Patient Eligibility

All patients provided written informed consent before study enrollment. Patients were included in the study if they were 18 years of age or older and had histologically or cytologically confirmed pancreatic adenocarcinoma not amenable to curative surgical resection. Patients were required to have documented or suspected extrapancreatic metastatic (stage IVb) disease; those with locally advanced unresectable disease only were not eligible. Extrapancreatic metastases did not have to be measurable by formal Response Evaluation Criteria in Solid Tumors Group (RECIST) criteria. No prior treatment for pancreatic cancer was allowable except for fluorouracil or gemcitabine-based chemoradiotherapy administered either in the postoperative adjuvant setting or for locally advanced unresectable disease. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 to 2 and an expected survival of at least 12 weeks. Adequate hematologic, renal, and hepatic function were required as defined by the following: absolute neutrophil count ≥ 2,000/μL, platelet count ≥ 100,000/μL, hemoglobin ≥ 10 g/dL, creatinine level ≤ 2.0 mg/dL, bilirubin level ≤ 2.0 mg/dL, and AST and ALT ≤ 3× the upper limit of normal (ULN; ≤ 5× ULN in patients with liver metastases). Patients were allowed to have undergone biliary stenting or a surgical bypass procedure to correct obstructive jaundice. Female patients of childbearing potential must have had a negative urine pregnancy test before study entry, and all fertile patients must have agreed to practice effective birth control during and for 3 months after trial.

Patients were excluded if they had another presently active malignancy or history of another active malignancy within the last 5 years except for superficial basal cell carcinoma of the skin. Patients with CNS metastases, who were pregnant or lactating, who could not maintain adequate unassisted oral or enteral (GI tube) intake to maintain a reasonable state of nutrition, or who had any concurrent disease that, in the opinion of the treating physician, would constitute a hazard for participation in this study, were also excluded.

Study Design and Treatment

This was a phase II, single-center, open-label, single-arm study of gemcitabine administered as FDR infusion combined with low-dose cisplatin. The trial was approved by the Committee on Human Research at the University of California at San Francisco (San Francisco, CA). Patients initially received gemcitabine 1,000 mg/m² in 500 mL of normal saline by intravenous infusion at the infusion rate of 10 mg/m²/min, immediately followed by cisplatin 20 mg/m² in 500 mL of normal saline infused intravenously during 30 minutes. Both drugs were to be administered on days 1 and 8 of each treatment cycle, with treatment cycles to be repeated every 21 days. This dose schedule was based on a phase I study performed previously by Tempero et al (unpublished data).

Dose adjustments were made depending on the toxicity observed with each treatment cycle. The gemcitabine dose was reduced to 75% or 50% of the starting dose based on grade 3 or 4 toxicities, respectively, whereas the cisplatin dose was either fixed at 20 mg/m² or withheld based on toxicities. Treatment was delayed until full recovery from any grade 3 or 4 event. In addition, if a dose reduction was required due to hematologic toxicity (neutropenia or thrombocytopenia), treatment was changed to an every-other-week dosing schedule (days 1 and 15 of a 28-day cycle); this revised treatment schedule was then maintained for the duration of therapy. Subsequent dose re-escalation was allowable at the discretion of the treating physician.

Patients who could not resume study treatment for 2 weeks from the time of last treatment because of unresolved toxicities were removed from the study. Such patients were allowed to continue receiving the same treatment regimen, off study, after recovery from treatment-related toxicity. In addition, patients were removed from study if any of the following occurred: progressive disease based on radiographic and/or clinical criteria, patient withdrawal of consent or noncompliance, or the development of more than one episode of grade 4 or 5 toxicity.

Supportive Care

Antiemetic agents, including dexamethasone and 5-hydroxytryptamine-3 antagonists (granisetron or ondansetron), were administered before each treatment as prophylaxis. In addition, lorazepam and/or perchlorperazine were added at the discretion of the treating physician. All of the above were allowable for the management of acute and delayed nausea and vomiting. Granulocyte colony-stimulating factor could be administered with subsequent cycles of treatment if severe, recurrent, or symptomatic episodes of neutropenia occurred, and erythropoietin was allowed for the treatment of anemia. Transfusion of blood products was permissible but discouraged.

Evaluation

Efficacy was measured by time to tumor progression (TTP) and overall survival. TTP was defined as the time from initial therapy to the first objective documentation of tumor progression (for patients with measurable disease) or to the date of death, if death was ascribed to progression of disease. Patients initially without measurable disease were included in the TTP analysis based either on the appearance of new measurable lesions or on strongly suggestive radiographic evidence of progression of nonmeasurable disease (eg, peritoneal carcinomatosis). TTP was censored for patients who did not have objective evidence of tumor progression at the time of study discontinuation or who died as a result of causes unrelated to pancreatic cancer. Overall survival was defined as the time from initial therapy to the date of death; in the absence of confirmation of death, survival was censored at the last date of follow-up.

Abdominal computed tomography scans with contrast were performed at baseline and repeated every two cycles and at the end of treatment. Objective responses as defined by RECIST criteria were not a planned end point of this study. Patients with measurable disease at baseline (≥ 2 cm in maximal dimension) were assessed for radiographic response; however, because objective response was not a planned study end point, response confirmation with serial radiographs was not required.

Serum CA 19-9 levels were measured at the start of each treatment cycle and at the end of treatment using commercially available assays. A biomarker response was defined as a reduction in CA 19-9 values by ≥ 50% from baseline in those patients with a twofold or greater elevation at baseline. Changes in CA 19-9 alone were not the sole basis for making decisions regarding whether to continue or stop treatment.

