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Japanese Journal of Clinical Oncology Pages 745-748

Cisplatin Plus Oral Etoposide in the Treatment of Patients with Advanced Small Cell Lung Cancer
Introduction
Patients And Methods
Results
   Patient Characteristics
   Actual Dose of Etoposide Administered
   Tumor Response
   Survival
   Toxicity
Discussion
Acknowledgments
References
Cisplatin Plus Oral Etoposide in the Treatment of Patients with Advanced Small Cell Lung Cancer

Cisplatin Plus Oral Etoposide in the Treatment of Patients with Advanced Small Cell Lung Cancer

Hitoshi Asamoto1, Masaaki Kawahara2, Fumiyuki Iwami3, Mutsuo Kuba4, Kiyoyuki Furuse2, Tomohide Tamura5, Nagahiro Saijo6 and Masanori Shimoyama7 for Japan Clinical Oncology Group

1Department of Respiratory Diseases, Kyoto National Hospital, Kyoto, 2Department of Internal Medicine, National Kinki Central Hospital for Chest Diseases, Sakai, 3Department of Internal Medicine, National Minami Kyushu Hospital, Kagoshima, 4Department of Internal Medicine, National Okinawa Hospital, Okinawa, 5Medical Oncology Division, National Cancer Center Hospital, Tokyo, 6Pharmacology Division and Medical Oncology Division, National Cancer Center of Research Institute and Hospital, Tokyo and 7Nagoya National Hospital, Nagoya, Japan

Background: toposide is a highly schedule-dependent drug. We investigated combination chemotherapy of oral etoposide and intravenous cisplatin for small cell lung cancer (SCLC).
Methods: Fifty-seven patients with SCLC with extensive disease (ED) or limited disease (LD) with pleural effusion registered in the 21 institutions of the Japan Clinical Oncology Group were treated with oral etoposide 40 mg/m2/d for 21 days and cisplatin 80 mg/m2 on day 1 of every 28-period day. The entry period was between February 1992 and August 1995. The actual percentages of patients treated with etoposide were 93.6, 89.5, 92.3 and 96.9% in the first, second, third and fourth cycles, respectively.
Results: Nine patients(15.8%) achieved a complete response resulting in an overall response rate of 82.5% (95% confidence interval, 70.1-91.3%). Leukopenia and thrombocytopenia of grade 3 or 4 were observed in 36 (49.1%) and 8 (14.0%) patients, respectively. Anemia of grade 3 or 4 occurred in 28 (49.1%) patients. Nausea, vomiting, anorexia and alopecia were common adverse events. One patient died of hemoptysis due to grade 4 thrombocytopenia.The mean survival time was 47.0 weeks.
Conclusions: This dose and schedule of administration of etoposide in combination with cisplatin are considered to be clinically active. However, prolonged gastrointestinal toxicity of oral etoposide was a problem in comparison with the standard etoposide platinum regimen given by intravenous administration.

Key words: small cell lung cancer - chemotherapy - CDDP + oral etoposide

INTRODUCTION

Lung cancer is the most common cause of cancer death in men in Japan. Approximately 20% of all lung cancers are small cell lung cancers (SCLC). SCLC is a tumor that is highly sensitive to chemotherapy, for which intensive combination chemotherapy with cisplatin and etoposide is one of the most widely used regimens (1). Etoposide is usually administered over 3 days because of its schedule dependency (2). Recent studies indicate that etoposide produces DNA damage by interacting with topoisomerase II (3) and that its prolonged administration may enhance its effectiveness against tumor cells (4) and cisplatin and oral etoposide at a dose of 50 mg/m2/d can be combined safely (4).

A 5-day schedule of etoposide administration was reported to be superior to the same dose in a 1-day schedule (2). Therefore, the importance of multiple- day scheduling of this oral agent was highlighted for the treatment of SCLC. However, it was shown recently that single-drug oral etoposide daily for 5 days or more was inferior to the standard regimen of intravenous multidrug chemotherapy against SCLC (5-7). However, combination chemotherapy of low-dose oral etoposide and intravenous cisplatin may still be an interesting strategy and no conclusive data on the efficacy of this combination have been obtained. If this regimen has an equal or better efficacy and equal or worse toxicity compared with standard intravenous etoposide plus cisplatin, its administration has an advantage in the out-patient clinic. We present the results of a phase II study of 59 patients with SCLC with extensive disease (ED) or limited disease (LD) treated with cisplatin and a 21-day schedule of low-dose oral etoposide.

