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Phase II Study of Irinotecan Plus Cisplatin in Patients With Advanced Non–Small-Cell Lung Cancer

From the Vanderbilt University, Nashville, TN; Duke University, Durham, NC; University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA; The Cancer Treatment and Research Center, San Antonio, TX; and Pharmacia & Upjohn, Kalamazoo, MI.

Address reprint requests to Russell F. DeVore III, MD, Vanderbilt University Medical Center, 1956 TVC, Nashville, TN 37232; email russell.devore{at}mcmail.vanderbilt.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate the antitumor efficacy and safety of a combination of irinotecan (CPT-11) and cisplatin in patients with inoperable non–small-cell lung cancer (NSCLC). A secondary objective was to characterize the pharmacokinetics and pharmacodynamics of CPT-11 and its active metabolite, SN-38.

PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC were treated with repeated 4-week courses comprising CPT-11 (60 mg/m²) administered on days 1, 8, and 15, and a single dose of cisplatin (80 mg/m²) after CPT-11 administration on day 1.

RESULTS: Fifty-two patients were enrolled, including 33 men and 19 women. The median age was 61 years (range, 29 to 79 years). Southwest Oncology Group performance status was 0 in 12 patients, 1 in 32 patients, and 2 in eight patients. Eleven and 41 patients had stage IIIB and IV disease, respectively. Objective responses occurred in 28.8% of patients (15 of 52; 95% confidence interval, 16.5% to 41.2%). The median survival duration was 9.9 months (range, 1.6 to 30.8 months). The 1-year survival rate was 37%. Grade 3/4 adverse events consisted primarily of nausea (32.7% ) or vomiting (13.5%), late-onset diarrhea (17.3%), and neutropenia (46.1%). The study design led to preferential modification of CPT-11 doses, resulting in CPT-11 dose attenuations to 40 mg/m² in the majority of patients (31 of 52; 60%), whereas dose reductions of cisplatin were uncommon. CPT-11 pharmacokinetic parameters were comparable to those reported previously in single-agent studies.

CONCLUSION: CPT-11/cisplatin is an active combination regimen with manageable toxicity in the therapy of stage IIIB/IV NSCLC. Future studies should be designed with schedules and dose modification provisions that avoid unnecessary CPT-11 dose reductions to exploit more directly the therapeutic synergy of these agents.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
MOST PATIENTS (70%) with non–small-cell lung cancer (NSCLC) have locally advanced or metastatic disease at the time of diagnosis.^1,2 Even in patients with resectable stages I and II disease, the 5-year survival rate is approximately 50%. When these patients recur, approximately 80% will recur at distant sites.² Current treatment recommendations for patients with inoperable NSCLC call for platinum-based chemotherapy plus radiation for patients with locally advanced disease and chemotherapy for patients with metastases.³ These regimens can modestly extend the length of survival in some patients. The fact remains that the prognosis is poor for the overwhelming majority of patients with inoperable NSCLC. In controlled studies, 5-year survival rates range from 5% to 30% for patients with stage III disease, and are even more unfavorable for patients with stage IV disease.³ Therefore, the development of effective systemic therapies is critical if a positive impact on long-term survival is to be achieved.

Irinotecan (CPT-11 [Camptosar; Pharmacia & Upjohn, Kalamazoo, MI]) is a water-soluble prodrug that is metabolized in vivo to an active metabolite, SN-38. SN-38 binds to topoisomerase-I, an enzyme that relieves torsional strain in DNA during DNA replication or transcription and stabilizes topoisomerase-I in a complex with DNA. During cell division, DNA replication forks collide with these enzyme—DNA complexes, resulting in double-stranded DNA breaks and subsequent programmed cell death.^4,5

