What is the clinical benefit of radiotherapy to the bone for metastatic disease from NSCLC?

From Cancer Guidelines Wiki

Introduction

Bone metastases are a common site of metastasis from lung cancer. Pain is a presenting symptom in many cases.[1] Other potential complications include pathologic fracture, nerve root compression or spinal cord compression.

The risk of pathological fracture should be assessed before prescribing palliative radiotherapy. The Mirel score[2] has been suggested as a risk assessment tool, with high sensitivity but low specificity.[3] Mirel’s recommendations are to proceed with radiotherapy for scores ≤7 and to refer for prophylactic fixation for scores ≥9. Clinical judgement should be used for a score of 8. Patient factors such as performance status, metastatic tumour burden, suitability for systemic therapies and fitness for anaesthetic should also be taken into account. See Table 1. Scoring System from Mirels et al 1989.

Back to top

Radiotherapy dose and fractionation for palliative radiotherapy to bony metastases

Cost-effectiveness of radiotherapy

Cost-effectiveness studies of randomised controlled trials from the Netherlands,[4][5] USA[6] and Australia[7] also show a cost saving for single fraction radiotherapy, even when accounting for the higher rate of retreatment. Konski et al[6] calculated an incremental cost effectiveness ratio US$6973/QALY when comparing 8Gy in 1 fraction to 30Gy in 10 fraction. Australian data show a cost saving of between AU$795 -$1468 for single fraction radiotherapy compared to five fractions.[7]

Back to top

Clinical benefit of palliative radiotherapy

There are no randomised trials of radiotherapy compared to best supportive care and analgesia alone. However many trials of radiotherapy fractionation in patients with painful bony metastases (not at risk of pathological fracture) show a clear palliative benefit from radiotherapy.[8][9][10]

There have been three contemporary meta-analyses comparing the effect of single fraction radiotherapy (commonly 8Gy) to fractionated regimens (commonly 20-25Gy/5 fractions, 24Gy/6 fractions, 30Gy/10 fractions).[8][9][10] These included bony metastases from all primary sites. Response was measured using a number of different scales but essentially was pain reduction by at least one category or 50%. All meta-analyses have shown no difference in pain response by radiotherapy fractionation. Higher biological doses are not associated with greater pain relief.[10]

The most recent meta-analysis of 5000 patients showed an overall response rate of 58% with single fraction and 59% with fractionated radiotherapy.[8] Complete response rates were 23% and 24% respectively. Single fraction was associated with a slightly higher rate of pathologic fracture (3.2% versus 2.8%) and spinal cord compression (2.8% versus 1.9%) but this was not statistically significant. Retreatment however, was significantly greater in the single fraction arm, 20% versus 8%.

Steenland et al performed the largest randomised trial of radiotherapy in patients with bony metastases. 1171 patients were randomised to 8Gy in 1 fraction or 24Gy in 6 fractions.[4] 25% of patients had lung cancer. Response was defined as a reduction of 2 points from the initial pain score. Overall response rates were 71% for single fraction and 73% for fracionated radiotherapy and complete response rates were 14% in each arm.[4][11] Patients receiving single fraction were significantly more likely to receive retreatment (25% versus 7%) and sustain a pathological fracture (4% versus 2%).

In lung cancer, the overall response rate for pain was 58% for single fraction and 62% for multiple fractions. The mean time to response was three weeks and mean duration of response was 11 weeks in lung cancer. Retreatment in lung cancer patients was 32% for the single fraction arm and 5% for the fractionated arm.

There has been one randomised trial which compared 8Gy in 1 fraction to 4Gy in 1 fraction.[12] Lung cancer patients comprised 35% of the study population. The actuarial response rate at 4 weeks was significantly better for the 8Gy than the 4Gy arm, 80% vs 68% respectively.This difference remained significant up to a year after treatment. Twice as many patients in the 4Gy arm needed retreatment.

The majority of trials have included patients with painful bony metastases. There is one trial that specifically recruited patients with neuropathic pain from bony metastases and showed similar efficacy between 8Gy in 1 fraction and 20Gy in 5 fractions.[13] There was no difference in the incidence of spinal cord or cauda equina compression.

Back to top

Toxicity

There is no difference in acute toxicity or quality of life between single fraction and fractionated radiotherapy treatment for painful bony metastases.[8][10][4]

Back to top

Adjuvant radiotherapy

There are no prospective trials that have evaluated the role of adjuvant radiotherapy following surgery for fixation of a pathological or impending pathological fracture. Townsend et al[14] performed a retrospective analysis of 64 orthopaedic procedures where surgery alone was performed in 29 and adjuvant radiotherapy was given in 35. The median dose was 30Gy in 10 fractions. The proportion of patients who were ambulant at any time post-operatively was 53% in the radiation group compared with 12% in the surgery only group. The need for a second orthopaedic procedure to the same site was reduced from 15% to 3%. On multivariate analysis, adjuvant radiotherapy was the only prognostic factor for improved functional status after surgery.

The trials of radiotherapy fractionation are not necessarily applicable to the post-operative setting. If bone healing is the endpoint, a multifraction schedule (30Gy in 10 fractions) has been shown to have significantly higher rates of recalcification than single fraction (8Gy in 1 fraction).[15]

Back to top

Evidence summary and recommendations

Evidence summary Level References
Palliative radiotherapy can relieve pain from bony metastases.

Last reviewed December 2015

I [8], [9], [10]
A single 8Gy fraction is superior to a single 4Gy fraction of radiotherapy in providing pain relief.

