Afonso Ribeiro

A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma

Background5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) is superior to gemcitabine in patients with metastatic pancreatic cancer who have a good performance status. We investigated this combination as neoadjuvant therapy for locally advanced pancreatic cancer (LAPC).MethodsIn this retrospective series, we included patients with unresectable LAPC who received neoadjuvant FOLFIRINOX with growth factor support. The primary analysis endpoint was R0 resection rate.ResultsEighteen treatment-naïve patients with unresectable or borderline resectable LAPC were treated with neoadjuvant FOLFIRINOX. The median age was 57.5 years and all had ECOG PS of 0 or 1. Eleven (61 %) had tumors in the head of the pancreas and 9 (50 %) had biliary stents placed prior to chemotherapy. A total of 146 cycles were administered with a median of 8 cycles (range 3-17) per patient. At maximum response or tolerability, 7 (39 %) were converted to resectability by radiological criteria; 5 had R0 resections, 1 had an R1 resection, and 1 had unresectable disease. Among the 11 patients who remained unresectable after FOLFIRINOX, 3 went on to have R0 resections after combined chemoradiotherapy, giving an overall R0 resection rate of 44 % (95 % CI 22–69 %). After a median follow-up of 13.4 months, the 1-year progression-free survival was 83 % (95 % CI 59-96 %) and the 1-year overall survival was 100 % (95 % CI 85-100 %). Grade 3/4 chemotherapy-related toxicities were neutropenia (22 %), neutropenic fever (17 %), thrombocytopenia (11 %), fatigue (11 %), and diarrhea (11 %). Common grade 1/2 toxicities were neutropenia (33 %), anemia (72 %), thrombocytopenia (44 %), fatigue (78 %), nausea (50 %), diarrhea (33 %) and neuropathy (33 %).ConclusionsFOLFIRINOX followed by chemoradiotherapy is feasible as neoadjuvant therapy in patients with unresectable LAPC. The R0 resection rate of 44 % in this population is promising. Further studies are warranted.

EUS visualization and direct celiac ganglia neurolysis predicts better pain relief in patients with pancreatic malignancy (with video)

BACKGROUND EUS-guided celiac plexus neurolysis (EUS-CPN) improves pain control in patients with pancreatic cancer. EUS allows visualization of the celiac ganglion. OBJECTIVE To determine predictors of response to EUS-CPN in a cohort of 64 patients with pancreatic malignancy. DESIGN Retrospective analysis of prospective database. SETTING Academic medical center. PATIENTS Sixty-four patients with pancreatic cancer referred for EUS between March 2008 and January 2010. INTERVENTIONS EUS-CPN injected directly into celiac ganglia when visible by linear EUS or bilateral injection at the celiac vascular trunk. MAIN OUTCOME MEASUREMENTS Predictors of pain improvement at week 1 by univariate and multivariate analysis. RESULTS At week 1, 32 patients (50%) had a symptomatic response. In a multivariate model with 8 potential predictors, visualization of the ganglia was the best predictor of response; patients with visible ganglia were >15 times more likely to respond (odds ratio 15.7; P<.001). Tumors located outside the head of the pancreas and patients with a higher baseline pain level were weakly associated with a good response. LIMITATIONS Retrospective design and lack of blinding. CONCLUSIONS Visualization of celiac ganglia with direct injection is the best predictor of response to EUS-CPN in patients with pancreatic malignancy.

Endoscopic ultrasound restaging after neoadjuvant chemotherapy in esophageal cancer.

BACKGROUND:The role of endoscopic ultrasound (EUS) to evaluate treatment response postneoadjuvant therapy for restaging esophageal cancer prior to surgical resection is uncertain. Accuracy of EUS is lower but potential to predict response to chemoradiation indicates that EUS may be helpful prior to surgery.OBJECTIVE:To determine staging accuracy of EUS after neoadjuvant chemotherapy, predictors of tumor response, and survival in locally advanced esophageal cancer.METHODS:Single-center retrospective evaluation of patients with locally advanced esophageal cancer on a prospective chemotherapy study. Patients who underwent EUS without FNA pre- and postchemotherapy were included.RESULTS:A total of 49 patients (43 men and 6 women) were evaluated with EUS pre- and postneoadjuvant chemotherapy. Forty-seven patients had tumor localized at the GE junction and two had mid-esophageal lesions. The median survival time was 53 months. Tumor and nodal staging accuracy postchemotherapy were 60% (27 of 45). T-stage accuracy postchemotherapy was superior in patients without a response to chemotherapy (95.7% vs 26.1%, p < 0.0001). More than 50% in reduction of tumor thickness postchemotherapy was associated with tumor downstage and better survival. N0 disease on final pathology was the best predictor of improved survival.CONCLUSION:Accuracy of EUS postchemotherapy is lower than initial staging accuracy; therefore the ability to predict downstaging based on EUS is marginal. Pathology N1 disease postchemotherapy is the best predictor of survival. EUS staging postneoadjuvant chemotherapy should focus on improving nodal staging accuracy with FNA.

