Prospective Randomized Phase III Trial of Etoposide/Cisplatin Versus High-Dose Epirubicin/Cisplatin in Small-Cell Lung Cancer

doi:10.3816/CLC.2004.n.031

Clinical Lung Cancer

Volume 6, Issue 3, November 2004, Pages 175-183

https://doi.org/10.3816/CLC.2004.n.031 Get rights and content

Abstract

High-dose epirubicin plus cisplatin was compared with the reference regimen of etoposide/cisplatin in small-cell lung cancer (SCLC). Four hundred two previously untreated patients with SCLC were randomized to receive etoposide 100 mg/m² on days 1-3 and cisplatin 100 mg/m² on day 1 or epirubicin 100 mg/m² and cisplatin 100 mg/m² on day 1 every 21 days for a total of 6 cycles. Patients were stratified according to treatment center and extent of disease (limited disease, n = 207; extensive disease, n = 195). Patients with limited disease were treated with thoracic radiation therapy after completion of chemotherapy, and those who exhibited a complete response were advised to receive prophylactic cranial irradiation. The primary endpoint was survival, and secondary endpoints were time to progression (TTP), response, toxicity, and costs. Patient characteristics were generally well balanced in the 2 arms, even though more patients in the epirubicin/cisplatin arm had > 5% weight loss and poor Karnofsky performance index compared with the etoposide/cisplatin arm. One hundred thirty-four patients (66.3%) in the etoposide/cisplatin arm and 126 (63.0%) in the epirubicin/cisplatin arm received all 6 planned cycles of chemotherapy. Response rate, TTP, and survival did not differ significantly between the 2 arms. Grade 3/4 neutropenia and toxic deaths occurred more frequently in the etoposide/cisplatin arm. Epirubicin/cisplatin showed a similar activity with a slightly lower toxicity profile than the reference regimen of etoposide/cisplatin. The epirubicin/cisplatin regimen may be recommended in the treatment of SCLC.

