Prolonged Administration of Oral Etoposide in Non-Small-Cell Lung Cancer: A Phase II Trial By Thomas M. Waits, David H. Johnson, John D. Hainsworth, Kenneth R. Hande, Melodie Thomas, and F. Anthony Greco Purpose: The trial was undertaken to investigate the activity and toxicity of a prolonged schedule of oral etoposide in the treatment of advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Between March 1989 and August 1990, 25 patients with advanced NSCLC were treated with oral etoposide 50 mg/m'/d for 21 consecutive days, repeated every 28 to 35 days. The median patient age was 60 years (range, 38 to 84 years); male:female ratio was 12:13. Eight patients had stage IIIB disease; 17 had stage IV. Seventy-six percent of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. No patient had received previous chemotherapy with standard agents; nine patients had received previous or concurrent radiation therapy. Plasma etoposide concentrations were measured to estimate etoposide bioavailability and kinetics. Results: Five of 22 patients (23%; 95% confidence interval [CI], 10% to 43%) had partial responses. Median response duration was 5 months (range, 2 to 6 months). Four of five responders were female. Besides alopecia,
which occurred in all patients, myelosuppression was the most common toxicity, but was mild or moderate in most patients. Median leukocyte nadir during course 1 was 3,200/p.L; only four of 69 courses produced a leukocyte nadir less than 1,000/pL. Severe thrombocytopenia (< 75,000/IL) did not occur. Gastrointestinal toxicity was uncommon. Median peak etoposide concentration was 3.4 pg/mL. A mean serum etoposide concentration greater than 1 pg/mL was maintained for more than 13 hours; the plasma concentration-time curve (AUC) was estimated to be 90% of that predicted after an identical dose of etoposide given intravenously. Conclusions: Etoposide given by this dose and schedule has moderate activity as first-line systemic therapy for advanced NSCLC. In previously untreated patients, chronic oral etoposide is well tolerated, and incorporation into combination regimens should be feasible. Etoposide bioavailability may be increased at lower oral doses. J Clin Oncol 10:292-296. o 1992 by American Society of Clinical Oncology.
T
used alone in the treatment of metastatic NSCLC.15 Because it is schedule-dependent, etoposide is usually administered intravenously over 3 to 5 days; the clinical superiority of a 5-day schedule versus a 1-day schedule has been demonstrated in the treatment of small-cell lung cancer.6 With the availability of oral etoposide, durations of therapy longer than 5 days are now being investigated. We previously demonstrated the feasibility of administering oral etoposide 50 mg/m 2 for 21 consecutive days7 and reported a 46% response rate in the treatment of relapsed or refractory small-cell lung cancer using this dose and schedule.8 We have now completed a similar phase II study using chronic oral etoposide (50 mg/m 2/d for 21 consecutive days) in the
HERE ARE APPROXIMATELY 150,000 new cases of non-small-cell lung cancer (NSCLC) each year, the majority of which are locally advanced or metastatic at the time of diagnosis and are not amenable to surgical resection.1 2,' It is clear that effective systemic therapy is needed to improve the survival and cure rates of these patients. Given the paucity of new agents with novel mechanisms of action, it is unlikely that there will be a marked advance in treatment outcome in the near future. Because effective new agents are scarce, it is important that currently available agents be used in the most efficacious manner. Etoposide is a phase-specific, schedule-dependent agent that produces a 5% to 15% response rate when
treatment of advanced NSCLC and report the results of this trial herein. From the Division of Medical Oncology, Vanderbilt University Medical School, Nashville, TN. Submitted July 1, 1991; acceptedSeptember 21, 1991. Supportedin part by a grantfrom Bristol-Myers Oncology Laboratories, Evansville, IN. Address reprint requests to Thomas M Waits, MD, Division of Medical Oncology, 1956 The Vanderbilt Clinic, Nashville, TN 372325536. © 1992 by American Society of Clinical Oncology. 0732-183X/92/1002-0013$3.00/0
292