Full dose neoadjuvant FOLFIRINOX is associated with prolonged survival in patients with locally advanced pancreatic adenocarcinoma

BACKGROUND The efficacy of FOLFIRINOX for metastatic pancreatic cancer has led to its use in patients with earlier stages of disease. This study retrospectively analyzed a cohort of patients with locally-advanced pancreatic cancer (LAPC) treated with FOLFIRINOX. METHODS Between 2008 and 2013, 51 treatment-naïve patients with LAPC at a single institution received first-line FOLFIRINOX with neoadjuvant intent, at the full dose as described in the PRODIGE 4/ACCORD 11 study. Combined chemoradiation was administered for those who remained unresectable after maximum response to chemotherapy. The primary outcome measure was overall survival (OS), and secondary outcomes were progression-free survival (PFS) and margin-negative (R0) resection rate, and toxicity profile. RESULTS A total of 429 cycles of FOLFIRINOX were given with a median of 8 cycles (range 2-29) per patient; 66% of cycles were full dose. After chemotherapy, 27 (53%) received chemoradiation. The median OS was 35.4 months (95% CI 25.8-45). Ten (4 borderline resectable and 6 unresectable) patients had successful R0 resections; those who had R0 resections had a significantly longer survival than those who did not (3-year OS rate 67% versus 21%, log rank p = 0.042). Increasing number of full-dose cycles was significantly associated with increased survival. The toxicity profile was similar to previous reports of this regimen. CONCLUSIONS FOLFIRINOX is feasible as neoadjuvant therapy for LAPC. Although the R0 resection rate was only 20%, the median OS of almost 3 years appears promising. Dose intensity and duration were associated with increased survival in this study, arguing against dose attenuated versions of this regimen.

Notch Signaling Drives Stemness and Tumorigenicity of Esophageal Adenocarcinoma

Esophageal adenocarcinoma ranks sixth in cancer mortality in the world and its incidence has risen dramatically in the Western population over the last decades. Data presented herein strongly suggest that Notch signaling is critical for esophageal adenocarcinoma and underlies resistance to chemotherapy. We present evidence that Notch signaling drives a cancer stem cell phenotype by regulating genes that establish stemness. Using patient-derived xenograft models, we demonstrate that inhibition of Notch by gamma-secretase inhibitors (GSI) is efficacious in downsizing tumor growth. Moreover, we demonstrate that Notch activity in a patients ultrasound-assisted endoscopic-derived biopsy might predict outcome to chemotherapy. Therefore, this study provides a proof of concept that inhibition of Notch activity will have efficacy in treating esophageal adenocarcinoma, offering a rationale to lay the foundation for a clinical trial to evaluate the efficacy of GSI in esophageal adenocarcinoma treatment.

Evaluation of Fine Needle Aspiration vs. Fine Needle Capillary Sampling on Specimen Quality and Diagnostic Accuracy in Endoscopic Ultrasound–Guided Biopsy

OBJECTIVE To compare percutaneous and endoscopic ultrasound (EUS)-guided biopsy techniques. STUDY DESIGN From July 2005 to February 2006, all patients referred for EUS-guided fine needle aspiration (FNA) were considered. If inclusion criteria were met, the first 2 biopsy passes were performed without suction (fine needle capillary [FNC] sampling). Two additional passes were performed using the same needle with 10 mL of applied suction (FNA). A single blinded pathologist later retrospectively evaluated each set of slides. Fifty-three patients met inclusion criteria. The study group comprised pancreatic masses (23), lymph nodes (26), subepithelial masses (3) and liver lesion (1). There were 38 malignant and 15 benign lesions. RESULTS No statistically significant differences were found with the scoring systems considered in the study. In the subgroups of patients with pancreatic masses, lymph nodes, benign disease and malignant disease, no statistically significant outcomes were noted. CONCLUSIONS No difference exists between quality and diagnostic accuracy of specimens obtained from EUS-guided tissue acquisition via FNC and FNA. The decision to use FNC or FNA should be left to the discretion of the individual endosonographer.

