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Analysis of prognostic factors in 766 patients with small cell lung cancer (SCLC): the role of sex as a predictor for survival.

The data of 766 patients participating in three German multicentre trials were analysed with regard to the relationship between baseline characteristics and prognosis in small cell lung cancer (SCLC). The central aim of this analysis has been to evaluate the role of gender as an independent prognostic factor in SCLC. The minimum follow-up period for the 652 male and 114 female patients was 36 months. Female patients were shown to have a higher complete remission rate (35% vs 25%), a superior median survival (ms) (12.1 months (mo) vs 9.8 mo), and a favourable 2-year survival rate (2ys) (19% vs 8%) to male ones. Various other prognostic factors have been proved to be significant, such as extent of disease, clinical performance status, and history of smoking, whereas weight loss prior to chemotherapy and age have been less important factors. We have been able to ascertain that women's responses were better than those of male patients independent of any other relevant prognostic variable. Furthermore, results were found to be even more advantageous for female patients with additional favourable prognostic parameters, i.e. for patients with limited disease (ms 15.2 mo vs 12.0 mo; 2ys 29% vs 9%) or with good performance status (ms 13.4 mo vs 10.4 mo; 2ys 24% vs 7%). A most remarkable observation was made in that the favourable prognostic effect of the female gender was restricted to patients aged less than 60 years (ms 13.3 mo vs 10.1 mo; 2ys 26% vs 5%), whereas for older women no advantages over men's results were established (ms 9.3 ml vs 9.1 mo; 2ys 8% vs 7%). A proportion of 32% of female patients with limited disease aged less than 60 years achieved a 3-year survival rate. We conclude (a) that sex constitutes a major prognostic factor in SCLC and is especially useful as a predictor for long-term survival, and (b) that the favourable prognostic value of the female sex is restricted to younger patients.

Age Factors↗

The selection of antibodies for targeted therapy of small-cell lung cancer (SCLC) using a human tumour spheroid model to compare the uptake of cluster 1 and cluster w4 antibodies.

Spheroids of a small-cell lung cancer (SCLC) cell line POC were used to evaluate the uptake and penetration of two antibodies recognising different SCLC antigens. Spheroids approximately 300-400 microns in diameter were incubated with 1 microgram ml-1 125I-labelled NY.3D11, an antibody which reacts with the cluster 1 group antigen (neural cell adhesion molecule; NCAM) and [125I]SWA11, which binds to the cluster w4 antigen. The rate of uptake of both antibodies was similar; an initially rapid phase was seen during the first 8 h and maximum uptake occurred by 24 h. The mean uptake per spheroid at 24 h was 0.97 ng for [125I]NY.3D11 and 0.45 ng for [125I]SWA11. An objective measurement of antibody penetration into spheroids was developed using a computerised image analysis of immunostained sections of spheroids. The concentration of antibody and incubation times were varied. Both antibodies penetrated the spheroids to a depth of 50 microns after 30 min. This increased to about 100 microns after 4 h incubation with 1 or 100 micrograms ml-1 SWA11. The results with 1 microgram ml-1 NY.3D11 were similar, but in the presence of 100 micrograms ml-1 NY.3D11 penetration into the spheroid was deep and diffuse. These results demonstrate a major concentration-dependent difference in the uptake and penetration of cluster 1 and cluster w4 antibodies in this spheroid model and they have implications for the selection of antibodies for targeted therapy of SCLC.

Antibodies, Monoclonal↗

Randomised trial of four-drug vs less intensive two-drug chemotherapy in the palliative treatment of patients with small-cell lung cancer (SCLC) and poor prognosis. Medical Research Council Lung Cancer Working Party.

