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Journal of Clinical Oncology, Vol 22, No 23 (December 1), 2004: pp. 4762-4771 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.04.024 Fluorouracil, Doxorubicin, and Streptozocin in the Treatment of Patients With Locally Advanced and Metastatic Pancreatic Endocrine CarcinomasFrom the Departments of Surgical Oncology and Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to James C. Yao, MD, Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jyao{at}mdanderson.org
PURPOSE: The role of systemic chemotherapy in the management of pancreatic endocrine carcinoma (islet cell carcinoma; PEC) is an area of considerable controversy. Response rates ranging from 6% to 69% have been reported for streptozocin-based chemotherapy. We retrospectively studied 84 patients with locally advanced or metastatic PEC who had been treated with fluorouracil, doxorubicin, and streptozocin (FAS) to determine the objective response rate, duration of progression-free survival (PFS), and duration of overall survival (OS). PATIENTS AND METHODS: Eligible patients had histologic or cytologic confirmation of their tumor and measurable disease on computed tomography or magnetic resonance imaging scans. Response to treatment was evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors Committee. RESULTS: Sixty-one of the patients were male and 23 were female, with a median age of 54 years (range, 24 to 78 years). The response rate (RR) to FAS was 39%, with a median response duration of 9.3 months. The 2-year PFS rate was 41%, and the 2-year OS rate was 74%. The extent of liver metastatic disease correlated with a worse PFS (P = .01 by log-rank test) and a worse OS (P < .0001 by log-rank test). Analyses showed that metastatic replacement of more than 75% of the liver and prior chemotherapy were independently associated with inferior PFS. CONCLUSION: Patients with locally advanced or metastatic PEC who are treated with FAS may have a reasonable RR, and responders may experience longer PFS and OS. The volume of metastases in the liver is the most important predictor of outcome.
Pancreatic endocrine carcinomas (PECs), also known as islet cell carcinomas, are rare neoplasms of neuroectodermal origin.1 Most are sporadic; however, they may also develop in the setting of multiple endocrine neoplasia type I, von Hippel-Lindau disease, neurofibromatosis 1, and tuberous sclerosis.2 Multiple hormones and peptides are frequently produced by PECs. Functioning PECs release biologically active substances, or hormones, that produce distinct clinical syndromes. These hormones include gastrin, insulin, glucagon, somatostatin, vasoactive intestinal polypeptide, growth hormone-releasing factor, and adrenocorticotropic hormone. Nonfunctioning PEC may also secrete a number of amines and peptides (eg, neurotensin, the  -subunit of human chorionic gonadotropin, neuron-specific enolase, pancreatic polypeptide, and chromogranin A); however, these are inactive and do not produce recognizable clinical syndromes. Because of their indolent nature, the diagnosis is often delayed (4 to 6 years) and PECs become clinically apparent when they already are inoperable or metastatic.2 Despite their indolent course, PECs can be aggressive and resistant to therapy. Complete surgical resection is the treatment of choice for localized cancers. However, PECs frequently are unresectable because of distant metastatic disease or local extension of the tumor. Because of the heterogeneity, the varying degree of aggressiveness, and the lack of a standard approach to their management, these cancers offer a special challenge.3 The therapeutic options include cytoreductive surgery, biotherapy with interferon alfa, suppression of hormonal production with somatostatin analogs, hepatic artery embolization or chemoembolization, and systemic chemotherapy. Somatostatin analogs are effective in controlling hormone-related symptoms.4 Treatment with interferon alfa may result in a biochemical response, in which fewer patients realize reduction in tumor volume. Embolization and chemoembolization, which may decrease tumor bulk and help control the symptoms associated with excessive hormones, are generally reserved for patients with metastatic tumors that failed to respond to other treatments. Systemic chemotherapy has been evaluated, with variable rates of tumor response. Single chemotherapeutic agents used include streptozocin, fluorouracil (FU), doxorubicin, chlorozotocin, and dacarbazine, but usually produce low response rates (RRs). Combinations of streptozocin-based chemotherapy may produce a higher RR. The combination of streptozocin with doxorubicin is a frequently used first-line regimen based on the Eastern Cooperative Oncology Group randomized trial.5–8 However, more recent studies, reporting response rates as low as 6%, have failed to confirm these results.9,10 Previous studies have used the triple chemotherapy of FU, doxorubicin, and streptozocin (FAS) and shown promising RR, although the number of patients analyzed was small.7,8 Therefore, the role of systemic chemotherapy in advanced PEC remains to be determined. In this study, we retrospectively examined the objective tumor RR, duration of progression-free survival (PFS), and duration of overall survival (OS) in 84 patients with locally advanced or metastatic PEC treated with combination FAS chemotherapy.
