Treatment of small cell lung cancer

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Abstract

Treatment of small cell lung cancer (SCLC) remains a significant challenge for the oncologists. Attempts to improve the results of first-line treatment have all failed so far and no real progress has been made in last years, emphasizing the need for novel strategies of treatment and the development of validated biomarkers. Patients with limited disease and good performance status should be considered for concomitant chemoradiotherapy, followed by prophylactic cranial irradiation. Patients with extensive disease should be treated with a platinum-based chemotherapy (cisplatin or carboplatin); chest radiotherapy can be considered in patients achieving extra-thoracic complete response and prophylactic cranial irradiation is recommended for patients responsive to initial chemotherapy. A large number of molecular-targeted drugs and immunomodulators are currently in clinical development: however, only a better understanding of molecular biology of SCLC and the identification of molecular markers predictive of response to targeted agents will lead to advances in the treatment of SCLC.

Introduction

Lung cancer is the first cause of cancer death worldwide [1]. Small cell lung cancer (SCLC) accounts for 15–20% of all lung cancers and it is the most aggressive lung-cancer subtype: median overall survival (OS) is about 12 months and long term survival is rare [2], [3]. Tobacco smoking is the main cause of disease (95% of patients): in particular, the risk of developing SCLC increases with the number of cigarettes smoked each day and with the duration of smoking. The traditional staging system developed by the Veteran's Administration Lung Cancer Study Group in the United States classifies SCLC into two stages, according to the extent of disease [4]. Limited disease (LD)-SCLC, diagnosed approximately in 30% of patients, is confined to one hemithorax with regional lymph node metastasis and can be encompassed within a single radiation port, while extensive disease (ED)-SCLC, affecting the remaining 70% of patients, extends beyond the boundaries of a single radiation field. Recently, the International Association of the Study of Lung Cancer has proposed to adopt the classification based on tumor, node, metastasis staging (TNM, seventh edition) to better define the risk categories, prognosis, and specific treatment [5]. Initial staging procedures should encompass a computed tomography (CT) scan with contrast of the chest and abdomen. If the metastatic stage is not obvious on the CT scan or clinical findings suggest bone or brain involvement, further imaging with bone scintigraphy and CT or 2-fluor-2-deoxy-d-glucose positron emission-tomography (FDG-PET) CT scan or magnetic resonance imaging (MRI) of the brain are recommended [6].

Chemotherapy remains the cornerstone of treatment for both limited-stage and extensive-stage SCLC. However, surgery can be considered in selected cases, such as T1-2 N0 stage, where surgical resection followed by chemotherapy and for unforeseen, pathological, N1 and N2 disease, by adjuvant radiotherapy may be indicated [6].

The present review has the purpose to critically summarize the available evidence for the systemic treatment of SCLC, discussing several issues associated with the first- and second-line treatment, and with the development of new drugs.

Section snippets

Limited disease

Combined modality therapy including chemotherapy and radiotherapy is the cornerstone of treatment of LD-SCLC. During the 1970s, the cyclophosphamide, doxorubicin and vincristine (CAV) regimen was demonstrated to be effective and well tolerated and became the standard treatment for patients with SCLC [7]. The feasibility of a combined therapy strategy with CAV regimen and radiotherapy was first showed by Feld et al. almost 30 years ago. One hundred fifty-three patients with LD-SCLC and 167

Extensive disease

Chemotherapy is the standard treatment for ED-SCLC. The combination of cisplatin and etoposide (EP) or carboplatin and etoposide (EC) up to 4–6 cycles remains the most widely used regimen, with an objective response rate ranging from 50% to 90%. However, the median OS is still 7–9 months, and only 2% of patients survive for 5 years [24]. Various studies have been designed in attempts to test further and more effective regimens, including alternating chemotherapy schedules, regimens with 3–4

Second-line treatment

SCLC is usually considered a chemo-sensitive disease, because the majority of patients obtain an objective response with first-line treatment. However, in most cases the duration of the responses is limited and almost all patients need further therapy due to disease progression, but second-line treatments produce much lower activity [52], [53].

Similarly to other chemo-sensitive tumors, patients with relapsed SCLC are usually classified at failure of first-line treatment into different

Agents in development

Several targeted agents are being evaluated in SCLC (Table 3). Angiogenesis is one of the most exploited target in this disease: VEGFR 2 and 3 are frequently expressed by SCLC cells and VEGF is frequently found at high levels in the patients’ serum. Interesting, preliminary results have been obtained with aflibercept, that is a recombinant human fusion protein that binds to vascular endothelial growth factor (VEGF), inhibiting interaction with its receptors. The addition of aflibercept to

Conclusions

Integrated therapeutic approaches that represent the current standard in the treatment of LD-SCLC or ED-SCLC are summarized in Fig. 1. Patients with LD-SCLC and good performance status should be considered for concomitant chemioradiotherapy, followed by prophylactic cranial irradiation; in patients with T1-2 N0 stage surgery may be considered, and resection should be followed by chemotherapy. Patients with ED-SCLC should be treated with a platinum-based chemotherapy (cisplatin or carboplatin);

Conflict of interest

The authors confirm no conflict of interest for content of this article.

Reviewers

Dr. Martin Frueh, Rorschacherstrasse 95, St. Gallen, Switzerland.

Dr. Lucio Crino, Perugia Hospital, Department of Medical Oncology, S. Andrea delle Fratte, I-06156 Perugia, Italy.

Dr. Andrea Ardizzoni, University Hospital, Division of Medical Oncology, Via Gramsci 14, I-43100 Parma, Italy.

Acknowledgements

The Thoraco-Pulmonary Medical Oncology and the Clinical Trials Unit of the National Cancer Institute of Napoli are partially supported by Associazione Italiana per la Ricerca sul Cancro (AIRC).

Alessandro Morabito was born on September 1, 1967 in Naples, Italy. He received his M.D. Degree (1991) and specialty in Oncology (1995) at the University Federico II of Naples. Dr. Morabito is Director of the Thoraco-Pulmonary Medical Oncology of the National Cancer Institute of Naples. The research fields of major interest in the last years were lung cancer, clinical trials and target-based agents. Dr. Morabito is active member of the American Society of Clinical Oncology (ASCO) from 2001 and

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    Alessandro Morabito was born on September 1, 1967 in Naples, Italy. He received his M.D. Degree (1991) and specialty in Oncology (1995) at the University Federico II of Naples. Dr. Morabito is Director of the Thoraco-Pulmonary Medical Oncology of the National Cancer Institute of Naples. The research fields of major interest in the last years were lung cancer, clinical trials and target-based agents. Dr. Morabito is active member of the American Society of Clinical Oncology (ASCO) from 2001 and he has published more than 170 articles in International Journals, achieving a total Impact Factor of about 1000 points, Citation Index exceeding 7000 and H index of 38.

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