This randomised trial was conducted to compare a four-drug chemotherapy regimen as a control vs a less intensive two-drug regimen in terms of quality of life (QL), tumour response and survival in the palliative treatment of patients with small-cell lung cancer (SCLC) and poor prognosis. A total of 310 patients with extensive SCLC or limited disease but poor performance status were allocated at random to two chemotherapy regimens, each given on 3 consecutive days at 3 week intervals for three cycles: etoposide, cyclophosphamide, methotrexate and vincristine (ECMV, 154 patients) or etoposide and vincristine (EV, 156 patients). QL was assessed by patients using the Rotterdam Symptom Checklist, the Hospital Anxiety and Depression Scale and a daily diary card. Specific disease- and treatment-related symptoms were recorded by clinicians. The levels of palliation were high and similar in the two groups, although the ECMV regimen was on balance superior in palliating physical symptoms and reducing psychological distress. The EV regimen caused less toxicity, particularly mucositis, which, using Kaplan-Meier curves, occurred in an estimated 34% of patients compared with 54% in the ECMV group. The estimated rates of WHO grade 2 or worse haematological toxicity were 21% in the EV compared with 38% in the ECMV patients. There was no overall difference in response or survival; the median survival periods were 141 days in the ECMV group and 137 in the EV group and the survival rates 37% and 38% at 6 months and 12% and 10% at 1 year respectively. Nevertheless, 37 ECMV patients died within 3 weeks of starting the first cycle of chemotherapy (24 of them during the 2nd week) compared with 18 (9) EV patients. The EV regimen is a useful palliative regimen for patients with SCLC and poor prognosis.

Activities of Daily Living↗

Indomethacin-induced activation of the death receptor-mediated apoptosis pathway circumvents acquired doxorubicin resistance in SCLC cells.

Small-cell lung cancers (SCLCs) initially respond to chemotherapy but are often resistant at recurrence. A potentially new method to overcome resistance is to combine classical chemotherapeutic drugs with apoptosis induction via tumour necrosis factor (TNF) death receptor family members such as Fas. The doxorubicin-resistant human SCLC cell line GLC4-Adr and its parental doxorubicin-sensitive line GLC4 were used to analyse the potential of the Fas-mediated apoptotic pathway and the mitochondrial apoptotic pathway to modulate doxorubicin resistance in SCLC. Western blotting showed that all proteins necessary for death-inducing signalling complex formation and several inhibitors of apoptosis were expressed in both lines. The proapototic proteins Bid and caspase-8, however, were higher expressed in GLC4-Adr. In addition, GLC4-Adr expressed more Fas (3.1x) at the cell membrane. Both lines were resistant to anti-Fas antibody, but plus the protein synthesis inhibitor cycloheximide anti-Fas antibody induced 40% apoptosis in GLC4-Adr. Indomethacin, which targets the mitochondrial apoptotic pathway, induced apoptosis in GLC4-Adr but not in GLC4 cells. Surprisingly, in GLC4-Adr indomethacin induced caspase-8 and caspase-9 activation as well as Bid cleavage, while both caspase-8 and caspase-9 specific inhibitors blocked indomethacin-induced apoptosis. In GLC4-Adr, doxorubicin plus indomethacin resulted in elevated caspase activity and a 2.7-fold enhanced sensitivity to doxorubicin. In contrast, no effect of indomethacin on doxorubicin sensitivity was observed in GLC4. Our findings show that indomethacin increases the cytotoxic activity of doxorubicin in a doxorubicin-resistant SCLC cell line partly via the death receptor apoptosis pathway, independent of Fas.

Antibiotics, Antineoplastic↗

Infectivity enhanced, hTERT promoter-based conditionally replicative adenoviruses are useful for SCLC treatment.

Treatment of advanced small-cell lung cancer (SCLC) remains one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and it also has an extremely poor prognosis. As a result, new therapeutic approaches are needed. Telomere maintenance to the regulation of replicative lifespan strongly implies that alterations in telomere biology play an important role during malignant transformation. Cancers that exhibit high levels of telomerase activity, such as all of the SCLC, were examined in a previous study. In this study, we turned the expression of human telomerase reverse transcriptase (hTERT) by tumors to a therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 (early region 1) is controlled by the hTERT promoter. This virus achieved good levels of viral replication in SCLC cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with a tropism modification of the virus to express the knob domain of Ad3 (serotype 3 adenovirus), and this improved infectivity for cancer cells. Conversely, the hTERT promoter has low activity in normal tissues, and the CRAd caused no damage to normal lung fibroblast cells. Since the telomerase activity is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that the use of hTERT promoter-based CRAds may be a potentially effective strategy for cancer treatment.

Adenoviridae↗

A randomized pilot study of SRL172 (Mycobacterium vaccae) in patients with small cell lung cancer (SCLC) treated with chemotherapy.

