Lung Cancer 28 (2000) 63 – 68 www.elsevier.nl/locate/lungcan
Paclitaxel/ifosfamide or navelbine/ifosfamide chemotherapy for advanced non-small cell lung cancer: CALGB 9532 Michael C. Perry a,*, Daniel C. Ihde b, James E. Herndon II c, Michael L. Grossbard d, Sara J. Grethein e, James N. Atkins f, Everett E. Vokes g, Mark R. Green h a
Di6ision of Hematology/Oncology, Room 524, Uni6ersity of Missouri/Ellis Fischel Cancer Center, 115 Business Loop 70 W, Columbia, MO, USA b Washington Uni6ersity Jewish Hospital, St Louis, MO, USA c CALGB Statistical Center, Durham, NC, USA d Massachusetts General Hospital, Boston, MA, USA e SUNY Health Science Center at Syracuse, Syracuse, NY, USA f Wake Forest Uni6ersity School of Medicine, Winston-Salem, NC, USA g Uni6ersity of Chicago Medical Center, Chicago, IL, USA h Medical Uni6ersity of South Carolina, Charleston, SC, USA Received 2 August 1999; received in revised form 18 November 1999; accepted 24 November 1999
Abstract In order to explore non-cisplatin containing regimens for advanced non-small cell lung cancer, Cancer and Leukemia Group B conducted a randomized Phase-II study of two novel combinations, paclitaxel/ifosfamide and vinorelbine/ifosfamide. Both regimens were active with a 38% response rate (95% CI: 24%, 53%) and 31% (95% CI: 18%, 47%), respectively. Median survivals were 8.5 and 7.4 months. Toxicity, mostly neutropenia, was acceptable. These two combinations establish a ‘proof of principle’ that non-cisplatin containing regimens also have activity in this setting. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Non-small cell lung cancer; Non-cisplatin containing regimens; Paclitaxel/ifosfamide; Vinorelbine/ifosfamide
The authors carried out this study for the Cancer and Leukemia Group B, Chicago, IL. * Corresponding author. Tel.: + 573-882-4979; fax: + 573884-6050. E-mail address: [email protected]
Non-small lung cancer (NSCLC) is responsible for more cancer deaths in the United States than the combined annual number of deaths from colorectal, breast, and prostate cancers, the malignant neoplasms which are currently the second, third, and fourth leading causes of cancer death .
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Among the most useful chemotherapeutic agents in this disease are those of the platinum family, in particular cisplatin and carboplatin . Unfortunately, the toxicity profile of cisplatin includes neurotoxicity, nephrotoxicity, and ototoxicity, which can sometimes be both severe and protracted. A search for similar but less toxic agents then lead to the development of carboplatin. Carboplatin is associated with less nausea, emesis, and neurotoxicity than cisplatin, but has more myelosuppression. Several large cooperative groups, particularly in the US, have continued to utilize cisplatin, at least partially related to the fact that a large meta-analysis of 52 randomized trials in non-small cell lung cancer uniformly utilized cisplatin as the control drug . The current standard of care in the United States for treatment of advanced nonsmall cell lung cancer has been to use either cisplatin or carboplatin in combination with another cytotoxic drug with a different mechanism of action. To expand the repertoire of active combinations against non-small cell lung cancer beyond platinum-based regimens, investigators at the University of Chicago and elsewhere began to develop chemotherapy regimens which did not include members of the platinum family . A Phase-I study of dose escalation involving vinorelbine (daily ×3 to maximum tolerated dose) and ifosfamide (2 g/m2 on days 1 – 3) required G-CSF support. Cycles were repeated every 21 days. Forty-two patients were entered, all but one with performance status of 0 or 1. Despite the use of G-CSF dose-limiting toxicities were neutropenia and sepsis at a maximum-administered vinorelbine dose of 35 mg/m2 for 3 days, combined with ifosfamide at 1.6 gm/M2 on days 1 – 3. The overall response rate was 40%, with a 1 year survival of 48%. Pharmacokinetic analysis showed that vinorelbine was cleared 1.5 – 2 times faster than in single agent once-weekly studies. At nearly the same time, the University of Chicago also performed a Phase-I study of ifosfamide and paclitaxel with G-CSF support . Again, a fixed dose of ifosfamide at 1.6 g/m2 thrice daily was given, with paclitaxel dosing escalated until the MTD was defined in an effort to
determine the maximum tolerated dose of paclitaxel with G-CSF support. Cycles were repeated every 21 days. Thirty-one patients with non-small cell lung cancer were entered. The dose-limiting toxicity was granulocytopenia, which increased with increasing doses of paclitaxel. Other toxicities were generally mild. Ifosfamide plus paclitaxel appeared to be an active treatment regimen, with a 23% response rate in all patients who received paclitaxel doses of 250 mg/m2 or higher. One-year survival was 25%. Further investigation of these two regimens was felt to be warranted. The study reported here was designed as a randomized phase-II trial of two non-cisplatin containing chemotherapy regimens, vinorelbine/ ifosfamide and paclitaxel/ifosfamide in advanced NSCLC. This study was open for patient accrual from 15 July 1995 through 15 July 1996.
