Role of pelvic chemoradiation therapy in patients with initially metastatic anal canal cancer: A National Cancer Database review.

BACKGROUND: Although the management of localized anal canal squamous cell carcinomas is well established, the role of pelvic chemoradiation (CRT) in the treatment of patients presenting with synchronous metastatic (stage IV) disease is poorly defined. This study used a national cancer database to compare the overall survival (OS) rates of patients with synchronous metastatic disease receiving CRT to the pelvis and patients treated with chemotherapy (CT) alone. METHODS: This study included adult patients with anal canal squamous cell carcinomas presenting with synchronous metastases diagnosed from 2004 to 2012. Multiple imputation and 2:1 propensity score matching were used to create a matched data set for testing. The proportional hazards model was used to estimate the hazard ratio (HR) for the effect of the treatment group on OS. With only patients in the matched data set, the OS of the treatment groups was estimated with the Kaplan-Meier method by treatment group. RESULTS: This study started with an unmatched data set of 978 patients, and 582 patients were selected for the matched data set: 388 in the CRT group and 194 in the CT-alone group. The HR for the group effect was 0.75 (95% confidence interval [CI], 0.61-0.92; P = .006). The median OS was 21.1 months in the CRT group (95% CI, 17.4-24.0 months) and 14.6 months in the CT group (95% CI, 12.2-18.4 months). The corresponding 5-year OS rates were 23% (95% CI, 18%-28%) and 14% (95% CI, 7%-21%), respectively. CONCLUSIONS: In this large series analyzing OS in patients with stage IV anal cancer, CRT was associated with improved OS in comparison with CT alone. Because of the lack of prospective data in this setting, this evidence will help to guide treatment approaches in this group of patients.

Comparison of neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy for esophageal cancer: a meta-analysis.

Aim: To compare the clinical efficacy of neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant chemotherapy (nCT) for esophageal cancer. Methods: Randomized controlled trials reporting on the comparison of nCRT and nCT for esophageal cancer were identified. Results: Three eligible randomized controlled trials were identified and included with a total of 375 patients (189 nCRT, 186 nCT). Outcomes showed that compared with nCT group, R0 resection and pathologic complete response (pCR) rates were significantly increased in nCRT group. However, no significant difference was seen in 3- and 5-year progression-free survival or 3- and 5-year overall survival. Conclusion: The addition of radiotherapy to neoadjuvant chemotherapy results in higher R0 resection rate and pCR rate, without significantly impacting survival.

The role of external beam radiotherapy in the treatment of hepatocellular cancer.

Hepatocellular carcinoma (HCC) is increasing in incidence and mortality. Although the prognosis remains poor, long-term survival has improved from 3% in 1970 to an 18% 5-year survival rate today. This is likely because of the introduction of well tolerated, oral antiviral therapies for hepatitis C. Curative options for patients with HCC are often limited by underlying liver dysfunction/cirrhosis and medical comorbidities. Less than one-third of patients are candidates for surgery, which is the current gold standard for cure. Nonsurgical treatments include embolotherapies, percutaneous ablation, and ablative radiation. Technological advances in radiation delivery in the past several decades now allow for safe and effective ablative doses to the liver. Conformal techniques allow for both dose escalation to target volumes and normal tissue sparing. Multiple retrospective and prospective studies have demonstrated that hypofractionated image-guided radiation therapy, used as monotherapy or in combination with other liver-directed therapies, can provide excellent local control that is cost effective. Therefore, as the HCC treatment paradigm continues to evolve, ablative radiation treatment has moved from a palliative treatment to both a "bridge to transplant" and a definitive treatment.

Total neoadjuvant therapy for rectal cancer: An emerging option.