Patients Approval for data collection and analyses was obtained from The University of Texas M.D. Anderson Cancer Center (Houston, TX) institutional review board. The study group included 84 consecutive patients with locally advanced and metastatic PEC who received FAS at The University of Texas M.D. Anderson Cancer Center between January 1992 and September 2003. To be eligible, patients also had to have histologic or cytologic confirmation of their tumor and measurable disease on computed tomography (CT) or magnetic resonance imaging (MRI) scans. Serum levels of chromogranin A were measured before (n = 60) and within 4 months (n = 49) of the first cycle of chemotherapy. The amount of liver metastasis was classified as less than 50%, 50% to 75%, and more than 75%.
Chemotherapy
Evaluation of Tumor Response Duration of overall response was defined as the time between the initial documented response and the first date of recurrence or progression. Duration of SD was defined as the time between the date treatment started and the first date of recurrence or progression.
Statistical Analysis
Response to Treatment We identified 84 patients (61 males and 23 females) with locally advanced or metastatic PEC treated with FAS. The median age at the time of initiation of chemotherapy was 54 years (range, 24 to 78 years). The clinical characteristics of the patients are listed in Table 1. Sixty-four of the tumors were nonfunctioning, 11 were gastrinomas, three were insulinomas, three were glucagonomas, two were vasoactive intestinal polypeptide tumors, and one was an adrenocorticotropic hormone-producing PEC. All eight locally advanced tumors were nonfunctioning.
Eleven of 84 patients were previously treated with somatostatin analogs (n = 5), hepatic artery chemoembolization (n = 4), or both (n = 1); one additional patient underwent radiofrequency ablation of the liver. One patient continued receiving the somatostatin analogs during his treatment with FAS chemotherapy. In addition, three patients received somatostatin analogs along with FAS. Of the entire group of 84 patients, 33 (39%; 95% CI, 27 to 50) responded to chemotherapy, 42 (50%) had SD, and disease progressed in nine (11%). Four patients were able to have curative resection of their tumors after PR. The median duration of response was 9.3 months (range, 2.3 to 51 months), and the median time to response was 3.9 months (0.7 to 14.2 months). None of the 11 patients with metastatic gastrinomas responded to chemotherapy, compared with 33 of 73 patients (45%) with all other tumor types (P = .002 by Fisher's exact test). Four of nine patients (44%) with functioning tumors other than gastrinomas responded to FAS. RRs by hormone production status are listed in Table 2. Figure 1 shows CT scans of three patients who responded dramatically to chemotherapy. Patients with locally advanced tumors did not differ from those with metastatic tumors in terms of RR. Similarly, the volume of liver disease was not statistically associated with different RR. The RR for the group of patients (n = 21) with extrahepatic distant metastases with or without liver involvement was 19% compared with 47% for the group of patients (n = 55) with liver metastases only (P = .03 by Fisher's exact test; Table 2). Previous treatment with other chemotherapy or other modalities did not affect RR.
Pretreatment measurements of serum chromogranin A were available for 60 patients. Forty-five of 54 metastatic tumors (83%) showed increased pretreatment levels of chromogranin A, compared with two of six locally advanced tumors (33%; P = .01 by Fisher's exact test). Chromogranin A measurements within 4 months of the initiation of chemotherapy were available for 49 patients. Response to chemotherapy was associated with a decrease in the pretreatment levels of serum chromogranin A of at least 30% (12 of 24 v six of 27; P = .04 by Fisher's exact test). Neither tumor type nor disease extension was significantly associated with the decrease in serum chromogranin A levels after chemotherapy. Thirty-seven patients who experienced disease progression during or after the treatment, as well as four patients with SD, were subsequently treated using other modalities including second-line chemotherapy, hepatic artery chemoembolization, somatostatin analogs, or interferon.
