European Journal of Cancer 40 (2004) 515–520
`
`www.ejconline.com
`
`The doxorubicin-streptozotocin combination for the treatment of
`advanced well-differentiated pancreatic endocrine carcinoma:
`a judicious option?
`
`Th. Delaunoita, M. Ducreuxa,*, V. Boigea, C. Dromainb, J.-C. Sabourinc, P. Duvillardc,
`M. Schlumbergerd, T. de Baeree, P. Rougiera, P. Ruffief, D. Eliasg, P. Lasserg, E. Baudind
`aDepartment of Gastroenterology, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif, France
`bDepartment of Radiology, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif, France
`cDepartment of Pathology, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif, France
`dDepartment of Endocrinology, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif, France
`eDepartment of Interventional Radiology, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif, France
`fDepartment of Medical Oncology, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif, France
`gDepartment of Surgery, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif, France
`
`Received 18 August 2003; received in revised form 11 September 2003; accepted 15 September 2003
`
`Abstract
`
`Due to their rarity, only few trials have studied the role of the doxorubicin-streptozotocin (DS) combination in advanced well-
`differentiated pancreatic endocrine carcinomas (AWDPEC). However, the published results are inconsistent. We reviewed all
`AWDPEC (5-year period, 45 patients) treated in our institution with the DS combination for: objective response rate (ORR),
`progression-free survival, overall survival (OS) and toxicity. An ORR of 36% (95% Confidence Interval (CI) 22–49) was obtained,
`with 16 partial responses (PR). The mean duration of PR was of 19.7 months. Two and 3-year OS rates were 50.2 and 24.4%,
`respectively. Toxicities were mainly digestive (grade 53 vomiting, 13%) and haematological (grade 53 neutropenia, 24%).
`Previous systemic chemotherapy and malignant hepatomegaly were associated with a poorer ORR (P=0.033, P=0.016) and OS
`(P=0.008, P=0.045). Multivariate analysis demonstrated previous chemotherapy as the only independent predictive-factor for
`survival (P=0.013). In conclusion, our data confirm the sensitivity of AWDPEC to the DS combination, with an ORR of 36% and
`a remarkable median response duration of 19.7 months, and suggests that it could be considered as a valid option in first-line
`therapy.
`# 2003 Elsevier Ltd. All rights reserved.
`
`Keywords: Neuroendocrine carcinoma; Chemotherapy; Pancreas
`
`1. Introduction
`
`Pancreatic endocrine carcinomas (PECs) are rare
`malignancies, accounting for less than 2% of all gas-
`trointestinal tract malignant tumours and less than 1%
`of endocrine tumours [1]. They can be classically divi-
`ded in 2 groups, based on the potential presence of
`typical clinical symptoms at disease onset: ‘‘functional’’
`and ‘‘non-functional’’ pancreatic tumours, respectively
`[2–4]. Approximately half of PECs express at least one
`active hormone, such as insulin, gastrin, glucagon or
`
`* Corresponding author. Tel.: +33-1-4211-4308; fax: +33-1-4211-
`5228.
`E-mail address: ducreux@igr.fr (M. Ducreux).
`
`0959-8049/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
`doi:10.1016/j.ejca.2003.09.035
`
`somatostatin. These are responsible for intermittent and
`often typical, but non-specific, symptomatology. Non-
`functional tumours are usually diagnosed at a later
`stage, based upon symptoms related to the tumour
`burden itself [4].
`Therapeutic management of PEC represents a chal-
`lenge for the physician. Treatment choice is dictated by
`pathological differentiation and the stage at diagnosis,
`as well as by the presence of hormone-related symp-
`toms. Well-differentiated PEC (WDPEC) are usually
`slow-growing tumours that sometimes allow for ther-
`apeutic abstention. However, they can display acceler-
`ated progression, requiring a much more aggressive
`attitude to treatment. In the case of localised WDPEC,
`surgery remains the only curative treatment. However,
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`in the peculiar situation of multiple gastrinomas as part
`of the MEN1 syndrome, the debate is still open.
