Synergy with no overlapping toxicities has been demonstrated for the combination of irinotecan ( Camptosar, CPT-11) and gemcitabine (Gemzar) in vitro. Results of a single-institution phase I study in which patients with
ABSTRACT: Synergy with no overlapping toxicities has been demonstrated for the combination of irinotecan ( Camptosar, CPT-11) and gemcitabine (Gemzar) in vitro. Results of a single-institution phase I study in which patients with previously untreated pancreatic cancer were given irinotecan and gemcitabine were promising, with two of three patients achieving a partial response. Because of the favorable outcome of the phase I study, a multicenter phase II trial was undertaken in previously untreated patients with pancreatic carcinoma. Data from other sites entering patients in this phase II study have been analyzed, and a multicenter phase III trial of single-agent gemcitabine vs the irinotecan combination in first-line treatment of patients with locally advanced or metastatic pancreatic cancer is underway. [ONCOLOGY 14(Suppl 14):31-33, 2000]
Carcinoma of the pancreas is among themost lethal of all solid tumors. In 2000, 28,200 deaths due to pancreatic cancerare expected to occur in the United States. Pancreatic cancer is the ninthleading 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 theUnited States, responsible for about 5% of all American cancer deaths occurringeach year. In the United States, the 5-year survival rate for all patients witha new diagnosis of pancreatic cancer is 4%, regardless of race or ethnicity.Worldwide, 170,000 cases and 168,000 deaths caused by pancreatic cancer areanticipated this year.
The efficacy of antitumor treatment of advanced pancreaticcarcinoma is modest. Prior to the recent approval of gemcitabine (Gemzar) asfirst-line therapy for patients with locally advanced or metastatic disease,there were little data to demonstrate a survival benefit for chemotherapycompared with best supportive care or for combination chemotherapy comparedwith fluorouracil (5-FU) alone.
In 1997, Burris et al reported the results of a phase IIItrial comparing gemcitabine and 5-FU chemotherapy in patients with locallyadvanced or metastatic pancreatic cancer who had not received priorchemotherapy. Gemcitabine was given at 1,000 mg/m2 weekly for up to sevenconsecutive weekly doses, followed by a 1-week rest period and then 1,000 mg/m2weekly for 3 out of 4 consecutive weeks. 5-FU was administered weekly as a 600mg/m2 bolus. The primary end point of this trial was clinical benefit response.Secondary end points were overall survival, response rate, and time toprogression of disease.
A total of 126 patients were randomized to receive treatment: 63with gemcitabine and 63 with 5-FU. There were statistically significantimprovements in the frequency of clinical benefit, time to progression ofdisease, and overall survival favoring therapy with gemcitabine. These data andthe results of a parallel phase II trial of gemcitabine alone in patients withpancreatic cancer and prior 5-FU-based chemotherapy led to the approval ofgemcitabine for first- and second-line therapy.
Despite the approval of gemcitabine for first- and second-linetherapy for pancreatic cancer, the outlook for the large majority of patientsremains unfavorable. The frequency of a clinically beneficial response withfirst-line therapy with gemcitabine in patients with pancreatic cancer was 24%.The median survival was 5.7 months, and the objective response rate was adisappointing 5.4%. Given these data, it is obvious that new agents andcombinations need to be explored as first-line therapy for this disease.
Three topoisomerase I inhibitors have been evaluated in patientswith advanced pancreatic cancer. Stehlin et al used 9-nitrocamptothecin in107 patients with advanced disease. Among 60 patients who received at least twocycles of therapy, "response" (an amalgam of objective tumorregression, marker falls, and clinical benefit) was reported in 32% of patients.Another 32% were called "stable." The reported median survival among57 previously untreated patients was 7.3 months.
At least four phase II trials evaluating topotecan (Hycamtin) inpatients with pancreatic cancer have been reported. Scher et al treated 35patients with pancreatic cancer and no prior chemotherapy using a schedule oftopotecan (1.5 mg/m2 daily ´ 5) as a short intravenous infusion. Cycles wererepeated every 3 weeks. Among 30 evaluable patients, there were 2 partialresponders (10%) and 11 additional patients (36%) with stable disease. Themedian survival for all evaluable patients was 19 weeks. O’Reilly et alevaluated 27 similar patients using an identical regimen of topotecan. They sawno responses among these patients. In this series, the median survival was 17.5weeks.
Two other trials have evaluated topotecan as a 21-day continuousinfusion in patients with previously untreated pancreatic cancer. Maino etal saw no responders among 15 patients treated with topotecan at 0.7 mg/m2/d, whereas Stevenson reported 2 partial responders (8%) and 3additional patients (12%) with stable disease among 26 patients treated withtopotecan at 0.5 to 0.6 mg/m2/d. The median survival, which was 20 weeks in theStevenson series, was not reported by Maino et al.
Irinotecan has also been tested for pancreatic cancer by atleast two groups of investigators. Wagener et al enrolled 34 previouslyuntreated European patients with advanced pancreatic cancer in their study.Irinotecan was infused at 350 mg/m2 over 30 minutes once every 3 weeks. Among 32evaluable patients, there were 3 partial responses (9%). Thirteen additionalpatients (39%) had stable disease. The median survival was 5.2 months.
