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Journal of Clinical Oncology, Vol 26, No 3 (January 20), 2008: pp. 474-479 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.2810 Human Immunodeficiency Virus–Associated Squamous Cell Cancer of the Anus: Epidemiology and Outcomes in the Highly Active Antiretroviral Therapy Era
From the Department of Medicine, Baylor College of Medicine; and the Houston Center for Quality of Care and Utilization Studies, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX Corresponding author: Elizabeth Y. Chiao, MD, MPH, Houston Center for Quality of Care and Utilization Studies, Michael E. DeBakey Veterans Affairs Medical Center (152), 2002 Holcombe Blvd, Houston, TX 77030; e-mail: echiao{at}bcm.edu
Purpose To evaluate and determine predictors of squamous cell carcinoma of the anus (SCCA) outcomes in the highly active antiretroviral therapy (HAART) era for HIV-positive and -negative individuals using large national Veterans Affairs (VA) Administration databases. Patients and Methods We used the VA administrative databases to perform a retrospective cohort study in 1,184 veterans diagnosed with SCCA between 1998 and 2004. We calculated HIV infection rates and used logistic regression to identify epidemiologic factors that were associated with HIV infection. Kaplan-Meier curves and Cox proportional hazards models were calculated to compare survival between HIV-positive and HIV-negative veterans. Results In our cohort, 175 patients (15%) were HIV positive. The median age of the HIV-negative and -positive patients was 63 and 49 years, respectively (P < .001). Individuals with HIV were eight times more likely to be male (P = .01) and three times more likely to be African American (P < .001). There were no differences between HIV-positive and HIV-negative individuals in the receipt of treatment. The 2-year observed survival rates were 77% and 75% among HIV-positive and HIV-negative individuals, respectively. In multivariate Cox analysis, significant predictors of survival were age, sex, metastasis at diagnosis, and comorbidity score. HIV infection did not affect survival. Conclusion A noteworthy proportion of individuals with SCCA in the VA system are HIV positive. HIV-associated SCCA seems mainly to be a disease among younger men. Survival of SCCA is equivalent between HIV-positive and HIV-negative individuals in the HAART era. Treatment should not be withheld or deintensified based on HIV status.
The incidence of squamous cell cancer of the anus (SCCA) in the United States has increased by approximately 96% in men and 39% in women over the last two to three decades.1,2 Like squamous cancer of the cervix, SCCA has been associated with high-risk human papilloma virus infection acquired through sexual behavior.3-5 HIV-infected individuals, regardless of HIV risk factor, have a high prevalence of human papilloma virus infection and are at higher risk for anal dysplasia and SCCA.6-8 Prospective cohort studies among HIV-positive individuals have found an increased risk for SCCA of 33 to 222 times that of the general population.9-12 In addition to the increased risk for developing SCCA, HIV-infected individuals may have higher SCCA-related morbidity and mortality. Among HIV-infected individuals with SCCA, the 5-year survival ranges from 47% to 60%,10,13 which is lower than the 73% 5-year disease-free survival rate reported in the general population.14 Before the introduction of highly active antiretroviral therapy (HAART), several observational studies found that HIV infection was associated with poorer outcomes after combined chemoradiotherapy for individuals with SCCA compared with those without HIV infection.15-18 The introduction of HAART has increased the survival of HIV-infected individuals and has dramatically decreased the morbidity and mortality from opportunistic infections and HIV-defining malignancies.19,20 For SCCA, small studies in the HAART era have found that HIV-positive and -negative individuals have similar outcomes.21,22 However, other studies found that HIV-positive individuals tolerated therapy poorly and had worse outcomes than patients without HIV.16,23 Because SCCA is a relatively rare cancer and because HIV information is not routinely collected through cancer registries, the majority of these studies are small case series. Thus, the statistical power to evaluate survival differences between HIV-positive and HIV-negative individuals is often inadequate. We used a large cohort of both HIV-positive and HIV-negative patients with SCCA in the HAART era from the national Veterans Affairs (VA) database system to evaluate the effect of HIV on the epidemiology and outcomes of invasive SCCA.
