Japanese Journal of Clinical Oncology 30:487-493 (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: JCOG Trial 9408
1Division of Medical Oncology, National Cancer Center Hospital, Tokyo, 2Division of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba and 3Japan Clinical Oncology Group Data Center, Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Background: The aim was to determine the maximum tolerated dose (MTD) and recommended dose of irinotecan hydrochloride (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: Nine refractory or advanced LC patients (eight at level 1, one at level 2) were entered in this study, of whom two at level 1 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 level 1, a CPT-11 dose of 40 mg/m2. The MTD of CPT-11 was 40 mg/m2. Therapeutic efficacy could be assessed in seven patients, of whom two achieved a partial response.
Conclusions: This regimen was too toxic and the recommended dose was outside the levels in 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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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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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)] to the induction chemotherapy, most patients relapsed and the median survival times are 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 response rate of weekly treatment with CPT-11 as a single agent 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 compares favorably with the 40–50% response rates reported for a combination of etoposide and cisplatin, which is now considered to be one of the most effective salvage chemotherapies (1).
Several investigators have reported a lack of cross-resistance to camptothecins and topoisomerase II inhibitors in preclinical studies (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 have reported antagonistic effects on cytotoxicity in vitro (16,17). Therefore, we planned a phase I–II study of long-term administration of etoposide plus weekly administration of CPT-11 as a second-line or salvage chemotherapy for patients with relapsed or refractory SCLC. This phase I study included patients with unresectable non-small cell lung cancer (NSCLC) without or with prior chemotherapy (one regimen or none), 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 recommended dose of CPT-11. Once the recommended dose has been determined, pharmacokinetic and phase II studies will follow at the recommended dose for patients with relapsed or refractory SCLC.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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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 or none) 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 or evaluable lesions; adequate organ functions [hematological function (WBC
4000/mm3, Hb 9.0 g/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 <2x upper limit of normal range) 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 Clinical Trial Review Committee of the Japan Clinical Oncology Group (JCOG) (21) and institutional review board of the National Cancer Center. Pretreatment evaluation included a complete history, physical examination and laboratory tests including complete blood cell (CBC) count with differential and platelet count, serum chemistry to check renal and hepatic functions, electrolytes, CRP and tumor markers. In addition, all patients underwent chest roentgenogram, ECG, urinalysis, 24 h creatinine clearance, indocyanine green test, computed tomography (CT) scan of the brain and thorax, ultrasonography or CT scan of the abdomen, radionuclide bone scan and bone marrow aspiration. CBC, serum chemistry, electrolytes, urinalysis and chest roentgenogram were performed at least once a week. Tests of measurable disease parameters were repeated every 4 weeks.
Patients were treated continuously with 25 mg/m2/day of etoposide diluted 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 (22) reported that 25 mg/m2/day for 14 days of etoposide was the MTD when combined with cisplatin, with leukocytopenia as the dose-limiting toxicity (DLT). According to previous studies (7,18,22), 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) (23).
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 (24).
We planned to treat at least three patients at each dose level. If one of three at a given dose experienced any toxicity defined as DLT, three additional patients were treated at the same dose level. 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 one-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 (25). 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 and MTD. Patients were treated with at least two courses unless disease progression or unacceptable toxicity was encountered or the patient’s wishes intervened. Both CPT-11 and etoposide were reduced by 25% for patients who had episodes of hematological DLT. If the patients experienced grade 3 or 4 leukocytopenia, neutropenia or febrile neutropenia, CPT-11 and etoposide were withheld and granulocyte colony-stimulating factor (G-CSF) was permitted. In the case of stable disease after two courses, subsequent therapy was left to the discretion of the physician in charge of the patient. In the case 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) (26). 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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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Eight patients at the National Cancer Center Hospital and one patient at the National Cancer Center Hospital East were entered in this study from 1995 through 1996. The characteristics of these patients are listed in Table 1. A total of 16 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. Dose escalation to level 2 was made and one patient (case 4) was treated with 60 mg/m2 of CPT-11. However, one patient at level 1 (case 2), who is described later in detail, died of respiratory failure during the second course, which was diagnosed as treatment-related death (TRD). Registration to level 2 was suspended and an additional five patients (cases 5–9) were registered at level 1 to re-evaluate toxicities. Two out of the five additional patients were excluded from the evaluation of toxicities. One (case 7) refused the treatment on day 11 of the first course because of surgery for anal prolapse with severe pain and bleeding and one (case 8) was taken off therapy on day 12 of the first course because of rapid progression of tumor. Among the additional three evaluable patients, one (case 5) suffered from hypotension under 60 mmHg with tachypnea and needed catecholamine from day 11 to day 25 of the first course. Hypotension was accompanied by fever of 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 recovered to normal values on day 8 (early morning on the day of CPT-11 administration). Blood culture was negative. Administration of etoposide was discontinued and broad-spectrum antibiotics were started immediately. As recovery from leukocytopenia with G-CSF support and cessation of fever were observed, hypotension and abnormal laboratory findings recovered to the normal range. Although etoposide-induced hypotension has been reported, septic shock due to infection associated with neutropenia was considered to be the cause of hypotension in this case and judged as DLT. This study was then closed at level 1, because DLT was observed in two of six evaluable patients at level 1. Except for pulmonary toxicity and hypotension, the principle toxicity was hematological: leukocytopenia, neutropenia and thrombocytopenia. Two of seven 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 per 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 the bilateral lower lung fields. Sputum cytology revealed squamous cell carcinoma. A chest roentgenogram revealed atelectasis of the right lower lobe and a 7 x 5 cm mass in the left lower lobe without lymphadenopathy (Fig. 1a). A systemic survey revealed no distant metastasis outside the thorax. A diagnosis of advanced squamous cell lung cancer with pulmonary metastasis was made and MVP therapy [mitomycin C (MMC) 8 mg/m2 on day 1, vindesine 3 mg/m2 on days 1 and 8, cisplatin 80 mg/m2 on day 1] was started. Two courses of MVP therapy resulted in disease progression.
