Irinotecan/Gemcitabine Followed by Twice-Weekly Gemcitabine/Radiation in Locally Advanced Pancreatic Cancer

May 2, 2002

Early clinical studies combining irinotecan (CPT-11, Camptosar) and gemcitabine (Gemzar) have yielded encouraging results. Gemcitabine administered via a twice-weekly schedule results in an enhanced radiation-sensitizing effect.

ABSTRACT: Early clinical studies combining irinotecan (CPT-11, Camptosar) and gemcitabine (Gemzar) have yielded encouraging results. Gemcitabine administered via a twice-weekly schedule results in an enhanced radiation-sensitizing effect. This multi-institution phase II trial of induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation has been initiated to determine the activity of this regimen in patients with unresectable pancreatic cancer. Patients received two cycles of induction irinotecan (100 mg/m² IV) and gemcitabine (1,000 mg/m² IV) on days 1 and 8 of each 3-week cycle. Following the induction therapy, patients without disease progression received twice-weekly gemcitabine at 40 mg/m² and radiation. Nine patients have been enrolled in the study to date. Median patient age was 71 years (range: 65-85 years). The major toxicity observed thus far was grade 3/4 neutropenia. Grade 3/4 nonhematologic toxicity was rarely observed and included dehydration (12%) and diarrhea (12%), which were likely related to the irinotecan. No treatment-related deaths have occurred. These preliminary data suggest that this regimen is well tolerated. Although the data are limited, tumor progression during the induction chemotherapy has not been observed thus far (radiographically or biochemically [CA-19-9]). [ONCOLOGY 16(Suppl 5):25-28, 2002]

In 2002, an estimated 30,300 new cases of pancreaticcancer will be diagnosed, and 29,700 people will die from the disease. Theoverall 5-year survival rate for patients with pancreatic cancer ranges fromless than 1% to less than 5% with little improvement in survival observed in thepast 20 years.[1] Approximately two-thirds of all pancreatic cancer patientshave metastatic disease at the time of diagnosis,[2,3] while the majority of theremaining patients have locally advanced unresectable disease.[4,5]

Several chemotherapeutic agents have been evaluated either alone or incombination in patients with metastatic pancreatic cancer, but the resultscontinue to be disappointing: reproducible objective response rates range from0% to 20% and median survival times are less than 6 months.[6-9] Results forpatients presenting with locally advanced (nonmetastatic) unresectable diseasehave also been disappointing. The combination of concurrent fluorouracil (5-FU)and ionizing radiation therapy for patients with unresectable disease hasresulted in a twofold increase in median survival: approximately 10 months vs 5months.[10-12] Despite these limited benefits, many consider external beamradiation and concurrent 5-FU as the standard therapy for locally advancedpancreatic cancer.

In an attempt to improve systemic disease control, which could possiblyimpact overall survival, investigators at several centers are testingneoadjuvant chemotherapy strategies. Such strategies have potential advantagesfor patients with pancreatic cancer. The morbidity of definitive chemoradiationis not insignificant, and can thwart the possibility of using systemicchemotherapy. In addition, preoperative chemotherapy allows the oncologist toidentify those patients with aggressive disease who are destined to progressquickly—specifically, patients with micrometastatic disease who are lesslikely to benefit from a course of locoregional chemoradiotherapy. Whileinduction chemotherapy has several potential advantages, a challenge forinvestigators is to discover a regimen with consistent activity in pancreaticcancer.

Irinotecan/Gemcitabine for Advanced Pancreatic Cancer

Results of phase I and II clinical trials have demonstrated that single-agentirinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin[CPT-11, Camptosar]), a camptothecin analog, has activity in pancreatic cancer.In previously untreated patients with advanced pancreatic cancer, Sakata et alreported an 11% partial response rate (4 out of 35 patients) using irinotecan at100 mg/m²/wk or 150 mg/m² every other week.[13] Wagener et al observed threepartial responses among 32 patients (9%) with pancreatic cancer who receivedirinotecan at 350 mg/m² by 30-minute intravenous infusion every 3 weeks.[14]Response durations were 7.2, 7.5, and 7.8 months.

In contrast, O’Reilly et al evaluated topotecan (Hycamtin), anothertopoisomerase I inhibitor, in 27 previously untreated advanced pancreatic cancerpatients, and noted no responses.[15] Scher et al, however, reported three (10%)partial responders in a similar patient cohort receiving a comparable topotecandosing schedule. Additional information on this combination has been discussedby Rocha Lima et al elsewhere in this supplement.

Use of a gemcitabine/irinotecan combination regimen seems attractive, basedon the complementary toxicity profiles, different mechanisms of cytotoxicity,and overlapping antitumor activity spectra of the two compounds.[16]

Concurrent Radiation and Gemcitabine

Early results of limited phase I/II trials that combined radiation andgemcitabine have been reported.[17-20] Data from a phase I study from WakeForest University/University of North Carolina Chapel Hill determined that themaximum tolerated dose of concurrent twice-weekly gemcitabine with upperabdominal radiation was 40 mg/m² given each Monday and Thursday of theradiation.[21] The preliminary Cancer and Leukemia Group B report of thisregimen in the phase II setting indicated that it was safe and feasible. Whileonly four local (in-field) failures were observed, systemic disease progressionlimited median survival to 13.7 months and 7.8 months in patients with EasternCooperative Oncology Group (ECOG) performance status of 0 and 1 to 2,respectively.

