Radiation Oncology/Melanoma/Randomized

Cutaneous Melanoma: Randomized Trials In process of crosslinking from Cutaneous Melanoma chapter Prevention Sunscreen: Australia; 2011 (1992-6) 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 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 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 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 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 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 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 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 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 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 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 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