Prolonged Administration of Oral Etoposide in Patients With Relapsed or Refractory Small-Cell Lung Cancer: A Phase II Trial By David H. Johnson, F. Anthony Greco, John Strupp, Kenneth R. Hande, and John D. Hainsworth Twenty-two patients with recurrent small-cell lung
cancer (SCLC) were treated with single-agent etoposide 50 mg/m 2 /d by mouth for 21 consecutive days. Eleven patients had received previous chemotherapy with cyclophosphamide, doxorubicin, and vincristine (CAV) or etoposide (CAE) or both (CAVE). Four of the latter patients also received salvage treatment with cisplatin and etoposide (EP). Nine patients had been treated with EP as induction therapy, while two patients had received high-dose cyclophosphamide, etoposide and cisplatin (HDCEP). Altogether, 18 patients had received previous intravenous etoposide. The median time off chemotherapy was 4.5 months (range, 1 to 28.9 months). Ten patients (45.5%; 95% confidence interval [CI], 27% to 65%) achieved a complete or partial response. Responses were most common in patients who had responded to previous chemotherapy and who had not received any treat-
HE TREATMENT of small-cell lung cancer (SCLC) has not improved greatly during the past 5 to 10 years.1, 2 Unfortunately, there is also little possibility of a major therapeutic advance in the near future given the paucity of new agents with novel mechanisms of action.3 As a result of the lack of new agents for this disease, our group has tried to investigate new ways of using currently available agents in an attempt to improve treatment results. Etoposide is a commonly used agent with broad antineoplastic activity and has proved particularly effective against SCLC.4 Laboratory and clinical data indicate etoposide is both phase-specific and scheduledependent. 5" Because of its schedule dependency, etoposide is usually administered over 3 to 5 days.4'8 However, longer durations of etoposide administration have not been extensively evaluated. With the availability of oral etoposide, more prolonged administration of this agent is easily achieved. We recently reported on the results of a phase I trial in which etoposide was given by mouth for 21 consecutive days.9 In addition to determining a maximally tolerated dose of 50 mg/m 2/d, we observed objective responses in several malignancies generally con-
ment in the 90 days before initiation of oral etoposide. Median response duration was 4 months (range, 1.5 to 9.5 months) and median survival was 3.5 + months (range, 1.0 to 15+ months). Leukocyte and platelet nadirs were 1,800/uL and 160,000/pL, respectively, during cycle 1 of treatment and occurred between days 21 and 28. Overall, total leukocyte count decreased to less than 1,000/gL during 10 of 56 cycles (18%). Five patients required six hospitalizations for neutropenia and fever. There were two toxic deaths due to sepsis. Platelet counts less than 50,000/ML occurred in 14 cycles (25%). Alopecia developed in all patients; gastrointestinal toxicity was uncommon. This schedule of etoposide administration warrants further study in combination with other active agents in previously untreated patients with SCLC. J Clin Oncol 8:1613-1617. e 1990 by American Society of ClinicalOncology.
sidered to be unresponsive to etoposide.' The promising results of the phase I study prompted us to undertake a phase II study using a 21-day schedule of etoposide administration in previously treated SCLC patients. PATIENTS AND METHODS Twenty-two patients were entered into this phase II trial between July 1988 and January 1990. Eligibility requirements included a histologic diagnosis of SCLC and prior treatment with at least one combination chemotherapy regimen. Additional eligibility requirements included measurable disease, performance status of _s 2 on the Eastern
From the Division of Medical Oncology, Department of Medicine, Vanderbilt University Medical Center, and the Nashville Veterans Administration Medical Center, Nashville, TN. Submitted November 16, 1989; accepted April 11, 1990. Supported in part by a grantfrom Bristol-Myers, and by the Veterans Administration. Presented in part at the 26th Annual Meeting of the American Society of Clinical Oncology, May 1990, Washington, DC. Address reprintrequests to David H. Johnson, MD, 1956 The VanderbiltClinic, Nashville, TN 37232-5536. © 1990 by AmericanSociety of Clinical Oncology. 0732-183X/90/0810-0004$3.00/0
Journal of Clinical Oncology, Vol 8, No 10 (October), 1990: pp 1613-1617
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Cooperative Oncology Group scale, total leukocyte count _> 3,000/1uL, a platelet count > 100,000/pjL, serum creatinine less than 2 mg/dL, serum bilirubin less than 2 mg/dL (unless due to disease involving the liver), a life expectancy of _ 12 weeks, no therapy for at least 3 weeks before initiation of oral etoposide, and signed informed consent. Before receiving oral etoposide, all patients had the following studies performed: complete blood cell (CBC) counts with differential, electrolytes, liver function chemistries, 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/m2/d. Although food has not been shown to interfere with etoposide absorption,' 0 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 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 with the number of capsules to be taken written in for each treatment day in order to insure accuracy. A "pill count" was conducted at the completion of each cycle of therapy. Consenting patients had serum etoposide levels obtained as part of an ongoing pharmacokinetics study. During treatment, a CBC, differential, and platelet count were obtained weekly. Etoposide was discontinued if the leukocyte count fell below 2,000/gL and/or platelets fell below 75,000/fL. At the end of each 21-day cycle, etoposide was discontinued and patients underwent an evaluation on day 28. Patients who demonstrated an objective response or stable disease were given another cycle of oral etoposide. However, therapy was not initiated until counts were adequately recovered (ie, leukocytes > 3,000/ipL and platelets > 100,000/ML). Patients who had leukocyte nadirs less than 2,000/FL 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 included 15 men and seven women; median age of 62 years (range, 46 to 82 years); median performance status of 1 (0 to 2); median number of prior chemotherapy regimens, one (one to three); and median time off chemotherapy before starting oral etoposide, 4.5 months (1 to 28.9 months). Eleven patients had received previous cyclophosphamide, doxorubicin, and either vincristine (CAV) or etoposide (CAE) or both (CAVE). Four of these patients
