V O L U M E 2 2 䡠 N U M B E R 2 3 䡠 D E C E M B E R 1 2 0 0 4
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`Fluorouracil, Doxorubicin, and Streptozocin in the
`Treatment of Patients With Locally Advanced and
`Metastatic Pancreatic Endocrine Carcinomas
`Maria A. Kouvaraki, Jaffer A. Ajani, Paulo Hoff, Robert Wolff, Douglas B. Evans, Richard Lozano,
`and James C. Yao
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`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 retrospec-
`tively 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.
`
`J Clin Oncol 22:4762-4771. © 2004 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`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 sclero-
`sis.2 Multiple hormones and peptides are
`frequently produced by PECs. Function-
`
`ing PECs release biologically active sub-
`stances, or hormones, that produce distinct
`clinical syndromes. These hormones in-
`clude gastrin, insulin, glucagon, somatosta-
`tin,
`vasoactive
`intestinal
`polypeptide,
`growth hormone–releasing factor, and ad-
`renocorticotropic hormone. Nonfunction-
`ing PEC may also secrete a number of
`amines and peptides (eg, neurotensin, the
`␣-subunit of human chorionic gonadotro-
`pin, neuron-specific enolase, pancreatic
`
`From the Departments of Surgical
`Oncology and Gastrointestinal Medical
`Oncology, The University of Texas M.D.
`Anderson Cancer Center, Houston, TX.
`
`Submitted April 5, 2004; accepted
`September 16, 2004.
`
`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 con-
`flicts of interest are found at the end of
`this article.
`
`Address reprint requests to James C.
`Yao, MD, Department of Gastrointesti-
`nal Medical Oncology, Unit 426, The
`University of Texas M.D. Anderson
`Cancer Center, 1515 Holcombe Blvd,
`Houston, TX 77030; e-mail: jyao@
`mdanderson.org.
`
`© 2004 by American Society of Clinical
`Oncology
`
`0732-183X/04/2223-4762/$20.00
`
`DOI: 10.1200/JCO.2004.04.024
`
`4762
`
`Downloaded from ascopubs.org by 189.224.17.9 on November 18, 2016 from 189.224.017.009
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2011
`Par v. Novartis, IPR 2016-01479
`Page 1 of 10
`
`

`
`Chemotherapy for PECs
`
`polypeptide, and chromogranin A); however, these are in-
`active 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 somatosta-
`tin analogs, hepatic artery embolization or chemoemboli-
`zation, 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 asso-
`ciated with excessive hormones, are generally reserved for
`patients with metastatic tumors that failed to respond to
`other treatments.
`Systemic chemotherapy has been evaluated, with vari-
`able rates of tumor response. Single chemotherapeutic
`agents used include streptozocin, fluorouracil (FU), doxoru-
`bicin, 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 re-
`sults.9,10 Previous studies have used the triple chemotherapy of
`FU, doxorubicin, and streptozocin (FAS) and shown promis-
`ing 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 objec-
`tive tumor RR, duration of progression-free survival
`(PFS), and duration of overall survival (OS) in 84 pa-
`tients with locally advanced or metastatic PEC treated
`with combination FAS chemotherapy.
`
`PATIENTS AND METHODS
`
`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 con-
`secutive 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
`The regimen included an intravenous 400 mg/m2 bolus of
`FU daily on days 1 to 5; a 400 mg/m2 bolus of streptozocin daily on
`days 1 to 5, and a 40 mg/m2 bolus of doxorubicin on day 1. Cycles
`were repeated every 28 days. The median number of chemother-
`apy cycles was four (range, one to 16) and the median duration of
`treatment was 3.9 months (range, 5 days to 15.5 months). Full
`blood counts including absolute neutrophil counts and platelets,
`as well as biochemical studies, were obtained before the first course
`and every course thereafter in all patients. Doses were reduced at
`the beginning of the treatment in patients with hyperbiliru-
`binemia or uncontrolled diabetes. Reduction of streptozocin dose
`to 300 mg/m2 was adjusted for patients with uncontrolled diabetes
`because streptozocin may damage normal pancreatic cells. Doses
`were also adjusted at the start of a subsequent course if grade 3 or
`4 toxicity was observed. Occasionally, grade 1 to 2 toxicities led to
`dose reduction or to delay of the treatment. All patients were
`re-evaluated every 8 weeks after the initiation of treatment to
`assess their clinical status and their response to therapy. The eval-
`uation comprised a complete physical examination and tumor
`measurement by CT or MRI. Fasting tumor markers, bone scan,
`and somatostatin receptor scintigraphy were obtained as needed.
