

Infection with high-risk human papillomavirus (hrHPV) is a prerequisite for the development of the majority of anogenital malignancies with more than 90% of cervical carcinomas being caused by hrHPV.⁷ High rates of hrHPV infection (>90%) have been reported in biopsies from people living with HIV with anal intraepithelial neoplasia grade 2 or 3 (defined as high grade squamous intraepithelial lesion [HSIL]) and cancer.⁸ HPV16 is the most common hrHPV in HSIL and AC in both patients without HIV and patients with HIV.^9,10 While factors such as female sex, several sexual partners, genital warts, cigarette smoking, and receptive anal intercourse have all been linked to the occurrence of AC, they have also been increasing over the past 30 years.¹¹

Patients with local-regional AC were once frequently scheduled for abdominoperineal amputation, but in many cases, the 5-year mortality was very high (40%-70%). To date, the standard of care for nonmetastatic anal squamous cell carcinoma (SCC) is concurrent chemoradiotherapy (CCRT). The chemotherapy regimen usually is mitomycin combined with either fluorouracil or capecitabine.¹² This treatment modality is associated with an improvement of 1-year survival from 78% to 81%.¹² However, 5-year survival from anal SCC decreases dramatically from 78% in those with the local disease to only 18% in those with distant disease.¹³ For example, 5-year survival in patients with a tumor size of ≤5 cm is predicted to be 85%, while in patients with a tumor size of >5 cm is only 45%,¹⁴ this is because the stage at diagnosis is one of the key factors for the outcome. Histology type, grade, and site of cancer are also significant independent prognostic factors for overall survival (OS).¹⁴

In this study, we investigated anal SCC disease presentation and factors associated with treatment outcomes including OS and local recurrence-free survival (LRFS) among patients with anal SCC with and without HIV.

METHODS

Study Design and Subjects

This retrospective cohort study retrieved all consecutive patients with histologically confirmed anal SCC aged 18 years or older and of both sexes treated at Ocean Road Cancer Institute (ORCI), Dar es Salaam, Tanzania from January 2014 to December 2019. Baseline and follow-up data were extracted from the patient's medical records using data extraction forms, and phone calls were used to supplement information on vital statistics such as death and other missing information. All patients with anal SCC who met the inclusion criteria were followed from the day of completion of treatment to a maximum of 2 years because of data availability. Similarly, patients with complete remission (CR) at the end of treatment were followed for 2 years to determine the LRFS. The end point of follow-up was alive, dead, or loss to follow-up at 2 years. Censoring was done to those who had lost to follow-up. Patients with shorter than 2 years of follow-up were also included in the study, and the time contributed to the study was used to estimate the outcomes. All the study procedures were approved by the ORCI research ethics committee and the Muhimbili University of Health and Allied Sciences (Approval No.: MUHAS-REC-11-2021-899).

Treatment Used

Radiotherapy (RT) techniques used for definitive treatment of anal SCC at ORCI were either 3-dimensional conformal radiotherapy (3D-CRT) or 2-dimensional RT (2D-RT) with anterior posterior and posterior anterior fields with or without chemotherapy. Patients underwent two phases of treatment; first phase was large pelvis fields, whereby 45 Gy in 25 fractions, 5 days a week was delivered, and second phase was boost dose to the primary tumor, whereby 14 Gy in seven fractions, 5 days a week was delivered. 2D-RT was the only available RT technique before 2018 while 3D-CRT was used from end of 2018. Patients who were treated with CCRT were given mitomycin 10 mg/m² intravenous (IV) bolus once daily on D1 and D25 in combination with flourouracil 1,000 mg/m²/d IV continuous infusion once daily on D1-4 and D22-25 or oral capecitabine 825 mg/m² twice daily on days of RT. Cisplatin 75 mg/m² IV bolus once on D1 plus fluorouracil 1,000 mg/m²/d IV continuous infusion once on D1-4 every 4 weeks were given in metastatic setting. Twenty Gy in five fractions or 30 Gy in 10 fractions was also given as palliative therapy for symptomatic relief. The report from computed tomography scan was used to determine the treatment response, and patients with no lesion on radiological investigation after treatment were defined as CR.

Statistical Analysis

Statistical Package for Social Sciences version 23 and GraphPad Prism 8.0.1 were used for analysis. Categorical data were analyzed by proportions while mean, median, standard deviation (SD), and range were used to analyze continuous variables. Sociodemographic, clinicopathological characteristics, and treatment modality were prognostic variables in univariate analysis, and those variables with P < .2 in univariate analysis were used as prognostic variable for multivariate Cox regression. To test for association between the possible risk factors (independent variables) and the OS or LRFS (dependent variables), univariate and multivariate Cox regression models were used. The Kaplan-Meier curve was used to estimate the OS. The 95% CI with a P < .05 was considered statistically significant.