PATIENTS AND METHODS Twenty-five patients were entered into this phase II trial between March 1989 and August 1990. Eligibility requirements included a histologic diagnosis of NSCLC, measurable disease, performance status of _ 3,000/jiL, platelet count > 100,000/ttL, serum creatinine level < 2 mg/dL, serum bilirubin level < 2 mg/dL (unless due to disease involving the liver), a life expectancy of > 12 weeks, and signed informed
Journal of Clinical Oncology, Vol 10, No 2 (February), 1992: pp 292-296
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293
ORAL ETOPOSIDE FOR NON-SMALL-CELL LUNG CANCER consent. Patients were ineligible if they had received previous standard chemotherapy; previous radiotherapy was allowed. No patient had received any previous therapy within 3 weeks of study entry. Before receiving oral etoposide, all patients had the following studies performed: complete blood cell (CBC) counts with differential, electrolytes test, routine chemistry panel, and a chest roentgenogram. Additional radiographic studies were obtained as clinically indicated and as necessary to document measurable disease. Etoposide was administered orally in the form of soft gelatin capsules for 21 consecutive days at a dose of 50 mg/m /d. Although food has not been shown to interfere with etoposide absorption,5 patients were instructed to take the entire daily dose each morning before eating. Antiemetics were not routinely used. As etoposide is available only in 50-mg capsules, it was necessary to make some approximations in the calculated daily dose. For example, if a patient was calculated to receive 85 mg/d, etoposide was given as 100 mg, 100 mg, and 50 mg on 3 consecutive days, respectively, and the schedule was repeated for 21 days (ie, average daily dose, 83.3 mg). Patients were given a calendar noting the number of capsules to be taken for each treatment day to insure accuracy. A pill count was conducted at the completion of each cycle of therapy. Plasma etoposide levels were measured in consenting patients to determine plasma peak and trough levels with this dose. Plasma samples were obtained at varying times after a 100-mg oral dose, and a composite plasma concentration-time curve (AUC) using samples from all patients was constructed. Etoposide concentrations were determined by reverse-phase high-performance liquid chromatography (HPLC) as described previously.' During treatment, a CBC count, a differential count, and a platelet count were obtained weekly. Etoposide was discontinued if the leukocyte count fell below 2 ,000/IpL or if the platelet count fell below 75,000/pL. At the end of each 21-day course, etoposide was discontinued, and patients underwent an evaluation on day 28. Patients who demonstrated an objective response or stable disease were given another course of oral etoposide. Repeat courses were initiated when the leukocyte count was greater than 3,000/piL and the platelet count was greater than 100,000/1 L. Patients who had leukocyte nadirs less than 2,000/piL or who required discontinuation of etoposide before day 21 had a dose reduction to 75% on the subsequent cycle. No patient had a dose escalation. Etoposide was continued until patients demonstrated evidence of tumor progression or experienced unacceptable toxicity. Tumor response was assessed after two cycles of treatment. Standard response criteria were used. A complete response required total resolution of all measurable disease for at least 4 weeks. Partial response required a greater than 50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions without the development of any new lesions. Stable disease was defined as less than 50% regression or less than 25% progression of lesions. All others were considered to have progressive disease. Patient characteristics are detailed in Table 1. Seventeen patients (68%) had stage IV disease, and the remainder had stage IIIB. Nineteen patients (76%) had ECOG performance status 0 or 1. Fourteen patients had received no previous therapy. Six patients had received previous radiotherapy (primary lung tumor, five; metastatic femur lesion, one), and three received concurrent local radiation therapy (whole-brain, one; skeletal lesions, two). Two patients had previously received treatment with an investigational 1 sulfonylurea derivative."