PATIENTS AND METHODS

Fifty-nine patients were registered in this trial by the 21 institutions of the Japan Clinical Oncology Group between February 1992 and August 1995. Eligibility requirements included a histological diagnosis of SCLC with ED or LD with pleural effusion without prior treatment, performance status of <2 on the Eastern Cooperative Oncology Group scale, measurable disease, total leukocyte count between 4000 and 12 000/mm3, platelets >100 000/mm3, Hb >9.5g /dl, serum bilirubin <1.5 mg/dl, BUN <25mg/dl, serum creatinine within upper normal limit, GOT and GPT within twice the value of the upper normal limit, a life expectancy of >12 weeks and a documented informed consent. Etoposide was administered orally for 21 consecutive days at a dose of 40 mg/m2/d and cisplatin 80 mg/m2 on day 1 every 28 days. As etoposide is available only in 25-mg capsules, it was necessary to make some approximations for the calculated daily dose. For example, if a patient was calculated to receive 65 mg/d, etoposide was given in doses of 75, 75 and 50 mg on three consecutive days and the schedule was repeated every 21 days. Etoposide was discontinued if the leukocyte count fell below 2000/mm3 and/or platelets fell below 75 000/mm3.

At the end of each 21-day cycle, etoposide was discontinued and patients were evaluated on day 28. Patients who demonstrated an objective response or stable disease underwent another cycle of this oral regimen if the total leukocyte and platelet counts were adequately recovered. Patient who had leukocyte nadirs less than 2000/m3 before day 21 had a dose reduction to 75% in the subsequent cycle. Tumor response and toxicity were defined according to the WHO criteria (8). Tumor response was assessed after each cycle of treatment. Patients were evaluable for response if they had received at least 2 weeks of treatment and patients with progressive disease (PD) were taken off the study when it appeared. Duration of response was calculated from the first day of treatment.

RESULTS

Patient Characteristics

Of the 59 patients enrolled in this study, two patients were excluded, of whom one had received prior radiotherapy and the other refused the treatment. Thus the response and toxicity of this combination chemotherapy were determined in 57 patients. The patient characteristics are shown in Table 1.

Actual Dose of Etoposide Administered

The percentages of the etoposide doses actually administered were 96.3, 89.5, 92.3 and 96.9%, in the first, second, third and fourth cycles, respectively. The mean interval between administrations was 34.9, 34.4 and 34,5 days between the first and second, second and third and third and fourth administrations, respectively.

Table 1. Patient characteristics
No. of patients 57
Male/female 51/6
Median age (years) 66
Age range (years) 38-75
ECOG performance status*
   0 12
   1 32
   2 13
Disease stage (%)
   LD with pleural effusion 3 (5.3)
   ED 54(94.7)
*Eastern Cooperative Oncology Group.

Table 2. Response to CDDP and oral etoposide
  No. of patients Response Response rate (%)
CR PR NC PD NE
Overall 57 9 38 6 3 1 82.5
Stage
   III 3 1 1 1 0 0 66.7
   IV 54 8 37 5 3 1 83.3
Gender
   Male 51 8 34 6 2 1 82.4
   Female 6 1 4 0 1 0 83.3
PS
   0 + 1 44 8 28 6 2 0 81.8
   2 13 1 10 0 1 1 84.6
NE, not evaluated.

Tumor Response

Of the 57 eligible patients, nine achieved a CR (15.8%), 38 had a PR (66.7%), six had NC (10.5%), three experienced PD (5.3%) and in one (1.8%) the response could not be evaluated. Among the three LD patients with pleural effusion, one had a CR and the others had PR and NC. The overall response rate was 82.5% (95% CI: 70.1-91.3%). The differences in response rate between males and females and between PS 0 + 1 and 2 were not statistically significant (Table 2).The CR rate was higher in the PS 0 + 1 group (18.2%) than in the PS 2 group (7.7%), but there was no significant difference between them (p = 0.3621).

Survival

The projected median survivals for the 54 ED and three LD patients with effusion were 46 and 62 weeks, respectively. The overall median survival of the 57 patients was 47.0 weeks (Table 3, Fig. 1).


Figure 1. Survival of patients given CDDP + oral etoposide (Kaplan-Meier method).