also received "salvage" therapy with etoposide and cisplatin (EP) before treatment with oral etoposide. Nine patients were treated initially with EP with or without thoracic radiotherapy, while two patients had received high-dose cyclophosphamide, etoposide, and cisplatin (HDCEP) in conjunction with granulocyte-macrophage colony-stimulating factor (GM-CSF). Four patients had not received any etoposide before entering this study, all of whom had received CAV. Twenty of 22 patients had responded to the chemotherapy regimen administered before the institution of oral etoposide. Two patients had not responded to any previous chemotherapy. Two additional patients were switched to oral etoposide after failing to respond to salvage chemotherapy (EP, one; lomustine [CCNU] plus methotrexate, one). The latter patients had responded to initial induction chemotherapy. RESULTS
Response and Survival All 22 patients were assessable for response. There were two complete and eight partial remissions for an overall response rate of 45.5% (95% confidence interval [CI], 27% to 65%11). Although our numbers are small, prior etoposide exposure did not appear to influence response to oral etoposide. Of the four patients without previous intravenous etoposide exposure, two responded. On the other hand, eight of 18 patients who had received previous etoposide had a response (P = 1.0; Fisher's exact test). Patients who failed to respond to initial induction therapy or who had progressed during salvage therapy were unlikely to respond to oral etoposide (P = .096, Fisher's exact test) (Table 1). Also, patients who had been off chemotherapy < 90 days were less likely to respond (P = .03, Fisher's exact test) (Table 2). Median duration of response was 4 months (range, 1.5 to 9.5 months), while median survival was 3.5+ months (range, 1.0 to 15 + months). Toxicity Patients received one to six cycles of oral
etoposide (median, two). As expected, the preTable 1. Response to Oral Etoposide Relative to Response to Prior Chemotherapy Response to Previous Chemotherapy
Complete Partial Progression
Response to Oral Etoposide CR
1 1 -
PR
SD
PD
Total
4 4 -
1 1 1
6 3
5/6 5/12 0/4
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
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21-DAY ORAL ETOPOSIDE IN SCLC Table 2. Response to Oral Etoposide Relative to Time Off Chemotherapy Time Off Chemotherapy Response to Oral Etoposide
< 90 Days
> 90 Days
Complete Partial Stable Progression Total responses to oral etoposide
1 0 2 5 1 (12.5%)
1 8 1 4 9 (64%)
dominant toxicity was myelosuppression, which was most severe in the most heavily pretreated individuals. Nadir leukocyte and platelet counts usually occurred between days 21 and 28. Median leukocyte nadir during cycle 1 was 1,800/gL (range, 200 to 6,700/AL), while the median platelet nadir was 160,000/AL (range, 10,000 to 399,000/AiL). Median (+ SE) leukocyte counts, hematocrit, and platelet counts during cycle 1 are shown in Fig 1. Of the 56 cycles of oral etoposide administered, 10 (18%) were associated with life-threatening leukopenia (ie, leukocytes < 1,000/1L) and 14 (25%) with severe thrombocytopenia (ie, platelets < 50,000/uL). Virtually all episodes of severe myelosuppression occurred during cycle 1 as dose adjustments were made in subsequent cycles. Etoposide was discontinued in four patients on day 14 because of leukopenia (< 2,000/ML) or thrombocytopenia (< 75,000/AL) or both. Etoposide was discontinued in two additional patients on days 17 and 18 because of thrombocytopenia. Sixteen patients completed a full 21 days of oral etoposide, although nine patients experienced their lowest leukocyte or platelet counts on day 21. There were six episodes of fever and neutropenia (granulocyte count < 500/ML) resulting in two toxic deaths (9%). The septic deaths occurred in heavily pretreated patients. Three patients required platelet transfusions for platelet counts less than 20,000/gL. Although no hemorrhagic episode was documented, one patient required a hospital admission due to a fall in hematocrit from 33% to 13% during cycle 1. No bleeding was identified. The latter patient had previously received HDCEP plus GM-CSF during which he had experienced prolonged myelosuppression. The median interval between the initiation of oral etoposide and the start of cycle 2 was 36 days (range, 27 to 57 days). All patients at risk experienced total or near
total alopecia. Additional toxicities were generally mild. Only one patient complained of nausea, which was easily controlled with prochlorperazine. There were no episodes of emesis. Mild mucositis occurred in three patients, all of whom experienced simultaneous leukopenia less than 1,000/gL. DISCUSSION The 45.5% response rate obtained with our 21-day schedule of low-dose oral etoposide is higher than that usually reported for singleagent etoposide in recurrent SCLC.' 2-'5 In previous studies, etoposide usually was given intrave7 -J
6 5
X
0
4 3
a0 o C)
2
co x
1 0
4) 35U
300
"-" 250 x
200 0)
150 100 50
0 40
,
35 E
E E o
30
E
I
25
I
0
7
14
21
28
35
Treatment Day Fig 1. Median leukocyte counts, platelet counts, and hematocrit levels during cycle 1 of oral etoposide. Error bars: ± SE.
