Does the addition of adjuvant intraoperative tumor bed chemotherapy during midgut neuroendocrine tumor debulking procedures benefit patients?

BACKGROUND: Midgut neuroendocrine tumor (NET) patients are often diagnosed at advanced stages with extensive mesenteric nodal and hepatic metastasis. The only potentially curative treatment is surgical tumor eradication. Despite an aggressive resection, macro and microscopic residual disease still may remain in the resection bed. We hypothesize that the application of 5-fluorouracil (5-FU) within the tumor bed will help eliminate microscopic residual disease. METHODS: Records of 189 patients who underwent extensive cytoreductive surgeries during 2003-2012 for advanced, midgut NETs with extensive mesenteric lymphadenopathy were reviewed. Eighty-six patients (46%) who had 5-FU saturated gel foam strips secured into their mesenteric resection sites served as the study group and a matching 103 patients (54%) who did not have such an intra-operative chemotherapy served as controls. Survival from the time of diagnosis and post-operative complications between the two groups were compared. RESULTS: Mortality rates at 30, 60 and 90 days post-operatively were 4%, 0%, 0% versus 2%, 0%, 2% for study and control groups, respectively. Major complications (Grades III & IV) at the same intervals were 0, 0, 1 versus 2, 3, 2 for study and control groups, respectively. Median survival was 236 months versus 148 months for the study and control groups, respectively 24 (P=0.15). CONCLUSIONS: Intraoperative tumor resection bed chemotherapy is a safe adjuvant without discernible toxicity. This procedure may provide survival benefits to midgut NET patients with extensive mesenteric lymphadenopathy undergoing extensive cytoreductive surgery. Further study in prospective trials must be conducted to determine definitive benefit to the NET patient.

Plasma Pancreastatin Predicts the Outcome of Surgical Cytoreduction in Neuroendocrine Tumors of the Small Bowel.

OBJECTIVES: Elevated pancreastatin (PST) levels have been shown to be associated with poor prognosis in small bowel neuroendocrine tumors (NETs). We hypothesized that plasma PST levels that remain elevated following surgical cytoreduction portend a poor prognosis in well-differentiated small bowel NETs. METHODS: Patients diagnosed with small bowel NETs who underwent surgical cytoreduction at our institution were identified. Demographics, histopathologic characteristics, and biochemical data were collected. Only patients who had serial preoperative PST (PreopPST) and postoperative PST (PostopPST) levels were included in this study. Patients were sorted into groups by PST level to assess their response to surgical cytoreduction (group 1, PreopPST/PostopPST normal; group 2, PreopPST elevated/PostopPST normal; group 3, PreopPST/PostopPST elevated). Survival rates were calculated from the date of surgery. RESULTS: PreopPST and PostopPST levels were collected from 300 patients. Patients in groups 1 (n = 74) and 2 (n = 81) had a significant survival advantage compared with patients in group 3 (n = 145) (P < 0.0001). Kaplan-Meier 5- and 10-year survival rates were as follows: group 1: 93% and 82%; group 2: 91% and 65%; and group 3: 58% and 34%, respectively. CONCLUSIONS: Serial monitoring of plasma PST is useful in predicting long-term survival following surgical cytoreduction and can be helpful to identify patients who have a poor prognosis.

Plasma Neurokinin A Levels Predict Survival in Well-Differentiated Neuroendocrine Tumors of the Small Bowel.

OBJECTIVES: Elevated neurokinin A (NKA) levels are associated with poor prognosis in patients with small bowel neuroendocrine tumors. We hypothesized that patients with NKA levels that remain elevated despite treatment with surgical cytoreduction have a poor prognosis. METHODS: Patients diagnosed with small bowel neuroendocrine tumors who underwent surgical cytoreduction at our institution were identified. Demographics, histopathologic characteristics, and biochemical data were collected. Patients were grouped by the trend of their NKA levels (group 1, continuously normal; group 2, transiently elevated but normalized after therapy; group 3, remained elevated despite therapy). Survival rates were calculated from the date of the patient's first NKA level. RESULTS: Serial NKA values after surgical cytoreduction were monitored in 267 patients. Kaplan-Meier 2-year, 5-year, and 10-year survival rates were as follows: group 1 (n = 157), 97%, 89%, and 62%; group 2 (n = 78), 99%, 90%, and 78%; and group 3 (n = 32), 88%, 69%, and 0%. Survival rates were statistically significant between groups 1 and 3 and between groups 2 and 3 (P < 0.01). CONCLUSIONS: Serial monitoring of plasma NKA levels is useful in identifying patients who have a poor prognosis. Elevated NKA levels can indicate the need for immediate therapeutic intervention.