The treatment of locally advanced rectal cancer (LARC) has benefited from improved surgical techniques and from the implementation of neoadjuvant chemoradiotherapy (CRT), which have markedly decreased the rates of local recurrence. However, distant metastatic disease remains the most significant cause of death for these patients. Although adjuvant chemotherapy (ChT) after neoadjuvant CRT and definitive surgery is commonly recommended, the value of adjuvant systemic therapy remains less clear. Trials evaluating adjuvant ChT for rectal cancer have been handicapped by poor compliance rates and inconsistent survival results. Shifting systemic therapy delivery to the neoadjuvant setting has the promise to improve compliance rates, reduce toxicity, and decrease distant relapse rates. Recently, multiple prospective trials have reported on the use of total neoadjuvant therapy (TNT) for patients with LARC, incorporating both ChT and CRT in the neoadjuvant setting. Here, the authors review the promising results from those trials. Because the studies have largely focused on pathologic outcomes (primarily pathologic complete response rates), ongoing phase 2 and 3 trials are now underway assessing the long-term disease-related outcomes with TNT. In addition to improving survival, TNT has the potential to increase the pool of patients with LARC who are eligible for organ preservation, which is also being evaluated. Cancer 2017;123:1497-1506. © 2017 American Cancer Society.

Neoadjuvant long-course chemoradiation remains strongly favored over short-course radiotherapy by radiation oncologists in the United States.

BACKGROUND: Short-course radiotherapy (SC-RT) and long-course chemoradiotherapy (LC-CRT) are accepted neoadjuvant treatments of rectal cancer. In the current study, the authors surveyed US radiation oncologists to assess practice patterns and attitudes regarding SC-RT and LC-CRT for patients with rectal cancer. METHODS: The authors distributed a survey to 1701 radiation oncologists regarding treatment of neoadjuvant rectal cancer. Respondents were asked questions regarding the number of patients with rectal cancer treated, preference for SC-RT versus LC-CRT, and factors influencing regimen choice. RESULTS: Of 1659 contactable physicians, 182 responses (11%) were received. Approximately 83% treated at least 5 patients with rectal cancer annually. The majority of responding radiation oncologists (96%) preferred neoadjuvant LC-CRT for the treatment of patients with locally advanced rectal cancer and 44% never used SC-RT. Among radiation oncologists using SC-RT, respondents indicated they would not recommend this regimen for patients with low (74%) or bulky tumors (70%) and/or concern for a positive circumferential surgical resection margin (69%). The most frequent reasons for not offering SC-RT were insufficient downstaging for sphincter preservation (53%) and a desire for longer follow-up (45%). Many radiation oncologists indicated they would prescribe SC-RT for patients not receiving chemotherapy (62%) or patients with a geographic barrier to receiving LC-CRT (82%). Patient comorbidities appeared to influence regimen preferences for 79% of respondents. Approximately 20% of respondents indicated that altered oncology care reimbursement using capitated payment by diagnosis would impact their consideration of SC-RT. CONCLUSIONS: US radiation oncologists rarely use neoadjuvant SC-RT despite 3 randomized controlled trials demonstrating no significant differences in outcome compared with LC-CRT. Further research is necessary to determine whether longer follow-up coupled with the benefits of lower cost, increased patient convenience, and lower acute toxicity will increase the adoption of SC-RT by radiation oncologists in the United States. Cancer 2017;123:1434-1441. © 2016 American Cancer Society.

Nonoperative management of rectal cancer.

Surgery has long been the primary curative modality for localized rectal cancer. Neoadjuvant chemoradiation has significantly improved local control rates and, in a significant minority, eradicated all disease. Patients who achieve a pathologic complete response to neoadjuvant therapy have an excellent prognosis, although the combination treatment is associated with long-term morbidity. Because of this, a nonoperative management (NOM) strategy has been pursued to preserve sphincter function in select patients. Clinical and radiographic findings are used to identify patients achieving a clinical complete response to chemoradiation, and they are then followed with intensive surveillance. Incomplete, nonresponding and those demonstrating local progression are referred for salvage with standard surgery. Habr-Gama and colleagues have published extensively on this treatment strategy and have laid the groundwork for this approach. This watch-and-wait strategy has evolved over time, and several groups have now reported their results, including recent prospective experiences. Although initial results appear promising, several significant challenges remain for NOM of rectal cancer. Further study is warranted before routine implementation in the clinic.

Role of Adjuvant Radiotherapy in Locally Advanced Colonic Carcinoma in the Modern Chemotherapy Era.