Table 1. Patient Characteristics (N
25) Na. of Patients
Median age (range), years Male/female Stage (%) IIIB IV ECOG performance status 0 1 2 Histology Squamous carcinoma Adenocarcinoma Large-cell carcinoma Poorly differentiated NSCLC Previous therapy None Radiation therapy Investigational chemotherapy
60 (38-84) 12/13 8 (32) 17(68) 2 17 6 9 8 4 4 14 9 2
RESULTS
Efficacy Twenty-two patients received at least one full course of etoposide and were evaluated for treatment response. Three patients received less than one course of therapy and were considered unassessable. The reasons for an incomplete course of therapy in these patients included voluntary discontinuation of therapy after 2 weeks (one patient), sudden death of unknown cause after 12 days of therapy with blood cell counts normal (one patient), and recurrent supraventricular tachycardia due to pericardial involvement (etoposide stopped by treating physician; one patient). The median number of treatment courses administered was two (range, one to seven courses). Five patients had objective responses to therapy, for a response rate of 23% (95% confidence interval [CI], 10% to 43%). All responses were partial. Four of the five responders were women. One of eight patients with stage IIIB disease responded, as did four of 17 stage IV patients. Six additional patients experienced temporary stabilization of measurable lesions. Response durations were 2, 4, 5, 5, and 6 months, respectively. The median duration of disease stabilization was 3 months. Median survival was 5 months (range, 1 to 19 months), and the actual 1-year survival was 28%. Toxicity Myelosuppression was the most frequent toxicity but was modest and easily tolerated in most patients. The median leukocyte nadir count for cycle 1 was 3,200/piL,
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WAITS ET AL
294 with four patients experiencing grade 3 and two experiencing grade 4 leukopenia (Table 2). Life-threatening leukopenia (< 1,000/p.L) occurred in four of 69 treatment cycles (6%), and four patients required hospitalization for treatment of neutropenia and fever. All four patients recovered and were discharged in good condition. Thrombocytopenia was not a problem, as no patient developed a platelet count less than 100,000/pLL, and there were no bleeding complications. Eight patients required RBC transfusions during therapy. Discontinuation of etoposide before completion of 21 days was required in 14 courses (20%). Five patients required dose reductions in subsequent courses because of myelosuppression. Of the 18 patients who received more than one course, 11 began the second course on day 28 as planned. In the remaining seven patients, the second course was started between days 29 and 35, for the following reasons: myelosuppression, four patients; patient request, two patients; stomatitis, one patient. Radiation therapy was associated with increased myelosuppression. Three of four patients who developed a leukocyte count of less than 1,000/IpL received previous or concomitant radiation therapy. Likewise, three of eight patients requiring RBC transfusions had received or were receiving radiation therapy. The observed nonhematologic toxicities are listed in Table 3. Severe alopecia was seen in all patients who completed at least one course of therapy. Nausea was also common (44% of patients), but was not severe in any patient (grade 1, seven patients; grade 2, five patients). Other side effects were uncommon and sometimes difficult to differentiate from the systemic effects of advanced lung cancer (eg, weakness, anorexia).
Table 3. Nonhematologic Toxicity Grade
Alopecia Nausea/vomiting Anorexia Stomatitis Weakness Diarrhea
Plasma etoposide concentrations were measured in 58 plasma samples drawn at various times after the oral administration of 100 mg of etoposide. A composite AUC is shown in Fig 1. The mean peak plasma concentration was 3.4 p.g/mL. A plasma etoposide concentration greater than 1 txg/mL was maintained for longer than 13 hours after an oral dose. The plasma AUC calculated from the composite curve in Fig 1 was 2,117
2
3
4
0 7 0 4 2 1
22 5 3 0 1 1
0 0 1 0 0 0
0 0 0 0 0 0
tjg/mL x min. The AUC is 88% of the predicted AUC after 100 mg of etoposide given intravenously." DISCUSSION
The results of this phase II study demonstrate modest activity of chronic oral etoposide when used as initial therapy for advanced NSCLC. Although scheduledependent differences in etoposide activity against NSCLC can be definitively addressed only with a randomized comparison, the 23% response rate obtained with our 21-day schedule of etoposide compares favorably with previously reported response rates using etoposide in standard schedules. Prior studies with etoposide as a single agent have used intravenous doses ranging from 60 to 150 mg/m 2/d for 1 to 5 days and produced response rates ranging from 5% to 15%.2,7-9 Oral etoposide has not
been extensively investigated; however, a 35% response 8 E
I SI 4 6
2
z 0 z
PharmacokineticStudies
1
uj z
I
0 0
013
a
0.8
w
.
I
•
*6 ·
0
0 a0. Uj
· ·
·
2 0.2
U) 4I -J
Table 2. Hematologic Toxicity--Cycle 1
I
U
Grade
Leukopenia Thrombocytopenia
8 2
3 0
4 0
2 0
2
I
I
I
4
6
8
I
I
I
I
10 12 14 16 TIME (HOURS)
I
18
I
I
I
20 22 24
Fig 1. The 24-hour AUC after a 100-mg oral etoposide dose. This composite curve was constructed using serum levels from multiple patients receiving this dose.