Hepatocellular Carcinoma (HCC) with Portal Vein Invasion, Masquerading as Pancreatic Mass, Diagnosed by Endoscopic Ultrasound-Guided Fine Needle Aspiration (EUS-FNA)

Hepatocellular carcinoma (HCC) is a common cause of death among patients with cirrhosis, with epidemiologic data suggesting that the mortality rate in the United States is on the rise [1]. Although screening for HCC ultrasound and AFP every 6 months in patients with cirrhosis is recommended for early detection, small lesions are often missed. Portal vein thrombosis secondary to HCC invasion often results in clinical decompensation and is a contraindication to resection or liver transplantation [2]. As portal vein thrombosis secondary to clot is common among patients with cirrhosis, determination of a clear etiology is important in these patients. We report a case of HCC with portal vein thrombosis mimicking pancreatic cancer. The diagnosis was made by endoscopic ultrasound (EUS) and the presence of tumor thrombus in the portal vein was confirmed by fine needle aspiration (FNA).

EUS-guided fiducial placement after radical prostatectomy before targeted radiation therapy for prostate cancer recurrence

p fi r g t a n r r t u w o e d Intensity-modulated radiotherapy (IMRT) is a modality of image-guided radiation therapy that allows the delivery of high treatment doses while minimizing the effects on adjacent organs. IMRT is well-tolerated, with similar or less toxicity than 3-dimensional conformal radiotherapy. IMRT, however, requires the placement of fiducial markers to guide treatment delivery. Fiducials are particularly important in patients after radical prostatectomy because of the lack of a definitive target. Challenges also exist in clearly delineating the prostate bed because of postsurgical anatomical changes, such as shortening of the urethra. EUS-guided placement of gold fiducial markers before targeted radiation therapy is a novel clinical application of therapeutic linear EUS. Yang et al recently reported on 16 patients with newly diagnosed prostate cancer who underwent EUS placement of fiducials into the prostate gland before IMRT. Herein, we discuss a new application of linear EUS in patients with tumor recurrence after radical prostatectomy. Fiducials were placed into the prostate fossa in 6 postprostatectomy patients before salvage IMRT.

Phase II study of gemcitabine, oxaliplatin, and cetuximab in advanced pancreatic cancer.

ObjectiveLittle progress has been made in the treatment of pancreatic cancer (PC). This study evaluated the clinical activity of gemcitabine, oxaliplatin, and cetuximab (GOC) in patients with locally advanced or metastatic PC. MethodsThe study primary endpoint was progression-free survival (PFS). Eligible, chemotherapy-naive PC patients were treated with gemcitabine (1000 mg/m2 over 100 min) on day 1, oxaliplatin (100 mg/m2) on day 2, every 2 weeks, and weekly cetuximab, (loading dose of 400 mg/m2 on cycle 1 day 1 and 250 mg/m2 thereafter). It was expected that GOC treatment would extend the median PFS from 5.8 to 7.54 months, a relative increase of 30%, compared with gemcitabine and oxaliplatin (historical control). ResultsA total of 41 evaluable patients were enrolled. The overall response rate was 24%. Median PFS time was 6.9 months and median overall survival (OS) was 11.3 months. Patients with locally advanced disease had longer median PFS (12.4 vs. 4.7 mo) and OS (15.7 vs. 6.4 mo) compared with patients with metastatic disease. The most common grade 3 to 4 toxicities included neutropenia (32%), infection (with normal or grade 1 to 2 neutropenia, in 24%), neuropathy (17%), fatigue (15%), and rash (7%). Five patients (12%) discontinued study treatment without evidence of progression. Rash was not a significant prognostic factor affecting PFS or OS. ConclusionsGOC is a feasible combination with an acceptable toxicity profile. However, GOC did not significantly extend PFS in the overall patient population to consider it for further development.

Endoscopic ultrasound guided fine needle aspiration with fluorescence in situ hybridization analysis in 104 patients with pancreatic mass

Diagnosis of pancreatic malignancy is often based on cytological specimens collected by endoscopic ultrasound guided fine needle aspiration (EUS FNA). Several factors can decrease sensitivity of EUS FNA for pancreatic cancer: well‐differentiated tumors, pancreatitis, blood, necrosis and slides with low cellularity. The objective of this study is to report on the use of fluorescence in situ hybridization (FISH) analysis combined with cytology in pancreatic masses.