Table 3. Survival of patients given CDDP + oral etoposide
Survival Weeks (median) (50% CI)
Stage III (n = 3) 61.9 (21.6-65.4)
Stage IV (n = 54) 46.0 (39.3-54.1)
Overall (n = 57) 47.0 (39.3-54.3)

Table 4. Toxicity (in 57 assessable patients)
Toxicity WHO grade Toxicity [ge]grade 3 (%)
1 2 3 4
Leukopenia 6 22 19 9 49.1
Anemia 7 19 21 7 49.1
Thrombocytopenia 7 12 5 3 14.0
Elevation of GOT 18 8 0 0 0.0
Anorexia 16 30 8 0 14.0
Nausea/vomiting 18 12 12 2 24.6
Stomatitis 8 2 0 0 0.0
Diarrhea 6 2 0 0 0.0
Alopecia 19 17 8 0 14.0
Fever 11 10 0 0 0.0
Proteinuria 21 1 0 0 0.0
Hematuria 10 1 0 0 0.0
Peripheral neuropathy 4 1 0 0 0.0


Toxicity

Toxicity was determined for the 57 patients. There was one treatment-related death by hemoptysis due to the decrease in peripheral platelet count. Twenty-eight patients (49.1%) received all four planned courses of treatment (median three per patient, range 1-4). Of the four patients receiving only one cycle of therapy, two died during or immediately after cycle one, one refused further therapy and in one patient therapy was discontinued because of pneumothorax immediately after one cycle in spite of a good response. The main reasons for discontinuing chemotherapy included patient refusal due to anorexia and nausea caused by oral etoposide and long-term hospitalization.

Fourteen patients had two courses and 11 had three. Nine of the discontinuations were due to refusal by the patients, six were due to adverse effects including nausea or decrease in peripheral blood leukocytes and platelets, eight were due to poor response to the chemotherapeutic drugs and two were due to complete response.

The hematological toxicities with their maximum grade during the entire course are shown in Table 4. Leukopenia and anemia of grades 3 and 4 were most commonly observed in 49% of the patients. Thrombocytepenia of grades 3 and 4 was also observed in 14%.

Non-hematological toxicities during all courses of treatment are listed in Table 4. Anorexia was most commonly observed and usually continued until the end of etoposide medication. Nausea and vomiting were also commonly observed, occurring not only on day one in association with CDDP but also during the days when the patients received oral etoposide, in which 24.6% of the patients had grades 3 and 4. Other toxicities of the alimentary system such as stomatitis and diarrhea were observed, but they were mild and transient. Alopecia was also commonly observed.

Approximately 46% of the patients in this study showed elevation of serum GOT, but it was mild and transient. Low-grade hematuria and proteinuria were also observed. Neutropenic fever occurred in 21 patients, but it was grade 1 or 2 in all of them.

DISCUSSION

The incidence of lung cancer has increased steadily in Japan in recent years and is the leading cause of cancer-related death in men. Approximately 40 000 lung cancer-related deaths were reported in Japan in 1994 (9), accounting for more than 8000 SCLC-related deaths per year. The prognosis of extensive SCLC remains very poor in spite of the progress in combination chemotherapy. Souhami et al. (10) reported that only 5-10% of patients with extensive SCLC survive 2 years.

Etoposide is one of the most active schedule-dependent agents against SCLC (4) and combination chemotherapy of cisplatin and etoposide is the most widely used treatment of this disease (1). Clark and Cottier (11) demonstrated that prolonged administration of oral etoposide was very effective in the three different schedules of treatment with the single agent oral etoposide in previously untreated patients with SCLC.

Johnson et al. (12) reported that oral etoposide was effective even against SCLC refractory to standard chemotherapy. However, the Medical Research Council Lung Cancer Working Party (5) demonstrated that patients treated with 50 mg of oral etoposide twice daily for 10 days every 3 weeks for four cycles had a lower response rate and poorer performance status than those receiving the standard intravenous multidrug chemotherapy (EV or CAV) in a randomized controlled trial. Clark (13) reported that oral etoposide alone was inadequate palliative chemotherapy in comparison with the regimen of CAV or ETP + VCR in SCLC based on their randomized controlled trial. Miller et al. (6) compared two regimens consisting of etoposide 130 mg/m2/d i.v. for 3days and cisplatin 25 mg/m2/d i.v. for 3 days every 21 days for eight courses versus etoposide 50 mg/m2/d orally for 21 days and cisplatin 33 mg/m2/d i.v. for 3 days every 28 days for six courses, and concluded that the two regimens did not result in differences in tumor response or survival. However, a significantly higher rate of severe hematological toxicity was observed with the 21-day oral etoposide treatment schedule. On the other hand, Fukuoka et al. (14) demonstrated that a combination regimen of chronic daily administration of oral etoposide in combination with cisplatin was effective in patients with etoposide-sensitive malignancies including SCLCs. They stated that this combination regimen was safe and recommended doses on this schedule are 40 mg/m2/d of oral etoposide for 21 days and 80 mg/m2 of cisplatin i.v. on day 1.

In our study, we showed that a combination regimen according to this schedule was effective and tolerable in the treatment of advanced SCLC and that the median survival was superior to that obtained by Roth et al. (15) and similar to those reported by Miller et al. (6) and Fukuoka et al. (16) for the trials of extended SCLC.

