Neuroendocrine tumors (NETs) comprise a heterogeneous group of rare malignancies. These tumors can be classified according to their organ of origin as well as according to their degree of differentiation.1 Well-differentiated endocrine carcinomas are considered low-grade malignancies, but 20% to 50% of patients present with metastases at the time of diagnosis.2, 3 Once metastases are present, patients are usually not curable, but may live for long periods of time, up to several years. Several treatment options are available for patients with metastatic disease, ranging from watchful waiting to chemotherapy, transcatheter arterial chemoembolization, and liver transplantation for liver metastases. The precise role and the best sequence for these different therapies are currently not known for several reasons: rarity and heterogeneity of the disease, lack of randomized trials, and lack of consensus between experts. The European Neuroendocrine Tumor Society has recently released guidelines for pathological diagnosis and staging of endocrine tumors,4, 5 which derive from consensus conferences held in 2006 and 2007. These guidelines may help homogenize the management of these rare tumors in the future.
Most reports have addressed the efficacy of chemotherapy in the first-line setting, with response rates of 20% to 35%.6 Combinations including streptozocin, 5-fluorouracil, or doxorubicin have yielded only modest response rates, and are associated with significant toxicity. These combinations are, however, considered to be the most efficient regimens available for patients with carcinoid and pancreatic islet cell tumors.7-9 Currently few data exist regarding chemotherapy for metastatic endocrine carcinoma beyond first line. A prospective study from the Eastern Cooperative Oncology Group investigated the activity of single-agent dacarbazine in patients failing streptozocin-based regimens and reported only modest activity in this setting.10 Although there is currently no standard therapy after failure of streptozocin combination chemotherapy, several treatment options are available aside from chemotherapy: promising results with peptide receptor radionuclide therapy were recently reported by Kwekkeboom et al using (177Lu-DOTA0, Tyr3)octreotate11; several targeted therapies are also currently under active investigation, and preliminary reports of promising activity have been recently reported for everolimus and sunitinib.12, 13 However, chemotherapy regimens with less associated toxicity than streptozocin-based regimens are needed.
Gemcitabine is a nucleoside analog with structural similarities to cytarabine, and was widely used in the treatment of patients with advanced pancreatic adenocarcinoma.14 Kulke et al reported its use as a single agent in 18 patients with metastatic NETs. Although treatment was well tolerated, no radiological responses were observed, 65% of patients experienced disease stabilization, and the median overall survival was <1 year.15
Oxaliplatin is a platinum analogue with a favorable safety profile in comparison with other platinum derivatives and has significant activity in various gastrointestinal cancers.16-19 Tetzlaff et al first reported the response to an oxaliplatin-based regimen in a patient with metastatic carcinoid tumor in 2005.20 Bajetta et al recently reported the interesting results of a phase 2 trial of capecitabine and oxaliplatin combination in patients with advanced untreated neuroendocrine tumor. The response rate in the 27 patients with low-grade neuroendocrine tumor was 30% (8 of 27).21 Several phase 2 trials are currently ongoing with oxaliplatin-based regimens in patients with well-differentiated NETs.21-23
The favorable toxicity profile of gemcitabine-oxaliplatin combination (GEMOX), together with the significant antitumor activity in several gastrointestinal malignancies,17, 19 led us to evaluate its efficacy and tolerability for patients with metastatic NETs who failed 1 or several previous chemotherapy regimens and/or biotherapy. To our knowledge, the current study is the first to evaluate GEMOX in this setting.
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- MATERIALS AND METHODS
- Conflict of Interest Disclosures
We report here our experience with GEMOX chemotherapy for the treatment of patients with well-differentiated advanced progressive NETs. In our hands, this combination was feasible, with acceptable toxicity in the setting of heavily pretreated patients, albeit doses were adapted for 5 patients. Six patients discontinued chemotherapy because of oxaliplatin-related neurotoxicity, no grade 4 toxicity was observed, and no treatment-related death was recorded. The overall response rate was 17%, 67% of patients had stable disease, and the median PFS was 7 months.
