Cancer of the anal canal in a patient with HIV

Issue: August 10, 2008

ByLuqman Dad, MD

A 48-year-old man with HIV diagnosed more than 20 years prior who has been treated with protease inhibitor-based highly active antiretroviral therapy regimen presented to our clinic with rectal bleeding and anal mass since three months. His CD4+ T-lymphocyte count was 620 cells/mcL and he had an undetectable HIV-1 viral load.

Luqman Dad, MD
Luqman Dad

Flexible sigmoidoscopy revealed a firm infiltrative process involving the anal canal. Biopsy of the lesion located at about 4 cm from the anal verge revealed invasive squamous cell carcinoma of the anal canal. Staging CT of the chest, abdomen and pelvis was significant for a lesion measuring about 1.4 cm in maximal dimension. There was no abdominal or pelvic adenopathy. At the time, the patient complained of a sharp, throbbing pain in the anal region that was refractory to pain medications. The patient continued to have bright red blood per rectum. He denied any fevers, night sweats or chills. His weight was stable. He had no abdominal pain or cramping. The patient’s history is significant for unprotected anal intercourse and anal warts treated with cryotherapy five years prior. Laboratory data at the time included a hemoglobin of 13, hematocrit of 37, white blood cell count of 3.0, absolute neutrophil count of 1.7, and platelet count was 147. Digital rectal exam revealed a firm 1 cm × 2 cm lesion involving the left side of the anal sphincter. No palpable inguinal lymphadenopathy. He had an excellent performance status and continues to work full-time at a local convenience store.

How will you manage this patient?

A) Treat with sphincter-sparing local excision with either pre- or postoperative 5-FU–based chemotherapy.
B) HIV positivity is a direct contraindication to chemotherapy, hence radiation therapy alone is indicated for this early-stage lesion.
C) Combination of 5-FU and mitomycin-C concurrent with radiation therapy.
D) 5-FU and mitomycin-C chemotherapy alone.
E) Watchful waiting.

Luqman Dad, MD, is currently a Resident Physician in the Department of Radiation Medicine at Roswell Park Cancer Institute. He would like to acknowledge his mentor at Roswell Park, Dr. Gary Yang, for his continued guidance and support.

CASE DISCUSSION

HIV/AIDS is associated with a broad spectrum of neoplasms, including Kaposi sarcoma, lymphomas, human papillomavirus-related cervical cancer, Castleman’s disease, leiomyomas, leiomyosarcomas, hepatitis B-related hepatocellular carcinomas and anogenital carcinomas. Both HIV and HPV coinfected patients are at an increased risk for the development of anal malignancies.

The above case is of a stage I squamous cell carcinoma of the anal canal in a patient with underlying HIV infection. Briefly we will review the literature for the current management of anal cancer in the general population, followed by a discussion of relevant points regarding the management of anal cancer in the patient with HIV.

The management of anal cancer has evolved through the years; combined modality therapy for anal cancer replaced the abdominal pelvic resection more than two decades ago and remains the standard of care as confirmed by data from three large, prospective randomized trials. Results from a series of trials established that concurrent chemoradiation is better than radiation alone. Researchers from a prior U.S. phase-3 randomized trial (Radiation Therapy Oncology Group [RTOG 87-04]) had demonstrated significant improvement in local control and colostomy-free survival with the addition of mitomycin to concurrent fluorouracil plus radiation. In RTOG 87-04, the researchers established the use of concurrent fluorouracil-mitomycin plus radiation as the standard primary therapy of anal canal carcinoma. Cisplatin had been postulated as an alternative chemotherapy to mitomycin-C, with the hope of down-staging tumor prior to concurrent chemoradiotherapy; chemoradiation was thought to be more effective for smaller anal carcinoma than for large ones.

Most recently, the final manuscript of RTOG 9811 was published in the Journal of the American Medical Association in April 2008 comparing 5-FU and mitomycin-C with radiation therapy to induction cisplatin and radiation therapy for anal cancer. In this trial, consisting of the largest cohort of patients prospectively studied with anal cancer to date, the researchers emphasized that the 5-FU/mitomycin-C/radiation therapy arm remains the standard of care for the treatment of anal cancer, not the induction cisplatin arm. The primary endpoint of RTOG 98-11 was disease-free survival not overall survival; the pattern of failure was similar for both arms. From this most recent trial, it is important to note the superiority of colostomy-free survival using mitomycin-C.

Currently, the standard of care for HIV-negative patients with invasive anal carcinoma is concomitant radiation therapy and chemotherapy, 5-FU and mitomycin-C. Furthermore, this treatment approach has been examined and successfully administered in HIV-positive patients, specifically in those with CD4+ T lymphocyte counts greater than 200 cells/mcL. In the literature researchers have reported an incidence of at least grade-3 hematologic toxicity in HIV-positive patients receiving combined modality therapy with 5-FU and mitomycin-C ranging from 22% to 56%. This is compared with the frequency in the HIV-negative population of patients with anal cancer of only 5% to 20%. Although there is a paucity of evidence on the relationship between CD4+ cell count and incidence of acute toxicities, data from one retrospective review demonstrated that a count less than 200 was associated with an increased toxicity because 88% of such patients had a severe adverse event.

Although there are no prospective data set powered to detect the advantage of a particular modality for the treatment of anal cancer in the HIV-positive population, we continue to rely on small retrospective experiences that support the use of combined modality treatment with 5-FU and mitomycin-C with radiation therapy. The advent of newer radiation techniques, such as intensity-modulated radiation therapy for the treatment of anal cancer as studied in the recently closed to accrual RTOG trial 0529 will provide further light on potential methods to reduce the incidence of adverse effects of treating a cancer, that is for the most part a curable disease entity.

For more information:

Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008;299:1914-1921.

Bartelink H, Roelofsen F, Eschwege F, 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;15:2040-2049.

Edelman S, Johnstone PA. Combined modality therapy for HIV-infected patients with squamous cell carcinoma of the anus: outcomes and toxicities. Int J Radiat Oncol Biol Phys. 2006;66:206-211.

Flam M, John M, Pajak TF, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol. 1996;9:2527-2539.

Frisch M, Biggar RJ, Goedert JJ. Human papilloma-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst. 2000;92:1500-1510.

Hoffman R, Welton ML, Klencke B, et al. The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer. Int J Radiat Oncol Biol Phys. 1999;44:127-131.

Klencke BJ, Palfesky JM. Anal cancer: an HIV-associated cancer. Hematol Oncol Clin N Am. 2003;17:859-872.