Dose Intensity and Toxic Reactions The grade 3 or 4 toxic reactions to FAS are listed in Table 3. In total, grade 3 or 4 toxic reactions occurred in 19 of 84 patients (23%). The most common toxic reactions attributable to the whole treatment included nausea, vomiting, myelosuppression, and fatigue. In addition, alopecia was almost invariably observed. Mild nausea and vomiting occurred in most patients, usually within the 5 days of the treatment. Mild to moderate diarrhea (fewer than seven episodes per day) and mild mucositis also developed in some patients. One patient developed intolerable vomiting and diarrhea intractable to treatment and required hospitalization for dehydration. Eleven patients developed grade 3 or 4 neutropenia (absolute neutrophil counts, < 1.0 x 109/L), and three of them were admitted to the hospital for neutropenic fever. In addition, one of these three patients had grade 4 thrombocytopenia (platelets, 19 x109/L). None of the patients developed heart failure, although two had borderline left ventricular ejection fractions. In addition, two patients experienced acute myocardial infraction; one after the first and the other after the third course of treatment, and thus chemotherapy was withheld for them thereafter. One patient developed pulmonary embolism after the first treatment and was admitted to the hospital, and as a result there was a delay in the administration of the subsequent courses.
Clinical Outcome In the entire study group of 84 patients, the median PFS was 18 months. At 2 years, PFS was 41% (95% CI, 26 to 56; Fig 2). After a median follow-up of 14 months (range, 2 to 62 months) for survivors, 39 of the patients (46%) treated with FAS had PD or experienced relapse after an initial CR or PR.
Median OS was 37 months. At 2 years, OS was 74% (95% CI, 61 to 87; Fig 2). Fifty-nine patients (70.5%) were alive; five patients were alive with no evidence of disease (one because of a CR to chemotherapy and the other four because of curative resection of the primary tumor, metastases, or both), 54 patients were alive with disease, and 25 patients were dead as a result of disease.
Univariate Survival Analysis
At 2 years, the PFS rate for patients with liver metastases (LM)
In 30 patients for whom there were data on tumor grade (histologic grade information was not available on patients whose diagnoses were made by fine needle aspiration), high-grade tumors correlated with shorter PFS (P = .003 by log-rank test). OS did not significantly differ between patients with low- and high-grade tumors. Patients who received FAS as a second-line chemotherapy showed a statistical trend toward a worse PFS compared with those patients who had not received previous chemotherapy for their disease (P = .05 by log-rank test; Table 4), but there was no difference in OS. Tumor type was not significantly associated with PFS or OS, although patients with gastrinomas showed a statistical trend toward a worse outcome. Moreover, complete resection of the primary tumor was not associated with different PFS or OS.
Multivariate Survival Analysis
In this study, we observed that 39% of patients with locally advanced or metastatic PEC had major response (CR or PR by RECIST criteria) after treatment with FAS. Many of the responses were dramatic and durable (Fig 1). The median duration of tumor response in our series was 9.8 months (range, 2.3 to 51 months), which is comparable to the previously published data.6,7,9,15 The RR was slightly lower than the 55% (95% CI, 23% to 83%) noted in a previous study from our institution that used the same regimen, but this difference could be accounted for because the number of patients included in that study was small.7 Other studies using a combination of streptozocin with FU and/or doxorubicin showed higher RRs.5,6,9,16 However, biochemical, physical examination, and radioisotope scan findings were used as indicators of response for some patients in these studies.6,9,17 Moreover, patients without radiologically measurable tumors were included in some of the previous studies.6,17 If only radiologic parameters were used to assess RR, then the RR decreased to between 6% and 35%.9,10,16,18 Using variable criteria to assess tumor response, other combination chemotherapies (without streptozocin) resulted in RRs ranging from 9% to 50%.19–24 The possible association between histologic type and response to FAS was also analyzed in this study. Interestingly, none of our patients with gastrinomas responded to chemotherapy. In a study that included only patients with gastrinomas treated with the FAS, the RR was 40%.8 However, in that study, the radiologic criteria used to assess tumor response were different; PR was defined as a reduction in tumor size by 25% using unidimensional measurements, whereas RECIST defined PR as a reduction by 30% using unidimensional measurements, and the WHO defines it as a reduction by 50% using bidimensional measurements. Other studies of combination chemotherapy consisting of streptozocin with FU or doxorubicin in a limited number of patients with gastrinomas also showed variable RRs ranging from 5% to 64%.5,6,9,16,25 The discrepancy in RR among different series may be due to the generally small number of patients with gastrinomas included in most studies or, once again, to the different criteria used to assess tumor response. The variability in tumor aggressiveness could also be responsible for the variable response to chemotherapy observed in patients with gastrinomas. A recent study of the time course and growth pattern of gastrinomas in a series of 19 untreated patients showed that 26% of the