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He was then entered in 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 leukocytopenia and neutropenia. The tumor sizes showed almost no change and the second course was started at 3-week intervals. On day 18, fever of 38°C and dyspnea suddenly appeared. The intravenous catheter was removed immediately and then antibiotics and O2 cannulation were started. Blood culture revealed no pathogens. A chest roentgenogram showed bilateral diffuse ground-glass shadows (Fig. 1b). Sulfamethoxazole and trimethoprim targeting for pneumocystis carinii (P. carinii) were added to the antibiotics, but his symptoms became worse and he died on day 24 after the initiation of the second course of chemotherapy. An autopsy was performed. Macroscopically, both lungs were swollen and heavy and weighed 724 g (left) and 840 g (right). Histologically, hyaline membrane formation, intra-alveolar edema and marked infiltration of inflammatory cells were observed diffusely throughout both lungs (Fig. 2). No pathognomonic microorganisms were detected by PAS and Grocott stains. Immunohistochemical stains for P. carinii and cytomegalovirus were negative. A diagnosis of diffuse alveolar damage, probably induced by drugs, was made. The two tumors, one located in the right lower lobe and the other invading the left upper and lower lobes, were pathologically diagnosed as double primary squamous cell carcinomas based on the difference of tumor growth pattern and the degree of differentiation.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Karato et al. (27) first reported a phase I study of a combination chemotherapy with CPT-11 and etoposide in patients with refractory solid tumors as topoisomerase-targeting chemotherapy. Their results were encouraging, especially for NSCLC, because five to seven previously untreated NSCLC patients achieved partial responses. Major toxicities were neutropenia and diarrhea and no pulmonary toxicity was observed. However, a subsequent phase II study performed at the recommended doses with G-CSF support for NSCLC (28) 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 (29) 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 for SCLC, because this study was closed at level 1 owing to the MTD.
In previous studies (28–30), major DLTs of combination chemotherapy with CPT-11 and etoposide were leukocytopenia and diarrhea. In this study, we observed no severe diarrhea, although moderate hematological toxicities occurred.
Pulmonary toxicity was observed in previous studies of CPT-11 alone (19,31) or in combination chemotherapy including CPT-11 (27–30). The mechanism of pulmonary toxicity of CPT-11 is unknown, and is considered to be related to 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, diagnosed as a TRD. They concluded that leukocytopenia and diarrhea were DLTs, although infrequent and sporadic in appearance, and the severity of pulmonary toxicity 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, four patients with pulmonary toxicity were reported, who responded well to steroid therapy (28,29). 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 received 240 mg/m2 (360 mg/body) as the total dose of CPT-11. The total dose was small to induce the toxicity, because pulmonary toxicity has been reported in patients who received a median total dose of 750 mg/m2 (range, 400–1000 mg/m2) of CPT-11 (19). It was possible that prior MVP therapy influenced the pulmonary toxicity. MMC is a well-known alkylating agent inducing pulmonary toxicity and the frequency ranged from 3 to 12% after a 20 mg/m2 total dose (31). Vindesine has also been reported to cause acute diffuse pulmonary infiltrates and respiratory failure, especially in combination with MMC. The incidence of pulmonary toxicity with a combination of these drugs was as high as 39% (32). 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. One has to consider pulmonary toxicity when using CPT-11, in spite of the fairly low cumulative dose compared with dose-inducing pulmonary toxicity reported as a single agent, for patients previously treated with cytotoxic agents for which pulmonary toxicity has been reported.
The other DLT observed in this study was hypotension requiring catecholamine. Hypotension caused by CPT-11 or etoposide has been reported, but drug-induced hypotension is a minor toxicity which is known to be a hypersensitivity reaction. In this study, the patient who experienced hypotension also showed a fever of 39°C, leukocytopenia, high CRP value and organ damage. 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, although no bacteria were detected by blood culture.
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 in spite of the considerably low dose of CPT-11.
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Acknowledgment |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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We thank Dr Yoshihiro Matsuno, Clinical Laboratory Division, National Cancer Center Hospital, Tokyo, for his helpful comments on the preparation of the manuscript.
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FOOTNOTES |
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+ For reprints and all correspondence: Tetsu Shinkai, Division of Medical Oncology, National Cancer Center Hospital East, 5–1, Kashiwanoha 6-chome, Kashiwa, Chiba, 277-8577, Japan. E-mail: tshinkai@ncc.go.jp
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Received June 29, 2000; accepted September 11, 2000.
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