Induction chemotherapy, concurrent chemoradiation and surgery for Pancoast tumour.

The traditional treatment of Pancoast tumour with local approaches (surgery, radiotherapy or a combination of both) leads to a poor outcome due to the high rate of incomplete resection and the lack of systemic control. The aim of the present prospective feasibility study was to determine whether a trimodality approach improves local control and survival. Patients with stage IIB-IIIB Pancoast tumour received induction chemotherapy (three courses of split-dose cisplatin and etoposide or paclitaxel) followed by concurrent chemoradiotherapy (a course of cisplatin/etoposide combined with 45 Gy hyperfractionated accelerated radiotherapy). After restaging, eligible patients underwent surgery 4-6 weeks post-radiation. A total of 31 consecutive patients with T3 (81%) or T4 (19%) Pancoast tumour were enrolled in the study. Induction chemoradiotherapy was completed in all patients without treatment-related deaths. Grade 3-4 toxicity was observed in 32% of cases. In total, 29 (94%) patients were eligible for surgery. Complete resection was achieved in 94% of patients. The post-operative mortality rate was 6.4% and major complications arose in 20.6% of the patients. The median survival was 54 months with 2- and 5-yr survival rates of 74 and 46%, respectively. In conclusion, this intensive multimodality treatment of Pancoast tumour is feasible and improves local resectability rates and long-term survival as compared with historical series.

New targeted treatments in lung cancer--overview of clinical trials.

Combination chemotherapy has been established as the cornerstone of systemic treatment for advanced lung cancer in the last ten to fifteen years. However, improvements with new drug combinations in recent years have been rather small and a general outcome plateau has been reached with one-year survival rates of about 40% and two-year survival rates of less than 15%. Survival over three to four years is still a rare event in this disease, and more and more efforts are being made to develop innovative systemic treatment strategies with mechanisms of action different from conventional cytotoxic drugs. These molecular targeted agents have made a strong move forward in the management of this disease since Gefitinib--a small molecule EGF-receptor tyrosine kinase inhibitor--was registered in 2003 by the FDA and a number of further countries for the third-line treatment of non-small-cell lung cancer. Since then, every month findings have been reported about new cellular targets on lung-cancer cells and, consequently, new agents aiming at these molecular targets are being developed, preclinically. Some of these agents have already been tested in the clinics within phase-I, phase-II and some even within randomised phase-III trials. In this review we will try to summarise the current knowledge and data on the clinical activity of these new drugs in lung cancer and to give a perspective on the future for these new treatment principles. The most promising strategies have been aiming at the EGF-receptor family, serum-VEGF and the VEGF-receptor family (VEGF-1 and -2, respectively). Results from pivotal registration trials are expected within the next one or two years for a number of these new drugs, and the standards of care for advanced lung cancer may change dramatically, comparable to what we have seen in other solid tumours such as metastasised breast and colon cancer.

A phase I clinical and pharmacokinetic study of the camptothecin glycoconjugate, BAY 38-3441, as a daily infusion in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. PATIENTS AND METHODS: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. RESULTS: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses > or = 470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses > or = 320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. CONCLUSIONS: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.

Preoperative treatment strategies in stage III non-small cell lung cancer.

Recent experience has emphasized the need to include systemic chemotherapy in combined-modality management of locally advanced non-small cell lung cancer stage III. If definitive surgery is planned in these situations, preoperative application of drugs-induction chemotherapy-has many advantages in comparison to postoperative delivery. Patients' compliance to treatment, achievable dose intensities of drugs, possible locoregional downstaging, and frequent postoperative problems following complex resections are some of the arguments favouring preoperative chemotherapy. Despite numerous phase-II investigations, little evidence from randomized phase-III trials has been generated. Early inclusion of radiotherapy prior to definitive resection may help to improve preoperative downstaging. Besides available mature phase-II data, phase-III results from ongoing randomized trials are lacking to define the overall value of such a complex approach. Important issues in the future will aim at individualizing these intensive programs according to findings in clinical prognostic factor analyses and to prospectively validate a prognostic risk stratification. Data from translational and molecular research may further help to develop such evidence-based guidelines.

Combined modality therapy in NSCLC.

Combined modality treatment has 'come out of age' and increasingly represents standard of care for a rapidly growing number of patients in locally advanced stages of NSCLC. Modern progress of treatment techniques as well as possibilities for supportive interventions will lead to lesser treatment toxicities, better patient's compliance to treatment protocols and combinations of different modalities with a more efficient outcome. This number will further increase, as more and more centres in Europe are setting up the logistics of multidisciplinary treatment groups for patients with lung cancer. Standard of care for most disease stages is currently under investigation in large randomised phase-III trials. Further research in the forthcoming years has to address questions of treatment individualisation (risks, prognosis, need for local control in the individual patient, biological evaluation of tumour aggressiveness, DNA-fingerprinting of tumours, evaluation of MRD-status, treatment in the community). New drugs or treatment principles with different mechanisms of action such as antiangiogenesis factors, signal-transduction inhibitors, immunotherapy, antisense-oligonucleotides or gene(replacement) therapy may stimulate further clinical research. This may eventually define 'new modalities of treatment' thus leading to modern 'second-generation combined-modality protocols' including some of the new principles.