How to improve loco-regional control in stages IIIa–b NSCLC?: Results of a three-armed randomized trial from the Swedish Lung Cancer Study Group

doi:10.1016/j.lungcan.2008.10.021

Lung Cancer

Volume 65, Issue 1, July 2009, Pages 62-67

https://doi.org/10.1016/j.lungcan.2008.10.021 Get rights and content

Abstract

Background

A combination of chemotherapy and radiotherapy is the treatment base for locally advanced non-small cell lung cancer (NSCLC). However, both loco-regional and distant failure is frequent. Attempts to improve the loco-regional control were made in three separate phase II studies in Swedish University Hospitals, where accelerated radiotherapy or concurrent daily or weekly chemotherapy with conventional radiotherapy were tested. Comparatively good results from these studies lead to this national randomized phase II study, the RAKET-study, where the different concepts were investigated on a wider basis for further phase III studies.

Methods

Inoperable stage III non-small cell lung cancer patients in good performance status (PS < 2) were equally randomized to either of three arms in eight institutions. All arms started with two cycles of induction chemotherapy: paclitaxel 200 mg/m² and carboplatin AUC6. Arm A: a third identical cycle was given concomitant with start of accelerated radiotherapy, 1.7 Gy BID to 64.6 Gy in 4.5 weeks. Arm B consisted of daily concomitant paclitaxel 12 mg/m² with conventionally fractionated radiotherapy: 2 Gy to 60 Gy in 6 weeks. Arm C: weekly concomitant paclitaxel 60 mg/m² and identical radiotherapy to 60 Gy. Primary endpoint: TTP. Secondary: OS, toxicity, QL and relapse pattern.

Results

Between June 2002 and May 2005 152 patients were randomized and of them 151 were evaluable: 78 men and 73 women, median age 62 years (43–78), 55% had performance status 0 and 45% PS 1. Thirty-four percent had stage IIIa and 66% IIIb. Histology: adenocarcinoma 48%, squamous cell carcinoma 32% and 20% non-small cell carcinoma. The three arms were well balanced. Toxicity was manageable with 12% grades 3–4 esophagitis, 1% grades 3–4 pneumonitis and there was no clear difference between the arms. The QL data did not differ either. Median time to progression was 9.8 (8.3–12.7) months (8.8, 10.3 and 9.3 months for arms A, B and C, respectively). Median survival was 17.8 (14.4–23.7) months (17.7, 17.7 and 20.6 months for A, B and C, respectively). The 1-, 3- and 5-year overall survival was 63, 31 and 24%. Sixty-nine percent of the patients relapsed with distant metastases initially and 31% had loco-regional tumor progression, without significant differences between treatment arms. Thirty-four percent developed brain metastases.

Conclusions

Treatment results are quite equal by intensifying the loco-regional treatment either by accelerated fractionated radiotherapy or daily or weekly concomitant chemo-radiotherapy both in terms of survival, toxicity and quality of life. The optimal treatment schedule for patients with locally advanced NSCLC is still to be decided and investigated in future clinical studies. Relapse pattern with distant metastases and especially brain metastases is a great problem and need further research for better therapy options and higher cure rate for this patient group.

Introduction

Induction chemotherapy and radiotherapy has been the treatment base for locally advanced non-small cell lung cancer (NSCLC). However, both loco-regional and distant failure is frequent. Attempts to improve the loco-regional control were made in three separate phase II studies in different Swedish University Hospitals. Accelerated fractionated radiotherapy combined with induction and concomitant chemotherapy was used in one study [1], [2]. Induction chemotherapy followed by concomitant daily paclitaxel with conventional fractionated radiotherapy followed by adjuvant chemotherapy was explored in a phases I–II setting in a second study [3]. The third study investigated induction chemotherapy followed by weekly paclitaxel and carboplatin combined with conventional fractionated radiotherapy [4]. Comparatively good results from these studies lead to this national randomized phase II study, the RAKET-study, where the different concepts were investigated on a wider basis with time to progression as primary endpoint for a further phase III study. An interim analysis was planned where one arm could be stopped if it did not meet the efficacy rate of clinical interest (TTP > 12 months) and a conversion to a two armed randomized phase III study would then be possible. A second goal was to achieve a national unity in the treatment strategies for this patient group.

Section snippets

Objectives

One hundred and fifty patients were planned for this study equally randomized to three treatment arms where the primary objective was time to progression (TTP) and secondary objectives were response, overall survival, toxicity, quality of life (QLQ) and relapse pattern. Additionally, possible prognostic and predictive factors should be looked for.

Patient eligibility

The main inclusion criteria were non-resectable or medically inoperable patients with histological or cytological confirmed NSCLC stage IIIa or IIIb

Patient characteristics

Between June 2002 and May 2005 152 patients were randomized and 151 of them were evaluable, one patient had stage IV disease at inclusion and was excluded. There were 78 men and 73 women, median age was 62 years (range 43–78), 55% had performance status 0 and 45% PS 1. Mean pretreatment pulmonary function: FEV₁ 2.1 L (range 0.8–4.5). Pretreatment weight loss >10% was seen in 20 patients (13%). Thirty-four percent had stage IIIa and 66% IIIb. Adenocarcinoma was the most common histology in 48%,

Discussion

Both local and distant relapse is frequent in locally advanced stage III NSCLC.