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295
ORAL ETOPOSIDE FOR NON-SMALL-CELL LUNG CANCER
rate using 200 mg/m 2 for 5 consecutive days, every 3 weeks has been reported.3 In addition, the response rate and median survival achieved with this prolonged schedule of oral etoposide is comparable to that seen with 12 combination regimens. -16 One other study has been reported using the same dose and schedule of etoposide as in our study. In a phase II trial conducted by the Hoosier Oncology Group, Saxman et al"7 observed two responses in 30 patients treated (7% response rate). The discrepancy in response rates between our study and that by Saxman et al is unexplained, but may be related to low numbers of patients and possibly to differences in the patient populations. The median performance status in both studies was approximately the same (80% on the Karnofsky scale in the Saxman et al study and 1 on the ECOG scale in our study). However, 80% of the patients in the study by Saxman et al were men, versus only 48% of our population. Four of our five responders were women; thus, this sex distribution difference in the two studies may account for some of the difference in response rates and would be consistent with other studies that have demonstrated increased response rates for women.'" Most patients tolerated this etoposide regimen well. Besides alopecia, myelosuppression was the most frequent drug-related toxicity, but was severe in only four of 69 courses. None of the patients in this group had received previous myelosuppressive systemic therapy, so it is not surprising that myelosuppression was less frequent and severe than that produced with this regimen in salvage therapy of either small-cell lung cancer or lymphoma.'"9 When compared with our phase II study in refractory small-cell lung cancer, the present group showed a higher median leukocyte nadir during
the first course of therapy (3,000/.LL v 1,800/gpL), fewer episodes of leukocyte counts less than 1,000/gLL (6% v 18% of courses), and fewer episodes of platelet counts less than 50,000/ýL (0% v 25%). The toxicity profile in this study was similar to that observed in the Hoosier Oncology Group Study, where patients were also previously untreated with systemic therapy. The mild to moderate myelosuppression observed in these patients suggests that this dose and schedule of etoposide could be integrated into combination regimens in previously untreated patients. Rigorous pharmacokinetic studies to determine percentage drug absorption and drug half-life were not performed in any of these patients. However, the composite AUC constructed using samples collected from multiple patients at varying times after drug administration provides useful data concerning this dose of oral etoposide. First, maximum plasma levels did not vary greatly among these patients. Second, plasma levels of greater than 1 jpg/mL were maintained for an estimated 13 hours of each 24-hour period. The duration of plasma drug levels greater than 1 1±g/mL was found by Slevin et al6 to correlate with tumor response better than peak drug levels or total AUC achieved. Finally, drug availability at a 100-mg dose appears higher (90% v 50%) than that previously found using oral etoposide at higher doses (ie, 400 mg). In summary, oral etoposide given at a dose of 50 mg/m 2/d for 21 consecutive days has moderate activity when given as initial systemic therapy for advanced NSCLC. This method of administration was well tolerated by most patients, and integration into a combination regimen should be feasible. The place of oral etoposide in the therapy of NSCLC awaits further study.
REFERENCES 1. Bonomi P: Recent advances in etoposide therapy for nonsmall cell lung cancer. Cancer 67:254-259, 1991 (suppl) 2. Ruckdeschel JC: Etoposide in the management of non-small lung cancer. Cancer 67:250-253, 1991 (suppl) 3. Pedersen AG, Hansen HH: Etoposide (VP-16) in the treatment of lung cancer. Cancer Treat Rev 10:245-264, 1983 4. O'Dwyer PJ, Leyland-Jones B, Alonso MT, et al: Etoposide (VP-16-213): Current status of an active anticancer drug. N Engl J Med 312:692-700, 1985 5. Fleming RA, Miller AA, Stewart CF: Etoposide: An update. Clin Pharmacy 8:274-293, 1989 6. Slevin ML, Clark PI, Malik S, et al: A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 7:1333-1340, 1989 7. Hainsworth JD, Johnson DH, Frazier SR, et al: Chronic daily administration of oral etoposide-A phase I trial. J Clin Oncol 7:396-401, 1989
