What is the clinical benefit of radiotherapy to the lung primary in stage IV NSCLC?

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What is the clinical benefit of radiotherapy to the lung primary in stage IV NSCLC?

Palliative thoracic radiotherapy

Introduction

The aim of palliative radiotherapy in stage IV Non-Small Cell Lung Cancer (NSCLC) is to alleviate symptoms and improve quality of life. This has to be balanced against toxicity and costs of treatment and the need to attend for treatment for a number of days to weeks.

The cost-utility of different fractionation schemes has been analysed using data from the study by Kramer et al which randomised patients between 30Gy in 10 fractions and 16Gy in 2 fractions.[1] The higher dose provided significantly greater Quality Adjusted Life Years (20 weeks versus 13 weeks) but at greater societal cost. However the cost utility ratio was estimated to be US$40900 per QALY which is within the range of acceptable cost effectiveness for medical interventions.

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Radiotherapy fractionation scheme for palliative radiotherapy to the lung primary in stage IV NSCLC

Clinical benefit of palliative radiotherapy

Stevens et al conducted a systematic review of 14 randomised controlled trials which randomised between different doses of palliative radiotherapy.[2] These trials were heterogeneous in terms of the performance status of the study population, tumour pathology (NSCLC, SCLC, no pathological diagnosis) and tumour stage (stage III, stage IV or patients who were deemed unsuitable for curative treatment). In the majority of trials the endpoint was symptomatic response although this was measured using different instruments and by patients and/or clinicians at various time points. A meta-analysis was not performed due to heterogeneity of study population and outcomes measured.

All studies showed an improvement in symptoms from lung cancer with no significant difference in palliative benefit between the different fractionation regimens. There was no difference in radiological response. Toxicity was mild overall but was greater in arms with higher radiotherapy dose. The three studies which examined quality of life showed mixed findings and no clear advantage to a particular radiotherapy dose. Four studies showed an improvement in survival with higher radiation doses (20Gy in 5 fractions - 50Gy in 25 fractions). The meta-analysis showed a statistically significant improvement in one year survival with fractionated regimens in patients with good performance status (RR=0.95, CI: 0.90-0.99) but not in those with poor performance status (RR=0.96, CI 0.91-1.02).

The main symptoms palliated by thoracic radiotherapy are cough, dyspnoea, chest pain and haemoptysis. Cough is improved in 20-65% of patients, dyspnoea in 40-55%, chest pain in 39-80% and haemoptysis in 39-95%.[3][4][5][6] The median duration of palliative benefit for cough is 56-78 days, chest pain 56-74 days and haemoptysis 64-146 days.[3][4] This duration of palliation equates to 50% or more of the patients remaining survival time.

None of the trials showed any superiority of a particular radiotherapy dose and fractionation in achieving symptomatic response.[2] A higher radiotherapy dose (30Gy in 10 fractions) has been associated with a longer duration of response and a slower progression of symptoms.[7] There is greater improvement in quality of life with higher radiotherapy doses (20Gy in 5 fractions).[8] Higher doses (20Gy in 5 fractions, 30-39Gy in 10-13 fractions) have also been associated with a two month improvement in median survival and a 5-9% increase in one year survival and 3% at two years.[2][5][8][7] This survival benefit is largely in those patients with stage III NSCLC and good performance status but Kramer et al also demonstrated this for patients with stage IV NSCLC and good performance status.

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Toxicity of radiotherapy

Palliative thoracic radiotherapy may cause fatigue, oesophagitis and pneumonitis. Acute toxicity is generally mild and self-limiting.[2] Higher radiotherapy doses have been associated with increased toxicity particularly oesophagitis which can occur in 40-56% of patients.[3][4] More recent trials have shown no difference in acute toxicity between lower and higher doses of radiotherapy.[8][7] Late toxicity is uncommon, however, radiation myelitis has been documented in up to 2.5% of patients receiving 17Gy/2 fractions and 39Gy/13 fractions.[3][4][5] This can be reduced by limiting the spinal cord dose to LQED2 of 48Gy.[9]

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Optimal timing of palliative radiotherapy to the primary lung cancer in stage IV NSCLC

Timing of radiotherapy

In patients with minimal thoracic symptoms there is no advantage to immediate radiotherapy. A randomised trial of immediate versus delayed radiotherapy in these patients demonstrated that the chance of being alive and without moderate symptoms at six months was the same regardless of whether initial radiotherapy was given or not.[10] Only 42% of patients who did not receive initial radiotherapy, required it later for symptoms. There was no difference in psychological distress between the two patient groups.

