ORIGINAL ARTICLE
`
`Lack of Efficacy of Streptozocin and Doxorubicin in Patients
`With Advanced Pancreatic Endocrine Tumors
`
`A. David McCollum, MD,* Matthew H. Kulke, MD,† David P. Ryan, MD,§ Jeffrey W. Clark, MD,§
`Lawrence N. Shulman, MD,† Robert J. Mayer, MD,† Sylvia Bartel, RPH,‡ and
`Charles S. Fuchs, MD, MPH†
`
`Background: The combination of streptozocin and doxorubicin has
`been considered the standard palliative chemotherapy regimen in
`patients with advanced pancreatic endocrine tumors (PETs). How-
`ever, a recent review failed to confirm high antitumor activity in
`patients with advanced PETs.
`Methods: We retrospectively reviewed the records of 16 consecu-
`tive patients who received streptozocin and doxorubicin for ad-
`vanced PETs at Dana Farber/Partners Cancer Care institutions.
`Baseline patient characteristics, radiographic response to therapy,
`treatment-related toxicity, progression-free and overall survival
`were analyzed.
`Results: One patient demonstrated an objective partial response to
`therapy (objective response rate 关ORR兴, 6%; 95% confidence inter-
`val 关CI兴, 0 –18%). Six patients achieved stable disease (38%; 95%
`CI, 14 – 62%) and 9 patients demonstrated disease progression on
`initial restaging (56%; 95% CI, 33–77%). The median progression-
`free survival and overall survival were 3.9 months (95% CI, 2.8 –
`8.8) and 20.2 months (95% CI, 9.7–37.4), respectively.
`Conclusions: In this retrospective cohort, the combination of strep-
`tozocin and doxorubicin failed to demonstrate substantial antitumor
`activity in patients with advanced PET. Our findings underscore the
`need for new therapeutic options in this patient population.
`
`Key Words: pancreatic endocrine tumor, islet cell carcinoma,
`streptozocin, chemotherapy
`
`(Am J Clin Oncol 2004;27: 485– 488)
`
`From the *Baylor University Medical Center-Charles A. Sammons Cancer
`Center, Dallas, Texas; †Dana Farber Cancer Institute, Department of
`Medical Oncology, and Brigham and Women’s Hospital, Department of
`Medicine, Boston, Massachusetts; ‡Dana Farber Cancer Institute, Depart-
`ment of Pharmacy, Boston, Massachusetts; and §Massachusetts General
`Hospital, Division of Hematology/Oncology, Boston, Massachusetts.
`Reprints: A. David McCollum, MD, Baylor-Charles A. Sammons Cancer
`Center, 3535 Worth St., Suite 240, Dallas, TX 75246. E-mail: david.
`mccollum@usoncology.com
`Copyright © 2004 by Lippincott Williams & Wilkins
`ISSN: 0277-3732/04/2705-0485
`DOI: 10.1097/01.coc.0000135343.06038.eb
`
`Pancreatic endocrine tumors (PETs), also called pancreatic
`
`islet cell carcinomas, are rare with an annual incidence
`around 0.4 per 100,000.1 Surgical resection is the only cur-
`ative therapy; unfortunately, many patients have locally un-
`resectable or metastatic disease at presentation. As a result of
`the indolent nature of PETs, such patients are often initially
`managed with expectant observation. When treatment is pur-
`sued, various strategies have been investigated, including
`hepatic arterial embolization (HAE), palliative cytoreductive
`interferon-␣, and systemic
`surgery, somatostatin analogs,
`cytotoxic chemotherapy. Although the hormonally mediated
`symptoms of PETs can be effectively palliated with the use of
`somatostatin analogs (eg, octreotide), such therapy rarely
`results in objective tumor regression.2–7
`Several chemotherapeutic agents have been evaluated
`and found to have tumor response rates of 7% to 25%,
`including streptozocin, doxorubicin, and 5-fluorouracil (5-
`FU).8 Through a series of randomized trials, the combination
`of streptozocin and doxorubicin has become a widely ac-
`cepted standard in this disease with reported response rates of
`69%.9,10 However, Cheng and Saltz recently reported the
`experience with this regimen at Memorial Sloan-Kettering
`Cancer Center.11 Among 16 patients with advanced PETs
`who received streptozocin plus doxorubicin, only 1 patient in
`their series had a documented partial response (objective
`response rate 关ORR兴, 6%). Given this discordance in the
`literature, we examined the efficacy of streptozocin and
`doxorubicin in a cohort of patients with advanced PETs
`treated at the Dana Farber/Partners Cancer Care institutions.
