Jill Weber

Prognostic Validity of a Novel American Joint Committee on Cancer Staging Classification for Pancreatic Neuroendocrine Tumors

PURPOSE The American Joint Committee on Cancer (AJCC) staging manual (seventh edition) has introduced its first TNM staging classification for pancreatic neuroendocrine tumors (NETs) derived from the staging algorithm for exocrine pancreatic adenocarcinomas. This classification has not yet been validated. METHODS Patients with pancreatic NETs treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I to IV) based on the new AJCC classification. Kaplan-Meier analyses for overall survival (OS) were performed based on age, race, histologic grade, incidental diagnosis, and TNM staging (European Neuroendocrine Tumors Society [ENETS] v AJCC) using log-rank tests. Survival time was measured from time of initial diagnosis to date of last contact or date of death. Multivariate modeling was performed using Cox proportional hazards regression. Weighted Cohens κ coefficient was computed to evaluate the agreement of ENETS and AJCC classifications. RESULTS We identified 425 patients with pancreatic NETs. On the basis of histopathologic grade, 5-year survival rates for low-, intermediate-, and high-grade tumors were 75%, 62%, and 7%, respectively (P < .001). When using the ENETS classification, 5-year OS rates for stages I, II, III, and IV were 100%, 88%, 85%, and 57%, respectively (P < .001). Subsequently, using the AJCC classification, 5-year OS rates for stages I, II, III, and IV were 92%, 84%, 81%, and 57%, respectively (P < .001). Both the novel AJCC classification and the ENETS classification were highly prognostic for survival. CONCLUSION The AJCC TNM classification for pancreatic NETs is prognostic for OS and can be adopted in clinical practice.

Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated.

PURPOSE Stereotactic body radiation therapy (SBRT) provides high rates of local control (LC) and margin-negative (R0) resections for locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC), respectively, with minimal toxicity. METHODS AND MATERIALS A single-institution retrospective review was performed for patients with nonmetastatic pancreatic cancer treated with induction chemotherapy followed by SBRT. SBRT was delivered over 5 consecutive fractions using a dose painting technique including 7-10 Gy/fraction to the region of vessel abutment or encasement and 5-6 Gy/fraction to the remainder of the tumor. Restaging scans were performed at 4 weeks, and resectable patients were considered for resection. The primary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS Seventy-three patients were evaluated, with a median follow-up time of 10.5 months. Median doses of 35 Gy and 25 Gy were delivered to the region of vessel involvement and the remainder of the tumor, respectively. Thirty-two BRPC patients (56.1%) underwent surgery, with 31 undergoing an R0 resection (96.9%). The median OS, 1-year OS, median PFS, and 1-year PFS for BRPC versus LAPC patients was 16.4 months versus 15 months, 72.2% versus 68.1%, 9.7 versus 9.8 months, and 42.8% versus 41%, respectively (all P>.10). BRPC patients who underwent R0 resection had improved median OS (19.3 vs 12.3 months; P=.03), 1-year OS (84.2% vs 58.3%; P=.03), and 1-year PFS (56.5% vs 25.0%; P<.0001), respectively, compared with all nonsurgical patients. The 1-year LC in nonsurgical patients was 81%. We did not observe acute grade ≥3 toxicity, and late grade ≥3 toxicity was minimal (5.3%). CONCLUSIONS SBRT safely facilitates margin-negative resection in patients with BRPC pancreatic cancer while maintaining a high rate of LC in unresectable patients. These data support the expanded implementation of SBRT for pancreatic cancer.

Prognostic Validity of the American Joint Committee on Cancer Staging Classification for Midgut Neuroendocrine Tumors

PURPOSE The American Joint Committee on Cancer (AJCC) staging manual has introduced a TNM staging classification for jejunal-ileal (midgut) neuroendocrine tumors (NETs). This classification has not been validated in a population consisting solely of midgut NETs. The purpose of this study was to test the prognostic validity of the classification in such a population. METHODS Patients with jejunal and ileocecal NETs who were treated at the Moffitt Cancer Center between 2000 and 2010 were assigned stages (I through IV). Kaplan-Meier analyses for overall survival (OS) were performed on the basis of TNM stage and pathologic grade. Multivariate modeling was performed using Cox proportional hazards regression. RESULTS We identified 691 patients with jejunal-ileocecal NETs. The AJCC classification in aggregate was highly prognostic for OS (P < .001). Five-year OS rates for stages I through IV were 100%, 100%, 91%, and 72%, respectively. The survival difference between stages III and IV was significant (P < .001); the difference between stages I/II versus III was not statistically significant (P = .1). Among patients with stage IIIB tumors, 5-year survival rates were 95% for resectable tumors versus 78% for unresectable mesenteric tumors (P = .02). A proliferative threshold of five mitoses per 10 high-power fields (HPF) was of greater prognostic value than a threshold of two mitoses per 10 HPF for discriminating between low- and intermediate-grade tumors. CONCLUSION Stage I and II midgut NETs are associated with identical survival rates. Stage IIIB tumors are heterogeneous, with significant differences in survival observed between resectable mesenteric lymph nodes versus unresectable masses in the root of the mesentery. A higher mitotic cutoff of five per 10 HPF may lead to improved prognostic differentiation between low- and intermediate-grade tumors. Revisions to the current AJCC staging and grading classification may be warranted.

