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Simple Summary: While anti-PD1 antibodies have demonstrated efficacy in some patients with metastatic anal cancer, these agents have no proven benefit for those with localized disease treated with chemoradiation. Difficulty procuring fresh tumor tissue required for RNA and protein expression analysis has limited extensive molecular profiling for this rare cancer. Our team utilized a novel digital spatial profiling technology on pretreatment anal cancer specimens to identify biomarkers associated with recurrence after chemoradiation. We observed that recurrent tumors had higher baseline expression of immune checkpoint biomarkers, higher MAPK signaling activation and higher PI3K/Akt signaling activation. These findings provide a rationale that supports future clinical trials with immunotherapy that seek to improve survival beyond chemoradiation for patients with localized squamous cell cancer of the anus. The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of FoxP3, MAPK-activation markers (BRAF, p38-MAPK) and PI3K/Akt activation (phospho-Akt) within the tumor regions. The TME was characterized by the higher protein expression of immune checkpoint biomarkers such as PD-1, OX40L and LAG3. For patients with recurrent SCCA, the higher mean protein expression of fibronectin was observed in the tumor and TME compartments. No significant differences in RNA expression were observed. The higher baseline expression of immune checkpoint biomarkers, together with markers of MAPK and PI3K/Akt signaling, are associated with recurrence following chemoradiation for patients with localized SCCA. These data provide a rationale towards the application of immune-based therapeutic strategies to improve curative-intent outcomes beyond conventional therapies for patients with SCCA. [ABSTRACT FROM AUTHOR]

BACKGROUND The current study was conducted to determine whether quantified pathologic response assessed as a percentage of residual tumor cells is predictive of recurrence-free survival (RFS) in patients with rectal cancer. METHODS The authors studied 251 patients with rectal adenocarcinoma who were treated with neoadjuvant chemoradiation and radical resection. Quantified pathologic response was defined as an estimated percentage of residual cancer cells in relation to the tumor bed: complete, no residual cancer cells; near-complete, ≤ 5% residual cancer cells; major, > 5%, and < 50% residual cancer cells; and minor, ≥ 50% residual cancer cells. The reproducibility of quantified pathologic response between 2 pathologists was assessed using tumors from 55 randomly selected patients who did not demonstrate a complete response. RESULTS Pathologic response was complete in 21% of patients, near-complete in 20% of patients, major in 37% of patients, and minor in 22% of patients. Nineteen percent of patients had ypT0N0 disease, 27% had ypT1-2N0 disease, 21% had ypT3-4N0 disease, and 33% had N+ disease. The 5-year RFS rates by category of quantified pathologic response were as follows: complete, 95%; near-complete, 88%; major, 69%; and minor, 61% ( P < .001). Major and minor response, high histologic grade, and perineural invasion were found to be significant predictors of decreased RFS on multivariate analysis. The 5-year RFS rates for patients with ypT3-4 or N+ disease were better for those with a near-complete response (94%) compared with those with a major (64%) or minor (61%) response ( P < .02). Moderate to substantial agreement was observed between the 2 pathologists (κ = 0.72). CONCLUSIONS Quantified pathologic response is a predictor of RFS in patients with rectal adenocarcinoma and stratifies patients with high pathologic stage disease. Cancer 2013;119:4231-4241. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Weekly or daily cisplatin and 5-fluorouracil (5-FU)-based chemoradiation was evaluated for patients with locally advanced squamous cell carcinoma (SCC) of the anal canal treated at a single institution over a 20-year period. METHODS A retrospective, single-institution analysis was conducted of patients receiving concurrent 5-FU/cisplatin and radiotherapy for locally advanced SCC from 1989 to 2009. Endpoints included clinical complete response rate, local recurrence rate, colostomy-free survival, disease-free survival (DFS), overall survival, and treatment-related toxicity. RESULTS A total of 197 patients were evaluable. The majority had American Joint Committee on Cancer stage II (41%) or stage III (46%) disease; most were T2 (44%) or T3 (27%); bulky nodal disease (N2-N3) was noted in 24% of patients. Patients received weekly (20 mg/m2) or daily (4 mg/m2) cisplatin during radiotherapy. Median radiation dose was 55 Gy. Clinical complete response was observed in 185 patients (94%). After a median follow-up of 8.6 years, local recurrence rate was 11%. Sixteen patients (8%) developed distant metastases. The 5-year DFS was 81%, the 5-year overall survival was 86%, and the 5-year colostomy-free survival was 88%. By univariate analysis, N-stage was a poor prognostic indicator for 5-year DFS ( P = .02, 95% confidence interval = 1.17-2.01) and distant metastases ( P = .046, 95% confidence interval = 1.09-2.13). Increased T-stage correlated with the necessity for salvage surgery ( P = .01). CONCLUSIONS The combination of weekly/daily cisplatin and 5-FU-based chemotherapy with concurrent radiotherapy is an effective regimen, and our long-term results indicate that cisplatin is an alternative to mitomycin C and may be considered for the treatment of locally advanced SCC of the anal canal. Cancer 2013;119:3769-3775. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Purpose: To assess the efficacy and limitations of definitive chemoradiation for adenocarcinoma of the anal canal and to propose a treatment strategy that addresses the limitations of treatment.Methods and Materials: Between 1976 and 1998, 16 patients with localized adenocarcinoma of the anal canal were treated with radiotherapy with or without chemotherapy with curative intent. Available histologic slides were reviewed for evidence of primary adenocarcinoma of anal duct origin. The treatment results for these patients were compared with those of a group of patients with epidermoid histologic features who were all treated with definitive chemoradiation (55 Gy with concurrent 5-fluorouracil and cisplatin, n = 92) between 1989 and 1998. The hospital records were reviewed for all patients. Patients with epidermoid carcinoma presented with more advanced primary tumors (42% vs. 19% Stage T3 or greater). All adenocarcinoma patients were treated with radiotherapy (median dose 55 Gy): 11 received concurrent 5-fluorouracil-based chemotherapy and 5 received radiotherapy alone. The initial surgical procedures included abdominoperineal resection, excisional biopsies (n = 5), and local excision (n = 1). Abdominoperineal resection was performed as salvage therapy after local recurrence in 5 patients. The Kaplan-Meier method was used to calculate 5-year actuarial pelvic control, distant disease control, disease-free survival, and overall survival. The median follow-up was 45 months (range 5–196) for patients with adenocarcinoma and 44 months (range 9–115) for patients with epidermoid histologic features.Results: Both local and distant recurrence rates were significantly greater in the adenocarcinoma patients. Of 16 patients with adenocarcinoma, 7 (5-year actuarial rate 54%) had recurrence at the primary site compared with 16 (5-year actuarial rate 18%) of 92 patients with epidermoid histologic features (p = 0.004). Distant disease developed in more patients with adenocarcinoma (5-year actuarial rate 66%) than in patients with epidermoid carcinoma (5-year actuarial rate 10%, p <0.001). The 5-year actuarial disease-free survival and overall survival rate for adenocarcinoma patients was 19% and 64%, respectively, compared with 77% (p <0.0001) and 85% (p = 0.017) for those with epidermoid carcinoma.Conclusion: Patients with localized adenocarcinoma of the anus treated with definitive chemoradiation had high rates of pelvic failure and distant metastasis compared with comparably staged patients with epidermoid histologic features treated similarly. On the basis of these limitations, we recommend preoperative chemoradiation followed by abdominoperineal resection to maximize pelvic disease control and consideration of adjuvant chemotherapy to address the problem of micrometastatic disease. [Copyright &y& Elsevier]