CPT-11 has been approved by the United States Food and Drug Administration for the treatment of metastatic colorectal cancer refractory to fluorouracil.^6-12 CPT-11 also has shown activity in other tumor types, including gastric cancer,¹³ squamous cell cancer of the cervix,^14,15 pediatric and adult CNS tumors,¹⁶ non-Hodgkin's lymphoma,¹⁷ T-cell leukemia–lymphoma,¹⁸ and pancreatic cancer.¹⁹ In vitro studies have demonstrated the activity of CPT-11 in small-cell lung cancer and NSCLC cell lines,^20,21 and in vivo studies have documented the radiosensitizing properties of this agent in lung tumor xenografts.²² Preliminary data in humans suggest that CPT-11, as monotherapy or in combination with cisplatin, etoposide, or vindesine plus cisplatin, is active in metastatic NSCLC.^9,23-30

Because cisplatin is one of the most active chemotherapeutic agents for NSCLC, the combination of CPT-11 with cisplatin is a logical area of investigation. In this open-label, nonrandomized, multicenter phase II study, we assessed the antitumor activity and safety of CPT-11/cisplatin therapy in patients with newly diagnosed inoperable NSCLC and also evaluated the pharmacokinetics of CPT-11.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Adult patients were enrolled onto the study if they met the following criteria: (1) histologic diagnosis of NSCLC; (2) stage IIIB or IV disease (patients with recurrent disease that was stage IIIB or IV upon restaging after surgery were eligible); (3) bidimensionally measurable disease, at least one area of which had not been subject to prior irradiation; (4) no prior chemotherapy or immunotherapy; (5) completion of any previous radiation therapy more than 2 weeks before enrollment and recovery from any adverse effects; (6) performance status of 0, 1, or 2 according to the Southwest Oncology Group scale, with a predicted life expectancy of at least 12 weeks; and (7) adequate organ function as documented by granulocyte count > 1,500/mL, platelet count > 100,000/mL, hemoglobin level 9 g/dL, serum creatinine level 1.5 mg/dL, total bilirubin level 2.0 mg/dL, and serum AST three times the institutional upper limit of normal.

Patients were not eligible for study enrollment if they had any of the following: (1) active or uncontrolled infection; (2) significant cardiovascular disease (uncontrolled hypertension, unstable angina, active congestive heart failure, myocardial infarction within the previous 6 months, uncontrolled serious arrhythmia); (3) prior malignancies, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient had been disease-free for 5 years; (4) pregnancy, lactation, or refusal to use effective contraception; (5) CNS involvement with tumor; (6) pneumonitis or uncontrolled large pleural effusions; or (7) uncontrolled diabetes mellitus (random blood glucose 200 mg/dL).

All study candidates were required to provide written informed consent as approved by local institutional review boards before initiation of any study procedures.

Treatment and Patient Evaluation
Before treatment, patients underwent medical history and physical examination, electrocardiogram, audiometry, pulmonary function testing (including determinations of vital capacity, forced vital capacity, forced expiratory volume in one second, forced expiratory flow from 25% to 75% of vital capacity, and carbon monoxide diffusing capacity), laboratory evaluation (complete blood count, serum chemistries, and pregnancy testing for women of childbearing potential), and baseline tumor measurement.

CPT-11/cisplatin therapy was given in 4-week courses. CPT-11 was administered as a 90-minute intravenous infusion on days 1, 8, and 15 at a starting dose of 60 mg/m². Also on day 1, a 30-minute intravenous infusion of cisplatin 80 mg/m² was administered 2 hours after the completion of CPT-11. These doses and treatment schedule were based on prior experience developed by Masuda et al.²⁷

Patients received standard intravenous hydration with 5% dextrose in normal saline or normal saline for 2 hours before and 3 to 4 hours after cisplatin administration. In addition, patients received intravenous mannitol just before and immediately after the dose of cisplatin. Cholinergic symptoms that occurred during or within 1 hour after receiving CPT-11 were treated with atropine (1 mg or as needed).^31,32 Dexamethasone 10 mg was administered as part of the pretreatment antiemetic regimen unless a relative or absolute contraindication to corticosteroid use was identified. Additional antiemetic agents such as lorazepam, ondansetron, and granisetron were allowed, and the latter two agents were recommended before administration of each cisplatin dose. Loperamide was provided as therapy for delayed diarrhea.³³ Patients were instructed to begin taking loperamide at the first sign of diarrhea (ie, first poorly formed or loose stool, or first episode of one to two more bowel movements than usual in 1 day) that occurred more than 12 hours after CPT-11 administration. Loperamide was taken in the following manner: 4 mg at the first onset of diarrhea, then 2 mg every 2 hours around the clock until diarrhea-free for at least 12 hours. During the night, patients were allowed to take 4 mg every 4 hours.