Data Sources We conducted the study using data from the national VA administrative databases. The study was approved by the institutional review board for Human Subject Research for Baylor College of Medicine and Affiliated Hospitals. The Patient Treatment File (PTF) contains discharge diagnoses since 1981, coded according to the ninth revision of the International Classification of Diseases (ICD-9). The Outpatient Clinic File (OPC) was started in 1997. This database contains a primary ICD-9 diagnosis code and up to nine additional diagnoses for each outpatient encounter. The Beneficiary Identification and Records Locator Subsystem Death File contains all deaths of veterans reported by the VA, the Social Security Administration, the Department of Veterans Affairs cemetery system, and funeral directors. The data are updated twice monthly with the National Death Index. Between 90% and 95% of deaths among veterans are captured by using the Beneficiary Identification and Records Locator Subsystem Death File and the PTF.24
Study Population To ensure accurate diagnoses, we limited the sample to include only those individuals who had the ICD-9 codes of interest documented at least once from an inpatient encounter or documented at least twice from an outpatient visit with a physician or physician equivalent. Infection with HIV was identified by ICD-9 codes V08, 042, 043, 044, and 798.5 from the PTF or OPC files at any time. To validate the ICD-9 codes used for invasive and in situ SCCA, we conducted a chart review and searched records with ICD-9 codes 154.2, 154.3, 230.5, and 230.6 within the Michael E. DeBakey VA Medical Center in Houston for SCCA documentation. We identified 42 patients with invasive and in situ SCCA with these ICD-9 codes documented in either two outpatient visits or one inpatient visit. Of these 42 individuals, 37 had confirmed in situ or invasive SCCA documented in the clinical chart, yielding a positive predictive value of 88% in our algorithm.
Classifying Patient Characteristics SCCA characteristics. We limited the survival analyses to individuals with a diagnosis of invasive SCCA only. To define the presence of metastasis at diagnosis, we identified patients who had ICD-9 codes indicating the presence of metastatic cancer, including 196.0, 196.1, 196.3, 196.8, 196.9, 197.0 to 197.3, 197.7, 198.2 to 198.5, 198.7, 198.81, 198.82, 198.89, and 199.2, within a year of the diagnosis date (to allow time for the patients to be evaluated for metastasis). Disease comorbidity. We calculated an overall disease comorbidity score for each patient. We used an approach adapted for use in administrative databases that was published by Deyo et al.25 In brief, each patient was assigned a summary score at the date of the SCCA diagnosis identifying the presence or absence of 17 predefined comorbid illnesses. These illnesses were weighted by severity and were calculated based on ICD-9 codes identified in the PTF and OPC 1 year before and including the visit when the SCCA diagnosis was made. We excluded the ICD-9 codes for SCCA and HIV from the comorbidity coding. Treatment. Chemotherapy, radiotherapy, and surgery were coded together into a cancer-directed therapy variable. We used the following codes identified in either the PTF or OPC files to identify patients who received surgery: ICD-9 Clinical Modification codes 4904 and 493 to 494, and Current Procedural Terminology (CPT) codes 46610 to 46612, 46615, 46922, 46924, and 46937 to 46938. For chemotherapy treatment, we used ICD-9 code 99.25 and CPT codes 96400 to 96550. For radiotherapy, we used ICD-9 codes V581, V662, and V672; ICD-9 procedure codes 92.2 to 92.3; and CPT codes 77401 to 77417 and 77750 to 77800.
Statistical Analyses Kaplan-Meier estimates of survival among patients with invasive SCCA over the follow-up period were stratified by HIV status, and the log-rank test was used to calculate for differences in survival between the groups. To adjust for the effect of demographic and clinical features on survival, we used Cox proportional hazards regression models to fit the data. The model covariates included sex, ethnicity, age, comorbidity score, and presence of metastasis. Wald statistics were calculated for the Cox model parameter estimates to assess the effect of these covariates. The model parameter estimates and SEs were used to calculate adjusted hazard ratio estimates and the 95% Wald CIs for these ratios. The proportional hazard assumption was fulfilled in all models. Because there were only 47 HIV-negative women and only one HIV-positive woman, we conducted sensitivity analyses deleting all female patients to ensure that these small numbers did not skew our statistical results. Our subanalyses including only male patients yielded similar results to analyses of all patients (data not shown).