Prognostic Factors in Typical and Atypical Pulmonary Carcinoids.

BACKGROUND: Typical and atypical carcinoids represent approximately 2% of all lung tumors. Survival of patients with typical bronchial carcinoids, unlike the survival of patients with most lung tumors, is generally long but dependent on stage. We report the findings of the Ochsner Medical Center/Louisiana State University (LSU) Health Sciences Center neuroendocrine tumor (NET) program. METHODS: A database with all patients seen at the Ochsner Medical Center/LSU NET program was queried for patients with bronchopulmonary NET. We included patients who had confirmed pathologic bronchopulmonary carcinoid and who had at least 1 clinic visit. Patients with large or small cell NETs or diffuse idiopathic pulmonary neuroendocrine cell hyperplasia were excluded. RESULTS: A total of 169 patients seen from January 1996 to March 2015 met the inclusion criteria. The mean age at diagnosis was 53 years. Of the tumors, 51% percent (86/169) were well-differentiated, 12% (21/169) were moderately differentiated, and 85% and 53% were positive on positron emission tomography and octreotide scanning, respectively. The 5- and 10-year survival rates were 88% and 81% for well-differentiated tumors and 80% and 42% for moderately differentiated tumors, respectively. The 10-year survival rates stratified by Ki-67 index ranges 0-2%, >2%-10%, and >10% were 90%, 72%, and 44%, respectively (P<0.05). CONCLUSION: Overall, patients with bronchial carcinoids have long 5- and 10-year survival rates. We found significant survival differences between nodal status, differentiation status, and carcinoid phenotype. Interestingly, the difference in survival stratified by Ki-67 indices was statistically significant despite its absence in the World Health Organization grading system. As with gastroenteropancreatic NETs, Ki-67 index could become a valuable prognostic indicator for bronchial carcinoids.

Aggressive Surgical Approach to the Management of Neuroendocrine Tumors: A Report of 1,000 Surgical Cytoreductions by a Single Institution.

BACKGROUND: Neuroendocrine tumors (NETs) are rare neoplasms. Our group has treated more than 2,000 NET patients and has performed more than 1,000 surgical cytoreductive procedures. STUDY DESIGN: Records of 834 NET patients who underwent surgical cytoreduction at our institution were reviewed. Demographic information, intraoperative findings, extent of disease, complications, and survival rates were calculated. RESULTS: Eight hundred patients underwent 1,001 cytoreductive operations. Sixty-five percent had small bowel primaries. One hundred and thirty-eight patients presented with an unknown primary site, which was localized intraoperatively in 89% of these cases. The intraoperative complication rate was 9%. The incidence of intraoperative carcinoid crisis was 1%. Mean ± SD operative time was 368 ± 146 minutes. Mean ± SD hospital stay was 9 ± 10 days. Minor postoperative complications occurred after 43% of procedures and major postoperative complications were noted after 19% of procedures. The 30-day postoperative mortality rate was 2%. Median overall survival (OS) for patients with pancreatic NETs was 124 months. The 5-, 10-, and 20-year OS rates for patients with pancreatic NETs were 67%, 51%, and 36%, respectively. The life expectancy difference (between OS and actuarial survival) after surgical cytoreduction for patients with pancreatic NETs was 16.6 years. Median OS for patients with small bowel NETs was 161 months. The 5-, 10-, and 20-year OS rates for patients with small bowel NETs were 84%, 67% and 31%, respectively. The life expectancy difference after surgical cytoreduction for patients with small bowel NETs was 11.7 years. CONCLUSIONS: Surgical cytoreduction in NET patients has low morbidity and mortality rates and results in prolonged survival. We believe that surgical cytoreduction should play a major role in the care of patients with NETs.

The Role of Capecitabine/Temozolomide in Metastatic Neuroendocrine Tumors.

