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Treatment of Pancreatic Cancer With Docetaxel and Granulocyte Colony-Stimulating Factor: A Multicenter Phase II Study

From the Department of Medical Oncology, School of Medicine, University of Crete, Crete; Departments of Clinical Therapeutics, Pathophysiology, and Surgery, School of Medicine, University of Athens, Athens; Department of Medical Oncology, Ippokration General Hospital of Athens, Athens; and Third Department of Medical Oncology, Agii Anargyri Anticancer Hospital of Athens, Athens, Greece.

Address reprint requests to Vassilis Georgoulias, MD, PhD, Department of Medical Oncology, University General Hospital of Heraklion, PO Box 1352, 71110 Heraklion, Crete, Greece; email georgoul{at}med.uch.gr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the efficacy and tolerance of single-agent docetaxel and granulocyte colony-stimulating factor in patients with advanced pancreatic cancer.

PATIENTS AND METHODS: Thirty-three chemotherapy-naive patients (median age, 65 years) with histologically confirmed pancreatic cancer were treated, after appropriate premedication, with docetaxel (100 mg/m²) and granulocyte colony-stimulating factor (150 µg/m²/d subcutaneously days 2 through 10) every 3 weeks. World Health Organization performance status was 0 to 1 in 28 patients (85%) and 2 in 5 patients (15%). Twenty-nine patients had stage III and IV disease.

RESULTS: One complete response (3%) and one partial response (3%) were observed for an overall response rate of 6% (95% confidence interval, 2.1% to 14.2%). Nineteen patients (58%) had stable disease and 12 (36%) had progressive disease. The duration of the two objective responses was 10 and 28 weeks, and the median time to tumor progression was 20 weeks. The median overall survival was 36 weeks. The actuarial 1-year survival was 36.4%. The performance status improved in seven of 21 assessable patients (24%) and pain improved in 14 of 21 (67%) assessable patients; five patients (29%) experienced weight gain during treatment. Disease-related asthenia, anorexia, vomiting, and diarrhea improved in 29%, 15%, 67%, and 47% of the assessable patients, respectively. Serum concentrations of CA 19-9 were decreased by more than 50% in seven patients (35%). Grade 3 and 4 neutropenia occurred in four patients (12%) and eight patients (24%), respectively, with two episodes of febrile neutropenia. There were no treatment-related deaths. Grade 3/4 asthenia occurred in three patients.

CONCLUSION: Although docetaxel has a marginal objective activity in pancreatic cancer, it seems to have an important effect on tumor growth control, conferring a clinical benefit.

	INTRODUCTION

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TREATMENT OF pancreatic cancer remains difficult and disappointing. Radical surgical excision of the tumor is possible in only 5% to 10% of patients. Both radiation and chemotherapy are frequently used for palliation in patients with locally advanced and metastatic disease, but overall survival is, in general, less than 6 months.^1,2

Fluorouracil (5-FU), mitomycin, doxorubicin or epirubicin, lomustine, and streptozocin have shown limited single-agent activity against pancreatic cancer, with responses ranging from 8% to 37%.^3-8 More recently, gemcitabine, a new nucleoside analog, has shown a marginal activity in pancreatic cancer, with 11% of patients experiencing objective responses^8,9; however, gemcitabine resulted in significant clinical benefit in terms of weight gain, reduction of analgesic consumption, and improvement of performance status in both chemotherapy-naive^9-11 and 5-FU–refractory¹² patients. In addition, the comparison of 5-FU and gemcitabine in patients with advanced pancreatic cancer demonstrated that gemcitabine produced significantly better clinical benefit and survival than 5-FU.¹⁰

Docetaxel, a new semisynthetic taxoid, has a broad spectrum of antitumor activity.¹³ Docetaxel binds to the ß-subunit of tubulin in the microtubules, thus promoting the polymerization of tubulin into stable microtubules and inhibiting the formation of stable microtubule bundles.^14,15 This disruption of the normal equilibrium leads to cell death. In murine tumor models, docetaxel produced a 100% cure rate of early-stage pancreatic ductal adenocarcinoma; in more advanced stages, the drug could cure more than 80% of animals.¹⁶ A preliminary analysis of a docetaxel phase II trial of 42 patients with pancreatic cancer showed an objective response rate of 20% in 30 assessable patients, with a median survival ranging from 212 to 442 days, depending on the extent of the disease.¹⁷

