NIHR Signal Postoperative radiotherapy reduces survival after surgery to remove non-small cell lung cancer

Published on 28 February 2017

Postoperative radiotherapy increases the risk of death by 18% for patients with non-small cell lung cancer that has been removed by surgery.

Just over half of patients (53%) given radiotherapy after surgery survived to two years following treatment. This compared to 58% of patients who did not receive postoperative radiotherapy.

Previous evidence had suggested that postoperative radiotherapy may be beneficial after curative surgery. This Cochrane review contradicts this, drawing on data from 2,343 people across 11 good quality trials. It demonstrates that postoperative radiotherapy may have a detrimental effect on survival and cancer recurrence rates.

Most of the trials are from over 30 years ago, so there is the possibility that newer radiotherapy techniques may be less harmful. Nevertheless, this review provides the best evidence to date that postoperative radiotherapy may not be appropriate as a routine treatment for non-small cell lung cancer.

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Why was this study needed?

Lung cancer is the second most common cancer in the UK with 37,453 new cases registered in 2014. The majority of lung cancers are non-small cell, and about 1 in 5 will be eligible for potentially curative surgical resection. There were 5,342 procedures in 2014. Postoperative radiotherapy has been proposed as a strategy that could improve survival, though its role has remained unclear.

An earlier review from 2009 suggested that the effects of postoperative radiotherapy may vary by age, sex, tumour subtype or stage. Since then, better statistical methods have been developed that reduce risk of bias, and cancer staging systems have been updated.

This Cochrane review aimed to update the evidence in the light of these new developments and to assess the effects of postoperative radiotherapy in people with surgically removed non-small cell lung cancer. The reviewers further aimed to clarify whether particular patient groups may gain greater benefit.

What did this study do?

This systematic review and meta-analysis included individual patient data for 2,233 patients from 11 trials comparing postoperative radiotherapy with surgery alone. The researchers excluded three trials included in the previous review due to incomplete data or poor methodology. 

The main outcome of interest was overall survival. The researchers also gathered data on recurrence-free survival, defined as time from randomisation to first cancer recurrence or death from any cause. They analysed results by patients’ age, sex, tumour type and stage.

The trials date from 1966 to 2007 in countries including Belgium, Italy, Korea and Slovenia.  Delivery of postoperative radiotherapy varied considerably across trials.  Follow-up was to an average of 4.5 years.

All included trials were assessed to have low risk of bias, suggesting they were reliable.

What did it find?

  • Of the 2,343 patients 1,511 died during follow-up. Postoperative radiotherapy adversely affected survival, increasing the risk of death by 18% compared to patients who received surgery alone (hazard ratio [HR] 1.18, 95% confidence interval [CI] 1.07 to 1.31). The absolute chances of a person surviving for two years after surgery were 58% if they had surgery alone and 53% if they had post-operative radiotherapy. The difference in survival between the two groups seemed to start about four months after surgery.
  • Patients who received surgery alone without postoperative radiotherapy were 12% more likely to survive with no recurrence of cancer in the lung (HR 1.12, 95% CI 1.01 to 1.24) and 13% more likely to survive with no distant cancer spread (HR 1.13, 95% CI 1.02 to 1.24). However, when looking at overall recurrence-free survival, regardless of site, the difference between groups just fell short of statistical significance so this could be a chance finding (HR 1.10, 95% CI 0.99 to 1.21).
  • Patient factors of age, gender, stage or subtype of cancer did not influence the effect of radiotherapy upon survival.
  • The review did not look at possible adverse effects of treatment or impact on quality of life. However, the authors considered that it would be unlikely that any benefits in these areas would offset the detrimental effect of radiotherapy on survival rates.

What does current guidance say on this issue?

Current NICE guidelines last updated in 2011 do not explicitly refer to postoperative radiotherapy for non-small cell lung cancer. NICE recommends that patients who are considered suitable for multimodal treatment (surgery, radiotherapy and chemotherapy in any combination) are assessed by the relevant specialists. Postoperative chemotherapy is recommended for patients who have responded well to surgery, but postoperative radiotherapy is not mentioned.

What are the implications?

The findings provide the best level of evidence to date that postoperative radiotherapy reduces the chance of survival for patients with non-small cell lung cancer who have had curative surgery, and should not be routinely used. 

Many of the trials were dated and delivered radiotherapy by cobalt machines, which has been largely replaced by newer linear accelerator radiotherapy. It is not clear whether this newer treatment is less harmful than older methods.

On the evidence currently available clinical teams may consider reviewing the benefits and harms of this treatment, if they have not already done so.