2. Materials and methods
2.1. Patient selection Eligibility criteria included histologic documentation of NSCLC, stage IIIB or IV disease, no prior chemotherapy, measurable or evaluable disease, age \ 18 years, performance score of 0–1 (CALGB criteria), and provision of informed consent. Required laboratory data included: granulocytes \ 1800/ml, platelets \ 100 000/ml, creatinine B2× upper limit of normal (ULN), and bilirubinB1.5× ULN. Patients were excluded for central nervous system metastases, stage IIIB disease eligible for other CALGB protocols of combined CT/RT, history of prior cancer, or other serious medical/ psychiatric illnesses.
2.2. Therapy Chemotherapy on regimen I consisted of paclitaxel 250 mg/m2 over 3 h on day 1, with ifosfamide 1.6 Gm/m2 IV bolus on days 1, 2, 3; mesna 400 mg/m2 IV was given with ifosfamide, and again 4 and 6 h later. G-CSF was given at 5 mg/kg/day SQ days 6 through ANC\ 10 000/ml. Therapy was repeated every 21 days for six cycles
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unless tumor progression, unacceptable toxicity, or patient refusal occurred. Chemotherapy on regimen II consisted of vinorelbine 30 mg/m2 over 6 – 10 min on days 1,2, and 3, with ifosfamide 1.6 Gm/m2 IV bolus on days 1, 2, 3; mesna 400 mg/m2 IV was given with ifosfamide, and again 4 and 6 hours later. G-CSF was given at 5 mg/kg/day SQ days 6 through ANC\10 000/ml. Therapy was repeated every 21 days for six cycles unless tumor progression, unacceptable toxicity, or patient refusal occurred.
2.3. Statistical methods The primary goal of this study was to evaluate the activity of two chemotherapy regimens, paclitaxel/ifosfamide and vinorelbine/ifosfamide in patients with stage IIIB/IV or recurrent non-small cell lung cancer. For each treatment regimen, the study was designed to differentiate between a 14% level of activity (P B 0.15) and a 30% level of activity (P] 0.3). Forty-five patients were to be accrued to each arm, and if fewer than ten patients responded (complete response, partial response, or regression of evaluable disease), the null hypothesis would be accepted, and it would be concluded that that arm did not have sufficient activity to merit further investigation. The study was designed with a =b =0.1, i.e. the probability of concluding that the treatment is ineffective (P5 0.14) when in reality P ]0.3 (or vice versa) is 0.10. Kaplan–Meyer curves were used to describe survival and failure-free survival. Survival was defined as the time between study entry and death or last known follow-up. Failure-free survival was computed as the time between entry and disease progression, death or last known follow-up. Toxicities were tabulated by the most severe occurrence experienced by each individual patient. Standard criteria for response, progression, and relapse were used. Complete response required disappearance of all measurable or evaluable disease, signs, symptoms, and biochemical changes related to the tumor, lasting at least 4 weeks post-therapy, during which time no new lesions could appear. Partial response required a reduction of ] 50% in the sum of the products of the
perpendicular diameters of all measurable lesions lasting at least 4 weeks post-therapy, during which time no new lesions could appear and no existing lesion could progress. Regression of evaluable disease implied a definite decrease in tumor size agreed upon by two independent investigators, and no new lesions for \ 8 weeks. Stable disease implied a B 50% reduction and a B 25% increase in the sum of the products of two perpendicular diameters of all measured lesions, and the appearance of no new lesions for \ 8 weeks. Progression or relapse required an increase in the product of the perpendicular diameters of any measured lesion by \25% over the size present at entry on study.
2.4. Patient characteristics One-hundred patients were accrued. Two patients were deemed ineligible because of a PS of 2, and five patients never received protocol treatment (one patient withdrew consent, three patients were determined to be ineligible after study registration but before treatment initiation, and one patient for unknown reasons). With these patients excluded from analyses, the outcomes from 93 patients (48 on paclitaxel/ifosfamide and 45 vinorelbine/ifosfamide) were examined. Included were 59 men (63%) and 34 women (37%). Eighty-four percent had stage-IV or recurrent disease. Median age was 63 years (range 32–81). Thirty patients (32%) had a performance score of 0. Sixty-seven percent (63) of patients had a weight loss of B 5%.
3. Results Eighteen of 48 (38%; 95% confidence interval: 24%, 53%) patients in the paclitaxel/ifosfamide arm had either a complete (2) or a partial response (16). Median survival for the 48 patients was 8.5 months with a median failure-free survival of 4.8 months. (Figs. 1 and 2) A 1-year survival estimate of 35% (95% CI: 24%, 52%) was observed. Fourteen of 45 eligible patients (31%, 95%
M.C. Perry et al. / Lung Cancer 28 (2000) 63–68
Fig. 1. Probability of survival by treatment regime.
confidence interval: 18%, 47%) on the vinorelbine/ ifosfamide arm had either a complete response (2), a partial response (11),or regression of evaluable disease (1). Median survival for the 45 pa-
tients was 7.4 months (95% CI: 5.3, 13.3 months) with a median failure-free survival of 2.4 months. (Figs. 1 and 2). A one-year survival estimate of 38% (95% CI: 26%, 55%) was observed.