8. Johnson DH, Greco FA, Strupp J, et al: Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: A phase II trial. J Clin Oncol 8:1613-1617, 1990 9. Hande KR, Wolff SN, Greco FA, et al: Etoposide kinetics in patients with obstructive jaundice. J Clin Oncol 8:1101-1107, 1990 10. Hainsworth JD, Hande KR, Satterlee WG, et al: A phase I clinical study of N-[(4-chlorophenyl)amino] carbonyl-2,3 dihydro1H-indene-5-sulfonamide (LY186641). Cancer Res 49:5217-5220, 1989 11. Hande KR, Wedlund PJ, Noone RM, et al: Pharmacokinetics of high-dose etoposide (VP-16-213) administered to cancer patients. Cancer Res 44:379-382, 1984 12. Bonomi PD, Finkelstein DM, Ruckdeschel JC, et al: Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small cell lung cancer: A study of
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WAITS ET AL
the Eastern Cooperative Oncology Group. J Clin Oncol 7:16021613, 1989 13. Ruckdeschel JC, Finkelstein DM, Mason BA, et al: Chemotherapy for metastatic non-small-cell bronchogenic carcinoma: EST 2575 generation V-A randomized comparison of four cisplatin-containing regimens. J Clin Oncol 3:72-79, 1985 14. Rapp E, Pater JL, Willan A, et al: Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer-Report of a Canadian multicenter randomized trial. J Clin Oncol 6:633-641, 1988 15. Ruckdeschel JC, Finkelstein DM, Ettinger DS, et al: A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol 4:14-22, 1986 16. Klastersky J, Sculier JP, Lacroix H, et al: A randomized
study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer protocol 07861. J Clin Oncol 8:1556-1562, 1990 17. Saxman S, Logie K, Stephens D, et al: Phase II trial of daily oral etoposide in patients with surgically unresectable non-small cell lung cancer. Proc Am Soc Clin Oncol 9:119, 1990 18. O'Connell JP, Kris MG, Gralla RJ, et al: Frequency and prognostic importance of pretreatment clinical characteristics in patients with advanced non-small-cell lung cancer treated with combination chemotherapy. J Clin Oncol 4:1604-1614, 1986 19. Hainsworth JD, Johnson DH, Greco FA: Chronic daily administration of oral etoposide in refractory lymphoma-A phase II trial. Eur J Cancer 26:818-821, 1990
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which occurred in all patients, myelosuppression was the most common toxicity, but was mild or moderate in most patients. Median leukocyte nadir during course 1 was 3,200/p.L; only four of 69 courses produced a leukocyte nadir less than 1,000/pL. Severe thrombocytopenia (< 75,000/IL) did not occur. Gastrointestinal toxicity was uncommon. Median peak etoposide concentration was 3.4 pg/mL. A mean serum etoposide concentration greater than 1 pg/mL was maintained for more than 13 hours; the plasma concentration-time curve (AUC) was estimated to be 90% of that predicted after an identical dose of etoposide given intravenously. Conclusions: Etoposide given by this dose and schedule has moderate activity as first-line systemic therapy for advanced NSCLC. In previously untreated patients, chronic oral etoposide is well tolerated, and incorporation into combination regimens should be feasible. Etoposide bioavailability may be increased at lower oral doses. J Clin Oncol 10:292-296. o 1992 by American Society of Clinical Oncology.
T
used alone in the treatment of metastatic NSCLC.15 Because it is schedule-dependent, etoposide is usually administered intravenously over 3 to 5 days; the clinical superiority of a 5-day schedule versus a 1-day schedule has been demonstrated in the treatment of small-cell lung cancer.6 With the availability of oral etoposide, durations of therapy longer than 5 days are now being investigated. We previously demonstrated the feasibility of administering oral etoposide 50 mg/m 2 for 21 consecutive days7 and reported a 46% response rate in the treatment of relapsed or refractory small-cell lung cancer using this dose and schedule.8 We have now completed a similar phase II study using chronic oral etoposide (50 mg/m 2/d for 21 consecutive days) in the
HERE ARE APPROXIMATELY 150,000 new cases of non-small-cell lung cancer (NSCLC) each year, the majority of which are locally advanced or metastatic at the time of diagnosis and are not amenable to surgical resection.1 2,' It is clear that effective systemic therapy is needed to improve the survival and cure rates of these patients. Given the paucity of new agents with novel mechanisms of action, it is unlikely that there will be a marked advance in treatment outcome in the near future. Because effective new agents are scarce, it is important that currently available agents be used in the most efficacious manner. Etoposide is a phase-specific, schedule-dependent agent that produces a 5% to 15% response rate when