A multicenter phase II trial was designed to evaluate the efficacy and tolerance of docetaxel in patients with locally advanced and metastatic pancreatic cancer; all patients received prophylactic granulocyte colony-stimulating factor (G-CSF) to prevent the need for docetaxel dose reductions.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
Patients who were 18 to 75 years of age with histologically or cytologically confirmed pancreatic adenocarcinoma and bidimensionally measurable disease and who had not received prior chemotherapy or radiotherapy were enrolled onto the study. Other eligibility criteria included a World Health Organization (WHO) performance status of 0 to 2; a life expectancy of at least 3 months; absence of biliary tract obstruction; adequate hematologic parameters with an absolute granulocyte count greater than 1,500/dL and a platelet count greater than 120,000/dL; normal renal (serum creatine concentration < 1.2 mg/dL) and liver (total serum bilirubin concentration < 1.5 mg/dL) function tests; normal cardiac function with no history of angina pectoris or congestive heart failure; and no CNS involvement. Prior surgery was allowed, but at least 3 weeks must have passed since the date of surgery. Patients with overt infections, malnutrition, or a second primary malignancy (unless adequately treated nonmelanomatous skin or in-situ cervical cancer) were excluded from the study. All patients gave written informed consent.

Treatment
All patients were treated on an outpatient basis. Docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) was administered as an intravenous infusion at the dose of 100 mg/m² in 250 mL of normal saline over a 1-hour time period. All patients received standard premedication with 4 mg dexamethasone orally 12 and 4 hours before the docetaxel administration and with 4 mg every 6 hours for 2 subsequent days. Standard antiemetic treatment with ondansetron was administered to all patients. In addition, patients received recombinant human G-CSF (Granocyte; Rhône-Poulenc Rorer) at the dose of 150 µg/m² from day 2 to day 10 posttreatment. Treatment was repeated every 3 weeks, provided that patients had sufficiently recovered from drug-related side effects. Treatment was continued for at least six cycles or until disease progression (at the physician's discretion). The protocol was approved by the ethical committees of the participating hospitals.

Dose adjustment criteria were based on the hematologic parameters. The docetaxel dose was reduced by 25% in cases of chemotherapy-induced febrile neutropenia or grade 4 neutropenia or thrombocytopenia lasting for more than 5 days; in the absence of fever, the dose of docetaxel was reduced by 15% in cases of grade 3 neutropenia and grade 2 thrombocytopenia lasting for more than 5 days. A 1-week treatment delay and a 20% dose reduction was performed in patients with grade 3 asthenia or grade 2/4 neurotoxicity. Toxicities were graded according to the WHO guidelines.¹⁸

Patient Evaluation
Pretreatment evaluation included a complete medical history and physical examination, a complete blood cell (CBC) count with differential and platelet counts; a standard biochemical profile, serum carcinoembryonic antigen and CA 19-9 determinations, an 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 on clinical indication. During treatment, CBC counts (with differential and platelet counts) were performed weekly; in case of grade 3/4 neutropenia or grade 4 thrombocytopenia, CBC count was evaluated daily until the absolute granulocyte count was 1,000/dL and the platelet count was 50,000/dL. A detailed medical history was taken and a physical examination was completed before each course of treatment to document symptoms of disease and toxicities of treatment. Biochemical tests, electrocardiograms, carcinoembryonic antigen and CA 19-9 determinations, and chest x-rays were performed every 3 weeks. A neurologic evaluation was performed by clinical examination every 3 weeks; motor and sensory conduction velocity tests were conducted in cases of grade 3 or 4 neurotoxicity. Lesions were measured after each cycle if they were assessable by physical examination or by chest x-ray; lesions assessable by ultrasound or/and computed tomography scan were evaluated after three courses. All responses were confirmed by an external board of independent radiologists.