BACKGROUND: The role of adjuvant radiation therapy (RT) in the treatment of resected, locally advanced colon cancer is unclear. One randomized controlled trial (Intergroup-0130) addressed this question but failed to meet its accrual goals. Since this trial, few attempts have been made to reassess the role of RT in this clinical setting. METHODS: Sixty-two patients with non-metastatic, American Joint Committee on Cancer 7th edition stage T4 colonic adenocarcinoma were treated at our institution between 2000 and 2013. All underwent curative-intent surgery. Sixteen patients underwent resection only, 33 patients received adjuvant chemotherapy (ChT), and 13 patients received adjuvant chemoradiation therapy (CRT). RESULTS: Patients receiving adjuvant CRT were more likely to have T4b (vs. T4a) disease and were more likely to undergo R1 or R2 resection compared with those receiving adjuvant ChT alone. Despite this, multivariate analysis demonstrated that treatment with adjuvant CRT (vs. adjuvant ChT) enhanced locoregional control and disease-free survival (hazard ratio 0.044 and 0.145, respectively; p < 0.05). CONCLUSIONS: Adjuvant RT for T4 colon cancers may be appropriate in select patients, specifically those with T4b lesions and/or residual disease following resection.

Evaluation of Adjuvant Radiation Therapy for Resected Gallbladder Carcinoma: A Multi-institutional Experience.

PURPOSE: The role of adjuvant radiation for gallbladder carcinoma (GBC) is uncertain. We combine the experience of six National Cancer Institute-designated cancer centers to explore the impact of adjuvant radiation following oncologic resection of GBC. METHODS: Patients who underwent extended surgery for GBC at Johns Hopkins, Mayo Clinic, Duke University, Oregon Health & Science University, University of Michigan, and University of Texas MD Anderson between 1985 and 2008 were reviewed. Patients with metastatic disease at surgery, gross residual disease, or missing pathologic information were excluded. RESULTS: Of the 112 patients identified, 61 % received adjuvant radiation, 93 % of whom received concurrent chemotherapy. Median follow-up of surviving patients was 47.3 (range 2.2-167.7) months. Patients who received adjuvant radiation had a higher rate of advanced T-stage (57 vs. 16 %, p < 0.01), lymph node involvement (63 vs. 18 %, p < 0.01), and positive microscopic margins (37 vs. 9 %, p < 0.01) compared with patients managed with surgery alone, but overall survival (OS) was comparable between the two cohorts (5-year OS: 49.7 vs. 52.5 %, p = 0.20). Lymph node involvement had the strongest association with poor OS (p < 0.01). Adjuvant radiation was associated with decreased isolated local failure (hazard ratio 0.17, 95 % confidence interval 0.05-0.63, p = 0.01). However, 71 % of recurrences included distant failure. CONCLUSIONS: Following oncologic resection for GBC, adjuvant radiation may offer improved local control compared with observation. The benefit of adjuvant radiation beyond chemotherapy alone should therefore be explored. Certainly, the high rate of distant failure highlights the need for more effective systemic therapy.

Neoadjuvant radiation therapy does not increase perioperative morbidity among patients undergoing gastrectomy for gastric cancer.

BACKGROUND: Neoadjuvant radiation therapy (RT) as a component of the multimodality treatment of gastric cancer has demonstrated promising results. Data regarding its effect on perioperative safety are limited. METHODS: Adults undergoing gastrectomy for gastric cancer in the 2005-2011 National Surgical Quality Improvement Program were included. Groups were defined by neoadjuvant RT use, and then propensity-matched based on preoperative variables. Multivariable logistic regression was performed to assess neoadjuvant RT as an independent predictor of outcomes. RESULTS: Among 2,764 patients identified, 55 (2.0%) were treated with neoadjuvant RT. Patients who received neoadjuvant RT were more likely to have received preoperative chemotherapy and steroids, and experienced weight loss (all P < 0.01). After matching, however, there were no preoperative differences. At time of surgery, total (vs. partial) gastrectomy was more common among patients who underwent neoadjuvant RT (70.9 vs. 46.7%, P < 0.01), and operative time was longer (290 vs. 236 min, P < 0.01). There were no differences in overall complications (23.6 vs. 29.7%, P = 0.49) or 30-day mortality (3.6 vs. 3.6%, P = 0.99). CONCLUSIONS: Neoadjuvant RT was not associated with increased morbidity or mortality following resection for gastric cancer. These findings support the ongoing investigation of neoadjuvant RT as part of the multidisciplinary management of resectable gastric cancer.

