2006 em a /em ), thalidomide (Kulke em et al /em
2006 em a /em ), thalidomide (Kulke em et al /em . 2?h following ingestion of the first TMZ capsule regardless of the co-administration of metoclopramide 20mg orally. Two patients developed grade I neutropenia that required discontinuation of TMZ capsules for 1 week. One patient developed Grade II thrombocytopenia, and TMZ treatment was discontinued and restarted 3 weeks after the platelet count recovered. Two patients developed mild hypertension, most probably related (R)-GNE-140 to BVZ that was treated with oral antihypertensives. There were no side effects related to the use of the somatostatin (R)-GNE-140 analogue. All patients had elevated CgA levels before initiation of treatment. Of the 14 evaluable patients, 57% (8/14) had a 50C100% drop, 35% (5/14) had a 25C50% drop or 25% increase and 7% (1/14) had increase in CgA levels. Radiological responses included one (7%) complete response (CR), eight (57%) partial responses (PRs), three (21%) stable diseases (SDs) and two (14%) progressive diseases (PDs). Fifty-seven per cent (8/14) of patients achieved a PR after a median of 12.5 (range 8C20) cycles. Two of these patients completed 12 and 16 cycles, respectively, and their best radiological responses are shown in Fig. 1. Three (21.5%) patients had prolonged periods of SD; no radiological change was detected over a median of 12.6 (range 11C15) cycles. Two (14%) patients had PD after the fourth and sixth cycles and discontinued their treatment. In evaluable patients, the median TTP was 36 weeks (range 10C60 weeks, mean 33.50, s.d. 14.37, 95% confidence interval=25.2C41.8). In our cohort of patients, only five had tumour with Ki-67 6%. Of these, one had PD (lung), three had SD and only one had a PR as described in the first case above. Open in a separate window Figure 1 Downstaging of gastroenteropancreatic tumours (arrows) after TeBeSa combination therapy. MRI details shown before treatment (a) and (c) and after six cycles (b) and (d) for two patients with a pancreatic (a)/(b) and a duodenal tumour (c)/(d). During the past 4 years, there have been six reports showing activity of TMZ in patients with advanced NETs. These included a monotherapy protocol (Ekeblad em et al /em . 2007), three different combinations of TMZ with BVZ (Kulke em et al /em . 2006 em a /em ), thalidomide (Kulke em et al /em . 2006 em b /em ) and everolimus (Kulke em et al /em . 2010) and two reports investigating the combination of TMZ with capecitabine (Strosberg em et al /em . 2011, Welin em et al /em . 2011). However, previous protocols differ from that used in this study in the TMZ administration schedule, as in all of these studies, TMZ was administered at a higher dose for fewer days (Kulke em et al /em . 2006 em a /em , em b /em , 2010, Ekeblad em et al /em . 2007, Strosberg em et al /em . 2011, Welin em et al /em . 2011). Our study, although sample size is small, supports the use of a (R)-GNE-140 continuous daily dose of 100?mg TMZ as the overall response rate (PR and CR rate) was 64%, compared with previously reported that ranged between 16 and 45% (Kulke em et al AMLCR1 /em . 2006 em a /em , em b /em , 2010). There have been two studies testing TMZ monotherapy or in combination with capecitabine in advanced NETs reporting different response rates (70 and 33%; Strosberg em et al /em . 2011, Welin em et al /em . 2011). This difference could be attributed to the different histological groups of patients included in the two studies as well as to the fact that in the first study patients were chemotherapy naive. In our study, 80% of patients were previously treated with chemotherapy. Although we did not examine MGMT expression, the high percentage of responses observed is in accordance with an earlier observation, suggesting that protracted administration of TMZ even leads to significant and prolonged depletion of MGMT activity (Tolcher em et al /em . 2003). However, a recent retrospective study on patients with advanced NETs receiving TMZ suggested that MGMT (R)-GNE-140 methylation status did not correlate with clinical responses (Welin em et al /em . 2011). In our small cohort of patients, therapeutic responses were accompanied by a grade III vomiting and mild myelosuppression that were manageable compared to previous studies, which reported grade IIICIV myelosuppression (Kulke em et al /em . 2006 em b /em , Ekeblad em et al /em . 2007). In studies thus far, the majority of responses to chemotherapy, including TMZ, have been observed in pancreatic NETs (Kulke em et al /em . 2006 em a /em , em b /em , Ekeblad em et al /em . 2007, Modlin em et al /em . 2008, Strosberg em et al /em . 2011, Welin em et al /em . 2011). Although our study has limitations such as the heterogeneity of tumour subtypes and the small number of patients included (Kulke em et al /em . 2011), it supports the investigation of metronomic TMZ chemotherapy in pancreatic and (R)-GNE-140 non-pancreatic NETs. It has previously been suggested that NETs with Ki-67 LI more than 10% maybe responsive to chemotherapy at an earlier line compared with NETs with Ki-67 LI 5% that are preferably treated with biological therapies (Oberg 2002)..