# Radiation Oncology/Melanoma/Overview

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Malignant Melanoma Overview

## Overview

* Lentigo maligna - type of melanoma in-situ, induced by long-term cumulative UV injury. Slow horizontal growth of atypical melanocytes, that are partially replacing the basal layer of epidermis, with no evidence of dermal invasion
* Lentigo maligna melanoma (10-15%) - arise from lentigo maligna precursor lesion. Most benign behavior. Occupational sun exposure, frequently on head and neck. Typically in the elderly
* Superficial spreading melanoma (70%) - often arise from a pigmented dysplastic nevus. Associated with intermittent sun exposure, most common on trunk and extremities. Initial radial growth over many years has 5% metastatic potential; following vertical growth has 35-80% metastatic potential
* Nodular melanoma (10-15%) - most malignant type. Arises de novo. Early vertical growth.
* Acral lentiginous melanoma (5%) - occur on palms, soles, and subungal areas. High incidence in blacks, asians, and hispanics. Commonly metastatic
* Desmoplastic melanoma (1-3%) - pronounced neurotropism, and locally aggressive behavior. Frequent local recurrences, but lymph and distal mets are rare. Often amelanotic
* mucosal melanoma (1%) - arise from mucosal epithelium of respiratory, GI and GU tracts
* ocular melanoma (5%) - arise mostly in uvea or conjunctiva
* NCDB; 1998 (1985-1994) PMID 9781962 -- "The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society." (Chang AE, Cancer. 1998 Oct 15;83(8):1664-78.)
** Population study. 84,836 cases of melanom reported to National Cancer Data Base
** Outcome: cutaneous 91.2%, ocular 5.2%, mucosal 1.3%, unknown primary 2.2%
** Cutaneous: Stage 0 15%, Stage I 48%, Stage II 23%, Stage III 9%, Stage IV 5%
** Ocular: uveal 85%, conjunctival 5%, other sites 10%
** Mucosal: H&N 55%, female genital tract 18%, anal/rectal 24%, urinary tract 3%

## Lentigo maligna

* Subtype of melanoma in-situ
* Usually occurs in elderly patients, usually on the face
* Slow horizontal growth. May progress to lentigo maligna melanoma
* Treatment is surgery with negative margins. When surgery is undesirable, RT or topical Imiquimod may be used

## Prevention

Sunscreen:
* Australia (1992-6) No PMID yet -- "Reduced Melanoma After Regular Sunscreen Use: Randomized Trial Follow-Up" (Green AC, J Clin Oncol online early release 6 December 2010)
** 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.

## Adjuvant systemic therapy

Interferon alfa 2b:
* EORTC 18952, 2005 (1996-2000) - PMID 16198768 — "Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial." Eggermont AM et al. The Lancet 2005; 366:1189-1196.
** 1388 pts. Thickness > 4mm, Stage IIb-III. Randomized to 1) 13 months or 2) 25 months of IFN-alfa-2b vs 3) observation.
** Median f/u 4.6 yrs. For 25-month group, 7.2% increase in distant metastases free interval (S.S.) and 5.4% increase in OS (p=0.12); for 13-month, N.S. difference for DMFI and OS. 18% of pts went off study due to toxicity or refusal of treatment.
** Conclusion: does not improve outcome.
Autoimmunity as a prognostic factor:
* Hellenic Cooperative Oncology Group, 2006 (1998-2004) — "Prognostic Significance of Autoimmunity during Treatment of Melanoma with Interferon." Gogas H et al. N Engl J Med Feb 16 2006; 354:709-718.
** 200 pts (subgroup of a larger study) receiving interferon alfa-2b after surgery for Stage IIB, IIC, or III melanoma. Tested blood for the presence of antithyroid, antinuclear, anti-DNA, and anticardiolipin autoantibodies before and after treatment.
** Median f/u 45 mo. Autoantibodies in 26% of pts. 108 of 148 pts without autoantibodies had a relapse (median RFS 16 mo) vs 7 of 52 pts with autoantibodies (median RFS not reached). Median time to detection of autoantibodies was after 3 mo of treatment.
** Conclusion: development of autoimmunity was an independent prognostic factor for improved RFS and OS.