Analysis of perioperative radiation therapy in the surgical treatment of primary and recurrent retroperitoneal sarcoma.

BACKGROUND: Radiation therapy (RT) is increasingly utilized in conjunction with surgery for the treatment of retroperitoneal soft tissue sarcomas (RPS). Despite multiple theoretical advantages of RT, its role in the surgical management of this disease remains ill defined. METHODS: Patients undergoing surgery for RPS from 1990 to 2011 were identified. Patients were classified as having primary or recurrent disease, and then further stratified by the use of perioperative RT. Primary outcomes, including overall survival (OS) and recurrence-free survival (RFS), were estimated using the Kaplan-Meier method with comparisons based on the log rank test. Cox-proportional hazards modeling was used to estimate the independent effect of RT on survival. RESULTS: Ninety-four patients met final inclusion criteria. After adjusting for confounding variables, perioperative RT remained independently associated with a reduced risk of recurrence (HR 0.34, P < 0.01) and death (HR 0.30, P = 0.02). CONCLUSIONS: In this retrospective series, perioperative RT is an independent predictor of improved OS and RFS. These results provide additional support for the use of RT in the multimodality treatment of retroperitoneal sarcoma.

Patterns of recurrence after trimodality therapy for esophageal cancer.

BACKGROUND: Patterns of failure after neoadjuvant chemoradiotherapy and surgery for esophageal cancer are poorly defined. METHODS: All patients in the current study were treated with trimodality therapy for nonmetastatic esophageal cancer from 1995 to 2009. Locoregional failure included lymph node failure (NF), anastomotic failure, or both. Abdominal paraaortic failure (PAF) was defined as disease recurrence at or below the superior mesenteric artery. RESULTS: Among 155 patients, the primary tumor location was the upper/middle esophagus in 18%, the lower esophagus in 32%, and the gastroesophageal junction in 50% (adenocarcinoma in 79% and squamous cell carcinoma in 21%) of patients. Staging methods included endoscopic ultrasound (73%), computed tomography (46%), and positron emission tomography/computed tomography (54%). Approximately 40% of patients had American Joint Committee on Cancer stage II disease and 60% had stage III disease. The median follow-up was 1.3 years. The 2-year locoregional control, event-free survival, and overall survival rates were 86%, 36%, and 48%, respectively. The 2-year NF rate was 14%, the isolated NF rate was 3%, and the anastomotic failure rate was 6%. The 2-year PAF rate was 9% and the isolated PAF rate was 5%. PAF was found to be increased among patients with gastroesophageal junction tumors (12% vs 6%), especially for the subset with ≥ 2 clinically involved lymph nodes at the time of diagnosis (19% vs 4%). CONCLUSIONS: Few patients experience isolated NF or PAF as their first disease recurrence. Therefore, it is unlikely that targeting additional regional lymph node basins with radiotherapy would significantly improve clinical outcomes.

Short-course versus long-course chemoradiation in rectal cancer--time to change strategies?

OPINION STATEMENT: There is significant debate regarding the optimal neoadjuvant regimen for resectable rectal cancer patients. Short-course radiotherapy, a standard approach throughout most of northern Europe, is generally defined as 25 Gy in 5 fractions over the course of 1 week without the concurrent administration of chemotherapy. Long-course radiotherapy is typically defined as 45 to 50.4 Gy in 25-28 fractions with the administration of concurrent 5-fluoropyrimidine-based chemotherapy and is the standard approach in other parts of Europe and the United States. At present, two randomized trials have compared outcomes for short course radiotherapy with long-course chemoradiation showing no difference in respective study endpoints. Late toxicity data are lacking given limited follow-up. Although the ideal neoadjuvant regimen is controversial, our current bias is long-course chemoradiation to treat patients with locally advanced, resectable rectal cancer.

