Chemoradiation after FOLFIRINOX for borderline resectable or locally advanced pancreatic cancer.

BACKGROUND: The safety and efficacy of FOLFIRINOX (FX) followed by consolidative chemoradiation (CRT) in borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) has not been extensively studied. We sought to evaluate outcomes and toxicities of this regimen. METHODS: A retrospective review was performed of 33 patients with BRPC or LAPC treated with FX followed by CRT. Radiotherapy was directed at the primary tumor and any involved nodes (84.8% received 50-50.4 Gy with standard fractionation and concurrent capecitabine, while 15.2% of patients received 36 Gy in 15 fractions with weekly gemcitabine). Toxicities of FX and CRT were graded using Common Terminology Criteria for Adverse Events (CTCAE v4.0), and radiographic response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST). Overall survival (OS), distant metastasis-free survival (DMFS), and local control (LC) were calculated using Kaplan-Meier analyses, and a Cox proportional hazards model was used to assess the impact of clinicopathologic factors on OS. RESULTS: Median follow-up was 19.9 months and patients received a median of 6.4 months of chemotherapy (range, 2.2-12.0 months). There were more T4 tumors than T3 tumors (70% vs. 30%). Grade ≥3 toxicities were low, including fatigue (9.1%), diarrhea (6.1%), neuropathy (6.1%), and dehydration (6.1%). R0 surgical resection was achieved in 5 patients (15.2%) after CRT. Median OS was 22.0 months (91% at 1 year and 45% at 2 years). Median DMFS was 17.8 months (69% at 1 year and 35% at 2 years). LC was 84% at 1 year and 55% at 2 years. CONCLUSIONS: OS is promising with the use of FX in BRPC and LAPC, and consolidative CRT was well tolerated in this cohort. Therefore, the role of radiation after multi-agent chemotherapy should be further evaluated in prospective trials.

A Long-Term Survivor of Metastatic Pancreatic Adenocarcinoma: Free of Recurrence 12 Years After Treatment of Oligometastatic Disease.

Aggressive local therapy for patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC) has traditionally not been pursued due to high rates of distant progression. We describe a 62-year-old male initially presenting with resectable PDAC who underwent the Whipple procedure but developed multiple liver metastases within two months of starting adjuvant gemcitabine. Oxaliplatin was added to the regimen and complete resolution of the liver lesions resulted. He remained disease-free for five years until re-staging revealed a small lung nodule. This was resected and confirmed to be metastatic PDAC. After additional adjuvant gemcitabine, the patient remained free of recurrence for 12 years after diagnosis of metastatic disease and ultimately passed away from complications of ascending cholangitis associated with stricture at the biliary-enteric anastomosis site. He had no evidence of disease recurrence at the time of death. Next-generation sequencing of the tumor was unrevealing, showing only an activating mutation of KRAS and a deleterious mutation of tumor protein p53 (TP53). Our case suggests that while the prognosis for metastatic PDAC is poor, the population is nonetheless heterogeneous. Prognostic biomarkers are needed for the identification of patients for whom aggressive local treatment of oligometastatic PDAC may be warranted.

Capecitabine as a Radiosensitizer in Adjuvant Chemoradiotherapy for Pancreatic Cancer: A Retrospective Study.

