Pathologic Response to Primary Systemic Therapy With FOLFIRINOX in Patients With Resectable Pancreatic Cancer.

BACKGROUND: Primary systemic therapy in resectable pancreatic cancer is currently under investigation. FOLFIRINOX has been shown to be effective in both the adjuvant and metastatic settings and is increasingly being used on and off study in the neoadjuvant setting. The objective pathologic response elicited by this regimen in truly resectable disease has not as yet been widely reported. METHODS: This analysis focuses on 14 patients with resectable pancreatic cancer who were treated in a pilot study of primary systemic therapy, using 4 cycles of neoadjuvant FOLFIRINOX before surgery. A dedicated pancreatic pathologist reviewed all of the subsequent surgical specimens to assess the degree of tumor regression elicited by this approach, according to the scoring system proposed by Evans. RESULTS: Four patients (28.6%) had Evans grade I, 4 (28.6%) Evans grade IIa, 2 (14.2%) Evans grade IIb, and 4 (28.6%) Evans grade III response to the primary systemic therapy. There were no Evans grade IV responses. CONCLUSIONS: The results are intriguing with 28% of the specimens showing destruction of <10% of tumor cells, and only 28% achieving >90% destruction of tumor cells. The significant variation in response once again confirms the known heterogeneity in the biology of this cancer and clearly FOLFIRINOX is not equally effective in all patients. Future studies evaluating primary systemic therapy in pancreatic cancer should examine the optimal duration of therapy before surgery and should include a standardized pathologic grading scheme to better enable comparison of results.

Preoperative Modified FOLFIRINOX Treatment Followed by Capecitabine-Based Chemoradiation for Borderline Resectable Pancreatic Cancer: Alliance for Clinical Trials in Oncology Trial A021101.

IMPORTANCE: Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported. OBJECTIVE: To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting. DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014. INTERVENTIONS: Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan hydrochloride, 400 mg/m2 of leucovorin calcium, and then 2400 mg/m2 of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2 orally twice daily) prior to pancreatectomy. MAIN OUTCOMES AND MEASURES: Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate. RESULTS: The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration. CONCLUSIONS AND RELEVANCE: The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial's completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01821612.

Pancreatic cancer and FOLFIRINOX: a new era and new questions.

FOLFIRINOX (FFX) was introduced to clinical practice in 2010 following publication of the PRODIGE 4/ACCORD 11 study, which compared this novel regimen to gemcitabine in metastatic pancreatic cancer. Median overall survival, progression-free survival, and objective responses were all superior with FFX and there was improved time to definitive deterioration in quality of life. Despite initial concerns over toxicity, there has been rapid uptake of this regimen, both revolutionizing management and opening the door to innovative research. As experience with FFX has accrued, many questions have arisen including the management of toxicities, the impact of frequent modifications, the optimal number of cycles, integration with other regimens and modalities, interpretation of radiologic and serologic response, utility of molecular signatures, and potential benefit in unique clinical settings such as pre- and postsurgery. This review will closely examine these issues, not only to summarize current knowledge but also to fuel scientific debate.

CA 19-9 nonproduction is associated with poor survival after resection of pancreatic adenocarcinoma.

BACKGROUND: Carbohydrate antigen (CA) 19-9 is the most common serum biomarker used in pancreatic adenocarcinoma (PC). Elevated preoperative levels have been shown to correlate with more advanced stage, greater risk of unresectability, and overall worse survival. The prognostic value of CA 19-9 nonproduction, which is present in an estimated 5% to 15% of the population, is unclear. We sought to determine whether CA 19-9 nonproduction was associated with worse survival after PC resection. METHODS: We retrospectively reviewed our institution's prospective pancreatic database for all PC patients with documented preoperative CA 19-9 values who underwent resection with curative intent from March 1992 to August 2009. After excluding 10 perioperative deaths, 200 patients remained for analysis. RESULTS: Mean and median follow-up was 23.3 and 16.1 months, respectively. Median survival in months for patients with preoperative CA 19-9 levels in U/mL by category was as follows: normal (5.1 to 36.9): 32, nonproduction (≤ 5): 21, mildly elevated (37 to 99.9): 35, highly elevated (100+): 16. Factors significantly associated with worse overall survival were: nonwhite race, nonproduction or highly elevated preoperative CA 19-9 (≥ 100 U/mL), estimated blood loss ≥ 1 L, tumor size (≥ 2 cm), lymph node-positivity, and advanced (3/4) histologic grade. On multivariate analysis, only CA 19-9 nonproduction or highly elevated production, estimated blood loss ≥ 1 L, advanced histologic grade, and node positivity remained significant in the final model. CONCLUSIONS: CA 19-9 nonproduction is not associated with improved survival after pancreatic cancer resection, as has previously been asserted, when compared with patients with normal and elevated levels.

Comprehensive review of the diagnosis and treatment of biliary tract cancer 2012. Part II: multidisciplinary management.

Biliary tract cancers (gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma and selected periampullary cancers) accounted for 12,760 new cases of cancer in the USA in 2010. These tumors have a dismal prognosis with most patients presenting with advanced disease. Early, accurate diagnosis is essential, both for potential cure where possible and for optimal palliative therapy in all others. This review examines the currently available and emerging technologies for diagnosis and treatment of this group of diseases.

Comprehensive review of the diagnosis and treatment of biliary tract cancer 2012. Part I: diagnosis-clinical staging and pathology.