Definition of Response
A complete response (CR) required the disappearance of all measurable and assessable disease in all disease sites, including normalization of abnormal laboratory values, with no new lesions. A partial response (PR) required a greater than 50% decrease in the sum of the products of the perpendicular diameters of all measurable lesions, with no new lesion or progression of assessable disease. Progressive disease (PD) was defined as follows: (1) a 50% increase or an increase of 10 cm² (whichever is smaller) in the sum of the products of measurable lesions over the smallest sum observed, (2) clear worsening of any lesion that had disappeared, or (3) failure to return for evaluation because of deteriorating condition (unless deterioration was clearly unrelated to the cancer). Stable disease (SD) was characterized as disease that did not meet the criteria for either CR, PR, or PD. All responses were required to be maintained for more than 4 weeks.¹⁹

Assessment of Clinical Benefit
The assessment of pain relief was based on both the consumption of analgesics (narcotics and nonnarcotics) 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 more than 50% decrease in analgesics consumption with no need for narcotics, in combination with a patient's evaluation of a more than 50% decrease in pain intensity, was characterized as pain improvement. A 50% increase in analgesics consumption, in combination with a 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 daily number of episodes. A more than 50% decrease in the number of episodes was characterized as improvement, whereas a more than 50% increase in this number 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.

Statistical Methods
The duration of response was calculated from the day of the first demonstration of response until disease progression; the time to tumor progression (TTP) was estimated from study entry until the documented progression of the disease, and the overall survival was measured from study entry until death. Actuarial probability of survival and the median TTP were estimated by the method of Kaplan and Meier²⁰; confidence intervals for response rates were calculated using methods for exact binomial confidence intervals.²¹ Comparison of variables was performed using the log-rank test.

	RESULTS

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Patient Demographics
From January 1996 to February 1997, 33 patients were enrolled onto this multicenter study; their characteristics are listed in Table 1. The median age was 65 years (range, 35 to 78 years) and 19 patients (58%) were men. Twelve patients (36%) had a performance status (WHO) of 0. Four patients (12%) with stage II disease were considered inoperable because of congestive heart failure (two patients), respiratory insufficiency (one patient), and low performance status (one patient), whereas 10 (30%) and 19 (58%) had stage III and IV disease, respectively. Ten patients (30%) were receiving narcotics and 17 patients (52%) were receiving noncorticosteroid analgesics at the time of entry. All patients were assessable for response and toxicity.

Compliance With the Treatment
A total of 162 chemotherapy cycles were administered. The median number of cycles per patient was three (range, two to 13 cycles) and the median interval between cycles was 21 days (range, 21 to 24 days). The median dose-intensity was 33 mg/m²/wk (range, 24 to 33 mg/m²/wk), which was exactly the planned dose according to the protocol. Nine cycles (6%) were delayed for the following reasons: grade 3 or 4 neutropenia (three cycles) and nonneutropenic infection (one cycle); five additional cycles were delayed because of patients' requests for reasons unrelated to the disease or the treatment. One patient refused to continue treatment after the first cycle for personal reasons unrelated to treatment. At the time of analysis, 30 patients have stopped treatment for the following reasons: PD (15 patients); deterioration of performance status (five patients); early death (one patient); patients' requests after they had completed 10 and 13 chemotherapy cycles (two patients), and physicians' decision after the patients had received six cycles (seven patients).

Response to Treatment and Survival
Responses were analyzed on an intent-to-treat basis. For the 33 eligible patients, there was one CR (3%) and one PR (3%) for an overall response rate of 6% (95% confidence interval, 2.1% to 14.2%). Nineteen patients (58%) had SD and 12 (36%) had PD. One patient who refused further treatment after the first cycle as well as one patient who died 15 days after the first cycle were considered to have PD. The median duration of the two responses was 10 and 28 weeks; the median TTP was 20 weeks (range, 8 to 36 weeks; Fig 1). For patients achieving SD, the median duration of SD was 14 weeks (range, 4 to 28 weeks). The median overall survival was 36 weeks (range, 8 to 108 weeks), and the 1-year survival rate was 36.4% (Fig 2). The median survival of 29 patients with stage III and IV disease was also 36 weeks (range, 4 to 108 weeks). There was no survival difference between the stage III patients (median, 40 weeks; range, 16 to 76 weeks) and stage IV patients (median, 36 weeks; range, 8 to 108 weeks). However, the median overall survival for patients achieving SD was significantly higher than that of patients with PD (48 v 24 weeks; P = .0043).

View larger version (7K): [in this window] [in a new window]   Fig 1. TTP of patients with pancreatic adenocarcinoma treated with docetaxel.