`Chemotherapy was continued until disease progression, unac-
`ceptable toxicity, or patient intolerance. Cardiac function was
`evaluated in all patients after the sixth or seventh course of che-
`motherapy by echocardiogram. Doxorubicin was reduced or dis-
`continued when the left ventricular ejection fraction was reduced
`more than 10% to 15% of the initial value, or if it was below the
`lower normal limit.
`
`Evaluation of Tumor Response
`All CT or MRI reports were available, and the original films
`were also re-evaluated independently by two physicians (M.A.K.
`and J.C.Y.). Patients were considered assessable only if measurable
`disease was present. Response to treatment was evaluated in this
`study using the new international criteria proposed by the Re-
`sponse Evaluation Criteria in Solid Tumors (RECIST) Commit-
`tee11; complete response (CR) was defined as the disappearance of
`all lesions. Partial response (PR) was defined as at least a 30%
`reduction in the tumor load, estimated as the sum of the longest
`diameters (LD) of all measurable lesions, taking as a reference the
`baseline sum of LD. Progressive disease (PD) was defined as at
`least a 20% increase in the tumor load, taking as a reference the
`smallest sum of LD recorded since the treatment started or devel-
`opment of new lesions in a previously uninvolved site. Stable
`disease (SD) was defined as disease that showed neither sufficient
`shrinkage nor increase to qualify as either PR or PD.
`Duration of overall response was defined as the time be-
`tween 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.
`
`www.jco.org
`
`4763
`
`Downloaded from ascopubs.org by 189.224.17.9 on November 18, 2016 from 189.224.017.009
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2011
`Par v. Novartis, IPR 2016-01479
`Page 2 of 10
`
`

`
`Kouvaraki et al
`
`Statistical Analysis
`The comparisons between response and tumor characteris-
`tics, disease extension, or laboratory features were based on ␹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 mea-
`sured by the method of Kaplan and Meier.12 The statistical differ-
`ences in PFS between groups of patients were estimated by the
`log-rank test.13 The statistical independence between prognostic
`variables was evaluated by multivariate analysis using the Cox
`proportional hazards model.14 All statistical calculations were per-
`formed using StatView (Abacus Concepts, Berkeley, CA). Differ-
`ences were considered statistically significant when the P value was
`less than .05.
`
`RESULTS
`
`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 character-
`istics 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 va-
`soactive intestinal polypeptide tumors, and one was an ad-
`renocorticotropic hormone–producing PEC. All eight
`locally advanced tumors were nonfunctioning.
`Eleven of 84 patients were previously treated with so-
`matostatin analogs (n ⫽ 5), hepatic artery chemoemboliza-
`tion (n ⫽ 4), or both (n ⫽ 1); one additional patient
`underwent radiofrequency ablation of the liver. One pa-
`tient 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 me-
`dian 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 meta-
`static 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 ad-
`vanced 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
`
`Table 1. Characteristics of 84 Patients Included in the Study
`
`Characteristic
`
`No. of Patients
`
`54
`24-78
`
`2.6
`0.2-199
`
`Sex
`Male
`Female
`Age at treatment, years
`Median
`Range
`Interval from diagnosis to treatment,
`months
`Median
`Range
`Tumor type
`Functioning
`Gastrinoma
`Insulinoma
`Glucagonoma
`VIPoma
`ACTH-producing PEC
`Nonfunctioning
`Inheritance
`MEN1
`Sporadic
`Tumor status
`Locally advanced
`
`Metastatic
`
`% of liver replaced by metastases
`ⱕ 50/⬎ 50
`ⱕ 75/⬎ 75
`Treatment trial
`First line
`Second line
`
`61
`23
`
`20
`11
`3
`3
`2
`1
`64
`
`4
`80
`
`8 (all nonfunctioning
`tumors)
`76 (73 LM [18 plus
`ODM]/3 ODM)
`
`44/29
`61/12
`
`79
`5
`
`Abbreviations: VIPoma, vasoactive intestinal polypeptide; ACTH, adre-
`nocorticotropic hormone; PEC, pancreatic endocrine carcinoma; MEN1,
`multiple endocrine neoplasia type I; LM, liver metastases; ODM, other
`distant metastases.
`
`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 chemother-
`apy 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 ad-
`vanced tumors (33%; P ⫽ .01 by Fisher’s exact test). Chro-
`mogranin 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 lev-
`els after chemotherapy.
