NETest in advanced high-grade gastroenteropancreatic neuroendocrine neoplasms.

Molecular blood biomarkers are lacking for high-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). To histologically distinguish between neuroendocrine carcinoma (NEC), neuroendocrine tumors G3 (NET G3), adenocarcinoma and MINEN is often challenging. The mRNA-based NETest has diagnostic, prognostic and predictive value in neuroendocrine tumors G1-2 but has not been studied in HG GEP-NEN. Patients with advanced HG GEP-NEN were prospectively included in an observational study. A blood sample was collected before the start of chemotherapy and pseudonymised before NETest was performed. NETest results are expressed as an activity index (NETest score) from 0 to 100. The normal score cut-off is 20. Histological sections were pseudonymised before centralized pathological re-evaluation. Samples from 60 patients were evaluable with the NETest. Main primary tumor sites were colon (14), rectum (12), pancreas (11) and esophagus (7). Re-classification: 30 NEC, 12 NET G3, 3 HG-NEN ambiguous morphology, 8 MiNEN, 3 adenocarcinomas with neuroendocrine differentiation (ADNE), 3 adenocarcinomas and 1 NET G2. Elevated NETest (>20) was seen in 38/45 (84%) HG GEP-NEN, all 17 large-cell NEC (100%), 11/13 (85%) small-cell NEC, all ambiguous cases and 7/12 (64%) NET G3. NETest was elevated in 5/8 (63%) MiNEN, 2/3 ADNE, however not in 3 adenocarcinomas. Median survival was 10.2 months (9.6-10.8 95%CI) for evaluable HG GEP-NEN treated with palliative chemotherapy (n = 39), and survival was significantly shorter in patients with NETest >60 with an OS of only 6.5 months. This is the first study to evaluate use of the NETest in advanced HG GEP-NEN. The NETest was almost always elevated in GEP-NEC and in all large-cell NEC. The NETest was also frequently elevated in NET G3 and MiNEN, however cases were limited. Baseline NETest was not predictive for benefit of chemotherapy, however a NETest >60 was prognostic with a shorter survival for patients receiving chemotherapy.

Results after surgical treatment of liver metastases in patients with high-grade gastroenteropancreatic neuroendocrine carcinomas.

BACKGROUND: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are generally characterized by synchronous metastases, high aggressiveness and a dismal prognosis. Current international guidelines do not recommend surgical treatment of liver metastases, however the existing data are scarce. The aim of this study was to evaluate the results of curatively intended resection/radiofrequency ablation (RFA) of liver metastases in patients with metastatic GEP-NEC. METHODS: 32 patients with a diagnosis of high-grade gastroenteropancreatic neuroendocrine neoplasm (Ki-67 > 20%) and with intended curative resection/RFA of liver metastases, were identified among 840 patients from two Nordic GEP-NEC registries. Tumor morphology (well vs poor differentiation) was reassessed. Overall survival (OS) and progression-free survival (PFS) was assessed by Kaplan-Meier analyses for the entire cohort and for subgroups. RESULTS: Median OS after resection/RFA of liver metastases was 35.9 months (95%-CI: 20.6-51.3) with a five-year OS of 43%. The median PFS was 8.4 months (95%-CI: 3.9-13). Four patients (13%) were disease-free after 5 years. Two patients had well-differentiated morphology (NET G3) and 20 patients (63%) had Ki-67 ≥ 55%. A Ki-67 < 55% and receiving adjuvant chemotherapy were statistically significant factors of improved OS after liver resection/RFA. CONCLUSION: This study shows a long median and long term survival after liver surgery/RFA for these selected metastatic GEP-NEC patients, particularly for the group with a Ki-67 in the relatively lower G3 range. Our findings indicate a possible role for surgical treatment of liver metastases in the management of this patient population.

A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial.

