Radiation Oncology/Melanoma/Primary

Melanoma: Management of the Primary Site Primary Surgery Wide excision, with clinical margin depending on Breslow thickness: In situ: 0.5 cm <=1 mm: 1.0 cm 1-2 mm: 1.0 - 2.0 cm >2 mm: 2.0 cm Sentinel lymph node biopsy for lesions > 1 mm thick For lesions < 1 mm thick, SLN biopsy is not routine, but should be considered if LVI, mitotic rate > 0, or Clark level IV-V, or young age. Randomized UK Melanoma Study Group (1993-2001) -- surgical margin 1 cm vs. 3 cm Randomized. 900 patients, high risk melanoma, thickness >=2.0 mm, trunk or limbs. Excluded palms and soles. Arm 1) 1 cm excision margin vs. Arm 2) 3 cm excision margin. ELND or SLND or adjuvant therapy not allowed. 2004 14973217 — "Excision margins in high-risk malignant melanoma." (Thomas JM, N Engl J Med. 2004 Feb 19;350(8):757-66.) Median F/U 5 years Outcome: local recurrence 1 cm 3.3% vs. 3 cm 2.9% (NS), in-transit/nodal recurrence 32% vs. 28%. No difference in DSS or OS. Median OS after locoregional recurrence 28 months vs. 18 months (p=0.05) Conclusion: Higher locoregional recurrence rate with 1 cm margins in high risk melanomas, but no difference on survival Intergroup Melanoma Surgical Trial (1983-89) -- surgical margin 2 cm vs 4 cm Randomized. 468 patients intermediate thickness (1.0-4.0 mm) melanoma, on trunk or proximal extremity. Arm 1) 2cm surgical margin vs Arm 2) 4 cm surgical margin. Secondary randomization to observation vs ELND (see below). Also, nonrandomized 272 patients with distal extremity or H&N enrolled prospectively to 2 cm excision (Group B) 2001 11258773 (Free full text) — "Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas." (Balch CM et al. Ann Surg Oncol. 2001 Mar;8(2):101-8.) Median F/U 10 years Outcome: surgical margin 2 cm 0.4% vs. 4cm 0.9% (NS), anytime failure 2.1% vs. 2.6% (NS). 10-year DSS 70% vs. 77% (NS). LR profoundly affected by presence of ulceration (RR approx 6) LR impact: LR strongly associated with survival. 5-yr OS of 9% for pts with LR as first relapse (n=13), 11% for any LR (n=28), vs 5-yr OS 86% if no LR. Higher LR for head/neck 9.4%, vs 5.3% dist ext, 3.1% trunk, 1.1% prox ext. Patient who had LR all died of melanoma within 10 years. Conclusion: 2 cm margins are safe for intermediate thickness melanomas Swedish Melanoma Study Group (1982-1990) -- surgical margin 2 cm vs 5 cm Randomized. 769 patients, intermediate thickness (0.9 - 2.0 cm). Excluded H&N, distal extremities, vulva. Arm 1) resection margin 2 cm vs. Arm 2) resection margin 5 cm 1996 8646678 -- "Resection margins of 2 versus 5 cm for cutaneous malignant melanoma with a tumor thickness of 0.8 to 2.0 mm: randomized study by the Swedish Melanoma Study Group." (Ringborg U, Cancer. 1996 May 1;77(9):1809-14.) Median F/U 5.8 years Outcome: Local recurrence 2 cm 0.8% vs. 5 cm 1.0% (NS) No difference in DFS, DSS, or OS Conclusion: Recommend excision margin of 2 cm France/UK (1981-2000) -- surgical margin 2 cm vs. 5 cm Randomized. 337 patients, melanoma <=2.0 cm. Excluded age >70, toe/nail/finger, and acral melanoma. Arm 1) 2 cm excision vs. Arm 2) 5 cm excision. Second randomization for adjuvant isoprinosine 2003 12673721 -- "Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1-mm thick)." (Khayat D, Cancer. 2003 Apr 15;97(8):1941-6.) Median F/U 16 years Outcome: Local recurrence 2 cm 0.6% vs. 5 cm 1.8 cm (NS). Median TTR 3.5 years. 10-year DFS 85% vs. 83% (NS). No difference for second randomization. Conclusion: Surgical margin of 2 cm sufficient for melanoma <=2 mm WHO Melanoma Programme Trial #10 (1980-?) -- surgical margin 1 cm vs 3 cm Randomized. 612 patients with clinical Stage I melanoma, thickness <=2 mm. Facial or digital melanoma excluded. Arm 1) 1 cm surgical margin vs. Arm 2) 3 cm surgical margin 1991 2009058 -- "Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma." (Veronesi U, Arch Surg. 1991 Apr;126(4):438-41.). Mean F/U 8 years Outcome: Local recurrence 1cm 1.3% vs 3 cm 0% (NS). 