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JOHNSON ET AL
nously in a standard 3- to 5-day schedule, and response rates were typically 10% or less.'13,14 The intravenous dosages of etoposide have ranged from 80 mg/m 2/d for 5 consecutive days to 125 mg/m 2/d for 3 days.'13' 14 One group reported a
response rate of 23% using oral etoposide (200 mg/d) for 5 consecutive days.' 5 Unlike the patient populations reported in earlier studies using single-agent etoposide in relapsed SCLC, most of our patients had received etoposide as a component of their induction regimens. Although we recognize the difficulties of comparing results from individual pilot studies, these observations suggest the 21-day schedule of oral etoposide may be more efficacious in recurrent SCLC. In addition, the results obtained with our 21-day schedule of etoposide administration rival that of the most active, multiagent "salvage" regimens used in relapsed SCLC.'1216 For example, we observed a 52% response rate using etoposide and cisplatin intravenously over 3 consecutive days in SCLC patients relapsing after CAV-based chemotherapy. 16 The response rates to our chronic oral etoposide regimen and our salvage EP regimen are not significantly different. As reported by other investigators,1 7 responses were most common in patients who had been off chemotherapy for at least 90 days and who had responded to previous treatment. As noted above, prior exposure to etoposide did not appear to influence the likelihood of response to oral etoposide. No patient who failed to respond to initial chemotherapy subsequently responded to oral etoposide. The gastrointestinal absorption of etoposide is known to be erratic 8s's and it is possible that some nonresponding patients failed to obtain adequate absorption of the orally administered etoposide. Not all of our patients had plasma levels measured, thus we cannot be certain each patient was totally compliant. However, as all patients at risk did experience alopecia, it is probably safe to assume our patients were reasonably compliant. In patients who did have plasma etoposide levels measured, trough levels drawn just before the next daily dose ranged from 0.5 to 6.0 Ag/mL (K. Hande, unpublished data, 1990). On the basis of these preliminary data, serum etoposide levels greater than 0.5 pg/mL appear to have been maintained for most of the 21 days of treatment. With a half-life of 8 hours, peak
serum concentrations would be estimated to be 2 to 20 Ag/mL. It is possible that the lower total dose given to our patients resulted in more complete absorption, which in turn could account for the higher response rate. Studies to assess this possibility are ongoing. The hematologic toxicity of chronic oral etoposide was as expected in this population, with the most significant toxicities occurring during cycle 1 of treatment. Patients who tolerated cycle 1 without major difficulty were unlikely to encounter severe hematologic toxicities during subsequent cycles of therapy even without dose reductions. For those patients who did experience severe myelosuppression during cycle 1, a one time 25% dose reduction was usually all that was necessary to minimize myelosuppression during later courses of treatment. A possible explanation for the potential superiority of the 21-day schedule of etoposide administration can be obtained from two recent clinical trials conducted by Slevin et al.19' 20 These investigators randomized previously untreated SCLC patients to receive single-agent etoposide 500 mg/m2 intravenously over 24 hours, or to receive the same dose divided into 5 daily doses of 100 mg/m 2 over 2 hours. Overall response (89% v 10%) and median survival (10 months v 6.3 months) were significantly improved with the 5-day schedule confirming the schedule dependency of etoposide in this neoplasm.19 In attempting to explain the improved efficacy of the longer regimen, the pharmocokinetics of the two schedules were investigated. 2 1 The 5-day regimen resulted in five well-defined, short-lived peak plasma levels of etoposide compared with a single broad and sustained peak seen with the 1-day schedule. The length of time etoposide concentrations exceeded 10 Ag/mL in the 1-day regimen was double that observed in the 5-day schedule. On the other hand, etoposide concentrations greater than 1 Aig/mL were maintained for a longer interval with the 5-day schedule as compared with the 1-day treatment. These data led Slevin et al to conclude that the longer duration of low serum levels of etoposide obtained with the 5-day regimen was responsible for the greater efficacy of the longer schedule, since high etoposide concentration per se did not appear to account for the schedule dependency of etoposide.'1921 In
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21-DAY ORAL ETOPOSIDE IN SCLC
vitro studies using lymphoma and bronchogenic carcinoma cell lines would appear to support this hypothesis. 7 More recently, Slevin et al compared a 5-day regimen of etoposide administration with an 8-day schedule but observed no differences in response or survival. 20 However, the duration of etoposide levels greater than 1 ug/mL in the 8-day regimen was found to be identical to that obtained with their 5-day regimen, which may explain their results. Interestingly, the hematologic toxicity of the 8-day regimen was significantly less than the 5-day regimen suggesting
