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Table 1.  Association of HIV Status With Short-term Outcomes in Patients With Anal Squamous Cell Carcinomaa
Association of HIV Status With Short-term Outcomes in Patients With Anal Squamous Cell Carcinomaa
Table 2.  Association of HIV Status With Long-term Outcomes in Patients With Anal Squamous Cell Carcinomaa
Association of HIV Status With Long-term Outcomes in Patients With Anal Squamous Cell Carcinomaa
1.
Oehler-Jänne  C, Huguet  F, Provencher  S,  et al.  HIV-specific differences in outcome of squamous cell carcinoma of the anal canal: a multicentric cohort study of HIV-positive patients receiving highly active antiretroviral therapy.  J Clin Oncol. 2008;26(15):2550-2557.PubMedGoogle ScholarCrossref
2.
Kim  JH, Sarani  B, Orkin  BA,  et al.  HIV-positive patients with anal carcinoma have poorer treatment tolerance and outcome than HIV-negative patients.  Dis Colon Rectum. 2001;44(10):1496-1502.PubMedGoogle ScholarCrossref
3.
Place  RJ, Gregorcyk  SG, Huber  PJ, Simmang  CL.  Outcome analysis of HIV-positive patients with anal squamous cell carcinoma.  Dis Colon Rectum. 2001;44(4):506-512.PubMedGoogle ScholarCrossref
4.
Fraunholz  I, Rabeneck  D, Gerstein  J,  et al.  Concurrent chemoradiotherapy with 5-fluorouracil and mitomycin C for anal carcinoma: are there differences between HIV-positive and HIV-negative patients in the era of highly active antiretroviral therapy?  Radiother Oncol. 2011;98(1):99-104.PubMedGoogle ScholarCrossref
5.
Seo  Y, Kinsella  MT, Reynolds  HL, Chipman  G, Remick  SC, Kinsella  TJ.  Outcomes of chemoradiotherapy with 5-fluorouracil and mitomycin C for anal cancer in immunocompetent versus immunodeficient patients.  Int J Radiat Oncol Biol Phys. 2009;75(1):143-149.PubMedGoogle ScholarCrossref
6.
Chiao  EY, Giordano  TP, Richardson  P, El-Serag  HB.  Human immunodeficiency virus–associated squamous cell cancer of the anus: epidemiology and outcomes in the highly active antiretroviral therapy era.  J Clin Oncol. 2008;26(3):474-479.PubMedGoogle ScholarCrossref
Research Letter
January 2018

Association of HIV Status With Outcomes of Anal Squamous Cell Carcinoma in the Era of Highly Active Antiretroviral Therapy

Author Affiliations
  • 1Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla
  • 2Department of Gastroenterology, University of California, San Diego, La Jolla
  • 3Clinical and Translational Research Institute, University of California, San Diego, La Jolla
JAMA Oncol. 2018;4(1):120-122. doi:10.1001/jamaoncol.2017.2844

The treatment of anal cancer in patients who are seropositive for HIV (HIV-positive) has been controversial for more than 3 decades. Current treatment guidelines recommend that healthy HIV-positive patients receive standard fluorouracil and mitomycin C concurrent chemoradiotherapy, but some investigators question whether these patients experience more severe toxic effects or worse long-term outcomes that might necessitate a modified treatment approach. This study investigates the influence of HIV status on patient outcomes in a national cohort of US veterans.

Methods

This study was approved by the institutional review board of the Veterans Administration (VA) San Diego, and the need for informed consent was waived. The data were not deidentified because they were accessed from within the secure VA Informatics and Computing Infrastructure, which includes patient-level data collected for the use of VA researchers. From a nationwide VA database, we identified patients with clinical stage I through III anal squamous cell carcinoma diagnosed between 2000 and 2015 who were treated with definitive chemoradiotherapy. Outcomes included completion of chemotherapy, radiotherapy treatment breaks, acute toxic effects, cause-specific (tumor recurrence/progression or treatment toxic effects) ostomy rates, and cause-specific mortality. We used multivariable logistic regression models to analyze completion of chemotherapy, radiotherapy treatment breaks, and acute toxic effects, each on a complete-case basis. All-cause mortality was analyzed using the Cox proportional hazards regression model; ostomy rates and cause-specific mortality were analyzed with competing risk regression models. Covariates in each model included HIV status, pretreatment positron-emission tomography, tumor stage, node stage, comorbidity, age, race, year of diagnosis, intensity-modulated radiotherapy, mitomycin C chemotherapy, and history of cancer. A 2-sided P < .05 defined statistical significance.

Results

The sample of 833 included 150 (18.0%) HIV-positive and 683 (82.0%) HIV-negative patients. Patients with HIV were more likely to be male (149 of 150 patients [99.3%] vs 617 of 683 [90.3%]; P < .001), younger (mean [SD] age, 55 [8.6] vs 63 [9.6] years; P < .001), and black (47 of 150 patients [31.3%] vs 63 of 683 [9.2%]; P < .001). There were no differences in tumor/node stage, comorbidity, chemotherapy regimen, or radiation dose. Among HIV-positive patients, the median pretreatment CD4 lymphocyte count was 370/µL (interquartile range, 205-543/µL) (to convert to cells ×109/L, multiply by 0.001), and 91% of patients had received highly active antiretroviral therapy (HAART) in the 6 months before cancer treatment.

