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
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
Streptozocin (Table 1) [1–14]
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
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
Abstract Advanced neuroendocrine tumors are incurable, and most patients 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.
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: [email protected] H. Takahashi · I. Ohno · S. Shimizu · S. Mitsunaga · M. Ikeda Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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Table 1 Outcomes for streptozocin-based chemotherapy No. patients Streptozocin Streptozocin Streptozocin + 5-FU Streptozocin + Doxorubicin Streptozocin + 5-FU / Doxorubicin Chlorozotocin Streptozocin + 5-FU Streptozocin + Doxorubicin Streptozocin + Doxorubicin + 5-FU Streptozocin + Doxorubicin Streptozocin + Doxorubicin Streptozocin + Doxorubicin Streptozocin + Doxorubicin + 5-FU Streptozocin + Doxorubicin Streptozocin + Liposomal Doxorubicin Streptozocin + 5-FU + Cisplatin Streptozocin + Capecitabine Streptozocin + Capecitabine + Cisplatin
Response rate (%)
50 42 42 33 44
50 36 63 19 45
33 33 36 11
30 45 69 55
16 16 45 84
PFS (median, months)
Survival (median, months)
NA NA
NA 16.5 26 10.9 NA
NA NA
Primary site
Author
Year
Reference
Pancreas only Pancreas only
Broder LE Moertel CG
1973 1980
1 2
Pancreas and others Pancreas only
Frame J Eriksson B
1988 1990
3 4
Pancreas only
Moertel C
1992
5
NA
18 16.8 26.4 >21
Pancreas only
Rivera E
1998
6
6 6 36 39
NA 3.9 16 18
>10 20.2 24 37
Pancreas only Pancreas only Pancreas only Pancreas only
Cheng PN McCollum AD Delaunoit T Kouvaraki MA
1999 2004 2004 2004
7 8 9 10
10 30
30 40
NA 13
12 52
Pancreas and others Pancreas only
Pavel M Fjallskog ML
2005 2008
11 12
79 44 42
33 12 16
9.1 10.2 9.7
31.5 26.7 17.5
Pancreas and others Pancreas and others
Turner NC Meyer T
2010 2014
13 14
NA
NA not available, PFS progression-free survival
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 patients 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 patients, 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 (PFS) time of 11–21 months, a median survival time of 21–38 months, and major adverse reactions consisting of
630
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Table 2 Outcomes for dacarbazine-based chemotherapy
Dacarbazine + 5-FU + Epirubicin Dacarbazine + 5-FU + Epirubicin Dacarbazine + 5-FU + Leucovorin Dacarbazine Dacarbazine + 5-FU + Epirubicin Dacarbazine + 5-FU + Epirubicin
No. patients
Response rate (%)
PFS (median, months)
Survival (median, months)
38
18
NA
30
30
18
Primary site
Author
Year
Reference
NA
Pancreas and others
Di Bartolomeo M
1995
16
NA
NA
Pancreas and others
Bajetta E
1998
17
27
NA
NA
Pancreas and others
Ollivier S
1998
18
50 82
34 24.4
NA 21
19.3 38
Pancreas only Pancreas and others
Ramanathan RK Bajetta E
2001 2001
19 20
39
44
11
21
Pancreas and others
Walter T
2010
21
NA not available, PFS progression-free survival
Table 3 Outcomes for temozolomide-based chemotherapy No. patients
Response rate (%)
PFS (median, months)
Survival (median, months)
Temozolomide + Thalidomide Temozolomide
11
45
>26
>26
36
14
7
16
Temozolomide + Capecitabine Temozolomide + Capecitabine Temozolomide + Capecitabine Temozolomide + Capecitabine Temozolomide + Capecitabine Temozolomide + Capecitabine
30
70
18
>24
18
56
14
83
7
43
12
24
28
43
>22
>29.1
21
57
16.5
NA
29
NA
4.7
20.2
Primary site
Author
Year
Reference
Pancreas and others Pancreas and others Pancreas only
Kulke MH Ekeblad S
2006
22
2007
23
Strosberg JR Fine RL
2011
24
2013
25
Saif MW
2013
26
Fine R
2014
27
Abbasi S
2014
28
Peixoto RD
2014
29
Pancreas and others Pancreas only Pancreas and others Pancreas and others Pancreas and others
NA not available, PFS progression-free survival
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 patients, 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 PFS 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, PFS, and survival time, and this combination, in particular, has attracted interest [24–29]. The Eastern Cooperative Oncology Group (ECOG) is currently conducting a