For subsequent treatment courses, the CPT-11 dose could be increased to 80, 105, or 125 mg/m² in stepwise increments in patients who did not experience dose-limiting drug toxicity, or it could be reduced to 50 or 40 mg/m² in stepwise decrements) in patients who experienced grade 2 toxicity. All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria. Table 1 lists the CPT-11 dose modification criteria during a course of therapy and for the next course of therapy, respectively. Dose modification provisions for cisplatin were not defined prospectively. Patients were to be discontinued from study participation if they withdrew consent, had disease progression, experienced unacceptable drug toxicity not responding to dosage modification, or developed an intercurrent, non–cancer-related illness that prevented therapy continuation or regular follow-up evaluation.

Patients were evaluated on a regular basis during treatment. The following assessments were performed before each 4-week therapy course: physical examination, performance status, weight, and full serum chemistries. Assessments before administration of each CPT-11 dose and during rest weeks included complete blood count and medical history. Pulmonary function and audiometry were evaluated after every second course of therapy or more often if clinically indicated.

Tumor response was assessed according to World Health Organization criteria (ie, measurable disease, assessable disease, nonassessable disease; complete response, partial response, stable disease, and progressive disease).³⁴ Tumor reassessment by the same imaging method used to establish baseline tumor measurement was generally performed after every two courses of therapy. Previously irradiated lesions were excluded from evaluation for tumor response. Whenever possible, patients with evidence of tumor response were to have confirmation within 4 to 6 weeks after the initial documentation of response. In addition, time to response (time from start of therapy to first observation of objective response), duration of response (time from first observation of objective response to first observation of progressive disease), time to tumor progression (time from start of therapy to first observation of progressive disease), and survival (time from start of therapy to death) were measured.

Pharmacokinetics
Concentrations and pharmacokinetic parameters of CPT-11 and its metabolite, SN-38, were determined for 24 hours after the first CPT-11 infusion (week 1), and repeated, if possible, after the third infusion (week 3). A baseline blood specimen was drawn immediately before initiation of the CPT-11 infusion. Additional specimens were then obtained at the end of the CPT-11 infusion, and at 1, 2, 4, and 24 hours after completion of the infusion. Venous whole-blood specimens (7 mL) were drawn into heparinized tubes and placed immediately into a slurry of ice and water. Plasma was collected as soon as possible by centrifuging the specimens at 1,000 to 1,200 x g (-3,000 rpm) for 20 minutes and then stored at -70°C until analysis.

Human plasma specimens were assayed for total concentrations of CPT-11 and SN-38 using validated, sensitive, and specific isocratic high-performance liquid chromatography methods with fluorescence detection.³⁵ The lower limit of quantitation of CPT-11 (expressed as the free base) and SN-38 (expressed as the monohydrate) was 1.28 ng/mL and 0.480 ng/mL, respectively. The mean assay precision expressed as the coefficient of variation of the estimated concentrations of quality control standards averaged 7.5%, 7.5%, and 8.3%, respectively, for low (~ 13.1 ng/mL), medium (~ 131 ng/mL), and high (~ 3,280 ng/mL) concentrations of CPT-11, and better than 11.2%, 6.6%, and 7.6%, respectively, for low (~ 1.17 ng/mL), medium (~ 11.7 ng/mL), and high (~ 293 ng/mL) concentrations of SN-38. Assay accuracy, expressed as the ratio (%) of the estimated to the theoretical quality control standard concentrations, averaged 101.6% to 102.5% for CPT-11 and 103.3% to 105.9% for SN-38.