8-year OS 1cm 90% vs. 3 cm 90% (NS); DFS 82% vs. 84% (NS). First event most frequently nodal relapse (7%). Conclusion: Narrow 1cm excision as effective as wide excision Retrospective Sydney Melanoma Unit; 2005 (1951-1996) 15650644 -- "Histopathologic excision margin affects local recurrence rate: analysis of 2681 patients with melanomas < or =2 mm thick." (McKinnon JG, Ann Surg. 2005 Feb;241(2):326-33.) Retrospective. 2681 patients, cutaneous melanoma <=2mm. SM-. Median F/U 7 years Outcome: 10-year LR 2.9%, predictors for LR were margin of excision and thickness. If margin 1cm excluded, margin status no longer significant. LR margin <8mm 3.8% vs. 8-15mm 1.6%. Margin status not predictive of survival Conclusion: Pathologic margin affected risk of LR, but only if <1 cm clinical. It does not affect survival MD Anderson; 1998 (1985-1996) 9641453 -- "Surgical margins and prognostic factors in patients with thick (>4mm) primary melanoma." (Heaton KM, Ann Surg Oncol. 1998 Jun;5(4):322-8.) Retrospective. 278 patients, thick primary melanoma >4 mm (median 6.0 mm), ulceration 57%. Median F/U 2.2 years Outcome: LR 12%. LR or margin width not associated with DFS or OS, but nodal status, thickness, and ulceration was Conclusion: 2cm margin sufficient Desmoplastic and/or Neurotropic Melanoma Desmoplastic melanomas were initially believed to have a high recurrence rate (~50% in early literature review from 1995). This may have been related to high rate of neurotropism, and high frequency with H&N location, which may compromise surgical margins However, desmoplastic melanoma with appropriate surgical resection appears to have local recurrence rate of 4-7%. Neurotropic desmoplastic melanoma had historically local recurrence of 20-30%, but Michigan data suggest low recurrence rate with appropriate surgical margins Role of initial adjuvant RT is not clear, but may be reasonable if SM are <1cm or with neurotropism. Whether RT has any impact on development of distant disease and overall survival has not been established Queensland Melanoma Project, Australia; 2008 (1997-2006) 18366400 -- "Desmoplastic melanoma: the role of radiotherapy in improving local control." (Foote MC, ANZ J Surg. 2008 Apr;78(4):273-6.) Retrospective. 24 patients with desmoplastic melanoma, surgical excision followed by postop RT. Median thickness 5.2 mm. SM <1 cm in 71% patients Outcome: 3-year in-field RFS 91%, OS 83% Conclusion: Adjuvant RT may have been effective in reducing rate of local recurrence Sydney Melanoma Unit, Australia 2008 (1996-2007) 18823042 -- "Desmoplastic neurotropic melanoma: a clinicopathologic analysis of 128 cases." (Chen JY, Cancer. 2008 Nov 15;113(10):2770-8.) Retrospective. 128 patients with desmoplastic neurotropic melanoma. Wide local excision. Median thickness 4 mm. SM >0.5 cm in 70%, >1 cm in 40%. Adjuvant RT in 21% (typically for thicker tumors (median thickness 7 mm), H&N locations, and close surgical margins). RT 33/6 or 50/25 Outcome: local recurrence surgery 6% vs surgery + RT 7%. No LR with surgery only if SM >1cm. Predictors were SM+ and H&N location. DM surgery 17% vs. surgery + RT 11%. Conclusion: Local recurrence lower than historical controls. When margins compromised (possibly <1cm), RT may reduce local recurrence 1998 (1979-1995) 9740077 -- "Desmoplastic and desmoplastic neurotropic melanoma: experience with 280 patients." (Quinn MJ, Cancer. 1998 Sep 15;83(6):1128-35.) Retrospective. 280 patients (desmoplastic melanoma 190, desmoplasti neurotropic melanoms 90). Male-female 1.7:1, median thickness 2.5 mm, amelanotic 44% Outcome: 5-year OS 75%. Local recurrence 11%, regional/in-transit 12%, distant mets 14%. Desmoplastic melanoma LR 7% vs. desmoplastic neurotropic melanoma 20% vs. historical overall melanoma 3%. As a function of thickness, comparable recurrence rate for desmoplastic melanoma. LR higher if SM <1 cm or if neurotropism present Conclusion: Comparable survival between DM, DNM, and other cutaneous melanomas. Lower rate of LN mets Michigan; 2005 (1997-2004) 16080180 -- "Wide excision without radiation for desmoplastic melanoma." (Arora A, Cancer. 