AIM: Pancreatic cancer remains one of the deadliest cancer diagnoses and is the fourth leading cause of cancer-related deaths in the U.S. Surgery is the mainstay of treatment for the 20% for whom the tumor is resectable, however, controversy exists over the appropriate adjuvant therapy where local recurrence rates remain strikingly high (50-85%). We aimed to evaluate the safety and efficacy of adding capecitabine (a known radiosensitizer by direct and abscopal effects) to concurrent radiation in the adjuvant setting after resection of pancreatic adenocarcinoma. PATIENTS AND METHODS: We conducted a retrospective study of 63 patients diagnosed from 2004-2013 with histopathologically-confirmed stage I/II pancreatic cancer treated with a surgical resection followed by adjuvant concurrent chemoradiation to at least 45 Gy using 3D planning and capecitabine at 1,600 mg/m(2)/day (Monday-Friday) for 6 weeks. This was combined with either 4 months of gemcitabine at 1,000 mg/m(2) weekly for 3 out of 4 weeks or capecitabine at 2,000 mg/m(2) for 14 days every 3 weeks for a total of 4 months. RESULTS: The majority of patients were over 65 years old (71%), male (60%), had negative surgical margins (79%), had pancreatic head or neck involvement (71%), Eastern Cooperative Oncology Group performance score of 1 (71%), and a cancer antigen 19-9 in the range of 11-100 U/ml at the time of diagnosis (51%). Of the 63 patients reviewed, 61 patients (97%) completed concurrent chemoradiotherapy. Treatment was halted in one patient due to gastritis and a second for gastrointestinal bleeding. Otherwise, adverse reactions during concurrent chemoradiotherapy were well-tolerated and the majority were Common Terminology Criteria for Adverse Events grades 1 and 2. Grade 3 toxicity was anorexia (n=2) and hand and foot syndrome (n=2) and GI bleeding (n=1). The only grade 4 toxicities were anorexia (n=1) and fatigue (n=1). The median follow-up of patients at the time of analysis was 36 months. The median survival of the entire cohort was 23.5 (range=8.5-42) months. The 1-, 2- and 3-year survival rates were 80%, 35% and 25%, respectively. CONCLUSION: Concurrent chemoradiation using capecitabine as a radiosensitizer in the adjuvant setting for pancreatic cancer was completed by the vast majority of patients in this series. Treatment was relatively well-tolerated, and its efficacy seems comparable to that for historical controls. This study probably represents the largest yet reported using capecitabine in this setting. Future studies including an increased sample size are required.

Locally advanced unresectable pancreatic cancer.

Twenty-five percent of patients with pancreatic cancer present with locally advanced disease that is unresectable, and the treatment strategy for these patients is controversial, with options including chemotherapy alone, concurrent chemoradiation, or induction chemotherapy followed by chemoradiation. Abstracts presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting (#4001, #4126, and #4024) addressed local control, quality of life, and prognostic factors associated with current regimens of induction chemotherapy and subsequent chemoradiation.

Current strategies in chemoradiation for esophageal cancer.

Chemoradiotherapy (CRT) has an important role in the treatment of esophageal cancer in both the inoperable and the pre-operative settings. Pre-operative chemoradiation therapy is generally given to 41.4-50.4 Gy with platinum or paclitaxel based chemotherapy. The most common definitive dose in the U.S. is 50-50.4 Gy. New advances in CRT for esophageal cancer have come from looking for ways to minimize toxicity and maximize efficacy. Recent investigations for minimizing toxicity have focused advanced radiation techniques such as IMRT and proton therapy, have sought to further define normal tissue tolerances, and have examined the use of tighter fields with less elective clinical target volume coverage. Efforts to maximize efficacy have included the use of early positron emission tomography (PET) response directed therapy, molecularly targeted therapies, and the use of tumor markers that predict response.

The effect of a lung cancer care coordination program on timeliness of care.

BACKGROUND: Timeliness of care improves patient satisfaction and might improve outcomes. The CCCP was established in November 2007 to improve timeliness of care of NSCLC at the Veterans Affairs Connecticut Healthcare System (VACHS). PATIENTS AND METHODS: We performed a retrospective cohort analysis of patients diagnosed with NSCLC at VACHS between 2005 and 2010. We compared timeliness of care and stage at diagnosis before and after the implementation of the CCCP. RESULTS: Data from 352 patients were analyzed: 163 with initial abnormal imaging between January 1, 2005 and October 31, 2007, and 189 with imaging conducted between November 1, 2007 and December 31, 2010. Variables associated with a longer interval between the initial abnormal image and the initiation of therapy were: (1) earlier stage (mean of 130 days for stages I/II vs. 87 days for stages III/IV; P < .0001); (2) lack of cancer-related symptoms (145 vs. 60 days; P < .0001); (3) presence of more than 1 medical comorbidity (123 vs. 82; P = .0002); and (4) depression (126 vs. 98 days; P = .029). The percent of patients diagnosed at stages I/II increased from 32% to 48% (P = .006) after establishment of the CCCP. In a multivariate model adjusting for stage, histology, reason for imaging, and presence of primary care provider, implementation of the CCCP resulted in a mean reduction of 25 days between first abnormal image and the initiation of treatment (126 to 101 days; P = .015). CONCLUSION: A centralized, multidisciplinary, hospital-based CCCP can improve timeliness of NSCLC care, and help ensure that early stage lung cancers are diagnosed and treated.

A comparison of three treatment strategies for locally advanced and borderline resectable pancreatic cancer.

