Oncology 1992;49(suppl 1):34 39

Division of Medical Oncology, Vanderbilt University School o f Medicine. Nashville. Tenn., USA

Prolonged Administration of Oral Etoposide plus Cisplatin in Extensive Stage Small Cell Lung Cancer

K e y w o rd s

A b s tra c t

Small cell lung cancer Etoposide

Etoposide is a highly schedule-dependent agent. We previously reported that a 2 1-day schedule of oral etoposide had good activity in small cell lung cancer (SCLC). The current phase II study was designed to lest the combination of 21-day oral etoposide with cisplatin in hopes of capitalizing on etoposide’s schedule dependency. Sixteen extensive stage SCLC patients were treated with cisplatin 100 mg n r day 1 plus 21 days of low-dose oral etoposide 50 mg/m day. Chemotherapy was repeated every 28 days for 4 cycles. Blood counts were monitored weekly, and etoposide was discontinued if the leukocyte or platelet count dropped below 2.0 x 109/lor75 x 109/1, respectively. Fifteen of 16 pa­ tients were evaluable for response; 13 achieved either a complete (13%) or par­ tial response (73%), for an overall response rate of 86% (95% confidence inter­ val, 62 -93%). Median response duration was approximately 7 months; median survival was not reached. Thirteen patients (81 %) received all the planned cy­ cles of chemotherapy. In cycle 1 of chemotherapy, the median leukocyte nadir was2.8 x 10’/1 (range, 0.1-6.3 x 109/1; median platelet nadir was 180 x I09/1 (range, 51 397 x 109/1). Life-threatening leukopenia (< 1.0 x 109/1) was un­ usual (2 of 58 cycles). There was 1 treatment-related death. One patient de­ veloped mild renal insufficiency that resolved after therapy. Nonhematologic toxicities were uncommon, but alopecia occurred in all patients. These data do not suggest that a major survival benefit will be derived for patients with exten­ sive stage SCLC by increasing the duration of etoposide administration when used in combination with cisplatin. A randomized study is needed to determine if this long-term schedule of etoposide plus cisplatin is superior to the standard schedule of etoposide plus cisplatin.

Combination chemotherapy has made a substantial impact on survival of patients with small cell lung cancer (SCLC). but little improvement in overall survival has been observed in the past decade [1,2]. The lack of recent

improvement is particularly evident in patients with exten­ sive disease; nearly all of them eventually die of SCLC, even if treated with intensive combination chemotherapy [1,2], There are very few promising new phase 11 drugs on

F. Anthony Greco. MD 1956 The Vanderbilt Clinic Nashville. TN 37232-55.16 (USA)

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F. Anthony Greco Patrick B. Murphy John D. Hainsworth Kenneth R. Hande David H. Johnson

Pa tie n ts and M e th o d s Sixteen patients with extensive stage SCLC have, thus far, been entered into this phase II trial. Only previously untreated patients were eligible. Extensive stage was defined as tum or outside the hemithorax and adjacent nodes and included patients with contra­ lateral supraclavicular node involvement or cytologically positive pleural effusions. We performed a physical examination, and ob­ tained a history, complete blood cell counts, serum chemistries, chest roentgenogram, computed tomography of the head, chest, and ab­ domen, bone scan, and bone marrow biopsy in every patient before therapy. No patient was excluded because of a particular metastatic site (including brain) or age. Patients had to have histologically con­ firmed measurable or evaluable disease, an Eastern Cooperative O n­ cology Group (ECOG) performance status o f 2 or less, serum creati­ nine less than 2 mg/dl, serum bilirubin below 2 mg/dl, and adequate bone marrow reserve (leukocyte count > 3.0 x 10‘'/1 and platelet c o u n t s 100 x lO’/l). Patients with elevated bilirubin or bone m ar­ row dysfunction secondary to metastatic disease were eligible. All pa­ tients gave informed consent. Patient characteristics are summarized in table 1. There were 10 men and 6 women with a median age of 54 years (range. 44-68) and a median ECOG performance status o f I (range, 0-2). The median number of metastatic sites was 3 (range, 2 5).

