Use of chemo-radiotherapy in locally advanced non-small cell lung cancer

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Abstract

Lung cancer is the leading cause of cancer mortality in the Western countries for both men and women. Approximately 40% of patients present with locally advanced and/or unresectable disease. While small improvements in outcome have occurred for this group of patients in the last decade, 5-year survival remains low, ranging from 5 to 20%. Distant metastases and loco-regional progression remain significant patterns of failure. Up to the late 1980s, the standard management for locally advanced non-small cell lung cancer (NSCLC) was conventional thoracic radiotherapy, but when treated with radiotherapy alone, less than 10% of patients survived for 5 years or more. 60–70% failed at distant sites and less than 20% achieved durable local control. The addition of chemotherapy reduces the rate of distant failure, improves survival and the combination of chemotherapy and radiotherapy has become the standard of care of patients with locally advanced NSCLC. Current developments aim to optimise individual components of combined modality schedules, increase their synergism and minimise toxicity.

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

References (54)

  • S Sugiura et al.

    Prognostic value of pleural effusion in patients with non-small cell lung cancer

    Clin. Cancer Res.

    (1997)
  • C.A Perez et al.

    Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-small-cell lung carcinomareport by the Radiation Therapy Oncology Group

    Cancer

    (1982)
  • R.W Byhardt et al.

    Response toxicity failure patterns, and survival in five Radiation Therapy Oncology Group (RTOG) trials for sequential and/or concurrent chemotherapy and radiotherapy for locally advanced non-small-cell carcinoma of the lung

    Int. J. Radiat. Oncol. Biol. Phys.

    (1988)
  • J.D Cox et al.

    A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gypossible survival benefit with 69.6 Gy in favorable patients with Radiation Therapy Oncology Group 83-11

    J. Clin. Oncol.

    (1990)
  • M.I Saunders et al.

    Experience with dose escalation using CHARTWEL (continuous hyperfractionated accelerated radiotherapy weekend less) in non-small-cell lung cancer

    Br. J. Cancer

    (1998)
  • J.A Hayman et al.

    Dose escalation in non-small cell lung cancer (NSCLC) using conformal 3-dimensional radiation therapy (C3DRT)update of a phase I trial

    Proc. Annu. Meet. Am. Soc. Clin. Oncol.

    (1999)
  • K Kubota et al.

    Role of radiotherapy in combined modality treatment of locally advanced non-small cell lung cancer

    J. Clin. Oncol.

    (1994)
  • H Wagner

    Treatment of locally advanced and metastatic non-small cell lung cancer

    Adv. Oncol.

    (1993)
  • R.O Dillman et al.

    A randomized trial of induction chemotherapy plus high dose radiation versus radiation alone in stage III non-small cell lung cancer

    N. Engl. J. Med.

    (1990)
  • R.O Dillman et al.

    Improved survival in stage III non-small-cell lung cancerseven year follow-up of cancer and leukemia group B (CALGB) 8433 trial

    J. Natl. Cancer Inst.

    (1996)
  • W.T Sause et al.

    Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588preliminary results of a phase III trial in regionally advanced unresectable non-small-cell lung cancer

    J. Natl. Cancer Inst.

    (1995)
  • T Le Chevalier et al.

    Significant effect of adjuvant chemotherapy on survival in locally advanced non-small-cell carcinoma

    J. Natl. Cancer Inst.

    (1992)
  • Chemotherapy in non-small cell lung cancera meta-analysis using updated data on individual patients from 52 randomized clinical trials

    Br. Med. J.

    (1995)
  • H Wagner

    Rational integration of radiation and chemotherapy in patients with unresectable stage IIIA or IIIB NSCLC

    Chest

    (1993)
  • J.S Lee et al.

    Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small cell lung cancerRadiation Therapy Oncology Group Protocol 91-06

    J. Clin. Oncol.

    (1996)
  • C Schaake-Koning et al.

    Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer

    N. Engl. J. Med.

    (1992)
  • K Furuse et al.

    Phase II study of concurrent radiotherapy and chemotherapy for unresectable stage III non-small-cell lung cancer

    J. Clin. Oncol.

    (1995)
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