Does preoperative therapy optimize outcomes in patients with resectable pancreatic cancer?

The objective of this study was to compare survival between all patients with radiographically resectable adenocarcinoma of the proximal pancreas who underwent preoperative chemoradiation therapy (PRE-OP CRT) or surgical exploration first (SURGERY) with "intention to resect." Pancreatic cancer patients who undergo resection after PREOP CRT live longer than patients who undergo resection without PREOP CRT, a difference that may be attributable to patient selection. We retrospectively identified 236 patients with pancreatic head adenocarcinoma seen between 1999 and 2007 with sufficient data to be confirmed medically and radiographically resectable. The outcomes of 144 patients who underwent PREOP CRT were compared to those of 92 patients who proceeded straight to SURGERY. The groups were similar in age and gender. Tumors were slightly larger in the PREOP CRT group (mean 2.5 cm vs. 2.1 cm, P < 0.01), and there were trends toward more venous abutment (54% vs. 39%, P = 0.06) and a higher Charlson comorbidity index (P = 0.1). In the PREOP CRT group, 76 patients (53%) underwent resection, 28 (19%) had metastatic and 17 (12%) locally unresectable disease after PREOP CRT, and 23 (16%) were not explored due to performance status or loss to follow-up. In the SURGERY group, 68 patients (74%) underwent resection. Sixteen patients (17%) had metastatic and eight patients (9%) locally unresectable disease at exploration. In patients who underwent resection, the PREOP CRT group had smaller pathologic tumor size and lower incidence of positive lymph nodes than the SURGERY group but no difference in positive margins or need for vascular resection. Median overall survival (OS) in patients undergoing resection was 27 months in the PREOP CRT group and 17 months in the SURGERY group (P = 0.04). Median OS in all patients treated with PREOP CRT or surgically explored with intention to resect was 15 and 13 months, respectively, with superimposable survival curves. Despite a lower resection rate, the PREOP CRT group as a whole had a similar OS to the SURGERY group as a whole. For patients who underwent resection, those in the PREOP CRT had longer survival than those in the SURGERY group, suggesting that PREOP CRT allows better patient selection for resection. PREOP CRT should be considered an acceptable alternative for most patients with resectable pancreatic cancer.

Corrigendum: Brain Metastases from Esophageal Squamous Cell Carcinoma: Clinical Characteristics and Prognosis.

[This corrects the article DOI: 10.3389/fonc.2021.652509.].

Comparing Outcomes of Oligometastases Treated with Hypofractionated Image-Guided Radiotherapy (HIGRT) with a Simultaneous Integrated Boost (SIB) Technique versus Metastasis Alone: A Multi-Institutional Analysis.

PURPOSE: We previously reported on the clinical outcomes of treating oligometastases with radiation using an elective simultaneous integrated boost technique (SIB), delivering higher doses to known metastases and reduced doses to adjacent bone or nodal basins. Here we compare outcomes of oligometastases receiving radiation targeting metastases alone (MA) versus those treated via an SIB. METHODS: Oligometastatic patients with ≤5 active metastases treated with either SIB or MA radiation at two institutions from 2013 to 2019 were analyzed retrospectively for treatment-related toxicity, pain control, and recurrence patterns. Tumor metastasis control (TMC) was defined as an absence of progression in the high dose planning target volume (PTV). Marginal recurrence (MR) was defined as recurrence outside the elective PTV but within the adjacent bone or nodal basin. Distant recurrence (DR) was defined as any recurrence that is not within the PTV or surrounding bone or nodal basin. The outcome rates were estimated using the Kaplan-Meier method and compared between the two techniques using the log-rank test. RESULTS: 101 patients were treated via an SIB to 90 sites (58% nodal and 42% osseous) and via MA radiation to 46 sites (22% nodal and 78% osseous). The median follow-up among surviving patients was 24.6 months (range 1.4-71.0). Of the patients treated to MA, the doses ranged from 18 Gy in one fraction (22%) to 50 Gy in 10 fractions (50%). Most patients treated with an SIB received 50 Gy to the treated metastases and 30 Gy to the elective PTV in 10 fractions (88%). No acute grade ≥3 toxicities occurred in either cohort. Late grade ≥3 toxicity occurred in 3 SIB patients (vocal cord paralysis and two vertebral body compression), all related to the high dose PTV and not the elective volume. There was similar crude pain relief between cohorts. The MR-free survival rate at 2 years was 87% (95% CI: 70%, 95%) in the MA group and 98% (95% CI: 87%, 99%) in the SIB group (p = 0.07). The crude TMC was 89% (41/46) in the MA group and 94% (85/90) in the SIB group. There were no significant differences in DR-free survival (65% (95% CI: 55-74%; p = 0.24)), disease-free survival (60% (95% CI: 40-75%; p = 0.40)), or overall survival (88% (95% CI: 73-95%; p = 0.26)), between the MA and SIB cohorts. CONCLUSION: Both SIB and MA irradiation of oligometastases achieved high rates of TMC and similar pain control, with a trend towards improved MR-free survival for oligometastases treated with an SIB. Further investigation of this technique with prospective trials is warranted.