that prolonged exposure to low levels of VP-16 may have enhanced cytotoxicity with less myelosuppression.20 In summary, a 21-day schedule of oral etoposide 50 mg/m 2/d is an active treatment for recurrent SCLC. Given the activity of this schedule, further study in previously untreated patients is warranted. Such studies are in progress. ACKNOWLEDGMENT The authors appreciate the assistance of Melodie Thomas, RN, and Sheryl Frazier, RN, in data acquisition, and thank Leigh Witherspoon who typed the manuscript.
REFERENCES 1. Johnson DH, Greco FA: Small cell carcinoma of the lung. Crit Rev Oncol Hematol 4:303-336, 1986 2. Seifter EJ, Ihde DC: Therapy of small cell lung cancer: A perspective on two decades of clinical research. Semin Oncol 15:278-299, 1988 3. Johnson DH: New drugs in the management of small cell lung cancer. Lung Cancer 5:221-231, 1989 4. Pedersen AG, Hansen HH: Etoposide (VP-16) in the treatment of lung cancer. Cancer Treat Rev 10:245-264, 1983 5. Dombernowsky P, Nissen NI: Schedule dependency of the antileukemic activity of the podophyllotoxin-derivative VP-16-213 (NSC-141540) in L1210 leukemia. Acta Path Microbiol Scand (A) 81:715-724, 1973 6. Cavalli F, Sonntag RW, Jungi F, et al: VP-16-213 monotherapy for remission induction of small cell lung cancer: A randomized trial using three dosage schedules. Cancer Treat Rep 62:473-475, 1978 7. Wolff SN, Grosh WW, Prater K, et al: In vitro pharmacodynamic evaluation of VP- 16-213 and implications for chemotherapy. Cancer Chemother Pharmacol 19:246249, 1987 8. Clark PI, Slevin ML: The clinical pharmacology of etoposide and teniposide. Clin Pharmacokinet 12:223-252, 1987 9. 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 10. Harvey VJ, Slevin ML, Joel SP, et al: The effect of food and concurrent chemotherapy on the bioavailability of oral etoposide. Br J Cancer 52:363-367, 1985 11. Simon R: Confidence intervals for reporting results of clinical trials. Ann Intern Med 105:429-435, 1986
12. Evans WK, Feld R, Osoba D, et al: VP-16 alone and in combination with cisplatin in previously treated patients with small cell lung cancer. Cancer 53:1461-1466, 1984 13. Issell BF, Einhorn LH, Comis RL, et al: Multicenter phase II trial of etoposide in refractory small cell lung cancer. Cancer Treat Rep 69:127-128, 1985 14. Antman K, Pomfret E, Karp G, et al: Phase II trial of etoposide in previously treated small cell carcinoma of the lung. Cancer Treat Rep 68:1413-1414, 1984 15. Matsui Y, Oshima S, Kado M, et al: Phase II study of oral VP-16-213 in small-cell lung cancer. Cancer 60:28822885, 1987 16. Porter LL, Johnson DH, Hainsworth JD, et al: Cisplatin and etoposide combination chemotherapy for refractory small cell carcinoma of the lung. Cancer Treat Rep 69:479481, 1985 17. Giaccone G: Identification of new drugs in pretreated patients with small-cell lung cancer. Eur J Cancer Clin Oncol 25:411-413, 1989 18. Harvey VJ, Slevin ML, Joel SP, et al: Variable bioavailability following repeated oral doses of etoposide. Eur J Cancer Clin Oncol21:1315-1319, 1985 19. Slevin ML, Clark PI, Joel SP, et al: A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 7:13331340, 1989 20. Slevin ML, Clark PI, Joel SP, et al: A randomized trial to examine the effect of more extended scheduling of etoposide administration in small-cell lung cancer. Proc Am Soc Clin Oncol 8:236, 1989 (abstr) 21. Clark PI, Joel SP, Slevin ML: A pharmacokinetic hypothesis for the clinical efficacy of etoposide in small-cell lung cancer. Proc Am Soc Clin Oncol 8:66, 1989 (abstr)
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cancer (SCLC) were treated with single-agent etoposide 50 mg/m 2 /d by mouth for 21 consecutive days. Eleven patients had received previous chemotherapy with cyclophosphamide, doxorubicin, and vincristine (CAV) or etoposide (CAE) or both (CAVE). Four of the latter patients also received salvage treatment with cisplatin and etoposide (EP). Nine patients had been treated with EP as induction therapy, while two patients had received high-dose cyclophosphamide, etoposide and cisplatin (HDCEP). Altogether, 18 patients had received previous intravenous etoposide. The median time off chemotherapy was 4.5 months (range, 1 to 28.9 months). Ten patients (45.5%; 95% confidence interval [CI], 27% to 65%) achieved a complete or partial response. Responses were most common in patients who had responded to previous chemotherapy and who had not received any treat-