To reduce the distant failure we used induction chemotherapy in all arms in this study. There are some data supporting that full dose induction chemotherapy reduces distant metastases whereas concomitant chemotherapy could improve the local control [6]. However, two recent studies did not show any additional value of induction chemotherapy when using concomitant chemoradiation [7], [8]. In earlier studies in Japan

Conflict of interest

The authors indicate no potential conflict of interest.

Acknowledgements

We would like to thank Ingmarie Johanson for help with to statistics, Camilla Palmqvist for monitoring the study and Bristol-Myers Squibb Scandinavia for an unrestricted grant to be able to accomplish the study.

References (31)

R. Simon
Optimal two-stage designs for phase II clinical trials
Control Clin Trials
(1989)
J. Jassem
Combined chemotherapy and radiation in locally advanced non small-cell lung cancer
Lancet Oncol
(2001)
M. Saunders et al.
Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: a randomised multicentre trial
Lancet
(1997)
D. Ball et al.
A randomised Phase III study of standard fractionation radiotherapy with or without concurrent carboplatin in inoperable non-small cell lung cancer: final report of an Australian multi-centre trial
Radiother Oncol
(1999)
C. Pallarés et al.
Induction chemotherapy with paclitaxel plus carboplatin followed by paclitaxel with concurrent radiotherapy in stage IIIB non-small-cell lung cancer (NSCLC) patients: a phase II trial
Lung Cancer
(2007)
D.I. Rosenthal et al.
Phase I study of paclitaxel given by seven-week continuous infusion concurrent with radiation therapy for locally advanced non-small cell lung cancer
J Thorac Oncol
(2006)
G.D. Zanelli et al.
Paclitaxel as a radiosensitisier: proposed schedule of administration based on in vitro data and pharmacokinetic calculations
Eur J Cancer
(1997)
A.H. Russell et al.
Profylactic cranial irradiation for lung cancer patients at high risk for development for of cerebral metastasis: results of a prospective randomised trial conducted by the radiation therapy oncology group
Int J Radiat Oncol Biol Phys
(1991)
J. Nyman et al.
Accelerated radiotherapy with docetaxel and cisplatin as induction and concomitant chemotherapy for stage III non-small cell lung cancer
Lung Cancer
(2000)
J. Nyman et al.
Accelerated hyperfractionated radiotherapy combined with induction and concomitant chemotherapy for inoperable non-small cell lung cancer—impact of total treatment time
Acta Oncol
(1998)

O. Brodin et al.

Daily paclitaxel and radiotherapy in patients with locally advanced non-small cell lung cancer. A phase I study

Proc Am Soc Clin Oncol

(2000)

F. Sirzén et al.

Phase II study of weekly paclitaxel and carboplatin with concurrent thoracic radiation therapy for locally advanced NSCLC

Proc Am Soc Clin Oncol

(2001)

E.E. Vokes et al.

Induktion chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small cell lung cancer: Cancer and Leukaemia Group B

J Clin Oncol

(2007)

Y.S. Gouda et al.

Randomized study of concurrent carboplatin, paclitaxel, and radiotherapy with or without prior induction chemotherapy in patients with locally advanced non-small cell lung cancer

J Egypt Natl Canc Inst

(2006)

K. Furuse et al.

Phase III study of concurrent versus sequential thoracic radiotherapy in combination wiyh mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer

J Clin Oncol

(1999)

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¹: Swedish Lung Cancer Study Group.

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How to improve loco-regional control in stages IIIa–b NSCLC?: Results of a three-armed randomized trial from the Swedish Lung Cancer Study Group

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Objectives

Patient eligibility

Patient characteristics

Discussion

Conflict of interest

Acknowledgements

Control Clin Trials

Lancet Oncol

Lancet

Radiother Oncol

Lung Cancer

J Thorac Oncol

Eur J Cancer

Int J Radiat Oncol Biol Phys

Accelerated radiotherapy with docetaxel and cisplatin as induction and concomitant chemotherapy for stage III non-small cell lung cancer

Lung Cancer

Accelerated hyperfractionated radiotherapy combined with induction and concomitant chemotherapy for inoperable non-small cell lung cancer—impact of total treatment time

Acta Oncol

Daily paclitaxel and radiotherapy in patients with locally advanced non-small cell lung cancer. A phase I study

Proc Am Soc Clin Oncol

Phase II study of weekly paclitaxel and carboplatin with concurrent thoracic radiation therapy for locally advanced NSCLC

Proc Am Soc Clin Oncol

Induktion chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small cell lung cancer: Cancer and Leukaemia Group B

J Clin Oncol

Randomized study of concurrent carboplatin, paclitaxel, and radiotherapy with or without prior induction chemotherapy in patients with locally advanced non-small cell lung cancer

J Egypt Natl Canc Inst

Phase III study of concurrent versus sequential thoracic radiotherapy in combination wiyh mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer

J Clin Oncol