Rodney F. Pommier

NANETS treatment guidelines: Well-differentiated neuroendocrine tumors of the stomach and pancreas

Well-differentiated neuroendocrine tumors (NETs) of the stomach and pancreas represent 2 major subtypes of gastrointestinal NETs. Historically, there has been little consensus on the classification and management of patients with these tumor subtypes. We provide an overview of well-differentiated NETs of the stomach and pancreas and describe consensus guidelines for the treatment of patients with these malignancies.

The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (NETs): Well-differentiated nets of the distal colon and rectum

Neuroendocrine tumors (NETs) of the distal colon and rectum are also known as hindgut carcinoids based on their common embryologic derivation. Their annual incidence in the United States is rising, primarily as a result of increased incidental detection. Symptoms of rectal NETs include hematochezia, pain, and change in bowel habits. Most rectal NETs are small, submucosal in location, and associated with a very low malignant potential. Tumors larger than 2 cm or those invading the muscularis propria are associated with a significantly higher risk of metastatic spread. Colonic NETs proximal to the rectum are rarer and tend to behave more aggressively. The incidence of rectal NETs in African Americans and Asians is substantially higher than in Caucasians. Colorectal NETs are generally not associated with a hormonal syndrome such as flushing or diarrhea. A multidisciplinary approach is recommended in diagnosing and managing hindgut NETs.

Treatment of metastatic carcinoid tumors using multimodality therapy of octreotide acetate, intra-arterial chemotherapy, and hepatic arterial chemoembolization

BACKGROUND Overall survival and quality of life in patients with metastatic carcinoid tumors depend on control of tumor growth and suppression of amine-induced symptoms. METHODS We report on a series of 10 patients with carcinoid tumors metastatic to the liver who were treated with long-term octreotide acetate therapy (100 to 500 micrograms three times a day), sequential intra-arterial 5-fluorouracil (5-FU) infusions, and hepatic tumor chemoembolization. RESULTS All 10 patients remained asymptomatic or had extremely mild symptoms after combined modality therapy (mean follow-up duration of 51.5 months). Sixty percent of the patients had a > 50% reduction of their tumor size (mean duration 42 months). An additional 30% experienced stabilization of tumor growth for 6 months or longer. Five of the 10 patients are currently alive. The mean group survival is 58 months since diagnosis (range 33 to 115) and 40 months since starting therapy (range 12 to 65). CONCLUSIONS Combining octreotide acetate, intra-arterial 5-FU, and tumor chemoembolization effectively retards tumor growth while providing excellent symptom control.

Synchronous colon primaries have the same prognosis as solitary colon cancers.

PURPOSE: This study was designed to determine the prognosis of patients with synchronous colon primary tumors. METHODS: An 18-year, multi-institutional database of 4,878 colon cancer patients was reviewed, and patients with synchronous tumors were identified. Survival for each group was calculated by the Kaplan-Meier method and compared using log-rank analysis. RESULTS: There were 160 patients (3.3 percent) with 339 synchronous tumors. Eight percent of these patients had more than two tumors at the time of diagnosis. TNM staging of all synchronous tumors was 12 percent Stage 0, 41 percent Stage I, 21 percent Stage II, 16 percent Stage III, and 7 percent Stage IV. Based on highest stage lesion, 1 percent of patients were at Stage 0, 28 percent Stage I, 33 percent Stage II, 25 percent Stage III, and 11 percent Stage IV. Disease-specific five-year survival by highest stage was 87 percent for Stage O or I, 69 percent for Stage II, 50 percent for Stage III, and 14 percent for Stage IV (all differences significant by log-rank test). These “highest stage” survivals for patients with synchronous tumors were not significantly different from survival of patients with same stage solitary tumors in our database or from survival of patients with solitary colon cancer in national tumor databases. CONCLUSION: For patients with synchronous colon cancers, survival is the same as for patients with solitary colon tumors on a stage-for-stage basis, when highest stage synchronous tumor is considered.

Pharmacokinetics, toxicity, and short-term results of cisplatin hyperthermic isolated limb perfusion for soft-tissue sarcoma and melanoma of the extremities

Fifty-nine patients with melanoma or soft tissue sarcoma of the extremities underwent hyperthermic isolated limb perfusion utilizing cisplatin and wide local excision. Doses of cisplatin ranged from 0.75 to 2 mg/kg. The mortality and morbidity rates were 0 and 6.8 percent, respectively. Pharmacokinetic studies indicate that cisplatin is rapidly bound to perfused tissues and remains bound for 1 month. Maximum tumor response in sarcomas occurs 1 to 2 weeks after perfusion, compared with 1 month after perfusions with l-phenylalanine mustard and actinomycin D. Local and regional recurrence rates were 0 and 3.4 percent, respectively, at 1 year. Further studies of hyperthermic limb perfusions with cisplatin are warranted.

Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (NET) have diverse clinical presentations. Patients with symptoms of hormone secretion may require specific medical interventions to control those symptoms prior to antitumor intervention. In some patients, tumors in the pancreas may be occult and specialized diagnostic imaging or surgery may be required for diagnosis. Other patients may present with more advanced disease, presenting with symptoms of tumor bulk rather than hormone secretion. Treatment options for patients with advanced pancreatic neuroendocrine tumors include surgical resection and hepatic directed therapies, including partial hepatectomy, hepatic artery embolization, or other ablative techniques. Streptozocin or temozolomide-based chemotherapy regimens are active against pancreatic NET, and can also play an important role in the palliation of patients with advanced disease. A number of biologically targeted agents targeting the VEGF and mTOR signaling pathways have recently shown promise, with recent trials showing treatment with the VEGFR tyrosine kinase inhibitor sunitinib or the mTOR inhibitor everolimus improves progression-free survival in patients with advanced NET.

Incidence and outcomes of contralateral breast cancers

BACKGROUND The significance of a contralateral breast cancer is largely unknown, making prophylactic mastectomy controversial. METHODS Differences between stages of initial and contralateral cancers were determined by t test. Survival distributions were compared by log-rank analyses and compared with Surveillance Epidemiology and End Results data for unilateral cancers. RESULTS Metachronous contralateral cancers occurred at a rate of .13% per year and were of significantly lower stage. Metachronous cancers adversely impacted survival for patients with low-stage initial cancers, but the interval between cancers was less than 36 months. Synchronous tumors occurred in 2.3% of patients; survival was worse than for patients with metachronous cancers. CONCLUSIONS Prophylactic mastectomy is unlikely to be beneficial because of the lower stages and low incidence of second cancers, even for patients with initial low-stage cancers.

Synchronous non-small cell lung cancers.

INTRODUCTION The few series of synchronous lung cancers have included small cell and carcinoid tumors. We wished to determine the prognosis for patients with synchronous non-small cell lung cancer (NSCLC). METHODS A database of 3034 lung cancer patients was reviewed for synchronous NSCLC. Survival was determined by Kaplan-Meier method and compared by log-rank analysis. RESULTS There were 27 patients (0.8%). Fourteen were completely resected (CR) and had a 5-year survival rate of 45% The 5-year survival rate for patients whose highest stage tumor was stage I or II was 38%, versus 0% for patients whose highest tumor stage of III (P = 0.01). The 5-year survival rate for patients with two stage I tumors was 41% versus 0% for patients with 2 stage III tumors (P = 0.03). The 5-year survival rate for patients treated with wedge resections was similar to that for patients treated with lobectomies or pneumonectomy (L/P). CONCLUSIONS We conclude that the prognosis for patients with synchronous NSCLC may not be dismal if both tumors are resectable and stage I or II. Wedge resections are an alternative for those who cannot tolerate L/P.

Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study

Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigators discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.

Serum peptide profiles in patients with carcinoid tumors

BACKGROUND Patterns of elevated serum peptides may reveal additional markers and permit better classification of tumors based on (secondary) peptide secretion. METHODS Fasting peptide profiles were obtained from 31 carcinoid patients. vasoactive intestinal peptide (VIP), pancreatic polypeptide (PP), neurotensin, substance P, gastrin-releasing polypeptide (GRP), calcitonin, gastrin, and pancreastatin were measured. Peptide elevation patterns were correlated with disease sites, syndrome, and survival. RESULTS Elevations in patients were as follows: VIP 0%, PP 13%, neurotensin 10%, substance P 20%, GRP 3%, calcitonin 10%, and gastrin 3%. There were no consistent patterns of elevated peptides with regard to site or syndrome. Pancreastatin was elevated in 81% of profiles and was the only abnormal peptide in 57% of patients. CONCLUSION Peptide profile results do not permit improved classification, predict syndrome development, or correlate with survival. In contrast, pancreastatin is elevated in most cases and may be utilized to monitor disease progression and evaluate response to therapy.