2005 Oct 1;104(7):1462-7.) Retrospective. 49/65 patients with cutaneous desmoplastic melanoma. Wide excision (>2 cm in 63%, >1cm in 100%), most H&N patients required reconstruction. No RT given. Mean thickness 4.2 mm, 38% had thickness >4 mm. Neurotropism in 32%. Mean F/U 3.7 years, minimum 2 years Outcome: Local recurrence 4% (1 neurotropic, 1 not). LN mets no neurotropism 4% vs neurotropism 28% (SS) Conclusion: Local recurrence considerably less than historically reported; careful attention to appropriate margins produces excellent local control University of Florida; 2005 16062083 -- "Neurotropic melanoma of the head and neck with clinical perineural invasion." (Newlin HE, Am J Clin Oncol. 2005 Aug;28(4):399-402.) Retrospective. 3 patients with clinical perineural invasion. 2 patients incomplete resection, and received definitive RT 74.4 Gy BID. 1 patient postop RT after multiple recurrences of desmoplastic neurotropic melanoma. Conclusion: RT may provide relatively long-term local control in patients with clinical perineural invasion UCLA; 2003 (1976-1997) 12784232 -- "Efficacy of radiation therapy in the local control of desmoplastic malignant melanoma." (Vongtama R, Head Neck. 2003 Jun;25(6):423-8.) Retrospective. 44 patients, desmoplastic melanoma, H&N 68%, neurotropism 48%. Local recurrence in 21/44 (48%), and extent of SM couldn't be determined. 14/21 local recurrences received postop RT (32% overall). Median dose 50 Gy (44-66 Gy), no regional LN coverage. Indications for RT: R2 resection, R1 resection, deliberate close SM, surgical concern about adequacy of resection, or multiply recurrent tumor Outcome: Local recurrence RT 0% vs. no RT 57% (SS). DM rate comparable no RT 35% vs. RT 40% (NS). No difference in recurrence rate by neurotropism. Local control in 4/4 patients with R1/R2 disease Conclusion: Postop RT effective in recurrent disease; consider RT as part of initial adjuvant treatment; consider RT as primary treatment if cannot clear margins Harvard; 1995 (1985-1992) 7812919 -- "Desmoplastic neurotropic melanoma. A clinicopathologic analysis of 28 cases." (Carlson JA, Cancer. 1995 Jan 15;75(2):478-94.) Retrospective. 28 patients, desmoplastic neurotropic melanoma. Most H&N (75%) and amelanotic (57%), associated LM in 56%. Mean thickness 4.1 mm. Outcome: Local recurrence 27%, visceral mets 11%, survival 81%. Literature review composite LR 50% (22-77%) Conclusion: Present at more advanced stage locally, but may be associated with better survival stage for stage Adjuvant RT to Primary Site MDACC; 2004 - 14768409 -- "Radiotherapy for cutaneous malignant melanoma: rationale and indications." (Ballt MT, Oncology (Williston Park). 2004 Jan;18(1):99-107) Review. Recommend RT to primary for: desmoplastic melanoma, positive margins, locally recurrent disease, Brewslow > 4 mm with ulceration or satellitosis Sydney Melanoma Unit, Australia; 2000 (1989-98) - 10618610 — "Locally advanced melanoma: results of postoperative hypofractionated radiation therapy." (Stevens G, Cancer. 2000 Jan 1;88(1):88-94.) Retrospective. 174 patients treated with postop RT (primary n=35, or lymph nodes n=139). RT 33/6 over 18 days. Median F/U 2.5 years For primary site (Group A): RT given initially (n=11) or after recurrence and re-exsision (n=21). Indications: SM+, SM close, desmoplastic histology, PNI, satellitosis, early/multiple recurrences For adjuvant LN (Group B): RT given initially (n=107) or after recurrence (n=35). Indications: SM+, ECE, multiple LN+, large LNs, PNI, LVI, parotid node involvement Outcome: In-field local recurrence 11%. Recurrence rate if RT given in <18 days 4% vs. >=18 days 15% (p=0.06). 5-year OS Group A 49% vs. Group B 38% (p=0.07) Toxicity: symptomatic lymphedema 58%, worse if initial dissection. Conclusion: Postop RT improved local control compared with published series. Adjuvant RT should be considered for high risk patients, including SM+, desmoplasia with neurotropism, multiple LN+, and large LN with ECE Princess Margaret; 1981 (1958-1979) 7306920 -- "Radiotherapy in nonlentiginous melanoma of the head and neck." (Harwood AR, Cancer. 