Epidemiology of HIV-Associated SCCA Table 1 lists the characteristics of all patients with a new diagnosis of SCCA identified in the VA PTF and OPC between FY 1998 and 2004 by HIV status. We identified 1,184 patients with a new diagnosis of SCCA. Of these, 175 patients (15%) were HIV positive. The median age of HIV-negative individuals with SCCA was 63 years (interquartile range, 54 to 71 years), whereas the median age of HIV-positive patients was 49 years (interquartile range, 43 to 55 years). Fifty-five percent of the HIV-positive individuals with SCCA were younger than 50 years compared with only 12% of HIV-negative individuals (unadjusted odds ratio [OR] = 0.1; 95% CI, 0.1 to 0.2; P < .001; data not shown). Figure 1 shows the age distribution of both cohorts. Among the HIV-positive individuals, patients aged 45 to 49 years represented the largest percentage, whereas among HIV-negative individuals, the largest percentage of patients was greater than age 75.
Among HIV-infected individuals with SCCA, only 1% were female compared with 5% of HIV-negative individuals (OR = 8.5; 95% CI, 1.2 to 62.0; P = .01). In addition, 33% of HIV-infected SCCA patients were classified as African American compared with only 14% of HIV-negative patients (OR = 3.0; 95% CI, 2.1 to 4.3; P < .001). A somewhat higher proportion of HIV-positive SCCA patients (62%) were diagnosed during later years (2001 to 2004) compared with HIV-negative SCCA patients (58%); however, this difference was not statistically significant. Individuals with HIV, compared with those without HIV, were not statistically more likely to have a comorbidity score of more than 1 (12.% v 15%, respectively) or have metastatic disease at diagnosis (8% v 9%, respectively), but they were less likely to have invasive cancer (89% v 95%, respectively; OR = 0.5; P = .004). In addition, there was no statistically significant difference in receipt of cancer-directed therapy between HIV-positive individuals and HIV-negative individuals (62% v 65%, respectively). Table 2 shows the multivariable analyses for characteristics associated with HIV infection among SCCA patients. Although in univariate analysis HIV-infected individuals were less likely to be diagnosed with invasive disease, in multivariable analyses adjusting for age, sex, year of diagnosis, and comorbidity score, this was no longer statistically significant (P = .19). In the full multivariable model, HIV-infected patients were younger, less often female, and more often African American (Table 2).
Overall Survival Among patients with invasive SCCA (n = 1,112), 359 patients died (32.3%). The overall average follow-up time was 32 months (32 v 30 months in the HIV-negative and -positive groups, respectively). Thirty-nine HIV-positive individuals (25%) and 320 HIV-negative individuals (34%) died during follow-up. Figure 2 shows the Kaplan-Meier estimates for overall survival of the HIV-positive and HIV-negative patients with SCCA. For the HIV-infected group, the Kaplan-Meier survival estimates do not decrease to less than 66% with 4 years of follow-up. The overall log-rank  2 test for heterogeneity of survival between the HIV-positive and HIV-negative SCCA patients was not significant (P = .16). The calculated 2-year overall survival rate was 77% in HIV-positive patients and 75% in HIV-negative patients.
Adjusted Hazard Ratios Table 3 lists the unadjusted and adjusted hazard ratios for death. The adjusted and unadjusted hazard ratios were similar. In the fully adjusted model, HIV status was not associated with an increased risk of death. Instead, increasing age was associated with a 2% increase per year in the hazard ratio (P < .001); female sex was associated with a 60% decrease in the hazard ratio (P = .03); the presence of metastasis was associated with a 60% increase in the hazard ratio (P = .002); and having a comorbidity score of more than 1 was associated with a 90% increase in the hazard ratio (P < .001).
