Carboplatin plus gemcitabine in patients with inoperable or metastatic pancreatic cancer: a phase II multicenter study by the Hellenic Cooperative Oncology Group

N. Xiros1,*, P. Papacostas2, T. Economopoulos1, G. Samelis2, E. Efstathiou3, E. Kastritis3, H. Kalofonos4, A. Onyenadum4, D. Skarlos5, A. Bamias6, H. Gogas7, D. Bafaloukos8, E. Samantas9 and P. Kosmidis10

1 Second Department of Internal Medicine, Propaedeutic & Research Institute, University General Hospital ‘Attikon’, University of Athens; 2 Oncology Unit, Ippokration Hospital; 3 Department of Clinical Therapeutics, University of Athens, Athens; 4 Division of Oncology, University of Patras, Patras; 5 Second Department of Medical Oncology, ‘Henry Dynan’ Hospital, Athens; 6 Department of Oncology, University of Ioannina, Ioannina; 7 First Department of Medicine, Laiko Hospital, University of Athens; 8 Oncology Department, Metropolitan Hospital; 9 Third Department of Medical Oncology, ‘Agii Anargiri’ Hospital; 10 Department of Oncology, ‘Hygeia’ Hospital Athens, Greece

* Correspondence to: Dr N. Xiros, Second Department of Internal Medicine, Propaedeutic & Research Institute, University General Hospital ‘Attikon’, University of Athens, 1 Rimini Str., 124 62 Haidari, Athens, Greece. Tel: +30-210-5831255/5831260; Fax: +30-210-5326454; Email: nxiros{at}otenet.gr


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:: In the present phase II multicenter study, we assessed the efficacy and tolerability of the combination of gemcitabine and carboplatin in patients with advanced pancreatic cancer.

Patients and methods:: Patients with previously untreated, locally advanced or metastatic pancreatic cancer were treated with gemcitabine 800 mg/m2 on days 1 and 8 and carboplatin at an AUC of 4 on day 8 of a 3-week cycle, for a total of six cycles. Primary end points were response rate and clinical benefit; secondary end points were, survival, time to progression (TTP) and toxicity.

Results:: A total of 50 patients were enrolled in the study, 47 of whom were eligible for treatment. The median age was 63 years (range 34–76) and the median Karnofsky performance status (PS) was 80%. Patients received a median of six cycles (range 1–11). Among 35 patients evaluable for response, eight (17%) achieved partial response; 15 (32%) and 12 (25%) patients had stable and progressive disease, respectively. The median overall survival was 7.4 months; the median TTP was 4.4 months and the 1-year survival was 28%. The observed clinical benefit response was remarkable. After the second cycle of chemotherapy, 21 of 31 (68%) patients experienced pain improvement and reduced analgesic consumption. At the same time, 35% and 56% of our patients significantly improved their Karnofsky PS and weight, respectively. Overall, the treatment was well tolerated. The most common grade 3–4 toxicities were hematological, including 8% anemia, 6% neutropenia and 13% thrombocytopenia.

Conclusions:: The combination of gemcitabine plus carboplatin is a moderately active treatment for patients with locally advanced and metastatic pancreatic cancer. This regimen has an acceptable toxicity profile and provides a significant clinical benefit, and hence warrants further investigation.

Key words: carboplatin, gemcitabine, pancreatic cancer


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The overall survival rate of patients with pancreatic cancer, depending on the extent of disease and performance status (PS) at diagnosis, is extremely disappointing [1Go]. Surgery is the only curative option. At diagnosis, only 10–20% are resectable, and among these local recurrence occurs in up to 85% [2Go, 3Go]. Therefore, in the majority of patients with either unresectable or metastatic disease, effective systemic treatment will become even more important for prolonging survival. Until now, chemotherapy has not been proven effective in patients with pancreatic cancer. The actual response rate to chemotherapy with 5-fluorouracil (5-FU) in many studies is below 10% [2Go]. Many efforts to improve the efficacy of 5-FU by either biochemical modulation with leucovorin or interferon, or combination with mitomycin C, doxorubicin and streptozotocin, have failed [3Go]. The protracted infusion of 5-FU in combination with cisplatin has been proven to be slightly more effective, at the expense of increased toxicity [4Go, 5Go].