1981 Dec 15;48(12):2599-605.) Retrospective. 37 patients with superficial spreading or nodular melanoma of H&N. Surgery R2 margin (n=6), surgery with close or R1 margin (n=15), recurrent disease (n=16). Variety of RT schedules Outcome: Local control in gross disease 4/6 (67%), microscopic disease 14/15 (93%), recurrent disease 2/16 (12%) Radiobiology: Control improved with higher dose/fx, especially <4 Gy 25% vs >4 Gy 71% Conclusion: Nonlentiginous melanoma not radioresistant, RT deserves further study Institution?; 1958 13533685 -- "Malignant melanoma; a combined surgical and radiotherapeutic approach." (Dickson RJ, Am J Roentgenol Radium Ther Nucl Med. 1958 Jun;79(6):1063-70.) Retrospective. 234 patients (local excision 71, radical excision 42, local excision + adjuvant RT 121). RT given with radium (brachytherapy or teleradium) or orthovoltage x-rays, dose 50/10 Outcome: No local control. OS comparable between radical surgery and local surgery + RT Definitive RT Lentigo maligna & Lentigo maligna melanoma Surgical excision would be considered the first line treatment However, in elderly patients large lesions can often be present on the face, and radiotherapy may be warranted if they have significant comorbidities Historically, Grenz or soft X-ray therapy was used, with success rate >90% In Europe, the Miescher technique was popular, involving contact therapy (50% depth dose 1mm) and use of very high doses Lesions may take up to 2 years to completely regress, and careful clinical follow up is required Zurich; 2002 (1950-2000) 12072074 — "A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays." (Farshad A, Br J Dermatol. 2002 Jun;146(6):1042-6.) Retrospective. 150 patients (LM 96, LMM 57). 90% of lesions were on the face (cheek & nose 46%, eye & ear & temple 24%). Grenz rays (12 kV) in 64%, contact x-rays (20-30 kV). Dose LM 100/10 - 120/10 @10-12 Gy/fx at 3-4 day intervals. Dose LMM 42/6 - 54/6 @ 7-9 Gy/fx at 3-4 day intervals. Margin 7-10 mm. Mean F/U 8 years Outcome: Recurrence rate 7% (LM 5%, LMM 3%); mean TTR 3.8 years. LR 5/7, LN 2/7 Conclusion: RT is curative for LM and LMM. Munich; 2000 (1987-1998) 10954659 -- "Fractionated radiotherapy of lentigo maligna and lentigo maligna melanoma in 64 patients." (Schmid-Wendtner MH, J Am Acad Dermatol. 2000 Sep;43(3):477-82.) Retrospective. 64 patients (LM 42, LMM 22). In LMM patients, excision of nodular part prior to RT. RT superficial x-rays, 100/10 over 2 weeks. Median F/U 1.2 years Outcome: Recurrence LM 0%, LMM 9% (both salvaged with excision) Toxicity: Cosmetic outcomes good or excellent Conclusion: Fractionated RT effective method Westmead Hospital, Australia; 1996 8826745 -- "Radiotherapy for melanotic freckles." (Christie DR, Australas Radiol. 1996 Aug;40(3):331-3.) Retrospective. 5 patients, 7 lentigo maligna. RT equivalent to at least 44/11 Outcome: No local failures Toxicity: Favorable cosmetic result in all patients Conclusion: RT safe and effective Princess Margaret 1994 (1968-1988) 8053696 -- "Lentigo maligna of the head and neck. Results of treatment by radiotherapy." (Tsang RW, Arch Dermatol. 1994 Aug;130(8):1008-12.) Retrospective. 54 patients with LM of H&N region, treated with surgery (33%) or RT (67%) Outcome: LC surgery 3-years 94% vs. RT 5-years 86%. No metastases Toxicity: Poor cosmesis 11% (pallor, atrophy, or telangiectasia) Conclusion: Conventional fractionated RT simple and effective; excellent alternative to surgery 1983 (1958-1982) 6863069 -- "Conventional fractionated radiotherapy for 51 patients with lentigo maligna and lentigo maligna melanoma." (Harwood AR, Int J Radiat Oncol Biol Phys. 1983 Jul;9(7):1019-21.) Retrospective. 