RESULTS

Characteristics of the Study Subjects

A total of 64 subjects with a diagnosis of anal SCC were retrieved between January 2014 and December 2019; however, 59 subjects met the study inclusion criteria. The mean age of individuals with anal SCC was 53.9 (SD±10.5) years at the time of diagnosis, and over two-thirds (49; 83.1%) were female patients. Twenty-three patients (39%) were younger than 50 years (Table 1). Most participants presented with locally advanced (38; 64.4%) disease, and unfortunately, none had stage I disease (Table 1). Histological grade 1 (well differentiated) and 2 (moderately differentiated) contributed approximately 79.2% of all graded tumors, whereas histological grading was not reported in 15.2% (Table 1). Of the 52 (88.1%) participants with known HIV infection status, 38 (64.4%) were HIV-positive and the HIV status of seven (11.9%) participants was not documented (Table 1). There were no significant differences between patients with HIV and patients without HIV in age group, sex, disease stage, and histological grade (Table 2). As per Tanzania national guideline for management of HIV AIDS, patients who are HIV-positive with cancer are considered as stage IV disease and they are initiated on highly active antiretroviral therapy.¹⁵

TABLE 1.

Sociodemographic and Clinicopathological Characteristics of the Study Participants/Cohort (N = 59)

TABLE 2.

Distribution of Sociodemographic and Clinicopathological Characteristics of Anal Squamous Cell Carcinoma by HIV Status at Presentation (N = 59)

Treatment Modalities and Outcomes

Either CCRT or RT alone was used to treat patients with anal SCC at ORCI. Most study participants (53; 89.8%) were treated definitively with CCRT (62.7%) and RT alone (27.1%). While CCRT is the standard of care for treatment of anal SCC, some clinicians decided to prescribe RT alone to 16 patients who could not tolerate chemotherapy. Six participants (10.2%) received palliative therapy only because of metastatic disease and poor performance status at presentation. Palliative therapy was in the form of best supportive care, low-dose chemotherapy, or RT for symptomatic relief. The two radiation delivery techniques used at ORCI for anal SCC treatment were 2D-RT for 52 participants (88.11%) and 3D-CRT for seven participants (11.9%) (Table 3). This is because most of the patients in the cohort were treated before 2018 where 2D-RT was the only RT technique available at ORCI. The use of 3D-CRT started at the end of 2018.

TABLE 3.

Anal Squamous Cell Carcinoma Treatment Modalities Used (N = 59)

To determine the survival of patients with anal SCC treated at ORCI, we used the retrieved 2-year outcome data. The OS was 86.4% at the end of 2 years of the study follow-up (OS for stage II, III, and IV were 100%, 86.6%, and 50.0%, respectively, at the end of the 2 years of follow-up; Fig 1). Disease stage and tumor grade were significantly associated with 2-year OS at a univariate level, and only tumor grade maintained statistical significance in the multivariate analysis model (Table 4).

FIG 1.

Association between 2-year overall survival with disease stage among patients with anal squamous cell carcinoma treated at Ocean Road Cancer Institute.

TABLE 4.

Factors Associated With Survival in Study Participants/Cohorts

In the cohort of 53 participants (89.8%) who were treated definitively, 26 (49%) patients attained CR at the end of treatment. Those who had CR were mainly female patients (20; 76.9%), and 22 (84.6%) were treated with CCRT (Appendix Table A1). Of the 26 patients who attained CR at the end of treatment, 24 (91.3%) had LRFS at the end of 2 years of study follow-up. Logistic regression was performed to determine predictors of LRFS, and none was significantly associated with 2-year LRFS (Table 5).

TABLE 5.

Factors Associated With LRFS in Study Participants/Cohorts

DISCUSSION

This study investigated the clinicopathological characteristics and outcomes of anal SCC patients with and without HIV infection treated at ORCI in Tanzania. Our analysis found that most of the patients had locally advanced disease at the time of presentation, and more than half of the study cohort was HIV-positive. The rate of CR was 49% at the end of treatment while the 2-year OS and LRFS were 86.4% and 91.3%, respectively.