Gemcitabine (difluorodeoxycytidine; dFdC) is a nucleoside analog with activity in a broad spectrum of solid tumors [6Go]. In two phase II trials, the objective response rate of gemcitabine chemotherapy in pancreatic cancer was 11% and 6.3%, with a median survival of 5.6 and 6.3 months, respectively [7Go, 8Go]. In a randomized study, gemcitabine showed a modest survival advantage (1-year survival 18% versus 2%) over 5-FU [9Go]. Moreover, a considerable improvement was observed beyond that suggested by the objective response rates in most studies of gemcitabine therapy in pancreatic cancer. As a result, the term ‘clinical benefit response’ was introduced as a primary end point to evaluate the efficacy of gemcitabine, and the drug is now considered as the reference treatment for advanced pancreatic cancer [9Go–11Go]. Clinical benefit response is defined as a composite assessment of pain, performance status and weight [9Go].

The activity of the newer chemotherapeutic agents topotecan, irinotecan, raltitrexed and temozolamide, with response rates of 7–15% in small phase II studies [12Go–15Go], is considered rather limited. Low response rates have also been reported in phase II studies with paclitaxel and docetaxel [16Go–21Go], which are generally considered as inactive in pancreatic cancer.

The combination of gemcitabine with 5-FU has recently been studied in phase I and phase II studies [3Go, 21Go]. Both studies have shown favorable results in terms of clinical benefit and response. Several combinations of gemcitabine with other active drugs, such as cisplatin, docetaxel and oxaliplatin, have been studied in phase II clinical trials in advanced pancreatic cancer.

In an effort to improve the efficacy of gemcitabine in patients with advanced pancreatic cancer, we decided to combine this drug with carboplatin. The rationale for the combination of these two active drugs was the different mechanism of action, the acceptable toxicity of each one as single agent and their easy outpatient administration.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient selection
Patients were eligible to enter into the study if they had histologically or cytologically confirmed adenocarcinoma of the pancreas that was either unresectable or metastatic. Further inclusion criteria were the presence of bidimensionally measurable disease, age 18–75 years, an anticipated life expectancy of > 12 weeks and a baseline Karnofsky PS of ≥ 50%.

Furthermore, patients were required to have adequate renal (serum creatinine level < 1.5 mg/dl) and liver functions (total bilirubin level < 1.5 mg/dl and transaminase levels < 2x upper limits of normal) and adequate bone marrow reserve (leucocyte count ≥ 4000/µl, absolute neutrophil count ≥2000/µl and platelet count ≥100 000/µl). Patients who had received prior chemotherapy or radiotherapy for pancreas carcinoma, as well as patients with ampullary or periampullary carcinoma, were excluded from the study. Patients with central nervous system metastases and second primary malignancies, except for adequately treated basal cell cancer, squamous cell skin cancer or in situ cervical cancer, were also excluded. Additional exclusion criteria were active infection and any other uncontrolled concurrent medical illness. A minimum of 2 weeks was required to have elapsed in cases of prior abdominal exploration or palliative surgery. Informed consent was obtained from all patients, in accordance with institutional and federal guidelines, before study entry.