Approximately 30% of the patients in our study did not agree to receive the full cycle of this regimen, mainly because of gastrointestinal toxcities including prolonged nausea and anorexia. About 95% of the patients complained of anorexia during this study. Therefore, supportive care for improving compliance should be devised to obtain better clinical effects with this regimen.

Acknowledgments

This project was supported by Grants-in-Aid for Cancer Research from the Japanese Ministry of Health and Welfare. We express our gratitude to Mr Toshiyuki Ijima and Miss Miyuki Niimi for statistical analysis of this trial.

References

1. Loehrer P, Einhorn L, Greco FA. Cisplatin plus etoposide in small cell lung cancer. Semin Oncol 1988;15:2-8. MEDLINE Abstract

2. Slevin ML, Clark PI, Joel SP, Malik S, Osborne RJ,Gregory WM, et al. Randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 1989;7:1333-40. MEDLINE Abstract

3. Greco FA, Murphy PB, Hainsworth JD,Hande KR, Johmson DH. Prolonged administration of oral etoposide plus cisplatin in extensive stage small cell lung cancer. Oncology 1992;49(Suppl):34-9. MEDLINE Abstract

4. Murphy PB, Hainsworth JD, Greco FA, Hande KR, DeVore RF, Johnson DH. A phase II trial of cisplatin and prolonged administration of oral etoposide in extensive-stage small cell lung cancer. Cancer 1992;69:370-5. MEDLINE Abstract

5. Medical Research Council Lung Cancer Working Party. Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small cell lung cancer: a stopped multicentre randomized trial. Lancet 1996;348:563-6.

6. Miller AA, Herndon JE, Hollis DR, Ellerton J, Longleben A, Richards F, et al. Schedule dependency of 21-day oral versus 3-day intravenous etoposide in combination with intravenous cisplatin in extensive-stage small-cell lung cancer: A randomized phase III study of the cancer and leukemia group B. J Clin Oncol 1995;13:1871-9. MEDLINE Abstract

7. Sauhami RL, Spiro SG, Rudd RM, DeElvira MCR, James LE, et al. Five-day oral etoposide treatment for advanced small-cell lung cancer. Randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 1997;89:577-80.

8. Miller AB, Hoogstrafen B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207-14. MEDLINE Abstract

9. Tominaga S. Background of increase in lung cancer in Japan. Naika 1996;78:1996-2011 (in Japanese).

10. Souhami RL, Braubury I, Geddes DM, Spiro SG,Harper P, Tobias JS. The prognostic significance of laboratory parameters measured at diagnosis in small cell carcinoma of the lung. Cancer Res 1985;45:2878-82. MEDLINE Abstract

11. Clark PI, Cottier B. The activity of 10-, 14- and 21-day schedule of single-agent etoposide in previously untreated patients with extensive small cell lung cancer. Semin Oncol 1992;19(Suppl):36-9. MEDLINE Abstract

12. Johnson DH, Greco FA, Strupp, Hande KR,Hainsworth JD. Prolonged administration of oral etoposide in patients with relapsed or refractory small cell lung cancer. A phase II trial. J Clin Oncol 1990;8:1613-7. MEDLINE Abstract

13. Clark PI: Oral etoposide alone is inadequate palliative chemotherapy for small cell lung cancer.A randomized trial. Proc.ASCO 1996;15:377.

14. Fukuoka M, Masuda N, Negoro S, Tamuta T, Kudoh S, Kusunoki Y, et al. A phase I study of chronic daily dosing of oral etoposide in combination with cisplatin for patients with advanced cancer.Cancer 1991;68:284-8. MEDLINE Abstract

15. Roth BJ, Johnson DH, Einhorn LH, Schacter LP, Cherng NC, Cohen HJ, et al.: Randomized study of cyclophosphamide, doxorubicin and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small cell lung cancer. A phase III study of the Southeastern Cancer Study Group. J Clin Oncol 1992;10:282-91. MEDLINE Abstract

16. Fukuoka M, Furuse K, Saijo N, Nishiwaki Y, Ikegami H, Tamura T, et al. Randomized trial of cyclophosphamide, doxorubicin and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 1991;83:855-61. MEDLINE Abstract

Received June 29, 1998; accepted September 11, 1998
For reprints and all correspondence: Hitoshi Asamoto, Department of Respiratory Diseases, Kyoto National Hospital, Fukakusa, Fushimi-ku, Kyoto, 612-8555, Japan
Abbreviations: SCLC, small cell lung cancer; ED, extensive disease; LD, limited disease; CR, complete response; PR, partial response; NC, no change; PD, progressive disease; PS, performance status; EV, etoposide + vincristine; CAV, cyclophosphamide + adriamycin + vincristine

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