BACKGROUND: Neuroendocrine tumors (NETs) are commonly treated with multimodality therapy. The combination of capecitabine and temozolomide (CAPTEM) has been suggested as a treatment option for patients with metastatic NETs. We present our experience with CAPTEM. METHODS: Data on NET patients who were placed on CAPTEM and received at least one cycle were obtained from a Velos eResearch database. Response rate was calculated by RECIST 1.1. Overall survival and progression-free survival (PFS) were calculated by the Kaplan-Meier survival method. RESULTS: A total of 29 patients (17 male and 12 female) were included. Median age at CAPTEM initiation was 58 years (range: 26-77). Primary tumors included 9 small bowel (31%), 15 pancreas (52%), 3 lung (10%), and 2 rectum (7%). Median number of CAPTEM cycles was 8 (range: 1-55). Partial response occurred in 5 patients (5 of 29, 17%); 14 patients (14 of 29, 48%) had stable disease, and 10 patients (10 of 29, 34%) had progressive disease. A total of 3 (20%) and 5 (33%) pancreatic NETs experienced partial response and stable disease, respectively. A total of 2 (14%) and 9 (64%) nonpancreatic NETs experienced partial response and stable disease, respectively. Partial response was noted in 1 patient (13%) and stable disease in 5 patients (63%) with Ki-67 values of less than 2%. In patients with Ki-67 values of 2%-20%, partial response was noted in 3 (19%) and stable disease in 8 (50%). Partial response and stable disease were noted in 1 patient each (20%) with Ki-67 values greater than 20%. Median PFS was 12 months. Adverse reactions caused dose reductions in 24% of patients. CONCLUSION: Although adverse reactions were experienced, most patients tolerated this regimen. CAPTEM should be considered as a reasonable treatment option for metastatic NET patients. IMPLICATIONS FOR PRACTICE: The role of chemotherapy in neuroendocrine tumors has evolved in recent years. The results of this study suggest that the combination of capecitabine and temozolomide provides an adequate treatment option and may prolong survival in patients with a wide variety of metastatic neuroendocrine tumors. Although prospective data are needed, this research adds to the abundance of retrospective experience with this combination that appears to show that capecitabine and temozolomide could potentially be an option for patients with advanced neuroendocrine tumors who have progressed on standard treatment.

Obturator Canal Lymph Node Metastasis from Rectal Carcinoid Tumors: Total Mesorectal Excision May Be Insufficient.

BACKGROUND: Optimal surgical treatment for small early rectal carcinoids is controversial. Large tumors (greater than 2 cm) and those with imaging evidence of lymph node metastasis are generally treated by low anterior resection (LAR) with total mesorectal excision (TME). We first observed and reported that midgut carcinoid with extensive mesenteric lymphadenopathy often develops alternated lymphatic drainage pathways. We hypothesize that rectal carcinoids have the same potential to develop alternated lymphatic pathways outside the mesorectal envelope, which allows tumor deposits to be missed by traditional TME. METHODS: Twenty-two consecutive rectal carcinoid surgical patient charts were reviewed to determine if alternated lymphatic drainage occurred and resulted in extra-mesorectal metastasis. We attempted to identify any risk factor(s) that may lead to developing such alternated lymphatic drainage pathways. RESULTS: Thirteen patients underwent initial LAR with TME (13/22, 59 %) and nine underwent a staged debulking for locoregional residual disease or regional/distant metastasis after previous resection (9/22, 41 %). Fourteen (14/22, 64 %) underwent radio-guided surgery in attempt to achieve a higher level of pelvic/distant metastatic disease detection and debulking. Six patients (6/22, 27 %) had obturator canal lymph node metastases confirmed histologically. CONCLUSIONS: Based on our study, at least 27 % of rectal carcinoid patients may have extra-mesorectal metastasis that would be missed by the traditional TME. Radio-guided surgery can identify and remove such metastasis. The effect of having such extra-mesorectal metastasis and its surgical removal on long-term survival has yet to be determined.

Elevated Plasma Pancreastatin, but Not Chromogranin A, Predicts Survival in Neuroendocrine Tumors of the Duodenum.

BACKGROUND: Neuroendocrine tumors (NETs) of the duodenum are rare, heterogeneous, and often indolent neoplasms. We hypothesized that elevated pancreastatin levels are an indicator of a poor prognosis in well-differentiated duodenal NETs. STUDY DESIGN: Data from patients diagnosed with a primary duodenal NET were analyzed. Patients that underwent esophogogastroduodenoscopy, endoscopic ultrasound, or exploratory surgery to localize their neoplasm and whose tumors were confirmed histologically were included. RESULTS: Eighty-four patients were diagnosed with duodenal NETs from January 1991 to January 2014. Seventy-five percent and 21% of patients had their tumor localized by esophogogastroduodenoscopy and endoscopic ultrasound, respectively. The remaining 4% were localized during exploratory surgery. The 5-year Kaplan-Meier survival rate for the entire cohort (N = 84) was 80%. Survival sorted by normal vs abnormal pancreastatin level was statistically significant (p < 0.0001). Five-year survival rates were 94% and 37% for normal and abnormal pancreastatin, respectively. In contrast, survival sorted by normal vs abnormal plasma chromogranin A level was not statistically significant (p = 0.24). CONCLUSIONS: Patients with primary duodenal NETs have high 5-year survival rates. Serial monitoring of plasma pancreastatin levels can identify patients who have a poor prognosis.