BACKGROUND: SRL172 is a suspension of heat killed Mycobacterium vaccae, that has been found to be a potent immunological adjuvant when used with autologous cells in animal models. This is a phase II study to test the clinical activity, feasibility and safety of combining SRL172 with chemotherapy to treat patients with small cell lung cancer (SCLC). METHODS: Patients were randomized to receive chemotherapy with (n=14) or without (n=14) SRL172. The chemotherapy was either platinum-based (MVP, n=10) or anthracycline-based (ACE, n=18). SRL172 was given intradermally on day 0, weeks 4, 8 and then 3-6 monthly. RESULTS: The treatment arms were well balanced for disease extent (43% with limited stage in each arm). The toxicity of chemotherapy and overall response at 12-15 weeks (57%) was the same for both treatment regimens. Median survival was 8.6 months and 12.9 for patients treated with chemotherapy alone and with the combination respectively (P=0.10). The survival trend was similar for both disease extent and chemotherapy regimen employed in favour of combination chemotherapy with SRL172. CONCLUSIONS: There is a trend to improved median survival in SCLC with the combination of chemotherapy and SRL172 with no increased toxicity and irrespective of drug regimen. A phase III study examining chemotherapy in combination with SRL172 in SCLC is now underway.

Aged↗

A national survey of the chemotherapy regimens used to treat small cell lung cancer (SCLC) in the United Kingdom.

Many chemotherapy regimens are used for treating SCLC in the United Kingdom, but it is not known, in any detail, which regimens are used, by which specialists, for which types of patient. We conducted a survey among all medical and clinical oncologists, respiratory physicians and general physicians with respiratory interest in the United Kingdom to find out. The questionnaire asked for the number of SCLC patients treated annually; how many were given chemotherapy; the drugs, doses and schedules chosen according to prognostic group (as defined by the clinician); and the reasons for choice of regimen. 1214 questionnaires were sent out, and responses were received from 1070 (88%) clinicians; 266 (25%) of these treated SCLC with chemotherapy. Of 4674 patients given chemotherapy annually, 36% were given it by clinical oncologists, 30% by medical oncologists, 27% by respiratory physicians, and 7% by general physicians. In all, 34 regimens were reported with 151 different combinations of dose and schedule. In 2311 good prognosis patients, 23 regimens were used, the commonest being ACE (doxorubicin, cyclophosphamide, etoposide), ICbE (ifosfamide, carboplatin, etoposide), CAV (cyclophosphamide, doxorubicin, vincristine), CbE (carboplatin, etoposide), and PE (cisplatin, etoposide). In 1517 poor prognosis patients, 21 regimens were used, the commonest being CAV, EV (etoposide, vincristine), CbE, CAV alternating with PE, and oral etoposide. 452 patients were treated regardless of prognosis and for 219 no prognostic criteria were specified. The remaining 175 were given second-line chemotherapy or were given regimens chosen to avoid toxicity or because of intercurrent disease or other reasons. The main reasons affecting choice of regimen were routine local practice, patients' convenience, quality of life considerations, trial results and cost. The results show wide variation in routine practice and will be useful in reporting and planning clinical trials and in deciding on local treatment policies.

Adult↗

In vivo and in vitro growth of SCLC cells derived from biopsies.

In order to increase the availability of SCLC cells derived from biopsies, in vivo and in vitro growth methods were investigated. The cells grown in both conditions were periodically monitored for reactivity with 2 monoclonal antibodies (MAbs): MLuC1 directed against SCLC cells and IM1 which recognizes the class II antigen on activated lymphocytes and macrophages. About 50% of the 28 analyzed SCLC specimens were found to proliferate in one or both systems. The in vitro-grown cells exhibited the same heterogeneity found in the original cell suspensions and moreover, in some cases only normal cells were recovered after several in vitro passages. From the subcutaneous transplanted tumors a large number of MLuC1-positive tumor cells could easily be recovered, thus indicating the validity of the in vivo methodology. The MBr1 MAb, directed against an epithelial antigen, was found to react with about 50% of the 26 tested tumors, mainly those which demonstrated in vivo and/or in vitro growth capacity. These data suggest that only some tumors, presumably with peculiar biological characteristics, can efficiently grow in these artificial systems.

