Controversial results of surgical treatment after induction chemotherapy, especially in relation to the extent of resection, have previously been reported. Mortality and morbidity were studied in the surgical arm of the European Organisation for Research and Treatment of Cancer (EORTC) 08941 trial. EORTC 08941 is a multicentre, prospective, randomised, phase-III trial of surgical resection versus radiotherapy in patients with proven stage IIIA-N2 nonsmall cell lung cancer after an objective response to platinum-based induction chemotherapy. Operative results in the 167 patients randomised in the surgical arm are presented within this study. Among these patients, one switched to the radiotherapy arm and 17 patients did not get any protocol treatment or information is not yet available. Radical resection with negative surgical margins was obtained in 74 patients (49.7%). In 61 patients (40.9%), a pathological down-staging to N0 or N1 was present. Operative 30-day mortality was 4.0%. Post-operative complications were mainly pneumonia, respiratory insufficiency, arrhythmias, air leak, cardiac decompensation, empyema and bronchopleural fistula. In total, 12 (8.1%) patients underwent re-operation due to positive margins, haemothorax, empyema and bronchopleural fistula. In conclusion, surgical resection after induction chemotherapy in the multicentre European Organisation for Research and Treatment of Cancer trial has yielded acceptable rates of morbidity and mortality.

The aim of this study was to document the activity and toxicity of paclitaxel (Taxol)/carboplatin when used as induction chemotherapy in patients with stage IIIA N2 non-small cell lung cancer (NSCLC) prior to definitive local treatment within a large, ongoing comparative study (EORTC 08941). 52 eligible, consenting, chemotherapy-naı̈ve patients with NSCLC, median age of 60 years, stage IIIA N2 disease and the ability to tolerate a pneumonectomy received paclitaxel 200 mg/m2 as a 3-h infusion followed by carboplatin at an area under the concentration curve (AUC) of 6 every 3 weeks for three courses. Most patients received three courses. No grade 3/4 anaemia or thrombocytopenia was documented. Over all of the cycles, 6% (3 patients) experienced grade 3 leucopenia while 63% (32/51 patients) experienced grade 3-4 neutropenia. There was 1 patient (2%) with febrile neutropenia, no early or toxic deaths and no hypersensitivity reactions. Severe non-haematological toxicity was uncommon, with the exception of grade 3 alopecia in 39%, lethargy in 8% and myalgia in 6%. Of the eligible patients (n=52), there was one complete response (CR) and 32 partial responses (PR), resulting in a response rate of 64% (95% Confidence Interval (CI) 49%–76%). Of the 15 eligible patients randomised to surgery after induction chemotherapy, 3 patients did not receive surgery and 2 patients (n=12) had no tumour in the mediastinal nodes (17%). Resections were considered complete in 2 of the 12. Median survival for all eligible patients (n=52) was 20.5 months (95% CI 16.1–31.2), with an estimated 1-year survival rate of 68.5% (95% CI 55.2–81.7). In patients with N2 stage IIIA NSCLC, paclitaxel/carboplatin is an active and very well-tolerated induction regimen.

The aim of this study was to document the activity and toxicity of paclitaxel (Taxol)/carboplatin when used as induction chemotherapy in patients with stage IIIA N2 non-small cell lung cancer (NSCLC) prior to definitive local treatment within a large, ongoing comparative study (EORTC 08941). 52 eligible, consenting, chemotherapy-naive patients with NSCLC, median age of 60 years, stage IIIA N2 disease and the ability to tolerate a pneumonectomy received paclitaxel 200 mg/m(2) as a 3-h infusion followed by carboplatin at an area under the concentration curve (AUC) of 6 every 3 weeks for three courses. Most patients received three courses. No grade 3/4 anaemia or thrombocytopenia was documented. Over all of the cycles, 6% (3 patients) experienced grade 3 leucopenia while 63% (32/51 patients) experienced grade 3-4 neutropenia. There was 1 patient (2%) with febrile neutropenia, no early or toxic deaths and no hypersensitivity reactions. Severe non-haematological toxicity was uncommon, with the exception of grade 3 alopecia in 39%, lethargy in 8% and myalgia in 6%. Of the eligible patients (n = 52), there was one complete response (CR) and 32 partial responses (PR), resulting in a response rate of 64% (95% Confidence Interval (CI) 49%-76%). Of the 15 eligible patients randomised to surgery after induction chemotherapy, 3 patients did not receive surgery and 2 patients (n = 12) had no tumour in the mediastinal nodes (17%). Resections were considered complete in 2 of the 12. Median survival for all eligible patients (n = 52) was 20.5 months (95% Cl 16.1-31.2), with an estimated 1-year survival rate of 68.5% (95% CI 55.2-81.7). In patients with N2 stage IIIA NSCLC, paclitaxel/carboplatin is an active and very well-tolerated induction regimen. (C) 2003 Elsevier Science Ltd. All rights reserved.

