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PubMed1989

The role of ifosfamide and cyclophosphamide in the multi-modality treatment after surgery for cure for small-cell bronchial carcinomas (SCLC).

For the optimisation of the therapy for small cell bronchial carcinomas (SCLC), surgery is used to eliminate the primary tumor and its regional lymph nodes and chemo- and radiotherapy for the general treatment of micrometastasis. After patho-histological examination of the operation specimen, randomization for two arms is performed for a standard chemotherapy (CAV) or a sequential chemotherapy using three different drug combinations. Thereafter all disease-free patients receive prophylactic cranial irradiation (PCI). Preliminary evaluations in December 1987, of 112 patients from 19 cooperating departments show that the survival rate projected for 2 yr of 43 patients at stage pT1-3 N0 M0 is 76%, of 43 patients at stage pT1-3 N1 M0 it is 63% and of 26 patients at stage pT1-3 N2 M0 it is 38%.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Mediastinal emphysema and small cell lung cancer (SCLC): a case-report.

We present a case of a 59-year-old man with small cell lung cancer (SCLC) who developed heavy thoracic pain because of spontaneous mediastinal emphysema. Autopsy documented a mucosal lesion in the posterior tracheal wall with air leak towards the mediastinum. The occurrence of spontaneous mediastinal emphysema in patients with small cell lung cancer has rarely been described in the literature.

Aged↗

PubMed2003

Long-term survival in SCLC after treatment with paclitaxel, carboplatin and etoposide--a phase II study.

PURPOSE: We evaluated the toxicity and feasibility of adding paclitaxel to a standard platinum/etoposide regimen in the first-line treatment of patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: Eighty-nine patients with limited disease (LD) or extensive disease without distant metastases (ED I) were treated in this multi-centered phase II trial between April 1996 and June 1997. Paclitaxel administration (175 mg/m(2) by a 1 h intravenous infusion) was immediately followed by a 30 min infusion of carboplatin at an area under the concentration time curve (AUC) of 5 on day 1 and etoposide 50 mg orally twice daily (bid) was given on days 2-8. Courses were repeated every 21 days. Patients who had an objective response continued treatment for a maximum of 6 courses. RESULTS: Eighty-four patients were assessable for response. Overall response rate (RR) was 82.1% with 17.8% complete remissions and 64.3% partial remissions. Median survival for LD patients was 20.5 months with a 1 year survival rate of 71.4% and a 3 year survival rate of 21.4%. Median survival of ED I patients was 11 months with a 1 year survival rate of 31.3% and a 3 year survival rate of 3.1%. Overall median survival was 18.1 months with a 1 year survival rate of 56.8% and a 3 year survival rate of 14.8%. Median progression-free intervals were 12.3 months for patients with LD stage of the disease and 8 months with ED I stage. Grade 3/4 toxicity was primarily hematologic. Grade 3/4 leucopenia occurred in 16.0% of courses and febrile episodes were detected in 0.3% of courses. Non-hematologic toxicities were uncommon. Grade 3 GI-tract toxicities or peripheral neuropathy appeared in less than 1% of the courses. Toxicities were detected according to WHO toxicity criteria. CONCLUSION: Paclitaxel can be added at full dose (175 mg/m(2)) to a carboplatin/etoposide combination while maintaining a tolerable toxicity profile. Efficacy data, RR, progression-free interval and survival in both, extensive and limited stage patients compare favorably with other reported data. This new regimen will be further evaluated in comparison to standard regimens in a phase III trial.

Adult↗

PubMed1998

Envelope and long terminal repeat sequences of an infectious murine leukemia virus from a human SCLC cell line: implications for gene transfer.

Development of methods for gene transfer into specific cell types or tissues is important for experimental research as well as clinical therapeutical approaches. We report here the cloning and characterization of the envelope (env) gene and the U3 region of a retrovirus from an infected human Small Cell Lung Cancer (SCLC) cell line. The replication of this murine retrovirus is also fully supported by other lung cancer cell lines of different histological origin. We present evidence that a long terminal repeat (LTR)-beta-galactosidase (beta-Gal) reporter construct performed as well as an analogous cytomegalovirus (CMV) promoter beta-Gal construct in the human lung epithelial cell line A549 and in the human larynx carcinoma cell line HEp2.