These data support that gemcitabine/irinotecan is an active systemic regimenin pancreatic cancer and that radiation with concurrent twice-weekly gemcitabineprovides effective local tumor control for patients with locally advancedpancreatic cancer. The phase II trial reported herein is assessing the effectsof these regimens used in combination for patients with locally advanced,unresectable pancreatic cancer. The trial objectives are to determine time todisease progression, local control, and survival for patients receivinginduction gemcitabine/irinotecan followed by twice-weekly gemcitabine andconcurrent radiation.

Materials and Methods

Patient Eligibility and Treatment

Eligibility criteria are outlined in Table1. Patients with nonmetastatic,unresectable pancreatic cancer were eligible for study entry. ECOG performancestatus of 1 to 2 and life expectancy of at least 6 months were required, as werenormal laboratory assessments of granulocyte, hemoglobin, platelet, and serumcreatinine levels. All patients provided written informed consent.

Patients received two cycles of induction chemotherapy consisting ofirinotecan at 100 mg/m² IV over 90 minutes and gemcitabine at 1,000 mg/m² IVover 30 minutes on days 1 and 8 of each 3-week cycle along with appropriatepremedications and hydration. Following induction therapy, patients withoutdisease progression received twice-weekly gemcitabine at 40 mg/m² on each Mondayand Thursday of the radiation (Figure 1).

Radiation therapy consisted of an initial 45 Gy in 180-cGy daily fractionsdelivered to the tumor and peripancreatic nodal regions plus a 1.0- to 2.0-cmmargin (to account for setup variation, patient motion, and tumor volumeuncertainty). The celiac axis was treated at the discretion of the radiationoncologist. An additional 5.4-Gy boost was delivered in 180-cGy daily fractionsto the original tumor volume with a 1.0-cm margin. The fields were individuallydesigned and configured based on tumor volume and location. Four-field beamarrangements and 10- to 15-mV photon energies were required. In general, afour-field approach utilized anterior-posterior and left and right lateralbeams. The spinal cord dose was limited to 45 Gy.

Dose Modifications and Response and Toxicity Criteria

During induction chemotherapy, patients had irinotecan and gemcitabine dosesreduced or withheld if they experienced a nadir granulocyte count of less than1,500/µL or a platelet count of less than 100,000/µL (Table2). The irinotecandose was reduced 75% in cases of grade 2 diarrhea, and was withheld in patientswith grade 3 or 4 diarrhea. During concurrent chemoradiation, gemcitabine waswithheld in patients experiencing grade 2 or higher hematologic toxicity untilblood counts recovered.

Standard Response Evaluation Criteria in Solid Tumors (RECIST) criteria wereused for response determination. Toxicity was graded according to NationalCancer Institute Cancer Therapy Evaluation Program Common Toxicity Criteria,version 2.0. Patients were removed from the study if they had diseaseprogression, unacceptable toxicity as determined by the treating physician, or atreatment delay of greater than 2 weeks, or if they refused to participate.

Results

Patient Characteristics

Nine patients have been enrolled in the study to date, seven of whomcompleted therapy as planned: one patient refused further therapy after thefirst dose while a second patient is currently under treatment. Neither patientis assessable for toxicity or survival. The median patient age was 71 years(range: 65-85 years) and 33% of patients were female. Performance status was 0in four patients and 1 in five patients.

Efficacy

Two of eight patients (29%) had an objective response to treatment. Nocomplete responses were observed. All of the seven evaluable patients haveprogressed, with liver metastasis (n = 4) as the most common site of failure,followed by the lungs. One patient has progressed in the radiation field (14%)as the initial failure site. Median overall survival in this preliminaryanalysis is 9 months from registration (10 months from diagnosis). The medianpretreatment CA-19-9 level was 426 U/mL (range: 15-14,167 U/mL). A reductionin CA-19-9 from pretreatment of greater than 50% was observed in two patients,and that greater than 35% was observed in another two patients.

Toxicity

Seven patients were assessable for toxicity. The major toxicity was grade 3/4neutropenia (n = 3). Grade 4 thrombocytopenia and anemia occurred infrequently.Grade 3/4 nonhematologic toxicity was rarely observed and included dehydration(12%) and diarrhea (12%), which were likely related to the irinotecan. Notreatment-related deaths have occurred. Four of the seven patients required dosereductions or held doses. Two patients did not complete induction chemotherapyas planned due to neutropenia but did go on to receive the concurrenttwice-weekly gemcitabine and radiation. Four patients have completed all 10doses of twice-weekly gemcitabine, with thrombocytopenia representing thedose-limiting toxicity.

Conclusions

This is a preliminary report of a multicenter, phase II study of inductionirinotecan/gemcitabine chemotherapy followed by radiation and twice-weeklygemcitabine in patients with locally advanced pancreatic cancer. These earlyresults indicate that this approach is safe in such patients. The observed grade3/4 toxicities were limited to those expected in patients receiving irinotecanand gemcitabine, and were primarily gastrointestinal and hematologic in nature.Although the data so far are limited to eight patients, no local tumorprogression has been demonstrated radiographically, biochemically (CA-19-9), orclinically during the induction chemotherapy.

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