`
`METHODS
`We searched the computerized pharmacy records of the
`Dana Farber Cancer Institute, the Brigham and Women’s
`Hospital, and the Massachusetts General Hospital to identify
`patients who had been treated with streptozocin between
`January 1990 and April 2002. We restricted our cohort to 16
`patients who had a histologically confirmed diagnosis of
`neuroendocrine carcinoma arising in the pancreas. We ex-
`cluded patients with carcinoid tumors, patients without mea-
`
`American Journal of Clinical Oncology • Volume 27, Number 5, October 2004
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`McCollum et al
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`American Journal of Clinical Oncology • Volume 27, Number 5, October 2004
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`surable disease, and patients who had received prior therapy
`with either streptozocin or doxorubicin. We reviewed the
`individual medical records and searched public records for
`baseline patient and tumor characteristics, treatment details,
`response information, toxicity information, and vital status.
`All pertinent radiographic studies were reviewed with a
`trained radiologist
`to confirm objective tumor responses,
`which were categorized according to the Response Evalua-
`tion Criteria in Solid Tumors (RECIST) criteria.12
`This analysis was designed to assess the efficacy of
`streptozocin plus doxorubicin in a cohort of patients with
`advanced PET. Progression-free survival (PFS) was defined
`as the time from treatment initiation to radiographic docu-
`mentation of PD or death, and overall survival (OS) was
`defined as the time from treatment initiation to death from
`any cause. The distributions of duration of PFS and OS were
`estimated using Kaplan-Meier methodology.13
`
`RESULTS
`The baseline patient demographics and tumor charac-
`teristics are shown in Table 1. The median age of the cohort
`was 52 years (range, 28 –72 years), and most patients (56%)
`had a normal initial performance status. The majority of the
`tumors were nonsecretory. All of the patients had metastatic
`disease in the liver; other sites included intraabdominal
`lymph nodes and bone. Only 2 patients had received prior
`therapy.
`All patients received at least 1 cycle of streptozocin and
`doxorubicin as described in the previous cooperative group
`trial.10 Three patients received a reduction in the dose of
`doxorubicin because of thrombocytopenia (1 patient) or im-
`paired liver function tests (2 patients). One of these patients
`subsequently had the dose of doxorubicin escalated.
`Objective tumor response data are summarized in Table
`2. Only 1 patient demonstrated a radiographically docu-
`mented partial response to therapy, and there were no com-
`plete responses (ORR, 6%; 95% confidence interval 关CI兴,
`0 –18%). Six patients (38%; 95% CI, 14 – 62%) had stable
`disease as their best response, and 9 patients (56%; 95% CI,
`33–77%) had progressive disease. Notably, among the 9
`patients with radiographically documented progressive dis-
`ease, 1 patient had a glucagon level that fell from 391 pg/mL
`to 65 pg/mL, and another patient was reported to have
`“clinical evidence of response” with regression of hepato-
`megaly noted on examination. However, concurrent imaging
`studies in these patients demonstrated disease progression.
`As of May 2002, 15 patients had died, and 1 patient
`with stable disease was still alive. Kaplan-Meier curves for
`overall survival and progression-free survival are shown in
`Figure 1. The median progression-free survival was 3.9
`months (95% CI, 2.8 – 8.8 months; Fig. 1A). The median
`overall survival was 20.2 months (95% CI, 9.7–37.4 months;
`Fig. 1B), and survival at 1 year was 56% (9 patients).
`
`TABLE 1. Baseline Characteristics of Patients With
`Advanced Pancreatic Endocrine Tumors
`
`Characteristic
`
`Age, median (range)
`Gender
`Male
`Female
`ECOG performance status
`0
`1
`2
`Sites of metastases
`Liver
`Abdominal lymph node
`Bone
`Hormone
`Nonfunctioning
`Gastrin
`Insulin
`VIP
`Glucagon
`Prior therapy
`None
`Gemcitabine
`5-FU, MMC, CDDP
`
`Patients
`(n ⴝ 16)
`
`52 (28–72)
`
`6 (38%)
`10 (62%)
`
`9 (56%)
`6 (38%)
`1 (6%)
`
`16 (100%)
`4 (25%)
`1 (6%)
`
`9 (56%)
`4 (25%)
`1 (6%)
`1 (6%)
`1 (6%)
`
`14 (88%)
`1 (6%)
`1 (6%)
`
`Percentages might not equal 100% as a result of rounding.
`ECOG, Eastern Cooperative Oncology Group; VIP, vasoactive intestinal
`peptide; 5FU, 5-fluorouracil; MMC, mitomycin C; CDDP, cisplatin.
