Combined Radiation and Chemotherapy for Carcinoma of the Anal Canal

Carcinoma of the anal canal is an uncommon clinical entity. Nevertheless, this malignancy is important for both the radiation and medical oncologist, for a variety of reasons. First, while uncommon, anal canal carcinoma will account for an estimated 3,400 cases of cancer and 410 cancer deaths in 1997.[1] Second, the evolution of the current treatment approach, from radical surgery to organ-sparing therapy, has served as a model for the development of treatment strategies in other disease sites. Third, further studies of the biology of this disease and its relationship to human papillomavirus (HPV) may lead to radically different treatment strategies in the future.

Radiation Therapy

Over the past two decades, radiation therapy has supplanted radical surgery as the treatment of choice for most patients with anal carcinoma, offering equivalent survival with an improved functional and cosmetic result. The optimal doses of radiation therapy, optimal radiation techniques, and role of combined-modality therapy have been investigated in numerous phase II trials. Although these trials demonstrated encouraging results in terms of local control, disease-free survival, and overall survival, interpretation of their results is problematic, for two reasons. First, heterogeneous treatment approaches were often employed within the same trial. Second, heterogeneous groups of patients were often included in the same trial.

The inclusion of heterogeneous groups of patients is a result of the unique biology of the anal canal. The epithelial lining is complex and contains a cloaca-derived transitional cell component. During embryologic development, approximation of this lining to the squamous epithelium results in a pluripotent tissue capable of developing a spectrum of neoplastic lesions, including squamous cell carcinoma, a basaloid (nonkeratinizing or transitional) squamous variant, and basaloid small cell carcinoma. Furthermore, other confounding conditions may include squamous cell carcinoma of the anal margin, which has a predictably better prognosis, and anal carcinomas arising in the context of AIDS.[2] Therefore, only randomized trials, which eliminate selection bias, will permit definitive conclusions to be made about optimal therapy.

In their authoritative review, Stafford and Martenson appropriately emphasize the role of randomized trials. Their conclusion—that radiation therapy combined with fluorouracil and mitomycin (Mutamycin) improves local control rates and colostomy-free survival—which is based largely on the results of the Intergroup, United Kingdom Coordinating Committee on Cancer Research (UKCCCR), and European Organization for Research and Treatment of Cancer (EORTC) trials, is likely correct. Despite the failure of these trials to demonstrate an improvement in overall survival, the possibility of avoiding radical surgery, with its concomitant functional and cosmetic effects, is worth the additional myelosuppression and mucosal toxicities.

Unanswered Questions

Many questions remain, however. Optimal radiation therapy and optimal chemotherapy still need to be defined, as noted by Stafford and Martenson. Newer chemotherapeutic agents recently approved by the FDA or currently in clinical trials, such as the quinazoline-based folate analogs (ZD1694 [Tomudex] and AG337 [Thymitaq]), taxanes (paclitaxel [Taxol] and docetaxel [Taxotere]), topoisomerase I inhibitors (topotecan, [Hycamtin] and irinotecan [Camptosar]), nucleosides (gemcitabine [Gemzar], doxifluridine, and uracil-ftorafur [UFT]), and novel platinum compounds (iproplatin, tetraplatin), remain to be tested in patients with anal carcinomas. These agents may be either as effective as or more efficacious than older agents but less toxic.

The use of effective tumor markers may also be useful in the management of anal carcinoma. Recently, Petrelli and colleagues described the use of a squamous cell carcinoma antigen for monitoring the efficacy of therapy in patients with anal carcinomas.[3] In that study, the sensitivity of this approach was 76%, the specificity was 86%, and the positive predictive value was 62%. Furthermore, in at least one patient, use of the antigen allowed for the detection of recurrent disease months before it became clinically evident.

Association with HPV

The association of benign perineal lesions, such as condylomata, carcinoma in situ, and frank carcinoma of the anal canal, with HPV has long been known.[4] Recent studies have documented the association of carcinoma with integration of the transforming viruses HPV 16 and 18, both in squamous cell and basaloid variant carcinomas.[5] Furthermore, HPV-positive tumors are more likely to be found in the anal canal than perianally.[6]

The clinical utility of identifying HPV-induced malignant transformation remains to be elucidated. However, in one study, antibody responses to the E2 viral antigen appeared to correlate with disease status.[7]

Summary

The public health implication for tumors of the anal canal are not as formidable as those for tumors of the remainder of the gastrointestinal tract. Nevertheless, this disease is an important model for developing multidisciplinary treatment strategies. Combi- nations of radiation and chemotherapy have improved the functional outcome for thousands of patients with anal cancer. Further progress will depend on technologic advances in delivering radiation, such as brachytherapy or conformal radiation; more effective, less toxic systemic agents; the use of high-quality tumor markers; and novel biological strategies, where appropriate, to exploit the viral associations of this disease.

References:

1. Parker SL, Tong T, Bolden S, et al: Cancer statistics, 1997. CA Cancer J Clin 47:5-27, 1997.

2. Gal AA, Meyer PR, Taylor CR: Papillomavirus antigens in anorectal condyloma and carcinoma in homosexual men. JAMA 257:337-340, 1987.

3. Petrelli NJ, Palmer M, Herrera L, et al: The utility of squamous cell carcinoma antigen for the follow-up of patients with squamous cell carcinoma of the anal canal. Cancer 70:35-39, 1992.

4. Taxy JB, Gupta PK, Gupta JW, et al: Anal cancer, microscopic condyloma, and tissue demonstration of human papillomavirus capsid antigen and viral DNA. Arch Pathol Lab Med 113:1127-1131, 1989.

5. Vincent-Salomon A, de la Rochefordiere A, Salmon R, et al: Frequent association of human papillomavirus 16 and 18 DNA with anal squamous cell and basaloid carcinoma. Mod Pathol 9:614-620, 1996.

6. Williams GR, Lu QL, Love S, et al: Properties of HPV positive and negative anal carcinomas. J Pathol 173:166A, 1994.

7. Heino P, Goldman S, Lagerstedt U, et al: Molecular and serological studies of human papillomavirus among patients with anal epidermoid carcinoma. Int J Cancer 53:377-381, 1993.