Table!. Patient characteristics(n= 16) Median age. years Range Sex. M E ECOG performance status 0 1 2 Tumor sites Lung Bone Pleural effusion Liver Bone marrow Brain Lymph nodes Adrenal Median Range

54 44-68 10/6 1 9 6 16 10 6 6 9 5 3 1 3 2-5

Patients were treated with 4 courses of cisplatin 100 m g/nr i.v. on day 1 and oral etoposide 50 mg nr/day for 21 consecutive days. Courses were repeated at 28-day intervals. Patients were hydrated with normal saline for 6 - 12 h before cisplatin therapy and continued to be hydrated for up to 24 h after therapy. Antiemetics included metoclopramide, diphenhydramine, thiethylperazine, lorazepam, and dexamethasone. Etoposide was usually given intravenously on days I and 2 of therapy at 25 m g/nr/day (i.e., during hospitalization) and subsequently was given orally (50 mg, nr/day) in the form of a soft gelatin capsule. Patients were instructed to keep the etoposide refrigerated and to take the entire daily dose each morning before breakfast. Given the limitation o f 50-mg capsules, and approxim a­ tion of the daily dose was made in some patients. Each patient was given a calendar w ith the numbers of capsules to be taken w ritten in for each treatment day. Plasma etoposide levels w'ere measured in consenting patients at various times (from 1 to 24 h) after drug administration to ensure compliance and to determine drug levels. Etoposide concentrations were determined by reverse phase high performance liquid chromatography as previously described [

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Total and differential leukocyte counts and platelet counts were obtained each week during treatment. Etoposide was discontinued if the total leukocyte count was below 2.0 x lO’/l or the platelet count was below 75 x I09/1. Etoposide was discontinued on day 22 and cycle 2 was begun on day 29, provided the leukocyte count was above 3.0 x 10s1 land the platelet count above 100 x 10, /l. If the leukocyte or platelet count had not reached these levels by day 29, therapy was delayed for I w'eck and restarted on day 36 without a dose reduction. If a patient had cessation o f etoposide earlier than day 21, the leuko­ cyte nadir was below 2.0 x 10’/1, or the platelet count was below 75 x 10’/l. subsequent ctopos:dc doses were reduced by 25%. Cis­ platin dose was reduced by 50% in patients with serum creatinine levels above 1.5 mg/dl on the day of expected therapy and was discon­ tinued in patients with serum creatinine levels above 2.5 mg/dl.

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the horizon. Several derivatives of previously available ac­ tive drugs are available, but offer little, if any, therapeutic advantage over the older drugs [3]. It is important, therefore, that currently available drugs be used in the most effective manner. Further examination of etoposide's schedule dependency is an example of the approach that we are studying. Etoposide is one of the most active drugs against SCLC [4,5]. Several randomized studies have demonstrated that etoposide is an important component of initial induction therapy and may be necessary to maximize median sur­ vival for SCLC patients [5], Nonetheless, the optimal method of administering etoposide is not well defined. Slevin et al. [6] demonstrated unequivocally the impor­ tance of multiday etoposide scheduling when treating pa­ tients with SCLC. These investigators found that a 5-day schedule of etoposide administration was superior to the same dose in a 1-day schedule. We and others have demon­ strated that etoposide could be administered for even more prolonged intervals using a relatively low dose given orally with good results in both previously treated [7. 8] and un­ treated patients [9], To test the prolonged oral etoposide schedule in combination chemotherapy, we combined low-dose daily oral etoposide with cisplatin in previously untreated, extensive stage SCLC patients. The purpose of this study was to determine the toxicity and feasibility of delivering this combination and to estimate its efficacy.

Table 2 . 1lematologic toxicity

ECOG toxicity grade

0

1

2

3

4

Leukocytes, x 10'’/l Cycle 1. No. episodes All cycles

> 4 .0 1 5

3.0-3.9 5 14

2.0-2.9 3 22

1.0 1.9 5 13

< 1.0 1 2

Platelets, x 10"; 1 Cycle 1. No. episodes All cycles

> 150

75-150 2 12

50 74.9 9

25 49.9

Prolonged administration of oral etoposide plus cisplatin in extensive stage small cell lung cancer.

Etoposide is a highly schedule-dependent agent. We previously reported that a 21-day schedule of oral etoposide had good activity in small cell lung c...
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