Amino Acid Sequence↗

PubMed1989

A simple outpatient treatment with oral ifosfamide and oral etoposide for patients with small cell lung cancer (SCLC).

For the first time in a clinical study oral Ifosfamide was used: 65 elderly or unfit patients with small cell lung cancer (SCLC) were treated as outpatients with fractionated oral Ifosfamide and Etoposide. Forty patients (62%) had extensive stage (ED) disease. The median age of the patients was 66 years. In the 60 patients evaluable for response the objective response rate was 90% with a complete response (CR) rate of 32% and a partial response (PR) rate of 58%. The overall median survival of all 65 patients was 11 months (13 months for LD, 9.5 months for ED). In those patients with LD achieving a CR or a PR radiotherapy was given to the mediastinum. No prophylactic cranial irradiation was given. There was a rapid improvement in the responding patients' performance status and symptoms generally with the first treatment cycle. Overall haematological toxicity was mild, with intravenous antibiotics only being required in 4% of the courses and with only one treatment-related death from septicaemia. A higher than expected rate of CNS toxicity was seen (30%). This was generally mild and always fully reversible and consisted mainly of forgetfulness, occasionally hallucinations, nightmares and somnolence. In only one case did encephalopathy necessitate early termination of treatment. This raises the question of whether Ifosfamide metabolism differs quantitatively or qualitatively when given by the oral route as opposed to the usual intravenous route. We conclude that this simple outpatient based treatment gives a high response rate with rapid improvement in symptoms.

Administration, Oral↗

PubMed1993

A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party.

A total of 458 eligible patients, from 21 centres, with histologically or cytologically confirmed SCLC were allocated at random to three chemotherapy regimens, each given at 3-week intervals. In two regimens, etoposide, cyclophosphamide, methotrexate and vincristine were given for a total of either three courses (ECMV3) or six courses (ECMV6). In the third regimen, etoposide and ifosfamide were given for six courses (EI6). Patients with limited disease (56% of the total) also received radiotherapy to the primary site after the third course of chemotherapy in all three groups. A partial response occurred in 45% of 144 ECMV3 patients, 48% of 141 ECMV6, and 53% of 141 EI6 patients assessed, and a complete response in a further 15%, 9%, and 13% respectively, giving total response rates of 60%, 57%, and 67%, respectively. There was no overall survival advantage to any of the three regimens. At 1 year, 24%, 29%, and 30% of patients were alive, and at 2 years 7%, 8%, and 9%, respectively. The median survival time was 7.4 months in the ECMV3 group, 8.6 months in the ECMV6 group and 8.8 months in the EI6 group. The individual factors: poor performance status, extensive disease, the presence of dysphagia and a raised white blood cell count on admission adversely affected prognosis. The results do not exclude the possibility of a minor survival advantage with the two 6-course regimens. The findings on quality of life are presented in the companion paper (MRC Lung Cancer Working Party, 1993b).

Adult↗

PubMed1993

A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). II: Quality of life. Medical Research Council Lung Cancer Working Party.

