Carcinoma of the pancreas is among the most lethal of all solid tumors. In 2000, 28,200 deaths due to pancreatic cancer are expected to occur in the United States. Pancreatic cancer is the ninth leading cause of cancer in women and the tenth leading cause of cancer in men. Cancer of the pancreas is the fourth leading cause of cancer deaths in the United States, responsible for about 5% of all American cancer deaths occurring each year. In the United States, the 5-year survival rate for all patients with a new diagnosis of pancreatic cancer is 4%, regardless of race or ethnicity. Worldwide, 170,000 cases and 168,000 deaths caused by pancreatic cancer are anticipated this year.
The efficacy of antitumor treatment of advanced pancreatic carcinoma is modest. Prior to the recent approval of gemcitabine(Drug information on gemcitabine) (Gemzar) as first-line therapy for patients with locally advanced or metastatic disease, there were little data to demonstrate a survival benefit for chemotherapy compared with best supportive care or for combination chemotherapy compared with fluorouracil(Drug information on fluorouracil) (5-FU) alone.
In 1997, Burris et al reported the results of a phase III trial comparing gemcitabine and 5-FU chemotherapy in patients with locally advanced or metastatic pancreatic cancer who had not received prior chemotherapy. Gemcitabine was given at 1,000 mg/m2 weekly for up to seven consecutive weekly doses, followed by a 1-week rest period and then 1,000 mg/m2 weekly for 3 out of 4 consecutive weeks. 5-FU was administered weekly as a 600 mg/m2 bolus. The primary end point of this trial was clinical benefit response. Secondary end points were overall survival, response rate, and time to progression of disease.
A total of 126 patients were randomized to receive treatment: 63 with gemcitabine and 63 with 5-FU. There were statistically significant improvements in the frequency of clinical benefit, time to progression of disease, and overall survival favoring therapy with gemcitabine. These data and the results of a parallel phase II trial of gemcitabine alone in patients with pancreatic cancer and prior 5-FU-based chemotherapy led to the approval of gemcitabine for first- and second-line therapy.
Despite the approval of gemcitabine for first- and second-line therapy for pancreatic cancer, the outlook for the large majority of patients remains unfavorable. The frequency of a clinically beneficial response with first-line therapy with gemcitabine in patients with pancreatic cancer was 24%. The median survival was 5.7 months, and the objective response rate was a disappointing 5.4%. Given these data, it is obvious that new agents and combinations need to be explored as first-line therapy for this disease.
Three topoisomerase I inhibitors have been evaluated in patients with advanced pancreatic cancer. Stehlin et al used 9-nitrocamptothecin in 107 patients with advanced disease. Among 60 patients who received at least two cycles of therapy, "response" (an amalgam of objective tumor regression, marker falls, and clinical benefit) was reported in 32% of patients. Another 32% were called "stable." The reported median survival among 57 previously untreated patients was 7.3 months.
At least four phase II trials evaluating topotecan(Drug information on topotecan) (Hycamtin) in patients with pancreatic cancer have been reported. Scher et al treated 35 patients with pancreatic cancer and no prior chemotherapy using a schedule of topotecan (1.5 mg/m2 daily ´ 5) as a short intravenous infusion. Cycles were repeated every 3 weeks. Among 30 evaluable patients, there were 2 partial responders (10%) and 11 additional patients (36%) with stable disease. The median survival for all evaluable patients was 19 weeks. O’Reilly et al evaluated 27 similar patients using an identical regimen of topotecan. They saw no responses among these patients. In this series, the median survival was 17.5 weeks.
Two other trials have evaluated topotecan as a 21-day continuous infusion in patients with previously untreated pancreatic cancer. Maino et al saw no responders among 15 patients treated with topotecan at 0.7 mg/m2/d, whereas Stevenson reported 2 partial responders (8%) and 3 additional patients (12%) with stable disease among 26 patients treated with topotecan at 0.5 to 0.6 mg/m2/d. The median survival, which was 20 weeks in the Stevenson series, was not reported by Maino et al.
Irinotecan has also been tested for pancreatic cancer by at least two groups of investigators. Wagener et al enrolled 34 previously untreated European patients with advanced pancreatic cancer in their study. Irinotecan(Drug information on irinotecan) was infused at 350 mg/m2 over 30 minutes once every 3 weeks. Among 32 evaluable patients, there were 3 partial responses (9%). Thirteen additional patients (39%) had stable disease. The median survival was 5.2 months.
Sakata et al treated 61 patients with advanced pancreatic cancer with either 100 mg/m2 of irinotecan weekly or 150 mg/m2 of irinotecan every 2 weeks. A total of 35 patients were reported to be evaluable for response. Four patients responded, for an overall response rate of 11.4%. Responses were seen in patients with both primary lesions (3 of 29; 10.3%) and liver metastases (2 of 19; 10.5%). Fifteen additional patients (42%) had a minor response or no change as their best response.
These trials suggest that topoisomerase I inhibitors are active in patients with advanced pancreatic cancer. The objective response rates and median survivals are similar to those seen with gemcitabine. However, no randomized trials comparing gemcitabine with any of the topoisomerase I agents in patients with cancer of the pancreas have been reported thus far.