Study regimen
Treatment was delivered to all patients on an outpatient basis. Gemcitabine (Elli-Lilly, Indianapolis, IN, USA) was given on days 1 and 8 at a dose of 800 mg/m2 in 250 ml normal saline intravenously for 60 min. Carboplatin was administered at an area under the curve (AUC) of 4 in 500 ml normal saline over 60 min on day 8. We selected this schedule (carboplatin on day 8), to avoid treatment delay on eighth day. Treatment was repeated every 3 weeks. Patients were treated with six cycles of chemotherapy unless disease progression or unacceptable toxicity occurred during chemotherapy. Standard antiemetic treatment with ondansetron was given to all patients only on the day of administration of chemotherapy. Recombinant human granulocyte colony-stimulating factor was used only in cases with granulocytopenia of grade ≥3, and during chemotherapy the use of corticosteroids was not allowed.

Adverse reactions were evaluated according to World Health Organization (WHO) criteria [22Go]. In the event of hematological toxicity that occurred at any time during treatment, the following dose modifications were applied. If WHO grade 3 neutropenia and/or thrombocytopenia grade 2 occurred, the dose of carboplatin was decreased to AUC 3. If grade 4 neutropenia and/or thrombocytopenia grade 3 occurred, the drugs were administered at dose of gemcitabine 600 mg/m2 and carboplatin AUC 3. Treatment could be delayed up to 2 weeks until hematological toxicity resolved or at least improved to grade 1. Any patient who required >2 weeks for recovery from treatment-related toxicity was taken off study. Moreover, patients could be discontinued from the study at their own or investigators' request.

Patient evaluation
Prior to treatment, each patient was evaluated by medical history, physical examination, full blood cell count with differential and platelet count, blood chemistry, tumor markers (CEA and CA 19-9), urine analysis, electrocardiogram, and vital signs. Additionally, ultrasound of the upper abdomen and computed tomography (CT) scans of the chest and abdomen were also performed. Further imaging studies were performed upon clinical indication. Karnofsky PS, weight, disease-related symptoms and especially pain, as well as analgesic consumption, were evaluated at baseline and at the completion of second, fourth and sixth cycle of chemotherapy thereafter. During chemotherapy, full blood cell counts with differential and biochemical test were performed weekly. A detailed physical examination was completed before each cycle of chemotherapy and tumor markers were determined every other cycle. A CT scan was repeated every third cycle of chemotherapy to assess objective response. At the end of treatment, all clinical, laboratory and imaging studies were repeated and the patients underwent follow-up examinations every 2 months.

Study end points and assessment of response and toxicity
Primary end points were the assessment of response rate and clinical benefit. Secondary end points included survival, time to progression (TTP) and toxicity. Survival and TTP analyses included all eligible patients on an intention-to-treat basis. All patients were evaluable for toxicity from the time of their first dose of chemotherapy and only those who had received two cycles of chemotherapy or more were considered for evaluation of clinical benefit and response rate. Response was defined according to WHO criteria [22Go].

Clinical benefit response is a composite assessment of clinical parameters including pain, PS and weight loss, and was evaluated according to previously established criteria [9Go]. The assessment of pain relief was based on both the consumption of analgesics and the patient's own evaluation of pain using an optical scale [9Go], graded from 0 (no pain) to 10 (maximum pain necessitating analgesics for relief). Our patients received either narcotics (fentanyl) or non-steroidal anti-inflammatory drugs (NSAIDs). Pain improvement was characterized by a > 50% reduction in analgesic consumption coupled with the patient's own evaluation of a >50% decrease in pain intensity. Pain deterioration was defined as any increase of initial pain intensity by > 50% of the patient's own evaluation prior to treatment, coupled with increased or at least stable analgesic consumption. Karnofsky PS improvement was defined as ≥ 20 points from baseline sustained for ≥ 4 weeks, and weight gain ≥ 7% from baseline (excluding third-space fluid) sustained for ≥ 4 weeks [9Go]. For the evaluation of other disease-related symptoms such as anorexia, nausea, vomiting and weakness, as well as general feeling, we designed a simplified scale for the purposes of our study. Vomiting was assessed according to the number of daily episodes; a > 50% decrease in number was characterized as improvement whereas a > 50% increase was characterized as worsening. For other symptoms such as nausea, anorexia and weakness, the patients were asked to grade these symptoms using a scale from 0% (no symptom) to 100% (maximum intensity of symptom). Any increase or decrease of > 20% of baseline value was characterized as improvement or worsening, respectively. The patient's general feeling was graded as very good, good, moderate or poor.

