# Radiation Oncology/Melanoma/Randomized

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Cutaneous Melanoma: Randomized Trials
In process of crosslinking from Cutaneous Melanoma chapter

## Prevention

Sunscreen:
* Australia; 2011 (1992-6) PMID 21135266 -- "Reduced Melanoma After Regular Sunscreen Use: Randomized Trial Follow-Up" (Green AC, J Clin Oncol. 2011 Jan 20;29(3):257-63.)
** 1621 pts (ages 25-75) randomized to daily vs discretionary use of sunscreen application to head and arms in combination with beta carotene or placebo supplements. Followed through 2006.
** 11 new primary melanomas in the daily sunscreen group vs 22 in the discretionary group (HR=0.50). Reduction in invasive melanomas (3 vs 11) was substantial compared with preinvasive melanomas.
** Conclusion: Melanoma may be preventable by regular sunscreen use in adults.

## Surgical Margins

* 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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

## Lymph Node Evaluation

* Multicenter Selective Lymphadenecomy Trial (MSLT-I) (1994-2002) -- SLNB vs. observation
** Randomized. 1,269 patients. Clinically localized primary cutaneous melanoma, wide local excision, intermediate Breslow thickness (1.2-3.5 mm). Arm 1) SLNB + LND if node positive vs. Arm 2) observation + LND if nodal relapse
** 2006 PMID 17005948 -- "Sentinel-node biopsy or nodal observation in melanoma." (Morton DL, N Engl J Med. 2006 Sep 28;355(13):1307-17.) Median F/U 5 years
*** Outcome: 5-year DFS SLNB 78% vs. observation 73% (SS), but this was predominately due to expected nodal relapse in the observation arm. 5-year DSS 87% vs. 87% (NS). LN+ SLNB 16% immediately vs. observation 5-year failure 16% (NS), however, higher LN+ burden in delayed arm SLNB 1.4 vs observation 3.3 (SS) indicating disease progression during observation
*** SLN Status: 5-year DSS SLN- 90% vs. SLN+ 72% (SS). If LN+, 5-year DSS SLNB+ 72% vs. observation LN+ 52% (SS). If SLN+, 70% had only that LN+, 28% had 2-3 LN+, and 2% had 4+ LN+
*** Conclusion: No overall survival difference. However, staging by SLNB can identify patients with LN+, whose survival is improved by immediate LND
* Intergroup Melanoma Surgical Trial (1983-1989) -- elective LND vs. observation
** Randomized. 740 patients, Stage I-II melanoma, intermediate Breslow thickness (1.0-4.0 mm). WLE minimum margin 2cm. . Planned subgroup analysis based on previously known risk factors
** 2000 PMID 10761786 (Free full text) — "Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial." (Balch CM, Ann Surg Oncol. 2000 Mar;7(2):87-97.) Median F/U 10 years
*** Outcome: 10-year OS ELND 77% vs. observation 73% (NS). In non-ulcerated subgroup, ELND 84% vs observation 77% (SS). In thinner subgroup (Breslow 1.0-2.0), ELND 86% vs. observation 80% (SS). In extremity subgroup, ELND 84% vs. observation 78% (p=0.05)
*** Negative predictors: Breslow thickness, ulceration, age >60
*** Conclusion: No benefit overall; however, survival benefit for select patient populations (non-ulcerated, thickness 1.0-2.0, extremity).
* WHO Melanoma Trial #14 (1982-1989) -- immediate LND vs delayed LND
** Randomized. 240 patients. Trunk melanoma, Breslow thickness >=1.5 mm (median 3.3 mm). WLE with 3cm margin. Arm 1) immediate LND vs. Arm 2) delayed LND until clinical metastases
** 1998 PMID 9519951 -- "Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme." (Cascinelli N, Lancet. 1998 Mar 14;351(9105):793-6.) Mean F/U 11 years
*** Outcome: 5-year OS delayed LND 51% vs. immediate LND 62% (NS)
*** LN Status: LN+ in delayed LND 37% vs. immediate LND 22%. Median TTF 8 months. Survival of patients with immediate LN+ better than with delayed LN+ (p=0.04)
*** Conclusion: No difference. However, immediate LND offers improved survival in patients with LN mets
* Mayo Clinic (1971-1976) -- immediate LND vs delayed LND
** Randomized, 3 arms. 173 patients, localized malignant melanoma. Arm 1) delayed LND until clinical progression vs Arm 2) delayed LND 3 months after primary surgery vs. Arm 3) immediate LND. H&N and midline lesions excluded. Breslow depth <1.5mm in 57%
** 1978 PMID 638981 -- "A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Preliminary results." (Sim FH, Cancer. 1978 Mar;41(3):948-56.)
*** Outcome: 5-year OS delayed LND 63% vs. short delayed LND 56% vs. immediate LND 54% (NS)
*** LN Status: positive LN delayed LND 16% vs short delayed LND 9% vs. immediate LND 4%
*** Conclusion: Elective LND not beneficial in management of melanoma
** 1986 PMID 3747613 -- "Lymphadenectomy in the management of stage I malignant melanoma: a prospective randomized study." (Sim FH, Mayo Clin Proc. 1986 Sep;61(9):697-705.)
*** Outcome: No difference in OS or DMFS
*** Prognostic factors: level of invasion, thickness
*** Conclusion: No difference
* WHO Cooperative Trial (1967-1974) -- immediate LND vs delayed LND
** Randomized. 553 patients, Stage I (T1-3N0) melanoma of the extremities (83% lower extremities), Breslow thickness >=1mm in 90%, >=4mm in 31%. Satellite nodules permitted. Tumors >5 cm excluded. Wide local excision with at least 3cm margin. Arm 1) immediate LND vs Arm 2) delayed LND until clinically positive LNs detected. For lower extremity, inguino-illiac LND; for upper extremity, axillary en bloc resection including pectoralis minor
** 1982 PMID 7074555 -- "Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities." (Veronesi U, Cancer. 1982 Jun 1;49(11):2420-30.)
*** Outcome: 5-year OS immediate LND 68% vs delayed LND 69% (NS); 10-year OS 9% vs. 13% (NS). No subset benefited from immediate LND.
*** LN status: Frequency of LN+ in immediate arm 20% vs. frequency of clinical LN failure in delayed arm 22%. Mean TTF 13 months. No survival difference between patients with initially positive LN and with delayed positive LNs. 5-year OS 46% vs. 41% (NS)
*** Conclusion: Delayed LND as effective as immediated dissection in Stage I melanoma of extremities

