Should Planned Surgery be Considered for Large, Localized Anal Cancers?

Issue: May 2017

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Yes.

Sometimes a paradigm changes in medicine without a full understanding of the consequences of that paradigm shift.

We can all think of examples in our individual specialties where we wish we could go back and answer a question differently before the shift occurred. In gastrointestinal oncology, the abandonment of primary surgery for anal cancer is an example of one of those paradigm shifts we wish did not go as far as it did.

Prior to chemoradiation, surgery was the primary treatment modality for anal cancer. Local excision was used for small tumors, and abdominoperineal resection (APR) was used for large or node-positive tumors.

When Norman D. Nigro, MD, and his team at Wayne State University began treating patients with squamous cell cancer of the anal canal with combined-modality therapy and found that the first three patients achieved complete responses to therapy, the need for surgery came into question. Subsequently, his series and others demonstrated that combined-modality therapy could cure most patients with anal cancer and avoid an APR — as well as the dreaded permanent colostomy.

The paradigm shifted, and for the past 40 years an APR is employed for patients with persistent or recurrent disease. There is a feeling among clinicians that this is perfectly reasonable because you can “salvage” a patient who relapses with an APR.

Although this paradigm shift is a good thing for patients with T1/2 and node-negative tumors — who have a 3-year PFS that exceeds 80% — the same cannot be said for patients with T3/4 or node-positive tumors, who experience a recurrence rate between 30% and 40%.

Further, we make our judgement as to whether someone has had a complete response to therapy based on inadequate information. PET scans, CT scans, MRIs and anoscopy miss microscopic disease in 30% to 40% of patients with T3/4 or node-positive disease. We rely on close follow-up to pick up clinical recurrences. Although most recurrences are local–regional, this does not guarantee the ability to perform a margin-negative — and thus curative — resection.

Small surgical series have had consistent numbers over the past 30 years. Approximately 60% of patients will be candidates for a curative resection if they experience a recurrence after combined-modality therapy, and only 50% to 60% of those who undergo a potentially curative operation will be cured.

A recent experience from France was informative in that none of the patients who experienced a positive margin during a salvage APR were cured. Also, a locally recurrent pelvic cancer is one of the most difficult conditions in which to attain adequate palliation. In short, it is awful.

It is unreasonable to expect high-risk patients to enroll on a randomized trial designed to evaluate the role of a planned APR after combined-modality therapy for the management of anal cancer. However, it is reasonable to perform a multicenter phase 2 study that prospectively evaluates high-risk patients who, after hearing the facts, give their informed consent for an APR.

I know I am not alone among my gastrointestinal oncology colleagues when I say that driving home at night after seeing a patient who has had a local recurrence, I wonder if an immediate APR after combined-modality therapy could have avoided the recurrence. And, I wonder if I would opt for an immediate APR if I had a locally advanced anal cancer.

References:
Ajani JA, et al. JAMA. 2008;doi:10.1001/jama.299.16.1914.
James RD, et al. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70086-X.
Lefevre JH, et al. Ann Surg Onc. 2012;doi:10.1245/s10434-012-2485.

David P. Ryan, MD, is associate professor in the department of medicine at Harvard Medical School. He can be reached at dpryan@mgh.harvard.edu. Disclosure: Ryan reports no relevant financial disclosures.

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No.

Surgery should be reserved for persistent or recurrent disease. Unlike many gastrointestinal cancers for which the mainstay of treatment is surgery, the vast majority of anal squamous cell carcinomas can be cured with definitive chemoradiation alone. Prior to the 1970s, anal squamous cell carcinoma was treated with abdominoperineal resection (APR), a morbid operation that requires a permanent colostomy and, consequently, has a significant impact on the patient’s quality of life.

A surgeon at Wayne State University first documented the exquisite chemo- and radiosensitivity of anal squamous cell carcinomas with a small series of patients who received neoadjuvant chemoradiation prior to surgery. All had a pathologic complete response. Today, the national standard of care for nonmetastatic anal squamous cell carcinomas is doublet chemotherapy with radiation.

In the modern era, approximately 90% of patients with anal squamous cell carcinomas achieve a complete response to chemoradiotherapy. However, for a small percentage of patients, surgical intervention is required after chemoradiation.

In ACT II — a randomized phase 3 trial that included 940 patients with T2/T4N0 or any node-positive anal squamous cell carcinomas — 112 patients ultimately needed surgery, either for persistent/recurrent disease (n = 98) or treatment-related morbidity (n = 14). Extent/stage of tumor did seem to correlate with the need for ultimate surgical intervention.

Colostomy-free survival at 3 years was significantly higher for patients with T1/T2 disease than for patients with T3/T4 disease (84% vs. 61%). The results of ACT II taught us that, although surgical salvage was required for a nonnegligible percentage of patients with large and locally invasive tumors, the majority of T3/T4 patients were still cured with chemoradiation alone. Planning surgery for all patients with large, localized anal squamous cell carcinomas would guarantee quality of life–limiting morbidity for a significant number of patients who would have remained cancer free without an operation.

Further, an important lesson of ACT II is that patients continued to respond to chemoradiation up until 26 weeks after treatment. Planned surgical resection in the first 6 months after chemoradiation for all patients with large, localized anal squamous cell carcinomas also would risk excising a dying tumor that may have completely resolved without additional intervention.

Therefore, at our institution, it is not our practice to plan surgery for patients with large, localized anal squamous cell carcinomas. Instead, surgical salvage is reserved for biopsy-proven disease that is progressing on follow-up exams or persistent longer than 26 weeks after the completion of chemoradiation.

For more information:
James RD, et al. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70086-X.
National Comprehensive Cancer Network guidelines. Version 1. 2017. Available at: www.nccn.org/professionals/physician_gls/f_guidelines.asp.
Nigro ND, et al. Dis Colon Rectum. 1974;17:354-356.

Emma B. Holliday, MD, is assistant professor in the department of radiation oncology at The University of Texas MD Anderson Cancer Center. She can be reached at ebholliday@mdanderson.org. Disclosure: Holliday reports no relevant financial disclosures.