U. Gatzemeier

Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy

The aim of this study was to determine the usefulness of recombinant human granulocyte colony stimulating factor (r-metHuG-CSF) following conventional chemotherapy for small cell lung cancer. 130 previously untreated patients were randomised to receive either r-metHuG-CSF (230 micrograms/m2) or placebo on days 4-17 following CDE (cyclophosphamide, doxorubicin and etoposide) chemotherapy. Over all cycles, 53% of 64 patients on placebo and only 26% of 65 patients on r-metHuG-CSF had at least one experience of neutropenia with fever defined as a neutrophil count less than 1.0 x 10(9)/l and a temperature > or = 38.2 degrees C (P < 0.002). It resulted in a reduction in the requirement for parenteral antibiotics from 58% in placebo patients compared with 37% in the r-metHuG-CSF group (P < 0.02), and a significant reduction in the incidence of infection-related hospitalisation. Chemotherapy doses were reduced by 15% or more at least once in 61% of the placebo group compared with 29% in the r-metHuG-CSF group (P < 0.001). 47% of the patients treated with placebo and 29% of the patients treated with r-metHuG-CSF experienced at least one cycle with a delay of 2 days or more in the administration of chemotherapy (P < 0.04). r-metHuG-CSF was well tolerated. There were no significant differences between the two groups in terms of response or survival.

Phase III Comparative Study of High-Dose Cisplatin Versus a Combination of Paclitaxel and Cisplatin in Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSEnNew effective chemotherapy is needed to improve the outcome of patients with advanced non-small-cell lung cancer (NSCLC). Paclitaxel administered as a single agent or in combination with cisplatin has been shown to be a potentially new useful agent for the treatment of NSCLC.nnnPATIENTS AND METHODSnBetween January 1995 and April 1996, 414 patients with stage IIIB or IV NSCLC were randomized to received either a control arm of high-dose cisplatin (100 mg/m(2)) or a combination of paclitaxel (175 mg/m(2), 3-hour infusion) and cisplatin (80 mg/m(2)) every 21 days.nnnRESULTSnCompared with the cisplatin-only arm, there was a 9% improvement (95% confidence interval, 0% to 19%) in overall response rate for the paclitaxel/cisplatin arm (17% v 26%, respectively; P=.028). Median time to progression was 2.7 and 4.1 months in the control and paclitaxel/cisplatin arm, respectively (P=.026). The study, however, failed to show a significant improvement in median survival for the paclitaxel/cisplatin arm (8.6 months in the control arm v 8.1 months in the paclitaxel/cisplatin arm, P=.862). There was more hematotoxicity, peripheral neuropathy, and arthralgia/myalgia on the paclitaxel/cisplatin arm, whereas the high-dose cisplatin arm produced more ototoxicity, nausea, vomiting, and nephrotoxicity. Quality of life (QOL) was similar overall between the two arms.nnnCONCLUSIONnThis large randomized phase III trial failed to show a significant improvement in survival for the paclitaxel/cisplatin combination compared with high-dose cisplatin in patients with advanced NSCLC. However, the paclitaxel/cisplatin combination did produce a better clinical response, resulting in an increased time to progression while providing a similar QOL.

Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients.

PURPOSEnTo assess whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the toxicity of chemotherapy and alters delivered dose-intensity. To assess the feasibility of dose-intensification of chemotherapy in small-cell lung cancer (SCLC) and determine whether it has an impact on outcome.nnnMATERIALS AND METHODSnPatients with good- or intermediate-prognosis SCLC entered a prospective multicenter study that involved a 2 x 2 factorial design with randomization to six cycles of chemotherapy with ifosfamide 5 g/m2, carboplatin 300 mg/m2, etoposide 120 mg/m2 intravenously (I.V.) on days 1 and 2 and 240 mg/m2 orally on day 3, and vincristine 0.5 mg/m2 I.V. on day 15 (V-ICE) every 3 weeks (intensified arm) or every 4 weeks (standard arm). A second double-blind randomization to subcutaneous GM-CSF (250 microg/m2/d) or placebo for 14 days between chemotherapy cycles was made.nnnRESULTSnThree hundred patients were entered. Myelosuppression was the main toxicity, with no significant difference in the incidence or grade between treatment groups. The incidence of febrile neutropenia and bacteriologically confirmed sepsis was unaffected by chemotherapy schedule or use of GM-CSF. Twenty-six percent greater dose-intensity was delivered in the intensified arm, with a trend for greater dose-intensity for those who received GM-CSF. Eighty-three percent of patients achieved a response (51% complete response [CR] rate), with no significant difference in response rates between treatment groups. Survival was significantly increased in the intensified compared with the standard arm (P = .0014); median survival rates were 443 versus 351 days and 2-year survival rates were 33% versus 18%, respectively.nnnCONCLUSIONnGM-CSF does not reduce the incidence of complications from myelosuppression of aggressive chemotherapy. Dose intensification of V-ICE to a 3-week schedule in SCLC is not associated with increased toxicity, but appears to improve survival significantly. Future studies should aim to deliver chemotherapy in maximal-tolerated dose-intensities.

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210u2009mgu2009m−2 PPX or 75u2009mgu2009m−2 docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, P<0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210u2009mgu2009m−2 resulted in increased neurotoxicity compared with docetaxel.

Combination chemotherapy with carboplatin, etoposide, and vincristine as first-line treatment in small-cell lung cancer.

