Cytotoxic chemotherapy for pancreatic neuroendocrine tumors

J Hepatobiliary Pancreat Sci (2015) 22:628 633 DOI: 10.1002/jhbp.257 TOPIC Cytotoxic chemotherapy for pancreatic neuroendocrine tumors Takuji Okusaka Hideki Ueno Chigusa Morizane Shunsuke Kondo Yasunari Sakamoto Hideaki Takahashi Izumi Ohno Satoshi Shimizu Shuichi Mitsunaga Masafumi Ikeda Published online: 3 May 2015 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery Abstract Advanced neuroendocrine tumors are incurable, and most will succumb to the disease. Chemotherapies with cytotoxic agents such as streptozocin, 5-fluorouracil, or temozolomide have been frequently used as drug therapies for neuroendocrine tumors. Streptozocin, which is the only approved cytotoxic agent available for the treatment of this disease in many countries, has been considered a key agent for the treatment of advanced neuroendocrine tumors based on the results of phase III studies. However, the widespread acceptance of streptozocin-based chemotherapy for this indication has been limited by concerns regarding toxicity. Recent prospective and retrospective studies showed the promising activity of a temozolomide-based regimen, although an adequate prospective controlled study defining the role of temozolomide in the treatment of neuroendocrine tumors is lacking. The promising activity of cytotoxic agents awaits confirmation; solid evidence-based recommendations and treatment decisions are needed for the optimal use of chemotherapy against this disease. Keywords Chemotherapy Fluoropyrimidine Neuroendocrine tumor Streptozocin Temozolomide therapy with alkylating agents, such as streptozocin and temozolomide. Chemotherapy primarily with platinumcontaining drugs, such as cisplatin and carboplatin, have been used for poorly differentiated type, i.e. neuroendocrine carcinoma (NEC), according to the protocols for small-cell lung cancer. Because of this considerable variation in treatment regimens according to the degree of differentiation, a precise pathological diagnosis is necessary before starting treatment. In this article, we review the results in prospective and retrospective studies of cytotoxic chemotherapy for NET G1/G2 and discuss the place of cytotoxic chemotherapy for this disease. Chemotherapies with alkylating agents, such as streptozocin, dacarbazine, and temozolomide, combined with the antimetabolites 5-FU and capecitabine and/or the anthracycline anticancer drugs doxorubicin and epirubicin have been assessed the most frequently and are in widespread use for the treatment of NET G1/G2. However, solid evidence of effectiveness obtained in a large-scale, phase 3 clinical trial has not been obtained for any of these regimens, and a global consensus on a standard treatment has not yet been established. Introduction The main cytotoxic chemotherapy regimens used to treat well-differentiated pancreatic neuroendocrine tumors (NETs) (i.e. NET G1/G2) have consisted primarily of anticancer drug T. Okusaka ( ) H. Ueno C. Morizane S. Kondo Y. Sakamoto Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan e-mail: tokusaka@ncc.go.jp H. Takahashi I. Ohno S. Shimizu S. Mitsunaga M. Ikeda Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan Streptozocin (Table 1) [1 14] Streptozocin is a nitrosourea alkylating agent that is known to be taken up into cells by the glucose transport protein GLUT2 and to cause cell damage. Because GLUT2 is strongly expressed in pancreatic beta cells, streptozocin has been widely used to create animal models of diabetes mellitus. In 1980, Moertel et al. conducted a randomized study comparing streptozocin alone and streptozocin + 5-FU. Based on their results, which showed a response rate of 36% and a median survival time of 16.5 months in the streptozocin-alone group and a response rate of 63% and a median survival time of 26 months in the streptozocin + 5-FU group; they reported

