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01-05-2019 | Melanoma | Original Article

Safety assessment of anticancer drugs in association with radiotherapy in metastatic malignant melanoma: a real-life report

Radiation/systemic drug combo in metastatic melanoma

Authors: Emmanuelle Couty, Alexis Vallard, Sandrine Sotton, Sarra Ouni, Max-Adrien Garcia, Sophie Espenel, Chloe Rancoule, Majed Ben Mrad, Anne-Catherine Biron, Jean-Luc Perrot, Julien Langrand-Escure, Nicolas Magné

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2019

Abstract

Purpose

To assess the safety of the association of radiotherapy (RT) and systemic treatments for patients with metastatic malignant melanoma (mMM).

Methods

A retrospective analysis included consecutive patients treated with palliative RT, and at least one line of systemic therapy for mMM between 2001 and 2016. Treatments were defined as sequential or concomitant when RT and the systemic drug were administered, respectively, at more or less than five half-lives from each other.

Results

92 patients were included. They had 110 palliative RT treatments. RT was delivered with a “conventional” chemotherapy (mainly fotemustine and/or dacarbazine) and a “modern” systemic therapy (BRAF inhibitors, association of BRAF and MEK inhibitors, immunotherapy), respectively, in 88 (80%) and 22 (20%) cases. Systemic treatments and RT were mainly concurrently performed (n = 61, 55.5%). Regarding acute grade ≥ 3 toxicity, no difference was reported between sequential and concomitant groups either in the whole cohort (p = 1) or in the subgroup of patients receiving “modern” systemic therapies (p = 1). Acute and late grade ≥ 3 toxicities only occurred with vemurafenib. BRAF inhibitors and RT produced more severe infield adverse events than other associations (p = 0.001) with two deaths.

Conclusion

In our series, compared to sequential administration, concomitant association of systemic anticancer drugs and palliative RT did not increase toxicity in mMM patients. BRAF inhibitors and RT produced severe infield toxicities. Prospective studies are needed to better characterize the toxicity of each association.

Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, Bastholt L, Grob J-J, Malvehy J, Newton-Bishop J, Stratigos AJ, Pehamberger H, Eggermont AM, European Dermatology Forum (EDF) et al (2016) Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline—update 2016. Eur J Cancer Oxf Engl 1990 63:201–217. https://doi.org/10.1016/j.ejca.2016.05.005 CrossRef

Guillot B, Dalac S, Denis MG, Dupuy A, Emile JF, De La Fouchardiere A, Hindie E, Jouary T, Lassau N, Mirabel X, Piperno Neumann S, De Raucourt S, Vanwijck R (2017) French updated recommendations in Stage I to III melanoma treatment and management. J Eur Acad Dermatol Venereol 31:594–602. https://doi.org/10.1111/jdv.14064 CrossRefPubMed

Coit DG, Thompson JA, Algazi A, Andtbacka R, Bichakjian CK, Carson WE, Daniels GA, DiMaio D, Fields RC, Fleming MD, Gastman B, Gonzalez R, Guild V et al (2016) NCCN guidelines insights: melanoma, version 3.2016. J Natl Compr Cancer Netw 14:945–958CrossRef

Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C et al (2016) Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 17:1248–1260. https://doi.org/10.1016/S1470-2045(16)30122-X CrossRefPubMed

Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I et al (2015) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372:30–39. https://doi.org/10.1056/NEJMoa1412690 CrossRefPubMed

Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Chiarion-Sileni V, Lebbe C, Mandalà M et al (2017) Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol 28:1631–1639. https://doi.org/10.1093/annonc/mdx176 CrossRefPubMedPubMedCentral

Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. https://doi.org/10.1056/NEJMoa1200690 CrossRefPubMedPubMedCentral

Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C et al (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330. https://doi.org/10.1056/NEJMoa1412082 CrossRefPubMed

Schachter J, Ribas A, Long GV, Arance A, Grob J-J, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B et al (2017) Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 390:1853–1862. https://doi.org/10.1016/S0140-6736(17)31601-X CrossRefPubMed

10.

Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJM, Lutzky J et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723. https://doi.org/10.1056/NEJMoa1003466 CrossRefPubMedPubMedCentral

11.

Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain J-F, Testori A, Grob J-J, Davidson N, Richards J, Maio M et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526. https://doi.org/10.1056/NEJMoa1104621 CrossRefPubMed

12.

Henderson MA, Burmeister BH, Ainslie J, Fisher R, Di Iulio J, Smithers BM, Hong A, Shannon K, Scolyer RA, Carruthers S, Coventry BJ, Babington S, Duprat J et al (2015) 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 16:1049–1060. https://doi.org/10.1016/S1470-2045(15)00187-4 CrossRefPubMed

13.

Agrawal S, Kane JM, Guadagnolo BA, Kraybill WG, Ballo MT (2009) The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for clinically advanced, high-risk, lymph node-metastatic melanoma. Cancer 115:5836–5844. https://doi.org/10.1002/cncr.24627 CrossRefPubMed

14.

Danish HH, Patel KR, Switchenko JM, Gillespie TW, Jhaveri J, Chowdhary M, Abugideiri M, Delman KA, Lawson DH, Khan MK (2016) The influence of postoperative lymph node radiation therapy on overall survival of patients with stage III melanoma, a National Cancer Database analysis. Melanoma Res 26:595–603. https://doi.org/10.1097/CMR.0000000000000292 CrossRefPubMedPubMedCentral

15.

Thariat J, Kirova Y, Milano G, Mornex F (2014) [Combination of stereotactic irradiation and chemotherapy or targeted therapies: state of the art and preliminary recommendations]. Cancer Radiother 18:270–279. https://doi.org/10.1016/j.canrad.2014.05.007 CrossRefPubMed

16.

Anker CJ, Grossmann KF, Atkins MB, Suneja G, Tarhini AA, Kirkwood JM (2016) Avoiding severe toxicity from combined BRAF inhibitor and radiation treatment: consensus guidelines from the Eastern Cooperative Oncology Group (ECOG). Int J Radiat Oncol Biol Phys 95:632–646. https://doi.org/10.1016/j.ijrobp.2016.01.038 CrossRefPubMedPubMedCentral

17.

Shargel L, Wu-Pong S, Yu ABC (2015) Applied biopharmaceuticals & pharmacokinetics, 7th edn. McGraw Hill Medical

18.

European Medicines Agency (EMA); Find Medicines. Human Medicines [Internet]. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124. Accessed 20 Jan 2019

19.

Common Terminology Criteria for Adverse Events v4.0 (CTCAE) [Internet]. http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf. Accessed 20 Jan 2019

20.

Kress M-AS, Jensen RE, Tsai H-T, Lobo T, Satinsky A, Potosky AL (2015) Radiation therapy at the end of life: a population-based study examining palliative treatment intensity. Radiat Oncol Lond Engl [Internet]. https://doi.org/10.1186/s13014-014-0305-4 (cited 2019 Jan 23) CrossRef

21.

Guadagnolo BA, Liao K-P, Elting L, Giordano S, Buchholz TA, Tina Shih Y-C (2013) Use of radiation therapy in the last 30 days of life among a large population-based cohort of elderly patients in the United States. J Clin Oncol 31:80–87. https://doi.org/10.1200/JCO.2012.45.0585 CrossRefPubMed

22.

Espenel S, Vallard A, Rancoule C, Garcia M-A, Guy J-B, Chargari C, Deutsch E, Magné N (2017) Melanoma: last call for radiotherapy. Crit Rev Oncol Hematol 110:13–19. https://doi.org/10.1016/j.critrevonc.2016.12.003 CrossRefPubMed

23.

Langrand-Escure J, Vallard A, Rivoirard R, Méry B, Guy J-B, Espenel S, Trone J-C, Ben Mrad M, Diao P, Rancoule C, Suchaud J-P, Fournel P, Guillot A et al (2016) Safety assessment of molecular targeted therapies in association with radiotherapy in metastatic renal cell carcinoma: a real-life report. Anticancer Drugs 27:427–432. https://doi.org/10.1097/CAD.0000000000000349 CrossRefPubMed

24.

