Japanese Journal of Clinical Oncology 30:122-127 (2000)
© 2000 Foundation for Promotion of Cancer Research
Phase I Study of a Weekly Infusion of Irinotecan Hydrochloride (CPT-11) and a 14-day Continuous Infusion of Etoposide in Patients with Lung Cancer: Japan Clinical Oncology Group 9408
1Division of Medical Oncology, National Cancer Center Hospital, Tokyo, 2Division of Medical Oncology, National Cancer Center Hospital East, Kashiwa, 3Pathological Division, National Cancer Center Research Institute, Tokyo and 4Japan Clinical Oncology Group Data Center, National Cancer Center Research Institute, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: To determine the maximum-tolerated dose (MTD) and acceptable dose level of CPT-11 in combination with a 14-day continuous infusion of etoposide in patients with refractory advanced lung cancer (LC), especially small cell lung cancer (SCLC).
Methods: Etoposide was administered continuously at 25 mg/m2/day for 14 days. The initial dose of CPT-11 was 40 mg/m2 given as a 90-min intravenous infusion on days 1, 8 and 15 and the dose escalation of CPT-11 was planned in increments of 20 mg/m2 until severe or life-threatening toxic effects were observed.
Results: Eight refractory advanced LC patients entered this study, of whom two were not assessable for toxicity because of patient’s refusal and progressive disease. One treatment-related death due to pulmonary toxicity and one patient with hypotension who needed catecholamine for more than 48 h were observed at a CPT-11 dose of 40 mg/m2. The MTD of CPT-11 was 40 mg/m2. Therapeutic efficacy could be assessed in six patients, of whom two achieved a partial response.
Conclusions: This regimen was too toxic and the recommended dose was outside this study. One has to consider pulmonary toxicity when using CPT-11, especially for patients previously treated with cytotoxic agents for which pulmonary toxicity has been reported.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Multiple regimens employing combination chemotherapy, with or without chest irradiation, have led to improved survival and significant palliation for the majority of patients with small cell lung cancer (SCLC). Despite high response rates [80–100% in limited disease (LD) and 60–80% in extensive disease (ED)] with the induction chemotherapy, most patients relapsed and the median survival times were 14–20 months in LD and 8–13 months in ED (1). Moreover, in relapsed patients, although salvage chemotherapy may provide significant palliation, response rates are <50% and the median survival time is about 4 months from the start of salvage chemotherapy (1). Improvement of systemic chemotherapy for SCLC is necessary to overcome the disappointing survival outcome.
Etoposide, a DNA topoisomerase II inhibitor, produced a response rate of 44% as a single agent in SCLC (2). On the basis of in vitro studies (3–5), it is considered that the degree of cell kill depends on the duration of exposure to etoposide. Long-term administration of etoposide has been clinically studied in patients with relapsed or refractory SCLC and resulted in a better outcome (6–8).
Irinotecan hydrochloride (CPT-11) had been semi-synthesized as a water-soluble derivative of camptothecin, a DNA topoisomerase I inhibitor, in an attempt to reduce its toxicity. The single-agent response rate of weekly treatment with CPT-11 against refractory or relapsed SCLC was reported to be 47% and the major toxicities were myelosuppression (predominantly leukocytopenia), diarrhea and pulmonary toxicity (9). This high response rate is favorably compared with the 40–50% response rates that are reported for a combination of etoposide and cisplatin, which now is considered to be the most effective salvage chemotherapy (1).
