Treatment of pancreatic cancer with a combination of irinotecan (CPT-11) and gemcitabine: a multicenter phase II study by the Greek Cooperative Group for Pancreatic Cancer

G. P. Stathopoulos1,+, S. K. Rigatos1, M. A. Dimopoulos2, T. Giannakakis3, G. Foutzilas4, C. Kouroussis5, D. Janninis6, G. Aravantinos6, N. Androulakis5, S. Agelaki5, J. G. Stathopoulos1 and V. Georgoulias5

1 First Department of Medical Oncology, Errikos Dynan Hospital of Athens; 2 Medical Oncology Unit, Department of Therapeutics, Athens Medical School, Alexandra Hospital, Athens; 3 First Department of Medical Oncology, Agii Anargyri Anticancer Hospital, Athens; 4 Medical Oncology Unit, AXEPA Hospital, Thessaloniki; 5 Department of Medical Oncology, University General Hospital of Heraklion, Crete; 6 Second Department of Medical Oncology, Agii Anargyri Anticancer Hospital, Athens, Greece

Received 12 July 2002; revised 17 October 2002; accepted 12 November 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The efficacy and toxicity of gemcitabine (GEM) and irinotecan (CPT-11) is evaluated in previously untreated patients with inoperable or metastatic pancreatic cancer.

Patients and methods:

From January 1999 to July 2001, 60 patients with pancreatic cancer (85% stage IV) were enrolled in a two-step extended phase II trial. Patients were treated with gemcitabine (1000 mg/m2 on days 1 and 8) and CPT-11 (300 mg/m2 on day 8) in cycles of 3 weeks. No prophylactic use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) was initially planned.

Results:

In an intention-to-treat analysis one (1.7%) complete and 14 (23.3%) partial responses were achieved [objective response rate (ORR) 24.7%; 95% confidence interval 14.04% to 35.96%]. Twenty-two (36.7%) and 23 (38.3%) patients had stable and progressive disease, respectively. The median duration of response was 5 months, the median time to tumor progression (TTP) was 7 months and the median overall survival 7 months. One-year survival was 22.5%. Pain improvement and asthenia during treatment were observed in 45% and 43% of patients, respectively; weight gain occurred in 19.5% of patients. Grade 3 anemia occurred in three (5%) patients who required transfusion of six packed red blood cell (RBC) units. Ten (16.7%) additional patients with grade 2 anemia were treated with recombinant erythropoietin. Grade 3 thrombocytopenia occurred in seven (11.7%) patients and grades 3 and 4 neutropenia in 27 (45%). Ten patients developed febrile neutropenia, two of whom died due to sepsis. Prophylactic use of rhG-CSF was eventually required in 93 (28.3%) of 329 administered cycles. Other toxicities were mild.

Conclusions:

The combination of gemcitabine and irinotecan is an active chemotherapy regimen against pancreatic cancer with a 25% ORR. Toxicity was acceptable for the great majority of patients but with a high percentage of hematopoietic growth factor administration.

Key words: combination, gemcitabine, irinotecan, pancreatic cancer


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Unresectable advanced or metastatic pancreatic cancer remains an incurable disease. In recent years, serious attempts to improve survival and quality of life have taken place by using new cytotoxic agents and combination chemotherapy regimens. Median survival without treatment or with palliation varies from 3 to 9 months [13]. Fluorouracil, adriamycin and mitomycin-C (FAM) chemotherapy or radiation combined with 5-fluorouracil have shown no increase in effectiveness, apart from negligible clinical benefits [48].

Gemcitabine, a new nucleoside analog, has shown an objective response in 11% of patients with advanced pancreatic cancer and a significant clinical benefit, improving body weight and performance status and reducing analgesic consumption [9]. Cisplatinum compounds and taxanes have also been investigated in pancreatic cancer [10]. Our group’s experience in treating chemotherapy-naïve pancreatic cancer patients with either docetaxel alone or docetaxel combined with gemcitabine resulted in 6% and 13% objective response rates (ORR) and 36 weeks and 26 weeks median survival, respectively [11, 12]; moreover, clinical benefit was observed in 67% and 43% of patients, respectively. In vitro studies have shown a synergistic effect of gemcitabine and irinotecan (CPT-11), since this combination inhibited the in vitro proliferation of 57% of cancer cells taken from patients with pancreatic cancer [13].