HE TREATMENT of small-cell lung cancer (SCLC) has not improved greatly during the past 5 to 10 years.1, 2 Unfortunately, there is also little possibility of a major therapeutic advance in the near future given the paucity of new agents with novel mechanisms of action.3 As a result of the lack of new agents for this disease, our group has tried to investigate new ways of using currently available agents in an attempt to improve treatment results. Etoposide is a commonly used agent with broad antineoplastic activity and has proved particularly effective against SCLC.4 Laboratory and clinical data indicate etoposide is both phase-specific and scheduledependent. 5" Because of its schedule dependency, etoposide is usually administered over 3 to 5 days.4'8 However, longer durations of etoposide administration have not been extensively evaluated. With the availability of oral etoposide, more prolonged administration of this agent is easily achieved. We recently reported on the results of a phase I trial in which etoposide was given by mouth for 21 consecutive days.9 In addition to determining a maximally tolerated dose of 50 mg/m 2/d, we observed objective responses in several malignancies generally con-
ment in the 90 days before initiation of oral etoposide. Median response duration was 4 months (range, 1.5 to 9.5 months) and median survival was 3.5 + months (range, 1.0 to 15+ months). Leukocyte and platelet nadirs were 1,800/uL and 160,000/pL, respectively, during cycle 1 of treatment and occurred between days 21 and 28. Overall, total leukocyte count decreased to less than 1,000/gL during 10 of 56 cycles (18%). Five patients required six hospitalizations for neutropenia and fever. There were two toxic deaths due to sepsis. Platelet counts less than 50,000/ML occurred in 14 cycles (25%). Alopecia developed in all patients; gastrointestinal toxicity was uncommon. This schedule of etoposide administration warrants further study in combination with other active agents in previously untreated patients with SCLC. J Clin Oncol 8:1613-1617. e 1990 by American Society of ClinicalOncology.
sidered to be unresponsive to etoposide.' The promising results of the phase I study prompted us to undertake a phase II study using a 21-day schedule of etoposide administration in previously treated SCLC patients. PATIENTS AND METHODS Twenty-two patients were entered into this phase II trial between July 1988 and January 1990. Eligibility requirements included a histologic diagnosis of SCLC and prior treatment with at least one combination chemotherapy regimen. Additional eligibility requirements included measurable disease, performance status of _s 2 on the Eastern
From the Division of Medical Oncology, Department of Medicine, Vanderbilt University Medical Center, and the Nashville Veterans Administration Medical Center, Nashville, TN. Submitted November 16, 1989; accepted April 11, 1990. Supported in part by a grantfrom Bristol-Myers, and by the Veterans Administration. Presented in part at the 26th Annual Meeting of the American Society of Clinical Oncology, May 1990, Washington, DC. Address reprintrequests to David H. Johnson, MD, 1956 The VanderbiltClinic, Nashville, TN 37232-5536. © 1990 by AmericanSociety of Clinical Oncology. 0732-183X/90/0810-0004$3.00/0
Journal of Clinical Oncology, Vol 8, No 10 (October), 1990: pp 1613-1617
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Cooperative Oncology Group scale, total leukocyte count _> 3,000/1uL, a platelet count > 100,000/pjL, serum creatinine less than 2 mg/dL, serum bilirubin less than 2 mg/dL (unless due to disease involving the liver), a life expectancy of _ 12 weeks, no therapy for at least 3 weeks before initiation of oral etoposide, and signed informed consent. Before receiving oral etoposide, all patients had the following studies performed: complete blood cell (CBC) counts with differential, electrolytes, liver function chemistries, 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/m2/d. Although food has not been shown to interfere with etoposide absorption,' 0 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 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 with the number of capsules to be taken written in for each treatment day in order to insure accuracy. A "pill count" was conducted at the completion of each cycle of therapy. Consenting patients had serum etoposide levels obtained as part of an ongoing pharmacokinetics study. During treatment, a CBC, differential, and platelet count were obtained weekly. Etoposide was discontinued if the leukocyte count fell below 2,000/gL and/or platelets fell below 75,000/fL. At the end of each 21-day cycle, etoposide was discontinued and patients underwent an evaluation on day 28. Patients who demonstrated an objective response or stable disease were given another cycle of oral etoposide. However, therapy was not initiated until counts were adequately recovered (ie, leukocytes > 3,000/ipL and platelets > 100,000/ML). Patients who had leukocyte nadirs less than 2,000/FL 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 included 15 men and seven women; median age of 62 years (range, 46 to 82 years); median performance status of 1 (0 to 2); median number of prior chemotherapy regimens, one (one to three); and median time off chemotherapy before starting oral etoposide, 4.5 months (1 to 28.9 months). Eleven patients had received previous cyclophosphamide, doxorubicin, and either vincristine (CAV) or etoposide (CAE) or both (CAVE). Four of these patients