treatment of advanced NSCLC and report the results of this trial herein. From the Division of Medical Oncology, Vanderbilt University Medical School, Nashville, TN. Submitted July 1, 1991; acceptedSeptember 21, 1991. Supportedin part by a grantfrom Bristol-Myers Oncology Laboratories, Evansville, IN. Address reprint requests to Thomas M Waits, MD, Division of Medical Oncology, 1956 The Vanderbilt Clinic, Nashville, TN 372325536. © 1992 by American Society of Clinical Oncology. 0732-183X/92/1002-0013$3.00/0
292
PATIENTS AND METHODS Twenty-five patients were entered into this phase II trial between March 1989 and August 1990. Eligibility requirements included a histologic diagnosis of NSCLC, measurable disease, performance status of _ 3,000/jiL, platelet count > 100,000/ttL, serum creatinine level < 2 mg/dL, serum bilirubin level < 2 mg/dL (unless due to disease involving the liver), a life expectancy of > 12 weeks, and signed informed
Journal of Clinical Oncology, Vol 10, No 2 (February), 1992: pp 292-296
Downloaded from ascopubs.org by University of Groningen on August 6, 2019 from 129.125.019.061 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
293
ORAL ETOPOSIDE FOR NON-SMALL-CELL LUNG CANCER consent. Patients were ineligible if they had received previous standard chemotherapy; previous radiotherapy was allowed. No patient had received any previous therapy within 3 weeks of study entry. Before receiving oral etoposide, all patients had the following studies performed: complete blood cell (CBC) counts with differential, electrolytes test, routine chemistry panel, and a chest roentgenogram. Additional radiographic studies were obtained as clinically indicated and as necessary to document measurable disease. Etoposide was administered orally in the form of soft gelatin capsules for 21 consecutive days at a dose of 50 mg/m /d. Although food has not been shown to interfere with etoposide absorption,5 patients were instructed to take the entire daily dose each morning before eating. Antiemetics were not routinely used. As etoposide is available only in 50-mg capsules, it was necessary to make some approximations in the calculated daily dose. For example, if a patient was calculated to receive 85 mg/d, etoposide was given as 100 mg, 100 mg, and 50 mg on 3 consecutive days, respectively, and the schedule was repeated for 21 days (ie, average daily dose, 83.3 mg). Patients were given a calendar noting the number of capsules to be taken for each treatment day to insure accuracy. A pill count was conducted at the completion of each cycle of therapy. Plasma etoposide levels were measured in consenting patients to determine plasma peak and trough levels with this dose. Plasma samples were obtained at varying times after a 100-mg oral dose, and a composite plasma concentration-time curve (AUC) using samples from all patients was constructed. Etoposide concentrations were determined by reverse-phase high-performance liquid chromatography (HPLC) as described previously.' During treatment, a CBC count, a differential count, and a platelet count were obtained weekly. Etoposide was discontinued if the leukocyte count fell below 2 ,000/IpL or if the platelet count fell below 75,000/pL. At the end of each 21-day course, etoposide was discontinued, and patients underwent an evaluation on day 28. Patients who demonstrated an objective response or stable disease were given another course of oral etoposide. Repeat courses were initiated when the leukocyte count was greater than 3,000/piL and the platelet count was greater than 100,000/1 L. Patients who had leukocyte nadirs less than 2,000/piL or who required discontinuation of etoposide before day 21 had a dose reduction to 75% on the subsequent cycle. No patient had a dose escalation. Etoposide was continued until patients demonstrated evidence of tumor progression or experienced unacceptable toxicity. Tumor response was assessed after two cycles of treatment. Standard response criteria were used. A complete response required total resolution of all measurable disease for at least 4 weeks. Partial response required a greater than 50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions without the development of any new lesions. Stable disease was defined as less than 50% regression or less than 25% progression of lesions. All others were considered to have progressive disease. Patient characteristics are detailed in Table 1. Seventeen patients (68%) had stage IV disease, and the remainder had stage IIIB. Nineteen patients (76%) had ECOG performance status 0 or 1. Fourteen patients had received no previous therapy. Six patients had received previous radiotherapy (primary lung tumor, five; metastatic femur lesion, one), and three received concurrent local radiation therapy (whole-brain, one; skeletal lesions, two). Two patients had previously received treatment with an investigational 1 sulfonylurea derivative."