The recently developed camptothecines have shown promising activity against pancreatic cancer. Irinotecan has been tested as a single agent and has produced a 9% ORR [14]. In a small phase II trial, 9-nitro-camptothecin given as oral treatment showed 28.6% objective responses [15]. Based on these data, we conducted a multicenter phase II study in order to evaluate the efficacy and toxicity of the gemcitabine plus irinotecan combination in patients with inoperable locally advanced and metastatic pancreatic cancer.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient population
Patients from 48 to 75 years of age with histologically- or cytologically-confirmed adenocarcinoma and bidimensionally measurable disease, and who were chemotherapy- and radiotherapy-naïve were enrolled in the study. Other eligibility criteria included a World Health Organization (WHO) performance status of 0, 1 or 2, a life expectancy of >=3 months, adequate granulocyte count >1500/dl, platelet count >120 000/dl, normal renal (serum creatine concentration <1.2 mg/dl) and liver (total serum bilirubin concentration <3 mg/dl provided serum transaminase and serum proteins were normal) function tests, normal cardiac function with no history of angina pectoris or congestive heart failure and no central nervous system (CNS) involvement. Prior surgery was allowed provided it had taken place at least 3 weeks prior to treatment. Patients with active infection, malnutrition or a second primary tumor (except for a non-melanoma skin epithelioma or in situ cervix carcinoma) were excluded from the study. All patients gave their written informed consent to participation in this study which was carried out with ethical committee approval.

Treatment
All patients were treated on an outpatient basis. Gemcitabine (Gemzar; Elli-Lilly, Indianapolis, IN, USA) was given on days 1 and 8 at a dose of 1000 mg/m2 in 500 ml normal saline intravenously (i.v.) for 60 min. Irinotecan (CPT-11; Aventis, Collegeville, Pennsylvania, PA, USA) was administered on day 8 at a dose of 300 mg/m2 in 500 ml normal saline i.v. for 90 min. Cycles were repeated every 21 days provided that patients had sufficiently recovered from drug-related side-effects. Standard antiemetic treatment with ondansetron was administered to all patients. Prophylactic recombinant human granulocyte colony-stimulating factor (rhG-CSF) was considered necessary in 29 of 60 patients. Patients with granulocytopenia grade >=3 received rhG-CSF in subsequent cycles at a dose of 150 µg/m2 subcutaneous (s.c.) from day 9 to day 15 inclusive. Treatment was administered for at least six cycles or until disease progression, at the physicians’ discretion. The protocol was approved by the Ethics and Scientific Committees of the participating hospitals.

Dose adjustment criteria were based on the hematological parameters. Irinotecan and gemcitabine doses were reduced by 25% in febrile or grade 4 neutropenia or thrombocytopenia lasting for >5 days and by 15% in grade 3 neutropenia and/or thrombocytopenia. Toxicities were graded according to WHO guidelines [16].

Evaluation of patients
Pretreatment evaluation included a complete medical history and physical examination, a full blood cell count with differential and platelet count, a standard biochemical profile (and creatinine clearance when necessary), serum carcinoembryonic antigen (CEA) and CA-19-9 determinations, electrocardiogram, chest X-rays, ultrasound of the upper abdomen and computed tomography scans of the chest and upper and lower abdomen. Additional imaging studies were performed upon clinical indication. Full blood counts with differential were performed weekly; in cases of grade 3/4 neutropenia or grade 4 thrombocytopenia, full blood counts with differential were evaluated daily until the absolute granulocyte count was >=1000/dl and the platelet count was >=75 000/dl. A detailed medical and physical examination was completed before each course of treatment in order to document symptoms of disease and toxicities of treatment. Biochemical tests, electrocardiogram (ECG), serum CEA and CA-19-9 determinations and chest X-rays were performed every 6 weeks. A neurological evaluation was performed by clinical examination every 6 weeks. Lesions were measured after each cycle if they were assessable by physical examination or by chest X-ray; lesions assessable by ultrasound or CT scan were measured after three courses.