PURPOSEnThe antineoplastic activity of carboplatin and etoposide may be improved by the addition of vincristine (CEV) because of its low myelosuppressive potential and its activity in small-cell lung cancer (SCLC). A phase II study with CEV was carried out.nnnPATIENTS AND METHODSnOne hundred twenty-one untreated patients with SCLC (63 with limited disease [LD], 58 with extensive disease [ED]) were treated with a combination of 300 mg/m2 intravenous (IV) on day 1, etoposide 140 mg/m2 IV daily on days 1 to 3, and vincristine 1.4 mg/m2 IV on days 1, 8, and 15 every 4 weeks.nnnRESULTSnA 90% rate overall response rate including 56% complete responses (CRs) was achieved in LD and an 83% overall response rate including 35% CRs was observed in ED. Median survival time was 13 months in limited disease and 9.5 months in extensive disease. The 24 and 36 months survival rates were 29% in LD and 9% in ED. Myelosuppression was the main form of toxicity.nnnCONCLUSIONnThe combination of CEV is a new active and well-tolerated regimen in the treatment of SCLC. Prospective randomized studies of CEV with conventional chemotherapy are warranted.

Clinical Phase II Trial of Treosulfan in Patients with Non-Resectable Non-Small-Cell Lung Cancer

Background: Treosulfan (L-threitol-1,4-bis-methanesulfonate, Ovastat®) is a prodrug of a bifunctional alkylating cytostatic. The compound is registered in several European countries for the treatment of patients with advanced ovarian carcinoma. Recent preclinical in vivo evaluation of treosulfan revealed comparably high antitumour activity against human tumour xenografts of small-cell and non-small-cell lung carcinomas as well as other tumour entities. Patients and Methods: A clinical phase II study was conducted in patients suffering from advanced, non-resectable non-small-cell lung carcinomas (stage IIIB and stage IV). 24 chemotherapeutically naive patients, including 4 patients that had a relapse after primary surgery/radiotherapy, were enrolled. Treosulfan was administered as a 0.5-hour intravenous infusion of 10 g/m2 every 4 weeks. Results: Twenty patients were evaluable for response. No objective tumour remission was documented. Ten patients (50%) showed stable disease (no change), including 2 patients that barely failed partial remission criteria. Ten patients (50%) progressed on therapy. Median survival time of all patients was 24.5 weeks. Haematological toxicity of treosulfan was evident. Five of 24 patients (21%) showed thrombocytopenia, 3 of 24 (13%) leucocytopenia, 2 of 23 (9%) granulocytopenia and 2 of 24 (8%) anaemia ≥ CTC grade III. Non-haematological side-effects were seldom and low-graded. Conclusion: Treosulfan was well tolerated in this group of non-pretreated nonsmall-cell lung cancer patients. However, no objective tumour remission was evident. Schlüsselwörter Treosulfan · Nichtkleinzelliges Bronchialkarzinom · Phase II · Chemotherapie

Clinical Outcome of Topotecan: New Strategies Play an Important Role in the Treatment of Lung Cancer, Other Solid Tumors, and Hemoblastosis

The symposium focused on the current use of and new indications for the semisynthetic camptothecin analogue topotecan (Hycamtin®). Camptothecins represent a novel class of antineoplastic agents directed at a new target, topoisomerase I. After the identification of the target by Liu and colleagues, the rapid development of camptothecin and its analogues began. Clinical activity of topotecan has been proven for a range of tumors, especially for ovarian and lung cancer. The incorporation of taxanes into first-line therapy of advanced ovarian cancer led to the question of the optimum treatment in recurrent disease. Final results of the phase III comparison between paclitaxel and topotecan therapy after failure of platinum treatment in advanced ovarian cancer show no statistically significant difference in survival, progression-free intervals and remission rates for both agents. Further studies evaluated topotecan therapy in patients previously treated with paclitaxel and a platinum compound. Responses were seen even in the refractory situation and the presented data on long-term application of topotecan underline the subjectively well-tolerated therapy with substantial clinical benefit for the patients. Additionally, combination therapies with topotecan show promising results not only in recurrent situations but also in first-line treatment as demonstrated by the spectrum of phase I and II data presented at the last ASCO meeting. In small-cell lung cancer topotecan has undergone the most extensive evaluation of all new chemotherapy agents. It is clearly active in second-line treatment, and shows promising results in first-line therapy. Additional benefit lies in the peneClinical Outcome of Topotecan: New Strategies Play an Important Role in the Treatment of Lung Cancer, Other Solid Tumors, and Hemoblastosis R. Kreienberga M. Freundb

80 Dose-intensification of V-ICE chemotherapy with GM-CSF in small cell lung cancer (SCLC)—A prospective randomised study of 301 patients

Patients (pts) with SCLC andxa0≤xa03 adverse prognostic features (Manchester system) were randomised in a multicentre prospective study to 6 courses of VICE chemotherapy (ifosfamide 5xa0g/m2, carboplatin 300xa0mg/m2, etoposide 120xa0mg/m2 iv dl, 2 & 240xa0mg/m2po d3, vincristine 0.5xa0mg/m2 d14) every 3 or 4 weeks (“intensified” & “standard” arms respectively). Pts received 14 days of granulocyte-macrophage colonystimulating factor (GM-CSF) or placebo (250xa0μg/m2/d) between each course in a double-blind fashion. Endpoints are to determine the effects of dose-intensity and GM-CSF on outcome. 301 pts were entered from 17 centres in Europe (70% from 4 centres) up to 1/94. Sixty-three percent hadxa0≤xa01 adverse prognostic feature and 41% had extensive stage disease (similar distribution in “fixed” and “intensive” arms). Overall, 30% greater dose-intensity was administered to pts in the “intensive” arm. Preliminary outcome assessments are: “fixed” arm—documented sepsis—28 pts, OR 76% (52% CR), 8—month survival 63%; “intensive” arm—documented sepsis-11 pts, OR 87% (47% CR), 8—month survival 75%. Detailed outcome analysis with assessment of the effects of GM-CSF will be performed in 6/95 with a minimum follow up of 1 year.