CPT-11 concentrations were expressed in free base units for pharmacokinetic analyses. The actual times of the initiation of drug infusion and of blood sampling were recorded, and the time interval relative to the start of drug infusion was used to calculate area under the concentration-time curves (AUC). CPT-11 and SN-38 plasma concentration data were analyzed by noncompartmental methods. The apparent terminal elimination rate constants (z) were determined by linear least-squares regression of plasma-concentration time points that were determined to lie in the terminal log-linear region of the plasma concentration-time profiles. The apparent elimination half-life was calculated as 0.693/z. Peak plasma concentrations (C_max) and the time at which they occurred were determined from individual patient CPT-11, SN-38, and SN-38G concentration-time curves. Plasma AUCs (AUC_0-24) were determined using the linear trapezoidal rule from time zero to the last sampling at which quantifiable drug concentrations were detected (C_last). CPT-11 plasma AUCs through infinite time (AUC_0-) were calculated by adding C_last/z to AUC_0-24. The systemic clearance and apparent volume of distribution of CPT-11 were calculated as dose/AUC_0- and clearance/z, where dose is the administered dose of CPT-11 expressed in free base equivalents.

Statistics
The primary goal of this study was to estimate the objective response rate of the combination of CPT-11 and cisplatin in patients with stage IIIB/IV NSCLC. The two-stage accrual design described by Simon³⁶ was used to ensure that the number of patients exposed to this therapy was minimized should the therapy prove ineffective. All patients were considered assessable for safety and efficacy. Estimates of 95% confidence intervals (CI) on response rate and 1-year survival were calculated. Time-to-event end points were calculated using Kaplan-Meier methods. Baseline patient characteristics were evaluated in univariate (Fisher's exact test) and multivariate (logistic regression) analyses to determine their possible effect on efficacy and safety parameters, including age (< 65 v 65 years), sex, stage of disease (IIIB v IV), performance status (0 v > 0), number of measured metastatic lesions (< 3 v 3), sites of measured disease, prior surgery, prior radiotherapy, and study center at which treatment was administered. Baseline bilirubin level was also included in the logistic regression model as a continuous variable in an analysis of predictors of first-course late-onset diarrhea and neutropenia. Statistical significance was assumed at P < .05. Dose-intensity for CPT-11 and cisplatin was calculated by dividing the total dose received by the number of weeks on study.

Pharmacodynamic relationships were explored using scatterplots of CPT-11 and SN-38 C_max and AUC_0- parameters versus highest-grade (National Cancer Institute) delayed diarrhea, neutropenia, nausea, or vomiting during course 1. The Spearman rank order correlation coefficient was used to assess the statistical significance of possible correlations between CPT-11 or SN-38 pharmacokinetic parameters and principal toxicities. Comparison of differences in pharmacokinetic parameters between week 1 and week 3 were performed with a Wilcoxon signed rank test.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
A total of 52 patients (33 men and 19 women) were enrolled onto the study (Table 2). The median age was 61 years (range, 29 to 79 years). Eleven patients (21.2%) had stage IIIB disease, and 41 patients (78.8%) had stage IV disease. The majority of patients (76.9%) had symptoms related to their NSCLC as evidenced by baseline performance status of 1 or 2. Multiple sites of disease were apparent in 46 patients (88.5%), although the predominant site of measurable disease was the lung (92.3%). None of the patients had undergone prior chemotherapy. Thirteen patients (25.0%) had undergone an attempt at primary surgical resection, and 11 (21.2%) had received prior radiotherapy to tumor sites.

Treatment Administration
A total of 216 courses (559 doses of CPT-11 and 216 doses of cisplatin) was administered. The median number of treatment courses per patient was four (range, one to 14). The cumulative median dose of CPT-11 administered was 455 mg/m² (range, 120 to 3,815 mg/m²). Sixty doses (9.3%) of CPT-11 (including a single day-1 dose, 27 day-8 doses, and 32 day-15 doses) and no doses of cisplatin were omitted during treatment. Planned dose-intensities for CPT-11 and cisplatin were 45 and 20 mg/m²/wk, respectively. Because CPT-11 was preferentially dose-modified, median dose-intensities for CPT-11 and cisplatin were 34.0 (75.5% relative dose-intensity) and 20.0 mg/m²/wk (100% relative dose-intensity), respectively. CPT-11 dose-intensity was not significantly influenced by baseline patient characteristics, including age, sex, stage of disease, performance status, number of measured metastatic lesions, prior surgery, prior radiotherapy, or study center at which treatment was given.