To our knowledge, this is the largest study describing HIV-associated SCCA and its outcomes in the HAART era. Our study is unique because we were able to compare outcomes in both HIV-positive and HIV-negative populations within one national health care system. We found that, in the post-HAART era, a noteworthy proportion, approximately 15%, of SCCAs occurred among veterans with HIV infection. We also found that, in the veteran population, HIV-positive veterans with SCCA were significantly younger, more likely to be male, and more likely to be African American compared with HIV-negative veterans with SCCA. This is in keeping with the epidemiology of HIV infection itself. HIV-positive veterans with SCCA were not significantly more likely to have metastatic disease at diagnosis and were equally likely to have received some sort of cancer-related treatment. Finally, we found that HIV infection did not statistically significantly affect survival in individuals infected with SCCA. Our findings may partially help explain recent increased SCCA incidence in young African American men reported from the Surveillance Epidemiology and End Results (SEER) program. The SEER program is a population-based registry that collects cancer incidence information in specific geographic areas and represents approximately 14% of the US population. Using SEER data, Johnson et al1 noted that, between 1994 and 2000, the incidence rates of SCCA increased the most rapidly among African American men. In addition, another recent SEER study showed that, in the HAART era (1996 to 2001), the incidence of SCCA doubled among men aged 35 to 54 years compared with the pre-HAART era (1982 to 1995). Our data support the hypothesis that national trends in SCCA incidence among young minority men may be partially a result of the effect of HIV-related SCCA. We found that survival was similar between HIV-positive and HIV-negative individuals with SCCA. Among individuals diagnosed with invasive SCCA, the 2-year survival rate was 77% for HIV-positive patients compared with 75% for HIV-negative patients. This similarity in survival may be somewhat explained by the fact that HIV-positive SCCA patients were as likely as HIV-negative SCCA patients to receive treatment. In addition, HIV-positive patients did not seem to be diagnosed any earlier or later than the HIV-negative patients based on presence of metastases or in situ cancer at diagnosis, when adjusted for age at diagnosis of SCCA. HAART is likely to be the main cause for our observation that HIV status did not affect survival in the multivariable survival model, which was adjusted for age, race, presence of metastatic disease, and comorbidity score. These results are in contrast to a number of small case series of HIV-infected patients that showed poor survival. For example, Bower et al10 reported on 26 HIV-infected individuals with SCCA who were treated in both the pre-HAART and HAART eras and found that the 5-year survival rate was 47%. Edelman and Johnstone26 evaluated 17 HIV-positive individuals with stage I to III SCCA from 1991 to 2004 (pre-HAART and HAART eras) who were treated with combined-modality therapy of radiotherapy and concurrent chemotherapy and found that the 18-month survival rate was 67%. Cleator et al13 reviewed outcomes for 12 patients treated between 1989 and 1999. They found that the 5-year actuarial survival rate was 60% but did not find a statistically significant survival improvement with HAART. From our study, it seems that, in the HAART era, the survival of individuals with SCCA has improved and is similar to the survival of HIV-negative individuals with SCCA. These findings support those of three recent small studies in the HAART era that report slightly improved survival. In the first study, Stadler et al27 found that the 2-year survival rate among 14 patients with HIV-related anal cancer was 17% in the pre-HAART era and 67% in the HAART era (P = .052). Blazy et al28 reported a 100% 2-year survival rate in nine HIV-positive patients on HAART with stage I to III SCCA. Finally, Oehler-Janne et al22 compared the survival of 10 HIV-positive patients with SCCA who were all taking HAART with the survival of 81 HIV-negative stage- and age-matched patients (all patients had stage I to III disease). They found that the 5-year overall survival rate was 70% in the HIV-positive patients and 69% in the HIV-negative patients. Thus, our HAART era study corroborates the findings of these small case series. There were some limitations to the use of VA administrative data. First, because we did not have access to actual medical records, we could not ascertain the stage of disease and details of the use of specific treatment modalities. However, using the ICD-9 codes for presence of metastasis and CPT codes for radiation