View larger version (8K): [in this window] [in a new window]   Fig 2. Actuarial survival of patients with pancreatic adenocarcinoma treated with docetaxel (Kaplan-Meier analysis).

Among 21 patients with performance status of 1 and 2 at entry, eight (38%) improved during treatment; in 11 patients (52%), performance status was unchanged, and in two patients, performance status deteriorated. Among 20 patients with elevated levels of CA 19-9 before treatment, a decrease of this marker was noted in 13 patients (65%); in seven patients (35%), the decrease of serum CA 19-9 concentration ranged from 50% to 100%. In two (10%) and five (25%) patients, CA 19-9 concentration was unchanged and increased, respectively.

Table 2 indicates that an improvement of disease-related symptoms could be observed during docetaxel administration. Indeed, in 14 (67%) of 21 patients with severe or moderate pain at the time of entry, pain improvement was noted, and narcotics could be substituted for noncorticosteroid analgesics in all 10 patients who were receiving before treatment with docetaxel; in the four remaining patients, the consumption of nonnarcotic analgesics was reduced by more than 50% (range, 50% to 85%). Pain was unchanged in five patients (24%) and only two (9%) experienced pain aggravation; nevertheless, none of these patients required narcotics for pain control during treatment. Weight loss was reported by 17 patients at the time of treatment initiation; five (29%) of these patients showed an increase in their weight, whereas the weight of nine (53%) and three (18%) patients was unchanged or decreased, respectively. Body weight gain was not associated with edema in any patient. Similarly, disease-related asthenia was improved in six (29%) of 21 patients, vomiting in six (67%) of nine patients, diarrhea in seven (47%) of 15 patients, and anorexia in four (15%) of 26 patients (Table 2).

Toxicity
All patients were assessable for toxicity (Table 3). Grade 3 anemia occurred in three patients (9%), requiring the transfusion of nine packed RBC units. Moreover, four additional patients with grade 2 anemia received recombinant human erythropoietin (100 IU/kg every other day for 6 weeks); a total of 10 erythropoietin courses were administered during the study. Grade 3 thrombocytopenia occurred in one patient (3%), but no hospitalization was required for platelet transfusions. Four (12%) and eight (24%) patients presented with grade 3 and 4 neutropenia, respectively. Neutropenia was of short-duration (median duration, 2 days [range, 2 to 5 days]) and was easily manageable with recombinant human G-CSF. Two patients (6%) developed febrile neutropenia and were successfully treated with intravenous antibiotics and recombinant human G-CSF. There were no treatment-related deaths. Nonhematologic toxicity was, in general, mild (Table 3). Grade 3 and 4 asthenia occurred in two and one patients, respectively, and moderate to severe nail changes occurred in four patients. Dyspnea, due to moderately severe allergic bronchoconstriction, occurred in one patient (3%).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Pancreatic adenocarcinoma is traditionally considered a chemoresistant tumor because objective responses with single-agent chemotherapy have rarely exceeded 15%; in addition, the median duration of survival has been generally less than 6 months.² Therefore, new active agents or chemotherapy regimens are needed to improve patients' quality of life and survival.

The present study demonstrated that docetaxel has a limited activity in previously untreated patients with locally advanced or metastatic adenocarcinoma of the pancreas. Indeed, two objective responses (one CR and one PR) could be documented among 33 eligible patients, for an overall response rate of 6%. In another phase II trial of docetaxel in patients with pancreatic cancer, objective responses were documented in 20% of 30 patients with metastatic disease; conversely, in 12 patients with locoregional disease, no objective responses could be documented but clinical improvement was noted in three patients.¹⁷ A preliminary study by Abbruzzese et al²² reported two PRs in 10 assessable patients, with both responders showing improvement in cancer-related pain and performance status. The reasons for these discrepancies are not obvious; however, the difficulty to measure the locoregional lesions in patients with pancreatic cancer is well known. Therefore, it is relatively easy to overestimate or underestimate the response. In the present study, the two objective responses occurred in patients with easily measurable disease (liver and lung localizations) and were confirmed by an external panel of independent reviewers. The observed response rate with docetaxel is, practically, similar to the 8% and 5.4% to 11% response rates obtained with high-dose paclitaxel and G-CSF¹⁹ and gemcitabine,^9-11 respectively.