Citation and Funding

Burdett S, Rydzewska L, Tierney J, et al. Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev. 2016;(10):CD002142. 

This project was funded by the UK National Health Service Research and Development Cancer Programme (grant number NCP/U034/51/01).

Bibliography

Hodkinson PS and Sethi T.  Advances in the treatment and prevention of lung cancer.  J R Coll Physicians Edinb. 2011;41(2):142-9.

NHS Choices. Lung cancer. London: Department of Health; 2015.

NICE.  Lung cancer: diagnosis and treatment. CG121.  London: National Institute for Health and Care Excellence; 2011. 

Office for National Statistics.  Cancer registration statistics, England: 2014.  Newport: Office for National Statistics; 2016.

Public Health England and Cancer Research UK.  National Cancer Intelligence Network.  Major resections by cancer site, in England; 2006 to 2010.  London: Public Health England; 2014.

Royal College of Physicians.  Lung cancer clinical outcomes publication 2016 (for the audit period 2014).  London: Royal College of Physicians; 2016.

Why was this study needed?

Lung cancer is the second most common cancer in the UK with 37,453 new cases registered in 2014. The majority of lung cancers are non-small cell, and about 1 in 5 will be eligible for potentially curative surgical resection. There were 5,342 procedures in 2014. Postoperative radiotherapy has been proposed as a strategy that could improve survival, though its role has remained unclear.

An earlier review from 2009 suggested that the effects of postoperative radiotherapy may vary by age, sex, tumour subtype or stage. Since then, better statistical methods have been developed that reduce risk of bias, and cancer staging systems have been updated.

This Cochrane review aimed to update the evidence in the light of these new developments and to assess the effects of postoperative radiotherapy in people with surgically removed non-small cell lung cancer. The reviewers further aimed to clarify whether particular patient groups may gain greater benefit.

What did this study do?

This systematic review and meta-analysis included individual patient data for 2,233 patients from 11 trials comparing postoperative radiotherapy with surgery alone. The researchers excluded three trials included in the previous review due to incomplete data or poor methodology. 

The main outcome of interest was overall survival. The researchers also gathered data on recurrence-free survival, defined as time from randomisation to first cancer recurrence or death from any cause. They analysed results by patients’ age, sex, tumour type and stage.

The trials date from 1966 to 2007 in countries including Belgium, Italy, Korea and Slovenia.  Delivery of postoperative radiotherapy varied considerably across trials.  Follow-up was to an average of 4.5 years.

All included trials were assessed to have low risk of bias, suggesting they were reliable.

What did it find?

  • Of the 2,343 patients 1,511 died during follow-up. Postoperative radiotherapy adversely affected survival, increasing the risk of death by 18% compared to patients who received surgery alone (hazard ratio [HR] 1.18, 95% confidence interval [CI] 1.07 to 1.31). The absolute chances of a person surviving for two years after surgery were 58% if they had surgery alone and 53% if they had post-operative radiotherapy. The difference in survival between the two groups seemed to start about four months after surgery.
  • Patients who received surgery alone without postoperative radiotherapy were 12% more likely to survive with no recurrence of cancer in the lung (HR 1.12, 95% CI 1.01 to 1.24) and 13% more likely to survive with no distant cancer spread (HR 1.13, 95% CI 1.02 to 1.24). However, when looking at overall recurrence-free survival, regardless of site, the difference between groups just fell short of statistical significance so this could be a chance finding (HR 1.10, 95% CI 0.99 to 1.21).
  • Patient factors of age, gender, stage or subtype of cancer did not influence the effect of radiotherapy upon survival.
  • The review did not look at possible adverse effects of treatment or impact on quality of life. However, the authors considered that it would be unlikely that any benefits in these areas would offset the detrimental effect of radiotherapy on survival rates.

What does current guidance say on this issue?

Current NICE guidelines last updated in 2011 do not explicitly refer to postoperative radiotherapy for non-small cell lung cancer. NICE recommends that patients who are considered suitable for multimodal treatment (surgery, radiotherapy and chemotherapy in any combination) are assessed by the relevant specialists. Postoperative chemotherapy is recommended for patients who have responded well to surgery, but postoperative radiotherapy is not mentioned.

What are the implications?

The findings provide the best level of evidence to date that postoperative radiotherapy reduces the chance of survival for patients with non-small cell lung cancer who have had curative surgery, and should not be routinely used. 

Many of the trials were dated and delivered radiotherapy by cobalt machines, which has been largely replaced by newer linear accelerator radiotherapy. It is not clear whether this newer treatment is less harmful than older methods.

On the evidence currently available clinical teams may consider reviewing the benefits and harms of this treatment, if they have not already done so.