`Thirty-seven patients who experienced disease pro-
`gression during or after the treatment, as well as four
`
`4764
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Downloaded from ascopubs.org by 189.224.17.9 on November 18, 2016 from 189.224.017.009
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2011
`Par v. Novartis, IPR 2016-01479
`Page 3 of 10
`
`

`
`Chemotherapy for PECs
`
`Table 2. Response to Chemotherapy
`
`Response Rate
`
`Stable Disease
`
`Progressive Disease
`
`Parameter
`
`No. of Patients
`
`All patients
`Tumor status
`Locally advanced
`Metastatic
`LM
`ⱕ 75%
`⬎ 75%
`Sites of metastases
`Liver only
`Liver ⫾ other sites
`Tumor type
`Gastrinomas
`All other PEC
`Decrease of chromogranin
`A after treatment
`ⱖ 30%
`⬍ 30%
`
`33
`
`2
`31
`
`27
`4
`
`27
`4
`
`0
`33
`
`12
`12
`
`P ⴱ
`
`NA
`NS
`
`NS
`
`.02
`
`.002
`
`.04
`
`%
`
`39
`
`25
`41
`
`44
`34
`
`49
`19
`
`45
`
`67
`36
`
`No. of Patients
`
`42
`
`6
`36
`
`26
`7
`
`22
`14
`
`9
`33
`
`6
`16
`
`%
`
`50
`
`75
`47
`
`43
`58
`
`40
`67
`
`8
`45
`
`33
`49
`
`No. of Patients
`
`9
`
`0
`9
`
`8
`1
`
`6
`3
`
`2
`7
`
`0
`5
`
`%
`
`11
`
`12
`
`13
`8
`
`11
`14
`
`18
`10
`
`15
`
`Abbreviations: NA, not applicable; NS, not significant; LM, liver metastases; PEC, pancreatic endocrine carcinoma.
`ⴱBy Fisher’s exact test.
`
`patients with SD, were subsequently treated using other mo-
`dalities including second-line chemotherapy, hepatic artery
`chemoembolization, somatostatin analogs, or interferon.
`Dose Intensity and Toxic Reactions
`Of the entire group of 84 patients, seven patients re-
`ceived a reduced first dose of FAS because of diabetes and
`mild renal insufficiency (n ⫽ 2), jaundice (n ⫽ 2), poor
`performance status (n ⫽ 2), and previous external-beam
`radiation therapy to the pelvis for colon carcinoma (n ⫽ 1).
`In subsequent chemotherapy courses (after the first
`course), eight patients needed dose reduction: three be-
`cause of grade 3 or 4 toxicity and five because of recurrent
`grade 1 or 2 toxicity. Delay in administration of the treat-
`ment occurred on 13 occasions because of grade 3 or 4
`toxicity (n ⫽ 7), or grade 1 or 2 toxicity (n ⫽ 4). Two
`additional patients had delays in the scheduled chemother-
`apy dates because they underwent surgery for reasons un-
`related to their disease. In eight patients, at least one of three
`drugs was withheld because of toxic reactions or poor tol-
`erance. In addition, doxorubicin was discontinued in five
`patients because they had received the maximum accumu-
`lated lifetime dose.
`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, vom-
`iting, 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 hospi-
`talization for dehydration. Eleven patients developed grade
`3 or 4 neutropenia (absolute neutrophil counts, ⬍ 1.0 ⫻
`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 ⫻109/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 em-
`bolism after the first treatment and was admitted to the
`hospital, and as a result there was a delay in the admin-
`istration 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, metas-
`tases, or both), 54 patients were alive with disease, and 25
`patients were dead as a result of disease.
`
`www.jco.org
`
`4765
`
`Downloaded from ascopubs.org by 189.224.17.9 on November 18, 2016 from 189.224.017.009
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2011
`Par v. Novartis, IPR 2016-01479
`Page 4 of 10
`
`

`
`Kouvaraki et al
`
`Fig 1. Patients with liver metastases who responded dramatically to chemotherapy. Patient 1, with (A) single hepatic metastasis, had (B) partial response (PR)
`after two cycles of fluorouracil, doxorubicin, and streptozocin (FAS). Patient 2, with (C) more than 75% metastatic replacement of the liver, showed (D) PR after
`four cycles of FAS. Patient 3, with (E) multiple metastatic sites on the liver, experienced (F) complete response after four cycles of FAS.
