Hyperfractionated Accelerated Reirradiation for Patients With Recurrent Anal Cancer Previously Treated With Definitive Chemoradiation.

Objectives: Although chemoradiation is the standard of care for anal cancer, limited data exist regarding pelvic reirradiation (re-RT) for recurrent disease. We investigated toxicity and outcomes in patients who received prior pelvic radiation therapy (RT), and subsequently underwent hyperfractionated accelerated re-RT to the pelvis for recurrent anal cancer. Materials and Methods: We reviewed records of 10 patients with recurrent anal squamous cell carcinoma who previously received pelvic RT to at least 30 Gy as a component of their chemoradiation and underwent re-RT in 1.5 Gy twice daily fractions to the pelvis, with either preoperative (N=7) or definitive (N=3) intent. Results: The 3-year disease-free survival and 3-year overall survival rates were 40% and 60%. Four patients recurred within the reirradiated field, with a 3-year freedom from local progression rate of 56%. Of the 7 patients treated with preoperative intent, 5 proceeded to surgery, of whom 3 are alive and disease-free at a median duration of 43 months. Of the 3 patients treated definitively with no surgery, all are alive and disease-free at a median duration of 84 months. Re-RT resulted in one grade 3 acute toxicity and no grade 3 or higher late complications. Conclusions: Hyperfractionated accelerated re-RT was well-tolerated in patients with previously irradiated anal cancer. Patients treated with either definitive re-RT or re-RT followed by surgical resection had excellent rates of overall survival and freedom from local progression. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Intraoperative Radiotherapy in the Era of Intensive Neoadjuvant Chemotherapy and Chemoradiotherapy for Pancreatic Adenocarcinoma.

Objectives: Improved outcomes with FOLFIRINOX or gemcitabine with nab-paclitaxel in the treatment of metastatic pancreatic adenocarcinoma (PDAC) have prompted incorporation of these regimens into neoadjuvant treatment of locally advanced unresectable PDAC. Whereas some patients remain unresectable on surgical exploration, others are able to undergo resection after intensive neoadjuvant treatment. We evaluated outcomes and toxicity associated with use of intensive neoadjuvant treatment followed by intraoperative radiotherapy (IORT) in combination with resection or exploratory laparotomy. Methods: We retrospectively analyzed patients with locally advanced unresectable or borderline-resectable PDAC who received intensive neoadjuvant treatment with induction chemotherapy and chemoradiotherapy followed by exploratory laparotomy in an IORT-equipped operating suite between 2010 and 2015. Surgical outcomes and overall survival (OS) were compared. Results: Of 68 patients, 41 (60.3%) underwent resection, 18 (26.5%) had unresectable disease, and 9 (13.2%) had distant metastases. Of 41 resectable patients, 22 received IORT for close/positive resection margins on intraoperative frozen section. There was no significant difference in operative times or morbidity with addition of IORT to resection. Median OS was 26.6 months for all patients who underwent resection, 35.1 months for patients who underwent resection and IORT, and 24.5 months for patients who underwent resection alone (P=NS). Of 18 patients with unresectable disease, all but 1 received IORT, with median OS of 24.8 months. IORT was associated with increased hospital stay (4 vs. 3.5 d), but no significant difference in operative times or morbidity. Conclusions: IORT in addition to intensive neoadjuvant chemotherapy and chemoradiotherapy was not associated with increased toxicity when used with resection or exploratory laparotomy, and was associated with encouraging survival rates in patients with close/positive margins and patients with unresectable disease. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Clinical and Economic Evaluation of Treatment Strategies for T1N0 Anal Canal Cancer.

