Patient Eligibility

Patients were eligible to enter the study if they had histologic or cytologic diagnosis of an adenocarcinoma of the pancreas that was either unresectable or metastatic. Participants were required to have a Southwest Oncology Group performance status of 0 to 2, a life expectancy of at least 3 months, and adequate hematologic, renal, and hepatic functions defined by the following parameters: neutrophil count ≥ 1,500/μL, platelet count ≥ 100,000/μL, creatinine ≤ 1.5 mg/dL, total serum bilirubin ≤ 3.0 mg/dL, and AST less than 2.5 times the upper limit of the institutional normal range (ULN). Patients were excluded if they had another active cancer within the preceding year except for adequately treated basal cell cancer, squamous cell skin cancer, or in situ cervical cancer. Additional exclusion criteria included previous chemotherapy for pancreatic cancer within the preceding 6 months or any prior therapy with gemcitabine. Before initiation of study treatment, all patients provided written informed consent in accordance with the guidelines of the Human Investigation Committees of Wayne State University and the University of Michigan.

Study Design and Treatment Plan

All treatment was delivered in the outpatient setting. Gemcitabine (Gemzar; Eli Lilly, Indianapolis, IN) was administered intravenously (IV) on days 1, 8, and 15 of each treatment cycle at a dose of 1,000 mg/m². Cisplatin 50 mg/m² was administered IV on days 1 and 15 after gemcitabine infusion and hydration. FU was administered as a continuous IV infusion via an indwelling venous catheter at a dose of 175 mg/m²/d from days 1 to 15. Cycles were repeated every 28 days.

Dose reductions were made on days 8 and 15 based on the toxicity encountered within a cycle as follows: gemcitabine, cisplatin, and FU were held for a neutrophil count or platelet count less than 500/μL or less than 25,000/μL, respectively, and full-dose chemotherapy was administered for a neutrophil count ≥ 500/μL and platelet count ≥ 25,000/μL. FU was dose-reduced by 20% for any grade 1 nonhematologic toxicity (excluding nausea, alopecia, or nephrotoxicity) encountered during a cycle of treatment. FU was held for a grade 2 nonhematologic toxicity. All three drugs were held for grade 3 or 4 nonhematologic toxicity.

A new cycle of therapy could begin if the neutrophil count was ≥ 1,500/μL, the platelet count was ≥ 100,000/μL, and all relevant nonhematologic toxicities were grade 2 or lower. Adjustment of the dose of each drug on day 1 of each cycle was dependent on the presence and the extent of toxicity in the preceding cycle. Dose adjustments on day 1 were as follows: a 20% dose reduction for gemcitabine and cisplatin for a nadir neutrophil count less than 1,000/μL or platelet count less than 75,000/μL. For nonhematologic toxicities, excluding alopecia, nephrotoxicity, nausea, or vomiting, only the FU dose was adjusted as follows: for grade 1 to 2 and 3 to 4 toxicities, the dose was reduced by 20% and 40%, respectively. Treatment for patients with renal toxicity was guided by the serum creatinine levels on the day of cisplatin administration. Patients with a serum creatinine of 1.6 to 2.0 mg/dL had a dose reduction of 50%. Patients with a serum creatinine greater than 2.1 mg/dL had the cisplatin dose held. Cisplatin dose was also adjusted based on the highest serum creatinine level during the previous cycle. For a creatinine of 2.1 to 3.0 mg/dL, the cisplatin dose was reduced by 25% in subsequent cycles, provided that the serum creatinine level had recovered to less than 1.5 mg/dL. Patients with a serum creatinine of 3.5 to 4.5 mg/dL had the subsequent dose of cisplatin reduced by 50% if the serum creatinine level on the day of the next treatment was less than 1.5 × ULN. When the serum creatinine level was greater than 4.5 × ULN, no additional therapy with cisplatin was allowed. The use of growth factor was permitted. When doses were reduced for toxicity, re-escalation of dose was not permitted.

Patients requiring a delay in therapy of longer than 2 weeks or requiring more than two dose reductions were removed from the study. In addition, patients were removed from the study for any of the following reasons: disease progression, unacceptable toxicity, withdrawal of consent, or initiation of chemoradiotherapy or surgery for patients with LA disease.