Combination Chemotherapy With Gemcitabine and Irinotecan
There are several reasons to consider combining gemcitabine and irinotecan. Both agents are active in a variety of solid tumors and can be administered on a weekly schedule. They demonstrate complementary, rather than overlapping, dose-limiting toxicities.
Theoretically, the topoisomerase I-dependent single-strand breaks stabilized by irinotecan offer sites for insertion of gemcitabine triphosphate during religation of DNA. In addition, preclinical studies by Bahadori et al have demonstrated synergistic cytotoxicity for the combination of gemcitabine and irinotecan in a variety of cell lines. For these reasons, we began a phase I evaluation of gemcitabine and irinotecan in 1997.
In our phase I trial of 19 patients,[16,17] a schedule of administration of days 1 and 8 every 3 weeks was used for both drugs. The dose of gemcitabine was fixed from the outset at 1,000 mg/m2 on days 1 and 8. The initial dose of irinotecan was 50 mg/m2 on days 1 and 8. Additional cohorts were treated at 75, 100, and 115 mg/m2. In each case, gemcitabine was given first over 30 minutes, followed immediately by a 90-minute infusion of irinotecan. The recommended phase II dose for further testing was 1,000 mg/m2 of gemcitabine and 100 mg/m2 of irinotecan, with each drug given on days 1 and 8 every 3 weeks.
The phase I trial population included seven previously untreated patients. Three patients with pancreatic cancer were treated with 100 or 115 mg/m2 of irinotecan. A fourth previously untreated patient, also treated with 115 mg/m2, had an adenocarcinoma of an unknown primary site, multiple liver metastases, and small bilaterally pulmonary nodules. The origin was presumed to be intra-abdominal, either pancreatic or biliary.
Among these four patients, three experienced partial responses lasting for 6, 12, and 13+ cycles of gemcitabine and irinotecan. Dose-limiting diarrhea occurred in two of seven patients treated at the 115-mg/m2 dose. Therapy for the individual with the adenocarcinoma of an unknown primary site was discontinued after the 13th cycle because of cumulative myelosuppression. Four months later, his disease recurred. He was again treated with the irinotecan combination, supported with granulocyte colony-stimulating factor, with good blood count tolerance and re-regression of disease. The previously untreated patient with pancreatic cancer who did not achieve a partial response (50% regression in the sum of the products of the perpendicular diameters of all measured lesions) had an excellent clinical benefit, with disappearance of pain and marked improvement in performance status that lasted for eight cycles of chemotherapy.
Based on the preclinical data and our phase I experience, a multi-institutional phase II trial of irinotecan was initiated. The recommended phase II dose of gemcitabine was 1,000 mg/m2 and of irinotecan was 100 mg/m2 on days 1 and 8 every 3 weeks. For patients who did not experience more than grade 1 nonhematologic toxicity or more than grade 2 hematologic toxicity during the first cycle of chemotherapy, the dose of irinotecan was escalated to 115 mg/m2 in subsequent cycles.
Eligibility criteria included previously untreated measurable or evaluable pancreatic carcinoma, performance status of 0 to 2, an absolute neutrophil count of 1,500/L and a platelet count of 100,000/L, creatinine level of 2.0 mg/dL, bilirubin of 1.5 mg/dL, and an SGOT (serum glutamic oxaloacetic transaminase) two times the upper limit of normal.
A total of 45 patients (27 men, 18 women) with locally advanced and metastatic pancreatic cancer were treated at eight sites. Median patient age was 60 years (range: 31 to 89 years). Three patients had undergone prior radiation.
Nine patients (20%) experienced a tumor response. A greater than 50% reduction in CA 19-9 from the pretreatment value to nadir measurement during chemotherapy occurred in 13 (32.5%). Median time to treatment failure was 2.9 months (range: 0.1 to 11.3+ months). Median survival was 6.0 months (range: 0.9 to 12.2+ months).
Toxicity was modestonly 4.2% experienced grade 3/4 vomiting, and 6.7% experienced grade 3/4 diarrhea. Grade 3/4 neutropenia was reported in 15.5% of patients, and grade 3/4 neutropenia was observed in 8.9%. No toxic deaths or neutropenic fever occurred.
Current phase II data suggest that topoisomerase I inhibitors have modest antitumor activity in patients with locally advanced or metastatic cancer of the pancreas. Preclinical data in several cell lines demonstrate synergy when gemcitabine and the topoisomerase I inhibitor irinotecan are used simultaneously. In our own phase I experience with the combination of gemcitabine and irinotecan, two of three previously untreated patients with pancreatic cancer achieved a partial response. For phase II testing, 1,000 mg/m2 of gemcitabine and 100 mg/m2 of irinotecan administered on days 1 and 8 every 3 weeks is recommended. Preliminary, single-institution data from a larger phase II study appear to support our phase I experience with the irinotecan/gemcitabine combination in previously untreated patients with pancreatic cancer.
Based on phase II results, patient accrual has begun at 75 institutions for a phase III trial of irinotecan and gemcitabine vs gemcitabine alone as first-line therapy for advanced and metastatic pancreatic cancer.