Last reviewed December 2015

II [12]
A single 8Gy fraction of radiotherapy provides equivalent pain relief to a fractionated course of radiotherapy to higher doses.

Last reviewed December 2015

I [8], [9], [10]
A single 8Gy fraction of radiotherapy is associated with higher rates of radiotherapy retreatment.

Last reviewed December 2015

I [8], [9], [10]
A single 8Gy fraction of radiotherapy is associated with higher rates of pathological fracture, although the absolute difference is less than 1-2%.

Last reviewed December 2015

I, II [8], [4]
There is no difference in toxicity and quality of life between single fraction radiotherapy and a fractionated course

Last reviewed December 2015

I, II [8], [4]
Adjuvant radiotherapy after fixation of a pathological fracture can improve functional status.

Last reviewed December 2015

III-3 [14]
Evidence-based recommendationQuestion mark transparent.png Grade
Patients who have pain from bony metastases (not at risk of pathological fracture) should be offered palliative radiotherapy.

Last reviewed December 2015

A
Evidence-based recommendationQuestion mark transparent.png Grade
A single fraction of 8Gy is recommended if the clinical endpoint is pain relief.

Last reviewed December 2015

A
Evidence-based recommendationQuestion mark transparent.png Grade
Patients who have had orthopaedic fixation of a pathological fracture may be considered for adjuvant radiotherapy.

Last reviewed December 2015

C


Practice pointQuestion mark transparent.png

Patients at risk of pathological fracture should be referred for prophylactic fixation prior to radiotherapy. The Mirel score is a useful tool in assessing this but patient factors should also be taken into account.
Last reviewed December 2015

Back to top

References

  1. Janjan NA, Lutz ST, Bedwinek JM et al.. American College of Radiology ACR Appropriateness Criteria. Bone Metastases. 2008 Abstract available at http://www.acr.org/SecondaryMainMenuCategories/quality_safety/app_criteria/pdf/ExpertPanelonRadiationOncologyBoneMETASTASESWorkGroup/BoneMETASTASESUpdateinProgressDoc1.aspx.
  2. Mirels H. Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures. Clin Orthop Relat Res 1989 Dec;(249):256-64 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2684463.
  3. Jawad MU, Scully SP. In brief: classifications in brief: Mirels' classification: metastatic disease in long bones and impending pathologic fracture. Clin Orthop Relat Res 2010 Oct;468(10):2825-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20352387.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 Steenland E, Leer JW, van Houwelingen H, Post WJ, van den Hout WB, Kievit J, et al. The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study. Radiother Oncol 1999 Aug;52(2):101-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10577695.
  5. van den Hout WB, van der Linden YM, Steenland E, Wiggenraad RG, Kievit J, de Haes H, et al. Single- versus multiple-fraction radiotherapy in patients with painful bone metastases: cost-utility analysis based on a randomized trial. J Natl Cancer Inst 2003 Feb 5;95(3):222-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12569144.
  6. 6.0 6.1 Konski A, James J, Hartsell W, Leibenhaut MH, Janjan N, Curran W, et al. Economic analysis of radiation therapy oncology group 97-14: multiple versus single fraction radiation treatment of patients with bone metastases. Am J Clin Oncol 2009 Aug;32(4):423-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19546803.
  7. 7.0 7.1 Pollicino CA, Turner SL, Roos DE, O'Brien PC. Costing the components of pain management: analysis of Trans-Tasman Radiation Oncology Group trial (TROG 96.05): one versus five fractions for neuropathic bone pain. Radiother Oncol 2005 Sep;76(3):264-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16153729.
  8. 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 2007 Apr 10;25(11):1423-36 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17416863.
  9. 9.0 9.1 9.2 9.3 9.4 Sze WM, Shelley M, Held I, Mason M. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of the randomised trials. Cochrane Database Syst Rev 2004;(2):CD004721 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15106258.
  10. 10.0 10.1 10.2 10.3 10.4 10.5 10.6 Wu JS, Wong R, Johnston M, Bezjak A, Whelan T, Cancer Care Ontario Practice Guidelines Initiative Supportive Care Group. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 2003 Mar 1;55(3):594-605 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12573746.
  11. van der Linden YM, Lok JJ, Steenland E, Martijn H, van Houwelingen H, Marijnen CA, et al. Single fraction radiotherapy is efficacious: a further analysis of the Dutch Bone Metastasis Study controlling for the influence of retreatment. Int J Radiat Oncol Biol Phys 2004 Jun 1;59(2):528-37 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15145173.
  12. 12.0 12.1 Hoskin P, Rojas A, Fidarova E, Jalali R, Mena Merino A, Poitevin A, et al. IAEA randomised trial of optimal single dose radiotherapy in the treatment of painful bone metastases. Radiother Oncol 2015 Jul;116(1):10-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26026485.
  13. Roos DE, Turner SL, O'Brien PC, Smith JG, Spry NA, Burmeister BH, et al. Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiother Oncol 2005 Apr;75(1):54-63 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15878101.
  14. 14.0 14.1 Townsend PW, Rosenthal HG, Smalley SR, Cozad SC, Hassanein RE. Impact of postoperative radiation therapy and other perioperative factors on outcome after orthopedic stabilization of impending or pathologic fractures due to metastatic disease. J Clin Oncol 1994 Nov;12(11):2345-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7669102.
  15. Koswig S, Budach V. Remineralization and pain relief in bone metastases after after different radiotherapy fractions (10 times 3 Gy vs. 1 time 8 Gy). A prospective study. Strahlenther Onkol 1999 Oct;175(10):500-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10554645.

Back to top

Appendices

Further resources

Back to top