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In total, we examined survival data from 22,528 people. Supplement 4 summarises the included manuscripts, 11 of which were abstracts [14–174]. The majority of manuscripts were observational cohort studies (100 (62.5 %)) and the remaining were randomized/non-randomized controlled trials (60 (37.5 %).
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Treatment of Extensive-Stage Small Cell Lung Cancer
2018, IASLC Thoracic Oncology
This chapter discusses first-line and second-line therapy for patients with extensive-stage small cell lung cancer (ED SCLC). As first-line therapy, a platinum agent plus etoposide or irinotecan remains the standard of care for the treatment of SCLC. However, despite an initially high response rate to frontline platinum-based chemotherapy, ED SCLC will universally relapse, often within 3 to 6 months. Topotecan is approved as a second-line treatment for patients with platinum-sensitive, relapsed disease based on symptom control. Patients who receive no further therapy have a median survival of less than 3 months. Despite progress in the understanding of genomic alterations and signaling pathways in SCLC, clinical experiments with tyrosine kinase inhibitors, other small-molecule inhibitors, other antiangiogenic agents have been disappointing. Recently the evaluation of epigenetic modifies, inhibitors of DNA repair and the cell cycle, immune checkpoint inhibitors and inhibitors of the Notch pathway are showing promising efficacy. No new agents with clinically relevant activity have been identified during the last two decades in ED-SCLC, underscoring the unmet need in this area.
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Citation Excerpt :
Most papers included a mean, median or a minimum – maximum age range, but some provided no mention of the age of participants at all. Upon further investigation, it appeared that these details were not simply lost in translation during the meta-analyses, but often failed to be included in the original articles selected for these reviews [19–59]. This is unfortunate because without the inclusion of the age distribution of participants in these original studies and subsequently in pooled or meta-analyses it is difficult to generalize findings to cancer patients of all ages.
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4993 potential papers were identified, but only three papers on breast cancer, three on lung cancer, and none on prostate cancer presented the age distribution of their participants. Except for one paper of breast cancer, participants ≥70 years in all other papers were underrepresented.
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Assessing the relative effectiveness and tolerability of treatments in small cell lung cancer: A network meta-analysis
2013, Cancer Epidemiology
Citation Excerpt :
All regimens are listed in Supplementary Table 2. Sixteen treatments were compared directly with EP in 18 trials [20–37]: (1) Cyclophosphamide plus Doxorubicin (CAV); (2) Cisplatin plus Etoposide plus Ifosfamide (VIP); (3) Cyclophosphamide plus Doxorubicin plus Etoposide plus GCSF [ACE (intensified)]; (4) Cisplatin plus Epirubicin (PEP); (5) Cisplatin plus Topotecan (TC); (6) Cisplatin plus Etoposide/Cyclophosphamide plus Doxorubicin plus Vincristine (CAV/EP); (7) Cisplatin plus Etoposide plus GCSF [EP (intensified)]; (8) Carboplatin (AUC5) plus Etoposide (EC); (9) Carboplatin (AUC5) plus Gemcitabin (GEMCAR); (10) Cisplatin plus Irinotecan (IP); (11) Cisplatin plus Cyclophosphamide plus Etoposide plus Epirubicin (CCEE); (12) Cisplatin plus Etoposide plus Megestrol acetate (EP + Ma); (13) Cisplatin plus Etoposide plus natural interferon alpha (EP + nIFNA-a); (14) Cisplatin plus Etoposide plus recombinant interferon alpha (EP + rIFNA-a); (15) Etoposide plus Ifosfamide (IE) and 16) Cisplatin plus Etoposide plus Paclitaxel (PET). The numbers of direct comparisons with EP for the outcomes CR, ORR, NP and FNP were 18, 17, 9 and 1, respectively.
Background: The combination of Cisplatin plus Etoposide (EP) is currently the standard treatment for small cell lung cancer (SCLC). However, a large number of alternative treatments (monotherapies and combinations) have been studied in randomized controlled trials (RCTs) to identify more effective treatments. Aim of the present study was to assess the relative effectiveness and tolerability of these treatments. Methods: PubMed, EMBASE and Cochrane Central Register of Controlled Trials were systematically searched to identify all RCTs that compared treatments for SCLC. Then, effectiveness of the treatments relative to the combination of Cisplatin plus Etoposide, reference treatment) was estimated by performing a network of treatments analysis. The analysis evaluated two efficacy outcomes (complete response – CR and objective response rate – ORR) and two tolerability outcomes (neutropenia and febrile neutropenia). All RCTs that provided data for calculating the odds ratios (OR) for the selected outcomes were considered. The network analysis involved direct and indirect analyses. Results: We identified 71 articles eligible for inclusion, involving 91 different treatments. In total, 16,026 patients were included in the analysis. In the direct analysis the combination of Cisplatin plus Cyclophosphamide plus Etoposide plus Epirubicin showed better response than EP for the ORR outcome, but with worse tolerability (presence of neutropenia). The indirect analysis revealed that the combination of Cisplatin plus Doxorubicin plus Etoposide (plus Vincrisitine) showed better response that EP for the ORR outcome. Conclusions: No therapy shows better response for the two efficacy outcomes (CR and ORR); though, Cisplatin plus Doxorubicin plus Etoposide plus Vincrisitine might be a promising therapy for SCLC. The results should be interpreted with caution because the network was dominated by indirect comparisons. Large scale head-to-head RCTs are needed to confirm the present findings.
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2013, Journal of Thoracic Oncology
Citation Excerpt :
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Small cell lung cancer (SCLC) is an aggressive malignancy that although initially sensitive to chemo- and radiation therapy, inevitably relapses resulting in poor survival. Increasing evidence suggests that immune responses against SCLC cells make immunotherapy a viable therapeutic approach. Furthermore, preclinical data have shown that certain chemotherapeutic regimens may augment the immunotherapeutic response in SCLC. This review discusses current evidence supporting immunotherapy for SCLC, progress made, and ongoing clinical trials.
We searched PubMed and abstracts presented at recent oncology congresses for publications on the clinical benefit of immunotherapy/checkpoint blockade for treatment of SCLC.
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Small lung cell cancer
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El cáncer microcítico de pulmón es una neoplasia de crecimiento rápido con buena respuesta inicial al tratamiento quimioterápico pero, en general, de corta duración. En estadio limitado el tratamiento de elección es una combinación de cisplatino y etopósido, junto con radioterapia de forma concomitante. La tasa de respuestas es alta y se puede conseguir un porcentaje apreciable de largos supervivientes. Sin embargo, en estadio diseminado a pesar de la quimioterapia la supervivencia global es muy corta, siendo muy escasos los pacientes que superan los 2 años. A pesar del desarrollo de multitud de nuevos fármacos en oncología, son muy pocos los que se muestran prometedores en esta neoplasia.
Small cell lung cancer is a rapid growing neoplasm with good initial response to chemotherapy treatment. However, the response is generally short-lived. In limited stage, the treatment of choice is a combination of cisplatin and etoposide, together with radiotherapy concomitantly. Response rate is high and a significant percentage of long survivals can be achieved. However, in disseminated stage, and despite the chemotherapy, global survival is very short, the patients hardly surviving more than 2 years. In spite of the development of many new drugs in Oncology, few of them have been promising in this cancer.

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Original ContributionProspective Randomized Phase III Trial of Etoposide/Cisplatin Versus High-Dose Epirubicin/Cisplatin in Small-Cell Lung Cancer

Abstract

Lancet

Lung Cancer

Eur J Cancer

Lung Cancer

Lung Cancer

Small-cell lung cancer

Chest

Cancer statistics

CA Cancer J Clin

Twenty years of phase III trials for patients with extensive- stage small-cell lung cancer: perceptible progress

J Clin Oncol

A meta-analysis of thoracic radiation therapy for small-cell lung cancer

N Engl J Med

Does thoracic irradiation improve survival and local control in limited- stage small-cell carcinoma of the lung? A meta-analysis

J Clin Oncol

Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer

J Clin Oncol

Randomized study of CODE versus alternating CAV/EP for extensive stage small-cell lung cancer: an Intergroup Study of the national cancer Institute of Canada Clinical trials Group and the Southwest Oncology Group

J Clin Oncol

Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer

J Natl Cancer Inst

Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group

J Clin Oncol

Epirubicin: an updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of breast cancer

Drugs

Original Contribution
Prospective Randomized Phase III Trial of Etoposide/Cisplatin Versus High-Dose Epirubicin/Cisplatin in Small-Cell Lung Cancer