Abstracts/Lung Cancer 12 (1995) 113-160 143

Purpose: A phase I trial was performed to evaluate the feasibility of escalating the dose of etoposide in dose-intensive ifosfamide, carboplatin, and etoposide (ICE) with gramdocytc-macrophage colony-stimulating factor (GM-CSF). Patients und Metho& lknty-four patients were entered between November 1990 and November 1991. Patients received ifosfamide 5 g/m* by continuous infusion over 48 hours, carboplatin 400 mg/m’ by intravenous bolus, and GM-CSF Spgkg/d subcutaneously from day 4 until neutrophil recovery. The etoposide dose was escalated, with six patients receiving 300 mg/m’ total dose (level I), six receiving 600 mg/mr (level 2). three receiving 900 mg/m* (level 3) and five receiving 1,200 mg/m’ (level 4). Level 4B consisted of three patients who received etoposide 1,200 mg/m* and GM-CSF 10 ug/kg/d. Cycles were repeated every 2 1 days. The maximum-tolerated dose (MTD) was prospectively defined as the dose level at which the next higher level produced greater than 7 days of grade 4 myelosuppression in two or more of six patients, Results: Twenty-three patients were assessable. The median duration of neutropenia was < 7 days on cycle 1 at all dose levels. The initial criteria for determination of the MTD was never achieved. However, seven of eight patients treated at levels 4 and 4B required hospitalization for neutropenic fever on cycle 1 of therapy, with three of four septic events occurring at these levels. Cumulative thrombocytopenia occurred at all dose levels, with 500/o of patients requiring platelet transmsions on cycle 3. This became the dose-limiting toxicity above level 3, The overall response rate was 48%. with 11 of 23 objective responses, including two complete responses (CRs). Seven of 11(64%) patients with non- small-cell lung cancer (NSCLC) responded, including one CR. Two of four (50%) heavily pretreated non-Hodgkin’s lymphoma (NHL) patients responded, with one CR Conclusion: The addition of GM-CSF to a dose-intensive ICE regimen permitted dose escalation of etoposide to 900 mg/m’, with cumulative thrombocytopenia as the dose-limiting toxicity. Carboplatin dosing by the area under the curve (AUC) may minimize thrombwytopenia. This appears to be an active regimen for patients with NSCLC and retractoty NHL.

A prospective randomized clinical trial comparing preventive and conventional use of rhGCSF in lung cancer patients receiving chemotherapy Nakamura H, Yamaji Y, Fujita J, Takigawa K, Mori Y, Kamei T et al. Department ofKagawaA4edical School, Kagawa 761-07. Lung Cancer (Japan) 1994;34:229-35. A prospective randomized clinical trial was conducted to test whether the preventive use of rhGCSF obtain better results than the conventional use of rhG-CSF for chemotherapy-induced neutropenia in lung cancer patients. A total of 26 patients, 22 of whom were evaluable, were entered in this study and were assigned to two groups. In Arm A (conventional use of rhG-CSF), subcutaneous (s.c.) administration of rhG-CSF at a dose of 50 p@rnr was given to the patients when the neutrophil counts became 2,OOO/i4l or less, whereas in Arm B (preventive use of rhG- CSF), S.C. administration of rhG-CSF at the same dose was fixed at days 4 to 18. All patients received the same chemotherapy wnsisting of 300 mg/m’ carboplatin at day 1, 30 mp/m2 adriamycin at day 1, 100 mg/m’ etoposide at days 1 to 3 by drip infusion. Sign.iticant ditferences were observed in terms of mean neutrophil nadir (l,547/pl in Arm B vs. 205 in Arm A; p<O.Ol) and the mean duration of neutropenia (<l,OOO/ul: 2.0 days in Arm B vs. 5.6 days in Arm A; p<O.Ol). Also Arm B showed a tendency to shorten the mean duration of neutropenia with fever (>37’C), days of administration of antibiotics and to reduce the episodes of infection. In conclusion, the preventive use of rhG-CSF may be effective to shorten the interval between chemotherapeutic cycles and to increase the tolerable dose intensity in lung cancer chemotherapy as compared to the conventional use of rhG-CSF.