J Hepatobiliary Pancreat Sci (2015) 22:628 633 629 Table 1 Outcomes for streptozocin-based chemotherapy (median, months) (median, months) Primary site Author Year Reference Streptozocin 50 50 NA NA Pancreas only Broder LE 1973 1 Streptozocin 42 36 NA 16.5 Pancreas only Moertel CG 1980 2 Streptozocin + 5-FU 42 63 26 Streptozocin + Doxorubicin 33 19 NA 10.9 Pancreas and Frame J 1988 3 Streptozocin + 5-FU / 44 45 NA NA Pancreas only Eriksson B 1990 4 Doxorubicin Chlorozotocin 33 30 18 Pancreas only Moertel C 1992 5 Streptozocin + 5-FU 33 45 NA 16.8 Streptozocin + Doxorubicin 36 69 26.4 Streptozocin + Doxorubicin 11 55 NA >21 Pancreas only Rivera E 1998 6 +5-FU Streptozocin + Doxorubicin 16 6 NA >10 Pancreas only Cheng PN 1999 7 Streptozocin + Doxorubicin 16 6 3.9 20.2 Pancreas only McCollum AD 2004 8 Streptozocin + Doxorubicin 45 36 16 24 Pancreas only Delaunoit T 2004 9 Streptozocin + Doxorubicin 84 39 18 37 Pancreas only Kouvaraki MA 2004 10 +5-FU Streptozocin + Doxorubicin 10 30 NA 12 Pancreas and Pavel M 2005 11 Streptozocin + Liposomal 30 40 13 52 Pancreas only Fjallskog ML 2008 12 Doxorubicin Streptozocin + Cisplatin 79 33 9.1 31.5 Pancreas and Turner NC 2010 13 Streptozocin + 44 12 10.2 26.7 Pancreas and Meyer T 2014 14 Streptozocin + + Cisplatin 42 16 9.7 17.5 that both a better response rate and a longer survival time were obtained using streptozocin + 5-FU [2]. In 1992, Moertel et al. conducted a 3-arm phase III comparative study comparing a chlorozotocin arm, a streptozocin + 5-FU arm, and a streptozocin + doxorubicin arm. Based on their results, which showed a response rate of 69% and median survival time of 26.4 months in the streptozocin + doxorubicin arm, they reported that significantly more favorable results were obtained in the streptozocin + doxorubicin arm, compared with the other two therapies [5]. Although both the response rate (69%) and the median survival time (26.4 months) obtained using streptozocin + doxorubicin in the phase III study were excellent, most subsequent studies have not confirmed these results [7 9]; consequently, the results of the previous phase III study are sometimes viewed with skepticism. Concerns over the adverse effects of this combination therapy, including gastrointestinal and renal toxicities, have also been pointed out. However, a streptozocin-containing regimen, streptozocin + 5-FU, has been shown to prolong the survival time of with gastrointestinal NETs in a phase III study [15], and streptozocin is considered to be a key drug in the treatment of pancreatic and gastrointestinal NETs. Dacarbazine (Table 2) [16 21] Dacarbazine is an alkylating agent that damages DNA through its diazomethane-mediated alkylating action, displaying an antitumor effect; the drug is used to treat malignant melanoma, Hodgkin lymphoma, sarcoma, and other cancers. Dacarbazine has also been used to treat pancreatic NETs for a relatively long time, and it has been assessed alone and in combination with 5-FU, epirubicin, leucovorin, and other agents. A phase II study of dacarbazine alone was conducted in 50 pancreatic NET, and relatively good results, with a response rate of 34% and a survival time of 19.3 months, were obtained [19]. Most studies for dacarbazinebased therapy have been conducted using a three-drug combination therapy with 5-FU and epirubicin, and such studies have reported response rates of 20% 40%, a progression-free survival () time of 11 21 months, a median survival time of 21 38 months, and major adverse reactions consisting of

630 J Hepatobiliary Pancreat Sci (2015) 22:628 633 Table 2 Outcomes for dacarbazine-based chemotherapy Primary site Author Year Reference Leucovorin 38 18 NA NA Pancreas and Di Bartolomeo M 1995 16 30 30 NA NA Pancreas and Bajetta E 1998 17 18 27 NA NA Pancreas and Ollivier S 1998 18 Dacarbazine 50 34 NA 19.3 Pancreas only Ramanathan RK 2001 19 82 24.4 21 38 Pancreas and Bajetta E 2001 20 39 44 11 21 Pancreas and Walter T 2010 21 Table 3 Outcomes for temozolomide-based chemotherapy Primary site Author Year Reference Thalidomide 11 45 >26 >26 Pancreas and Temozolomide 36 14 7 16 Pancreas and Kulke MH 30 70 18 >24 Pancreas only Strosberg JR 18 56 14 83 Pancreas and 2006 22 Ekeblad S 2007 23 2011 24 Fine RL 2013 25 7 43 12 24 Pancreas only Saif MW 2013 26 28 43 >22 >29.1 Pancreas and 21 57 16.5 NA Pancreas and 29 NA 4.7 20.2 Pancreas and Fine R 2014 27 Abbasi S 2014 28 Peixoto RD 2014 29 myelosuppression, mucocutaneous disorders, and nausea and vomiting [16, 17, 20, 21]. Temozolomide (Table 3) [22 29] Temozolomide is an oral alkylating agent that is used to treat glioblastoma and melanoma. Because the side-effects of temozolomide are mild and it is an oral drug, temozolomide chemotherapy is expected to be less stressful for, and several studies of combination therapies with other drugs have been conducted in addition to a study of temozolomide alone. When used as a monotherapy, the response rate was 14%, the median was 7 months, and the median survival time was 16 months [23]. While the results of temozolomide monotherapy were marginal, all the studies that have been conducted examining combination therapy with capecitabine have reported promising results with regard to the response rate,, and survival time, and this combination, in particular, has attracted interest [24 29]. The Eastern Cooperative Oncology Group (ECOG) is currently conducting a