## 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

## Treatment toxicity

Lymphedema after radiotherapy: Using hypofractionated RT At 5-yrs (needing compressive device, surgery, or medical treatment):
* Cervical - 11%
* Axillary - 30%
* Groin - 39%
    From PMID 16814209, 2006 — "Dispelling the myths surrounding radiotherapy for treatment of cutaneous melanoma." Stevens G et al. Lancet Oncol. 2006 Jul;7(7):575-83.

## Review

* University of Florida; 2008 PMID 18260153 -- "Adjuvant radiotherapy for cutaneous melanoma." (Mendenhall WM, Cancer. 2008 Mar 15;112(6):1189-96.)
* Moffitt Cancer Center; 2008 PMID 18596675 -- "Radiation therapy as primary and adjuvant treatment for local and regional melanoma." (Berk LB, Cancer Control. 2008 Jul;15(3):233-8.)
* Auckland, New Zealand; 2006 PMID 16814209 -- "Dispelling the myths surrounding radiotherapy for treatment of cutaneous melanoma." (Stevens G, Lancet Oncol. 2006 Jul;7(7):575-83.)
* Groningen, Netherlands; 2005 PMID 15707701 -- "Radiation therapy following lymph node dissection in melanoma patients: treatment, outcome and complications." (Bastiaannet E, Cancer Treat Rev. 2005 Feb;31(1):18-26. Epub 2004 Nov 18.)
* MD Anderson; 2004 PMID 14768409 Full text — "Radiotherapy for cutaneous malignant melanoma: rationale and indications." Ballo MT et al. Oncology (Williston Park). 2004 Jan;18(1):99-107
** Recommend RT to primary for: desmoplastic melanoma, positive margins, locally recurrent disease, Brewslow > 4 mm with ulceration or satellitosis
** Recommend RT to nodes for: extracapsular extension, >= 4 involved nodes, lymph node >= 3 cm in size, cervical lymph node location, recurrent nodal disease, sentinel lymph node positive but dissection not planned
* Dutch Melanoma Working Party, 1999 PMID 10465575 -- "Consensus on the management of malignant melanoma of the skin in The Netherlands. Dutch Melanoma Working Party." (Kroon BB, Melanoma Res 1999 Jun;9(3):207-12.)

## RT Utilization

* CCORE Australia; 2004 PMID 15022299 -- "Estimation of an optimal radiotherapy utilization rate for melanoma: a review of the evidence." (Delaney G, Cancer. 2004 Mar 15;100(6):1293-301.)
** Evidence-based estimate for proportion of patients who should receive RT
** Estimate: 23%. New South Wales utilization 13%, American College of Surgeons utilization 6%, SEER data 1%
** Conclusion: Shortfall in the use of RT in the treatment of melanoma

## Quality of Care

* American College of Surgeons; 2009 (2004-2005) PMID 19826131 -- "National assessment of melanoma care using formally developed quality indicators." (Bilimoria KY, J Clin Oncol. 2009 Nov 10;27(32):5445-51. Epub 2009 Oct 13.)
** Development of 26 valid quality indicators assessing structure, process, and outcome. 10 of these assessed at 1249 hospitals using NCDB registry data
** Outcome: Adherence at patient level 12-96%, at hospital level 4-83%. Most hospitals adherent with <=50% of indicators
** Conclusion: Considerable variation in quality of melanoma care in the U.S.
* Rush Medical Center; 2008 PMID 18600380 -- "Adverse outcomes associated with noncompliance with melanoma treatment guidelines." (Erickson Foster J, Ann Surg Oncol. 2008 Sep;15(9):2395-402. Epub 2008 Jul 4.)
** Retrospective. 327 patients with cN0 melanoma. Compliance with NCCN guidelines assessed. Mean F/U 4.2 years
** Outcome: Margin non-compliance 28%, lymph node non-compliance 17%. Postop complications: margin compliance 10% vs noncompliant 30% (SS); lymph node compliant 13% vs. non-compliant 33% (SS). Locoregional recurrence: margin compliant 6% vs non-compliant 24% (SS); lymph node compliant 6% vs non-compliant 33% (SS). 10-year OS margin compliant 84% vs. noncompliant 73% (SS). 10-year OS lymph node compliant 91% vs. noncompliant 47% (SS)
** Conclusion: Compliance with NCCN guidelines seems to improve outcome and decrease morbidity