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Endobronchial brachytherapy

Conventional external beam radiotherapy is delivered by a linear accelerator. An alternative way of delivering radiotherapy is via a catheter placed endobronchially at the site of the cancer. A radioactive seed travels through this catheter and releases radiation in close proximity to the cancer without the need to travel through healthy normal tissue. However the range of radiation delivered is small, in the order of 1-2cm, and this technique is not suitable for large extra-bronchial tumours.

Reveiz systematically reviewed 14 randomised controlled trials comparing endobronchial brachytherapy to external beam radiotherapy and other interventions such as chemotherapy and laser.[11] These trials had small study populations and were heterogeneous with regard to the range of radiotherapy doses and other treatment modalities. They found that external beam radiotherapy had greater palliative efficacy compared with brachytherapy alone. There was no evidence to support a combination of external beam radiotherapy and brachytherapy over external beam radiotherapy alone. Endobronchial brachytherapy should be reserved for select patients who have previously been treated with external beam radiotherapy and have symptomatic recurrent central endobronchial tumour.

There has been one randomised trial evaluating the dose of endobronchial brachytherapy.[12] 142 patients with centrally located malignant tumours were randomised between 4 fractions of 3.8Gy and 2 fractions of 7.2Gy. Local tumour response as assessed at bronchoscopy was significantly greater for the 2 fraction course. There was no significant difference in fatal haemoptysis or survival.

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Evidence summary and recommendations

Evidence summary Level References
Palliative thoracic radiotherapy can relieve symptoms due to primary lung cancer.

Last reviewed December 2015

I [2]
Lower doses of radiotherapy (10Gy in 1 fraction, 17Gy in 2 fractions) are equivalent to higher doses (20Gy in 5 fractions, 30-39Gy in 10-13 fractions and higher) in terms of symptom palliation.

Last reviewed December 2015

I [2]
In patients with good performance status, higher doses of radiotherapy (20Gy in 5 fractions, 30-39Gy in 10-13 fractions) give a modest survival benefit of approximately 5% at one year and 3% at two years and are associated with longer duration of symptom palliation.

Last reviewed December 2015

I, II [2], [7]
Acute toxicity of palliative thoracic radiotherapy is generally mild. Higher doses of radiotherapy are associated with greater acute toxicity particularly oesophagitis.

Last reviewed December 2015

I [2]
Patients with minimal thoracic symptoms do not benefit from immediate thoracic radiotherapy.

Last reviewed December 2015

II [10]
External beam radiotherapy is more effective for palliation of thoracic symptoms than endobronchial brachytherapy. There is no therapeutic advantage in giving both these treatment modalities over external beam radiotherapy alone.

Last reviewed December 2015

I [11]
Evidence-based recommendationQuestion mark transparent.png Grade
Patients who have thoracic symptoms of moderate severity from their primary lung cancer should be offered a course of palliative external beam thoracic radiotherapy.

Last reviewed December 2015

A
Evidence-based recommendationQuestion mark transparent.png Grade
Patients who are of poor performance status should be treated with lower doses of palliative thoracic radiotherapy (8-10Gy in 1 fraction, 16-17Gy in 2 fractions) as this provides equivalent symptomatic response to higher doses of radiotherapy (20Gy in 5 fractions, 30-39Gy in 10-13 fractions).

