Use of chemo-radiotherapy in locally advanced non-small cell lung cancer
Introduction
In the United States, lung cancer is the third most common cancer after prostate and breast cancer, but it is the leading cause of cancer death both in men and women [1]. Surgery is the main curative treatment for early stage non-small cell lung cancer (NSCLC), i.e. clinical stages I and II, but most patients with NSCLC have advanced disease at the time of presentation and are not candidates for curative surgery. Approximately a quarter of patients with NSCLC present with locally advanced (clinical stage III) disease and, even if the tumour appears confined to the chest, it is none the less too extensive to warrant surgical resection. The classification of stage III category was reviewed in 1997, but it still remains heterogeneous: it includes a prognostic spectrum of subgroups ranging from T3 lesions with a single involved hilar (N1) node to a large primary tumour that invades the contralateral mediastinum and supraclavicular lymph nodes (N3) and/or a malignant pleural effusion (T4) [2]. Considering all the potential presentations, there are multiple treatment approaches available for these patients. The T3N1 group is usually treated with primary surgery, while pre- or postoperative chemotherapy and/or radiation may be considered as adjuvant treatments. Patients with malignant pleural effusion are routinely considered as those with stage IV disease [3]. Their treatment approach is palliative, although the 1986 Union International Contre le Cancer (UICC) classification relocated them from stage IV to stage IIIB.
Up to the mid-1980s, for most patients with locally advanced NSCLC, the standard management was conventional external beam thoracic radiotherapy alone, delivered at a dose of 60 Gy over 6 weeks, with a classical fractionation of 1.8–2 Gy per day. However, the results of radiotherapy alone were very disappointing, with a median survival time of less than 1 year and 2- and 5-year survival rates of approximately 15 and 5%, respectively [4]. In a study delivering up to 70 Gy, Hazuka and colleagues reported local tumour progression as the first site of failure in 50% of patients [5]. These poor results in such a common disease have led towards a greater intensification of local therapy through the use of altered fractionation schemes, three-dimensional conformal thoracic radiotherapy (TRT), radiosensitisers as well as attempts to develop chemotherapy schedules in combination with standard or altered fractionation schemes. However, while local therapy will have no influence on survival if cells resistant to chemotherapy have escaped from the primary site, local control is still a prerequisite for cure. Indeed, failure pattern analyses in NSCLC demonstrate that both locally persistent (or recurrent) disease and metastases are significant problems [6]. We will present here the state of the art and the perspectives of these two modalities in locally advanced NSCLC.
Section snippets
Radiotherapy
Recent efforts to escalate the total radiation dose to improve local control and survival have been reported using multiple daily fractions of radiotherapy either through hyperfractionation, accelerated fractionation or Continuous Hyperfractionated Accelerated Radiotherapy (CHART).
Hyperfractionation includes a decreased dose per fraction (typically 1.0–1.2 Gy), an increased number of fractions and a conventional overall treatment time. The goal of hyperfractionation is the differential sparing
Chemotherapy
The value of adding radiotherapy to chemotherapy in stage III NSCLC has been assessed in a randomised study by Kubota and colleagues [12]. In this study, after two cycles of chemotherapy, patients with locally advanced disease were randomised to receive thoracic radiation or not. There were different chemotherapy regimens: (i) cisplatin 100 mg/m2 on day 1, vindesine 3 mg/m2 on days 1, 8 and 15; (ii) cisplatin 80 mg/m2 on day 1, vindesine 3 mg/m2 on days 1 and 8, mitomycin-C 8 mg/m2 day 1; (iii)
Combined chemoradiotherapy regimens
There are three major modalities of combining radiation and chemotherapy: (a) sequential, in which one modality is completed prior to the start of the other; (b) concurrent, where radiation and chemotherapy are given on the same days; and (c) alternating, in which courses of radiation and chemotherapy are alternated so that administration of the two modalities is completed over the same overall time period without concurrent administration [13].
Historically, the sequential trials were firstly
New drugs
The optimal chemotherapy regimen in the management of inoperable NSCLC is still unknown. Recently, several new chemotherapeutic agents have shown activity in chemotherapy-naive NSCLC and most of these agents have been proven to be in vitro potent radiosensitisers. These include paclitaxel, docetaxel, vinorelbine, gemcitabine and irinotecan. Several phase II studies testing new compounds alone or in combination with cisplatin given concurrently with radiation in locally advanced NSCLC have been
Conclusions
Future trials will be designed to integrate the optimal local and systemic strategies in locally advanced disease. Treatment strategies to enhance local control, such as altered fractionation or dose escalation with conformal RT, will need to be safely combined with systemic chemotherapy.
The question of the sequencing of both modalities has not been fully resolved, but there are several theoretical and some clinical data encouraging the use of concurrent delivery of radiotherapy and
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Elective nodal irradiation (ENI) vs. involved field radiotherapy (IFRT) for locally advanced non-small cell lung cancer (NSCLC): A comparative analysis of toxicities and clinical outcomes
2010, Radiotherapy and OncologyCitation Excerpt :The difference in tenure between the ENI-treating physicians and IFRT-treating physicians accounts for the difference in follow-up time between the two patient groups. Locally advanced NSCLC patients tend to progress within the first year of treatment and the median follow-up for the survivors in the IFRT group was 16.2 months [28–29]. While we cannot draw definitive conclusions regarding disease control and overall survival, our results suggest that IFRT reduces the risk of esophageal toxicity.
Tumor treating fields: Concept, evidence and future
2011, Expert Opinion on Investigational Drugs3D-conformal radiotherapy for inoperable non-small-cell lung cancer - A single centre experience
2007, Radiology and OncologyPemetrexed and its emerging role in the treatment of thoracic malignancies
2003, Expert Opinion on Investigational Drugs