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randomized phase II study examining temozolomide versus temozolomide + capecitabine (ClinicalTrials.gov Identifier: NCT01824875). The primary endpoint is PFS, and the estimated enrollment is 145 patients, with an estimated primary completion date of December 2014. Alkylating agents, including temozolomide, induce the methylation of the O6-position of guanine, which results in DNA mismatching and ultimately results in apoptosis and tumor cell death. O6-methylguanine DNA methyltransferase (MGMT) is known to specifically remove the methyl/alkyl group from the O6-position of guanine [30]. Kulke et al. reported that MGMT deficiency was associated with the temozolomide response in patients with NET, and they suggested that the MGMT status could be used as a predictive marker to identify NET patients 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 patients, 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 PFS of 9.8 months, and a median survival time of more than 24 months have been reported [35, 37]. When patients 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 patients 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 patients 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 patients 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 patients who cannot
Table 4 Outcomes for other regimens No. patients
Response rate (%)
PFS (median, months)
Survival (median, months)
5-FU + Chlorozotocin Paclitaxel
44
36
NA
25
24
8
3.2
18
Gemcitabine
18
0
8.3
11.5
Capecitabine + Oxaliplatin 5-FU + Irinotecan + Leucovorin Capecitabine + Oxaliplatin
27
30
NA
>24
20
5
9.1
NA
24
29
9.8
NA
NA not available, PFS progression-free survival
Primary site Pancreas only Pancreas and others Pancreas and others Pancreas and others Pancreas only Pancreas and others
Author
Year
Reference
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 patients who manifest symptoms because of their tumor burden or for patients in whom cytoreduction appears to provide a clinical advantage, such as patients 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 patients 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 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. Clarifying which patients should be treated and the optimal timing of the treatment are additional tasks that should be addressed in the future. Because pancreatic NET is a rare disease, a multicenter study will be needed, and a global-level initiative with the aim of establishing an optimal treatment algorithm is earnestly desired. Conflict of interest Research funding: Takuji Okusaka, Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd.
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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
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
Streptozocin (Table 1) [1–14]
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
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
Abstract Advanced neuroendocrine tumors are incurable, and most patients 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.
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: [email protected] H. Takahashi · I. Ohno · S. Shimizu · S. Mitsunaga · M. Ikeda Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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Table 1 Outcomes for streptozocin-based chemotherapy No. patients Streptozocin Streptozocin Streptozocin + 5-FU Streptozocin + Doxorubicin Streptozocin + 5-FU / Doxorubicin Chlorozotocin Streptozocin + 5-FU Streptozocin + Doxorubicin Streptozocin + Doxorubicin + 5-FU Streptozocin + Doxorubicin Streptozocin + Doxorubicin Streptozocin + Doxorubicin Streptozocin + Doxorubicin + 5-FU Streptozocin + Doxorubicin Streptozocin + Liposomal Doxorubicin Streptozocin + 5-FU + Cisplatin Streptozocin + Capecitabine Streptozocin + Capecitabine + Cisplatin
Response rate (%)
50 42 42 33 44
50 36 63 19 45
33 33 36 11
30 45 69 55
16 16 45 84
PFS (median, months)
Survival (median, months)
NA NA
NA 16.5 26 10.9 NA
NA NA
Primary site
Author
Year
Reference
Pancreas only Pancreas only
Broder LE Moertel CG
1973 1980
1 2
Pancreas and others Pancreas only
Frame J Eriksson B
1988 1990
3 4
Pancreas only
Moertel C
1992
5
NA
18 16.8 26.4 >21
Pancreas only
Rivera E
1998
6
6 6 36 39
NA 3.9 16 18
>10 20.2 24 37
Pancreas only Pancreas only Pancreas only Pancreas only
Cheng PN McCollum AD Delaunoit T Kouvaraki MA
1999 2004 2004 2004
7 8 9 10
10 30
30 40
NA 13
12 52
Pancreas and others Pancreas only
Pavel M Fjallskog ML
2005 2008
11 12
79 44 42
33 12 16
9.1 10.2 9.7
31.5 26.7 17.5
Pancreas and others Pancreas and others
Turner NC Meyer T
2010 2014
13 14
NA
NA not available, PFS progression-free survival
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 patients 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 patients, 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 (PFS) 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