Two patients had CPT-11 dose escalations to 80 mg/m². One of these patients received further dose escalation (to 105 mg/m²) and was able to sustain that dose level for nine courses of therapy. This patient achieved a partial response during the second course at this level of CPT-11. Thirty-eight (73%) of 52 patients underwent CPT-11 dose reductions at some time during treatment. Reasons for reductions included nausea (in 5.6% of courses), vomiting (in 8.3% of courses), asthenia (in 3.7% of courses), and neutropenia (in 4.2% of courses) that might have been expected with either agent. Late diarrhea, the most clearly CPT-11–related toxicity, resulted in dose reductions in only 6.5% of courses. The cisplatin dose was reduced in only 5.5% of courses, for grades 2 and 3 neutropenia, grade 3 nausea, and ototoxicity.

Efficacy
Of the 52 patients who participated in the study, confirmed objective tumor responses were observed in 15 (28.8% ; 95% CI, 16.5% to 41.2%; Table 3), including two complete and 13 partial responses. Stable disease was observed in 28 patients (53.8%), seven of whom experienced 50% tumor reduction not confirmed 4 weeks later, and eight of whom achieved a minor tumor response ( 25%, but < 50% reduction in total tumor area) that lasted for at least 4 weeks. The remaining nine patients (17.3%) had progressive disease or went off study before initial tumor reevaluation.

Of interest, one patient on this trial developed classical evidence of tumor lysis syndrome within 10 days of beginning therapy with CPT-11 and cisplatin.³⁷ This adverse event occurred in the setting of a dramatic clinical response.

Analysis of response rates by baseline patient characteristics indicated tumor response was more likely in patients who had undergone prior surgery (53.8% with prior surgery v 20.5% without prior surgery; P = .03) or chest irradiation (54.6% with prior chest irradiation v 22.0% without chest irradiation). Confirmed response rates according to treatment center ranged from 0% to 40%. Other patient characteristics including age, sex, stage of disease, performance status, number of metastatic lesions, and sites of measured disease were not predictive of response.

Median time to response was 1.6 months (range, 0.7 to 3.5 months), and median duration of response from the time of first evidence of objective response was 5.9 months (range, 1.0 to 10.6 months; Table 3). Median time to tumor progression was 5.1 months (range, 0.7 to 14.1 months), and median survival duration was 9.9 months (range, 1.6 to 30.8 months). The 1-year survival rate was 37%.

Multiple regression analysis of baseline patient characteristics indicated that prior surgery was predictive for improved time to tumor progression (median, 7.3 months with prior surgery v 3.7 months without prior surgery; P = .03). When the same baseline characteristics were included in a multiple regression model for survival, none were significantly predictive of better outcome.

Safety
There were no treatment-related deaths. Clinically important grade 3/4 nonhematologic toxicities experienced over all courses of therapy included expected gastrointestinal events of nausea (32.7% of patients), vomiting (13.5%), and late-onset diarrhea (17.3%; Table 4). Alopecia (61.5%) was also observed. Grade 3 asthenia was noted in 23.1% of patients; the extent to which this symptom was related to the underlying disease is unknown. Although audiometry showed expected subclinical cisplatin-related declines in high-frequency hearing loss,^38,39 clinically serious ototoxicity was unusual. Cisplatin-induced peripheral neuropathy was documented in 18 patients (34.6%), of which only two events (3.9%) were grade 3. Two patients (3.9%) had grade 3 increases in creatinine during treatment. One of these occurred in the patient with tumor lysis syndrome; it was transient and did not prohibit further therapy. The second patient was discontinued from the study after the third course of treatment because of renal dysfunction attributed to cisplatin.