Adult↗

[Ectopic hormone producing cells in non-small cell lung carcinoma (non-SCLC) and heterogeneity of lung cancer].

68 cases of non-SCLG were investigated by immunohisto-chemical technique to detect ectopic hormone producing cells and to study the heterogeneity of non-SCLC. Histologic heterogeneity was observed in 11 of 68 non-SCLC and 24 (35.3%) cases displayed hormone immunoreactivity. Ten cases were positive for NSE. More than one type of hormone producing cells could be detected in 11 tumors. Both neutral and acid mucoproteins in variable quantities were observed in 17 tumors that contained the hormone or NSE producing cells. The results indicate that there is functional heterogeneity in non-SCLC, and all types of lung carcinoma may have a common cellular origin.

Adult↗

[Cytogenetic studies on one human small cell lung cancer (SCLC) cell line, LTEP-sm].

Cytogenetic studies on LTEP-sm, the first SCLC cell line established in China, were carried out with G-banding techniques. Two 30-metaphase groups showing good G-banding patterns in generation 55 and 99 respectively were subjected to karyological analysis. The results are as follows: the modal number of chromosomes is 51-53 (generation 55) and 51-54 (generation 99). The cell line is hypotriploid. Six marker chromosomes were found. The frequency of interstitial deletion of the short arm of chromosome 3 (del 3p14-23) was as high as 26 (generation 55) and 28 (generation 99) in the two 30-metaphase groups analyzed. This result is in accordance with reports on the genetic markers of SCLC and SCLC variants published abroad. Another 5 marker chromosomes are: t(1;15) (1qter----1p22::15p12----15qter); del(1) (qter----p31:); del (7)(pter----q31:); t(6;9)(6pter----6q14:: 9q21----9qter); and del (12)(qter----p12.3). The incidence of the marker chromosomes was also calculated.

Carcinoma, Small Cell↗

[CMC chemotherapy regimen combined with surgery of small cell lung cancer (SCLC)].

From Dec. 1982 to Oct. 1984, 35 patients with SCLC proved by pathology or cytology, were treated by cyclophosphamide + methotrexate + CCNU (CMC) regimen combined with surgery in our hospital. All the patients received chemotherapy for more than 2 courses and the overall response rate was 85.7%, complete remission (CR) rate was 14.3%. Toxic reactions were tolerable to the patients. Treatment result was better in SCLC with localized than extensive disease. Operation was done for 9 out of 21 patients with localized lesions which had responded to chemotherapy. Of them, 1 died of postoperative complication, 2 were lost in follow-up and the rest 6 were disease-free for 8-32 months with a median survival time of 19 months. The 1 year survival rate was 75%. The results indicate that in limited disease of SCLC, successful chemotherapy combined with surgery can prolong the survival time. For patients with an limited disease which has given a CR, surgical resection should be strived for.

Adult↗

[Mega-dose chemotherapy with peripheral blood stem cell transplantation (PBS-CT) for small cell lung cancer (SCLC)].

Feasibility and the efficacy of mega-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) for small cell lung cancer (SCLC) were evaluated. Autologous peripheral blood stem cell (APBSC) was collected after induction chemotherapy (Extensive disease: CDDP+etoposide+ADM, Limited disease: CDDP+etoposide) followed by the administration of granulocyte colony stimulating factor (G-CSF). Five cases of ED and 2 cases of LD have been entered in the protocol so far. PBSC was harvested after the second course of induction chemotherapy, and a sufficient number of PBSC (CFU-GM > or = 1 x 10(5)/kg) could be harvested and cryopreserved in all 7 cases. After completion of 4 courses of induction chemotherapy, three patients who achieved CR or good PR were treated by the combination of CBDCA (1,600 mg/m2) plus etoposide (1,600 mg/m2) followed by APBSCT and G-CSF. Hematologic recovery after APBSCT was rapid (absolute granulocyte count > 500/microliters: 9-11 day, Plt > 3 x 10(4)/microliters:10-14 day) and no infectious episode nor bleeding tendency occurred throughout the treatment period. Although grade 3 gastrointestinal toxicity was seen in one patient, the mega-dose chemotherapy with APBSCT in SCLC was considered safe and feasible. Further clinical trials are needed to establish the role of mega-dose chemotherapy for the treatment of SCLC.