Citation and Funding

Burdett S, Rydzewska L, Tierney J, et al. Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev. 2016;(10):CD002142. 

This project was funded by the UK National Health Service Research and Development Cancer Programme (grant number NCP/U034/51/01).

Bibliography

Hodkinson PS and Sethi T.  Advances in the treatment and prevention of lung cancer.  J R Coll Physicians Edinb. 2011;41(2):142-9.

NHS Choices. Lung cancer. London: Department of Health; 2015.

NICE.  Lung cancer: diagnosis and treatment. CG121.  London: National Institute for Health and Care Excellence; 2011. 

Office for National Statistics.  Cancer registration statistics, England: 2014.  Newport: Office for National Statistics; 2016.

Public Health England and Cancer Research UK.  National Cancer Intelligence Network.  Major resections by cancer site, in England; 2006 to 2010.  London: Public Health England; 2014.

Royal College of Physicians.  Lung cancer clinical outcomes publication 2016 (for the audit period 2014).  London: Royal College of Physicians; 2016.

Postoperative radiotherapy for non-small cell lung cancer

Published on 12 October 2016

Burdett, S.,Rydzewska, L.,Tierney, J.,Fisher, D.,Parmar, M. K.,Arriagada, R.,Pignon, J. P.,Le Pechoux, C.

Cochrane Database Syst Rev Volume 10 , 2016

BACKGROUND: The role of postoperative radiotherapy (PORT) in the treatment of patients with completely resected non-small cell lung cancer (NSCLC) was not clear. A systematic review and individual participant data meta-analysis was undertaken to evaluate available evidence from randomised controlled trials (RCTs). These results were first published in Lung Cancer in 2013. OBJECTIVES: To evaluate the effects of PORT on survival and recurrence in patients with completely resected NSCLC. To investigate whether predefined patient subgroups benefit more or less from PORT. SEARCH METHODS: We supplemented MEDLINE and CANCERLIT searches (1965 to 8 July 2016) with information from trial registers, handsearching of relevant meeting proceedings and discussion with trialists and organisations. SELECTION CRITERIA: We included trials of surgery versus surgery plus radiotherapy, provided they randomised participants with NSCLC using a method that precluded prior knowledge of treatment assignment. DATA COLLECTION AND ANALYSIS: We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. We sought data on all participants from those responsible for the trial. We obtained updated individual participant data (IPD) on survival and date of last follow-up, as well as details on treatment allocation, date of randomisation, age, sex, histological cell type, stage, nodal status and performance status. To avoid potential bias, we requested information on all randomised participants, including those excluded from investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. MAIN RESULTS: We identified 14 trials evaluating surgery versus surgery plus radiotherapy. Individual participant data were available for 11 of these trials, and our analyses are based on 2343 participants (1511 deaths). Results show a significant adverse effect of PORT on survival, with a hazard ratio of 1.18, or an 18% relative increase in risk of death. This is equivalent to an absolute detriment of 5% at two years (95% confidence interval (CI) 2% to 9%), reducing overall survival from 58% to 53%. Subgroup analyses showed no differences in effects of PORT by any participant subgroup covariate.We did not undertake analysis of the effects of PORT on quality of life and adverse events. Investigators did not routinely collect quality of life information during these trials, and it was unlikely that any benefit of PORT would offset the observed survival disadvantage. We considered risk of bias in the included trials to be low. AUTHORS' CONCLUSIONS: Results from 11 trials and 2343 participants show that PORT is detrimental to those with completely resected non-small cell lung cancer and should not be used in the routine treatment of such patients. Results of ongoing RCTs will clarify the effects of modern radiotherapy in patients with N2 tumours.

Non-small cell lung cancer is the most common type of lung cancer, accounting for more than 80% of lung cancer cases. The main types of non-small cell lung cancer are: squamous cell carcinoma, adenocarcinoma and large-cell carcinoma.

Expert commentary

The use of post-operative radiotherapy has been shown to be beneficial in a number of common cancers. A previously published meta-analysis demonstrated that this was not true for non-small cell lung cancers, and that the addition of radiotherapy was detrimental. This updated review confirms that finding. Uncertainty remains as to whether post-operative radiotherapy may provide a benefit for those with higher stage disease, though this study found no such difference. An ongoing randomised control trial is assessing post-operative radiotherapy in stage III disease. Until the results are published, it is clear that patients should not be offered post-operative radiotherapy outside a trial.

Dr Charles Comins, Consultant Clinical Oncologist, Bristol Royal Infirmary

Categories

  •   Cancers, Respiratory disorders, Acute and general medicine