Peuvrel L, Ruellan A-L, Thillays F, Quereux G, Brocard A, Saint-Jean M, Aumont M, Drouet F, Dreno B (2013) Severe radiotherapy-induced extracutaneous toxicity under vemurafenib. Eur J Dermatol 23:879–881. https://doi.org/10.1684/ejd.2013.2193 CrossRefPubMed

25.

Churilla TM, Chowdhry VK, Pan D, de la Roza G, Damron T, Lacombe MA (2013) Radiation-induced dermatitis with vemurafenib therapy. Pract Radiat Oncol 3:e195–e198. https://doi.org/10.1016/j.prro.2012.11.012 CrossRefPubMed

26.

Pulvirenti T, Hong A, Clements A, Forstner D, Suchowersky A, Guminski A, McNeil C, Hersey P, Fogarty G, Kefford R, Long GV, Wang W (2016) Acute radiation skin toxicity associated with BRAF inhibitors. J Clin Oncol 34:e17–e20. https://doi.org/10.1200/JCO.2013.49.0565 CrossRefPubMed

27.

Saco M, Mitchell C (2014) Severe radiation dermatitis associated with concomitant vemurafenib therapy in a patient with metastatic melanoma. J Am Acad Dermatol 70:e135–e136. https://doi.org/10.1016/j.jaad.2013.10.046 CrossRefPubMed

28.

Wallach JB, Rietschel P, Kalnicki S, Fox JL (2014) BRAF inhibitor (vemurafenib) concurrent with radiation therapy for metastatic melanoma producing severe skin and oral cavity reactions. Pract Radiat Oncol 4:e213–e216. https://doi.org/10.1016/j.prro.2013.10.007 CrossRefPubMed

29.

Satzger I, Degen A, Asper H, Kapp A, Hauschild A, Gutzmer R (2013) Serious skin toxicity with the combination of BRAF inhibitors and radiotherapy. J Clin Oncol 31:e220–e222. https://doi.org/10.1200/JCO.2012.44.4265 CrossRefPubMed

30.

Schulze B, Meissner M, Wolter M, Rödel C, Weiss C (2014) Unusual acute and delayed skin reactions during and after whole-brain radiotherapy in combination with the BRAF inhibitor vemurafenib. Two case reports. Strahlenther Onkol 190:229–232. https://doi.org/10.1007/s00066-013-0474-3 CrossRefPubMed

31.

Boussemart L, Boivin C, Claveau J, Tao YG, Tomasic G, Routier E, Mateus C, Deutsch E, Robert C (2013) Vemurafenib and radiosensitization. JAMA Dermatol 149:855–857. https://doi.org/10.1001/jamadermatol.2013.4200 CrossRefPubMed

32.

Anker CJ, Ribas A, Grossmann AH, Chen X, Narra KK, Akerley W, Andtbacka RHI, Noyes RD, Shrieve DC, Grossmann KF (2013) Severe liver and skin toxicity after radiation and vemurafenib in metastatic melanoma. J Clin Oncol 31:e283–e287. https://doi.org/10.1200/JCO.2012.44.7755 CrossRefPubMed

33.

Merten R, Hecht M, Haderlein M, Distel L, Fietkau R, Heinzerling L, Semrau S (2014) Increased skin and mucosal toxicity in the combination of vemurafenib with radiation therapy. Strahlenther Onkol 190:1169–1172. https://doi.org/10.1007/s00066-014-0698-x CrossRefPubMed

34.

Hecht M, Zimmer L, Loquai C, Weishaupt C, Gutzmer R, Schuster B, Gleisner S, Schulze B, Goldinger SM, Berking C, Forschner A, Clemens P, Grabenbauer G et al (2015) Radiosensitization by BRAF inhibitor therapy-mechanism and frequency of toxicity in melanoma patients. Ann Oncol 26:1238–1244. https://doi.org/10.1093/annonc/mdv139 CrossRefPubMed

35.

Narayana A, Mathew M, Tam M, Kannan R, Madden KM, Golfinos JG, Parker EC, Ott PA, Pavlick AC (2013) Vemurafenib and radiation therapy in melanoma brain metastases. J Neurooncol 113:411–416. https://doi.org/10.1007/s11060-013-1127-1 CrossRefPubMed

36.