tumors did not grow at all (at a mean of 29 months), 32% grew slowly, and 42% grew rapidly.3 The limited number of patients in our study who had functioning tumors other than gastrinomas precludes definite conclusions about tumor sensitivity to chemotherapy. Previous studies also showed similar results in patients with functioning tumors other than gastrinomas.5,6,9,16 The RR for the 21 patients with distant metastases with or without liver involvement was 19% compared with 40% for the 55 patients with liver metastases only (P = .02 by Fisher's exact test). Furthermore, response to chemotherapy was associated with a greater than 30% decrease in the serum chromogranin A level. To the best of our knowledge, this is the first report of an association between an objective tumor response and a decrease in chromogranin A levels. The median time between the first cycle of chemotherapy and tumor response was 3.9 months. This indicates that PECs may respond slowly to chemotherapy, and thus patients with SD after the second cycle of chemotherapy should continue for at least four cycles. This observation may explain the failure of other small retrospective studies to confirm a major antitumor activity for streptozocin.6,8,10 That is, in most clinical trials, therapy must be continued until progression. However, knowing the indolent nature of this disease, many oncologists outside the setting of a clinical trial would stop chemotherapy if no objective tumor shrinkage were observed after 2 to 3 months of chemotherapy.6,8,10 The RR of our study group after the second cycle of FAS was only 13% and increased to 25% after the fourth cycle. It would be interesting to study prospectively whether the reduction in chromogranin A levels after two cycles of chemotherapy can predict RR. We observed an acceptable toxicity for FAS chemotherapy (Table 3). Nausea, vomiting, and myelosuppression did not significantly compromise patients' compliance. A previous trial from our institution also noted good tolerance to this regimen.7,8 There is considerable controversy about the role of two-drug chemotherapy with streptozocin and doxorubicin because of conflicting reports about response rates.5,6,10 Our study demonstrated that the FAS combination for PECs shows reasonable and durable RRs for patients. Other systemic chemotherapies, whether based on streptozocin or not, have shown lower RRs.8,9,16,19,20,22,26 Biologic agents such as somatostatin analogs or interferon alfa, alone or in combination, have been used in locally advanced or metastatic PECs and have shown symptomatic control, biochemical response, or tumorostatic effect.4,16,27–35 However, reported objective response rates have been disappointing.4,29–34,36,37 Liver-directed therapies, including embolization and chemoembolization, may decrease tumor bulk and help control the symptoms associated with excessive hormones, but they are generally reserved for patients without significant extrahepatic disease who have failed to respond to systemic therapy.38–43 The overall median PFS and OS values were 1.5 and 3.4 years, respectively, which is in agreement with previously published series.5,6,9,16,22 There was also a statistical trend toward longer OS for responders compared with nonresponders. Previous studies did not find a better OS for responders than for nonresponders, but the number of patients studied was small or the patients had gastrinomas only.7,8 Patients with low-grade tumors and those who received FAS as a first-line therapy had longer PFS. Previous studies showed similar findings.6,44 Like others, we did not find any significant association between PFS or OS and the histologic tumor type, the presence or absence of clinical syndrome, the interval between diagnosis and chemotherapy, and the performance of a curative resection of the primary tumor before chemotherapy.6,44,45 The extent of liver disease (> 75%) was significantly associated with shorter PFS and OS, and this was confirmed by multivariate analysis. Previous studies have also shown the importance of liver involvement to survival.45–47 Solorzano et al45 also reported significantly shorter OS for patients when more than 50% of their liver had been replaced by metastatic disease.45 In addition, Yu et al47 reported shorter 5- and 10-year survival probabilities for patients with gastrinomas and diffuse metastatic disease than for patients with single or limited bilobar metastatic liver disease. In conclusion, approximately 40% of patients with advanced or metastatic PECs responded to the FAS regimen. Because the median interval to response in our study was approximately 4 months, we recommend that patients with SD in the early evaluation (6 to 8 weeks) should continue to receive chemotherapy for at least four cycles. Our data also suggested that the value of chromogranin A after two to four cycles of FAS would be a useful surrogate marker for the response to chemotherapy.
The authors indicated no potential conflicts of interest.
Supported in part by a gift from Dr Raymond R. Sackler. Maria A. Kouvaraki and James C. Yao contributed equally to this manuscript. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 and Fisher's exact tests, as appropriate. PFS was measured from the beginning of treatment to progression, relapse, death, or last follow-up. OS was measured from the beginning of treatment to the time of last follow-up or death. Actuarial survival was measured by the method of Kaplan and Meier.
75% was 41% (95% CI, 24% to 57%), whereas all 12 patients with LM more than 75% had experienced disease progression by 14.2 months (P = .01 by log-rank test; 