Definition of response
A complete response (CR) implies the disappearance of all measurable or evaluable disease, signs and symptoms and biochemical changes related to the tumor for at least 4 weeks, during which time no new lesions may appear. A partial response (PR) implies a >50% reduction in the sum of the products of the perpendicular diameters of all measurable lesions compared with pretreatment measurements lasting for >=4 weeks, during which time no new lesions may appear and no existing lesions may enlarge. For hepatic lesions, a reduction of >30% in the sum of the measured distances from the costal margin at the midclavicular line and at the xiphoid process to the edge of the liver is required. Stable disease (SD) implies a <50% reduction and a <25% increase in the sum of the products of the two perpendicular diameters of all measured lesions and the appearance of no new lesions for 8 weeks. Progression or relapse implies an increase in the product of the two perpendicular diameters of any measurable lesion by >25% over the size present at entry into the study, or for patients who respond, the size at the time of maximum regression and the appearance of new areas of malignant disease (usually excluding central nervous system metastases). A two-step deterioration in performance status, >10% loss of pretreatment weight or increasing symptoms, in and of themselves do not constitute progression; however, the appearance of same should initiate a new evaluation of disease extent [17]. All responses had to be maintained for >4 weeks and be confirmed by an independent panel of radiologists.

Assessment of clinical benefit
The assessment of pain relief was based on both the consumption of analgesics (narcotics and non-narcotics) and the patient’s own evaluation of pain using a scale graded from 0 (no pain) to 10 (maximum pain necessitating narcotics for relief). A >50% decrease in analgesic consumption with no need for narcotics coupled with the patient’s evaluation of a >50% decrease in pain intensity was characterized as ‘pain improvement’. A 50% increase in the consumption of analgesics in combination with the patient’s evaluation of a 50% increase in pain intensity was characterized as ‘pain deterioration’. All other cases were characterized as ‘no change’. Symptoms of vomiting and diarrhea were assessed according to the number of daily episodes; a >50% decrease in their number was characterized as ‘improvement’ whereas a >50% increase was characterized as ‘deterioration’. All other cases were characterized as ‘no change’. In addition, patients were asked to grade their fatigue and anorexia using a scale of 0 (no fatigue or anorexia) to 10 (maximum fatigue or anorexia). A 50% decrease or increase in symptom intensity indicated ‘improvement’ or ‘deterioration’, respectively.

In total, 13 patients showed performance status improvement, 38 stable performance status and nine showed deterioration. Weight loss was present in 41 (68.3%) patients at enrollment; weight gain was observed in eight of 41 (19.5%) patients, whereas there was a deterioration in 13 of 41 (31.7%) patients.

Statistical design
This was an extended two-step phase II study. According to the trial design, 30 patients had to be enrolled during the first part of the trial and if an ORR <15% was achieved, the treatment would have been abandoned, otherwise 30 additional patients had to be enrolled. A total number of 60 patients was determined as the minimum number to ensure a 95% confidence interval (CI) of an estimate of ~15% of precision (width) at least 0.20 (using the exact binomial distribution). In fact, with 60 patients the 95% CI would be 0.59–0.240. The primary end point of the study was the efficacy of the regimen and the secondary end points were the overall duration of survival and tolerance. The duration of response was calculated from the day of the first demonstration of response until progressive disease (PD); time to tumor progression (TTP) was calculated from the day of entry into the study until documented PD; overall survival was calculated from the day of entry into the study until death. Median probability of survival and the median TTP were estimated by the Kaplan and Meier method; confidence intervals for response rates were calculated using methods for exact binomial confidence interval. Comparison of variables was performed using the chi-square test.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient demographics
From January 1999 to July 2001, 60 patients (41 male, 19 female) were enrolled in this multicenter study; their characteristics are listed in Table 1. The median age was 63 years (range 48–75). World Health Organization performance status was as follows: PS 0, six patients (10%); PS 1, 39 patients (65%); and PS 2, 15 patients (25%). The majority of the patients (85%) were stage IV. Sixteen (26.7%) patients underwent surgery [14 for biliary decompression (bypass) due to jaundice and were considered inoperable; these patients entered the study after their bilirubin level fell <2 mg/dl]; two patients had recurrent disease after tumor excision 3–6 months previously. The majority (88.3%) of patients had a moderate or low grade adenocarcinoma. Forty-one (68.3%) patients received analgesics at enrollment, seven (11.7%) of whom received opiates and four (6.7%) of whom received both opiates and non-opiate analgesics.