BACKGROUND: The optimal treatment strategy for locally advanced and borderline resectable pancreatic cancer is not known. We compared overall survival (OS), local control (LC), metastasis free survival (MFS), and percent of patients who were able to undergo successful surgical resection for three treatment strategies. METHODS: We retrospectively reviewed 115 sequentially treated cases of locally advanced (T4) or borderline resectable (T3 but unresectable) pancreatic cancer. Patients were treated with either chemotherapy alone (C), concurrent chemoradiation therapy (CRT), or chemotherapy followed by chemoradiation therapy (CCRT). We compared survival between groups using Kaplan-Meier analysis and Cox-proportional hazards models. RESULTS: Median follow-up was 18.7 months. Fifty-six (49%) patients had locally advanced disease. Of the patients who received chemotherapy up-front, 82/92 (89%) received gemcitabine-based chemotherapy. Of the patients receiving C alone, 11/65 (17%) were diagnosed with distant metastases or died before 3 months. The rate of successful surgical resection was 6/50 (12%) in patients treated with radiation therapy (CRT or CCRT). Median survival times for patients undergoing C, CRT, and CCRT were 13.9, 12.5, and 21.5 months respectively. Patients treated with CCRT experienced statistically significant improved OS and MFS compared to C alone (P=0.003 and P=0.012 respectively). There was no difference in LC between treatment groups. On multivariable analysis younger age (P=0.009), borderline resectable disease (P=0.035), successful surgery (P=0.002), and receiving chemotherapy followed by chemoradiation therapy (P=0.035) were all associated with improved OS. CONCLUSIONS: Treatment with CCRT is associated with improved median OS and MFS compared with C alone. This strategy may select for patients who are less likely to develop early metastases and therefore have a better prognosis.

Treatment of locally advanced pancreatic cancer: the role of radiation therapy.

Pancreatic cancer remains associated with an extremely poor prognosis. Surgical resection can be curative, but the majority of patients present with locally advanced or metastatic disease. Treatment for patients with locally advanced disease is controversial. Therapeutic options include systemic therapy alone, concurrent chemoradiation, or induction chemotherapy followed by chemoradiation. We review the evidence to date regarding the treatment of locally advanced pancreatic cancer (LAPC), as well as evolving strategies including the emerging role of targeted therapies. We propose that if radiation is used for patients with LAPC, it should be delivered with concurrent chemotherapy and following a period of induction chemotherapy.

Locally advanced pancreatic adenocarcinoma: where are we and where are we going? Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011.

Eight abstracts highlighting the continued evolution of the management of locally advanced pancreatic cancer were presented at the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium (Abstracts #195, #239, #259, #281, #287, #305, #307, #324). These studies address key issues including the role of novel targeted therapies, what chemotherapy regimen should be used in conjunction with radiotherapy, and whether locally advanced pancreatic cancer can be managed with chemotherapy alone.

A novel modified dynamic conformal arc technique for treatment of peripheral lung tumors using stereotactic body radiation therapy.

PURPOSE: To describe and compare a novel, modified dynamic conformal arc (MDCA) technique for lung stereotactic body radiation therapy with the standard noncoplanar beam (NCB) technique based on stereotactic body radiation therapy (SBRT) coverage, dose conformality, normal tissue constraints, and treatment time. MATERIALS AND METHODS: Twenty consecutive medically inoperable patients with early stage, peripheral, non-small cell lung cancer treated with SBRT using an NCB technique were re-planned with a novel MDCA technique. Treatment plans were compared based on Radiation Therapy Oncology Group (RTOG) 0236 criteria for planning treatment volume (PTV) coverage and normal tissue dose constraints, as well as high- and moderate-dose conformality. Treatment times necessary to deliver the NCB plans were compared with the times of a separate group of 12 consecutive patients treated with the MDCA technique at our institution. RESULTS: The MDCA technique resulted in improved coverage of the cranial and caudal regions of the PTV and generated plans that were significantly more conformal by all high-dose criteria proposed by the RTOG protocol. In terms of moderate-dose criteria, MDCA plans had a significantly lower maximum dose (2 cm from the PTV), whereas the ratio of the 50% dose volume to the volume of the PTV was equivalent between the 2 techniques. All normal tissue dose constraints proposed in the RTOG 0236 protocol were met by each plan, although the median lung V20 and mean lung dose were slightly higher in the MDCA plans, whereas the chest wall dose was slightly lower. A 42% reduction in treatment time was observed when patients treated with the NCB technique were compared with a separate cohort of 12 patients treated with the MDCA technique (P < .0001). CONCLUSIONS: The new MDCA technique described in this study resulted in enhanced PTV coverage, improved high- and moderate-dose conformality, simplified treatment planning, and reduced treatment time compared with results using the standard NCB technique.

