What is the clinical benefit of radiotherapy to the brain for patients with inoperable brain metastases from NSCLC?

From Cancer Guidelines Wiki

Palliative whole brain radiotherapy

Introduction

The brain is a common site of relapse in NSCLC. The risk of developing brain metastases after surgery is 10% for stage I and II NSCLC.[1] Brain relapse is higher in stage III NSCLC ranging from 27%-55% after curative treatment.[2][3][4] Brain metastases are usually symptomatic with symptoms from surrounding oedema (headache, nausea, vomiting) and/or associated neurological deficits.

Important factors to consider when determining the management of patients with brain metastases are:

  • Whether the metastases are solitary or multiple.
  • Whether the primary and/or extra-cranial disease is controlled or uncontrolled.
  • What the patient’s performance status and neurological status is.
  • Patient comorbidities that may impact on fitness for a particular treatment.

There are two prognostic models which may help guide treatment in patients with brain metastases.The RTOG has divided patients with brain metastases, from all primary sites, into three prognostic groups based on recursive partitioning analysis (RPA).[5]

  • RPA Class I – Age <65, Karnofsky performance index ≥=70, controlled primary cancer, no extra-cranial metastases. Median survival 7.1 months.
  • RPA Class II – All other patients not in Class I or II. Median survival 4.2 months.
  • RPA Class III – Karnofsky performance status < 70. Median survival 2.3 months.

Sperduto et al have devised a model specific to NSCLC which includes the variables of age, Karnofsky performance status (KPS), extra-cranial disease and the number of brain metastases.[6] See Figure 1. Non-small-cell and small-cell lung cancer Graded Prognostic Assessment (GPA) worksheet below.

Sperduto Figure 1 extract.PNG

Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved. Sperduto, PW et al: J Clin Oncol 30. (4), 2012: 419-25.

These prognostic models should be used to help guide treatment recommendations.

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Radiotherapy dose and fractionation for whole brain radiotherapy

Clinical benefit of whole brain radiotherapy in patients with brain metastases

There is only one randomised study which has compared WBRT plus best supportive care including steroids (BSC) compared to BSC alone for patients with brain metastases from NSCLC in whom the attending clinician was uncertain of the value of WBRT.[7] An interim analysis after randomisation of 151 patients, has shown no significant difference in survival (49 days in the WBRT group vs 51 days in the BSC BSC group) or quality of life. The final results of this trial have been presented in abstract form.[8] The study population of 538 patients was representative of the clinic population with a median age of 66 years, poor performance status (KPS<70) in 38% and the presence of extracranial metastases in 54%. There was no significant difference in median survival (65 days WBRT vs 57 days BSC), quality of life or steroid use between the groups.

Pease et al also conducted a systematic review which included non-randomised trials.[9] The median survival of patients undergoing radiotherapy was 3.2-5.8 months. Historical data shows a median survival of 2-3 months with best supportive care and steroids. They concluded that whole brain radiotherapy may have a survival gain of up to three months in patients of good performance status. This has to be interpreted with caution due to the non-randomised nature of the comparisons.

Tsao et al conducted a systematic review of 39 randomised controlled trials of whole brain radiotherapy in 10835 participants.[10] These trials included patients with brain metastases from different primary cancers, although in the majority of trials over half the participants had lung cancer. Compared to 30Gy in 10 fractions, higher doses and longer fractionation schemes resulted in similar survival, symptom control and improvement in neurological function.

There have been many randomised trials of different radiotherapy dose and fractionation schemes for whole brain radiotherapy.[11][12][13][14][15][16] These trials are heterogenous in nature. Older studies included patients with symptoms of brain metastases and confirmation based on EEG or radioisotope brain scans rather than CT or MRI scans which have been used in contemporary studies. 56-80% of patients in these studies had metastatic lung cancer. Trials included patients with both solitary and multiple brain metastases. The patients had a range of performance status and neurological function.