On-Study Evaluation

Standard treatment efficacy end points in relation to survival, objective response, time to disease progression, and duration of response were determined. Survival was defined as the time from the initiation of therapy to the date of death or last follow-up. Imaging studies, including computerized tomography, were performed at baseline, after every two cycles of therapy, and when there was clinical suspicion of disease progression. Tumor responses were categorized as complete, partial, progression, or stable. Complete response was defined as the disappearance of all measurable and assessable disease without the appearance of any new lesions. Partial response was defined as a 50% or greater reduction in the sum of the products of all measurable lesions compared with baseline measurements. Objective response required one confirmatory follow-up scan at least 3 weeks after the first documentation of response. Progressive disease was defined as a 25% or greater increase in the sum of the products of any measurable lesion, relative to either the baseline or the maximal response, or the appearance of any new lesions. Stable disease was defined as any change in tumor size that did not meet criteria for progressive disease or partial response and that persisted at the 4-month evaluation. Duration of response was defined as the time from complete or partial response until first objective evidence of disease progression or death from any cause. Duration of response was censored for patients who were removed from the study or who received antitumor therapy other than gemcitabine, cisplatin, and FU, including chemoradiotherapy or surgery. Time to progression was defined as the time from enrollment onto the study until progression or death. Toxicities were evaluated, at a minimum, on days 1, 8, and 15 of each cycle and graded according to the World Health Organization toxicity criteria.

Statistical Methods

This phase II trial was planned with two Fleming two-stage designs,²⁰ one design for LA patients and a separate design for metastatic patients. For the LA patients, we wished to determine whether the true resectability rate was 0.01 or less versus 0.15 or more. We used only the response-assessable LA patients because only they would be appropriate to determine whether the chemotherapy had rendered them surgically resectable. The two-stage design called for a maximum of 19 response-assessable patients, 10 in stage 1 and nine in stage 2. The design had a type I error of 0.015 and a power of 0.801. After accruing 12 LA patients, 10 were response-assessable and, thus, resectability assessable. With only one patient among them having been resected, the trial portion for LA patients was terminated without proceeding to stage 2. Final case review (with supplemental clinical information) indicated that four patients initially regarded as metastatic were actually LA, thus yielding 16 patients in total, 13 of whom were resectability assessable. The conclusion persisted that the revised sample proportion (one of 13 patients, 8%) better supported the null hypothesis that the true resectability rate was at most 0.01.

For the metastatic patients, we wished to determine whether the true 6-month survival rate was 0.50 or less versus 0.75 or more. For this end point, we used all registered patients with metastatic disease. The two-stage design called for a maximum of 30 patients, 15 in stage 1 and 15 in stage 2. The design had a type I error of 0.022 and a power of 0.796. At least nine, but at the most 12, 6-month survivors among the first 15 patients were required to proceed to stage 2. After the accrual of 15 patients, nine of them survived for at least 6 months, thus stage 2 was begun, and we enrolled another 15 metastatic patients. Final case review (with supplemental clinical information) indicated that one patient initially regarded as LA was actually metastatic, thus yielding 31 metastatic patients in total. Our conclusion was that the sample proportion (21 of 31 patients, 68%) better supported the alternative hypothesis that the true 6-month survival rate was at least 0.75.

Exact, minimum-width 90% confidence intervals (CIs) for response and toxicity rates were calculated using the Casella method,²¹ as implemented in StatXact software (Cytel Software Corporation, Cambridge, MA). ²² Standard Kaplan-Meier estimates of the censored response duration and censored survivorship functions were computed. Because of the small sample sizes, survival statistics were estimated more conservatively using linear interpolation among successive event times on the Kaplan-Meier curves.²³

Patient Characteristics

The characteristics of the patients on the study are listed in Table 1⇓. Forty-seven patients were enrolled onto the study between April 1999 and November 2001. The median age at study entry was 57 years (range, 28 to 78 years). There were more men (59%) than women. Ninety-one percent of patients had a performance status of 0 to 1. Sixteen patients had LA disease that was surgically unresectable. Thirty-one patients had metastatic disease (liver, n = 28, 90%; lung, n = 2, 7%; or other site, n = 1, 3%). No patient had received prior chemotherapy or radiation treatment.