also received "salvage" therapy with etoposide and cisplatin (EP) before treatment with oral etoposide. Nine patients were treated initially with EP with or without thoracic radiotherapy, while two patients had received high-dose cyclophosphamide, etoposide, and cisplatin (HDCEP) in conjunction with granulocyte-macrophage colony-stimulating factor (GM-CSF). Four patients had not received any etoposide before entering this study, all of whom had received CAV. Twenty of 22 patients had responded to the chemotherapy regimen administered before the institution of oral etoposide. Two patients had not responded to any previous chemotherapy. Two additional patients were switched to oral etoposide after failing to respond to salvage chemotherapy (EP, one; lomustine [CCNU] plus methotrexate, one). The latter patients had responded to initial induction chemotherapy. RESULTS
Response and Survival All 22 patients were assessable for response. There were two complete and eight partial remissions for an overall response rate of 45.5% (95% confidence interval [CI], 27% to 65%11). Although our numbers are small, prior etoposide exposure did not appear to influence response to oral etoposide. Of the four patients without previous intravenous etoposide exposure, two responded. On the other hand, eight of 18 patients who had received previous etoposide had a response (P = 1.0; Fisher's exact test). Patients who failed to respond to initial induction therapy or who had progressed during salvage therapy were unlikely to respond to oral etoposide (P = .096, Fisher's exact test) (Table 1). Also, patients who had been off chemotherapy < 90 days were less likely to respond (P = .03, Fisher's exact test) (Table 2). Median duration of response was 4 months (range, 1.5 to 9.5 months), while median survival was 3.5+ months (range, 1.0 to 15 + months). Toxicity Patients received one to six cycles of oral
etoposide (median, two). As expected, the preTable 1. Response to Oral Etoposide Relative to Response to Prior Chemotherapy Response to Previous Chemotherapy
Complete Partial Progression
Response to Oral Etoposide CR
1 1 -
PR
SD
PD
Total
4 4 -
1 1 1
6 3
5/6 5/12 0/4
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
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21-DAY ORAL ETOPOSIDE IN SCLC Table 2. Response to Oral Etoposide Relative to Time Off Chemotherapy Time Off Chemotherapy Response to Oral Etoposide
< 90 Days
> 90 Days
Complete Partial Stable Progression Total responses to oral etoposide
1 0 2 5 1 (12.5%)
1 8 1 4 9 (64%)
dominant toxicity was myelosuppression, which was most severe in the most heavily pretreated individuals. Nadir leukocyte and platelet counts usually occurred between days 21 and 28. Median leukocyte nadir during cycle 1 was 1,800/gL (range, 200 to 6,700/AL), while the median platelet nadir was 160,000/AL (range, 10,000 to 399,000/AiL). Median (+ SE) leukocyte counts, hematocrit, and platelet counts during cycle 1 are shown in Fig 1. Of the 56 cycles of oral etoposide administered, 10 (18%) were associated with life-threatening leukopenia (ie, leukocytes < 1,000/1L) and 14 (25%) with severe thrombocytopenia (ie, platelets < 50,000/uL). Virtually all episodes of severe myelosuppression occurred during cycle 1 as dose adjustments were made in subsequent cycles. Etoposide was discontinued in four patients on day 14 because of leukopenia (< 2,000/ML) or thrombocytopenia (< 75,000/AL) or both. Etoposide was discontinued in two additional patients on days 17 and 18 because of thrombocytopenia. Sixteen patients completed a full 21 days of oral etoposide, although nine patients experienced their lowest leukocyte or platelet counts on day 21. There were six episodes of fever and neutropenia (granulocyte count < 500/ML) resulting in two toxic deaths (9%). The septic deaths occurred in heavily pretreated patients. Three patients required platelet transfusions for platelet counts less than 20,000/gL. Although no hemorrhagic episode was documented, one patient required a hospital admission due to a fall in hematocrit from 33% to 13% during cycle 1. No bleeding was identified. The latter patient had previously received HDCEP plus GM-CSF during which he had experienced prolonged myelosuppression. The median interval between the initiation of oral etoposide and the start of cycle 2 was 36 days (range, 27 to 57 days). All patients at risk experienced total or near
total alopecia. Additional toxicities were generally mild. Only one patient complained of nausea, which was easily controlled with prochlorperazine. There were no episodes of emesis. Mild mucositis occurred in three patients, all of whom experienced simultaneous leukopenia less than 1,000/gL. DISCUSSION The 45.5% response rate obtained with our 21-day schedule of low-dose oral etoposide is higher than that usually reported for singleagent etoposide in recurrent SCLC.' 2-'5 In previous studies, etoposide usually was given intrave7 -J
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Treatment Day Fig 1. Median leukocyte counts, platelet counts, and hematocrit levels during cycle 1 of oral etoposide. Error bars: ± SE.
