While reviewing the results of the literature search, we limited our focus to prospectively conducted phase III studies. Only 4 interventional anal cancer studies have been performed to date.3–6
summarizes the prognostic factors established thus far by prospective analyses. The British study4
(n=585) and an RTOG study6
(n=310) have not reported a prognostic factor evaluation, however, the EORTC study5
(n=110) is only one that has reported a formal prognostic factor analysis. The EORTC found that nodal status (local control, p=0.003 and OS, p=0.0003), gender (male with worse outcome; DFS, p=0.01, and OS, p=0.011), and skin ulceration (DFS, p=0.0033 and OS, p=0.005) were prognostic but tumor size was not. We now report our analysis from the second RTOG study3
(n=644). For the RTOG 98-11 study, data for skin ulceration were not available.
Of all 4 reported randomized prospective phase III trials, the US GI Intergroup anal canal cancer trial RTOG 98-11 has the highest number of patients (n=682; 644 analyzed) studied to date,3
and the current analysis for prognostic factors provides additional understanding of the clinical biology of anal carcinoma. Data in this analysis establishes that tumor diameter is an independent pretreatment variable that predicts 5-year DFS and OS. The data also confirm two previously reported prognostic factors (nodal status and gender). In addition, the current analysis documents that anal cancer exhibits four types of clinical biology based on four subgroups of prognostic factor combinations. Greater understanding of clinical factors that drive clinical biology would reduce uncertainties that prevail today when treating patients with anal cancer. Knowledge that patients with >5cm tumor and N1 status has only 30% chance of being disease-free at 3 years allows one to more effectively communicate with our colleagues, patients, and their relatives. Such knowledge would also lead to newer therapeutic algorithms. In addition, identification of poorly performing groups that are likely to have treatment failure early could allow one to test novel therapy quickly because the endpoints are reached sooner in this group that they do in more favorable groups.
Reliable clinical prognostic parameters still do not account for inherent heterogeneity in outcome of individual patient. These unexpected patient outcomes, when patients are treated similarly, are multifactorial and can include type of therapy, toxicity, treatment completion but most likely include the degree of sensitivity to chemoradiation and to some extent patient’s genetic makeup. In the future, it would be important to combine clinical, epigenetic, genetic,22
and germ-line variables to develop a model that predicts response to therapy and prognosticates outcome. The first step in developing such sophisticated models could be the establishment of reliable prognostic factors and their interaction and the next step would be conduct biomarker studies from tissue repositories that might be available.
Approximately 25% of newly diagnosed patients fall into the worst prognostic category (>5cm tumor and N1 status). The current analysis does not provide any clue as to whether this group should be treated differently than other three groups with lower risk of experiencing a DFS or OS event. Since anal cancer is rare, many trials cannot be proposed. However, newer tools such as positron emission tomography23–25
could be incorporated for early assessment of response in a poor prognostic group. If validated, it would help avoid the morbidity of chemoradiation in some patients who can be offered surgery. We acknowledge that there is no data to support this notion and perhaps a combination of clinical and biology-based tools will provide some guidance in the future. It would appear that this group of patients is likely to end up with colostomy anyway even after the completion of chemoradiation.21
On the otherhand, one could also argue that patients with all the poor prognostic factors could benefit from more aggressive therapy.
In conclusion, our analysis of prospectively collected data establishes that tumor diameter is an independent prognosticator of DFS and OS. The analysis confirms that nodal status and gender are also independently prognostic. In addition, the analysis uncovers four subgroups, derived from combining prognostic factors, of anal cancers with differing clinical biology. Further understanding of the clinical biology of anal cancer could emerge from studying molecular biology and patient genetic along with clinical prognostic variables and imaging.