Treatment Administration

A total of 183 treatment cycles were administered, with a median of four cycles per patient (range, one to eight cycles). Five patients received less than one full cycle of treatment. Thirty-two patients (71%) required at least one dose reduction because of neutropenia (n = 17), mucositis (n = 10), thrombocytopenia (n = 4), or sepsis (n = 1).

Survival

The median survival time for the whole group of the treated patients was 8.6 months (90% CI, 6.8 to 11.2 months). The Kaplan-Meier estimate of survival is shown in Figure 1⇓. The 6-month and 1-year survival rates were 69% and 36%, respectively (Table 2⇓). Among the patients who died, the longest survival was 27.9 months. Eight patients are still alive, for a censoring rate of 17%.

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Fig 1.

The Kaplan-Meier estimate of the overall survival duration in the 47 patients with advanced pancreatic cancer enrolled onto the study. The dashed lines represent the 90% confidence intervals (CI) for each successive estimate of the survival rate (solid line). The 1-year survival rate was 36% (90% CI, 0.23 to 0.47).

Of the 31 patients with metastatic disease, the median survival was 8.5 months (90% CI, 3.0 to 9.1 months). The 6-month and 1-year survival rates were 66% (90% CI, 0.52 to 0.79) and 34% (90% CI, 0.19 to 0.49), respectively. In the 16 patients with LA disease, the median survival time was 10.3 months (90%, CI 6.3 to 12.8 months), and survival rates at 6-months and 1 year were 71% (90% CI, 0.52 to 0.90) and 35% (90% CI, 0.15 to 0.54), respectively. Survival by disease extent is shown in Figure 2⇓.

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Fig 2.

The Kaplan-Meier estimate of overall survival by disease extent. The solid line represents the 31 patients with metastatic disease, and the dashed line represents the 16 patients with locally advanced disease.

Objective Response

Results of the study were analyzed on an intent-to-treat basis. Eleven (23%) of the 47 patients (90% CI, 0.15 to 0.35) registered onto the study had a partial response. Among the 42 response-assessable patients, the partial response rate was 26% (90% CI, 0.17 to 0.39). For the 11 partial responders, the median response duration was 7.1 months (90% CI, 4.4 to 9.1 months). Twenty-seven (57%) of the 47 patients (90% CI, 0.44 to 0.70) had stable disease.

Of the 31 patients with metastatic disease, eight patients (26%; 90% CI, 0.14 to 0.41) had a partial response, and 19 (61%; 90% CI, 0.45 to 0.74) had stable disease. Of the 16 patients with LA disease, the objective partial response rate was 19% (90% CI, 0.07 to 0.39). Fifty percent of these patients (90% CI, 0.30 to 0.70) had stable disease. Ten of 16 patients without metastasis subsequently received chemoradiotherapy. Three patients underwent surgical exploration, and one had resection. Although the resected specimen had viable tumor, the patient is alive and continues to be disease-free at 30 months.

Time to Disease Progression

The median time to progression in all 47 patients was 7.2 months (90% CI, 5.0 to 9.5 months). The median time to disease progression in the patients with metastatic and LA disease were 5.7 months (90% CI, 3.0 to 9.1 months) and 7.2 months (90% CI, 4.1 to 11.0 months), respectively.

Toxicity

One registered patient did not receive any treatment and is not assessable for toxicity. Treatment was generally well tolerated in the outpatient setting. Two treatment-related deaths were reported. One patient suffered a gall bladder perforation in the first week of chemotherapy. Another patient died of overwhelming sepsis after a fourth cycle of chemotherapy. Thirteen patients required hospitalization for treatment-related complications (pneumonia, n = 3; electrolyte imbalance, n = 3; sepsis, n = 2; stroke, n = 1; renal failure, n = 1; mucositis, n = 1; gastritis, n = 1; and perforated gall bladder, n = 1). Grade 4 toxicities were observed in 17 patients, and 20 episodes of grade 4 toxicity were reported. The most common grade 3 to 4 toxicities were neutropenia (60%) and thrombocytopenia (42%). Thirteen patients required RBC transfusions, and two patients required platelet transfusions. Table 3⇓ lists the toxicities encountered in this study.