Grade 3 dyspnea was infrequently observed (5.8%), and any relationship with study drug was difficult to establish given the underlying pulmonary problems observed in this patient population. Because of reports from Japan of idiosyncratic adverse pulmonary events in patients with lung cancer,⁴⁰ pulmonary function tests were evaluated during therapy. There was no correlation between cumulative CPT-11 dose and changes in forced vital capacity, forced expiratory volume in one second, and carbon monoxide diffusing capacity from baseline.

The principal grade 4 hematologic toxicity was neutropenia (19.2% of patients; Table 5). Grade 4 anemia or thrombocytopenia were not observed. Six patients (11.5%) had neutropenic fever, defined as grade 4 neutropenia with simultaneous fever grade 2. There were no grade 3/4 drug-related infections. There were no statistically significant influences of age, sex, stage of disease, performance status, number of measured metastatic lesions, sites of measured disease, prior surgery, prior radiation therapy, baseline serum total bilirubin levels, or study center on the occurrence of first-course late-onset grade 3/4 diarrhea. Although baseline serum total bilirubin values were normal in all patients (range, 0.1 to 1.1 mg/dL), higher pretreatment bilirubin values within this range were associated with a greater incidence of first-course grade 3/4 neutropenia (P = .0007).

Pharmacokinetics
Pharmacokinetic data for 24 hours after dosing were available in 40 patients who received CPT-11 on week 1 of course 1 and in 22 patients who had specimen collection week 3 of course 1. Mean (± SD) pharmacokinetic parameters for CPT-11 and SN-38 in patients who had pharmacokinetic assessments performed for 24 hours after CPT-11 dosing on week 1 are listed in Table 6.

Peak CPT-11 concentrations were generally observed at the end of the infusion. Thereafter, concentrations decreased with a mean half-life of approximately 5.7 hours. Mean CPT-11 clearance was 16.7 ± 9.33 L/h/m². This value is comparable to those reported previously in single-agent studies of CPT-11,^12,41-44 demonstrating that coadministration of 80 mg/m² cisplatin 2 hours after the completion of CPT-11 administration had no effect on the pharmacokinetics of CPT-11.

SN-38 C_max levels were approximately 45-fold lower than the corresponding CPT-11 C_max levels. The time at which mean SN-38 peak concentrations were reached was within 1 hour after the end of the 90-minute infusion. Mean SN-38 AUC_0- values represented 3.8% ± 1.6% (range, 2.1% to 10.1%) of the corresponding CPT-11 AUC_0- values. The magnitude of this indirect measure of the conversion of CPT-11 to SN-38 is consistent with values reported previously.^43,45,46

Mean (± SD) CPT-11 and SN-38 pharmacokinetic values obtained in 16 patients who had pharmacokinetic assessments performed for 24 hours after the same dose of CPT-11 on both week 1 and 3 are listed in Table 7. CPT-11 AUC_0- was approximately 15% higher on week 3. Although this difference was statistically significant, there was considerable interpatient variability in the percent change (range, -25% to +66%), and the majority of patients (88%) had AUC_0- values on week 3 that were within 30% of those observed on week 1. Mean SN-38 AUC_0- values were similar on these two occasions. In light of this variability and the small magnitude of these temporal changes, it is unlikely that they would result in clinically relevant changes in the antitumor activity or safety of CPT-11.

Pharmacodynamics
Scatterplots demonstrating the relationships between CPT-11 or SN-38 C_max and AUC_0-( and highest grade of course-1 delayed diarrhea and neutropenia are shown in Figs 1 and 2. The results of the Spearman rank order correlation coefficient analysis suggested significant positive correlations between CPT-11 AUC_0- and intensity of delayed diarrhea and neutropenia, between SN-38 C_max values and intensity of neutropenia, and between SN-38 AUC_0- values and intensity of delayed diarrhea and neutropenia. However, there was considerable overlap in these pharmacokinetic parameters for patients who experienced grades 0 to 4 delayed diarrhea and neutropenia. This variability is reflected in correlation coefficients between pharmacokinetic parameters and the highest grade of delayed diarrhea and of neutropenia that only ranged between 0.13 to 0.53. As a result, these correlations do not allow predictive identification of patients who are at risk for severe diarrhea and neutropenia. Similar analyses demonstrated no significant correlations between CPT-11 and SN-38 pharmacokinetic parameters and intensity of nausea or vomiting.