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Table 1. Patient characteristics
 
Compliance with treatment
A total of 329 chemotherapy cycles were administered with a median number of six cycles/patient (range 2–9); the median interval between cycles was 23 days (range 21–39). Median dose intensity for irinotecan and gemcitabine was 90 mg/m2/week (range 44–100) and 563 mg/m2/week (range 316–600) corresponding to 90% and 96.5% of the planned dose, respectively. Seventy (21.3%) cycles were delayed due to hematological (28 cycles due to grade 3 or 4 neutropenia) and non-hematological (three cycles) toxicity; moreover, 39 cycles were delayed for reasons unrelated to treatment (late admission, imaging evaluation). Dose reduction was necessary in 22 (6.7%) cycles due to hematological (nine cycles) and non-hematologic (13 cycles) toxicity. One patient refused to continue treatment after the first cycle. Ten months after the study ended (last patient entrance), 11 (18.3%) patients are alive and 49 (81.7%) dead. Causes of death were disease progression in 43 patients, treatment-related toxicity in two patients and other reasons in four patients (suicide, one patient; cardiac arrest 18 days post-treatment, one patient; septic shock without granulocytopenia occurring 17 days post-chemotherapy, one patient and pulmonary embolism, one patient).

Response to treatment and survival
Responses were analyzed on an intention-to-treat basis. Out of 60 patients, there was one (1.7%) CR and 14 (23.3%) PRs in all sites of the disease, for an ORR of 25% (95% CI 14.04% to 35.96%). Twenty-two (36.7%) patients had stable disease and 23 (38.3%) PD. Bilirubin increase without recovery after endoscopic retrograde cholangio-pancreatography (ERCP) or stent set was considered as disease progression. Fourteen of 60 patients (23.3%) achieved responses observed in the pancreas (five of these responders had liver metastases and two had liver and lung metastases): eight of 36 patients (22.2%) in the liver and two of six patients (33.3%) in the lung. There were no responses in lymph nodes or peritoneal metastatic lesions. Among the nine patients with inoperable stage II and III disease, two (22.2%) objective responses were documented while 13 partial responses (25.5%) occurred in patients with stage IV disease. All of the responders had a PS of 1 or 2 (WHO). Median duration of response was 5 months (range 1.5–21 months) and median TTP was 7 months (range 2.5–22.5 months). The median overall survival time was 7 months (range 0.5–24 months) and the 1-year survival was 22.5%. Five (8.3%) patients were alive at 18 months and one patient at 24 months (Figure 1).



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Figure 1. Patient survival (Kaplan–Meier analysis).

 
Response according to stage was as follows: CR/PR 15 patients, locoregional two (13%) patients and metastatic 13/51 (25.5%) patients; SD/PD 45 patients, locoregional seven (15.6%), metastatic 38/51 (84.4%) ({chi}2 Pearson, P = 0.835). There was no statistically significant difference in either survival or response rate. Survival according to stage was as follows: locoregional, nine patients, median survival 8.5 months (range 3.5–17 months), 1-year survival 26.67%; metastatic, 51 patients, median survival 6.5 months (range 0.5–24 months) (P = 0.309, log-rank).

Increased pretreatment serum CEA and CA-19-9 levels were present in 28 (46.7%) and 46 (76.7%) patients, respectively. Levels of CEA and CA-19-9 were decreased or remained within pretreatment levels in seven (25%) and seven (15.2%) patients, respectively; conversely, CEA and CA-19-9 levels were increased in five (17.9%) and 15 (32.6%) patients, respectively. Table 2 shows response rates and tumor marker levels.


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Table 2. Efficacy results
 
Forty-seven (78.3%) patients suffered from pain at enrollment; pain improvement during treatment was observed in 27 (45%) patients, while six (10%) experienced an increase in pain intensity. Forty-one (68.3%) patients were under analgesic treatment at enrollment; seven (11.7%) were under narcotics, 30 (50%) under non-steroid analgesics and four (6.7%) under both. Three (27.3%) of 11 patients who were treated with opioids discontinued their use, whereas only one patient required an increase in the opioid dose. Ten (33.3%) of 30 patients who received non-steroid analgesics stopped their use, while one required an increase in dosage.