`WDPEC are considered relatively chemosensitive
`neoplasms and in cases of a high tumour burden and/or
`rapidly progressive metastatic disease, chemotherapy is
`an appropriate therapeutic option [5–9]. First data con-
`cerning chemotherapeutic effectiveness in WDPEC date
`back to 1968, when Murray-Lyon and colleagues
`reported a case of insulinoma responding to streptozo-
`tocin [9]. Since then, several chemotherapeutic agents,
`including doxorubicin and dacarbazine (DTIC), have
`been evaluated as single agent therapy. Both demon-
`strated interesting effects in advanced WDPEC (AWD-
`PEC), with 20–30% response rates, and a tolerable
`toxicity profile [6,8]. Later, Moertel and colleagues
`demonstrated, in a prospective randomised trial com-
`paring doxorubicin-streptozotocin (DS), streptozotocin/
`5-fluorouracil and chlortozotocin, an objective response
`rate (ORR) of 69% with a median survival of 26.5
`months in the DS arm, results that were significantly
`superior to those of the other 2 regimens. This associ-
`ation became thereafter a standard therapy for pro-
`gressive AWDPEC. However, a recent study failed to
`confirm the outstanding anti-tumour activity of the DS
`combination [10]. Such discrepant results prompted us
`to review our institution experience of DS in AWDPEC
`treatment, with three main aims: (1) ORR, (2) toxicity,
`(3) prognostic parameters of objective response and
`survival.
`
`2. Patients and methods
`
`2.1. Patients
`
`All patients included in our study had been followed
`in our institution from January 1995 to December 1999.
`Presence of histologically-confirmed measurable, but
`unresectable, AWDPEC was necessary for patient
`inclusion. Pathological diagnoses were all reviewed by a
`single pathologist and thereafter classified according to
`the updated World Health Organisation (WHO 2000)
`classification. Performance status (PS), as well as hae-
`matological and non-haematological
`(cardiac, renal,
`hepatic, digestive and neurological)
`toxicities were
`reviewed for all patients and graded numerically
`according to the WHO scale. Both functional and
`non-functional tumours were included in the study.
`Biological evaluation included dosage of: neuron-spe-
`cific enolase (NSE), calcitonin, glycoprotein a-subunit,
`5-hydroxyindolacetic acid (5-HIAA),
`in addition to
`gastrin and pancreatic peptides [11]. After 1996, chro-
`mogranin A replaced NSE measurement. Morphologi-
`cal investigations included, for each patient: abdominal
`computerised tomography scanner
`(CT-scan) and
`somatostatin receptor
`scintigraphy. Cardiac ultra-
`
`sonography was also performed to detect potential
`doxorubicin-induced cardiotoxicity.
`
`2.2. Treatment
`
`Patients were treated with combination of doxo-
`rubicin (intravenous (i.v.) injection of 50 mg/m2/day, on
`days 1 and 22 of each six-week treatment-cycle) and
`injection of 500 mg/m2/day for 5
`streptozotocin i.v.
`consecutive days, every six weeks). Any grade 3 or 4
`side-effects resulted in a 25% dose reduction for sub-
`sequent cycles. Treatment was stopped in cases of
`disease progression or life-threatening toxicity.
`
`2.3. Response and survival evaluation
`
`All patients were monitored every other month by
`radiological
`investigations,
`including CT-scan, ultra-
`sonography and/or magnetic resonance imaging (MRI).
`Objective
`response was
`evaluated through the
`measurement of one or more target lesions: primary
`tumour (if 530 mm), metastatic disease and/or lymph
`node involvement (if 520 mm). Patients were con-
`sidered as achieving a partial response (PR) when a
`tumour mass regressed in such a way that the product of
`its largest perpendicular dimensions was reduced by
`50%, while a minor response (MR) was defined as a
`reduction of 25% to 49%. Progressive disease (PD) was
`defined as an increase of 525% of these measurements,
`and stable disease (SD) as the lesions between PD and
`MR. Biochemical response was defined as a relevant
`marker level reduction of 550%. Time to progression
`was calculated from the first DS administration to dis-
`ease progression. Survival was calculated from the first
`DS administration.
`
`2.4. Statistical analysis
`
`Predictive factors of response were ascertained by the
`chi-square test. The Kaplan–Meier method was used to
`analyse overall survival (OS), and time to disease pro-
`gression. Prognostic factors for a longer survival were
`determined through univariate analysis with the log
`rank test. Variables tested consisted of: age, gender,
`performance status, primary tumour resection, presence
`of malignant hepatomegaly previous chemotherapy
`and/or chemoembolisation. Multivariate analysis was
`performed according to the Cox model using the BMDP
`software and the 2L program. Statistical significance
`was defined as P < 0.05.
`
`3. Results
`
`Between January 1995 and December 1999, 45 con-
`secutive patients suffering from unresectable AWDPEC
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`517
`
`were evaluated: 27 men (60%) and 18 women (40%)
`with a median age of 54 years (ranging from 22 to 75
`years). Patient characteristics are summarised in Table 1.
`Most patients had a PS41.