Several investigators have reported a lack of cross-resistance to camptothecins and topoisomerase II inhibitors (10–12).. Combination of topoisomerase I and II inhibitors, CPT-11 and etoposide would appear to be an extremely attractive strategy for cancer chemotherapy in view of their complementary functions (13–15), although other investigators reported antagonistic effects on cytotoxicity in vitro (16,17). Therefore, we started a phase I–II study of long-term administration of etoposide and weekly administration of CPT-11 as a second-line or salvage chemotherapeutic regimen for patients with relapsed or refractory SCLC. This phase I study was permitted the inclusion of patients with unresectable non-small cell lung cancer (NSCLC) without or with prior chemotherapy (
one regimen), because both agents, weekly CPT-11 and chronic oral etoposide, had been shown to be active for advanced NSCLC (18–20) and the aim of this phase I study was to determine the maximum tolerated dose (MTD) and acceptable dose of CPT-11. Once the recommended dose has been determined, a pharmacokinetic study and phase II study will follow at the recommended dose for patients with relapsed or refractory SCLC.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The eligibility criteria for this study were as follows: histologically or cytologically proven advanced lung cancer; chemotherapy-naive or pretreated (
one regimen) state in NSCLC or pretreated (one regimen) state in SCLC; Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2; age <75 years; having measurable lesions; adequate organ functions [hematological function (WBC 
4000/mm3, Hb 9.0g/dl, platelet count 100 000/mm3), renal function (serum creatine <1.5 mg/dl, creatinine clearance 50 ml/min), hepatic function (total bilirubin 2.0 mg/dl, serum transaminases 2 x upper limit of normal) and pulmonary function (PaO2 70 Torr)]; no evidence of bone marrow infiltration confirmed by bone marrow aspiration; no medical problems sufficiently severe to prevent compliance with the study requirements; and written informed consent of patients. Patients were not eligible if drug allergies for CPT-11 or etoposide existed. The protocol was approved by the Ethical Committee of the Japan Clinical Oncology Group (JCOG) and institutional review boards of the National Cancer Center Hospitals. Pretreatment evaluation included a complete history, physical examination and a laboratory evaluation including complete blood cell (CBC) count which included a differential smear and a platelet count, serum chemistry to check renal and hepatic functions, electrolytes, CRP and tumor markers. In addition, all patients underwent chest X-ray, ECG, urinalysis, 24-h creatinine clearance, indocyanine green test, computerized tomography (CT) of the brain and thorax, ultrasonography or CT of the abdomen, radionuclide bone scan and bone marrow aspiration. CBC, serum chemistry, electrolytes, urinalysis and chest X-ray were performed at least once a week. Tests of measurable disease parameters were repeated every 4 weeks.
Patients continuously received 25 mg/m2/day of etoposide dissolved daily in 1000 ml of 5% glucose for 14 days (total 350 mg/m2). We expected this fixed dose to be a safe one, because Kunitoh and Watanabe (21) reported that 25 mg/m2/day for 14 days of etoposide with cisplatin was the MTD, with leukocytopenia as the dose-limiting toxicity (DLT). According to previous studies (7,18,21), the maintenance of blood concentrations of etoposide above 1 µg/ml was needed for response, which was observed at a total dose of >300 mg/m2 (21.4 mg/m2/day on days 1–14) (22).
The dose of CPT-11 in 500 ml of normal saline or 5% glucose was infused i.v. over 90 min on days 1, 8 and 15. The starting CPT-11 dose was determined as 40 mg/m2 and the dosage was increased in subsequent increments of 20 mg/m2. As there are no clear guidelines for choosing the starting dose of CPT-11 combined with etoposide, we referred to a combination study of CPT-11 on days 1, 8 and 15 and cisplatin (80 mg/m2 i.v. on day 1), which recommended 60 mg/m2 of CPT-11 without significant toxicity (23).