Seven (11.7%) patients presented with diarrhea at enrollment; treatment resulted in the complete disappearance of diarrhea in three (42.9%) cases. There was no patient with deterioration of the diarrhea. Asthenia was present in 45 (75%) patients at enrollment; 22 (48.9%) patients had an improvement of this symptom after three cycles of treatment, whereas a deterioration was noted in nine (20%) patients.

Toxicity
All patients were assessable for toxicity (Table 3). Grade 3 anemia occurred in three (5%) patients who required transfusion of six packed RBC units. Ten (16.7%) additional patients with grade 2 anemia were treated with recombinant erythropoietin. Grade 3 thrombocytopenia occurred in seven (11.7%) patients and grade 4 in two (3.3%) patients. No patient required hospitalization for treatment of a hemorrhagic episode or platelet transfusions. Fourteen (23.3%) and 13 (21.7%) patients presented with grade 3 and 4 neutropenia, respectively. Ten (16.7%) patients developed febrile neutropenia (duration 2–7 days), nine of whom required hospitalization. Eight patients recovered uneventfully whereas two died due to sepsis. These two patients, who were among the first five patients treated, had no prophylactic administration of hematopoietic colony stimulating factor. Prophylactic administration of rhG-CSF was given to 29 (48.3%) patients during 93 (28.3%) of the cycles. Non-hematological toxicity was relatively mild (Table 3). Asthenia grade 2–3 was reported by 22 (36.7%) patients; grade 3 diarrhea occurred in five (8.3%) patients, skin eruption in three and grade 3 liver toxicity in one. Other adverse reactions or complications were edema in six (10%), cholinergic syndrome in two (3.3%), xerostomia in three (5%) and upper gastrointestinal (GI) hemorrhage in one patient. Finally, five patients developed non-neutropenic infections, two of whom required hospitalization for 4–11 days; all patients were uneventfully treated with wide-range antibiotics.


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Table 3. Hematological and non-hematological toxicity: worst grade (WHO) reported during treatment period
 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The results of the present study seem to indicate that the combination of irinotecan with gemcitabine is an active and relatively well-tolerated regimen for the treatment of patients with pancreatic cancer. Indeed, our observed 25% ORR (one CR and 14 PR) is a reasonably high response rate for this disease. Single-agent gemcitabine has shown a marginal objective activity in patients with pancreatic cancer, but the drug is now considered as the treatment of choice for this disease based on improvement of the quality of life and clinical benefit in a high percentage of patients [18, 19]. Camptothecins are also promising new agents against pancreatic cancer since the three representative drugs have given responses ranging from 9% to 28.6% [14, 15]. Indeed, topotecan, used as a single agent in advanced pancreatic cancer, has produced a 10% response rate [20]; 9-nitro-camptothecin, which as yet has been tested very little, has produced objective responses in four of 14 patients with pancreatic cancer, for an overall response rate of 28.6%; in addition, a high percentage of these patients experienced a substantial clinical benefit [15]. Irinotecan (CPT-11) was evaluated in a European Organisation for Research and Treatment of Cancer (EORTC) trial as a single agent resulted in 9% objective responses and a median survival of 5 months [20].