Biliary tract cancers (gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma, and selected periampullary cancers) accounted for 12,760 new cases of cancer in the USA in 2010. These tumors have a dismal prognosis with most patients presenting with advanced disease. Early, accurate diagnosis is essential, both for potential cure where possible and for optimal palliative therapy in all others. This review examines the currently available and emerging technologies for diagnosis and treatment of this group of diseases.

A phase II trial of neoadjuvant capecitabine combined with hyperfractionated accelerated radiation therapy in locally advanced rectal cancer.

OBJECTIVE: Preoperative treatment of rectal cancer with combined chemotherapy and radiation therapy has become a widely accepted strategy. The current challenge is to improve outcomes whereas minimizing morbidity and maximizing the potential for a sphincter sparing procedure. This study sought to evaluate the safety and efficacy of a combination of 2 novel approaches-accelerated, hyperfractionated radiation therapy and twice daily oral capecitabine. METHODS: Consenting patients with locally advanced T3-T4, N0-1, M0 rectal adenocarcinoma, located no further than 15 cm from the anal verge, were treated with twice daily fractions of 1.2 Gy M-F to a total of 50.4 Gy for T3 lesions and 55.2 Gy for T4 lesions. Concomitantly, the patients received capecitabine 825 mg/m twice per day 7 days per week. Patients were operated on 4 to 6 weeks after completion of therapy. RESULTS: Sixteen of 17 enrolled patients were eligible and all 16 completed the full course of treatment including definitive surgery. Eleven patients had a sphincter sparing procedure and 5 had an abdominoperineal resection. Tumor and/or nodal downstaging occurred in 81% of patients, 100% of resections were R0, and the sphincter preservation rate was 68%. There were 18% pathologic complete remissions and 68% of specimens were node negative with an additional 12% Nx owing to transanal excision. The therapy was well tolerated and there were no unexpected toxicities with only diarrhea reaching grade 3 in 4 patients. CONCLUSIONS: This novel approach to preoperative treatment of rectal adenocarcinoma was well tolerated and effective. Comparison with more established approaches appears justified.

A phase II trial of perifosine in locally advanced, unresectable, or metastatic pancreatic adenocarcinoma.

BACKGROUND: Perifosine, a heterocyclic alkylphosphocholine signal transduction inhibitor, has activity against multiple cell types in vitro. This is a phase II study to determine activity and toxicity of perifosine in pancreatic adenocarcinoma. PATIENTS AND METHODS: Previously untreated patients with locally advanced, unresectable, or metastatic pancreatic adenocarcinoma, performance status Eastern Cooperative Oncology Group 0 or 1, were enrolled. An oral loading dose of 900 mg was followed by 100 mg per day until progression or unacceptable toxicity. Response criteria in solid tumors (RECIST) methodology and a 2-stage design were used. Suspension could occur for inadequate response in the first cohort or for more than 25% grade 3 or greater toxicity. RESULTS: Ten patients were enrolled. Six received 1 month and 4 received 2 months of treatment. Four discontinued therapy as a result of progression and 2 because of clinical deterioration. Three died during treatment. One patient had stable disease but discontinued therapy as a result of unacceptable adverse events (95% confidence interval: 0.3-45%). There were no objective responses and all patients died of progressive disease. Median overall and progression-free survival was 1.85 months (95% confidence interval: 0.9-2.7) and 1.5 months (95% confidence interval: 0.9-1.9) respectively. CONCLUSION: The study was suspended and subsequently terminated as a result of unacceptable adverse events during the first stage. Perifosine does not appear to be worthy of further study in this group of patients.

Rationale and appropriate use of chemotherapy and radiotherapy for pancreatic ductal adenocarcinoma.

The emergence of effective systemic chemotherapy, along with the parallel development of new targeted cell signal inhibitors for pancreatic cancer treatment, has provided impetus for a re-examination of the appropriate use of chemotherapy and radiation therapy in this malignancy. In addition to exciting developments in the treatment of locally advanced and metastatic disease, new data have emerged regarding the efficacy of adjuvant and neoadjuvant therapy when combined with traditional surgical approaches such as a Whipple procedure. This review summarizes the sentinel clinical trials and discoveries that have influenced the development and deployment of scientifically based multidisciplinary care for today's patients, with a particular focus on modern radiation and chemotherapy.

Biliary adenofibroma: a rare neoplasm of bile duct origin with an indolent behavior.

We report a case of biliary adenofibroma in a 47-year-old woman, who presented with right upper quadrant pain for several months. Abdominal imaging revealed a 16-cm solid and cystic mass in the left hepatic lobe. Histologically, the tumor showed two distinct components: 1) cystic and tubular structures lined by low columnar to cuboidal biliary-type epithelium, and 2) a dense fibrous stroma composed of spindle-shaped cells with only mild nuclear pleomorphism and inconspicuous nucleoli. Mitoses and stromal invasion were absent. The glandular epithelium stained positively for keratin AE.3/Cam 5.2, cytokeratin 7, cytokeratin 19, carcinoembryonic antigen, and epithelial membrane antigen and had a low Ki-67 proliferative index. In addition, the epithelium was positive for D10 but did not stain for 1F6 or acid mucin with alcian blue stain. This staining pattern, similar to bile duct hamartoma (von Meyenburg complex) with which this tumor shares morphologic similarity, suggests that biliary adenofibroma originates from interlobular or larger bile ducts. Three years after a subtotal resection no metastasis or significant tumor growth was noted. However, given the marked nuclear p53 immunoreactivity and tetraploidy status observed in this tumor, we cannot exclude that biliary adenofibroma may represent a premalignant process that warrants complete resection and thorough histopathologic examination.