We planned to treat at least three patients at each dose. If one of three at a given dose experienced any toxicities defined as DLT, three additional patients were treated at the same dose. No dose escalation was accepted in the same patients. An MTD was regarded as one that produced any of the following DLT in at least a third of the patients at a given dose: non-hematological toxicity of grade 3 except for alopecia, nausea and vomiting; platelet count of <50 000/mm3; persistence of WBC <1000 /mm3 or absolute granulocyte count <500/mm3 for 4 days; WBC <1000/mm3 or absolute granulocyte count <500/mm3 with fever 38°C due to infection. Toxicity was graded according to the JCOG toxicity criteria (24). The evaluation of toxicities for dose escalation was done at the end of the first course. All the courses performed were, however, considered for evaluation of toxicities to determine DLT. Patients were treated for at least two courses unless disease progression or unacceptable toxicity was encountered or the patient’s wishes intervened. In the cases of stable disease after two courses, subsequent therapy was left to the discretion of the physician in charge of the patient. In the cases of complete or partial response, the therapy was continued until disease progression was observed. The response was defined according to the criteria of the World Health Organization (WHO) (25). A recommended dose of CPT-11 was regarded as one at the previous level defined as the MTD.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Seven patients at the National Cancer Center Hospital and one patient at the National Cancer Center Hospital East entered this study between 1994 and 1996. The characteristics of these patients are listed in Table 1. A total of 15 courses of treatment were given, for a median of two courses per patient (range, one to three courses). At first, three patients were treated at level 1 (cases 1–3). There were no DLT observed during the first course. However, one patient at level 1 (case 2), who is described later in detail, died of respiratory failure during the second course and pathologically diagnosed as treatment-related death (TRD). An additional five patients were registered at level 1 to re-evaluate toxicities. Two out of the five additional patients were excluded from evaluation of toxicities. One refused the treatment on day 11 of the first course because of operation for anal prolapse with severe pain and bleeding and one was taken off therapy on day 12 of the first course because of rapid progression of tumor. Among the additional three evaluable patients, one patient suffered from hypotension under 60 mmHg with tachypnea and needed catecholamine from day 11 to day 25 of the first course. Hypotension was accompanied with fever up to 39 °C. Laboratory findings revealed leukocytopenia (1800/mm3), high CRP value (13.9 mg/dl) and organ damage (GOT 376 IU/l, GPT 544 IU/l, LDH 864 IU/l, ALP 614 IU/l, total bilirubin 2.8 mg/dl, BUN 29 mg/dl, creatinine 1.4 mg/dl). These laboratory findings were normal on day 8 (early morning on the day of CPT-11 administration). Blood culture was negative. Administration of etoposide was stopped and broad-spectrum antibiotics were started immediately. Recovery from leukocytopenia with G-CSF support and cessation of fever were observed and hypotension and abnormal laboratory findings returned to the normal range. Although septic shock due to infection via central venous catheter was considered to be the cause of hypotension, drug-induced hypotension (especially etoposide) could not be denied and judged as DLT. This study was then closed at level 1, because DLT was observed in two of six evaluable patients. Except for pulmonary toxicity and hypotension, the principle toxicity was hematological: leukocytopenia, neutropenia and thrombocytopenia. Two of six patients achieved partial responses to this therapy. A summary of toxicities and therapeutic efficacy is given in Table 2.
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Case Report of TRD
A 73-year-old Japanese male presented with shortness of breath, cough, bloody sputum and left chest pain. He had smoked 10 cigarettes a day for 51 years. He had a past medical history of angina pectoris treated by percutaneous transluminal coronary angioplasty (PTCA) 6 years before admission. On physical examination, coarse crackles were detected over bilateral lower lung fields. Sputum cytology revealed squamous cell carcinoma. Chest X-ray revealed atelectasis of the right lower lobe and 7 x 5 cm mass of the left lower lobe without lymphadenopathy (Fig. 1A). A systemic survey revealed no distant metastasis. A diagnosis of advanced squamous cell lung cancer with pulmonary metastasis was made and MVP therapy [mitomycin C (MMC) 8 mg/m2, vindesine 3 mg/m2, cisplatin 80 mg/m2] was started. Two courses of MVP therapy resulted in disease progression.
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He then entered this study at 5-week intervals after the second course of MVP therapy. The first course of this study was finished without any significant toxicities except for 2-day duration of grade 3 neutropenia. Tumor size showed almost no change and the second course was started at 3-week intervals. On day 18, fever up to 38°C and dyspnea suddenly appeared. The intravenous catheter was removed as soon as possible and then antibiotics and O2 cannulation were started. Blood culture revealed no pathogens. Chest X-ray showed bilateral diffuse ground-glass shadows (Fig. 1B). Sulfamethoxazole and trimethoprim targeting for P. carinii were added to the antibiotics, but his symptoms became worse and he died on day 24. Autopsy was performed. Macroscopically, bilateral lungs were swollen and heavy and weighed 724 g (left lung) and 840 g (right lung). Histologically, hyaline membrane formation, intraalveolar edema and marked infiltration of inflammatory cells were observed diffusely all over the lungs (Fig. 2). No patholognomonic microorganisms were detected by PAS and Glocott stains. Immunofluorescence stains of anti-P. carinii antibody and anti-CMV antibody were negative. A diagnosis of diffuse desquamative pneumonia induced by drug was made.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Karato et al. (26) first reported a phase I study of a combination chemotherapy with CPT-11 and etoposide administered daily for three consecutive days every 3–4 weeks in patients with refractory solid tumors to observe the therapeutic efficacy and pharmacological aspects of topoisomerase-targeting chemotherapy. Their results were encouraging, especially for NSCLC, because five of seven previously untreated NSCLC patients achieved partial responses. Major toxicities were neutropenia and diarrhea and no pulmonary toxicity was observed. However, a prophylactic following phase II study performed at the recommended doses with G-CSF support for NSCLC (27) was only modestly effective, with toxicities of moderate diarrhea and pulmonary toxicity. With respect to SCLC, no studies have confirmed the efficacy of topoisomerase-targeting chemotherapy, although one phase I study (28) seemed to be active against SCLC, including refractory cases, with acceptable toxicity, which resulted in a 58% (seven of 12 patients) response rate. We failed to confirm the efficacy to SCLC, because this study was halted at level 1 due to the MTD and we could not performed further study in detail.