Relapse-free survival in patients with nonmetastatic, surgically resected pancreatic neuroendocrine tumors: an analysis of the AJCC and ENETS staging classifications.

Background:The risk of metastatic spread among patients with early-stage pancreatic neuroendocrine tumors has not been well established. The authors sought to evaluate whether the new TNM staging systems proposed by the American Joint Committee on Cancer (AJCC) and European Neuroendocrine Tumor Society (ENETS) are prognostic for relapse-free survival (RFS) after surgical resection. Methods:Patients with surgically resected localized or locally advanced pancreatic NETs treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I–III) based on the AJCC and ENETS classifications. RFS and overall survival were measured using Kaplan-Meier methodology, with log-rank testing for evaluation of the 2 tumor staging systems. Multivariate analysis was performed controlling for tumor grade, location, surgery type, functional hormonal status, and incidental diagnosis. Results:The authors identified 123 patients with nonmetastatic, surgically resected pancreatic NETs. When using the AJCC classification, 5-year RFS rates for stages I through III were 78%, 53%, and 33%, respectively (P < 0.01). Using the ENETS classification, 5-year RFS rates for stages I to III were 100%, 70%, and 53% (P < 0.18). When excluding patients who were referred after their metastatic recurrence, the 5-year RFS rates for stages I to III were 90%, 73%, and 66% according to the AJCC classification, and 100%, 84%, and 75% according to the ENETS classification. Recurrence rates peaked at approximately 2 years after surgery. Conclusions:The AJCC and ENETS TNM classifications for pancreatic NETs are prognostic for recurrence-free survival and can be adopted in clinical practice.

A phase II study of RO4929097 in metastatic colorectal cancer

BACKGROUND The Notch signalling pathway is activated in a variety of malignancies and has been implicated in colorectal cancer progression. One of the first steps in the Notch pathway activation is mediated by γ-secretase, a proteolytic enzyme which produces an activated intracellular Notch (ICN). RO4929097 is a selective inhibitor of γ-secretase. We tested the activity of RO4929097 in patients with metastatic, refractory colorectal cancer. PATIENTS AND METHODS Patients with metastatic colorectal cancer who had received at least two prior lines of systemic chemotherapy were enrolled on the study. Patients were treated with RO4929097 at its recommended phase II dose of 20mg daily, 3 days on and 4 days off continuously. Cycle length was 28 days. Imaging was performed every two cycles. Archival tissue specimens were stained immunohistochemically for components of the notch pathway: Notch1, ICN and the downstream target HES1. RESULTS Thirty-seven patients were enrolled of whom 33 were evaluable for toxicity and response. Immunohistochemical analysis of archival tissues demonstrated positive staining for the notch receptor as well as intracellular notch and the downstream gene HES1 in the majority of patients. Nevertheless, no objective radiographic responses were observed in this group and only six patients had stable disease as their best response. Median PFS was 1.8 months and median overall survival (OS) was 6.0 months. CONCLUSION In this study of RO4929097 in patients with refractory metastatic colorectal cancer, no radiographic responses were seen and time to progression was short, which suggests that RO4929097 at the study dose and schedule has minimal single agent activity in this malignancy.

Are patients with esophageal cancer who become PET negative after neoadjuvant chemoradiation free of cancer

BACKGROUND Esophageal cancer continues to increase in incidence. Many patients are presenting with stage II or greater disease and proceeding to neoadjuvant chemoradiation therapy before resection. Approximately 30% of patients will achieve a complete response and might not benefit from proceeding to resection. This study will examine the ability of PET to predict patients with a complete pathologic response. STUDY DESIGN A query of our IRB-approved esophageal database revealed 81 patients who underwent a pre- and postchemoradiation PET scan and then proceeded to esophageal resection. Statistical analysis was performed to determine the ability of PET to predict a complete pathologic response. RESULTS When comparing posttherapy PET with final pathology, it was determined that PET could not consistently differentiate a complete pathologic response from patients who still had persistent disease. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 61.8%, 43.8%, 70%, 35%, and 56%, respectively, for patients with a complete PET response after neoadjuvant therapy. CONCLUSIONS A complete PET response after neoadjuvant chemoradiation is not substantially predictive of a complete pathologic response. Patients should still be referred for resection unless distant metastases are identified.

Minimally invasive surgery for esophageal cancer: review of the literature and institutional experience.