J Hepatobiliary Pancreat Sci (2015) 22:628 633 631 randomized phase II study examining temozolomide versus temozolomide + capecitabine (ClinicalTrials.gov Identifier: NCT01824875). The primary endpoint is, and the estimated enrollment is 145, with an estimated primary completion date of December 2014. Alkylating agents, including temozolomide, induce the methylation of the O 6 -position of guanine, which results in DNA mismatching and ultimately results in apoptosis and tumor cell death. O 6 -methylguanine DNA methyltransferase (MGMT) is known to specifically remove the methyl/alkyl group from the O 6 -position of guanine [30]. Kulke et al. reported that MGMT deficiency was associated with the temozolomide response in with NET, and they suggested that the MGMT status could be used as a predictive marker to identify NET who are likely to respond to treatment with alkylating agents, such as temozolomide [31]. Other drugs (Table 4) [32 37] In addition to the alkylating agents described above, other anticancer drugs, including 5-FU, paclitaxel, gemcitabine, and oxaliplatin, have been used in clinical studies examining pancreatic NETs, but all of these studies were conducted using small numbers of, and no randomized controlled studies have been performed. The platinum-containing drug oxaliplatin is often used in the gastrointestinal tract in combination with other drugs, mainly with fluoropyrimidines, (including 5-FU and capecitabine). Some reports have described the use of oxaliplatin in combination with capecitabine in pancreatic NETs, and response rates of about 30%, a median of 9.8 months, and a median survival time of more than 24 months have been reported [35, 37]. When undergo treatment with gemcitabine [34] or FOLFIRI [36], which have been used to treat pancreatic cancer or colorectal cancer, the response rates have been only about 0% 5%. Discussion Almost all the clinical studies on cytotoxic chemotherapy for NETs have been conducted in the form of single-arm studies on small numbers of without a control group. The study by Moertel et al. was the sole randomized controlled study to report that cytotoxic chemotherapy, consisting of streptozocin + doxorubicin combination therapy, prolonged the survival time [5]; however, because of the small number of and the fact that it was reported in 1992 and is a relatively old study, the reliability of the results is poor. Consequently, no cytotoxic chemotherapy regimen for which a global consensus has been achieved has been established as a standard therapy. Because molecularly targeted drugs, including everolimus and sunitinib, have recently been shown to be useful in large-scale randomized controlled studies and have been accepted as a standard therapy [38, 39], the place of cytotoxic chemotherapy in the treatment of NETs has become even more uncertain. However, numerous reports of cytotoxic chemotherapy regimens have yielded promising results, and these findings are expected to play a certain role in the treatment of NETs. Pancreatic NETs progress relatively slowly. The general condition of is relatively good, even in unresectable cases, and long survival times are common. At present, no standard treatments have been established as a second-line therapy after molecularly targeted therapy, and cytotoxic chemotherapy is also expected to become positioned as a standard chemotherapy based on the results of high-quality randomized controlled studies examining who cannot Table 4 Outcomes for other regimens Primary site Author Year Reference Chlorozotocin 44 36 NA 25 Pancreas only Paclitaxel 24 8 3.2 18 Pancreas and Gemcitabine 18 0 8.3 11.5 Pancreas and + Oxaliplatin Irinotecan +Leucovorin + Oxaliplatin 27 30 NA >24 Pancreas and 20 5 9.1 NA Pancreas only 24 29 9.8 NA Pancreas and Bukowski RM 1992 32 Ansell SM 2001 33 Kulke MN 2004 34 Bajetta E 2007 35 Brixi-Benmansour H 2011 36 Ferrarotto R 2013 37

632 tolerate everolimus or sunitinib or have failed to respond to these drugs. In addition, the usefulness of both everolimus and sunitinib has been demonstrated in placebo-controlled phase III trials, but which of the two, molecularly targeted therapy or cytotoxic chemotherapy, is superior has not yet been ascertained. The response rates to molecularly targeted drugs are relatively low (sunitinib, 9.3% [39]; everolimus, 5% [38]), and a cytoreductive effect cannot be expected. However, several cytotoxic chemotherapy regimens that yield high response rates have been reported. Thus, cytotoxic chemotherapy could be considered as a first-line treatment for who manifest symptoms because of their tumor burden or for in whom cytoreduction appears to provide a clinical advantage, such as with locally advanced cases for which surgery is possible [40 42]. Although predictors associated with a response to chemotherapy have not been fully elucidated, some markers may have the potential to allow the selection of who may benefit from chemotherapy. Turner et al. reported that both the mitotic index and Ki67 were associated with a response to chemotherapy consisting of 5-fluorouracil, cisplatin, and streptozocin [13]. For the mitotic index, the response rate increased from 15% for tumors with a mitotic index of 0 1 to 55% for tumors with a mitotic index 5 (P=0.008); for Ki67, the response rate increased from 18% for a Ki67 value of <10% to 52% for a Ki67 value of >24% (P=0.019). Kulke et al. reported that MGMT deficiency was associated with a response to temozolomide. At present, the evidence for cytotoxic chemotherapy as a standard therapy is inadequate, but there is a strong possibility that its usefulness will be demonstrated, and proper evaluation using high-quality clinical studies is needed. 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