Dacarbazine + 5-FU + Epirubicin Dacarbazine + 5-FU + Epirubicin Dacarbazine + 5-FU + Leucovorin Dacarbazine Dacarbazine + 5-FU + Epirubicin Dacarbazine + 5-FU + Epirubicin
No. patients
Response rate (%)
PFS (median, months)
Survival (median, months)
38
18
NA
30
30
18
Primary site
Author
Year
Reference
NA
Pancreas and others
Di Bartolomeo M
1995
16
NA
NA
Pancreas and others
Bajetta E
1998
17
27
NA
NA
Pancreas and others
Ollivier S
1998
18
50 82
34 24.4
NA 21
19.3 38
Pancreas only Pancreas and others
Ramanathan RK Bajetta E
2001 2001
19 20
39
44
11
21
Pancreas and others
Walter T
2010
21
NA not available, PFS progression-free survival
Table 3 Outcomes for temozolomide-based chemotherapy No. patients
Response rate (%)
PFS (median, months)
Survival (median, months)
Temozolomide + Thalidomide Temozolomide
11
45
>26
>26
36
14
7
16
Temozolomide + Capecitabine Temozolomide + Capecitabine Temozolomide + Capecitabine Temozolomide + Capecitabine Temozolomide + Capecitabine Temozolomide + Capecitabine
30
70
18
>24
18
56
14
83
7
43
12
24
28
43
>22
>29.1
21
57
16.5
NA
29
NA
4.7
20.2
Primary site
Author
Year
Reference
Pancreas and others Pancreas and others Pancreas only
Kulke MH Ekeblad S
2006
22
2007
23
Strosberg JR Fine RL
2011
24
2013
25
Saif MW
2013
26
Fine R
2014
27
Abbasi S
2014
28
Peixoto RD
2014
29
Pancreas and others Pancreas only Pancreas and others Pancreas and others Pancreas and others
NA not available, PFS progression-free survival
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 patients, 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 PFS 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, PFS, 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
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randomized phase II study examining temozolomide versus temozolomide + capecitabine (ClinicalTrials.gov Identifier: NCT01824875). The primary endpoint is PFS, and the estimated enrollment is 145 patients, with an estimated primary completion date of December 2014. Alkylating agents, including temozolomide, induce the methylation of the O6-position of guanine, which results in DNA mismatching and ultimately results in apoptosis and tumor cell death. O6-methylguanine DNA methyltransferase (MGMT) is known to specifically remove the methyl/alkyl group from the O6-position of guanine [30]. Kulke et al. reported that MGMT deficiency was associated with the temozolomide response in patients with NET, and they suggested that the MGMT status could be used as a predictive marker to identify NET patients 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 patients, 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 PFS of 9.8 months, and a median survival time of more than 24 months have been reported [35, 37]. When patients 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 patients 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 patients 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 patients 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 patients who cannot
Table 4 Outcomes for other regimens No. patients
Response rate (%)
PFS (median, months)
Survival (median, months)
5-FU + Chlorozotocin Paclitaxel
44
36
NA
25
24
8
3.2
18
Gemcitabine
18
0
8.3
11.5
Capecitabine + Oxaliplatin 5-FU + Irinotecan + Leucovorin Capecitabine + Oxaliplatin
27
30
NA
>24
20
5
9.1
NA
24
29
9.8
NA
NA not available, PFS progression-free survival
Primary site Pancreas only Pancreas and others Pancreas and others Pancreas and others Pancreas only Pancreas and others
Author
Year
Reference
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 patients who manifest symptoms because of their tumor burden or for patients in whom cytoreduction appears to provide a clinical advantage, such as patients 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 patients 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 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. Clarifying which patients should be treated and the optimal timing of the treatment are additional tasks that should be addressed in the future. Because pancreatic NET is a rare disease, a multicenter study will be needed, and a global-level initiative with the aim of establishing an optimal treatment algorithm is earnestly desired. Conflict of interest Research funding: Takuji Okusaka, Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd.
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