A total of 458 eligible patients, from 21 centres, with microscopically confirmed SCLC were allocated at random to three chemotherapy regimens, each given at 3-week intervals. In two regimens, etoposide, cyclophosphamide, methotrexate and vincristine were given for a total of either three courses (ECMV3) or six courses (ECMV6). In the third regimen, etoposide and ifosfamide were given for six courses (E16). Patients with limited disease also received radiotherapy to the primary site after the third course of chemotherapy in all three groups. As reported by clinicians, 59% of the ECMV3, 67% of the ECMV6 and 63% of the EI6 patients experienced moderate or severe adverse reactions to their chemotherapy. The major symptoms of disease, cough, haemoptysis, chest pain, anorexia, and dysphagia, were palliated in 63% or more of patients and the median duration of palliation was 63% or more of survival, the results being similar in the three groups. Among patients with poor overall condition, physical activity and breathlessness on admission, the proportions who improved were higher in the EI6 group but the differences were small. In all three groups, levels of anxiety fell substantially during treatment. Levels of depression were lower and showed little change. As assessed by patients using a daily diary card, the patterns of nausea, vomiting, activity and mood, associated with courses of chemotherapy were very similar in the three groups. In the EI6 group there was less dysphagia and better overall condition between courses, but these advantages need to be weighed against the inconvenience of the 24-h infusions required, compared with the 30-min infusions of the other two regimens. As reported in the companion paper (MRC Lung Cancer Working Party, 1993a) there was no statistically significant survival advantage to any of the three regimens, although the results do not exclude the possibility of a minor survival advantage with the two six-course regimens. In conclusion, there was no major clinical gain from continuing chemotherapy beyond three courses or from using the ifosfamide regimen.

Adult↗

PubMed1996

Differential expression of DNA topoisomerase II alpha and -beta in P-gp and MRP-negative VM26, mAMSA and mitoxantrone-resistant sublines of the human SCLC cell line GLC4.

Sublines of the human small-cell lung carcinoma (SCLC) cell line GLC4 with acquired resistance to teniposide, amsacrine and mitoxantrone (GLC4/VM20x, GLC4/AM3x and GLC4/MIT60x, respectively) were derived to study the contribution of DNA topoisomerase II alpha and -beta (TopoII alpha and -beta) to resistance for TopoII-targeting drugs. The cell lines did not overexpress P-glycoprotein or the multidrug resistance-associated protein but were cross-resistant to other TopoII drugs. GLC4/VM20x showed a major decrease in TopoII alpha protein (54%; for all assays presented in this paper the GLC4 level was defined to be 100%) without reduction in TopoII beta protein; GLC4/AM3x showed only a major decrease in TopoII beta protein (to 18%) and not in TopoII alpha. In GLC4/MIT60x, the TopoII alpha and -beta protein levels were both decreased (TopoII alpha to 31%; TopoII beta protein was undetectable). The decrease in TopoII alpha protein in GLC4/VM20x and GLC4/MIT60x, was mediated by decreased TopoII alpha mRNA levels. Loss of TopoII alpha gene copies contributed to the mRNA decrease in these cell lines. Only in the GLC4/MIT60x cell line was an accumulation defect observed for the drug against which the cell line was made resistant. In conclusion, TopoII alpha and -beta levels were decreased differentially in the resistant cell lines, suggesting that resistance to these drugs may be mediated by a decrease in a specific isozyme.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

DEF-3(g16/NY-LU-12), an RNA binding protein from the 3p21.3 homozygous deletion region in SCLC.

DEF-3(g16/NY-LU-12) encodes a novel RNA binding protein isolated by positional cloning from an SCLC homozygous deletion region in 3p21.3 and, in parallel, as a differentially expressed gene during myelopoiesis from FDCPmix-A4 cells. DEF-3(g16/NY-LU-12) is ubiquitously expressed during mouse embryogenesis and in adult organs while human hematopoietic tissues showed differential expression. The mouse and human proteins are highly conserved containing two RNA recognition motifs (RRMs) and other domains associated with RNA binding and protein-protein interactions. A database search identified related proteins in human, rat, C. elegans and S. pombe including the 3p21.3 co-deleted gene, LUCA15. Recombinant proteins containing the RRMs of DEF-3(g16/NY-LU-12) and LUCA15 specifically bound poly(G) RNA homopolymers in vitro. These RRMs also show similarity to those of the Hu protein family. Since anti-Hu RRM domain antibodies are associated with an anti-tumor effect and paraneoplastic encephalomyelitis, we tested sera from Hu syndrome patients with the RRMs of DEF-3(g16/NY-LU-12) and LUCA15. These were non-reactive. Thus, DEF-3(g16/NY-LU-12) and LUCA15 represent members of a novel family of RNA binding proteins with similar expression patterns and in vitro RNA binding characteristics. They are co-deleted in some lung cancers and immunologically distinct from the Hu proteins.