In previous studies (27–29), major DLTs of combination chemotherapy with CPT-11 and etoposide were leukocytopenia and diarrhea. In this study, we experienced no severe diarrhea or grade 4 leukocytopenia.
Pulmonary toxicity was observed in previous studies of CPT-11 alone (19,30) or combination chemotherapy including CPT-11 (26–29). The mechanism of pulmonary toxicity of CPT-11 is unknown, considered to be related to both allergic reactions and direct cytotoxic effects. Masuda et al. (9) reported two patients (13%) with pulmonary toxicity of grade 3 or 4, with dyspnea on exertion and high fever (>38°C) in a weekly schedule with CPT-11. In one patient, pneumonitis responded well to steroid therapy, but in the other patient, pneumonitis did not subside with steroid therapy. The patient subsequently died from progressive respiratory insufficiency and was diagnosed as a TRD. They concluded that leukocytopenia and diarrhea were DLTs. Although infrequent and sporadic in appearance, the severity of pulmonary toxicity in the two patients suggests that this drug-induced pneumonitis might also be dose limiting. Fukuoka et al. (19) also reported six patients (8%) with pulmonary toxicity during a weekly schedule with CPT-11 and one died of respiratory failure.
In combination with CPT-11 and etoposide, Masuda et al. (28) reported one patient with drug-induced grade 2 pneumonitis during the third course, which responded well to steroid therapy. Oshita et al. (27) reported three patients with interstitial pneumonitis who recovered with corticosteroid treatment. On the other hand, Karato et al. (26) observed no pulmonary toxicity in combination with CPT-11 and etoposide. Because the incidence of pulmonary toxicity was not increased in combination with CPT-11 and etoposide, etoposide might have no synergic effect on the pulmonary toxicity of CPT-11.
In this study, pulmonary toxicity was observed during the second course, when the patient had been administered 240 mg/m2 (360 mg/body) as the total dose of CPT-11. The total dose was small to induce pulmonary toxicity, because a median total dose of CPT-11 of 750 mg/m2 has been reported (19). It was possible that two courses of MVP therapy influenced the pulmonary toxicity. MMC is a well-known alkylating agent inducing pulmonary toxicity and the frequency of pulmonary toxicity ranged from 3 to 12%. Pulmonary toxicity has been reported after a 20 mg/m2 total dose of MMC (31). Vindesine has also been reported to cause acute diffuse pulmonary infiltration and respiratory failure, especially in combination with MMC. The incidence of pulmonary toxicity with a combination of these drugs was as high as 39% (31). In this case, although the total dose of MMC was also small, 16 mg/m2 (24 mg/body), the synergistic adverse effects of MMC, vindesine and CPT-11 for pulmonary toxicity should be considered.
The other DLT observed in this study was hypotension requiring catecholamine. Hypotension caused by CPT-11 or etoposide has been reported, but this toxicity is minor, such as hypersensitivity reaction. In this study, the hypotensive patient also showed fever up to 39°C, leukocytopenia, high CRP value and organ damage. No bacteria were detected by blood culture. If the hypotension was induced by CPT-11 or etoposide, the reason for the fever was unclear. We suspected the cause of hypotension to be septic shock based on clinical course and laboratory findings, but a definite diagnosis of sepsis was not obtained and we finally judged that the treatment-related hypotension was DLT.