The largest randomised trial was performed by the RTOG.[11] Patients were divided patients according to their neurological function (NF). NF I patients had minor neurological findings and could function normally, NF II patients were able to carry out normal activities with minimal difficulties, NF III patients were seriously limited in performing normal activities, required nursing care or hospitalisation, and were confined to a bed or wheelchair and NF IV patients required hospitalisation, constant nursing care and may have been unable to communicate or in a coma. Overall, neurological function improved in 47-52% of cases. Lung cancer patients who were NF II showed improvement in 37-38% of cases, and those in NF III improved in 66-72% of cases. The median time to neurological improvement was three weeks for NF II and one to two weeks for NF III patients. The median duration of response for all patients was 10-12 weeks. Median survival was 15-18 weeks. With respect to all outcome measures there was no advantage to doses higher than 20Gy in 5 fractions.

Other authors have examined a more favourable subgroup of patients by limiting trial entry to those with good performance status, good neurological function and/or controlled primary cancer or no extra-cranial metastases.[17][13][14][15][16] Gelber evaluated the outcomes of favourable patients (ambulatory, with absent primary or no extracranial metastases) in the RTOG trial. These patients had a median survival of 25 weeks compared with 12 weeks for other patients, however there was no effect of radiotherapy fractionation on survival. They recommended 20Gy in 5 fractions for these patients. Other trials have used 30Gy in 10 fractions as a standard arm and have shown no improvement in outcomes with higher doses of radiotherapy.[13][14][16] Priestman compared 30Gy in 10 fractions with 12Gy in 2 fractions and found that median survival was better in the 30Gy arm (median 77d vs 84d, p=0.04).[15]

The response of specific symptoms to radiotherapy was headache 82-98%, nausea and vomiting 77--100%, motor loss 61-78%, impaired cognitive function 53-87%, cerebellar dysfunction 64-75%, cranial nerve palsy 59-71%, sensory loss 77%, cerebellar symptoms 59-77% and convulsions 76-95%.[11][15][13] The percentage of survival time spent in an improved or stable neurological state was 69-75% for ambulatory patients and 82-86% for non-ambulatory patients.[11]

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Toxicity

Toxicity was poorly reported in most trials. Many patients develop temporary alopecia.[15] Acute and late Grade 2 toxicities are seen in approximately 20 % of patients. Severe toxicities (Grade 3 and higher) are seen in 2% of cases, both in the acute and late setting.[16]

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Evidence summary and recommendations

Evidence summary Level References
Whole brain radiotherapy can palliate symptoms from brain metastases.

Last reviewed December 2015

I [10]
Radiotherapy doses of 20Gy in 5 fractions or 30Gy in 10 fractions are equivalent to higher doses in terms of survival, palliation of symptoms and neurological function.

Last reviewed December 2015

I, II [11], [10]
In patients with multiple brain metastases who are of good performance status, whole brain radiotherapy may improve survival compared with best supportive care.

Last reviewed December 2015

III-3 [9]
Patient age, performance status, status of extra-cranial disease and number of brain metastases are strong prognostic factors for survival.

Last reviewed December 2015

II, IV [5], [6]
In patients with adverse prognostic factors for whom the clinician is uncertain of the value of whole brain radiotherapy, the use of best supportive care and steroids results in similar overall survival and quality adjusted survival compared with whole brain radiotherapy.

Last reviewed December 2015

II [7]
Evidence-based recommendationQuestion mark transparent.png Grade
Patients with multiple brain metastases from lung cancer who have good prognostic factors, based on prognostic models, should be considered for whole brain radiotherapy.

Last reviewed December 2015

A
Evidence-based recommendationQuestion mark transparent.png Grade
For patients with multiple metastases a dose of 20Gy in 5 fractions or 30Gy in 10 fractions is adequate for palliation of symptoms and improvement in neurological function.

Last reviewed December 2015

B
Evidence-based recommendationQuestion mark transparent.png Grade
Patients with multiple brain metastases from lung cancer who have adverse prognostic factors, based on prognostic models, should be considered for best supportive care including steroids.