Reduced levels oftopuisomense IIa and IU3 in a multidrug-rrdstant lung-ancer cell line Evans CD, Mirski SEL, Danks MK, Cole SPC. Cancer Reseat& Laboratories, QueenS CJniversi@, Kingston, Ont. K7L 3N6. Cancer Chemother Pharmacol 1994;34:242-8. We have previously shown that the doxorubicin-selected multidrug- resistant small-cell hmg-cancer cell line H69AR is resistant to VP-Hi- induced single-strand DNA breaks as compared with its parental H69 cell line. Levels ofimmunoreactive topoisomerase IIa are also reduced in H69AR cells. In the present study, we found that cleaved complex formation in the presence of VP-16 was decreased in H69AR cells as compared with H69 cells. In addition, the m&ant cells contained lower levels of both topoisomerase Ba and topoisomerase IL8 protein and mRNA. However, these changes were not accompanied by a decmase in the P4-unknotting (strand-passing) activity of0.67 M NaCl nuclear extra& of H69AR cells, nor was there any di&ence in VP-16 inhiiition of unknotting activity in the H69 and H69AR nuclear extracts. These data suggest that reduced levels of topoisomerase Ha and II8 may contribute to the resistance of H69AR cells to VP-16 and other drugs that target these isoenzymes.

Combination chemotherapy with cyclophosphamide, epirubicin and etoposide in small cell hmg cancer Jassem J, Kamigka-Mlodkowska H, Jassem E, Slupek A, Zych J, Wtatr I?. et al. Dept. Oncology and Radiotherapy Gdansk Medical School, ul. Deqbinki 7, 80-211 Gdansk. Lung Cancer (Ireland) 1994;11:283- 91. From March 1987 to February 1991,136 patients with untreated small cell lung cancer (64 patients with limited disease and 72 with extensive disease), were treated as part ofa prospective multicenter study, with a combination of cyclophosphamide loo0 mg/m* i.v. on day 1, epirubicin 70 mg/m’ iv. on day 1 and etoposide 100 mg/m’ i.v. on days I, 3 and 5. Courses were repeated every 3 weeks. One-hundred thirty-four patients were evahrable. There were 42 (3 1%) complete responses and 66 (49”h) partial responses for an overall response rate of 80% 95% wnfldence interval 71-870/o). A complete response was seen in 24 patients (38%) with limited disease and in 18 patients (26%) with extensive disease, while a partial response was observed for 31(480/o) and in 35 (50%) patients, respectively. The median duration of response for all patients was 8.9 months (range, l-60+ months). The median duration of survival for the entire group was 11.4 months (12.5 months for limited disease and 9.8 months for extensive disease). The 2-year survival rate for the whole group was 13%. The main side-effects were myelosupression, alopecia, nausea and vomiting. Grade 4 toxicity was seen in 8.5% of patients. In wnclusion, the studied regimen was found to be active and well tolerated and may be considered as an alternative to standard chemotherapy combinations in SCLC.

Randomized comparison of etoposide-cisplatin vs. etoposide- carboplatin and irradiation in small-cell lung cancer Skarlos DV, Samantas E, Kosmidis P, Fountsilas G, Angelidou M, Palamldas P, et al. Hellenic Co-operative Oncology Gmup, Mesogeion 82, 115 27 AthenslAmbelokipi. AM Gnwl 1994;5:601-7. Purpose: To compare the etticacy and toxicity of etoposlde and cisplatin (EP) with etoposide and carboplatin (EC) in combination with irradiation in small-cell lung cancer (SCLC). Methods: previously untreated patients @ts) with SCLC and measurable or evaluable disease were randomized to receive either cisplatin 50 mg/mz on days 1-2 or carboplatin 300 mgl m* on day 1, both combined with etoposide 300 mpl mz on days 1-3 every 21 days for 6 treatment cycles. The vast majority of responding