Radiotherapy in the management of advanced melanoma patient with brain metastases

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Evidence

When is radiotherapy indicated for patients with distant brain metastases?

Systematic review evidence

Clinical trials evaluating the use of radiotherapy (RT) in the management of metastatic malignancy have predominantly included multiple histological tumour types, including melanoma. The systematic review for these guidelines focused on studies that included patients with melanoma only.

Brain metastasis

The role of RT alone or in combination with other modalities in the management of brain metastases is complex, in view of the recent advances in systemic therapies that are effective in patients with brain metastases. Multidisciplinary team input is therefore required (see Treatment approaches to brain metastases).

There have been numerous studies on the role of RT in the management of melanoma brain metastases. Whilst there have been several randomised trials evaluating the role of stereotactic radiosurgery (SRS) and whole brain RT (WBRT) in the management of brain metastases, the number of patients with melanoma brain metastases in these studies was generally small. The systematic review focused on studies that included melanoma only (or mainly melanoma). The studies were all non-randomised and mostly retrospective series. For melanoma patients with single or a small number of brain metastases, SRS provides a high rate of local control, as for other malignancies.[1] At 6 and 12 months, the local control rates are about 80% and 60%, respectively, and the overall survival (OS) rates 70% and 15%.[2][3][4] The dose of SRS is dependent on the size of the metastasis and should be prescribed as per published protocols.[5] The addition of WBRT after SRS may improve intracranial control, but with no OS benefit. For patients with multiple brain metastases, WBRT may provide some benefit but its role has not been directly compared with systemic therapy or supportive care alone.

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Non-systematic review evidence

Adjuvant whole brain radiotherapy after local treatment of single or oligo brain metastases

A total of four randomised trials reported results for selected patients with up to four brain metastases (any histologies) treated with SRS alone versus WBRT and SRS.[6][7][8][9] The addition of WBRT to SRS significantly improved local control of the SRS-treated lesions as well as distant brain control. However, WBRT did not provide an OS benefit and was associated with a decline in neurocognitive function. In a randomised, phase III trial of SRS to the surgical cavity versus WBRT in patients with one resected brain metastasis, SRS was associated with a significantly shorter time to intracranial progression than WBRT (6.4 months vs 27.5 months, HR 2.45, p<0.001).[10] The cognitive deterioration-free survival was better with SRS to the cavity (3.7 months vs 3.0 months, p<0.001) and there was no difference in the OS between the 2 groups. Hippocampal avoidance WBRT using intensity modulated RT has been shown in one phase II study to lessen the effect of WBRT on neurocognitive function.[11]

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Adjuvant stereotactic radiosurgery to surgical cavity

In a randomised, phase III study it was shown that the addition of a SRS boost to the surgical cavity significantly improved the 12-month freedom from local recurrence rate compared with observation in patients with 1–3 completely resected brain metastases (72% vs 43%, HR=0.46, p<0.015).[12] The benefit was seen in all histologies including melanoma. There was no difference in OS between the two groups. Multiple retrospective studies of SRS to the surgical cavity after resection of melanoma metastases have shown local control rates exceeding 70%, which is similar to surgery with postoperative WBRT.[13][14]

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Evidence summary and recommendations

Evidence summary Level References
Stereotactic radiosurgery (SRS) for melanoma brain metastases achieves a high rate of local control. III-2 [1], [3], [4], [15], [16]
Evidence-based recommendationQuestion mark transparent.png Grade
Stereotactic radiosurgery (SRS) may be considered for patients with single or a small number of brain metastases to maximise local control.
C


Evidence-based recommendationQuestion mark transparent.png Grade
For patients with multiple brain metastases, whole brain radiation therapy may provide some palliative benefits.
C



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There are no randomised controlled trials comparing surgery with SRS for local control and quality of life. Management of brain metastases should be discussed by a multidisciplinary team. Surgical resection of brain metastases is recommended for metastases in non-eloquent areas ≥1cm or symptomatic metastases. Stereotactic radiosurgery is recommended for small (<1cm, but maximum size to 3cm) or multiple metastases.