In the setting of first-line therapy for advanced disease, streptozocin-containing regimens produce objective response in 30% to 35% of patients with islet-cell carcinoma, with PFS of 18-24 months. However, PFS is usually shorter when patients receive these combinations as second-line therapy.27, 28 In patients with well-differentiated gastrointestinal endocrine carcinomas, streptozocin-based combinations (usually with 5-fluorouracil) show response rates of 10% to 20% with PFS of 5 to 7 months.8, 10 Other combinations such as 5-fluorouracil-epirubicin-dacarbazine seem to have similar activity.29 Finally, patients with metastatic pulmonary carcinoids are usually treated with platinum-based chemotherapy, but results are disappointing overall.30, 31
After failure with these “standard” first-line regimens, no single chemotherapy regimen has emerged as a standard for second-line therapy. In a randomized phase 2/3 study from the Eastern Cooperative Oncology Group, 67 patients with carcinoid tumors received dacarbazine in a crossover arm after failure of streptozotocin and doxorubicin or streptozotocin and fluorouracil combination. In this study, 5 of 61 (8.2%) evaluable patients had a response and 7 (11.3%) had stable disease; the PFS was not reported, but the overall survival was 11.9 months.10 In another arm of this study, 21 patients received single-agent dacarbazine either because they had previously received doxorubicin, fluorouracil, or streptozocin, or because they had renal or heart disease counterindicating streptozotocin and doxorubicin or streptozotocin and fluorouracil combination. In this latter arm, the response rate (PRs) was 9.5% (2 of 21), and the median PFS and overall survival were 4.1 and 8.8 months, respectively.10 In contrast, our results show that gemcitabine-oxaliplatin combination has significant activity in this setting, with a 17% response rate and a 7.0-month median PFS in patients with neuroendocrine tumors previously treated with chemotherapy (in most cases 2 or more previous regimens). Overall toxicity was mild; however, half of the patients discontinued treatment because of toxicity, in most cases because of oxaliplatin-related neurotoxicity.
Newer agents, such as paclitaxel, docetaxel, topotecan, and gemcitabine, have shown little activity as single agents.15, 32-34 More recently, temozolomide has been shown to have interesting single-agent activity with a favorable toxicity profile in previously treated patients.35 Several phase 2 trials have shown promising results with temozolomide-based combinations using antiangiogenic drugs such as bevacizumab or thalidomide,36, 37 and capecitabine-temozolomide was reported to produce responses in 59% to 71% of patients with advanced pancreatic endocrine tumor.38, 39
Current research focuses on the incorporation of antiangiogenic drugs and/or drugs targeting the mTOR pathway in the treatment of NETs either alone or in combination with conventional chemotherapy or interferon. Several phase 2 trials have been reported with agents such as temsirolimus,40 thalidomide,36 sorafenib,41 everolimus,12 sunitinib,13 and bevacizumab,22, 23, 42 and phase 3 trials are currently ongoing with everolimus, sunitinib, and bevacizumab. Some published results are promising, but others are either disappointing from the efficacy standpoint (temsirolimus)40 or raise concern regarding the safety of such agents in this setting (sorafenib).41
Preliminary results of 2 phase 2 trials of bevacizumab and oxaliplatin-based combinations seem to support the activity of oxaliplatin in the treatment of advanced NETs.22, 23 These combinations also include bevacizumab, which was previously shown to have activity in NETs37, 42; however, the reported response rate suggests increased activity with oxaliplatin-base chemotherapy. In a phase 2 trial, Bajetta et al reported a 27.5% response rate in 40 patients with neuroendocrine tumors treated with oxaliplatin and capecitabine.21 In this study, 27 patients had well-differentiated endocrine carcinomas; in this subgroup, the response rate was 30%, 48% of patients had stable disease as their best response, the median time to progression was 20 months, and median overall survival was 40 months. Toxicity was mild overall, and only 12.5% of patients experienced oxaliplatin-related paresthesia, which is likely because of the predetermined number of cycles of chemotherapy in this study.21
Although no definitive conclusions can be drawn from our series of patients because of the heterogeneity of the underlying disease, GEMOX combination seems active, given the heavily pretreated population. Interestingly, whereas gemcitabine as a single agent was shown to have little activity in this disease,15 the combination with oxaliplatin yielded an interesting response rate (17%), with a PFS of 7.0 months, which compares favorably with other agents in this setting, including targeted agents.41, 43, 44
Overall, our experience with GEMOX chemotherapy shows that this combination is feasible and has promising activity in patients with previously treated NETs.