## 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 PMID 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

## Supportive Care

* Denmark Psychoeducation (1991-2001)
** Randomized. 262 patients, primary malignant melanoma, T1-4N1-2aM0. Arm 1) control vs. Arm 2) six weekly 2-hour sessions of psychoeducation. Replication study of UCLA study
** 2007 PMID 18089864 -- "Survival after a psychoeducational intervention for patients with cutaneous malignant melanoma: a replication study." (Boesen EH, J Clin Oncol. 2007 Dec 20;25(36):5698-703.)
*** Outcome: No difference for OS or for recurrence; however, nonparticipants had 2x higher death rate
*** Conclusion: Psychoeducation doesn't increase survival
* UCLA (1985-1986)
** Randomized. 68 patients. Stage I-II melanoma, surgical treatment only (wide excision, some with LND). Arm 1) controls vs. Arm 2) 6 week structured psychiatric group intervention
** 1993 PMID 8357293 -- "Malignant melanoma. Effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later." (Fawzy FI, Arch Gen Psychiatry. 1993 Sep;50(9):681-9.)
*** Outcome: Death rate control 29% vs. intervention 9% (SS); recurrence rate 38% vs. 21%
*** Poor predictors: male, greater Breslow depth
*** Conclusion: Psychiatric intervention had beneficial impact on survival