Table 1. Patient Characteristics (N
25) Na. of Patients
Median age (range), years Male/female Stage (%) IIIB IV ECOG performance status 0 1 2 Histology Squamous carcinoma Adenocarcinoma Large-cell carcinoma Poorly differentiated NSCLC Previous therapy None Radiation therapy Investigational chemotherapy
60 (38-84) 12/13 8 (32) 17(68) 2 17 6 9 8 4 4 14 9 2
RESULTS
Efficacy Twenty-two patients received at least one full course of etoposide and were evaluated for treatment response. Three patients received less than one course of therapy and were considered unassessable. The reasons for an incomplete course of therapy in these patients included voluntary discontinuation of therapy after 2 weeks (one patient), sudden death of unknown cause after 12 days of therapy with blood cell counts normal (one patient), and recurrent supraventricular tachycardia due to pericardial involvement (etoposide stopped by treating physician; one patient). The median number of treatment courses administered was two (range, one to seven courses). Five patients had objective responses to therapy, for a response rate of 23% (95% confidence interval [CI], 10% to 43%). All responses were partial. Four of the five responders were women. One of eight patients with stage IIIB disease responded, as did four of 17 stage IV patients. Six additional patients experienced temporary stabilization of measurable lesions. Response durations were 2, 4, 5, 5, and 6 months, respectively. The median duration of disease stabilization was 3 months. Median survival was 5 months (range, 1 to 19 months), and the actual 1-year survival was 28%. Toxicity Myelosuppression was the most frequent toxicity but was modest and easily tolerated in most patients. The median leukocyte nadir count for cycle 1 was 3,200/piL,
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WAITS ET AL
294 with four patients experiencing grade 3 and two experiencing grade 4 leukopenia (Table 2). Life-threatening leukopenia (< 1,000/p.L) occurred in four of 69 treatment cycles (6%), and four patients required hospitalization for treatment of neutropenia and fever. All four patients recovered and were discharged in good condition. Thrombocytopenia was not a problem, as no patient developed a platelet count less than 100,000/pLL, and there were no bleeding complications. Eight patients required RBC transfusions during therapy. Discontinuation of etoposide before completion of 21 days was required in 14 courses (20%). Five patients required dose reductions in subsequent courses because of myelosuppression. Of the 18 patients who received more than one course, 11 began the second course on day 28 as planned. In the remaining seven patients, the second course was started between days 29 and 35, for the following reasons: myelosuppression, four patients; patient request, two patients; stomatitis, one patient. Radiation therapy was associated with increased myelosuppression. Three of four patients who developed a leukocyte count of less than 1,000/IpL received previous or concomitant radiation therapy. Likewise, three of eight patients requiring RBC transfusions had received or were receiving radiation therapy. The observed nonhematologic toxicities are listed in Table 3. Severe alopecia was seen in all patients who completed at least one course of therapy. Nausea was also common (44% of patients), but was not severe in any patient (grade 1, seven patients; grade 2, five patients). Other side effects were uncommon and sometimes difficult to differentiate from the systemic effects of advanced lung cancer (eg, weakness, anorexia).
Table 3. Nonhematologic Toxicity Grade
Alopecia Nausea/vomiting Anorexia Stomatitis Weakness Diarrhea
Plasma etoposide concentrations were measured in 58 plasma samples drawn at various times after the oral administration of 100 mg of etoposide. A composite AUC is shown in Fig 1. The mean peak plasma concentration was 3.4 p.g/mL. A plasma etoposide concentration greater than 1 txg/mL was maintained for longer than 13 hours after an oral dose. The plasma AUC calculated from the composite curve in Fig 1 was 2,117
2
3
4
0 7 0 4 2 1
22 5 3 0 1 1
0 0 1 0 0 0
0 0 0 0 0 0
tjg/mL x min. The AUC is 88% of the predicted AUC after 100 mg of etoposide given intravenously." DISCUSSION
The results of this phase II study demonstrate modest activity of chronic oral etoposide when used as initial therapy for advanced NSCLC. Although scheduledependent differences in etoposide activity against NSCLC can be definitively addressed only with a randomized comparison, the 23% response rate obtained with our 21-day schedule of etoposide compares favorably with previously reported response rates using etoposide in standard schedules. Prior studies with etoposide as a single agent have used intravenous doses ranging from 60 to 150 mg/m 2/d for 1 to 5 days and produced response rates ranging from 5% to 15%.2,7-9 Oral etoposide has not
been extensively investigated; however, a 35% response 8 E
I SI 4 6
2
z 0 z
PharmacokineticStudies
1
uj z
I
0 0
013
a
0.8
w
.
I
•
*6 ·
0
0 a0. Uj
· ·
·
2 0.2
U) 4I -J
Table 2. Hematologic Toxicity--Cycle 1
I
U
Grade
Leukopenia Thrombocytopenia
8 2
3 0
4 0
2 0
2
I
I
I
4
6
8
I
I
I
I
10 12 14 16 TIME (HOURS)
I
18
I
I
I
20 22 24
Fig 1. The 24-hour AUC after a 100-mg oral etoposide dose. This composite curve was constructed using serum levels from multiple patients receiving this dose.