Reported incidences of febrile neutropenia in cancer patients undergoing chemotherapy vary widely according to cancer site, chemotherapy regimen, patient characteristics and definition of febrile neutropenia. Human Colony Stimulating Factors are effective in reducing the rate or duration of febrile neutropenia allowing more intensive chemotherapy, but they are expensive. The economic consequences of prophylaxis with HCSFs reported in the literature vary from cost savings to high added costs. Guidelines for the use of primary prophylaxis with HCSF have recommended that this should be restricted for patients with an expected incidence of febrile neutropenia of > 40%. We developed a simple decision analytical model to assess the cost-effectiveness of prophylaxis of febrile neutropenia under various assumptions about the expected incidence of febrile neutropenia, effectiveness and cost of prophylaxis, cost of febrile neutropenia, and potential impact of prophylaxis on quality of life and life expectancy. The model was applied to lung cancer using data from the literature and from EORTC clinical trials. The model illustrates some main principles of economic evaluation and can be used to assess the cost-effectiveness of prophylaxis of febrile neutropenia taking into account the best availaible information on expected toxicity and associated costs with various chemotherapy regimens. Reported incidences of febrile neutropenia in cancer patients undergoing chemotherapy vary widely according to cancer site, chemotherapy regimen, patient characteristics and definition of febrile neutropenia. Human Colony Stimulating Factors are effective in reducing the rate or duration of febrile neutropenia allowing more intensive chemotherapy, but they are expensive. The economic consequences of prophylaxis with HCSFs reported in the literature vary from cost savings to high added costs. Guidelines for the use of primary prophylaxis with HCSF have recommended that this should be restricted for patients with an expected incidence of febrile neutropenia of > 40%. We developed a simple decision analytical model to assess the cost-effectiveness of prophylaxis of febrile neutropenia under various assumptions about the expected incidence of febrile neutropenia, effectiveness and cost of prophylaxis, cost of febrile neutropenia, and potential impact of prophylaxis on quality of life and life expectancy. The model was applied to lung cancer using data from the literature and from EORTC clinical trials. The model illustrates some main principles of economic evaluation and can be used to assess the cost-effectiveness of prophylaxis of febrile neutropenia taking into account the best availaible information on expected toxicity and associated costs with various chemotherapy regimens.

33. potentiation of morpholino doxorubicin by human liver microsomes. Cancer Res 1992,52,437e4384. Coley HM, Twentyman PR, Workman P. 9-Alkylmorpholinyl anthracyclines in multidrug resistance. Eur J Cuncer 1990, 26, 66%67. Slevin ML, Joel P. Prolonged oral etoposide in small cell lung cancer. Ann Oncoll993,4,529-532. MillwardMJ, Newell DR, Bahnano K,etal. Clinicalandpharmacokinetic study of BMY 40481 (etoposide phosphate). Froc Am Assoc Cancer Res 1992,33,529. Whitesell L, Geselowitz D, Chavany C, er al. Stability, clearance and disposition of intraventricularly administered oligonucleotides: implications for therapeutic application within the nervous system. Proc Nat1 Acad Sci USA 1993,90,4665-4669. Wilson JM. Vehicles for gene therapy. Nature 1993,365,691-692. Jain RK. Therapeutic implications of tumour physiology. Curr Opin Onco11991,3,1105-1108. Bagshawe KD. Towards generating cytotoxic agents at cancer sites. BrJ Cancer 1989,60,275-281. Powis G. Signalling targets for anticancer drug development. Trends PhormSci 1991,3,1105-1108. Brunton VG, Workman P. Cell-signalling targets for antitumour drug development. Cancer ChemotherPhutmac 1993,32,1-9. Wiebe VJ, Osborne CK, McGuire WL, De Gregario MW. Identification of estrogenic tamoxifen-resistant human breast tumours. J Clin Oncoll992,1O, 990-994. 34. Riley R, Workman P. DT-diaphorase and cancer chemotherapy. Biochem Pharmac 1992,8,1657-X69. 35. Newton P. Liquid chromatography-mass spectrometry: essential tool for drug research. LG-GC Znt, 8,706-714. 36. Morrison JG, Bisset D, Stephens IF, et al. The isolation and identification of cis-diammine-chloroplatinum(II)-DNA adducts by anion exchange chromatography and inductively coupled plasma mass spectrometry. ZntJ Oncoll993,2,33-37. 37. Stevens AN, Morris PG, Iles RA, Sheldon PW, Griffiths JR. 5Fluoruacil metabolism monitored by in viva 19F NMR. Br 3 Cancer 1984,50,113-117. 38. Hickman JA. Apoptosis induced by anticancer drugs. Cancer Metastusis Rev 1992,11,121-139. 39. Jackson RC. The kinetic properties of switch antimetabolites. 3 Nat1 Cancer Znst 1993,85,539-545. 40. Reidenberberg MM. Trends in clinical pharmacokinetics. Clin Phatmacokinet 1993,24, l-9. 41. Abernathy DR. Presidential address: notes of the American Society for Clinical Pharmacology and Therapeutics. Clin Phurtn Ther 1992, 51,475-477.