Objective: A comparative assessment of treatment alternatives for T1N0 anal canal cancer has never been conducted. We compared the outcomes associated with the treatment alternatives-chemoradiotherapy (CRT), radiotherapy (RT), and surgery or ablation techniques (surgery/ablation)-for T1N0 anal canal cancer. Materials and Methods: This retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results (SEER) registries linked with Medicare longitudinal data (SEER-Medicare database). Analysis included 190 patients who were treated for T1N0 anal canal cancer using surgery/ablation (n=44), RT (n=50), or CRT (n=96). The outcomes were reported in terms of survival and hazards ratios using Kaplan-Meier and Cox proportional hazards modeling, respectively; lifetime costs; and cost-effectiveness measured in terms of incremental cost-effectiveness ratio, that is, the ratio of the difference in costs between the 2 alternatives to the difference in effectiveness between the same 2 alternatives. Results: There was no significant difference in the survival duration between the treatment groups as predicted by the Kaplan-Meier curves. After adjusting for patient characteristics and propensity score, the hazard ratio of death for the patients who received CRT compared with surgery/ablation was 1.742 (95% confidence interval, 0.793-3.829) and RT was 2.170 (95% confidence interval, 0.923-5.101); however, the relationship did not reach statistical significance. Surgery/ablation resulted in lower lifetime cost than RT or CRT. The incremental cost-effectiveness ratio associated with CRT compared with surgery/ablation was $142,883 per life year gained. Conclusions: There was no statistically significant difference in survival among the treatment alternatives for T1N0 anal canal cancer. Given that surgery/ablation costs less than RT or CRT and might be cost-effective compared with RT and CRT, it is crucial to explore this finding further in this era of limited health care resources. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Hyperfractionated Accelerated Reirradiation for Patients With Recurrent Anal Cancer Previously Treated With Definitive Chemoradiation.

Objectives: Although chemoradiation is the standard of care for anal cancer, limited data exist regarding pelvic reirradiation (re-RT) for recurrent disease. We investigated toxicity and outcomes in patients who received prior pelvic radiation therapy (RT), and subsequently underwent hyperfractionated accelerated re-RT to the pelvis for recurrent anal cancer. Materials and Methods: We reviewed records of 10 patients with recurrent anal squamous cell carcinoma who previously received pelvic RT to at least 30 Gy as a component of their chemoradiation and underwent re-RT in 1.5 Gy twice daily fractions to the pelvis, with either preoperative (N=7) or definitive (N=3) intent. Results: The 3-year disease-free survival and 3-year overall survival rates were 40% and 60%. Four patients recurred within the reirradiated field, with a 3-year freedom from local progression rate of 56%. Of the 7 patients treated with preoperative intent, 5 proceeded to surgery, of whom 3 are alive and disease-free at a median duration of 43 months. Of the 3 patients treated definitively with no surgery, all are alive and disease-free at a median duration of 84 months. Re-RT resulted in one grade 3 acute toxicity and no grade 3 or higher late complications. Conclusions: Hyperfractionated accelerated re-RT was well-tolerated in patients with previously irradiated anal cancer. Patients treated with either definitive re-RT or re-RT followed by surgical resection had excellent rates of overall survival and freedom from local progression. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Intraoperative Radiotherapy in the Era of Intensive Neoadjuvant Chemotherapy and Chemoradiotherapy for Pancreatic Adenocarcinoma.

Objectives: Improved outcomes with FOLFIRINOX or gemcitabine with nab-paclitaxel in the treatment of metastatic pancreatic adenocarcinoma (PDAC) have prompted incorporation of these regimens into neoadjuvant treatment of locally advanced unresectable PDAC. Whereas some patients remain unresectable on surgical exploration, others are able to undergo resection after intensive neoadjuvant treatment. We evaluated outcomes and toxicity associated with use of intensive neoadjuvant treatment followed by intraoperative radiotherapy (IORT) in combination with resection or exploratory laparotomy. Methods: We retrospectively analyzed patients with locally advanced unresectable or borderline-resectable PDAC who received intensive neoadjuvant treatment with induction chemotherapy and chemoradiotherapy followed by exploratory laparotomy in an IORT-equipped operating suite between 2010 and 2015. Surgical outcomes and overall survival (OS) were compared. Results: Of 68 patients, 41 (60.3%) underwent resection, 18 (26.5%) had unresectable disease, and 9 (13.2%) had distant metastases. Of 41 resectable patients, 22 received IORT for close/positive resection margins on intraoperative frozen section. There was no significant difference in operative times or morbidity with addition of IORT to resection. Median OS was 26.6 months for all patients who underwent resection, 35.1 months for patients who underwent resection and IORT, and 24.5 months for patients who underwent resection alone (P=NS). Of 18 patients with unresectable disease, all but 1 received IORT, with median OS of 24.8 months. IORT was associated with increased hospital stay (4 vs. 3.5 d), but no significant difference in operative times or morbidity. Conclusions: IORT in addition to intensive neoadjuvant chemotherapy and chemoradiotherapy was not associated with increased toxicity when used with resection or exploratory laparotomy, and was associated with encouraging survival rates in patients with close/positive margins and patients with unresectable disease. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Clinical and Economic Evaluation of Treatment Strategies for T1N0 Anal Canal Cancer.