Safety was evaluated in terms of adverse events and clinical laboratory abnormalities, graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0). Adverse event assessments were performed on day 1 of each treatment cycle and at the end of treatment. Hematologic tests were performed at baseline, on days 1 and 8 (or 15) of each treatment cycle, and at the end of treatment. Renal and hepatic function tests were performed on day 1 of each treatment cycle and at the end of treatment.

Statistical Methods

The primary end point in this study was survival. A single-stage design was used. The original sample size of 48 patients was calculated to yield a probability of 82% that the observed median survival time will be greater than 8 months if the true median survival were 10 months. This was based on the assumptions that patient survival followed an exponential distribution and no patients would be lost to follow-up. Patients who were removed from study for reasons other than disease progression or treatment-associated toxicity were allowed to be replaced, although all patients were included in the final statistical analysis. Time to event end points and 1-year survival were derived by Kaplan-Meier methods. Radiographic response, treatment administration, adverse events, and laboratory abnormalities were summarized descriptively.

Patient Characteristics

A total of 51 patients were enrolled onto the study between August 2001 and June 2004. Data were collected through June 2005. No patients are still on study treatment at the time of this publication. Only two patients had metastases after resection of the primary site; all other patients presented with metastatic disease at the time of diagnosis. Forty of 51 patients (78.4%) had an elevated serum CA 19-9 level (> 2× ULN) at the time of study enrollment. Median follow-up time was 215 days (range, 36 to 999 days). Patient characteristics are listed in Table 1.

Treatment Administration

Patients received a median of four treatment cycles (eight doses). Approximately two thirds of study participants (62.7%) required adjustment of their dosing schedule to an every-other-week schedule. Of these patients, the median time to switching to the alternate schedule was after two cycles of treatment (range, one to 11 cycles). Patients who remained on the original dosing schedule for the entirety of treatment received a median of two cycles (range, one to 10 cycles), whereas those requiring a switch to the every-other-week schedule received a median number of six cycles (range, two to 16 cycles). Details of treatment administration, including the frequency of dose reductions and changes in schedule, are listed in Table 2.

Thirty-seven patients discontinued study treatment because of objective evidence of disease progression; an additional four patients discontinued treatment because of deteriorating quality of life attributed by the treating clinician to be secondary to progressive disease. Three participants chose to discontinue study treatment because of poor quality of life (generalized asthenia) attributable to therapy, although they did not formally meet criteria for removal from study. One patient chose to discontinue treatment because of concerns of fluid retention and a possible mild gemcitabine-associated infusion reaction during the eighth cycle. Four patients stopped treatment because of concomitant medical illness: one had an occluded stent, one had a hepatic abscess, one had cholecystitis, and one had pleural effusions (attributed to gemcitabine toxicity) with associated renal insufficiency (secondary to a combination of cumulative platinum dose and antihypertensive medications). The first two of these patients eventually resumed the same treatment regimen, off study, after their acute issues resolved; the third patient never resumed therapy and died 5 months later; the last patient, who had already received 16 cycles of treatment at the time therapy was discontinued, had resolution of his acute toxicities and remained in remission for 17 months after stopping treatment. Therapy was discontinued in two patients after a confirmed plateau in response, one after 14 cycles of therapy and one after 12 cycles; in the latter patient, the same regimen was resumed off study 2 months later when she developed progressive disease. Two patients relocated outside the area (Table 3).

Safety

Significant toxicities (grade 3/4) predominantly were hematologic in nature, most commonly neutropenia (Table 4). No occurrences of febrile neutropenia were recorded during the course of our study. Grade 3/4 anemia and thrombocytopenia occurred infrequently. Hematologic toxicities took place much more frequently on the days 1 and 8 dosing schedule, with much fewer occurrences when patients were subsequently switched to a days 1 and 15 schedule. Grade 3/4 nonhematologic toxicities were rare and included three instances each of liver function abnormalities and nausea/vomiting. No significant neurotoxicity was observed in this study. We documented three infectious complications (one pneumonia, one hepatic abscess, one ascending cholangitis); however, given that these occurred in the absence of neutropenia, they were believed unlikely to be attributable to study treatment. Details of adverse events are presented in Table 4.

Efficacy

All patients who received at least one infusion of study treatment were included in the survival analysis. Two patients died within the first 40 days of study enrollment. Objective response by RECIST criteria was not a planned end point of this study. However, after review of patients' films by the clinical study investigators, nine of 47 patients (19.1%) with measurable disease at baseline demonstrated a partial response and 28 patients (59.6%) had disease stabilization for at least two cycles. In addition, 22 of 40 patients (55.0%) with a two-fold or greater elevation of CA 19-9 at baseline showed a biomarker decline of at least 50% during the course of study treatment, 16 (40%) of whom had this degree of sustained biomarker decline for at least two consecutive measurements (Table 3).

The methods of Kaplan and Meier were used to calculate median TTP at 3.9 months (range, 0.5 to 30.3 months; 95% CI, 2.8 to 4.9 months) and median survival at 7.1 months (range, 1.2 to 34.3 months; 95% CI, 5.8 to 9.7 months; Figs 1 and 2). Estimated 1-year survival rate was 29%. Two patients are still alive, 20.1 and 34.3 months from the time of study enrollment, respectively.

Second-Line Treatment

Thirty-four of 51 patients (66.7%) went on to receive second-line treatment. This included a combination of docetaxel and irinotecan in 14 patients (part of an ongoing trial at our institution); capecitabine monotherapy in seven patients; vaccine-based therapy in three patients as part of a clinical trial; and rubitecan (Orathecin; Supergen, Dublin, CA) in one patient. Six patients who were removed from study for reasons other than disease progression continued receiving gemcitabine-based therapy as their next treatment.