`
`Toxicity in this cohort was moderate. One patient had
`documented grade 4 neutropenia (absolute neutrophil count
`⬍500 cells/mm), but no episodes of febrile neutropenia
`occurred. Alopecia was reported in 56% of patients. Nausea
`and vomiting were also reported commonly (50% and 25%,
`respectively). Seven patients (44%) experienced fatigue
`graded as mild to moderate in severity. Life-threatening
`toxicity was documented in 2 patients. One patient developed
`
`TABLE 2. Best Response to Streptozocin and Doxorubicin
`Among Patients With Advanced Pancreatic Endocrine
`Tumors
`
`No. of Patients
`(%)
`
`95% Confidence
`Intervals
`
`Complete response
`Partial response
`Stable disease
`Progressive disease
`
`0
`1 (6%)
`6 (38%)
`9 (56%)
`
`—
`0–18%
`14–62%
`33–77%
`
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`© 2004 Lippincott Williams & Wilkins
`
`Ex. 1101-0002
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`American Journal of Clinical Oncology • Volume 27, Number 5, October 2004
`
`Streptozocin and Doxorubicin in Advanced PET
`
`Our results differ considerably from the randomized
`trial reported by Moertel et al.10 Among the 36 patients who
`received streptozocin and doxorubicin in that study,
`the
`overall response rate was 69%. Moreover, the reported CR
`rate with streptozocin and doxorubicin in that trial was 14%.
`Despite this meaningful response rate, the median overall
`survival of the patients randomized to receive streptozocin
`plus doxorubicin was 2.2 years, similar to the 20.2-month
`median survival in our patients.
`Although the results of Moertel and colleagues were
`obtained from a prospective, randomized trial, their trial has
`several potential limitations. First, a substantial number of
`patients (23 patients, 18%) enrolled in the study were found
`to be ineligible, withdrew consent, or were not evaluable for
`response. These patients were not included in the final data
`analysis. Second, the investigators accepted “biologic re-
`sponse” as a major objective response. Notably, 1 patient in
`our analysis had such a “biologic response” despite the
`finding of disease progression on computed tomography scan.
`Lastly, the trial accepted clinical assessment of hepatomegaly
`as sufficient documentation of tumor response. These less
`rigorous methods of defining tumor response could poten-
`tially explain the discrepancy between our findings and those
`of Moertel and colleagues.
`Because of the rarity of PETs, our study was limited by
`the number of patients available for analysis. However,
`Cheng and Saltz also observed only 1 objective tumor re-
`sponse in a separate retrospective analysis of 16 consecutive
`patients with advanced PETs treated at Memorial Sloan-
`Kettering Cancer Center.11 Consequently, among the 32 pa-
`tients analyzed in 2 studies that used standard, contemporary
`response criteria, the overall response rate remains only 6%.
`Because the prior activity of streptozocin and doxorubicin
`was based on only 36 patients in the aforementioned random-
`ized trial,10 we believe that these retrospective findings call
`into question the use of this chemotherapy regimen in patients
`with advanced PETs. Moreover, our results underscore the
`importance of actively pursuing new and potentially more active
`agents in patients with advanced neuroendocrine tumors.
`
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`487
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`FIGURE 1. Kaplan-Meier curves of overall survival (A) and
`progression-free survival (B) in a cohort of patients with ad-
`vanced pancreatic endocrine tumors treated with streptozocin
`and doxorubicin.
`
`acute renal failure requiring hospitalization for fluid and
`electrolyte management. A second patient experienced severe
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`doxorubicin.
`
`DISCUSSION
`In this study, we found little clinically meaningful
`antitumor activity for the combination of streptozocin and
`doxorubicin in a cohort of patients with advanced pancreatic
`endocrine tumors treated at Dana Farber/Cancer Care Part-
`ners institutions. The radiographically documented overall
`response rate was 6%, and the majority of patients (56%) had
`progressive disease as the best response to therapy. As a
`result, progression-free survival was only 3.9 months. Nev-
`ertheless, consistent with the indolent nature of PETs, median
`overall survival was 20.2 months. Treatment with streptozo-
`cin and doxorubicin was reasonably tolerable in our analysis,
`although there was 1 treatment-related death.
`
`© 2004 Lippincott Williams & Wilkins
`
`Ex. 1101-0003
`
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`American Journal of Clinical Oncology • Volume 27, Number 5, October 2004
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`© 2004 Lippincott Williams & Wilkins
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`Ex. 1101-0004
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