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ORAL ETOPOSIDE FOR NON-SMALL-CELL LUNG CANCER
rate using 200 mg/m 2 for 5 consecutive days, every 3 weeks has been reported.3 In addition, the response rate and median survival achieved with this prolonged schedule of oral etoposide is comparable to that seen with 12 combination regimens. -16 One other study has been reported using the same dose and schedule of etoposide as in our study. In a phase II trial conducted by the Hoosier Oncology Group, Saxman et al"7 observed two responses in 30 patients treated (7% response rate). The discrepancy in response rates between our study and that by Saxman et al is unexplained, but may be related to low numbers of patients and possibly to differences in the patient populations. The median performance status in both studies was approximately the same (80% on the Karnofsky scale in the Saxman et al study and 1 on the ECOG scale in our study). However, 80% of the patients in the study by Saxman et al were men, versus only 48% of our population. Four of our five responders were women; thus, this sex distribution difference in the two studies may account for some of the difference in response rates and would be consistent with other studies that have demonstrated increased response rates for women.'" Most patients tolerated this etoposide regimen well. Besides alopecia, myelosuppression was the most frequent drug-related toxicity, but was severe in only four of 69 courses. None of the patients in this group had received previous myelosuppressive systemic therapy, so it is not surprising that myelosuppression was less frequent and severe than that produced with this regimen in salvage therapy of either small-cell lung cancer or lymphoma.'"9 When compared with our phase II study in refractory small-cell lung cancer, the present group showed a higher median leukocyte nadir during
the first course of therapy (3,000/.LL v 1,800/gpL), fewer episodes of leukocyte counts less than 1,000/gLL (6% v 18% of courses), and fewer episodes of platelet counts less than 50,000/ýL (0% v 25%). The toxicity profile in this study was similar to that observed in the Hoosier Oncology Group Study, where patients were also previously untreated with systemic therapy. The mild to moderate myelosuppression observed in these patients suggests that this dose and schedule of etoposide could be integrated into combination regimens in previously untreated patients. Rigorous pharmacokinetic studies to determine percentage drug absorption and drug half-life were not performed in any of these patients. However, the composite AUC constructed using samples collected from multiple patients at varying times after drug administration provides useful data concerning this dose of oral etoposide. First, maximum plasma levels did not vary greatly among these patients. Second, plasma levels of greater than 1 jpg/mL were maintained for an estimated 13 hours of each 24-hour period. The duration of plasma drug levels greater than 1 1±g/mL was found by Slevin et al6 to correlate with tumor response better than peak drug levels or total AUC achieved. Finally, drug availability at a 100-mg dose appears higher (90% v 50%) than that previously found using oral etoposide at higher doses (ie, 400 mg). In summary, oral etoposide given at a dose of 50 mg/m 2/d for 21 consecutive days has moderate activity when given as initial systemic therapy for advanced NSCLC. This method of administration was well tolerated by most patients, and integration into a combination regimen should be feasible. The place of oral etoposide in the therapy of NSCLC awaits further study.
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the Eastern Cooperative Oncology Group. J Clin Oncol 7:16021613, 1989 13. Ruckdeschel JC, Finkelstein DM, Mason BA, et al: Chemotherapy for metastatic non-small-cell bronchogenic carcinoma: EST 2575 generation V-A randomized comparison of four cisplatin-containing regimens. J Clin Oncol 3:72-79, 1985 14. Rapp E, Pater JL, Willan A, et al: Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer-Report of a Canadian multicenter randomized trial. J Clin Oncol 6:633-641, 1988 15. Ruckdeschel JC, Finkelstein DM, Ettinger DS, et al: A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol 4:14-22, 1986 16. Klastersky J, Sculier JP, Lacroix H, et al: A randomized
study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer protocol 07861. J Clin Oncol 8:1556-1562, 1990 17. Saxman S, Logie K, Stephens D, et al: Phase II trial of daily oral etoposide in patients with surgically unresectable non-small cell lung cancer. Proc Am Soc Clin Oncol 9:119, 1990 18. O'Connell JP, Kris MG, Gralla RJ, et al: Frequency and prognostic importance of pretreatment clinical characteristics in patients with advanced non-small-cell lung cancer treated with combination chemotherapy. J Clin Oncol 4:1604-1614, 1986 19. Hainsworth JD, Johnson DH, Greco FA: Chronic daily administration of oral etoposide in refractory lymphoma-A phase II trial. Eur J Cancer 26:818-821, 1990
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