Chowdhary M, Patel KR, Danish HH, Lawson DH, Khan MK (2016) BRAF inhibitors and radiotherapy for melanoma brain metastases: potential advantages and disadvantages of combination therapy. OncoTargets Ther 9:7149–7159. https://doi.org/10.2147/OTT.S119428 CrossRef

37.

Sambade MJ, Peters EC, Thomas NE, Kaufmann WK, Kimple RJ, Shields JM (2011) Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032. Radiother Oncol 98:394–399. https://doi.org/10.1016/j.radonc.2010.12.017 CrossRefPubMedPubMedCentral

38.

Eryılmaz MK, Mutlu H, Salim DK, Musri FY, Tural D, Başsorgun I, Coşkun H (2016) Ipilimumab may increase the severity of cutaneous toxicity related to radiotherapy. J Oncol Pharm Pract 22:533–536. https://doi.org/10.1177/10781550215572930 CrossRefPubMed

39.

Du Four S, Wilgenhof S, Duerinck J, Michotte A, Van Binst A, De Ridder M, Neyns B (2012) Radiation necrosis of the brain in melanoma patients successfully treated with ipilimumab, three case studies. Eur J Cancer 48:3045–3051. https://doi.org/10.1016/j.ejca.2012.05.016 CrossRefPubMed

40.

Kiess AP, Wolchok JD, Barker CA, Postow MA, Tabar V, Huse JT, Chan TA, Yamada Y, Beal K (2015) Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Int J Radiat Oncol Biol Phys 92:368–375. https://doi.org/10.1016/j.ijrobp.2015.01.004 CrossRefPubMedPubMedCentral

41.

Escorcia FE, Postow MA, Barker CA (2017) Radiotherapy and immune checkpoint blockade for melanoma: a promising combinatorial strategy in need of further investigation. Cancer J Sudbury Mass 23:32–39. https://doi.org/10.1097/PPO.0000000000000236 CrossRef

42.

Schiavone MB, Broach V, Shoushtari AN, Carvajal RD, Alektiar K, Kollmeier MA, Abu-Rustum NR, Leitao MM (2016) Combined immunotherapy and radiation for treatment of mucosal melanomas of the lower genital tract. Gynecol Oncol Rep 16:42–46. https://doi.org/10.1016/j.gore.2016.04.001 CrossRefPubMedPubMedCentral

43.

Barker CA, Postow MA, Khan SA, Beal K, Parhar PK, Yamada Y, Lee NY, Wolchok JD (2013) Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma. Cancer Immunol Res 1:92–98. https://doi.org/10.1158/2326-6066.CIR-13-0082 CrossRefPubMedPubMedCentral

44.

Nomura M, Otsuka A, Yoshimura M, Nonomura Y, Kaku Y, Matsumoto S, Muto M (2018) Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab. Cancer Chemother Pharmacol 81:823–827. https://doi.org/10.1007/s00280-018-3557-0 CrossRefPubMed

45.

Ahmed KA, Stallworth DG, Kim Y, Johnstone PS, Harrison LB, Caudell JJ, Yu HHM, Etame AB, Weber JS, Gibney GT (2016) Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol 27:434–441. https://doi.org/10.1093/annonc/mdv622 CrossRefPubMed

46.

Amin NP, Zainib M, Parker SM, Agarwal M, Mattes MD (2018) Multi-institutional report on toxicities of concurrent nivolumab and radiation therapy. Adv Radiat Oncol 3:399–404. https://doi.org/10.1016/j.adro.2018.04.015 CrossRefPubMedPubMedCentral

Title: Safety assessment of anticancer drugs in association with radiotherapy in metastatic malignant melanoma: a real-life report
Radiation/systemic drug combo in metastatic melanoma
Authors: Emmanuelle Couty
Alexis Vallard
Sandrine Sotton
Sarra Ouni
Max-Adrien Garcia
Sophie Espenel
Chloe Rancoule
Majed Ben Mrad
Anne-Catherine Biron
Jean-Luc Perrot
Julien Langrand-Escure
Nicolas Magné
Publication date: 01-05-2019
Publisher: Springer Berlin Heidelberg
Keywords: Melanoma
Melanoma
Systemic Therapy
Radiotherapy
Targeted Therapy
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03806-5

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