Purpose: We designed this Phase II trial to assess the efficacy and safety of the addition of bevacizumab to concurrent neoadjuvant capecitabine-based chemoradiation in locally advanced rectal cancer. Methods: Between April 2004 and December 2007, 25 patients with clinically staged T3N1 (n = 20) or T3N0 (n = 5) rectal cancer received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m2 orally twice daily only on days of radiation), followed by surgical resection a median of 7.3 weeks later. Results: Procedures included abdominoperineal resection (APR; 6 patients), proctectomy with coloanal anastamosis (8 patients), low anterior resection (10 patients), and local excision (1 patient). Eight (32%) of 25 patients had a pathologic complete response, and 6 (24%) of 25 had <10% viable tumor cells in the specimen. No patient had Grade 3 hand-foot syndrome, gastrointestinal toxicity, or significant hematologic toxicity. Three wound complications required surgical intervention (one coloanal anastamostic dehiscence requiring completion APR and two perineal wound dehiscences after initial APR). Five minor complications occurred that resolved without operative intervention. With a median follow-up of 22.7 months (range, 4.5–32.4 months), all patients were alive; one patient has had a recurrence in the pelvis (2-year actuarial rate, 6.2%) and 3 had distant recurrences. Conclusions: The addition of bevacizumab to neoadjuvant chemoradiation resulted in encouraging pathologic complete response without an increase in acute toxicity. The impact of bevacizumab on perineal wound and anastamotic healing due to concurrent bevacizumab requires further study. [Copyright &y& Elsevier]

Purpose: To evaluate patterns of locoregional failure, and predictors of recurrence and survival in patients treated with chemoradiation for anal cancer. Methods and Materials: Between September 1992 and August 2004, 167 patients with nonmetastatic squamous cell anal carcinoma were treated with definitive chemoradiation. The median dose of radiotherapy was 5500 cGy. Concurrent chemotherapy was given with 5-fluorouracil and cisplatin in 117 patients, 5-fluorouracil and mitomycin C in 24 patients, and other regimens in 26 patients. Results: The estimated 3-year rates of locoregional control, distant control, disease-free survival, and overall survival were 81%, 88%, 67%, and 84%, respectively. Multivariate analysis showed that higher T stage and N stage independently predicted for a higher rate of locoregional failure; higher N stage and basaloid subtype independently predicted for a higher rate of distant metastasis; and higher N stage and positive human immunodeficiency virus status independently predicted for a lower rate of overall survival. Among the patients who had locoregional failure, 18 (75%) had failure involving the anus or rectum, 5 (21%) had other pelvic recurrences, and 1 (4%) had inguinal recurrence. The 5 pelvic recurrences all occurred in patients with the superior border of the radiotherapy field at the bottom of the sacroiliac joint. Conclusions: Trials of more aggressive and innovative locoregional and systemic therapies are warranted in high-risk patients, based on their T and N stages. The majority of locoregional failures involve the anus and rectum, whereas inguinal recurrences occur rarely. Placing the superior border of the radiotherapy field at L5/S1 could potentially reduce pelvic recurrences. [Copyright &y& Elsevier]