Fig. 2. Probability of failure-free survival by treatment regime.
M.C. Perry et al. / Lung Cancer 28 (2000) 63–68 Table 1 Maximum toxicities reported (grades 3 or 4) Toxicity
Paclitaxel/ ifosfamide (%)
Vinorelbine/ ifosfamide (%)
WBC Granulocytes/ Bands Lymphocytes Infection Hemoglobin Dyspnea Motor Constipation Pain Malaise/fatigue Hyperglycemia
67 17 13 14 8 2 2 12 10
73 24 20 4 13 11 15 22 0
The non-cisplatin doublets evaluated in this randomized phase II trial show response rates and survivals similar to the cisplatin combinations. However, their cost, inconvenience, and toxicity make them poor choices for front-line therapy. What has been demonstrated is a ‘proof of principle’ that patients with non-small lung cancer now have additional options other than compounds drawn from the cisplatin family. In fact, it may be possible that one of the combinations discussed in this section could eventually be incorporated into standard therapy for non-small cell lung cancer, particularly if non-cross-resistant combinations are used in an attempt to increase responses and survival.
3.1. Toxicity The most frequent grade 3 or 4 toxicities with the paclitaxel/ifosfamide treatment arm were: neutropenia (59%), infections (17%), dyspnea (14%) anemia (13%), malaise/fatigue (12%), hyperglycemia (10%), and sensorimotor (8%). All other grade 3 or 4 toxicities were seen in B 10% of patients. There was one treatment-related death, from respiratory failure (see Table 1). Forty-three patients (96%) on the vinorelbine/ ifosfamide arm had at least one grade 3 or 4 toxicity of neutropenia, with 24% infections. Twenty percent of patients had grade 3 falls in hemoglobin, and 22% had malaise/fatigue of grade 3 or 4. Fifteen percent reported grade 3 or 4 pain, 11% of patients had grade 3 or 4 constipation, and 13% had sensorimotor toxicity. Other grade 3 or 4 toxicities were seen in less than 10% of patients. There was one treatment-related death due to neutropenic fever.
4. Discussion Chemotherapy of non-small cell lung cancer has, in most instances, been based on cisplatin and its congeners. Response rates range from 20 – 50% for various combinations, depending upon patient characteristics and other factors.
The authors wish to thank James W. Box and Elizabeth T. James for their assistance with data management. The research for CALGB 9532 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chairman). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. The following institutions participated in the study: CALGB Statistical Office, Durham, NC — Stephen George, PhD, supported by CA33601; Community Hospital-Syracuse CCOP, Syracuse, NY — Jeffrey Kirshner, MD, supported by CA45389; Dana Farber Cancer Institute, Boston, MA — George P. Canellos, MD, supported by CA32291; Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, NH — L. Herbert Maurer, MD, supported by CA04326; Duke University Medical Center, Durham, NC–Jeffrey Crawford, MD, supported by CA47577; Green Mountain Oncology Group CCOP, Bennington, VT — H. James Wallace Jr, MD, supported by CA35091;
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Long Island Jewish Medical Center, Lake Success, NY — Marc Citron, MD, supported by CA11028; Massachusetts General Hospital, Boston, MA — Michael L. Grossbard, MD, supported by CA12449; Mount Sinai Medical Center CCOP-Miami, Miami Beach, FL — Enrique Davila, MD, supported by CA45564; Mount Sinai School of Medicine, New York, NY — James F. Holland, MD, supported by CA04457; South New Jersey CCOP, Camden, NJ — Jack Goldberg, MD, supported by CA54697; Southeast Cancer Control Consortium CCOP, Goldsboro, NC — James N. Atkins, MD, supported by CA45808; Southern Nevada Cancer Research Foundation CCOP, Las Vegas, NV — John Ellerton, MD, supported by CA35421; SUNY Health Science Center at Syracuse, Syracuse, NY — Stephen L. Graziano, MD, supported by CA21060; University of Alabama Birmingham, Birmingham, AL — Robert Diasio, MD, supported by CA47545; University of California at San Diego, San Diego, CA — Stephen L. Seagren, MD, supported by CA11789; University of California at San Francisco, San Francisco, CA — Alan P. Venook, MD, supported by CA60138; University of Iowa Hospitals, Iowa City, IA —
Gerald H. Clamon, MD, supported by CA47642; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO — Michael C. Perry, MD, supported by CA12046; University of Tennessee Memphis, Memphis, TN — Harvey B. Niell, MD, supported by CA47555; Vermont Cancer Center, Burlington, VT — Hyman B. Muss, MD, supported by CA77406; Wake Forest University School of Medicine, Winston-Salem, NC — David D. Hurd, MD, supported by CA03927; Washington University School of Medicine, St Louis, MO — Nancy L. Bartlett, MD, supported by CA77440.
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