Brain Metastases from Esophageal Squamous Cell Carcinoma: Clinical Characteristics and Prognosis.

PURPOSE: Due to the low incidence of intracranial disease among patients with esophageal cancer (EC), optimal management for these patients has not been established. The aim of this real-world study is to describe the clinical characteristics, treatment approaches, and outcomes for esophageal squamous cell carcinoma (ESCC) patients with brain metastases in order to provide a reference for treatment and associated outcomes of these patients. METHODS: Patients with ESCC treated at the Fourth Hospital of Hebei Medical University between January 1, 2009 and May 31,2020 were identified in an institutional tumor registry. Patients with brain metastases were included for further analysis and categorized by treatment received. Survival was evaluated by the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Among 19,225 patients with ESCC, 66 (0.34%) were diagnosed with brain metastases. Five patients were treated with surgery, 40 patients were treated with radiotherapy, 10 with systemic therapy alone, and 15 with supportive care alone. The median follow-up time was 7.3 months (95% CI 7.4-11.4). At last follow-up, 59 patients are deceased and 7 patients are alive. Median overall survival (OS) from time of brain metastases diagnosis was 7.6 months (95% CI 5.3-9.9) for all cases. For patients who received locoregional treatment, median OS was 10.9 months (95% CI 7.4-14.3), and survival rates at 6 and 12 months were 75.6% and 37.2%, respectively. For patients without locoregional treatment, median OS was 3.0 months (95% CI 2.5-3.5), and survival rates at 6 and 12 months were 32% and 24%, respectively. OS was significantly improved for patients who received locoregional treatment compared to those treated with systematic treatment alone or supportive care (HR: 2.761, 95% CI 1.509-5.053, P=0.001). The median OS of patients with diagnosis-specific graded prognostic assessment (DS-GPA) score 0-2 was 6.4 months, compared to median OS of 12.3 months for patients with DS-GPA >2 (HR: 0.507, 95% CI 0.283-0.911). CONCLUSION: Brain metastases are rare in patients with ESCC. DS-GPA score maybe a useful prognostic tool for ESCC patients with brain metastases. Receipt of locoregional treatment including brain surgery and radiotherapy was associated with improved survival.

Ipilimumab and Radiation in Patients with High-risk Resected or Regionally Advanced Melanoma.