Antineoplastic Combined Chemotherapy Protocols↗

Similar chromosomal changes in cisplatin and oxaliplatin-resistant sublines of the H69 SCLC cell line are not associated with platinum resistance.

Small cell lung cancer (SCLC) initially responds well to DNA damaging drugs such as cisplatin, however this is transitory as resistance normally develops. To investigate whether changes in chromosomal copy number caused by platinum drug treatment contributes to platinum resistance, we have analyzed H69 SCLC cells and two low-level platinum-resistant sublines, H69CIS200 and H69OX400, derived by cisplatin and oxaliplatin treatment, respectively. Affymetrix 10K SNP array showed that cisplatin and oxaliplatin have independently caused similar changes including loss of segments 6q21-qter and 13pter-13q.14.11 and duplication of chromosome 21. Interestingly, despite using equally cytotoxic doses of drug in the development of the cell lines, oxaliplatin caused three times more chromosomal changes than cisplatin. The resistant cell lines lose their resistant phenotype after 3 months of drug-free culture. The revertant cell lines, denoted H69CIS200-S and H69OX400-S, were also analyzed by Affymetrix array to determine if chromosomal changes associated with resistance remain after the resistant phenotype is lost. In the H69OX400-S many of the changes observed in the resistant cells were absent suggesting that they contributed to the resistant phenotype including: loss of 1q23.3-qter, 10q11.23, and 19q13.12-q13.2 and duplication of segments 6p21.2-p12.3, 16q12.1-16q13, 16q21-q23.1, and 19q12. However, out of the similar changes induced by cisplatin and oxaliplatin, both the loss of 6q21-qter and gain of 21 were still present in the H69CIS200-S and H69OX400-S cells. This suggests that cisplatin and oxaliplatin induced similar changes due to inherent vulnerabilities in the H69 cells rather than changes associated with platinum resistance.

Antineoplastic Agents↗

Intracerebral and subcutaneous xenografts of human SCLC in the nude rat: comparison of monoclonal antibody localization and tumor infiltrating lymphocytes.

In the WAG/Rij nude rat, subcutaneous (s.c.) and intracerebral (i.c.) xenografts of the human SCLC cell line GLC-28 were evaluated for their growth behavior, in vivo monoclonal antibody binding and presence of tumor infiltrating lymphocytes. For the i.c. xenografts, two models of cerebral tumor growth were studied, one in the cerebral cortex and one in the lateral ventricle of the brain. In the s.c. and both i.c. xenografts models, in vivo localization of anti-carcinoma moab MOC-31 occurred within 4 hours after i.p. injection, with a maximal binding at 24 h after injection. A pronounced tumor infiltration of predominantly NK cells was observed for s.c. and intraventricular xenografts, but not for the GLC-28 tumors xenografted in the cerebral cortex. The presented nude rat/GLC-28 xenograft models may be used for the in vivo testing of experimental imaging techniques or alternative treatment strategies relevant to brain metastases of human SCLC.

Animals↗

Ifosfamide, epirubicin and cisplatin (IEP): another active combination for small cell lung cancer (SCLC).

Sixty-four SCLC patients (44 males and 20 females, median age 60 years, median PS 60%) were treated with an IEP regimen. Forty-nine cases were evaluable, 35 cases were limited disease (LD) and 14 cases were extensive disease (ED). Treatment consisted of ifosfamide 1.5 g/m2 i.v. infusion for 4 h on days 1 and 2 with mesna uroprotection; epirubicin 60 mg/m2 i.v. on day 1; and cis-platin 60 mg/m2 i.v. infusion over 2 h on day 3; repeated treatment every 4 weeks. Eighty percent response rate (95% confidence limit = 66.75% to 93.25%) was seen in LD with 22.8% CR. In ED, total response rate was 85.7% (95% confidence limit = 67.36% to 104.04%) with 21.4% CR. One-year survival of LD was 45.5% and ED was 17.6%. Treatment toxicity was moderate. Most common toxic effects included alopecia, leukopenia (28.5% grade 3, 14.3% grade 4) nausea and vomiting (50% grade 2, 15% grade 3) and anemia (26.5% grade 3 and 4). Addition of thoracic radiotherapy after complete chemotherapy (only CR and PR in LD cases) was a good prognostic factor. These results suggest that IEP regimen is one of the active combination for SCLC. The dosage of IEP in this study caused moderate toxicity.