The absolute bioavailability and pharmacokinetics of orally administered teniposide were investigated in 25 patients. All patients received 50 to 60 mg/m2 teniposide intravenously on day 1, before oral administration. Six patients received 60 mg/m2 as a single oral dose on day 8; 5 patients received 60 mg/m2 and 120 mg/m2 as a single oral dose on days 8 and 15, respectively; 5 patients received 120 mg/m2 and 240 mg/m2 as a single oral dose on days 8 and 15, respectively; 6 patients received 60 mg/m2 as a single oral dose on 5 consecutive days from days 8 to 12; and 3 patients received 50 mg/m2 three times a day at 6-hour intervals on day 8. The mean absolute bioavailability was 41.6% +/- 14.2% with a large interindividual variability (range, 19.7% to 71.4%) and a low intraindividual variability (range, 2.8% to 13.9%). At a dose of 240 mg/m2, the bioavailability was decreased, whereas administration of multiple doses on 1 day or 5 consecutive days increased the overall bioavailability. In conclusion, teniposide can be administered orally with a bioavailability comparable with that of etoposide. The schedule dependency of both drugs warrants investigations of oral administration for 21 or more days. A formulation of teniposide capsules of 50 mg or less would be most helpful to facilitate oral administration.

The first priorities for upfront chemotherapy in TCCB are to prove in randomized phase III trials that the addition of toxic chemotherapy to toxic standard locoregional treatment can improve survival and/or permit bladder preservation. If such proof is obtained, we will need to distinguish patients who benefit from chemotherapy from those who do not. One way to make such a distinction is to separate responders from nonresponders. The prognostic value of downstaging to P0 or noninvasive cancer is significantly different from the prognosis associated with the continued presence of invasive disease. The available data regarding clinical assessment of response still appear to indicate that only the demonstration of a lack of response (see Table 2: cIR, cSD, cPD, greater than or equal to cT2) is reliable, However, there may be some patients, who after two courses of chemotherapy, still show the presence of invasive bladder cancer together with signs of tumor cell kill and may be further downstaged to P0 during the next two courses of chemotherapy. The clinical assessment of cCR and cPR is too inaccurate to be used as a basis for decisions concerning continuation of chemotherapy or bladder preservation. The decision to leave the bladder untreated after a cCR carries the risk of jeopardizing cure. More studies on the evaluation of response of the primary tumor are needed, probably with a central role for the pathologist to evaluate not only the gross presence, minimal residual disease, or true absence of cancer but also the adequacy of site and deepness of the restaging TUR biopsy.

The aim of the study was to assess the response rate and toxicity of high-dose 24 h infusion of 5-fluorouracil (5FU) in metastatic adenocarcinoma of the pancreas. Patients with measurable disease, performance status 0–2, and no prior chemotherapy were registered to receive cycles of leucovorin (LV) 500 mg/m2 (or l-LV 250 mg/m2 over 1 h followed by 5FU 2.6 g/m2 over 24 h, weekly for 6 weeks, followed by a 2-week rest. The main endpoints were the response rate and toxicity. From 37 patients, 36 were the analysed for toxicity, and 33 were eligible and analysed for response. The median age was 59 years (range 28–74 years), and the median performance status was 1. Partial response was observed in three patients (9%) (95% Confidential Interval (CI): [2–24]%). Main grade 3/4 National Cancer Institute (NCI) common toxicity criteria toxicities (patients) were diarrhoea (n=3), vomiting (n=2) and hand–foot syndrome (n=5). Median time to progression was 7 weeks (95% CI: [6.4–11.7] weeks) and median survival 19 weeks (95% CI: [12–35] weeks). In conclusion, high-dose 5FU and folinic acid is well tolerated, but has only modest activity in pancreatic cancer.

