For patients with distant metastases (other than brain metastases), when is radiotherapy indicated?

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Introduction

Radiation therapy (RT) is an important cancer treatment modality that delivers high energy radiation to kill malignant cells by DNA damage. It is a useful treatment option for patients with metastatic melanoma. RT can provide beneficial palliation for metastatic disease such as cerebral metastases, bone pain, spinal cord compression and symptomatic soft tissue metastases. There is a general perception that melanoma is resistant to radiation based on in vitro data. However randomized clinical trials of fractionated RT have not demonstrated better outcomes with large fraction sizes and RT has been shown to be effective in controlling microscopic disease.[1][2]

Recent advances in RT treatment techniques have led to improved precision in treatment delivery, allowing higher dose within the target volume while sparing the surrounding normal tissue. Stereotactic radiosurgery (SRS) is the delivery of a single, very high dose of radiation using 3-dimensional coordinate system to a defined target and it is usually used in the treatment of brain metastasis. Stereotactic body RT (SBRT) uses similar setup as SRS but with hypofractionated (high dose per fraction in a few fractions) to any part of the body. Both deliver high, ablative doses that are effective in the control of metastases.[3]

Systematic review evidence

Clinical trials evaluating the use of RT in the management of metastatic malignancy predominantly include multiple histological types, including melanoma. The systematic review focused on studies that included patients with melanoma only.

Brain metastasis

Melanoma has a high propensity to metastasize to the brain. Up to 50% of patients with stage 4 disease will develop brain metastases during the course of their illness.[4] Control of brain metastasis is an important since progression of brain metastases often leads to deterioration in function and quality of life and/or neurologic death. The role of RT alone or in combination with other modalities in the management of brain metastases is complex with the recent advances in systemic therapies that are effective in brain metastasis. Multidisciplinary team input is therefore required (see Is multidisciplinary care of value in the management of melanoma?)

There have been numerous studies on the role of RT in the management of melanoma brain metastasis. Whilst there have been several randomized studies on the role of SRS and whole brain RT (WBRT) in the management of brain metastasis, the number of patients with melanoma brain metastasis in these studies was generally small. The systematic review focused on studies included melanoma only (or mainly melanoma).The studies were all non-randomised, mostly retrospective series. For patients with single or a small number of brain metastases, SRS provides high local control rate similarly to other malignancies.[5] At 6 and 12 months, the local control is about 80% and 60% and the overall survival is 70% and 15%.[6][7][8] The dose of SRS is dependent on the size of the metastases and should be prescribed as per published protocol.[9] The addition of WBRT after SRS may improve the intracranial control with no overall survival 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.

Evidence summary and recommendations

Evidence summary Level References
Stereotactic radiosurgery (SRS) to melanoma brain metastases achieves a high rate of local control. III-2 [5], [7], [8], [10], [11]
Evidence-based recommendationQuestion mark transparent.png Grade
Stereotactic radiosurgery (SRS) should 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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All melanoma patients with distant metastases should be reviewed at a multidisciplinary team meeting to ensure optimal drug, surgery and RT treatment combination.

Non-systematic review evidence

Adjuvant WBRT after local treatment of single or oligo brain metastases

A total of four randomised trials reported on selected patients with up to 4 brain metastases (any histologies) treated with SRS alone versus WBRT and SRS.[12][13][14][15] The addition of WBRT when added to SRS significantly improved local control of the SRS treated lesions as well as distant brain control. However WBRT did not provide an overall survival benefit and was associated with a decline in neurocognitive function. In a randomised, phase 3 trial of SRS to surgical cavity vs 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).[16] 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 overall survival between the 2 groups. Hippocampal avoidance WBRT using intensity modulated RT has been shown in one phase 2 study to lessen the effect of WBRT on neurocognitive function.[17]

Adjuvant stereotactic radiosurgery to surgical cavity

A randomised, phase 3 study showed the addition of SRS boost to the surgical cavity significantly improved the 12-month freedom from local recurrence compared with observation in patients with 1-3 completely resected brain metastases (72% vs 43%, HR=0.46, p<0.015).[18] The benefit was seen in all histologies including melanoma. There was no difference in the overall survival between the 2 groups. Multiple retrospective studies of SRS to the surgical cavity after resection of melanoma metastasis have shown local control rates greater than 70 %, which is similar to surgery with postoperative WBRT.[19][20]