We conclude that the regimen of a weekly infusion of CPT-11 and a 14-day continuous infusion of etoposide caused too severe toxicities to be considered for further assessment. However, in view of clinical studies with encouraging results of preclinical studies, a more effective and less toxic schedule and dose of topoisomerase I and II inhibitors are warranted.
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FOOTNOTES |
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+ For reprints and all correspondence: Tetsu Shinkai, Division of Medical Oncology, National Cancer Center Hospital, 1–1, Tsukiji 5-chome, Chuo-ku, Tokyo, Japan. E-mail: tshinkai@ncc.go.jpAbbreviations: JCOG, Japan Clinical Oncology Group; CPT-11, irinotecan hydrochloride; MTD, maximum tolerated dose; LC, lung cancer; SCLC, small cell lung cancer; LD, limited disease; ED, extensive disease; NSCLC, non-small cell lung cancer; ECOG, Eastern Cooperative Oncology Group; PS, performance status; WBC, white blood cell; Hb, hemoglobin; CBC, complete blood cell; ECG, electrocardiogram; CT, computerized tomography; DLT, dose-limiting toxicity; WHO, World Health Organization; TRT, treatment-related death; GOT, glutamic–oxaloacetic transaminase; GPT, glutamic–pyruvic transaminase; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; BUN, blood urea nitrogen; G-CSF, granulocyte colony-stimulating factor; MMC, mitomycin C; MVP, combination therapy of mitomycin C, vindesine and cisplatin; CODE, combination therapy of cisplatin, vincristine, doxorubicin and etoposide; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable
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REFERENCES |
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1 Elias AD. Small cell lung cancer: state-of-the-art therapy in 1996. Chest 1997;112:251S–258S.
2 Radice PA, Bunn PA Jr, Ihde DC. Therapeutic trials with VP-16-213 and VM-26: active agents in small cell lung cancer, non-Hodgkin’s lymphomas and other malignancies. Cancer Treat Rep 1979;63:1231–9.[ISI][Medline]
3 Drewinko B, Barlogie B. Survival and cycle-progression delay of human lymphoma cells in vitro exposed to VP-16-213. Cancer Treat Rep 1976;60:1295–1306.[ISI][Medline]
4 D’Incalci M, Erba E, Vaghi M, Morasca L. In vitro cytotoxicity of VP 16 on primary tumor and metastasis of Lewis lung carcinoma. Eur J Cancer Clin Oncol 1982;18:377–80.[ISI][Medline]
5 Hill BT, Whelan RD, Rupniak HT, Dennis LY, Rosholt MA. A comparative assessment of the in vitro effects of drugs on cells by means of colony assays or flow microfluorimetry. Cancer Chemother Pharmacol 1981;7:21–6.[ISI][Medline]
6 Johnson DH, Greco FA, Strupp J, 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.[Abstract]
7 Slevin ML. Low-dose oral etoposide: a new role for an old drug? J Clin Oncol 1990;8:1607–9.[ISI][Medline]
8 Einhorn LH, Pennington K, McClean J. Phase II trial of daily oral VP-16 in refractory small cell lung cancer: A Hoosier Oncology Group study. Semin Oncol 1990;17:32–5.[ISI][Medline]
9 Masuda N, Fukuoka M, Kusunoki Y, Matsui K, Takifuji N, Kudoh S, et al. CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 1992;10:1225–9.
10 Ferguson PJ, Fisher MH, Stephenson J, Li DH, Zhou BS, Cheng YC. Combined modalities of resistance in etoposide-resistant human KB cell lines. Cancer Res 1988;48:5956–64.
11 Sugimoto Y, Tsukahara S, Oh-hara T, Liu LF, Tsuruo T. Elevated expression of DNA topoisomerase II in camptothecin-resistant human tumor cell lines. Cancer Res 1990;50:7962–5.
12 Tan KB, Mattern MR, Eng WK, McCabe FL, Johnson RK. Nonproductive rearrangement of DNA topoisomerase I and II genes: correlation with resistance to topoisomerase inhibitors. J Natl Cancer Inst 1989;81:1732–5.