The first assessment of patients for the above-mentioned parameters was performed at the start of chemotherapy. Thereafter, they were evaluated after the second, fourth and sixth cycles of chemotherapy.

Statistical analysis
Sample size was based on overall response rate. According to Simon's two-stage minimal design, assuming that the expected overall response rate will be at least 25% and the minimum acceptable response rate 10%, a sample of 22 patients was required in the first step. If a minimum of three responses was observed, a total of 40 patients would be accrued. Thereby, if at least eight responses occurred the probability of accepting a treatment with a real response rate of < 10% would be 5%. On the other hand, the risk of rejecting a treatment (at the second stage) with a response rate of > 25% would be 20%.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients' characteristics
From October 2000 to December 2001, 50 patients were registered in this multicenter study. Three patients were non-eligible: two patients never received protocol treatment and one owing to violation of eligibility criteria. Overall, 47 patients (31 male, 16 female) were eligible for treatment; their characteristics are summarized in Table 1. The median age was 63 years (range 34–76). Twenty-two (47%) patients had undergone surgery at first diagnosis for either diagnostic (11 patients) or therapeutic reasons (six patients for palliation and five patients were radically operated with pancreaticoduedonectomy). The majority of patients (77%) had stage IV disease and 24 patients (51%) had liver metastases. The Karnofsky PS was as follows: 50–60% in 13 patients (28%), 70–80% in 24 patients (51%) and 90–100% in 10 patients (21%). Pain was the most common initial symptom among our patients (74.5%), followed by weight loss (45%), anorexia (40%) and fatigue (15%). New-onset diabetes was diagnosed in four (8.5%) patients and obstructive jaundice in six (13%). Endoscopic intervention and stent placement was performed in two patients with obstructive jaundice prior to chemotherapy.


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Table 1. Characteristics of 47 patients with advanced pancreatic cancer treated with gemcitabine plus carboplatin

 
A total of 221 chemotherapy cycles were administered, with a median number of six cycles delivered per patient (range one to 11). Six patients received more than six cycles of chemotherapy. Out of these six patients, four had stable disease and two patients had a partial response. These patients received more than six cycles on the basis of continued clinical benefit response. The median relative dose intensity for gemcitabine was 0.81 (range 0.5–1.0), whereas that for carboplatin was 0.93 (range 0.5–1.0). Hematopoietic growth factors were used in cases of grade 3 neutropenia or anemia.

Response to treatment
Responses were analyzed on an intention-to-treat basis. Out of 47 patients, 35 were evaluable for response. Twelve patients were non-evaluable for various reasons: four patients died early due to disease progression (after the first and second cycle of chemotherapy), five patients refused to continue after the first or second cycle, and three patients discontinued due to treatment-related toxicity. Treatment responses, TTP and survival data are summarized in Table 2. No complete remissions were observed. Eight patients (17%) achieved a partial response and 15 (32%) achieved disease stabilization. With a median follow up of 28.9 months (range 0.1–30.3), the median TTP was 4.4 months (range 0.1–30.3+) and the median survival was 7.4 months (range 0.1–30.3+). The 1-year survival was 28%. The overall survival and TTP curves are shown in Figure 1.


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Table 2. Summary of treatment results of 47 patients with advanced pancreatic cancer treated with gemcitabine plus carboplatin

 


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Figure 1. Kaplan–Meyer curves for overall survival (solid line) and time to tumor progression (dotted line).