`Forty-two out of 45 patients (93%) had metastatic
`disease when chemotherapy was started, including 87%
`with liver metastases,
`responsible for
`radiological
`malignant hepatomegaly in 56% of
`them. Eleven
`patients had received previous chemotherapy, including
`5-fluorouracil plus cisplatin (CDDP) or 5-fluorouracil
`plus streptozotocin. Six patients received more than one
`regimen prior to the DS administration. Chemoemboli-
`sation using doxorubicin had been previously per-
`formed in 4 patients. Sixteen patients (36%) had
`previously undergone pancreatic
`surgery. Twenty
`patients had documentation of tumour-related hormone
`
`Table 1
`Patient characteristics
`
`Total number of patients
`
`Gender male/female
`
`Median age (years)
`
`WHO performance status
`0
`1
`2
`3
`
`Metastatic sites
`Liver
`Lymph nodes
`Peritoneum
`Others
`
`Previous treatment
`Curative/palliative surgery
`Radiotherapy
`Chemotherapy
`Chemoembolisation
`Somatostatin analogues
`
`Functional tumour
`Insulinoma
`Gastrinoma
`Glucagonoma
`Vipoma
`Others
`
`Non-functional tumour
`
`Symptoms
`Abdominal pain
`Anorexia
`Vomiting
`Weight loss > 10%
`Abdominal mass
`Malignant hepatomegaly
`Peritoneal carcinomatosis
`Others
`
`WHO, World Health Organisation.
`
`N (%)
`
`45
`
`27/18
`
`54
`
`34 (75)
`7 (16)
`3 (7)
`1 (2)
`
`39 (87)
`18 (40)
`3 (7)
`12 (27)
`
`6 (13)/10 (22)
`4 (9)
`11 (24)
`4 (9)
`11 (24)
`
`20 (44)
`3 (7)
`2 (4)
`1 (2)
`2 (4)
`12 (27)
`
`25 (56)
`
`17 (38)
`3 (7)
`2 (4)
`6 (13)
`7 (16)
`25 (56)
`4 (9)
`19 (42)
`
`production. Among them, 10 were classified as having
`a functional tumour (including 3 insulinomas, and 2
`gastrinomas).
`
`3.1. Treatment
`
`Twenty-seven (60%) patients received 55 DS cour-
`ses, with 17 patients (38%) receiving 6 courses. The
`median cycle number was 4 (range 2–7), and the mean
`cycle number the standard error of the mean (SEM)
`was 4.2 1.7.
`
`3.2. Toxicity
`
`In our series, the DS treatment was globally well-tol-
`erated (Table 2). None of the patients developed severe
`chronic renal insufficiency. Grade 3–4 neutropenia and
`thrombocytopenia occurred in 11 (24%) and 8 (18%)
`patients, respectively, with 3 patients requiring hospital-
`isation for neutropenic fever. Three out of 45 patients
`(7%) developed grade 1–2 cardiac toxicity, leading to
`doxorubicin discontinuation in 2 of them (after 6 and 7
`chemotherapeutic courses, respectively). Other side-
`effects, including vomiting and diarrhoea, were mild and
`easily controlled with supportive care. No treatment-
`related death was reported.
`
`3.3. Response to therapy
`
`Based upon radiological monitoring, and according
`to WHO criteria, 16 of our patients (36%) achieved a
`PR (95% Confidence Interval
`(CI) 22 to 49%),
`corresponding to our overall response rate (ORR),
`whereas 7 (16%) patients achieved MR and 4 (9%) SD.
`Eighteen patients
`(40%)
`experienced progression.
`Among the responding patients, 14 (88%) received the
`
`Table 2
`Toxic side-effects of doxorubicin-streptozotocin treatment per patient
`
`WHO Grade N (%)
`
`0
`
`1
`
`2
`
`3
`
`4
`
`Digestive toxicity
`Vomiting
`Diarrhoea
`Stomatitis
`
`29 (64)
`39 (87)
`40 (89)
`
`7 (16)
`2 (4)
`2 (4)
`
`Nephrotoxicity
`
`39 (87)
`
`2 (4)
`
`Cardiotoxicity
`
`42 (93)
`
`1(2)
`
`Neurotoxicity
`
`45 (100)
`
`0
`
`Haematological toxicity
`Leucopenia
`Neuropenia
`Thrombocytopenia
`
`31 (69)
`30 (67)
`35 (78)
`
`2 (4)
`2 (4)
`0
`
`WHO, World Health Organisation.