`
`4766
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Downloaded from ascopubs.org by 189.224.17.9 on November 18, 2016 from 189.224.017.009
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2011
`Par v. Novartis, IPR 2016-01479
`Page 5 of 10
`
`

`
`Chemotherapy for PECs
`
`Table 3. Toxic Reaction to FAS of the 84 Patients Included in the Study
`
`Toxic Reaction
`
`Any toxic reactionⴱ
`Gastrointestinal
`Nausea or vomiting
`Diarrhea
`Mucositis
`Hematologic
`Leukopenia or neutropenia
`Thrombocytopenia
`Anemia
`Hemorrhage
`Pulmonary
`Cardiac
`Peripheral neuropathy
`Pain
`Vasculitis or phlebitis
`Fatigue
`Skin erythema
`Fever
`Headache
`Increased blood glucose
`
`No. of Patients With Grade
`3 or 4 Toxicity
`
`19
`
`1
`3
`4
`
`9
`1
`0
`0
`1
`2
`1
`1
`1
`4
`0
`2
`1
`1
`
`%
`
`22.6
`
`1.1
`3.5
`4.7
`
`10.7
`1.1
`
`1.1
`2.3
`1.1
`1.1
`1.1
`4.7
`
`2.3
`1.1
`1.1
`
`Abbreviation: FAS, flourouracil, doxorubicin, and streptozocin.
`ⴱAlopecia not included.
`
`Univariate Survival Analysis
`Survival analysis showed that responders had longer
`OS than nonresponders (97% at 2 years; 95% CI, 91% to
`100% for responders v 55.1% at 2 years; 95% CI, 35% to
`75% for nonresponders; P ⫽ .03 by log-rank test).
`At 2 years, the PFS rate for patients with liver metas-
`tases (LM) ⱕ 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; Table 4; Fig 3). At 2 years, the OS rate
`for patients with LM ⱕ 75% was 83% (95% CI, 70% to
`96%), whereas all 12 patients with LM more than 75%
`had died by 15.5 months (P ⬍ .0001 by log-rank test;
`Table 4; Fig 3).
`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 aspi-
`ration), 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 chemo-
`therapy showed a statistical trend toward a worse PFS
`compared with those patients who had not received pre-
`vious 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 statis-
`tical trend toward a worse outcome. Moreover, complete
`resection of the primary tumor was not associated with
`different PFS or OS.
`
`Multivariate Survival Analysis
`Multivariate analysis using the Cox proportional haz-
`ards model14 revealed that the extent of liver disease (more
`than 75% of liver replaced by metastases) and prior chemo-
`therapy were independently associated with shorter PFS,
`whereas only the extent of liver metastasis was indepen-
`dently associated with shorter OS (Fig 4). Other factors that
`entered the final model, along with the volume of liver
`metastases, were tumor histologic type, prior chemother-
`apy, and surgical resection of the primary tumor before
`chemotherapy (Table 5).
`
`Fig 2. Progression-free survival (PFS) and overall survival (OS) for the entire group of patients with locally advanced or metastatic pancreatic endocrine
`carcinoma (n ⫽ 84).
`
`www.jco.org
`
`4767
`
`Downloaded from ascopubs.org by 189.224.17.9 on November 18, 2016 from 189.224.017.009
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2011
`Par v. Novartis, IPR 2016-01479
`Page 6 of 10
`
`

`
`Kouvaraki et al
`
`Table 4. Univariate Analysis for 2-Year PFS and OS
`
`Variable
`
`2-Year PFS (%)
`
`95% CI
`
`LM
`ⱕ 75%
`⬎ 75%
`
`37
`All patients died
`by 14 months
`
`Tumor grade
`Low
`High
`Age, years
`⬍ 54
`ⱖ 54
`Trial of chemotherapy
`First line
`Second line
`Chromogranin A prior to treatment
`Increased
`Normal
`Histologic tumor type
`Gastrinoma
`All other PEC
`Curative resection before treatment
`Yes
`No
`
`94
`30
`
`26
`51
`
`37
`20
`
`50
`92
`
`0
`41
`
`50
`33
`
`20 to 54
`
`82 to 100
`2 to 61
`
`7 to 44
`28 to 74
`
`21 to 54
`15 to 55
`
`30 to 70
`78 to 100
`
`24 to 57
`
`23 to 78
`15 to 50
`
`P ⴱ
`
`.01
`
`.004
`
`.04
`
`.08
`
`NS
`
`NS
`
`NS
`
`2-Year OS (%)
`
`95% CI
`
`P ⴱ
`
`⬍ .0001
`
`96.6
`All patients died
`by 15.5 months
`
`50
`57
`
`65
`76
`
`69
`67
`
`81
`100
`
`33
`78
`
`86
`64
`
`90 to 100
`
`0 to 100
`8 to 100
`
`45 to 84
`55 to 97
`
`54 to 85
`13 to 100
`
`62 to 100
`
`0 to 68
`64 to 92
`
`60 to 100
`47 to 81
`
`NS
`
`NS
`
`NS
`
`NS
`
`NS
`
`NS
`
`Abbreviations: PFS, progression-free survival; OS, overall survival; NS, not significant; LM, liver metastasis; PEC, pancreatic endocrine carcinoma.
