Is adjuvant radiotherapy of value following resection of involved lymph nodes?

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Introduction

Melanoma has had a reputation as a disease that is more difficult to control with RT than most other histological types. Therefore, the use of adjuvant radiotherapy (RT) following surgery for locally advanced melanoma has not been accepted as standard management in the same manner as other common cancer types. Numerous retrospective studies have addressed this issue in melanoma, with mixed results as to the benefit of adjuvant RT following therapeutic lymph node dissection. It is likely that selection bias and lack of generalisability have contributed to the variability of results. A randomised controlled trial (RCT) has helped to resolve the uncertainty.

Locoregional tumour recurrence is frequently associated with significant morbidity. However, the role of adjuvant RT must be considered in the era of effective systemic therapy, where longer survival is now possible and late complications of treatment may cause considerable morbidity.

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Systematic review evidence

Randomised controlled trial

A single RCT was identified comparing regional lymph node dissection alone with regional lymph node dissection followed by adjuvant RT.[1][2] A total of 217 patients who had undergone complete cervical, axillary or inguinal lymphadenectomy for metastatic melanoma in the regional lymph node basin were randomised to surgery alone (n=108) versus surgery followed by adjuvant radiotherapy (n=109). The criteria for eligibility included the number of involved nodes (any involved parotid node, two involved nodes in cervical or axilla, three involved nodes in groin), the size of involved nodes (≥3 cm in cervical node, ≥4 cm for axillary or inguinal nodes) and extracapsular extension.

Adjuvant RT consisted of a mildly hypofractionated schedule (48 Gray in 20 fractions). The endpoints were lymph-node basin relapse, overall survival, relapse-free survival, late toxicity and quality of life.[1][2]

Results were reported at 3 and 5 years. At 3 years there was a significant reduction in lymph node basin relapse (31% vs 19%, p=0.04) but no difference in overall survival or relapse-free survival.[1] At 5 years the cumulative incidence for isolated lymph node basin relapse as a site of first relapse was 8.3% for adjuvant radiotherapy and 23% for surgery alone (p=0.002).[2] There was no difference in overall survival.[2] Quality of life was the same in both groups, but late toxicity was increased in the adjuvant RT arm, particularly in field fibrosis and leg oedema following inguinal treatment.[2]


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Cohort studies

There were eight retrospective cohort studies identified comparing lymph node dissection alone with adjuvant RT.[3][4][5][6][7][8][9][10] The endpoints were generally the infield recurrence rates and overall survival. All cohort studies suffered from selection bias, as melanomas with high risk features and considered more likely to suffer locoregional relapse were considered for adjuvant RT. Surgical technique and RT doses and schedules varied between studies. The results varied greatly between studies, with conflicting conclusions regarding both the local control and possible survival benefits of adjuvant RT. As a result of these uncertainties, these retrospective cohort studies were disregarded in this guideline.[3][4][5][6][7][8][9][10]

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Evidence summary and recommendations

Evidence summary Level References
Adjuvant RT following therapeutic lymph node dissection decreased the risk of locoregional recurrence but did not improve survival compared with surgery alone. II [1]
Adjuvant RT following therapeutic lymph node dissection increased late toxicity, especially soft tissue fibrosis in the treated lymph node basin and leg oedema after groin irradiation. II [2]
Evidence-based recommendationQuestion mark transparent.png Grade
Adjuvant RT following regional lymph node dissection may be considered following histopathological identification of high risk features if potentially effective systemic therapy is not available.
B



Practice pointQuestion mark transparent.png

Patients at high risk of locoregional recurrence are also at high risk of distant metastases. The decision to recommend adjuvant RT should be made in a multidisciplinary forum where all options for further local and systemic therapy are addressed. In particular, the role of local treatments including adjuvant RT is changing rapidly as effective systemic therapies become available.


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Adjuvant RT may be considered also for (i) positive margins (ii) after therapeutic dissection where further surgical clearance is not feasible (eg parotid) and (iii) further recurrence after surgery.

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References

  1. 1.0 1.1 1.2 1.3 Burmeister BH, Henderson MA, Ainslie J, Fisher R, Di Iulio J, Smithers BM, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol 2012 Jun;13(6):589-97 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22575589.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 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.
  3. 3.0 3.1 Agrawal S, Kane JM 3rd, Guadagnolo BA, Kraybill WG, Ballo MT. The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for clinically advanced, high-risk, lymph node-metastatic melanoma. Cancer 2009 Dec 15;115(24):5836-44 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19701906.
  4. 4.0 4.1 Barbour S, Mark Smithers B, Allan C, Bayley G, Thomas J, Foote M, et al. Patterns of Recurrence in Patients with Stage IIIB/C Cutaneous Melanoma of the Head and Neck Following Surgery With and Without Adjuvant Radiation Therapy: Is Isolated Regional Recurrence Salvageable? Ann Surg Oncol 2015 Jan 13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25582744.
  5. 5.0 5.1 Bibault JE, Dewas S, Mirabel X, Mortier L, Penel N, Vanseymortier L, et al. Adjuvant radiation therapy in metastatic lymph nodes from melanoma. Radiat Oncol 2011 Feb 6;6:12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21294913.
  6. 6.0 6.1 Gojkovič-Horvat A, Jančar B, Blas M, Zumer B, Karner K, Hočevar M, et al. Adjuvant radiotherapy for palpable melanoma metastases to the groin: when to irradiate? Int J Radiat Oncol Biol Phys 2012 May 1;83(1):310-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22035662.
  7. 7.0 7.1 Hamming-Vrieze O, Balm AJ, Heemsbergen WD, Hooft van Huysduynen T, Rasch CR. Regional control of melanoma neck node metastasis after selective neck dissection with or without adjuvant radiotherapy. Arch Otolaryngol Head Neck Surg 2009 Aug;135(8):795-800 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19687401.
  8. 8.0 8.1 Martin RC, Shannon KF, Quinn MJ, Saw RP, Spillane AJ, Stretch JR, et al. The management of cervical lymph nodes in patients with cutaneous melanoma. Ann Surg Oncol 2012 Nov;19(12):3926-32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22669449.
  9. 9.0 9.1 Pinkham MB, Foote MC, Burmeister E, Thomas J, Meakin J, Smithers BM, et al. Stage III melanoma in the axilla: patterns of regional recurrence after surgery with and without adjuvant radiation therapy. Int J Radiat Oncol Biol Phys 2013 Jul 15;86(4):702-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23773393.
  10. 10.0 10.1 Strojan P, Jancar B, Cemazar M, Perme MP, Hocevar M. Melanoma metastases to the neck nodes: role of adjuvant irradiation. Int J Radiat Oncol Biol Phys 2010 Jul 15;77(4):1039-45 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19910139.

Appendices


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