The most important prognostic factors for anal cancer are the T and N stages. Many studies over the past 25 years have demonstrated the importance of tumor size and extent and nodal involvement.6
Data from randomized trials have further elucidated the role of T and N stage. The European Organisation for Research and Treatment of Cancer (EORTC) performed a randomized trial in which 110 patients with anal cancer were randomized to receive either radiotherapy alone, or radiotherapy with concurrent 5-FU and mitomycin C.3
In this trial, patients with no nodal involvement had significantly higher rates of local control (P
= .0017) and overall survival (P
= .045) than patients with nodal involvement. In a multivariate analysis, nodal involvement was independently associated with both local control and survival. However, the extent of nodal involvement did not appear to affect outcomes, with N2–3 patients having similar outcomes as N1 patients. The size and number of involved nodes also did not affect outcomes. Moreover, in this trial, T stage, length of tumor, and circumferential extent of tumor were not significantly associated with local control or survival. Tumor thickness had a borderline significant association with survival (P
= .052), but not with local control. Since this trial included only 110 patients, the power to detect the prognostic roles of these different variables may have been limited.
The Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial in which 310 patients were randomized to receive either radiotherapy with concurrent 5-FU, or radiotherapy with concurrent 5-FU and mitomycin C.4
In this trial, patients underwent a biopsy 4–6 weeks after completion of chemoradiotherapy to assess tumor response. Tumor size was significantly associated with the rate of negative biopsies (P
= .02). Patients with tumor size < 5 cm had a 93% rate of negative biopsies, while patients with tumor size ≥ 5 cm had an 83% rate of negative biopsies. In addition, nodal status was significantly associated with the colostomy rate (P
= .009). Patients with no nodal involvement had a 13% colostomy rate, while patients with nodal involvement had a 28% colostomy rate.
Preliminary results were presented recently from the RTOG 98-11 trial, in which 682 patients were randomized to receive either radiotherapy with concurrent 5-FU and mitomycin C, or induction chemotherapy with 5-FU and cisplatin, followed by radiotherapy with concurrent 5-FU and cisplatin.5
Multivariate analysis showed that clinical node-positive status (P
< .0001) and tumor size > 5 cm (P
= .005) independently predicted for worse disease-free survival.
Recent retrospective studies have confirmed the prognostic roles of T and N stage. Investigators from the M. D. Anderson Cancer Center reported a retrospective study of 167 patients with nonmetastatic squamous cell anal carcinoma treated with definitive chemoradiotherapy.17
On multivariate analysis, higher T stage (P
= .023) and higher N stage (P
= .030) independently predicted for a higher rate of locoregional failure. The 3-year rate of locoregional control was 90% for Tx/T1, 86% for T2, 77% for T3, and 63% for T4 tumors. The 3-year rate of locoregional control was 84% to 88% for N0–2 and 39% for N3 tumors. On multivariate analysis, higher N stage also independently predicted for lower rates of distant control (P
< .001) and overall survival (P
= .001). The 3-year distant control rate was 94% for N0, 79% for N1, 75% for N2, and 76% for N3 patients. The 3-year overall survival rate was 93% for N0, 74% for N1, 74% for N2, and 56% for N3 patients.
A retrospective study from the Washington University School of Medicine evaluated 106 anal cancer patients treated with radiotherapy, with or without chemotherapy, and with or without surgery.18
Univariate analysis showed that tumor mobility (a surrogate for depth of invasion by the primary tumor) was significantly associated with the rate of freedom from disease (P
= .009). The 5-year ultimate freedom from disease rate was 89% for mobile tumors and 44% for tethered or fixed tumors. N stage (P
= .001) and TN stage (P
< .001) were also significantly associated with the rate of freedom from disease, on univariate analysis. The 5-year ultimate freedom from disease rate was 79% for node-negative and 27% for nodepositive tumors. When T and N stages were taken together, the 5-year ultimate freedom from disease rate was 87% for T1–2N0, 78% for T3N0 and 43% for either T4N0 or any node-positive tumors. On multivariate analysis, extent of disease (T1–2N0 vs. T3N0 vs. T4 or N+) was the only factor that independently predicted for ultimate freedom from disease, local control, and freedom from relapse.
