Can Chemotherapy Be Eliminated for Early-Stage Anal Cancer?
Although chemoradiation has been shown to be superior to radiation in terms of disease-free survival, local relapse, and colostomy-free survival, it is unclear whether these benefits apply to early-stage disease. Indeed, several retrospective series had previously reported excellent outcomes for patients with T1-2, N0, M0 disease with radiation alone.26,31-34
One recent retrospective analysis of 146 patients treated with radiation alone (71 patients) or chemoradiation (75 patients) raises doubts about the effectiveness of radiation alone.35 Locoregional control was improved in the chemoradiation arm (hazard ratio = 2.24), but the difference did not reach statistical significance (P = .064).35 This retrospective study, with heterogeneous treatment schedules and radiation dosing, however, limits the conclusions that may be drawn about radiation alone for earlystage anal cancer, especially among subgroups such as immunocompromised patients.
Unfortunately, neither the UKCCR nor the RTOG/EORTC studies analyzed the rate of primary tumor complete response based on T stage and treatment arm.16,18 The RTOG 87-04 study that randomized patients to mitomycin(Drug information on mitomycin) plus 5-FU with radiation vs. 5-FU plus radiation did include tumor stage–based analysis.17 In the RTOG 87-04 study, the colostomy rates decreased from 29% to 13% in the T3–4 population with the addition of mitomycin to 5-FU and radiation (P = .019). However, the reduction in colostomy rates from 15% in the mitomycin/5-FU plus radiation arm to 7% in the 5-FU plus radiation arm did not reach statistical significance in patients with stage T1–2, N0 disease.17 Although these data suggest a trend for benefit from chemoradiation compared with radiation alone in T1–2 tumors, it is unknown whether patients with stage T1, N0 disease would derive any benefit from chemotherapy in addition to radiation in general. T1, N0 patients do very well with radiation alone or with chemoradiation.13
Since a direct comparison between chemoradiation and radiation alone for T1, N0 anal cancer does not exist, mitomycin plus 5-FU and radiation is still recommended for this population. However, for the extremely elderly population or for patients with significant comorbidities, the elimination of mitomycin and the administration of 5-FU alone or in combination with cisplatin(Drug information on cisplatin) may be a reasonable approach, especially among hematologically compromised patients.
Treatment of HIV-Positive Patients With Anal Cancer
Early reports, which included a small series of patients, suggested a poorer survival and increased toxicity for patients with CD4 counts < 200 cells/mm3 and for patients who are not receiving highly active antiretroviral therapy (HAART).36-39 Full doses of chemoradiation (using 5-FU plus mitomycin or 5-FU plus cisplatin) were feasible, although at the cost of increased grade 3 and higher hematologic and gastrointestinal toxicities, treatment interruption, and the need for subsequent dose modification.37,38,40,41
The use of modern conformal radiation therapy with full doses of 5-FU and mitomycin in a HAART-treated population with a high median CD4 count and a low level of detectable viral titers was better tolerated, suggesting that early described toxicities were at least partly related to radiation techniques and uncontrolled HIV infection.42 More definitive conclusions come from recent single- and multi-institution series comparing the outcome of HIV-positive and HIV-negative anal cancers.43-46
In a series of 87 patients (21 HIV-positive) treated with mitomycin and radiation, Hogg et al reported an increased rate of infectious and gastrointestinal toxicities in the HIV-positive group.43 Both HIV-positive and HIV-negative groups were as likely to achieve a complete response (85% HIV-negative vs 81% HIV-positive). However, disease recurrence at 6 months was considerably higher in the HIV-positive group (29% vs 8%).
A multi-institutional, international, retrospective study compared the outcome of 40 HIV-positive anal cancer patients receiving HAART and chemoradiation to 81 HIV-negative anal cancer patients treated with mitomycin plus 5-FU and radiation.46 Complete response to chemoradiation was high in both HIV-positive (92%) and HIV-negative (96%) groups. HIV-positive patients were more likely to experience grade 3/4 skin and hematologic toxicity. Furthermore, HIV-positive patients were more likely to experience local failure (61% vs 13%) and showed a trend toward dying from anal cancer (5-year cancer-free survival of 68% vs 79%; P = .09).46
In a larger series from the US Department of Veterans Affairs (VA) database, the outcome of 175 patients with HIV-positive anal cancer was compared to that of 1,009 patients who were HIV-negative.45 No difference was reported between groups in terms of 2-year survival rates (77% for HIV-positive vs 75% for HIV-negative patients). There was also no difference in outcome based on HIV status in a multivariate analysis that considered HIV, age, sex, race, year of diagnosis, comorbidity score, and presence of metastases.45 The VA study did not, however, report on cancer-free survival, colostomy rates, or local relapse in both populations. Furthermore, the VA study did not adjust for stage of disease (with the exception of presence of metastases in both groups) as a variable affecting overall survival.45
In summary, the treatment of HIV-positive patients in the HAART era is feasible and can result in long-term cures. In this population, and in the presence of a good performance status, it is recommended that patients receive a curative-intent full dose of mitomycin plus 5-FU and radiation. However, these patients need to be monitored more closely, as they may be prone to increased hematologic, gastrointestinal, and skin toxicity. Aggressive follow-up should be conducted after treatment completion, as a higher rate of local relapse with a need for salvage abdominoperineal resection has been described.
Improvement in radiation treatments through IMRT is actively being investigated and applied in anal cancer.29,47 IMRT may reduce toxicity, allow for less treatment interruption, and therefore translate into better tumor control. This topic has been detailed in a prior issue of ONCOLOGY and will not be subject to discussion in this review.30
Improvements in systemic treatments are also being investigated. A particular area of interest is the targeting of epidermal growth factor targeting (EGFR). Targeting EGFR with the monoclonal antibody cetuximab(Drug information on cetuximab) (Erbitux) has been shown to improve the outcomes of squamous cell cancer of the head and neck when added to radiation therapy in a large phase III study.48 Similarly, the addition of cetuximab to platinum-based therapy in squamous cell cancer of the head and neck improved overall patient survial.49 This has led to the investigation of cetuximab with chemoradiation in anal cancer. A phase I study has shown the feasibility of adding this agent to cisplatin, 5-FU, and radiation therapy in anal cancer.50 Several phase II studies are currently evaluating this combination in the US and Europe in immunocompetent and HIV-positive anal cancer patients.
While extensive efforts have been made to evaluate combination chemotherapy and induction/maintenance strategies in anal cancer, inadequate attention has been paid to the molecular characterization of this disease. HPV-positive head and neck cancers behave more favorably and respond better to treatment than HPV-negative tumors.51 More efforts should be made to investigate the relevance of HPV-positivity in anal cancer in relationship to prognosis and treatment outcome.
Furthermore, it is time to investigate more effective chemotherapeutic regimens if we are to seriously address the role of induction chemotherapy in this disease site. It has long been shown that a combination of a taxane, 5-FU, and cisplatin when followed by radiation therapy results in superior overall survival in head and neck cancers, compared to fluorouracil plus cisplatin and radiation.52 Similar induction strategies and others incorporating anti-EGFR therapies need urgent investigation, particularly in patients with T3–4 or node-positive anal cancers.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.