`
`3 (7)
`2 (4)
`3 (7)
`
`4 (9)
`
`2 (4)
`
`0
`
`2 (4)
`2 (4)
`2 (4)
`
`5 (11)
`2 (4)
`0
`
`1 (2)
`0
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`3 (7)
`4 (9)
`4 (9)
`
`7 (16)
`7 (16)
`4 (9)
`
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`DS combination as first-line therapy. Interestingly, 6/16
`patients with PR were reconsidered for resection of
`metastatic sites. Curative resection of the lesions was
`obtained in 4 of these 6 patients. Two of them are free
`of disease 3 and 7 years, respectively after the beginning
`of DS administration.
`Complete follow-up was achieved for all patients.
`Two- and 3-year overall survival rates were 50.2 and
`24.4%, respectively (median survival was 24 months).
`Median progression-free survival was 16 months. Mean
`duration of objective response (OR) was 19.7 months,
`with 5 particularly long responses (24, 26, 27, 38+ and
`84+ months). Mean durations of MR and SD were
`16.1 and 18.3 months,
`respectively. A biological
`response was also observed in 9/10 (90%) patients
`suffering from functional tumours.
`Univariate analysis demonstrated that previous sys-
`temic chemotherapy and the presence of malignant
`hepatomegaly were significantly associated with worse
`outcomes in terms of OR and survival
`(Table 3).
`Indeed, patients treated with DS as a first-line therapy
`experienced a median survival of 22.4 months compared
`with 5.5 months for patients previously treated with
`chemotherapy (P=0.008). Chemoembolisation prior to
`treatment also worsened the OS prognosis (P=0.006).
`In a multivariate analysis using the Cox model, previous
`systemic chemotherapy was identified as the only inde-
`pendent significant prognostic factor of a shorter survival
`time (P=0.013).
`
`4. Discussion
`
`WDPEC are rare tumours usually considered by most
`authors to be rather chemosensitive, especially to strepto-
`zotocin-based regimens [5,7,12]. Moertel and colleagues
`
`in the only AWDPEC prospective rando-
`obtained,
`mised trial published to date, a remarkable ORR of
`69% with median survival of 26 months in 36 patients
`treated with the AS combination [7]. However, in light
`of the WHO criteria, this ORR is now considered to be
`an overestimation. Indeed, clinical regression of malig-
`nant hepatomegaly, as well as tumour marker decrease,
`was then regarded as treatment response.
`Based exclusively on WHO radiological response cri-
`teria, our study confirms WDPEC sensitivity to DS
`combination, with a significant ORR of 36%. A median
`survival of 24 months, and a quite remarkable mean
`response duration of 19.7 months were also noted. Due
`to a divergence in the evaluation criteria our results
`cannot be compared directly with those obtained by the
`Eastern Cooperative Oncology Group (ECOG)
`[7].
`However, the size of our AWDPEC series, which is the
`largest published to date, allows for the accurate eval-
`uation of ORR, progression-free and OS. We can also,
`using the same response criteria and study design, rea-
`sonably compare our results with the surprisingly mod-
`est ORR (6%) obtained by Cheng and colleagues in a
`recent retrospective analysis of 16 AWDPEC patients
`treated with the same DS combination regimen [10].
`To our knowledge, no data concerning previous
`administration of chemotherapy as a response and sur-
`vival prognostic factor in AWDPEC have been pub-
`lished.
`Sequence
`of
`the
`chemotherapy
`regimen
`administration appears nonetheless to play a certain
`role in AWDPEC management. Indeed, we demon-
`strated that previous
`systemic
`chemotherapy jeo-
`pardised the response to DS combination, as well as
`survival. This finding could, in part, be explained by the
`previous administration of 5-FU/streptozotocin given
`to some of the patients. Our results suggest that, since
`the DS combination appears to be the most effective
`
`Table 3
`Significant prognostic factors of response to therapy and overall survival in univariate analysis
`
`Response to therapy
`
`Overall survival
`
`Prior systemic chemotherapy
`Yes
`No
`
`Malignant hepatomegaly
`Yes
`No
`
`Prior chemoembolisation
`Yes
`No
`
`Previous primary tumour resection
`Yes
`No
`
`N, number of patients; NS, non-significant.
`
`N
`
`11
`34
`
`25
`20
`
`4
`41
`
`16
`29
`
`Objective
`response%
`
`P value
`
`18
`41
`
`24
`50
`
`0
`39
`
`31
`38
`
`0.0033
`
`0.016
`
`NS
`
`NS
`
`N
`
`13
`32
`
`25
`20
`
`4
`41
`
`16
`29
`
`Deaths%
`
`P value
`
`85
`53
`
`76
`45
`
`100
`56
`
`75
`55
`
`0.008
`
`0.045
`
`0.005
`
`NS
`
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`519
`
`treatment in AWDPEC (at last in our hands), this regi-
`men should therefore ideally be administered as first-
`line chemotherapy in patients with rapidly progressive
`disease.