51 patients (LM 23, LMM 28). RT orthovoltage (100-250 kV), minimum 1cm margin. Dose 35/5, 45/10, or 50/15 depending on size of lesion (<3cm, 3-5cm, >5cm) Outcome: LM local control 90%, 2 local failures, both salvaged. LMM local control 92%, 2 local failures, both salvaged; 1 regional/distant mets Conclusion: RT simple and effective for this form of melanoma 1982 7118548 -- "Radiation therapy for melanomas of the head and neck." (Harwood AR, Head Neck Surg. 1982 Jul-Aug;4(6):468-74.) Retrospective. 77 patients with melanoma of H&N (LM 13, LMM 18) Outcome: Local control LM 85%; LMM 94% Conclusion: RT simple and effective treatment for LM and LMM 1980 (1958-1977) 7379026 -- "The radiotherapy of lentigo maligna and lentigo maligna melanoma of the head and neck." (Dancuart F, Cancer. 1980 May 1;45(9):2279-83.) Retrospective. 23 cases (LM 8, LMM 15), treated with orthovoltage RT (100-280 keV). RT 35/5 to 45/10 to 50/20 to 60/25 fxs (mostly 45-50 in 10 fx) Outcome: LM 1/8 (12%) recurred at margin, and salvaged with further RT. LMM 1/15 (7%) recurred centrally, and was salvaged with excision. Time to regression up to 2 years Toxicity: majority excellent cosmesis Conclusion: Conventional fractionated orthovoltage RT deserves further consideration Institution?; 1976 942213 -- "Treatment of melanotic freckle with x-rays." (Kopf AW, Arch Dermatol. 1976 Jun;112(6):801-7.) Retrospective. 16 patients, lentigo maligna. Treated with Miescher technique Outcome: 5/16 (31%) local recurrence or persistence; 3/16 (19%) developed metastatic melanoma Conclusion: Procedure has been abandoned, pending further clarification Institution?; 1971 5091872 -- "Hutchinson's freckle treated by the Miescher technique utilizing a Grenz-Ray machine adapted for the purpose." (Orfuss A, Arch Dermatol. 1971 Apr;103(4):456-8.) Acral Melanoma Louisian State; 1999 10474984 -- "Radiotherapy of acral lentiginous melanoma of the foot." (Harwood AR, J La State Med Soc. 1999 Jul;151(7):373-6.) Case report. 4 acral lentiginous melanoma of foot. Treated by RT alone, using 0-7-21 technique (24/3) Outcome: LR excellent, all patients well palliated Conclusion: RT recommended if not suitable for surgery General Melanoma Frankfut, Germany; 1963 (1935-1960) 13953619 -- "Radiation therapy of primary and metastatic melanoma." (Hellriegel W, Ann N Y Acad Sci. 1963 Feb 15;100:131-41.) Retrospective. 259 patients (N0 64%, N+ 36%). RT 6000 r in 2 weeks using 60 kV, followed in 6-8 weeks by second course 4000-5000 r in 2 weeks. Alternatively 7000-8000 r in 4 weeks with electrons 15-20 MeV Outcome: 5-year OS 48%, 10-year OS 29%. If N0, 62% and 42%. If N+ 23% and 12%. By method of treatment: 5-year OS RT alone 62% vs. excision + RT 38% vs. RT + excision 86% Conclusion: Malignant melanoma can be successfully treated by RT; high doses are required Brachytherapy Lille, France; 2006 16508600 -- "[Interstitial brachytherapy in management of primary cutaneous melanoma: 4 cases] - [Article in French]" (Mortier L, Ann Dermatol Venereol. 2006 Feb;133(2):153-6.) Retrospective. 4 cases (3 LMM, 1 nodular), thick (>3mm) melanoma, treated with interstitial brachytherapy. Median F/U 4 years Outcome: No local relapse Toxicity: Cosmetic and functional outcome excellent Conclusion: Interstitial brachytherapy feasible for primary control, if surgery difficult or impossible Adjuvant Interferon DeCOG (2001-2004) -- Interferon x1.5 years vs x5 years Randomized. 840 patients, resected cutaneous melanoma, minimum thickness 1.5 mm, clinically N0 (SLN in 76%, SLN+ in 18%). Arm 1) IFN alpha2 3MU 3x/week x18 months vs Arm 2) same IFN x60 months 2010 20048184 -- "Efficacy of Low-Dose Interferon {alpha}2a 18 Versus 60 Months of Treatment in Patients With Primary Melanoma of >= 1.5 mm Tumor Thickness: Results of a Randomized Phase III DeCOG Trial." (Hauschild A, J Clin Oncol. 2010 Feb 10;28(5):841-6. Epub 2010 Jan 4.) Median F/U 4.3 years Outcome: Relapse-free survival 1.5 years 76% vs 5 years 73% (NS), DMFS 82% vs 80% (NS), OS 86% vs 85% (NS) Conclusion: Prolongation of IFN therapy showed no clinical benefit