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All melanoma patients with brain metastases should be reviewed by a multidisciplinary team to ensure optimal combination and sequencing of systemic drug therapy, surgery and RT treatments.


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Patients with single or a small number of brain metastases should be given the opportunity to discuss the advantages and disadvantages of adjuvant radiotherapy to the surgical cavity and/or the whole brain after local treatment of the individual metastases.

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References

  1. 1.0 1.1 Nieder C, Grosu AL, Gaspar LE. Stereotactic radiosurgery (SRS) for brain metastases: a systematic review. Radiat Oncol 2014 Jul 12;9:155 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25016309.
  2. Ahmed KA, Abuodeh YA, Echevarria MI, Arrington JA, Stallworth DG, Hogue C, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy. Ann Oncol 2016 Dec;27(12):2288-2294 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27637745.
  3. 3.0 3.1 Bernard ME, Wegner RE, Reineman K, Heron DE, Kirkwood J, Burton SA, et al. Linear accelerator based stereotactic radiosurgery for melanoma brain metastases. J Cancer Res Ther 2012 Apr;8(2):215-21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22842364.
  4. 4.0 4.1 Christ SM, Mahadevan A, Floyd SR, Lam FC, Chen CC, Wong ET, et al. Stereotactic radiosurgery for brain metastases from malignant melanoma. Surg Neurol Int 2015;6(Suppl 12):S355-65 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26392919.
  5. Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004 May 22;363(9422):1665-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15158627.
  6. Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006 Jun 7;295(21):2483-91 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16757720.
  7. Brown PD, Jaeckle K, Ballman KV, Farace E, Cerhan JH, Anderson SK, et al. Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. JAMA 2016 Jul 26;316(4):401-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27458945.
  8. Chang WS, Kim HY, Chang JW, Park YG, Chang JH. Analysis of radiosurgical results in patients with brain metastases according to the number of brain lesions: is stereotactic radiosurgery effective for multiple brain metastases? J Neurosurg 2010 Dec;113 Suppl:73-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21121789.
  9. Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 2011 Jan 10;29(2):134-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21041710.
  10. Brown PD, Ballman KV, Cerhan JH, Anderson SK, Carrero XW, Whitton AC, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 2017 Jul 4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28687377.
  11. Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol 2014 Dec 1;32(34):3810-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25349290.
  12. Mahajan A, Ahmed S, McAleer MF, Weinberg JS, Li J, Brown P, et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol 2017 Jul 4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28687375.
  13. Choi CY, Chang SD, Gibbs IC, Adler JR, Harsh GR 4th, Lieberson RE, et al. Stereotactic radiosurgery of the postoperative resection cavity for brain metastases: prospective evaluation of target margin on tumor control. Int J Radiat Oncol Biol Phys 2012 Oct 1;84(2):336-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22652105.
  14. Ling DC, Vargo JA, Wegner RE, Flickinger JC, Burton SA, Engh J, et al. Postoperative stereotactic radiosurgery to the resection cavity for large brain metastases: clinical outcomes, predictors of intracranial failure, and implications for optimal patient selection. Neurosurgery 2015 Feb;76(2):150-6; discussion 156-7; quiz 157 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25549189.
  15. Rades D, Sehmisch L, Huttenlocher S, Blank O, Hornung D, Terheyden P, et al. Radiosurgery alone for 1-3 newly-diagnosed brain metastases from melanoma: impact of dose on treatment outcomes. Anticancer Res 2014 Sep;34(9):5079-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25202094.
  16. Bates JE, Youn P, Usuki KY, Walter KA, Huggins CF, Okunieff P, et al. Brain metastasis from melanoma: the prognostic value of varying sites of extracranial disease. J Neurooncol 2015 Nov;125(2):411-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26354772.

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