`Previous doxorubicin chemoembolisation was also
`associated with a poor survival. Although statistically
`significant, this association might be biased by the fact
`that this option is usually performed in patients with
`substantial non-resectable and, in particular, advanced
`liver involvement. This assumption could also, in part,
`account for the fact that radiologically-confirmed hepa-
`tomegaly, secondary to major liver metastatic involve-
`ment, was also significantly associated with a short
`survival and poor tumour response to the DS combi-
`nation. Altogether, our results suggest that maintenance
`of DS administration should be reconsidered in the
`presence of a delayed response and of any poor survival
`and/or response prognostic factor, and especially in
`cases who have received previous systemic chemo-
`therapy.
`liver metastatic disease has gained
`Resection of
`acceptance as a potential curative option and,
`in
`patients with colorectal cancer, as one of the best
`approaches to improve survival [13,14]. Since neuro-
`endocrine carcinomas are often slow-growing tumours
`responsible for debilitating symptoms related to tumour
`burden and/or hormone production, aggressive resec-
`tions of advanced diseases have been encouraged by
`some authors [15–20]. Lo and colleagues studied 64
`hepatic resections for advanced PEC, and found a 5-
`year-survival rate of 49% and a disease-free survival at
`3 years of 53% for patients who had undergone a cura-
`tive resection [20]. Carty and colleagues reported even
`better results with a 5-year survival rate after complete
`resection of 79% [18]. However, since most patients
`suffering from metastatic WDPEC are diagnosed with
`major malignant and non-resectable liver enlargement,
`WDPEC are rarely considered for curative surgery. In
`selected individuals, liver transplantation should then be
`considered, based upon age, PS, symptoms, tumour
`growth rate and extension of the disease to other organs
`[21].
`Interestingly, in our series, 6/17 responding patients
`became
`candidates
`for
`resection, after
`significant
`tumour shrinkage was observed following DS adminis-
`tration. Curative resection was achieved in 4 cases,
`whereas palliative surgery was performed in 2 patients.
`As for metastatic CRC [22,23], one should keep in
`mind, for advanced WDPEC, the potential role of DS
`combination administered in a ‘‘neoadjuvant setting’’.
`The role of primary tumour resection remains con-
`troversial [24–30]. Two recent studies showed a better 5-
`year survival for patients with primary PEC resections
`(P < 0.001 in both studies) [29,30]. Madeira and collea-
`gues showed a significantly better 5-year overall survival
`rate when the tumour was < 3 cm (86% versus 42%,
`
`P=0.0011) [30]. Our study did not demonstrate any
`survival advantage for patients previously resected for
`their primary tumour. However, all of
`them were
`already suffering from metastatic liver disease at the
`time of resection, creating a bias in the survival
`evaluation.
`The DS combination therapy was associated with
`tolerable adverse events, with grade 3–4 toxicities lim-
`ited to gastrointestinal and/or haematological side-
`effects. Nausea and vomiting were also less common in
`our study than in the study of Moertel and colleagues,
`likely thanks to better prevention and management with
`new anti-emetic drugs. Although observed in 24% of
`the patients, grade 3–4 neutropenia was quite well tol-
`erated, with only 3 patients requiring hospitalisation for
`febrile neutropenia. The occurrence of nephrotoxicity
`was particularly low in our series, as well as cardiac
`toxicity, which is commonly observed following the use
`of anthracycline regimens. To prevent cumulative toxi-
`city, treatment was interrupted in the 2 patients experi-
`encing grade 2 cardiotoxicity. No death-related toxicity
`was observed in our series.
`Tumour growth control was achieved in 60% of our
`population, with a remarkable mean response duration
`(PR and MR of 19.7 and 16.1 months, respectively and
`stabilisation of 18.3 months).
`In conclusion, our data confirm that the doxorubicin-
`streptozotocin combination is an efficient option for
`advanced well-differentiated pancreatic endocrine carci-
`nomas, particularly when administered to chemo-naı¨ ve
`patients. It is a well-tolerated regimen that can lead to
`resection of metastatic liver disease and subsequent
`survival improvement.
`However, new drugs for the treatment of this disease
`need to be tested, particularly anti-angiogenic agents.
`
`Acknowledgements
`
`We thank Florence Neczyporenko, MD for her
`critical review of the manuscript, and Chantal Boursier
`for expert secretarial assistance.
`
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`NOVARTIS EXHIBIT 2012
`Roxane v. Novartis, IPR 2016-01461
`Page 6 of 6