Objective: A comparative assessment of treatment alternatives for T1N0 anal canal cancer has never been conducted. We compared the outcomes associated with the treatment alternatives-chemoradiotherapy (CRT), radiotherapy (RT), and surgery or ablation techniques (surgery/ablation)-for T1N0 anal canal cancer. Materials and Methods: This retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results (SEER) registries linked with Medicare longitudinal data (SEER-Medicare database). Analysis included 190 patients who were treated for T1N0 anal canal cancer using surgery/ablation (n=44), RT (n=50), or CRT (n=96). The outcomes were reported in terms of survival and hazards ratios using Kaplan-Meier and Cox proportional hazards modeling, respectively; lifetime costs; and cost-effectiveness measured in terms of incremental cost-effectiveness ratio, that is, the ratio of the difference in costs between the 2 alternatives to the difference in effectiveness between the same 2 alternatives. Results: There was no significant difference in the survival duration between the treatment groups as predicted by the Kaplan-Meier curves. After adjusting for patient characteristics and propensity score, the hazard ratio of death for the patients who received CRT compared with surgery/ablation was 1.742 (95% confidence interval, 0.793-3.829) and RT was 2.170 (95% confidence interval, 0.923-5.101); however, the relationship did not reach statistical significance. Surgery/ablation resulted in lower lifetime cost than RT or CRT. The incremental cost-effectiveness ratio associated with CRT compared with surgery/ablation was $142,883 per life year gained. Conclusions: There was no statistically significant difference in survival among the treatment alternatives for T1N0 anal canal cancer. Given that surgery/ablation costs less than RT or CRT and might be cost-effective compared with RT and CRT, it is crucial to explore this finding further in this era of limited health care resources. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Secondary OSCC Chemoprevention via Multiple Agents

Abstract. Over 1/3 of patients who have undergone oral squamous cell carcinoma (OSCC) surgical resections develop life-threatening and often untreatable recurrences. A variety of drugs, intended for management of recurrent or disseminated cancers, were designed to exploit cancer cells' reliance upon overexpressed receptors and gratuitous signaling. Despite their conceptual promise, clinical trials showed these agents lacked efficacy and were often toxic. These findings are consistent with evasion of pathway-targeted treatments via extensive signaling redundancies and compensatory mechanisms common to cancers. Optimal secondary OSCC chemoprevention requires long term efficacy with multifaceted, nontoxic agents. Accordingly, this study evaluated the abilities of three complementary chemopreventives i.e. the vitamin A derivative fenretinide (4-HPR, induces apoptosis and differentiation, inhibits signaling proteins and invasion), the estrogen metabolite 2-methoxyestradiol (2-ME, apoptosis-inducing, antiangiogenic) and the humanized monoclonal antibody to the IL-6R receptor tocilizumab (TOC, reduces IL-6 signaling) to suppress OSCC gratuitous signaling and tumorigenesis. Modeling studies demonstrated 4-HPR's high affinity binding at STAT3's dimerization site and c-Abl and c-Src ATP-binding kinase sites. Although individual agents suppressed cancer-promoting pathways including STAT3 phosphorylation, STAT3-DNA binding, and production of the trans-signaling enabling sIL-6R, maximal chemopreventive effects were observed with agent combinations. OSCC tumor xenograft studies showed that locally-delivered TOC, TOC+4-HPR and TOC+4-HPR+2-ME treatments all prevented significant tumor growth. Notably, the TOC+4-HPR+2-ME treatment resulted in the smallest overall increase in tumor volume. The selected agents employ diverse mechanisms to disrupt tumorigenesis at multiple venues i.e. intracellular, tumor cell-ECM and tumor microenvironment; beneficial qualities for secondary chemopreventives.

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