Adult↗

CNS relapse despite prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC).

CNS relapse after PCI may reflect either suboptimal radiation dose schedules or reseeding from other sites of active disease. A retrospective study has been undertaken to investigate these alternative mechanisms of treatment failure. Between August 1981 and December 1983, 30 patients with SCLC treated by induction chemotherapy, followed by high-dose cyclophosphamide (7 Gm/m2), were selected for PCI on the basis of clinical, radiological, and bronchoscopic CR. Pretreatment CT brain scans were normal in all patients, and 20 Gy mid-plane dose in 5 daily fractions were delivered by lateral fields to whole brain using megavoltage X rays and localizing check films. Progressive focal neurological signs of cranial metastases developed in 7/30 (23%) patients 3-11 months after PCI, confirmed on CT scanning in 4 patients. Relapse at other sites, predominantly the thorax, occurred in all seven patients at intervals of 1-6 months prior to CNS relapse. Published clinical data of tumor volume doubling times in SCLC predict longer CNS relapse-free intervals after PCI than those observed in our patients if reseeding was responsible for relapse. This suggests that incomplete eradication of intracranial disease is the main cause of CNS relapse after PCI. Higher equivalent radiation doses may improve the results of PCI.

Adult↗

Hyperfractionated radiotherapy alternating with multidrug chemotherapy in the treatment of limited small cell lung cancer (SCLC). Groupe Lyonnais d'Oncologie Thoracique.

From January 1986 through December 1988, 227 patients were included in a multi-institutional pilot study for small cell lung cancer (SCLC). Out of the 211 patients who fully completed the staging procedures, 77 (35%) appeared to have SCLC limited to the thorax. All patients received combination therapy consisting of AVI (Adriamycin, VP-16 and Ifosfamide), except during radiotherapy when the Adriamycin was omitted, plus twice daily fractionated 18 MV radiotherapy. Treatment protocol consisted of 4 initial courses of AVI, followed by 3 courses of radiotherapy alternating with modified chemotherapy (VP-16 and Ifosfamide), completed by 2 courses of initial chemotherapy (AVI). Radiotherapy consisted of 1.5 Gy/fraction, 2 fractions/day, 5 days/week in the first course, and 1.8 Gy/fraction, 2 fractions/day, 5 days/week, in the second and third courses, for a total tumor dose of 51 Gy, felt to be equivalent to 60 Gy at normal fractionation. CT treatment planning was employed to design a treatment consisting of multiport radiotherapy, using AP-PA and laterals or obliques beams. During the first course, the homolateral hemithorax received 9 Gy total dose on days 1, 3, 5. During the third course, 360 degrees arctherapy was generally used to boost the reduced tumor volume to a 51 Gy. Besides chest X ray and CT scan, staging and restaging procedures included fiberoptic bronchoscopy. Response rate after irradiation is 61%, with 46% complete responders and 51% local control. The median survival is 14 months, and disease-free survival 42% at 1 year. Complications consisted of cardiac toxicity in 2 patients, 1 death of acute pulmonary toxicity, and 4 instances of moderate chronic radiation pneumonitis. Thus, high doses of radiation can be delivered combined with chemotherapy using this protocol, with an acceptable toxicity and encouraging results in response rate and local control. A longer follow-up is needed to evaluate the impact of these results on survival.

Adult↗

First-line chemotherapy in metastatic small-cell lung cancer (SCLC).

The overall treatment results in metastatic small-cell lung cancer have not been changed in the last decades. The prognosis of the disease is still poor with median survival times of less than one year and nearly no chance of cure. This article intends to summarize the current status of treatment in m-SCLC and especially focuses on the aspects of choice of drugs and efforts of treatment intensification either by dose escalation or shortening of treatment intervals. Furthermore the currently available data about the activity of newer drugs, including taxanes and topoisomerase I inhibitors are reported. These cytostatic agents widen the therapeutic options in the treatment of SCLC and will hopefully improve the outcome of the patients in the next years.

Antineoplastic Combined Chemotherapy Protocols↗