Bone pain and spinal cord compression

RT is effective in relieving pain from bony metastasis with complete pain relief in 23% and overall response rate of 60%.[21] A systematic review of 27 randomised trials including a variety of malignancies showed that a single fraction of 8 Gy was as effective as multiple fractions in relieving bone pain. However, patients who received a single fraction of RT were 2.6 times more likely to require retreatment with RT than those treated with multiple fractions of RT.

For patients with spinal cord or cauda equina compression, urgent RT is recommended for those who are not surgical candidates. Improvement in neurologic function is variable, and is dependent on the neurological function prior to treatment.[22]

Skin, soft tissue and lymph node metastases

Skin and soft tissue metastases (including in transit disease), and lymph node metastases can be problematic, causing pain, bleeding or compression of surrounding normal structures. RT frequently provides symptomatic benefit and prolonged local disease control. In a randomised study that examined the effectiveness of two different RT schedules in the treatment of metastatic disease in soft tissue and nodal region showed an overall response rate of 58.7% and complete response rate of 23.8% [2]. This type of treatment is generally well tolerated.

See in-transit metastatic melanoma

Practice points

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


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Patients with painful bone metastasis should be considered for short course of RT for pain relief.


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RT should be considered in patients with problematic skin, soft tissue or nodal metastasis that have not responded to systemic therapy.

Issues requiring more clinical research study

Hippocampal avoidance WBRT: Randomised data are required to quantify the benefit of hippocampal avoidance whole brain radiation therapy in reducing effects on neurocognitive function. Best drug/RT combination and sequencing, response rate and toxicity: Future research should focus on the best combination RT and systemic therapy, especially immunotherapy, to understand the mechanism of synergy if any, the toxicty profile and ultimately to improve outcome.

Conclusions

Since the 2008 guideline was published, there have been major advances in systemic therapy for melanoma. The role of RT in combination with these newer systemic agents in patients with distant metastasis continues to evolve. With the prolongation of survival of patients with stage 4 melanoma, the delivery of RT needs to be carefully tailored to ensure long term symptom control with minimal acute and late toxicities.

References

  1. Henderson MA, Burmeister BH, Ainslie J, Fisher R, Di Iulio J, Smithers BM, et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol 2015 Jul 20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26206146.
  2. 2.0 2.1 Sause WT, Cooper JS, Rush S, Ago CT, Cosmatos D, Coughlin CT, et al. Fraction size in external beam radiation therapy in the treatment of melanoma. Int J Radiat Oncol Biol Phys 1991 Mar;20(3):429-32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1995527.
  3. Franceschini D, Franzese C, De Rose F, Navarria P, D'Agostino GR, Comito T, et al. Role of extracranial stereotactic body radiation therapy in the management of stage IV melanoma. Br J Radiol 2017 Jul 14;:20170257 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28707533.
  4. Chiarion-Sileni V, Guida M, Ridolfi L, Romanini A, Del Bianco P, Pigozzo J, et al. Central nervous system failure in melanoma patients: results of a randomised, multicentre phase 3 study of temozolomide- and dacarbazine- based regimens. Br J Cancer 2011 Jun 7;104(12):1816-21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21610711.
  5. 5.0 5.1 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.
  6. 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.
  7. 7.0 7.1 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.
  8. 8.0 8.1 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. Chow R, Hoskin P, Hollenberg D, Lam M, Dennis K, Lutz S, et al. Efficacy of single fraction conventional radiation therapy for painful uncomplicated bone metastases: a systematic review and meta-analysis. Ann Palliat Med 2017 Apr;6(2):125-142 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28249544.
  22. Freundt K, Meyners T, Bajrovic A, Basic H, Karstens JH, Adamietz IA, et al. Radiotherapy for oligometastatic disease in patients with spinal cord compression (MSCC) from relatively radioresistant tumors. Strahlenther Onkol 2010 Apr;186(4):218-23 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20354660.


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