Stage 3 non small cell lung cancer

Corresponding author: Mariano Provencio, MD, PhD. Servicio de Oncología Médica, Hospital Universitario Puerta de Hierro, C/Manuel de Falla, 1. Majadahonda 28222, Madrid, Spain. Tel: 91-191-6000; Fax: 91-191-6000. Email: moc.liamg@poicnevorpm.

Received 2010 Nov 22; Accepted 2011 Jan 7.

Copyright 2011 Journal of Thoracic Disease. All rights reserved.

Abstract

Most lung cancer patients are diagnosed with a non-resectable disease; and around 40% in advanced stages. Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease with great variations in its clinical extent which presents a major therapeutic challenge. Although chemo-radiotherapy treatment has become the most widely used, there is currently no consensus on the best standard treatment and the experience of the therapy team plays an important role in the decision taking. We review the treatment of inoperable stage III NSCLC and the role of concomitant vinorelbine in this clinical scenario.

Keywords: non-small cell lung cancer, stage III, chemo-radiotherapy, chemotherapy, vinorelbine

Introduction

Lung cancer is the most common and deadly tumour worldwide and approximately 1.3 million patients a year die of it (1). Non-small cell lung cancer accounts for 85% of all new cases diagnosed. Most patients are diagnosed with a non-resectable disease; and around 40% in advanced stages (2). Cure is unlikely in those patients with locally advanced non-small cell lung cancer (NSCLC) who do not receive radical surgery, and patients who receive chemotherapy and concomitant radiotherapy have a 3-year survival of approximately 27% (3). However, in limited disease (stage I, II, IIIA) patients who undergo surgical resection and the administration of cytostatic treatment achieve a 5-year survival of 51% (4), with an absolute benefit of 5.4% in 5-year survival, especially in patients with a good performance status (PS) (5).

At diagnosis, at least 40% of patients are already at an advanced stage, and a third have locally advanced disease (stage III) which is defined as a tumor that exceeds the structures of the lung itself, but without clinical evidence of distant spreading. These patients form a highly heterogeneous group with controversial treatment based on the combination of surgery, chemotherapy and radiotherapy.

In the past, radiotherapy was considered the standard therapy in IIIA and IIIB but demonstrated very low survival, poor local control and early development of distant disease. Patients with inoperable stage III treated only with thoracic radiotherapy experienced a median survival of 9-11 months, 2-year survival of 10-20% and 3-year survival of 5-10% (6).

There is no current consensus on the best standard treatment and the experience of the therapy team plays an important role in the decision taking.

Treatment of inoperable stage III nonsmall cell lung cancer (NSCLC)

There are various therapeutic options for the treatment of locally advanced NSCLC. The choice of which will depend on the patient's clinical situation, closely linked to their general situation, how far advanced the tumor is on diagnosis, and the experience at the hospital.

The use of induction chemotherapy treatment began after a series of clinical trials in the mid 1980s (7),(8).

In 1995, a meta-analysis based on individual data from 3,033 patients showed that combining chemotherapy and radiotherapy gave a statistically significant benefit (9). This difference was greater in those trials that had used platinum treatment, with a hazard ratio of 0.87 (P<0.005) in favor of combined chemotherapy and radiotherapy treatment.

From that time, various therapeutic designs have been investigated in the search for the best treatment sequence. This review briefly explains the main studies and their findings on each of the various types of treatment.

Sequential chemotherapy and radiotherapy vs exclusive radiotherapy

The pivotal trial was performed by the Cancer and Leukemia Group B (CALGB) 8433 (10), which randomized 155 patients in a sequential model of induction chemotherapy with cisplatin-vinblastine, followed by radiotherapy with 60 Gy, versus radiotherapy at the same dose. The study showed a significant improvement for the combination arm, with a median survival of 13.8 months vs 9.7 months (P=0.0066) and a difference in 3- and 5-year survival of 23% vs 11%, and 19% vs 7%, respectively.

A three-arm confirmatory study was conducted by the Radiation Therapy Oncology Group (RTOG), Southwest Oncology Group (SWOG) and ECOG (11). It randomized 450 patients to receive exclusive radiotherapy, chemotherapy with cisplatin-vinblastine followed by 60 Gy radiotherapy, or combined treatment with hyperfractionated radiotherapy (1.2 Gy per fraction, twice a day) to a total of 69.6 Gy. Median survival was 11.4 months for patients receiving exclusive radiotherapy; 13.2 months (P=0.04) for those receiving the combination; and 12 months for hyperfractionated radiotherapy. Overall survival was statistically greater for patients who received combined treatment than for those who had radiotherapy alone.

A third study, conducted by Le Chevalier et al. (12) with 353 patients, compared three induction chemotherapy cycles (cisplatin, vindesine, cyclophosphamide and lomustine) followed by radiotherapy and three more cycles, vs exclusive radiotherapy. With an average follow-up of 40 months, two-year survival of the radiotherapy group was 14% vs 21% for the combination arm (P=0.08). A second analysis (13), with a mean follow-up of 61 months, found statistically significant benefit in overall survival at 3 years of 12% vs 4% (P =0.04) (Table 1).

Table 1.

Studies of chemotherapy followed by radiotherapy vs radiotherapy alone

Author N° patientsTreatmentMean survival (months)Overall 5-year survivalDillman10
N: 155•Cisplatin-Vinblastine + RT13.8*19%*•RT9.77%Sause11
N: 458•Cisplatin-Vinblastine + RT13.2*8%*•Cisplatin-Vinblastine +hyperfractionated RT126%•RT11.45%Le Chevalier12,13
N: 353•Cisplatin-Vindesine-Cyclophosphamide-Lomustine + RT12*12%* (3-year data)•RT104%

Open in a separate window

* Statistically significant difference

After the publication of the above-mentioned the NSCLC Collaborative Group (7) meta-analysis (BMJ 1995), other meta-analyses (14),(15),(16), (17),(18) showed improved survival from the combination of cisplatin-based chemotherapy and radiotherapy vs radiotherapy alone, with a 5-year survival benefit of 2-4% which, although small, is considered to be clinically relevant.

Concurrent chemo-radiotherapy improves overall survival of patients with locally advanced NSCLC, compared with sequential chemo-radiotherapy. Nowadays platinum-based polychemotherapy is considered the standard treatment. The second drugs associated to platinum seems to have no large impact in survival, so it should be choice based on its toxicity profile. Cisplatin plus vinorelbine regimen is a good candidate for combination with concurrent radiotherapy because of its efficacy and safety. These results are highly promising, being even better than other concurrent chemotherapy studies, with very good tolerance and little toxicity. This leads us to compare this model with that thought to be most active in this situation, cisplatin-etoposide, which provides a median survival of 23.2 months (overall survival at 3 years of 26.1%, progression-free survival around 10 months) (50),(51),(52). How long can you live with stage 3 non

Can Stage 3 non

Is Stage 3 cancer a terminal?

Can Stage 3 lung cancer go into remission?