 
Clinical benefit
Clinical benefit response data are summarized in Table 3. Thirty-five (74.5%) patients had severe pain prior to treatment. All patients consumed regular analgesics in the form of either NSAIDs (25 patients) or fentanyl (12 patients) prior to treatment. Two patients on NSAIDs were also received fentanyl. After the second cycle of chemotherapy, 21 of 31 evaluable patients (68%) experienced a self-estimated pain intensity improvement >50%, two (6%) remained stable and eight (26%) worsened. After the second cycle of chemotherapy, 21 of 31 evaluable patients (68%) reduced the daily dose of analgesics by >50%. This beneficial effect of chemotherapy on disease-related pain remained constant in most patients after the fourth and the sixth cycle of chemotherapy. Thirty-seven patients had a Karnofky PS ≤80% at study entry. After completion of the second cycle of chemotherapy, nine of 26 evaluable patients (35%) improved by ≥20 points from baseline, whereas 12 patients (46%) remained stable and five (19%) worsened. Improved Karnofsky PS was observed in a considerable number of patients during chemotherapy. Twenty-one (45%) patients had significant weight loss at entry. After the second cycle of chemotherapy, nine of 16 evaluable patients (56%) with considerable weight loss prior to treatment experienced a weight gain of at least 7%. Similarly, a high percentage of patients experienced a considerable improvement in a number of other parameters, such as nausea, vomiting, appetite, weakness and general feeling (Table 4).


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Table 3. Results of clinical benefit response, analysis for evaluable patients

 

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Table 4. Results of clinical benefit response: analysis of secondary parameters for evaluable patients

 
Toxicity
All 47 patients were assessable for toxicity (Table 5). No toxic deaths were recorded. The chemotherapy regimen was well tolerated, and the main side-effects were hematological. The myelotoxicity nadir on day 8 was mild. Twelve patients had a delay between day 1 and day 8 in at least one cycle. Seven out of the 12 patients had a delay in only one cycle, three patients in two cycles, one patient in three cycles and one patient in four cycles. Grade 3–4 hematological toxicities were as follows: anemia in four patients (8%), neutropenia in six patients (13%) and thrombocytopenia in six patients (13%). Non-hematogical toxicity was relatively mild. Grade 2–3 nausea and vomiting was observed in 11 patients (23%) and diarrhea in three patients (6%). Transitory elevations in transaminases of grade 2–3 were noted in two patients (4%). One patient (2%) was hospitalized and appropriately treated due to febrile neutropenia.


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Table 5. Treatment-related toxicities for all cycles of chemotherapy

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Pancreatic cancer is one of the most chemotherapy-resistant tumors. For many years, 5-FU was been considered the drug of choice in treating patients with pancreatic cancer, with objective responses ranging from 0% to 60% in different published studies [9Go]. These great differences in response rates among the various studies are in part attributed to the difficulties associated with both the objective measurement of tumor size and the assessment of the degree of benefit afforded by any tumor shrinkage. Whereas for most cancers, tumor-related symptoms are closely related to tumor bulk, in the pancreatic cancer even small reductions in tumor size may result in significant clinical benefit as a result of the location of the tumor [8Go]. Therefore, the assessment of clinical benefit response in pancreatic cancer patients assumes a high priority. In this respect, gemcitabine has been proved by many studies to be more effective than the standard 5-FU chemotherapy in treating patients with pancreatic cancer. Although response rates for single-agent gemcitabine in patients with advanced pancreatic cancer remain only at ~10%, with minimal improvement in overall survival [23Go], this drug has been established as the gold standard in the treatment of pancreatic carcinoma over recent years.