Patients with HIV were as likely as HIV-negative patients to miss a second cycle of any chemotherapy (odds ratio [OR], 1.38; 95% CI, 0.77-2.47; P = .27), but were more likely to miss their second cycle of mitomycin C (OR, 2.03; 95% CI, 1.20-3.44; P = .008; Table 1). Fifty-eight HIV-positive patients (46%) experienced radiotherapy treatment breaks of 5 days or more, compared with 176 (33%) of HIV-negative patients (OR, 1.66; 95% CI, 1.07-2.56; P = .02), but there was no difference in breaks of 10 days or more. Patients with HIV were more likely to experience grade 3 or 4 hematologic toxic effects (OR, 2.18; 95% CI, 1.45-3.28; P < .001). Patients with HIV were more frequently hospitalized within 90 days of treatment for acute toxic effects (OR, 1.75; 95% CI, 1.16-2.66; P = .008), in particular for hematologic (OR, 2.20; 95% CI, 1.33-3.64; P = .002) but not gastrointestinal (OR, 1.35; 95% CI, 0.75-2.44; P = .32; Table 1) toxic effects. The long-term ostomy rate did not differ between HIV-positive and HIV-negative patients. We found increased noncancer mortality for the HIV-positive cohort, although there were no differences between cohorts in cancer-specific or all-cause mortality (Table 2).

Discussion

Studies evaluating the association of HIV status with cancer outcomes have produced mixed results, with some showing increased toxic effects1-3 or inferior long-term outcomes1-3 and others showing no difference.4-6 Earlier studies have been limited by smaller sample sizes, single-institution settings, or cohorts with uncontrolled HIV drawn before the availability of HAART. It is not clear that the higher rates of acute toxic effects observed in those studies still apply to a post-HAART cohort with better-controlled HIV disease.

We demonstrate that patients with HIV have a higher risk than HIV-negative patients for acute treatment-related toxic effects, especially hematologic toxic effects. However, this finding does not translate to inferior long-term outcomes, and HIV-positive patients showed survival and ostomy placement rates equivalent to those of their HIV-negative counterparts. These data point to the need to optimize treatment in this population to decrease or better manage acute toxic effects. Our results also paint an optimistic picture of the long-term prognosis for HIV-positive patients, reflecting the improvements in HIV disease control and supportive care for this vulnerable population.

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Article Information

Corresponding Author: James D. Murphy, MD, Department of Radiation Medicine and Applied Sciences, University of California, San Diego, 9452 Medical Center Dr, Altman Clinical and Translational Research Institute Building, La Jolla, CA 92037 (j2murphy@ucsd.edu).

Accepted for Publication: July 6, 2017.

Published Online: September 21, 2017. doi:10.1001/jamaoncol.2017.2844

Author Contributions: Drs Bryant and Murphy had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Bryant, Simpson, Murphy.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Bryant, Huynh-Le, Murphy.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Bryant, Huynh-Le, Simpson, Murphy.

Obtained funding: Bryant.

Administrative, technical, or material support: Murphy.

Study supervision: Simpson, Sharabi, Murphy.

Conflict of Interest Disclosures: None reported.

Funding/Support: The project described was partially supported by grant TL1TR001443 from the National Institutes of Health (NIH).

Role of the Funder/Sponsor: The NIH had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

References
1.
Oehler-Jänne  C, Huguet  F, Provencher  S,  et al.  HIV-specific differences in outcome of squamous cell carcinoma of the anal canal: a multicentric cohort study of HIV-positive patients receiving highly active antiretroviral therapy.  J Clin Oncol. 2008;26(15):2550-2557.PubMedGoogle ScholarCrossref
2.
Kim  JH, Sarani  B, Orkin  BA,  et al.  HIV-positive patients with anal carcinoma have poorer treatment tolerance and outcome than HIV-negative patients.  Dis Colon Rectum. 2001;44(10):1496-1502.PubMedGoogle ScholarCrossref
3.
Place  RJ, Gregorcyk  SG, Huber  PJ, Simmang  CL.  Outcome analysis of HIV-positive patients with anal squamous cell carcinoma.  Dis Colon Rectum. 2001;44(4):506-512.PubMedGoogle ScholarCrossref
4.
Fraunholz  I, Rabeneck  D, Gerstein  J,  et al.  Concurrent chemoradiotherapy with 5-fluorouracil and mitomycin C for anal carcinoma: are there differences between HIV-positive and HIV-negative patients in the era of highly active antiretroviral therapy?  Radiother Oncol. 2011;98(1):99-104.PubMedGoogle ScholarCrossref
5.
Seo  Y, Kinsella  MT, Reynolds  HL, Chipman  G, Remick  SC, Kinsella  TJ.  Outcomes of chemoradiotherapy with 5-fluorouracil and mitomycin C for anal cancer in immunocompetent versus immunodeficient patients.  Int J Radiat Oncol Biol Phys. 2009;75(1):143-149.PubMedGoogle ScholarCrossref
6.
Chiao  EY, Giordano  TP, Richardson  P, El-Serag  HB.  Human immunodeficiency virus–associated squamous cell cancer of the anus: epidemiology and outcomes in the highly active antiretroviral therapy era.  J Clin Oncol. 2008;26(3):474-479.PubMedGoogle ScholarCrossref
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