Adult↗

PubMed1989

Rationale for surgery as the first step in the multimodality treatment of small cell lung cancer (SCLC).

The role of surgery has to be reconsidered in combination with chemo/radiotherapy for patients with SCLC at early stages, determined by the pTNM-staging system. This combined multimodality treatment can be seen as a model-like example for the most effective progress gained during the last 20 years. Surgery followed by chemotherapy is used in ongoing cooperative studies. In other trials, chemotherapy is followed by surgery for responding patients. It seems reasonable to expect that after appropriate observation times the comparison of these ongoing trials would most probably lead to the conclusion that for stage I, II surgery should be the first step followed by chemo- and radiotherapy, whereas for stage III debulking chemotherapy should be given to distinguish responding patients, who may thereafter receive adjuvant surgery.

Carcinoma, Small Cell↗

PubMed1995

Detection at diagnosis of tumor cells in bone marrow aspirates of patients with small-cell lung cancer (SCLC) and clinical correlations.

BACKGROUND: Immunocytochemistry has often been used to identify tumor cells in bone marrow aspirate (BMA) of SCLC patients in order to improve the results of conventional histomorphology. However, whether the detection of bone marrow microlocalisation at diagnosis had implications for prognosis has not been clear. PATIENTS AND METHODS: Eighty-four slides (44 patients) and 66 bone marrow biopsies (from 42/44 patients) were evaluated. Cytospins of BMA were incubated with the monoclonal antibody (MAb) NCC-LU-243, recognising the cluster 1 antigen (NCAM) and then stained by the APAAP (alkaline phosphatase-anti-alkaline phosphatase) method. The relationship among BMA and PS (performance status), NSE (neuron-specific enolase), stage, survival was also studied. RESULTS: 33/84 (39%) BMA were positive for NCAM, compared with 8/66 (12%) bone marrow biopsies (p = 0.009), (17/44 and 6/42 patients, respectively). Moreover, BMA was positive for NCAM in 6/19 patients with limited disease. The presence of positive BMA did not correlate with PS, NSE or stage, but patients with positive BMA had shorter survivals than those with negative BMA (median survival: 7 and 12 months, respectively, p = 0.007). CONCLUSIONS: Bone marrow involvement detected by immunocytochemistry appears to be related to survival but not to parameters of tumor burden (NSE, stage), suggesting that this technique might help to select patients with better prognoses for new therapeutic strategies.

Antigens, CD↗

PubMed2004

Chemotherapy in elderly patients with advanced lung cancer. Part I: General aspects and treatment of small cell lung cancer (SCLC).

There is much uncertainty whether chemotherapy is beneficial for elderly patients with advanced lung cancer. Whereas age alone is not an adverse prognostic factor, decline of physiological function and comorbidity can result in higher rates of treatment-related toxicity, in particular myelosuppression. The higher incidence of comorbid conditions, frequently sharing the risk profile of the malignancy, can translate into worse survival. Therefore, a geriatric assessment of the patient's overall situation should guide decision-making. Mainstay of treatment of small cell lung cancer (SCLC), also in the elderly, is combination therapy. Several retrospective analyses reveal that in elderly patients often lower drug doses are delivered. However, the treatment outcome of these patients does not appear to be worse compared to younger patients. For functionally independent elderly patients, combination chemotherapy with carboplatin and etoposide, supported by optimized supportive care, possibly including hematopoietic growth factors (G-CSF) to minimize toxicity, should be considered. Special attention to renal function should be given and individualized drug dosing, adapted to the glomerular filtration rate, is mandatory. For patients with some functional dependence or showing a certain degree of comorbidity, preliminary data indicate that single-agent therapy with carboplatin can confer the same benefit as combination chemotherapy, but with reduced toxicity. Single agent oral etoposide, however, seems to be inferior to combination treatment and should not be given routinely in the treatment of this cohort. Further evaluation of these topics is needed, and can be achieved by trials specifically designed for elderly patients or patients with reduced performance status.