13 Kano Y, Suzuki K, Akutsu M, Suda K, Inoue Y, Yoshida M, et al. Effects of CPT-11 in combination with other anti-cancer agents in culture. Int J Cancer 1992;50:604–10.[ISI][Medline]
14 Kim R, Hirabayashi N, Nishiyama M, Jinushi K, Toge T, Okada K. Experimental studies on biochemical modulation targeting topoisomerase I and II in human tumor xenografts in nude mice. Int J Cancer 1992;50:760–6.[ISI][Medline]
15 Bertrand R, O’Connor PM, Kerrigan D, Pommier Y. Sequential administration of camptothecin and etoposide circumvents the antagonistic cytotoxicity of simultaneous drug administration in slowly growing human colon carcinoma HT-29 cells. Eur J Cancer 1992;28A:743–8.
16 D’Arpa P, Beardmore C, Liu LF. Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons. Cancer Res 1990;50:6919–24.
17 Kaufmann SH. Antagonism between camptothecin and topoisomerase II-directed chemotherapeutic agents in a human leukemia cell line. Cancer Res 1991;51:1129–36.
18 Waits TM, Johnson DH, Hainsworth JD, Hande KR, Thomas M, Greco FA. Prolonged administration of oral etoposide in non-small-cell lung cancer: a phase II trial. J Clin Oncol 1992;10:292–6.[Abstract]
19 Fukuoka M, Niitani H, Suzuki A, Motomiya M, Hasegawa K, Nishiwaki Y, et al. A phase II study of CPT-11, a new derivative of camptothecin, for previously untreated non-small-cell lung cancer. J Clin Oncol 1992;10:16–20.[Abstract]
20 Estape J, Palombo H, Sanchez-Lloret J, Agusti C, Grau JJ, Daniels M, et al. Chronic oral etoposide in non-small cell lung carcinoma. Eur J Cancer 1992;28A:835–7.
21 Kunitoh H, Watanabe K. Phase I/II and pharmacologic study of long-term continuous infusion etoposide combined with cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 1994;12:83–9.[Abstract]
22 Minami H, Shimokata K, Saka H, Saito H, Ando Y, Senda K, et al. Phase I clinical and pharmacokinetic study of a 14-day infusion of etoposide in patients with lung cancer. J Clin Oncol 1993;11:1602–8.
23 Masuda N, Fukuoka M, Takada M, Kusunoki Y, Negoro S, Matsui K, et al. CPT-11 in combination with cisplatin for advanced non-small-cell lung cancer. J Clin Oncol 1992;10:1775–80.
24 Tobinai K, Kohno A, Shimada Y, Watanabe T, Tamura T, Takeyama K, et al. and members of the Clinical Trial Review Committee of the Japan Clinical Oncology Group. Toxicity grading criteria of the Japan Clinical Oncology Group. Jpn J Clin Oncol 1993;23:250–7.
25 World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. Offset Publication 48. Geneva: World Health Organization 1979.
26 Karato A, Sasaki Y, Shinkai T, Eguchi K, Tamura T, Ohe Y, et al. Phase I study of CPT-11 and etoposide in patients with refractory solid tumors. J Clin Oncol 1993;11:2030–5.
27 Oshita F, Noda K, Nishiwaki Y, Fujita A, Kurita Y, Nakabayashi T, et al. Phase II study of irinotecan and etoposide in patients with metastatic non-small-cell lung cancer. J Clin Oncol 1997;15:304–9.
28 Masuda N, Fukuoka M, Kudoh S, Matsui K, Kusunoki Y, Takada M, et al. Phase I and pharmacologic study of irinotecan and etoposide with recombinant human granulocyte colony-stimulating factor support for advanced lung cancer. J Clin Oncol 1994;12:1833–41.
29 Ando M, Eguchi K, Shinkai T, Tamura T, Ohe Y, Yamamoto N, et al. Phase I study of sequentially administered topoisomerase I inhibitor (irinotecan) and topoisomerase II inhibitor (etoposide) for metastatic non-small-cell lung cancer. Br J Cancer 1997;76:1494–9.[ISI][Medline]
30 Negoro S, Fukuoka M, Masuda N, Takada M, Kusunoki Y, Matsui K, et al. Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. J Natl Cancer Inst 1991;83:1164–8.
31 Cooper JAD Jr, White DA, Matthay RA. Drug-induced pulmonary disease, part I: cytotoxic drugs. Am Rev Respir Dis 1986;133: 321–340.[ISI][Medline]
Received September 7, 1999; accepted December 24, 1999.
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