BACKGROUND Esophageal cancer represents a major public health problem in the world. Several minimally invasive esophagectomy (MIE) techniques have been described and represent a safe alternative for the surgical management of esophageal cancer in selected centers with high volume and surgeons experienced in minimally invasive procedures. METHODS The authors reviewed the most recent and largest studies published in the medical literature that reported the outcomes for MIE techniques. RESULTS In larger series, MIE has proven to be equivalent in postoperative morbidity and mortality to the open esophagectomy. However, MIE has been associated with less blood loss, reduced postoperative pain, decreased time in the intensive care unit, and shortened length of hospital stay compared with the conventional open approaches. Despite limited data, no significant difference in survival stage for stage has been observed between open esophagectomy and MIE. CONCLUSIONS The myriad of MIE techniques complicates the debate for defining the optimal surgical approach for the treatment of esophageal cancer. Randomized controlled trials comparing MIE with conventional open esophagectomy are needed to clarify the ideal procedure with the lowest postoperative morbidity, best quality of life after surgery, and long-term survival.

Increased survival associated with surgery and radiation therapy in metastatic gastric cancer: a Surveillance, Epidemiology, and End Results database analysis.

Patients with metastatic gastric cancer have poor survival. The purpose of this study was to compare outcomes of metastatic gastric cancer patients stratified by surgery and radiation therapy.

A multi-institutional, phase II open-label study of ganitumab (AMG 479) in advanced carcinoid and pancreatic neuroendocrine tumors

The IGF pathway has been implicated in the regulation of neuroendocrine tumor (NET) growth, and preliminary studies suggested that ganitumab (AMG 479), a human MAB against IGF1R, may have antitumor activity in this setting. We performed a two-cohort phase II study of ganitumab in patients with metastatic progressive carcinoid or pancreatic NETs (pNETs). This open-label study enrolled patients (≥18 years) with metastatic low- and intermediate-grade carcinoid or pNETs. Inclusion criteria included evidence of progressive disease (by Response Evaluation Criteria in Solid Tumors (RECIST)) within 12 months of enrollment, ECOG PS 0-2, and fasting blood sugar <160  mg/dl. Prior treatments were allowed and concurrent somatostatin analog therapy was permitted. The primary endpoint was objective response. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Sixty patients (30 carcinoid and 30 pNETs) were treated with ganitumab 18  mg/kg every 3 weeks, among whom 54 patients were evaluable for survival and 53 patients for response. There were no objective responders by RECIST. The median PFS duration was 6.3 months (95% CI, 4.2-12.6) for the entire cohort; 10.5 months for carcinoid patients, and 4.2 months for pNET patients. The OS rate at 12 months was 66% (95% CI, 52-77%) for the entire cohort. The median OS has not been reached. Grade 3/4 AEs were rare and consisted of hyperglycemia (4%), neutropenia (4%), thrombocytopenia (4%), and infusion reaction (1%). Although well tolerated, treatment with single-agent ganitumab failed to result in significant tumor responses among patients with metastatic well-differentiated carcinoid or pNET.

Cyst Fluid Carcinoembryonic Antigen Level Is not Predictive of Invasive Cancer in Patients with Intraductal Papillary Mucinous Neoplasm of the Pancreas

CONTEXT Cyst fluid CEA concentration>192 ng/mL has proven accurate to differentiate mucinous from non-mucinous pancreatic cystic neoplasms. It is unclear whether the degree of cyst fluid CEA elevation is predictive of malignant behavior in IPMNs. OBJECTIVES To determine whether elevated cyst fluid CEA concentrations were predictive of invasive cancer. DESIGN Cross sectional study. SETTING Single National Cancer Institute comprehensive cancer care center experience. PATIENTS 47 patients underwent preoperative EUS-FNA with cyst fluid analysis and surgical resection of an IPMN over a 9 year period. MAIN OUTCOME MEASUREMENTS Cyst fluid CEA concentrations among the four grades associated with IPMN (low grade dysplasia, moderate dysplasia, high grade dysplasia, and invasive cancer). RESULTS The mean±standard deviation cyst fluid CEA concentration increased as the pathology progressed from low grade dysplasia (1,261±1,679 ng/mL) to moderate dysplasia (7,171±22,210 ng/mL) to high grade dysplasia (10,807±36,203 ng/mL). However, the mean CEA level decreased (462±631 ng/mL) once invasive cancer developed (P=0.869). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of a cyst fluid CEA concentration greater than 200 ng/mL for the diagnosis of malignant IPMN (cases of high grade dysplasia and invasive IPMN) was 52.4%, 42.3%, 42.3%, 52.4% and 46.8%, respectively. LIMITATIONS Single center experience, small patient numbers, retrospective data collection. CONCLUSION The degree of cyst fluid CEA elevation is a poor predictor of malignant degeneration within IPMNs. Clinical management decisions regarding surgical resection should not be based upon degree of cyst fluid CEA elevation.