Aged↗

PubMed1989

Surgical resection in the treatment of stages I-II of small cell lung carcinoma (SCLC).

From 1981 to 1986, 17 patients with resected small cell lung carcinoma (SCLC) staged as I or II according to the new TNM classification were recruited for a prospective study to evaluate the effectiveness of surgery and postoperative chemotherapy (plus locoregional radiotherapy only when a nonradical resection was accomplished) in the treatment of early stages of the disease. Six patients received full protocol chemotherapy (6 courses) and 8 a mean of 79.1% of the planned courses. Three patients received non adjuvant treatment. Locoregional radiotherapy for residual disease was administered in 2 cases. One patient died for myelosuppression due to chemotherapy and 10 for recurrences of cancer, all within the 20th postoperative month. Metastases accounted 80% of overall recurrences. Six patients were alive and tumor-free at 18, 22, 39, 44, 47 and 51 months from resection. Actuarial observed 3-year survival was 32%.

Aged↗

PubMed2000

Phase I/II study of weekly irinotecan and paclitaxel in patients with SCLC.

This phase I/II nonrandomized, open-label study was designed to assess the safety and benefit of sequencing irinotecan (Camptosar, CPT-11) plus paclitaxel (Taxol) immediately after cisplatin (Platinol)/etoposide (VePesid, VP-16) or carboplatin (Paraplatin)/etoposide in patients with extensive small-cell lung cancer (SCLC). Ten patients were evaluable in phase I; all had previously been treated with cisplatin and etoposide, and five of the 10 had also previously received carboplatin and paclitaxel. All 10 patients were given a fixed dose of irinotecan (60 mg/m2) and escalating doses of paclitaxel weekly for 3 weeks. Three patients had grade 4 toxicities, one at the lowest dose level of paclitaxel (15 mg/m2). Two patients had grade 3 toxicities. The dose-limiting toxicity occurred at the 60 mg/m2 paclitaxel dose level, when the performance status of both patients in that group decreased to 60 (Karnofsky scale). Two patients had progressive disease after 1 month of treatment and did not receive cycle 2. Three of seven patients evaluable for response had complete remissions. A fourth patient had resolution of lymphangitic metastases and resolution of a partial small bowel obstruction but did not have measurable disease. The fifth patient had a partial remission. The ongoing phase II portion of the study is restricted to previously untreated patients who will receive at least one cycle of either cisplatin or carboplatin in combination with etoposide followed by irinotecan at 60 mg/m2 and paclitaxel at 50 mg/m2 dosed once weekly for 3 weeks.

Adult↗

PubMed2005

Vindesine and etoposide: A practical and well-tolerated therapy for elderly patients or patients in reduced clinical condition with extensive-stage small-cell lung cancer (SCLC).

BACKGROUND: Small-cell lung cancer is a disease affecting mostly elderly persons. Therefore, many patients show marked comorbidity and intensive chemotherapy is not possible in such patients. As the disease is most often in the 'extensive' stage at diagnosis, the therapy option is only palliative. MATERIALS/METHODS: [corrected] We used a combination therapy with vindesine and etoposide in treating 41 patients (median age: 63 years) over 155 cycles of chemotherapy. RESULTS: This treatment resulted in a response rate of 43.9% and a median survival time of 9.3 months and thus equals established schemes in its effectiveness. However, its rate of adverse effects (hematoxicity, gastrointestinal toxicity, neuropathy) is smaller than those of the established therapy schemes ACO, EPICO, or carboplatine/etoposide. CONCLUSIONS: Therapy of advanced SCLC with vindesine and etoposide can be applied in an ambulant setting and offers an improved quality of life with equivalent therapeutic effectivity. Therefore it is especially suitable for patients of older age and fragile condition due to comorbidity.

Adult↗

PubMed1991

Measurement of murine IgG and IgM concentrations in the SCLC MAb panel; effects of concentration on sensitivity and specificity.