The studies discussed above clearly show the important prognostic role of T and N stage. In addition to T and N stage, certain other clinical factors may be associated with outcomes in anal cancer patients. Some studies have indicated that women have better prognosis than men. In the EORTC randomized trial, women had significantly higher rates of local control (P
= .0028) and overall survival (P
= .0034) than did men.3
On multivariate analysis, gender was an independent predictor for both local control and survival. In the RTOG 98-11 trial, men had significantly lower rates of disease-free survival than women (P
A retrospective study from the Washington University School of Medicine showed that gender was significantly associated with rates of ultimate freedom from disease (P
The 5-year ultimate freedom from disease rate was 54% for men and 80% for women. However, there were imbalances in stage between men and women in this study, and gender was not an independent predictor of freedom from disease on multivariate analysis. Other studies have not found a significant association between gender and outcome.15
A large retrospective study from the M. D. Anderson Cancer Center reported that gender was not significantly associated with rates of locoregional control, distant metastasis, or overall survival.17
Hence, the prognostic role of gender is not completely clear.
A number of studies have investigated whether the degree of differentiation and histologic subtype affect prognosis. In the EORTC randomized trial, the degree of differentiation and the histologic subtype (squamous vs. other) were not found to be significant prognostic factors.3
A retrospective study of 242 patients from France reported that survival appeared to be better in patients with cloacogenic subtype; however, there was no significant difference in survival between three pathologic categories (cloacogenic vs. well-differentiated vs. moderately/poorly-differentiated).12
Investigators from the Princess Margaret Hospital conducted a study in 192 patients, in which they reported a trend toward greater tumor control in basaloid tumors than in squamous tumors (P
In the Washington University retrospective study discussed earlier, the degree of differentiation was not significantly associated with the rate of ultimate freedom from disease.18
There was a trend toward an improved 5- year rate of ultimate freedom from disease in patients with cloacogenic histology (84%), compared to those with squamous histology (66%), with a P
value of .06. However, on multivariate analysis, histologic subtype was not an independent prognostic factor.
In the M. D. Anderson retrospective study, the degree of differentiation was not significantly associated with rates of locoregional control, distant metastasis or overall survival.17
Basaloid subtype was significantly associated with a higher rate of distant metastasis, both on univariate and multivariate analysis (hazard ratio [HR] 4.23, P
= .003). On the other hand, other studies have indicated that there are no significant differences in prognosis between different histologic subtypes.6
Thus, conflicting data exist about the role of histologic subtypes, which is further complicated by the low reproducibility of identifying subtypes, even among experienced pathologists.21
The 2000 World Health Organization classification recommends that the generic term squamous cell carcinoma be used for all subtypes.22
As discussed above, most studies indicate that the degree of differentiation is unlikely to have an independent prognostic role in anal cancer. The role of differentiation degree is also limited by the lack of clear, well-described grading criteria.22
Since patients with human immunodeficiency virus (HIV) infection have a higher risk for developing anal cancer, studies have evaluated the effect of HIV status in patients with anal cancer. Most studies on HIV-positive patients treated with chemoradiotherapy indicate that these patients have rates of tumor response and locoregional control that are comparable to HIV-negative patients.23
However, HIV-positive patients experience higher rates of toxicity and demonstrate relatively lower rates of treatment compliance, which may affect outcomes.23
HIV-positive anal cancer patients also appear to have lower overall survival rates compared to HIV-negative patients, but this difference is likely due to their underlying disease and comorbidities. 17
Recent studies have investigated whether positron emission tomography (PET) could play a role in the evaluation of anal cancer patients. A prospective study in 21 patients with anal cancer showed that pretreatment PET scan identified involvement of pelvic lymph nodes in 4 (19%) patients and omental metastasis in 1 patient, which were not observed on computed tomography (CT) scan.32
Investigators from the Washington University School of Medicine reported a study in 41 patients with anal cancer in which PET/CT scans detected abnormal uptake in pelvic nodes in 5 patients (12%) with normal pelvic CT scans.33
Moreover, PET/CT scans detected abnormal uptake in 17% of groins that were negative by both CT and physical examination.33
Another prospective study of 62 patients with anal cancer demonstrated that PET scan had higher sensitivity for detecting nodal disease (92% vs. 72%) than conventional imaging.34
This study also showed that PET scan upstaged 15%, altered management intent in 3%, and altered radiation fields in 13% of patients.34
The National Comprehensive Cancer Network (NCCN) now recommends PET scan as part of the evaluation for patients with anal cancer.35