View larger version (22K): [in this window] [in a new window]   Fig 1. Relationship between CPT-11 Cmax and AUC0- values and highest grade of delayed diarrhea or neutropenia during the first course of therapy (n = 40).

View larger version (20K): [in this window] [in a new window]   Fig 2. Relationship between SN-38 Cmax and AUC0- values and highest grade of delayed diarrhea or neutropenia during the first course of therapy (n = 40).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
It has been apparent for some time that combination chemotherapy, usually containing a platinum analog, is more effective than single-agent therapy in the treatment of NSCLC. This general premise has been confirmed in a phase III trial of 612 patients with stage III or IV NSCLC in which a vinorelbine—cisplatin combination proved more efficacious than vinorelbine alone. The combination resulted in an objective response rate of 30%, median survival duration of 9.2 months, and 1-year survival rate of 35%.⁴⁷ Phase II trials assessing paclitaxel,^48,49 gemcitabine,^50,51 or docetaxel⁵² combined with cisplatin have resulted in response rates ranging from 33% to 54% with generally comparable survival data. Other phase II trials assessing paclitaxel combined with carboplatin have resulted in response rates ranging from 26% to 54%.^53-56 Median survival times from these studies have included values extending from 8.7 to 10.8 months.^53,54

Given evidence of single-agent CPT-11 activity in NSCLC and preclinical evidence of synergy with platinum,^57,58 combining CPT-11 with cisplatin was a necessary step in the further development of CPT-11 in the therapy of this disease. Phase I testing of the combination was conducted initially in Japan and showed promising response rates (43% to 54%).^23-27 A subsequent phase II study of CPT-11/cisplatin combination therapy in chemotherapy-naive patients with advanced NSCLC resulted in a 47.8% response rate⁵⁹ that compares favorably with those observed with combinations of a platinum and taxanes, gemcitabine, or vinorelbine.

The current United States phase II study is built on the work of Masuda et al^24,27 in the establishment of tolerable doses and schedules of combination CPT-11/cisplatin. It confirms the results of prior phase II trials in documenting an evidence of objective 28.8% (95% CI, 16.5% to 41.2%) of patients. The median survival duration of 9.9 months (range, 1.6 to 30.8 months) and 1-year survival rate of 37% observed in this study also are consistent with the findings of prior combination trials.^47-54 Exploratory analyses of the influence of patient baseline characteristics on response rate indicated that patients who had undergone prior surgery or radiotherapy to the primary tumor were more likely to respond. Those with prior surgery also had a significantly longer time to tumor progression. The reason for these findings is not readily apparent. It is possible that this combination of agents is more active in metastatic sites than at primary tumor sites; because inclusion of the primary sites among those evaluated for tumor response would not be possible in patients with surgically resected or irradiated primary cancers, response rates would seem higher in such patients if this hypothesis were true.

Protocol-specified CPT-11 dose attenuations in this study resulted in the majority of patients (60%) receiving less than one third of the recommended CPT-11 monotherapy dose (125 mg/m²). The protocol-specified lack of cisplatin dose adjustment may have exacerbated this situation. Relatively few dose modifications occurred as the result of a CPT-11–specific toxicity such as late-onset diarrhea (6.5% of courses). Modification of cisplatin doses for more common toxicities such as nausea and vomiting might have resulted in a more balanced administration of each drug relative to its usual single-agent dose.