BACKGROUND: Maintenance treatment (mt) with bevacizumab (bev) ± erlotinib (erlo) has modest effect after induction chemotherapy in metastatic colorectal cancer (mCRC). We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies with bev ± erlo and low-dose capecitabine (cap). PATIENTS AND METHODS: Included patients had mCRC scheduled for first-line therapy, Eastern Cooperative Oncology Group (ECOG) 0-1 and no major comorbidities. Treatment with XELOX/FOLFOX or XELIRI/FOLFIRI + bev was given for 18 weeks. After induction, patients without progression were eligible for randomization to mt; KRAS wild-type (wt) patients were randomized to bev ± erlo (arms wt-BE, N = 36 versus wt-B, N = 35), KRAS mutated (mut) patients were randomized to bev or metronomic cap (arms mut-B, N = 34 versus mut-C, N = 33). Primary end point was progression-free survival (PFS) rate (PFSr) at 3 months after start of mt. A pooled analysis of KRAS wt patients from the previous ACT study was performed. RESULTS: We included 233 patients. Median age was 64 years, 62% male, 68% ECOG 0, 52% with primary tumor in situ. A total of 138 patients started mt after randomization. PFSr was 64.7% versus 63.6% in wt-B versus wt-BE, P = 1.000; and 75% versus 66.7% in mut-B versus mut-C, P = 0.579, with no significant difference in median PFS and overall survival (OS). In the pooled cohort, median PFS was 3.7 months in wt-B (N = 64) and 5.7 months in wt-BE (N = 62) (hazard ratios 1.03, 95% confidence interval 0.70-1.50, P = 0.867). The frequency of any grade 3/4 toxicities during mt was: 28%/58%/18%/15% (wt-B/wt-BE/mut-B/mut-C). CONCLUSIONS: Addition of erlo to bev as mt in KRAS wt mCRC did not significantly improve PFS or OS, but it did increase toxicity. KRAS status does not seem to influence the outcome of treatment with erlotinib. Metronomic cap warrants further investigation in mt strategies, given our explorative results. CLINICALTRIALSGOV: NCT01229813.

Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.

BACKGROUND: As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. PATIENTS AND METHODS: Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals. RESULTS: The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. CONCLUSIONS: Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.

Intrahepatic and systemic therapy with oxaliplatin combined with capecitabine in patients with hepatic metastases from breast cancer.

BACKGROUND: The aim was to evaluate activity and toxicity of hepatic arterial infusion of oxaliplatin in combination with capecitabine in patients with metastatic breast cancer with liver metastases and limited extrahepatic disease. PATIENTS AND METHODS: Sixteen consecutive patients received capecitabine 13 00mg/m(2) daily combined with oxaliplatin 85 mg/m(2) every two weeks. Seven patients alternated between intrahepatic and systemic oxaliplatin, and in 9 oxaliplatin was primarily given intrahepatic. Five patients had liver-only metastases and 11 had additionally bone metastases. The patients had received median two previous chemotherapeutic regimens for metastatic disease. RESULTS: The response rate was 50% and the stable disease (≥6 months) rate 44%. Median progression free and overall survival was 7.9 and 19.2 months, respectively. The toxicity was moderate with abdominal pain, neuropathy, and hand foot syndrome as the most common adverse events. CONCLUSION: The combination of capecitabine and intrahepatic/systemic therapy with oxaliplatin was active in pretreated patients with liver metastasis from breast cancer.

A phase II study of thalidomide and temozolomide in patients with brain metastases from malignant melanoma: lymphopenia correlates with response.

BACKGROUND: Central nervous system (CNS) metastases develop in nearly half of patients with advanced melanoma and in 15-20% CNS is the first site of relapse. Median overall survival is short, ranging from two to four months, and one-year survival rate is only 10-15%. THA has been shown to have both anti-angiogenetic and immuno-modulating effects. TMZ is an oral alkylating agent with an excellent oral bioavailability and it is highly lipophillic with an ability to penetrate the blood-brain barrier. TMZ and THA in combination were tested in patients with brain metastases from malignant melanoma. METHODS: Between June 2004 and February 2007 patients with measurable metastatic melanoma in progression and PS ≤ 1 received TMZ in a dose of 150 mg/m(2) qd for seven days, followed by seven days off therapy and THA in 200 mg qd, both orally administered. Concomitant treatment with steroids was allowed. PBMCs were collected from the last 14 consecutive patients for evaluation of immune parameters. RESULTS: Forty screened patients were eligible and evaluable for response, and 39 were evaluable for toxicity. 25 patients had asymptomatic and 15 symptomatic brain metastases. The toxicity was primarily grade 1-2 with no grade 4 or treatment-related deaths. Four patients had thromboembolic events grade 3. One patient obtained a CR and five a PR in the CNS, while two had CR and four had PR outside CNS. Overall response rate was 17.5%. We found a significant positive correlation between lymphopenia and objective response. CONCLUSIONS: The combination treatment was well tolerated but with more frequent thromboembolic events compared to single drug TMZ or THA. The treatment demonstrated activity in CNS as well as outside CNS. The correlation between lymphopenia and objective response needs further investigation.