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1616
JOHNSON ET AL
nously in a standard 3- to 5-day schedule, and response rates were typically 10% or less.'13,14 The intravenous dosages of etoposide have ranged from 80 mg/m 2/d for 5 consecutive days to 125 mg/m 2/d for 3 days.'13' 14 One group reported a
response rate of 23% using oral etoposide (200 mg/d) for 5 consecutive days.' 5 Unlike the patient populations reported in earlier studies using single-agent etoposide in relapsed SCLC, most of our patients had received etoposide as a component of their induction regimens. Although we recognize the difficulties of comparing results from individual pilot studies, these observations suggest the 21-day schedule of oral etoposide may be more efficacious in recurrent SCLC. In addition, the results obtained with our 21-day schedule of etoposide administration rival that of the most active, multiagent "salvage" regimens used in relapsed SCLC.'1216 For example, we observed a 52% response rate using etoposide and cisplatin intravenously over 3 consecutive days in SCLC patients relapsing after CAV-based chemotherapy. 16 The response rates to our chronic oral etoposide regimen and our salvage EP regimen are not significantly different. As reported by other investigators,1 7 responses were most common in patients who had been off chemotherapy for at least 90 days and who had responded to previous treatment. As noted above, prior exposure to etoposide did not appear to influence the likelihood of response to oral etoposide. No patient who failed to respond to initial chemotherapy subsequently responded to oral etoposide. The gastrointestinal absorption of etoposide is known to be erratic 8s's and it is possible that some nonresponding patients failed to obtain adequate absorption of the orally administered etoposide. Not all of our patients had plasma levels measured, thus we cannot be certain each patient was totally compliant. However, as all patients at risk did experience alopecia, it is probably safe to assume our patients were reasonably compliant. In patients who did have plasma etoposide levels measured, trough levels drawn just before the next daily dose ranged from 0.5 to 6.0 Ag/mL (K. Hande, unpublished data, 1990). On the basis of these preliminary data, serum etoposide levels greater than 0.5 pg/mL appear to have been maintained for most of the 21 days of treatment. With a half-life of 8 hours, peak
serum concentrations would be estimated to be 2 to 20 Ag/mL. It is possible that the lower total dose given to our patients resulted in more complete absorption, which in turn could account for the higher response rate. Studies to assess this possibility are ongoing. The hematologic toxicity of chronic oral etoposide was as expected in this population, with the most significant toxicities occurring during cycle 1 of treatment. Patients who tolerated cycle 1 without major difficulty were unlikely to encounter severe hematologic toxicities during subsequent cycles of therapy even without dose reductions. For those patients who did experience severe myelosuppression during cycle 1, a one time 25% dose reduction was usually all that was necessary to minimize myelosuppression during later courses of treatment. A possible explanation for the potential superiority of the 21-day schedule of etoposide administration can be obtained from two recent clinical trials conducted by Slevin et al.19' 20 These investigators randomized previously untreated SCLC patients to receive single-agent etoposide 500 mg/m2 intravenously over 24 hours, or to receive the same dose divided into 5 daily doses of 100 mg/m 2 over 2 hours. Overall response (89% v 10%) and median survival (10 months v 6.3 months) were significantly improved with the 5-day schedule confirming the schedule dependency of etoposide in this neoplasm.19 In attempting to explain the improved efficacy of the longer regimen, the pharmocokinetics of the two schedules were investigated. 2 1 The 5-day regimen resulted in five well-defined, short-lived peak plasma levels of etoposide compared with a single broad and sustained peak seen with the 1-day schedule. The length of time etoposide concentrations exceeded 10 Ag/mL in the 1-day regimen was double that observed in the 5-day schedule. On the other hand, etoposide concentrations greater than 1 Aig/mL were maintained for a longer interval with the 5-day schedule as compared with the 1-day treatment. These data led Slevin et al to conclude that the longer duration of low serum levels of etoposide obtained with the 5-day regimen was responsible for the greater efficacy of the longer schedule, since high etoposide concentration per se did not appear to account for the schedule dependency of etoposide.'1921 In
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1617
21-DAY ORAL ETOPOSIDE IN SCLC
vitro studies using lymphoma and bronchogenic carcinoma cell lines would appear to support this hypothesis. 7 More recently, Slevin et al compared a 5-day regimen of etoposide administration with an 8-day schedule but observed no differences in response or survival. 20 However, the duration of etoposide levels greater than 1 ug/mL in the 8-day regimen was found to be identical to that obtained with their 5-day regimen, which may explain their results. Interestingly, the hematologic toxicity of the 8-day regimen was significantly less than the 5-day regimen suggesting
that prolonged exposure to low levels of VP-16 may have enhanced cytotoxicity with less myelosuppression.20 In summary, a 21-day schedule of oral etoposide 50 mg/m 2/d is an active treatment for recurrent SCLC. Given the activity of this schedule, further study in previously untreated patients is warranted. Such studies are in progress. ACKNOWLEDGMENT The authors appreciate the assistance of Melodie Thomas, RN, and Sheryl Frazier, RN, in data acquisition, and thank Leigh Witherspoon who typed the manuscript.