treatment, chemotherapy, and surgery procedures, we were able to approximate the frequency of any cancer-directed therapy in our cohort. Second, we did not have access to laboratory or pharmacy data and, therefore, were unable to evaluate the effect of CD4 counts and HAART utilization on survival and outcome. In addition, because we relied on ICD-9 codes and not actual HIV tests, we do not know what percentage of our cohort was never tested for HIV. Therefore, we may have underestimated the percentage of HIV-associated SCCA in our cohort. Third, we relied on ICD-9 codes to determine the diagnoses of SCCA and HIV, which may have limited accuracy. However, to decrease the risk for misclassification of diagnoses, we required that the diagnoses be documented in two separate physician or physician-equivalent visits or one inpatient hospital visit. Our group has also previously shown that HIV ICD-9 codes in the VA administrative databases are 98% predictive of a positive HIV test on record review. In addition, we conducted a chart validation study showing that the ICD-9 coding for SCCA has a positive predictive value of 88%. Finally, we were unable to determine SCCA-related mortality. However, we were able to determine all-cause mortality and adjust for other variables while approximating the severity of SCCA disease by including the presence of metastatic disease and addressing the burden of other comorbidities by including a comorbidity score. In summary, approximately 15% of all veterans diagnosed with SCCA were HIV positive. We also found that HIV-infected individuals with SCCA were significantly younger than HIV-negative individuals and were significantly more likely to be male and African American. HIV-positive individuals were not less likely to receive treatment compared with HIV-negative individuals and also had similar 2-year survival. Thus, in the HAART era and in the presence of similar treatment, HIV-infected patients with SCCA have comparable survival to HIV-negative patients with SCCA. Given these data, anyone diagnosed with SCCA should be considered for HIV testing, especially if they are male and younger than 70 years. In addition, standard treatment for invasive SCCA should be attempted for HIV-positive individuals. Future large-scale studies evaluating the benefit of early SCCA or anal dysplasia detection programs as well as specific treatment strategies for HIV-related SCCA are needed.
The author(s) indicated no potential conflicts of interest.
Conception and design: Elizabeth Y. Chiao, Hashem B. El-Serag Financial support: Hashem B. El-Serag Provision of study materials or patients: Elizabeth Y. Chiao, Hashem B. El-Serag Collection and assembly of data: Elizabeth Y. Chiao, Peter Richardson Data analysis and interpretation: Elizabeth Y. Chiao, Thomas P. Giordano, Peter Richardson, Hashem B. El-Serag Manuscript writing: Elizabeth Y. Chiao, Peter Richardson, Hashem B. El-Serag Final approval of manuscript: Elizabeth Y. Chiao, Thomas P. Giordano, Peter Richardson, Hashem B. El-Serag
Supported by Grant No. K23CA124318 from the National Cancer Institute, National Institutes of Health (E.Y.C.) and Grant No. K23MH67505 from the National Institute of Mental Health, National Institutes of Health (T.P.G.). Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Ann Intern Med 143:265-273, 2005 21. Holland JM, Swift PS: Tolerance of patients with human immunodeficiency virus and anal carcinoma to treatment with combined chemotherapy and radiation therapy. Radiology 193:251-254, 1994 22. Oehler-Janne C, Seifert B, Lutolf UM, et al: Local tumor control and toxicity in HIV-associated anal carcinoma treated with radiotherapy in the era of antiretroviral therapy. Radiat Oncol 1:29, 2006[CrossRef][Medline] 23. Place RJ, Gregorcyk SG, Huber PJ, et al: Outcome analysis of HIV-positive patients with anal squamous cell carcinoma. Dis Colon Rectum 44:506-512, 2001[CrossRef][Medline] 24. Page WF, Mahan CM, Kang HK: Vital status ascertainment through the files of the Department of Veterans Affairs and the Social Security Administration. Ann Epidemiol 6:102-109, 1996[CrossRef][Medline] 25. Deyo RA, Cherkin DC, Ciol MA: Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
70 years) for the analyses comparing HIV-positive and HIV-negative individuals. To demonstrate the distribution of the age groups graphically, we evaluated age using categories of 5-year intervals (< 35, 35 to 39, 40 to 44, 45 to 49, 50 to 54, 55 to 69, 70 to 75, and > 75 years). For the Cox regression analysis, we used age as a linear variable. We categorized race/ethnicity as African American, white, other (including Indian and Asian combined), or unknown. Year of diagnosis was identified as the year the first ICD-9 diagnosis of SCCA appeared in the VA outpatient or inpatient files. 