`ⴱBy log-rank test.
`
`DISCUSSION
`
`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 stud-
`ies using a combination of streptozocin with FU and/or
`doxorubicin showed higher RRs.5,6,9,16 However, biochem-
`ical, 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
`
`Fig 3. Association between progression-free survival (PFS), overall survival (OS), and tumor type for patients treated with streptozocin, doxorubicin, and
`fluorouracil. PEC, pancreatic endocrine carcinoma.
`
`4768
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Downloaded from ascopubs.org by 189.224.17.9 on November 18, 2016 from 189.224.017.009
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2011
`Par v. Novartis, IPR 2016-01479
`Page 7 of 10
`
`

`
`Chemotherapy for PECs
`
`Fig 4. Association between extent of liver metastasis (LM) and outcome: (A) progression-free survival (PFS) of patients with ⱕ 75% versus more than 75%
`liver replacement by metastases. (B) Overall survival (OS) of patients with ⱕ 75% versus more than 75% liver replacement by metastases.
`
`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 combi-
`nation 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. Interest-
`ingly, 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 How-
`ever, in that study, the radiologic criteria used to assess
`tumor response were different; PR was defined as a reduc-
`tion in tumor size by 25% using unidimensional measure-
`ments, whereas RECIST defined PR as a reduction by
`30% using unidimensional measurements, and the WHO
`
`defines it as a reduction by 50% using bidimensional mea-
`surements. 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 discrep-
`ancy in RR among different series may be due to the gener-
`ally 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 aggressive-
`ness 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 gas-
`trinomas 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
`
`Table 5. Univariate and Multivariate Analysis for PFS
`
`Variable
`
`Univariate HR
`
`95% CI
`
`Volume of liver metastases
`ⱕ 75%
`⬎ 75%
`Age, years
`ⱖ 54
`⬍ 54
`Trial of chemotherapy
`First line
`Second line
`Tumor type
`Gastrinoma
`All other PEC
`Resection of primary tumor prior to treatment
`Yes
`No
`
`0.4
`2.7
`
`0.5
`2.0
`
`0.4
`2.6
`
`1.8
`0.5
`
`0.5
`1.4
`
`0.2 to 0.8
`1.2 to 6.2
`
`0.2 to 0.9
`1.0 to 4.0
`
`0.1 to 1.1
`0.9 to 0.6
`
`0.8 to 4.0
`0.2 to 1.2
`
`0.3 to 1.6
`0.6 to 3.2
`
`P
`
`.01
`
`.03
`
`.06
`
`NS
`
`NS
`
`Multivariate HR
`
`95% CI
`
`0.3
`2.92
`
`0.3
`3.0
`
`0.2
`4.62
`
`1.8
`0.5
`
`0.6
`1.7
`
`0.1 to 0.8
`1.25 to 6.89
`
`0.92 to 0.99
`1.4 to 6.3
`
`0.05 to 0.7
`1.17 to 18.18
`
`0.8 to 4.2
`0.2 to 1.3
`
`0.2 to 1.4
`0.7 to 4.0
`
`Abbreviations: PFS, progression-free survival; HR, hazard ratio; NS, not significant; PEC, pancreatic endocrine carcinoma.
`
`www.jco.org
`
`P
`
`.01
`
`.005
`
`.01
`
`NS
`
`NS
`
`4769
`
`Downloaded from ascopubs.org by 189.224.17.9 on November 18, 2016 from 189.224.017.009
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`NOVARTIS EXHIBIT 2011
`Par v. Novartis, IPR 2016-01479
`Page 8 of 10
`
`

`
`Kouvaraki et al
`
`limited number of patients in our study who had function-
`ing tumors other than gastrinomas precludes definite con-
`clusions about tumor sensitivity to chemotherapy. Previous
`studies also showed similar results in patients with func-
`tioning 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 chemother-
`apy 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, know-
`ing the indolent nature of this disease, many oncologists out-
`side 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 sec-
`ond 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 chemother-
`apy (Table 3). Nausea, vomiting, and myelosuppression did
`not significantly compromise patients’ compliance. A
`previous trial from our institution also noted good tol-
`erance to this regimen.7,8
`There is considerable controversy about the role of two-
`drug chemotherapy with streptozocin and doxorubicin be-
`cause 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 che-
`motherapies, whether based on streptozocin or not, have
`shown lower RRs.8,9,16,19,20,22,26 Biologic agents such as soma-
`tostatin 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 chemo-
`embolization, 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 r