Updates in locally advanced pancreatic cancer. Highlights from the "2010 ASCO Annual Meeting". Chicago, IL, USA. June 4-8, 2010.

Pancreatic cancer is the 4th leading cancer cause mortality in both men and women. Pancreatic cancer is usually diagnosed in the advanced setting, and only 10-15% of patients present with operable disease. About 25% are locally advanced and unresectable and the rest are metastatic. Studies presented at the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting highlighted both current treatment options and promising novel therapeutic agents and approaches.

New developments in the treatment of locally advanced pancreatic cancer. Highlights from the 45th ASCO annual meeting. Orlando, FL, USA. May 29-June 2, 2009.

The results of the trials presented at this year's ASCO annual meeting underline the challenges of not only treating but also studying locally advanced pancreatic cancer, with any appreciable effect of treatment gained at the cost of considerable toxicity. That response was observed in small numbers of patients in the presented trials speaks to the importance of rational selection of treatment in individual patients in order to achieve maximal survival with minimal treatment-associated morbidity. Further understanding of tumor biology and identification of both prognostic and predictive factors will help define personalized treatment approaches for individual patients.

Combining epidermal growth factor receptor inhibitors and radiation therapy in pancreatic cancer: small step or giant leap?

Targeting the epidermal growth factor receptor (EGFR) with small molecule inhibitors or monoclonal antibodies in combination with chemotherapy and radiation is a theoretically appealing strategy in pancreatic cancer. EGFR inhibitors have shown efficacy as radiosensitizers and activity against metastatic pancreatic cancer when combined with gemcitabine. This paper examines the available clinical data, with a focus on locally advanced, unresectable disease. Further studies with a focus on understanding the basic biology of EGFR inhibition are needed to identify an optimal multi-modality regimen.

Stereotactic body radiation therapy (SBRT) in pancreatic cancer: is it ready for prime time?

Pancreatic cancer is a devastating disease with few effective treatment modalities. Stereotactic body radiation therapy is a novel technique that takes advantage of the technologic advancements in image guidance and radiation dose delivery to direct ablative doses to tumors with acceptable toxicity that was not previously achievable with conventional techniques. Recent literature contains reports of stereotactic body radiation therapy in patients with locally advanced pancreatic tumors. This paper presents a summary of the current data and highlights the limitations and the promise. Further clinical study in the form of multi-institutional trials is warranted to establish the role of stereotactic body radiation therapy as a comparable noninvasive alternative to surgery.

Prognostic significance of cyclooxygenase-2 in oropharyngeal squamous cell carcinoma.

PURPOSE: To determine the relative prognostic significance of cyclooxygenase (COX)-2 expression in patients with oropharyngeal squamous cell carcinoma (SCC). EXPERIMENTAL DESIGN: This retrospective cohort study included 82 patients with SCC referred to the Department of Therapeutic Radiology at Yale-New Haven Hospital (Connecticut) between 1980 and 1999 who were treated with primary external beam radiotherapy or gross total surgical resection and postoperative radiotherapy. A microarray of archival tumor tissue was constructed and stained with monoclonal antibodies directed against COX-2 and scored for intensity by a pathologist blinded to the clinical outcomes of the patients. COX-2 immunoreactivity and clinicopathological data were analyzed with respect to survival endpoints using bivariate and multivariate techniques. RESULTS: Frequency of COX-2 overexpression was 45%. In multivariate analysis, COX-2 positivity predicted poor 3-year survival (P = 0.02; odds ratio = 0.41; 95% confidence interval, 0.20-0.84). Increasing age was significantly associated with increased 3-year survival (P = 0.03; odds ratio = 1.04; 95% confidence interval, 1.004-1.09). Positive COX-2 status trended toward predicting decreased 3-year disease-free survival. CONCLUSIONS: COX-2 was the most important predictor of poor survival in this patient cohort. In patients with oropharyngeal SCC treated with external-beam radiation therapy, overexpression of COX-2 may affect clinical outcome, and COX-2 may therefore prove valuable both as a prognostic factor and as a therapeutic target.