AC is known to be 40-80 times more prevalent in patients with HIV compared with the general population.¹⁶ In this study, the rate of HIV infection among patients with anal SCC was similarly high at 64.4%. Factors related to the etiology of AC in patients with HIV include human papillomavirus (HPV) status especially HPV-16, sexual behaviors, and a history of smoking.¹⁶ Whether similar factors contributed to anal SCC in this population could not be assessed because of a lack of proper documentation. However, HIV infection and particularly HIV viral load and CD4 count have been reported to affect the OS of patients with AC.^16-18 Particularly, Camandaroba et al¹⁹ reported longer time to CR and worse disease-free survival among patients with anal SCC who were HIV-positive compared with patients with anal SCC who were HIV-negative in Latin America. However, in this study, the OS and LRFS were not significantly different between HIV-infected and HIV-uninfected patients with AC. It is possible that a small sample size limited our findings, or good HIV control has resulted in improvement of OS and LRFS to that of the patients with AC who are HIV-negative. This is also supported by a multicenter study conducted to look at outcomes of patients with metastatic AC according to HIV status where it was found that patients with metastatic AC who are HIV-positive on ART had similar outcomes to those without HIV.²⁰

Insufficient health education on cancer as well as delay in health-seeking health services have been mentioned as factors for late AC diagnosis, especially in low-income countries.²¹ In this study, the majority of patients with anal SCC (64.4%) presented with locally advanced disease while none had stage I disease. Currently, there are no active AC health education and screening programs in the country to facilitate early detection and referrals. As a result, advanced disease stage is common. Despite high 5-year survival from early stage anal SCC in the western countries, this decreases dramatically from 78% in local disease to only 18% in those with metastatic disease.¹³ This has been reflected in this study where the OS was the lowest for stage IV disease compared with stages II and III at 2 years of follow-up. Overall, the OS at 2 years in this study was unexpectedly high. This could be due to a short follow-up time as similar OS rates have been reported by the American Cancer Society, albeit at much longer follow-up periods of 5-10 years.²² Long-term remission and survival for this cohort are still unclear. Therefore, longitudinal studies are needed to investigate the 5-year and 10-year survival and recurrence rates among patients with anal SCC in these settings.

Definitive CCRT has been established as the standard of care that improves outcomes as well as the quality of life for patients with anal SCC.²³ In this study, the treatment decisions were according to the National Comprehensive Cancer Network evidence blocks for AC,²⁴ where CCRT was used. RT alone was given to those who could not tolerate chemotherapy, and adjustments to the dose were made accordingly to compensate for toxicities. Although the treatment intent is curative in RT alone, outcomes may not be the same in comparison with CCRT. A study by Northover et al²⁵ reports a trend of increasing 3-year OS by 7% for CCRT when compared with RT alone for curative intent. Similarly, our study reports a trend of rising 2-year survival by 6.5% in curative CCRT compared with curative RT alone. Furthermore, many studies report increasing recurrence for patients treated with curative RT alone in comparison with curative CCRT.^26-28 In this study, the rate of recurrence in the RT-alone group was higher than in the CCRT group. Standard pretreatment assessment (especially CD4 count for patients with HIV) and proper follow-up and intervention of toxicity during treatment are essential in CCRT and RT alone^29,30; however, these were not assessed in this study because of a lack of proper documentation.

This study is limited by the fact that data were retrieved retrospectively, and this was affected by poor documentation of clinical information including outcome variables that have limited the analysis. Particularly, long-term survival (5-year survival) could not be analyzed because of a lack of outcome information for most patients beyond 2 years. Similarly, data on treatment-related toxicity and interim clinical and radiological assessment were missing for most patients with no data on dose intensity. Correlation between anal SCC and hrHPV subtypes associated with AC in Tanzania could not be performed because of lack of HPV testing. Nevertheless, this study has highlighted the burden of anal SCC, late presentation, and high HIV prevalence among patients with anal SCC in Tanzania. Importantly, it establishes the baseline for anal SCC presentation and outcome in sub-Saharan Africa where such studies are seriously lacking. In the future, well-designed prospective studies are needed with proper documentation of clinical and laboratory parameters to support studies of anal SCC. Long-term studies to investigate survival (5-year and 10-year survival) of patients with anal SCC are also needed to determine treatment efficacy and practices in these settings.

In conclusion, anal SCC in Tanzania is associated with high HIV prevalence and locally advanced disease. While the 2-year OS and LRFS were high for patients with anal SCC, only tumor grade was independently associated with the OS in this cohort of patients with anal SCC.

APPENDIX

TABLE A1.

Social Demographic and Clinicopathological Profile of Study Cohort With Complete Remission (N = 26)

DATA SHARING STATEMENT

All data concerning this article are available in the article. Raw Excel files can be provided on request.

AUTHOR CONTRIBUTIONS

Conception and design: Emmanuel Mduma, Nazima Dharsee, Kandali Samwel, Salum J. Lidenge

Administrative support: Emmanuel Mduma, Nazima Dharsee

Provision of study materials or patients: Emmanuel Mduma

Collection and assembly of data: Emmanuel Mduma, Kandali Samwel, Salum J. Lidenge

Data analysis and interpretation: Emmanuel Mduma, Nazima Dharsee, Kandali Samwel, Chacha J. Mwita, Salum J. Lidenge

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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No potential conflicts of interest were reported.