In this study, we tested the hypothesis that the addition of carboplatin to gemcitabine would result in a more efficacious regimen for patients with pancreatic cancer. These two drugs have a different mode of action with no overlapping toxicities, and can be administered easily and safely on an outpatient basis. The doses of both drugs were certainly lower than those usually used, but this was due to the findings of our prior pilot studies, in which similar patients could not tolerate higher doses. According to the results of this study, the combination of gemcitabine with carboplatin seems to be active and well tolerated. No complete remissions were documented, but partial remission was achieved in eight patients (17%) and stable disease was observed in 15 additional patients (32%). The positive impact of the gemcitabine plus carboplatin combination chemotherapy is reflected by the observed median survival of 7.4 months in our patients. Moreover, stable disease in combination with clinical benefit response was a reasonable treatment goal in patients with pancreatic cancer. Of more importance is the fact that the clinical benefit response in the vast majority of patients was observed at the very early stage of treatment, mostly after the first cycle of chemotherapy, giving considerable relief to patients' disease-related symptoms. After completion of the second cycle of chemotherapy, clinical benefit response was observed in most patients. Pain improved in 68% of patients, with >50% reduction of analgesic consumption. Karnofsky PS improved by more >20% in 35% of patients, and 52% experienced a weight gain of >7% from baseline. This impressive response to treatment in terms of clinical benefit was associated with improvement in other clinical parameters, such as appetite, nausea, vomiting, weakness and general feeling. The improvement of these later parameters lasted for a considerable period of time, as shown by the evaluation of patients after the fourth and sixth cycles of chemotherapy. However, because our specially designed scale for the evaluation of disease-related symptoms has not been validated, no firm conclusions can be drawn. Thus, our data regarding the evaluation of these symptoms cannot be compared with the findings of other studies, which might have required a validated scale. Our patients had a clear and long-lasting improvement in their quality of life, outweighing the rather mild side-effects of treatment regimen.

The combination of gemcitabine with other active drugs has been tested in some phase II and phase III studies. In one phase III study, 327 patients with advanced pancreatic carcinoma not amenable to surgical resection were randomized to receive either gemcitabine alone or gemcitabine plus 5-FU weekly for 3 weeks on a 4-week schedule [24Go]. The median survival was 5.4 months for gemcitabine alone and 6.7 months for gemcitabine plus 5-FU (P=0.09). The authors concluded that the addition of 5-FU to single-agent gemcitabine did not improve the median survival of patients with advanced pancreatic carcinoma, and clinical trial resourses should address other combinations and novel agents. At that point, a recently published trial [25Go] concluded that the addition of the new molecule, farnesyltransferase inhibitor tipifarnib, does not prolong overall survival in patients with advanced pancreatic cancer, compared with single-agent gemcitabine. In this randomized, double-blind, placebo-controlled study, 688 patients with advanced pancreatic adenocarcinoma previously untreated with systemic therapy were assigned to receive either gemcitabine plus tipifarnib or gemcitabine plus placebo. The median overall survival was 193 days for the experimental arm and 182 days for the control arm (P=0.75). The 6-month and 1-year survival rates also were similar in the two groups (53% versus 49% for 6-month survival rate and 27% versus 24% for 1-year survival rate, for the experimental and control arm, respectively).

Gemcitabine has also been combined in same phase II studies with other drugs, such as irinotecan [26Go], docetaxel [27Go], oxaliplatin [19Go, 28Go], uracil–tegafur [29Go], capecitabine [30Go] and cisplatin [31Go]. Response rates ranged from 11% to 33% and the median survival from 6 to 11 months. These results do not suggest a clinically meaningful survival benefit for the patients over those treated with gemcitabine monotherapy.

In conclusion, the combination of gemcitabine and carboplatin is easily administered and well tolerated by patients with locally advanced or metastatic pancreatic carcinoma. The clinically meaningful benefit, as indicated by the improvement of disease-related symptoms, decreased analgesic consumption and improved PS warrants further investigation. However, it seems, although without a control arm, that the addition of carboplatin to standard gemcitabine treatment for advanced pancreatic cancer does not improve the overall survival. Response rate and survival remain unacceptably low.


    Acknowledgements
 
The authors wish to thank Mrs Sonia Chalkidou, MSc, for the statistical analysis.

Received for publication June 25, 2004. Revision received December 24, 2004. Accepted for publication December 27, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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