Sensitive, solid-phase enzyme immunoassays for detecting murine IgM and IgG were developed and used to quantitate immunoglobulin concentrations in the SCLC MAb panel. Among the IgM MAbs, most contained between 10-75 micrograms ml-1. At least three IgM MAbs, however, contained less than 2 micrograms ml-1 and six contained greater than 75 micrograms ml-1. Two of the three IgM's containing less than 2 micrograms ml-1 immunoglobulin were found to cluster with the negative controls. Among the IgG MAbs, the majority contained between 10-100 micrograms ml-1 Ig. At least five of the IgG MAbs contained greater than 100 micrograms ml-1; and six were less than 2 micrograms ml-1. Three of the MAbs containing less than 2 micrograms ml-1 IgG clustered with the negative controls. Many of the panel members containing greater than 50 micrograms ml-1 antibody were found to give nonspecific immunostaining on tissues and cell lines. Often this nonspecific immunostaining was eliminated when these MAbs were diluted. Although only a minority of the panel members contained very high or very low concentrations of antibody, the data highlight the inherent difficulties that may result, in part from this variable and suggest that efforts be made to normalise the Ig concentrations of panel members in future workshop panels.

Animals↗

PubMed1989

[A comparative randomized phase II study of CDDP, CDDP-carboquone (CQ) and CDDP-etoposide as second-line chemotherapy in small cell lung cancer (SCLC)].

51 SCLC patients who had received prior chemotherapies and had measurable lesions were randomized to CDDP, CDDP-CQ, and CDDP-etoposide treatment group. Prior chemotherapies of 49 complete cases were AVA (ADM, VCR, ACNU; 16 cases), TAVA (THP-ADM, VCR, ACNU; 17 cases), CAV (CPA, ADM, VCR; 4 cases) and others. The median period of 49 cases from prior chemotherapy to this chemotherapy was 4 weeks. In the CDDP alone group, CDDP was given at a dose of 80 approximately 100 mg/m2/4-5 weeks on Day 1, and in CDDP-CQ treatment group, patients were given the same dose of CDDP and CQ 6 mg/body on Day 1, 2. In CDDP-etoposide treatment group, the same doses of CDDP and etoposide 60 mg/m2 Day 1-5 (Total 300 mg/m2) were given. Response rate of the CDDP alone group was 6.7% (PR 1/total 15), that of CDDP-CQ group was 6.3% (PR 1/total 16), and in CDDP-etoposide group it was 16.7% (PR 3/total 18). In CDDP-CQ treatment, the main side effect was strong hematotoxicity (WBC; Grade 3, 5 patients, Grade 4, 2 Pl: Grade 3, 5 Grade 4, 3), and main hematotoxicity of CDDP-etoposide was leukopenia (W BC; Grade 3, 4 patients, Grade 4, 2 Pl; Grade 4, 1). In these patients, it was thought that CDDP was not useful in second chemotherapy, as not only CDDP alone but also the combination with CQ or etoposide.

Adult↗

PubMed1988

[Pathologic findings of small cell lung cancer (SCLC) after chemotherapy--analysis of 48 cases].

From 1980 to 1986, resected specimens from 48 SCLC patients after chemotherapy were studied pathologically. According to the pathologic changes, they were divided into four degrees: 1. The primary lesion disappeared and was replaced by fibrosis (6 cases, 12.5%); 2. Scanty residual cancer tissues were seen by microscopy (6 cases, 12.5%); 3. Degeneration and necrosis with fibrosis were present but active cancer tissues in small areas were found (18 cases, 37.5%), and 4. There was mild degeneration or no obvious changes (18 cases, 37.5%). Five specimens were examined by electron microscopy. The effect of chemotherapy in the primary lesion is more marked than that in the metastatic lymph nodes. The relationship between pathologic changes and response of chemotherapy and pathologic staging; comparison of clinical and pathologic staging and the prognosis of lymph node metastasis are discussed.

Adult↗