Most patients (58%) treated with docetaxel experienced SD that lasted for a median of 14 weeks. It is noteworthy that the overall survival of patients achieving SD was significantly higher (median, 12 months) than that of patients with PD (median, 6 months; P = .0043). Similarly, Rougier¹⁷ has reported SD in 30% of patients with metastatic disease and 25% of patients with locoregional disease; moreover, two patients achieved SD (20%) in the Abbruzzese et al trial.²² Taken together, these observations seem to indicate that docetaxel may have an effect on the tumor growth control. Conversely, the incidence of SD in the Southwest Oncology Group phase II trial of paclitaxel was very low (13%),¹⁹ suggesting that paclitaxel and docetaxel, although related, may display important differences in their effectiveness. This hypothesis is further supported by preclinical data demonstrating that the effective affinity of docetaxel for microtubule binding site is 1.9-fold greater than that of paclitaxel²³; moreover, docetaxel induces a two-fold greater decrease of the critical concentration of guanine triphosphate tubulin (required for tubulin assembly) than paclitaxel.^15,23

The gemcitabine studies have shown that several patients had an improvement in cancer-related symptoms and performance status.^9-12 Carmichael et al¹⁰ reported a 60% decrease of tumor markers in four of 16 patients with pancreatic cancer treated with gemcitabine, whereas improvement in performance status, pain score, analgesic consumption, and nausea was observed in 17.2%, 28.6%, 7.4%, and 27.3% of patients, respectively. In a randomized trial comparing gemcitabine with 5-FU in patients with pancreatic cancer, Burris et al¹¹ demonstrated a significantly higher clinical benefit in the gemcitabine arm (23.8%) than in the 5-FU arm (4.8%). In the present study, the performance status was improved in 24% of patients; moreover, cancer-related pain was improved in 67%, asthenia in 29%, anorexia in 15%, vomiting in 67%, and diarrhea in 47% of patients suffering from those symptoms at the time of treatment initiation (Table 2). In addition, CA 19-9 serum concentration decreased by at least 50% in 35% of patients, including the two patients who had objective responses. These observations strongly suggest that treatment of pancreatic adenocarcinoma with docetaxel may result in an important clinical benefit; it is reasonable to assume that this observation may be related to docetaxel-induced tumor growth control. Based on the literature data, this overall patients' clinical benefit with docetaxel seems to be superior than that observed with gemcitabine. A randomized comparative study is needed to confirm this hypothesis.

The survival data of the present study also seem interesting. Indeed, approximately 60% of the patients are alive at 6 months, whereas the overall probability for 1-year survival was 36.4%. These results are not due to the inclusion in the study of four patients with stage II disease, because the survival of patients with stage III and IV disease was similar to that of all patients (36 weeks). It should be mentioned that the reported median overall survival of patients treated with gemcitabine ranged from 3.8 to 6.3 months,^9,10,12 whereas that of untreated patients was 6 months.^6-8 A randomized trial comparing docetaxel and gemcitabine treatment could definitely answer the question of whether docetaxel confers a real survival benefit in patients with pancreatic cancer.

The toxicity profile of single-agent docetaxel with G-CSF support in patients with pancreatic adenocarcinoma was relatively mild. Indeed, 36% of the patients developed grade 3/4 neutropenia, with two episodes of febrile neutropenia and no treatment-related deaths. Similarly, 23% and 92% of patients treated with gemcitabine and paclitaxel plus G-CSF developed grade 3 and 4 neutropenia, respectively.^9,19 Conversely, the incidence of treatment-related nausea, vomiting, and diarrhea was significantly lower than that observed with gemcitabine and paclitaxel.^9,19 These results must be confirmed in well-designed controlled studies comparing docetaxel versus gemcitabine versus 5-FU, using the improvement of disease-related symptoms and the overall clinical benefit as end points. In addition, the favorable toxicity profile of docetaxel with G-CSF support suggests that docetaxel is a promising agent for the development of combination regimens for the treatment of pancreatic cancer.

	ACKNOWLEDGMENTS

 
Supported in part by a grant from the Cretan Association for Biomedical Research

	NOTES

 
N.A. is a recipient of a Cretan Association for Biomedical Research Fellowship.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted May 19, 1998; accepted February 18, 1999.

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