Lung cancer is the leading cause of cancer-related death in Portugal. Almost 3500 Portuguese are expected to be diagnosed with lung cancer in 2006; approximately 20% will have small cell lung cancer (SCLC). At presentation, 25% to 30% of patients will have local or regional disease, classified as limited stage disease. The concurrent chemovalidation therapy is the best choice. Once daily thoracic radiation therapy to doses in the range of 50 Gy to 60 Gy would reflect an accepted standard of care in daily practice. Because of the increase toxicity associated with hyper fractionated radiation, this approach is often limited to select patients. Etoposide plus cisplatin are synergistic, well tolerated and result in equal or superior survival compared with other regimens. This is the standard regimen for concomitant therapy in limited stage and for extensive disease SCLC. Despite good chemo sensitivity and radio sensitivity, the prognosis of SCLC is very poor because of the early development of resistance and the associated high tendency to recurrence, making second line treatment of SCLC a problem of real medical relevance. Topotecan now offers an effective and well tolerated monosubstance for second line therapy of recurrent SCLC. There has been a significant increase in median survival for patients with SCLC receiving topotecan plus symptomatic therapy versus symptomatic therapy. The efficacy of this drug is comparable to the efficacy of the three-drug combination CAV. The tolerability can be improved by means of toxicity-adapted dosing. In elderly and in patients with performance status 2, topotecan is also well tolerated and has good efficacy. Initial studies into weekly administration also demonstrate good efficacy. The combination of topotecan with cranial radiotherapy is well tolerated and effective in the treatment of cerebral metastases of SCLC. New classes of agents, such as antiangiogenic agents including bevacizumab, small molecule tyrosine kinase inhibitors and thalidomide are being evaluated with chemotherapy for patients with extensive stage SCLC.

[Small cell lung cancer--state of the art and future perspectives].

Preclinical perspectives on the use of platinum compounds in cancer chemotherapy.

Small cell lung cancer (SCLC) is generally sensitive to first-line chemotherapy, but limited disease often recurs and extensive disease is rarely curable. The most common first-line therapy regimen is cisplatin (Platinol; Bristol-Myers Squibb; Princeton, NJ) plus etoposide (Etopophos; Bristol-Myers Squibb)--PE, which is associated with overall response rates >80% in patients with limited SCLC. Although it is associated with median survival times of approximately 18-20 months for limited disease, PE yields median survival times of only approximately 8-12 months in patients with extensive disease, and symptom palliation becomes the primary therapeutic goal. The toxicities of PE may undermine quality of life and leave patients more susceptible to adverse events during subsequent therapies. Topotecan (HYCAMTIN; GlaxoSmithKline; Philadelphia, PA), an established treatment for recurrent SCLC, is being investigated in the first-line setting because of its novel mechanism of action; predictable, noncumulative, and manageable toxicities; and potential synergy with other active agents. Several recent phase II trials have generated promising results for topotecan-based combination regimens, including topotecan/paclitaxel (TAXOL; Bristol-Myers Squibb) (overall response rates 45%-100%), topotecan/etoposide (overall response, 95%), and topotecan, paclitaxel, and platinum agent triplets (overall response rates 51%-93%). The most frequent serious toxicity associated with these regimens was reversible and noncumulative neutropenia, which was generally manageable with supportive care. Additional clinical trials to investigate topotecan-based combination regimens and confirm their role in the first-line treatment of SCLC are under way.

Topotecan in the First-Line Treatment of Small Cell Lung Cancer

For more than 2 decades, combination chemotherapy has been the standard treatment for patients with small-cell lung cancer. Despite high initial response rates in both extensive- and limited-stage disease, long-term survival rates are only 10% to 20%. Camptothecins and taxanes are newer classes of agents that have shown significant activity against small-cell lung cancer. Their incorporation into chemotherapy regimens for small-cell lung cancer is being actively studied. In one randomized multicenter study, patients with advanced small-cell lung cancer treated with irinotecan (CPT-11, Camptosar) and cisplatin had a better survival time than patients receiving standard therapy. The combination of taxanes and irinotecan holds promise as an active regimen that may be tolerated better than cisplatin and irinotecan.

Camptothecin and taxane regimens for small-cell lung cancer.

Tumor heterogeneity makes combination chemotherapy one of the preferred modes of treatment regimens. In this work, sequential exposure of two anticancer agents, paclitaxel (Tx) followed by topotecan (TPT), was shown to have a synergistic effect on non-small cell lung cancer (NSCLC) cell line, NCI-H460. In order to improve patient compliance, the aforementioned concept was translated into a drug delivery system comprising of poly(d,l-lactide-co-glycolide) (PLGA)–chitosan composite particles. TPT-containing chitosan micro-/nanoparticles were prepared by the facile technique of electrospraying and encapsulated within PLGA microparticles using emulsion-solvent evaporation technique for delayed release of TPT. The formulation containing Tx- and TPT-loaded composite particles demonstrated synergism when exposed to NCI-H460 cellular aggregates (tumoroids) generated in vitro. Overall, the results of this study demonstrated the potential of the formulation containing Tx and PLGA–chitosan (TPT-loaded) composite particles for the treatment of lung cancer.

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Poly(d,l-lactide- co -glycolide)–chitosan composite particles for the treatment of lung cancer

Sequential dose-dense paclitaxel followed by topotecan in untreated extensive-stage small-cell lung cancer: a Spanish Lung Cancer Group phase II study

7142 Background: Nucleotide excision repair (NER) is the main DNA repair pathway. ERCC1, RRM1 and XPD are involved in the NER pathway, and tumor upregulation of these genes can lead to chemotherapy...

ERCC1, RRM1 and XPD mRNA expression as a predictive marker of outcome in non-small-cell lung cancer (NSCLC) patients after platinum/gemcitabine induction chemotherapy followed by surgery

L. Santome

Papers

Sequential dose-dense paclitaxel followed by topotecan in untreated extensive-stage small-cell lung cancer: a Spanish Lung Cancer Group phase II study

ERCC1, RRM1 and XPD mRNA expression as a predictive marker of outcome in non-small-cell lung cancer (NSCLC) patients after platinum/gemcitabine induction chemotherapy followed by surgery

Preliminary results of sequential dose-dense paclitaxel followed by topotecan in extensive small-cell lung cancer (SCLC): A phase II study

Phase II study of sequential dose-dense paclitaxel followed by topotecan in extensive small-cell lung cancer (SCLC)