Sakata et al treated 61 patients with advanced pancreaticcancer with either 100 mg/m2 of irinotecan weekly or 150mg/m2 of irinotecanevery 2 weeks. A total of 35 patients were reported to be evaluable forresponse. 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%) andliver metastases (2 of 19; 10.5%). Fifteen additional patients (42%) had a minorresponse or no change as their best response.
These trials suggest that topoisomerase I inhibitors are activein patients with advanced pancreatic cancer. The objective response rates andmedian survivals are similar to those seen with gemcitabine. However, norandomized trials comparing gemcitabine with any of the topoisomerase I agentsin 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 andirinotecan. Both agents are active in a variety of solid tumors and can beadministered on a weekly schedule. They demonstrate complementary, rather thanoverlapping, dose-limiting toxicities.
Theoretically, the topoisomerase I-dependent single-strandbreaks stabilized by irinotecan offer sites for insertion of gemcitabinetriphosphate during religation of DNA. In addition, preclinical studies byBahadori et al have demonstrated synergistic cytotoxicity for thecombination of gemcitabine and irinotecan in a variety of cell lines. For thesereasons, we began a phase I evaluation of gemcitabine and irinotecan in 1997.
In our phase I trial of 19 patients,[16,17] a schedule ofadministration of days 1 and 8 every 3 weeks was used for both drugs. The doseof gemcitabine was fixed from the outset at 1,000 mg/m2 on days 1 and 8. Theinitial dose of irinotecan was 50 mg/m2 on days 1 and 8. Additional cohorts weretreated at 75, 100, and 115 mg/m2. In each case, gemcitabine was given firstover 30 minutes, followed immediately by a 90-minute infusion of irinotecan. Therecommended phase II dose for further testing was 1,000 mg/m2 of gemcitabine and100 mg/m2 of irinotecan, with each drug given on days 1 and 8 every 3 weeks.
The phase I trial population included seven previously untreatedpatients. Three patients with pancreatic cancer were treated with 100 or 115mg/m2 of irinotecan. A fourth previously untreated patient, also treated with115 mg/m2, had an adenocarcinoma of an unknown primary site, multiple livermetastases, and small bilaterally pulmonary nodules. The origin was presumed tobe intra-abdominal, either pancreatic or biliary.
Among these four patients, three experienced partial responseslasting for 6, 12, and 13+ cycles of gemcitabine and irinotecan. Dose-limitingdiarrhea occurred in two of seven patients treated at the 115-mg/m2 dose.Therapy for the individual with the adenocarcinoma of an unknown primary sitewas discontinued after the 13th cycle because of cumulative myelosuppression.Four months later, his disease recurred. He was again treated with theirinotecan combination, supported with granulocyte colony-stimulating factor,with good blood count tolerance and re-regression of disease. The previouslyuntreated patient with pancreatic cancer who did not achieve a partial response(50% regression in the sum of the products of the perpendicular diameters of allmeasured lesions) had an excellent clinical benefit, with disappearance of painand marked improvement in performance status that lasted for eight cycles ofchemotherapy.
Based on the preclinical data and our phase I experience, amulti-institutional phase II trial of irinotecan was initiated. Therecommended phase II dose of gemcitabine was 1,000 mg/m2 and of irinotecan was100 mg/m2 on days 1 and 8 every 3 weeks. For patients who did not experiencemore than grade 1 nonhematologic toxicity or more than grade 2 hematologictoxicity during the first cycle of chemotherapy, the dose of irinotecan wasescalated to 115 mg/m2 in subsequent cycles.
Eligibility criteria included previously untreated measurable orevaluable pancreatic carcinoma, performance status of 0 to 2, an absoluteneutrophil count of 1,500/L and a platelet count of 100,000/L, creatinine levelof 2.0 mg/dL, bilirubin of 1.5 mg/dL, and an SGOT (serum glutamic oxaloacetictransaminase) two times the upper limit of normal.
A total of 45 patients (27 men, 18 women) with locally advancedand metastatic pancreatic cancer were treated at eight sites. Median patient agewas 60 years (range: 31 to 89 years). Three patients had undergone priorradiation.
Nine patients (20%) experienced a tumor response. A greater than50% reduction in CA 19-9 from the pretreatment value to nadir measurement duringchemotherapy occurred in 13 (32.5%). Median time to treatment failure was 2.9months (range: 0.1 to 11.3+ months). Median survival was 6.0 months (range: 0.9to 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 in15.5% of patients, and grade 3/4 neutropenia was observed in 8.9%. No toxicdeaths or neutropenic fever occurred.
Current phase II data suggest that topoisomerase I inhibitorshave modest antitumor activity in patients with locally advanced or metastaticcancer of the pancreas. Preclinical data in several cell lines demonstratesynergy when gemcitabine and the topoisomerase I inhibitor irinotecan are usedsimultaneously. In our own phase I experience with the combination ofgemcitabine and irinotecan, two of three previously untreated patients withpancreatic cancer achieved a partial response. For phase II testing, 1,000 mg/m2of gemcitabine and 100 mg/m2 of irinotecan administered on days 1 and 8 every 3weeks is recommended. Preliminary, single-institution data from a larger phaseII study appear to support our phase I experience with theirinotecan/gemcitabine combination in previously untreated patients withpancreatic cancer.
Based on phase II results, patient accrual has begun at 75institutions for a phase III trial of irinotecan and gemcitabine vs gemcitabinealone as first-line therapy for advanced and metastatic pancreatic cancer.
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