Last reviewed December 2015

A
Evidence-based recommendationQuestion mark transparent.png Grade
Patients who are of good performance status should be treated with higher doses (20Gy in 5 fractions, 30-39Gy in 10-13 fractions) of palliative thoracic radiotherapy in order to maximise duration of palliation and survival.

Last reviewed December 2015

B


Practice pointQuestion mark transparent.png

Patients with a centrally located lung cancer who are at risk of major airway obstruction should be considered for palliative thoracic radiotherapy, even in the absence of symptoms.
Last reviewed December 2015

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References

  1. van den Hout WB, Kramer GW, Noordijk EM, Leer JW. Cost-utility analysis of short- versus long-course palliative radiotherapy in patients with non-small-cell lung cancer. J Natl Cancer Inst 2006 Dec 20;98(24):1786-94 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17179480.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Stevens R, Macbeth F, Toy E, Coles B, Lester JF. Palliative radiotherapy regimens for patients with thoracic symptoms from non-small cell lung cancer. Cochrane Database Syst Rev 2015 Jan 1;1:CD002143 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25553505.
  3. 3.0 3.1 3.2 3.3 Medical Research Council Lung Cancer Working Party.. Inoperable non-small-cell lung cancer (NSCLC): a Medical Research Council randomised trial of palliative radiotherapy with two fractions or ten fractions. Report to the Medical Research Council by its Lung Cancer Working Party. Br J Cancer 1991;63(2):265-270. Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1705140.
  4. 4.0 4.1 4.2 4.3 Medical Research Council Lung Cancer Working Party.. A Medical Research Council (MRC) randomised trial of palliative radiotherapy with two fractions or a single fraction in patients with inoperable non-small-cell lung cancer (NSCLC) and poor performance status. Medical Research Council Lung Cancer Working Party. Br J Cancer 1992;65(6):934-941. Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1377484.
  5. 5.0 5.1 5.2 Macbeth FR, Bolger JJ, Hopwood P, Bleehen NM, Cartmell J, Girling DJ, et al. Randomized trial of palliative two-fraction versus more intensive 13-fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status. Medical Research Council Lung Cancer Working Party. Clin Oncol (R Coll Radiol) 1996;8(3):167-75 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8814371.
  6. Sundstrøm S, Bremnes R, Aasebø U, Aamdal S, Hatlevoll R, Brunsvig P, et al. Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 2004 Mar 1;22(5):801-10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14990635.
  7. 7.0 7.1 7.2 7.3 Kramer GW, Wanders SL, Noordijk EM, Vonk EJ, van Houwelingen HC, van den Hout WB, et al. Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol 2005 May 1;23(13):2962-70 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15860852.
  8. 8.0 8.1 8.2 Bezjak A, Dixon P, Brundage M, Tu D, Palmer MJ, Blood P, et al. Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 2002 Nov 1;54(3):719-28 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12377323.
  9. Macbeth FR, Wheldon TE, Girling DJ, Stephens RJ, Machin D, Bleehen NM, et al. Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The Medical Research Council Lung Cancer Working Party. Clin Oncol (R Coll Radiol) 1996;8(3):176-81 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8814372.
  10. 10.0 10.1 Falk SJ, Girling DJ, White RJ, Hopwood P, Harvey A, Qian W, et al. Immediate versus delayed palliative thoracic radiotherapy in patients with unresectable locally advanced non-small cell lung cancer and minimal thoracic symptoms: randomised controlled trial. BMJ 2002 Aug 31;325(7362):465 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12202326.
  11. 11.0 11.1 Reveiz L, Rueda JR, Cardona AF. Palliative endobronchial brachytherapy for non-small cell lung cancer. Cochrane Database Syst Rev 2012 Dec 12;12:CD004284 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23235606.
  12. Niemoeller OM, Pöllinger B, Niyazi M, Corradini S, Manapov F, Belka C, et al. Mature results of a randomized trial comparing two fractionation schedules of high dose rate endoluminal brachytherapy for the treatment of endobronchial tumors. Radiat Oncol 2013 Jan 7;8(1):8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23289530.

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Appendices

Further resources

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