Last reviewed December 2015

B

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References

  1. Hubbs JL, Boyd JA, Hollis D, Chino JP, Saynak M, Kelsey CR. Factors associated with the development of brain metastases: analysis of 975 patients with early stage nonsmall cell lung cancer. Cancer 2010 Nov 1;116(21):5038-46 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20629035.
  2. Gaspar LE, Chansky K, Albain KS, Vallieres E, Rusch V, Crowley JJ, et al. Time from treatment to subsequent diagnosis of brain metastases in stage III non-small-cell lung cancer: a retrospective review by the Southwest Oncology Group. J Clin Oncol 2005 May 1;23(13):2955-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15860851.
  3. Germain F, Wai ES, Berthelet E, Truong PT, Lesperance M. Brain metastasis is an early manifestation of distant failure in stage III nonsmall cell lung cancer patients treated with radical chemoradiation therapy. Am J Clin Oncol 2008 Dec;31(6):561-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19060588.
  4. Chen AM, Jahan TM, Jablons DM, Garcia J, Larson DA. Risk of cerebral metastases and neurological death after pathological complete response to neoadjuvant therapy for locally advanced nonsmall-cell lung cancer: clinical implications for the subsequent management of the brain. Cancer 2007 Apr 15;109(8):1668-75 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17342770.
  5. 5.0 5.1 Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997 Mar 1;37(4):745-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9128946.
  6. 6.0 6.1 Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol 2012 Feb 1;30(4):419-25 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22203767.
  7. 7.0 7.1 Langley RE, Stephens RJ, Nankivell M, Pugh C, Moore B, Navani N, et al. Interim data from the Medical Research Council QUARTZ Trial: does whole brain radiotherapy affect the survival and quality of life of patients with brain metastases from non-small cell lung cancer? Clin Oncol (R Coll Radiol) 2013 Mar;25(3):e23-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23211715.
  8. Mulvenna PM, Nankivell MG, Barton R, Faivre-Finn C, Wilson P, Moore B, et al. Whole brain radiotherapy for brain metastases from non-small lung cancer: Quality of life (QoL) and overall survival (OS) results from the UK Medical Research Council QUARTZ randomised clinical trial (ISRCTN 3826061). J Clin Oncol 2015;33(suppl; abstr 8005) Abstract available at http://meetinglibrary.asco.org/content/149588-156.
  9. 9.0 9.1 Pease NJ, Edwards A, Moss LJ. Effectiveness of whole brain radiotherapy in the treatment of brain metastases: a systematic review. Palliat Med 2005 Jun;19(4):288-99 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15984501.
  10. 10.0 10.1 10.2 Tsao MN, Lloyd N, Wong RK, Chow E, Rakovitch E, Laperriere N, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 2012 Apr 18;4:CD003869 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22513917.
  11. 11.0 11.1 11.2 11.3 11.4 Borgelt B, Gelber R, Kramer S, Brady LW, Chang CH, Davis LW, et al. The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980 Jan;6(1):1-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/6154024.
  12. Haie-Meder C, Pellae-Cosset B, Laplanche A, Lagrange JL, Tuchais C, Nogues C, et al. Results of a randomized clinical trial comparing two radiation schedules in the palliative treatment of brain metastases. Radiother Oncol 1993 Feb;26(2):111-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7681997.
  13. 13.0 13.1 13.2 13.3 Kurtz JM, Gelber R, Brady LW, Carella RJ, Cooper JS. The palliation of brain metastases in a favorable patient population: a randomized clinical trial by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1981 Jul;7(7):891-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/6171553.
  14. 14.0 14.1 14.2 Komarnicky LT, Phillips TL, Martz K, Asbell S, Isaacson S, Urtasun R. A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases (RTOG-7916). Int J Radiat Oncol Biol Phys 1991 Jan;20(1):53-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1993631.
  15. 15.0 15.1 15.2 15.3 15.4 Priestman TJ, Dunn J, Brada M, Rampling R, Baker PG. Final results of the Royal College of Radiologists' trial comparing two different radiotherapy schedules in the treatment of cerebral metastases. Clin Oncol (R Coll Radiol) 1996;8(5):308-15 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8934050.
  16. 16.0 16.1 16.2 16.3 Murray KJ, Scott C, Greenberg HM, Emami B, Seider M, Vora NL, et al. A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiat Oncol Biol Phys 1997 Oct 1;39(3):571-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9336134.
  17. Gelber RD, Larson M, Borgelt BB, Kramer S. Equivalence of radiation schedules for the palliative treatment of brain metastases in patients with favorable prognosis. Cancer 1981 Oct 15;48(8):1749-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/6169424.

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Appendices

Further resources

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