Late-onset diarrhea, although a relatively unusual toxic effect of most chemotherapeutic agents, is a potential concern with CPT-11 therapy. During initial evaluation of CPT-11 in colorectal cancer, grade 3/4 late-onset diarrhea was observed in approximately 31% of patients.⁶⁰ However, increasing clinical experience with CPT-11 has shown that this toxicity can be managed effectively and is less frequently observed as clinicians become familiar with the agent.³³ In the study reported here, the 17% incidence of late-onset grade 3/4 diarrhea was substantially lower than in these past experiences, most likely as a result of the lower CPT-11 doses and intensive use of loperamide.

Potential CPT-11–induced pulmonary toxicity has been described in early studies of the drug in Japan. In reports documenting use of the drug as therapy for lung cancer, several patients were said to have had a syndrome of dyspnea, fever, and reticular nodular pattern on chest radiograph.⁴⁰ In one report, the median total dose in these patients was 750 mg/m² (range, 400 to 1,000 mg/m²). Although dyspnea was observed in the current trial, it was largely attributed to pre-existing pulmonary disease. No constellation of symptoms consistent with those described in the Japanese reports was observed in this study. In addition, serial evaluations of pulmonary function in this study showed no obvious evidence of pulmonary compromise related to cumulative CPT-11 dose over a range of doses from 120 to 3,815 mg/m² (median, 455 mg/m²). Similar serial pulmonary function testing of patients with colorectal cancer who received CPT-11 have also documented no overt evidence of CPT-11–related cumulative lung toxicity (L.L.M., unpublished data). Based on these collective findings, sequential pulmonary function monitoring is not believed to be necessary in patients who receive CPT-11.

As with other chemotherapy regimens used in the therapy of NSCLC, the CPT-11/cisplatin combination resulted in myelosuppression. However, myelosuppression was clinically moderate with this regimen. Neutrophils were the primary cell line affected, with grade 4 neutropenia observed in 19.2% of patients. First-course grade 3/4 neutropenia was more commonly observed in patients with higher baseline serum total bilirubin levels, although all pretreatment serum bilirubin values were within the normal range. This correlation has been noted in past clinical experience with single-agent CPT-11 administration to patients with colorectal cancer (L.L.M., unpublished data). However, neutropenic fever was infrequent (11.5%), and no drug-related septicemia was noted. Grade 4 thrombocytopenia or anemia were not observed.

CPT-11 and SN-38 pharmacokinetic parameters were similar to those reported previously in single-agent CPT-11 studies, demonstrating that coadministration of cisplatin 80 mg/m² 2 hours after the completion of CPT-11 administration had no effect on the pharmacokinetics of CPT-11. Predictive correlations between CPT-11 or SN-38 pharmacokinetic parameters and intensity of delayed diarrhea, neutropenia, nausea, or vomiting were not observed.

In summary, this United States, multicenter trial of CPT-11/cisplatin therapy confirmed the activity and manageable toxicity of this regimen in the treatment of stage IIIB/IV NSCLC. Future studies should be designed to avoid unnecessary CPT-11 dose reductions and to exploit more directly the therapeutic synergy^50,51 of these agents. A recently developed regimen involving administration of CPT-11 65 mg/m² and cisplatin 30 mg/m² administered weekly for 4 weeks followed by a 2-week rest has shown promising activity in patients with a number of chemoresistant malignancies.⁶¹ This regimen has been designed to maximize concomitant administration of the agents, maintain intended doses over time, and minimize the inconvenience of prolonged hydration required with high doses of cisplatin. A phase II study of this regimen in NSCLC is ongoing.

	ACKNOWLEDGMENTS

 
Supported in part by National Institutes of Health General Clinical Research Center, Bethesda, MD, grant no. MOI RR00095 and a grant-in-aid from Pharmacia & Upjohn, Kalamazoo, MI.

	NOTES

 
Presented in part at the Thirty-Third Annual Meeting of the American Society of Clinical Oncology, Denver, CO, May 17-20, 1997 (abstr 1674).

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Ihde DC: Chemotherapy of lung cancer. N Engl J Med 327:1434-1441, 1992[Medline]

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Submitted November 23, 1998; accepted May 14, 1999.

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