REFERENCES 1. Johnson DH, Greco FA: Small cell carcinoma of the lung. Crit Rev Oncol Hematol 4:303-336, 1986 2. Seifter EJ, Ihde DC: Therapy of small cell lung cancer: A perspective on two decades of clinical research. Semin Oncol 15:278-299, 1988 3. Johnson DH: New drugs in the management of small cell lung cancer. Lung Cancer 5:221-231, 1989 4. Pedersen AG, Hansen HH: Etoposide (VP-16) in the treatment of lung cancer. Cancer Treat Rev 10:245-264, 1983 5. Dombernowsky P, Nissen NI: Schedule dependency of the antileukemic activity of the podophyllotoxin-derivative VP-16-213 (NSC-141540) in L1210 leukemia. Acta Path Microbiol Scand (A) 81:715-724, 1973 6. Cavalli F, Sonntag RW, Jungi F, et al: VP-16-213 monotherapy for remission induction of small cell lung cancer: A randomized trial using three dosage schedules. Cancer Treat Rep 62:473-475, 1978 7. Wolff SN, Grosh WW, Prater K, et al: In vitro pharmacodynamic evaluation of VP- 16-213 and implications for chemotherapy. Cancer Chemother Pharmacol 19:246249, 1987 8. Clark PI, Slevin ML: The clinical pharmacology of etoposide and teniposide. Clin Pharmacokinet 12:223-252, 1987 9. 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 10. Harvey VJ, Slevin ML, Joel SP, et al: The effect of food and concurrent chemotherapy on the bioavailability of oral etoposide. Br J Cancer 52:363-367, 1985 11. Simon R: Confidence intervals for reporting results of clinical trials. Ann Intern Med 105:429-435, 1986
12. Evans WK, Feld R, Osoba D, et al: VP-16 alone and in combination with cisplatin in previously treated patients with small cell lung cancer. Cancer 53:1461-1466, 1984 13. Issell BF, Einhorn LH, Comis RL, et al: Multicenter phase II trial of etoposide in refractory small cell lung cancer. Cancer Treat Rep 69:127-128, 1985 14. Antman K, Pomfret E, Karp G, et al: Phase II trial of etoposide in previously treated small cell carcinoma of the lung. Cancer Treat Rep 68:1413-1414, 1984 15. Matsui Y, Oshima S, Kado M, et al: Phase II study of oral VP-16-213 in small-cell lung cancer. Cancer 60:28822885, 1987 16. Porter LL, Johnson DH, Hainsworth JD, et al: Cisplatin and etoposide combination chemotherapy for refractory small cell carcinoma of the lung. Cancer Treat Rep 69:479481, 1985 17. Giaccone G: Identification of new drugs in pretreated patients with small-cell lung cancer. Eur J Cancer Clin Oncol 25:411-413, 1989 18. Harvey VJ, Slevin ML, Joel SP, et al: Variable bioavailability following repeated oral doses of etoposide. Eur J Cancer Clin Oncol21:1315-1319, 1985 19. Slevin ML, Clark PI, Joel SP, et al: A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 7:13331340, 1989 20. Slevin ML, Clark PI, Joel SP, et al: A randomized trial to examine the effect of more extended scheduling of etoposide administration in small-cell lung cancer. Proc Am Soc Clin Oncol 8:236, 1989 (abstr) 21. Clark PI, Joel SP, Slevin ML: A pharmacokinetic hypothesis for the clinical efficacy of etoposide in small-cell lung cancer. Proc Am Soc Clin Oncol 8:66, 1989 (abstr)
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