PURPOSE: In this prospective trial, we sought to assess the feasibility of concurrent administration of ipilimumab and radiation as adjuvant, neoadjuvant, or definitive therapy in patients with regionally advanced melanoma. PATIENTS AND METHODS: Twenty-four patients in two cohorts were enrolled and received ipilimumab at 3 mg/kg every 3 weeks for four doses in conjunction with radiation; median dose was 4,000 cGy (interquartile range, 3,550-4,800 cGy). Patients in cohort 1 were treated adjuvantly; patients in cohort 2 were treated either neoadjuvantly or as definitive therapy. RESULTS: Adverse event profiles were consistent with those previously reported with checkpoint inhibition and radiation. For the neoadjuvant/definitive cohort, the objective response rate was 64% (80% confidence interval, 40%-83%), with 4 of 10 evaluable patients achieving a radiographic complete response. An additional 3 patients in this cohort had a partial response and went on to surgical resection. With 2 years of follow-up, the 6-, 12-, and 24-month relapse-free survival for the adjuvant cohort was 85%, 69%, and 62%, respectively. At 2 years, all patients in the neoadjuvant/definitive cohort and 10/13 patients in the adjuvant cohort were still alive. Correlative studies suggested that response in some patients were associated with specific CD4+ T-cell subsets. CONCLUSIONS: Overall, concurrent administration of ipilimumab and radiation was feasible, and resulted in a high response rate, converting some patients with unresectable disease into surgical candidates. Additional studies to investigate the combination of radiation and checkpoint inhibitor therapy are warranted.

A safety and survival analysis of neoadjuvant bevacizumab with standard chemoradiation in a phase I/II study compared with standard chemoradiation in locally advanced rectal cancer.

INTRODUCTION: Bevacizumab is increasingly being tested with neoadjuvant regimens in patients with localized cancer, but its effects on metastasis and survival remain unknown. This study examines the long-term outcome of clinical stage II/III rectal cancer patients treated in a prospective phase II study of bevacizumab with chemoradiation and surgery. As a benchmark, we used data from an analysis of 42 patients with locally advanced rectal cancer treated with a contemporary approach of preoperative fluoropyrimidine-based radiation therapy. MATERIALS AND METHODS: Outcome analyses were performed on 32 patients treated prospectively with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery as well as 42 patients treated with standard fluoropyrimidine-based chemoradiation. RESULTS: Overall survival, disease-free survival, and local control showed favorable trends in patients treated with bevacizumab with chemoradiation followed by surgery. Acute and postoperative toxicity appeared acceptable. CONCLUSIONS: Neoadjuvant bevacizumab with standard chemoradiation and surgery shows promising long-term efficacy and safety profiles in locally advanced rectal cancer patients.

Plasma soluble VEGFR-1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer.

We explored plasma and urinary concentrations of two members of the vascular endothelial growth factor (VEGF) family and their receptors as potential response and toxicity biomarkers of bevacizumab with neoadjuvant chemoradiation in patients with localized rectal cancer. The concentrations of VEGF, placental growth factor (PlGF), soluble VEGF receptor 1 (sVEGFR-1), and sVEGFR-2 were measured in plasma and urine at baseline and during treatment. Pretreatment values and changes over time were analyzed as potential biomarkers of pathological response to treatment as well as for acute toxicity in patients with locally advanced rectal cancer treated prospectively in 2002-2008 with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery in a phase I/II trial. Of all biomarkers, pretreatment plasma sVEGFR-1-an endogenous blocker of VEGF and PlGF, and a factor linked with "vascular normalization"-was associated with both primary tumor regression and the development of adverse events after neoadjuvant bevacizumab and chemoradiation. Based on the findings in this exploratory study, we propose that plasma sVEGFR-1 should be further studied as a potential biomarker to stratify patients in future studies of bevacizumab and/or cytotoxics in the neoadjuvant setting.

Intensity-modulated radiation therapy for anal cancer: toxicity versus outcomes.

The treatment of cancer of the anal canal has changed significantly over the past several decades. Although the abdominoperineal resection (APR) was the historical standard of care, a therapeutic paradigm shift occurred with the seminal work of Nigro, who reported that anal canal cancer could be treated with definitive chemoradiation, with APR reserved for salvage therapy only. This remains an attractive approach for patients and physicians alike and the standard of care in this disease. Now, nearly four decades later, a similar approach continues to be utilized, albeit with higher radiation doses; however, this strategy remains fraught with considerable treatment-related morbidities. With the advent of intensity-modulated radiation therapy (IMRT), many oncologists are beginning to utilize this technology in the treatment of anal cancer in order to decrease these toxicities while maintaining similar treatment efficacy. This article reviews the relevant literature leading up to the modern treatment of anal canal cancer, and discusses IMRT-related toxicity and disease-related outcomes in the context of outcomes of conventionally treated anal cancer.