Between April 1988 and August 1989, 30 melanoma patients were entered in a multicentre Phase II study of dacarbazine (DTIC) 850 mg/m2 i.v. bolus on day 1, and recombinant interleukin-2 (rIL-2) (Cetus) 18 x 10(6) IU/m2/day i.v. continuous infusion on days 4-9. Six treatment cycles were given: the first two at an interval of 13 days, and further cycles at intervals of 20 days. Twenty patients are currently evaluable for toxicity and 18 for response. Two of these patients presented with metastatic intraocular melanoma. Median age was 48 years (range 18-83), and median Karnofsky index was 100 (range 80-100). Four patients had received prior radiotherapy and one had received prior immunotherapy. Seventeen patients received two cycles of treatment and nine patients received three or more cycles. Four patients responded (22%): two complete remissions and two partial remissions. Stable disease was seen in six patients (33%). Responses occurred in the lung, skin, spleen and lymph nodes. Seventy-five percent of the patients received the full dose of rIL-2 during cycle 1, whilst only 2 out of 9 (22%) received the planned dose on the third cycle. Rebound lymphocytosis of 5.3 x 10(3)/L (range 1.2-18.1) occurred 24-48 h after rIL-2, but was not predictive for response. Currently, there is no evidence that pretreatment with DTIC impacts negatively on the rIL-2-stimulated lymphocyte proliferation. The toxicity profile of this treatment regimen did not differ significantly from that already described for similar regimens of rIL-2. However, in this interim analysis, there was a trend for a higher percentage of patients (25%) to experience severe weight gain (greater than 10%). This study shows that this treatment regimen is active in metastatic melanoma, with acceptable toxicity. Further research will focus on using other chemotherapeutic agents and/or other biological response modifiers (e.g. interferons, tumour necrosis factor) in combination with rIL-2.

An International Consensus Report on the role of chemotherapy in small cell lung cancer (SCLC) resulting from a workshop sponsored by the International Association for the Study of Lung Cancer (IASLC) was published in early 1983 [l]. Since that publication, the results of many chemotherapy studies have been published. Consequently, a second consensus workshop was held in Helsingor, Denmark in June, 1989. This paper presents the consensus report on chemotherapy from that workshop.

Eleven patients with advanced nonseminomatous germ cell tumors (NSGCT), who relapsed after or were refractory to standard dose cisplatin-based remission induction chemotherapy, were treated in a phase II clinical trial with VP 16-213 2500 mg/m2 and cyclophosphamide 7 g/m2. Both drugs were given in maximally tolerable doses regarding extramedullary toxicity. Urothelial damage due to cyclophosphamide was prevented by the administration of mesnum. Autologous bone marrow was infused on day 7 to prevent long lasting medullary toxicity. Because of the disappointing results in the first three patients, a second treatment step was added. The next eight patients were treated with 2500 mg/m2 VP 16-213 divided and given on days 1-2-3 and after full bone marrow recovery with total doses of VP 16-213 2000 mg/m2 plus cyclophosphamide 7 g/m2 divided and given on days 29-30-31, followed by autologous bone marrow transplantation (ABMT) on day 35. Toxicity to high-dose VP 16-213 plus cyclophosphamide followed by ABMT consisted of mucositis, nausea, vomiting and diarrhea. No cardiac toxicity or hemorrhagic cystitis occurred. The mean duration of leukopenia and thrombopenia was 14 and 13 days respectively. The additional, preceding treatment with VP 16-213 as a single agent caused mucositis, and leukopenia and thrombopenia for a mean number of 9 and 6 days respectively. Seven responses were obtained: two complete responses of 46 and 66+ weeks respectively and five partial responses with a median response duration of 12 weeks. The median survival time was 40 weeks. This regimen of one or two courses with maximally tolerable doses of VP 16-213 plus cyclophosphamide and ABMT is not sufficient to salvage a substantial number of patients with relapsing or refractory NSGCT.