To date, published data concerning the combination of gemcitabine and CPT-11 in patients with pancreatic cancer is sparse. In clinical practice, these two agents were administered in pretreated patients with pancreatic adenocarcinoma, combined with leucovorin, 5-fluorouracil and cisplatin. There was a partial response in eight (23.5%) of 34 patients, with acceptable toxicity and a median overall survival of 10.3 months [21]. In our study, beyond the objective responses, 41% of patients experienced disease stabilization and only one-third showed disease progression. Moreover, the median survival time was 7 months and the 1-year survival was 22.5%. Burris et al. [9] have reported a ±20% 1-year survival with gemcitabine monotherapy. In addition, a substantial proportion of patients experienced clinical benefit and an improvement in tumor-related symptoms. These observations seem to indicate that the combination of gemcitabine with CPT-11 is an active regimen for the treatment of pancreatic cancer. There is a similar study with the same regimen combination which also reported an objective response of 24% [22]; the difference from our study was that irinotecan 100 mg/m2 was given on both days 1 and 8 together with gemcitabine 1000 mg/m2. This intensity of treatment resulted in a reduction in drug dosage. More planned doses were reduced or omitted on day 8 (20%) than on day 1 (5%). In all, 35 doses of gemcitabine and 23 doses of irinotecan were reduced. The combination of gemcitabine and docetaxel has produced a 13% PR with a median survival of 5.4 months [12]; further, the combination of gemcitabine with infusional 5-fluorouracil has shown a 19.2% ORR and a median survival of 10.3 months and 45% of patients experienced improved disease-related symptoms [8]. The combination of gemcitabine with paclitaxel has shown no objective responses and only disease stabilization in a small number of patients [10]. In another study, the administration of gemcitabine and cisplatin (CDDP) resulted in 11.5% objective responses with a median survival of 8.3 months while 57% of patients experienced disease stability [23]. A third study, also combining gemcitabine with cisplatin, reported a 31% ORR and clinical benefit in 45% of patients [24].

A recent phase I study combined gemcitabine (days 1 and 8) and oxaliplatin (day 1) in 18 patients with pancreatic cancer. These investigators defined the maximum tolerated dose (MTD) as gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2. Three of 18 patients achieved PR [25]. Liposomal doxorubicin (Caelyx) as a single agent in pancreatic cancer showed only stable disease in six of 22 patients [26]. The MTD of a phase I trial of combined gemcitabine and CPT-11 was 1000 mg/m2 and 100 mg/m2, respectively, given weekly for 4 weeks [27]; the dose of CPT-11 was lower than in our study and was justified by the weekly administration. In another study, 5-fluorouracil with gemcitabine only slightly improved median survival versus single-agent gemcitabine: 6.7 months and 5 months, respectively [28]. The combination of docetaxel with gemcitabine versus docetaxel with cisplatin in advanced pancreatic cancer in a phase II randomized trial led the authors to conclude mainly that there is a manageable toxicity profile and promising activity [29]. Finally, another trial compared gemcitabine alone or combined with 5-fluorouracil continuous infusion in 89 evaluable patients. A low percentage of response was reported and the median survival for both arms was 6 months [30].

An interesting observation in all of these studies including ours concerns the small group of patients, even those with stage IV disease, that survive over a year, which accounts for ~20% of enrolled patients. Moreover, some of those patients survive in the range of 18–24 months. Indeed, in the present study, five (8.3%) patients were still alive after 18 months and one patient after 24 months. No clinical or laboratory differences could be detected in this subset of patients when compared with other patients of the same stage who showed no response and who had a short survival. No difference in survival between locally advanced disease and metastatic disease was observed in our patients.

The toxicity profile of the gemcitabine and CPT-11 combination was mainly associated with myelosuppression. Grades 3 and 4 neutropenia occurred in 23.3% and 21.7% of patients, respectively. Ten patients developed febrile neutropenia and two patients died due to sepsis at the beginning of the study when prophylactic rhG-CSF was not programmed. In addition, 93 (28.1%) cycles necessitated prophylactic administration of rhG-CSF because the patients had developed grade 3 or 4 neutropenia in the previous cycles. In addition, 15% of patients presented with grade 3 and 4 thrombocytopenia but no platelet transfusion or hospitalization for hemorrhagic episodes were required. The non-hematologic toxicity of the gemcitabine/CPT-11 regimen was relatively mild.

In conclusion, the combination of gemcitabine with CPT-11 is an active chemotherapy regimen for patients with pancreatic cancer, rendering a 25% ORR. Myelotoxicity was the main adverse reaction producing grade 4 neutropenia in 21.7% of patients. Prophylactic administration of hematopoietic growth factor may be needed.


    Footnotes
 
+ Correspondence to: Dr G. P. Stathopoulos, Semitelou 5, 115 28 Athens, Greece. Tel: +3-010-7752600; Fax: +3-010-7251736; E-mail: dr-gps{at}ath.forthnet.gr Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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