Radiation Oncology/Merkel

Epidemiology

 * Incidence 0.4/100,000 in 2001 (up from 0.1/100,000 in 1986)
 * Stage (SEER data, 1973-2002)
 * Stage I: 55%
 * Stage II: 31%
 * Stage III: 6%
 * Median survival: 4 years


 * Incidence of cancer linked to Merkel cell polyomavirus. Virus DNA detected in 75% to 80% of Merkel Cell carcinoma specimens.

Pathology

 * Cutaneous malignancy of neuroendocrine origin
 * Initially described in 1972 as "trabecular carcinoma"
 * Nomenclature changed to MCC due to structural and IHC similarities to Merkel cells
 * Merkel cells were initially described as non-dendritic, non-keratinocyte epidermal cells that function as tactile skin receptors

Overview

 * High rate of local failure and regional recurrence (50-80%)
 * Considered highly radiosensitive
 * Management is controversial; surgery tends to be initial management, with some investigators suggesting margins of 3cm
 * Series from Australia show similar benefit with RT only versus RT preceded by surgery
 * Role of adjuvant RT is not well defined. However, a recent retrospective SEER analysis shows a significant survival benefit for all patients, and particularly for tumors >2cm
 * Only one prospective trial has been conducted to date (TROG 96:07), which suggests a benefit for concurrent chemo-RT in N+ patients

Staging
AJCC 7th Edition (2009) Note: This is a new staging system for MCC beginning with the 7th Edition. In previous versions, was included in non-melanoma skin cancer staging. Excludes: MCC of the eyelid

Primary Tumor:
 * T0 - no evidence of primary tumor
 * Tis - in situ
 * T1 - tumor <= 2 cm
 * T2 - >2 cm and <= 5 cm
 * T3 - > 5 cm
 * T4 - invades bone, muscle, fascia, or cartilage

Regional Lymph Nodes:
 * N0 - none
 * N1
 * N1a - micrometastasis
 * N1b - macrometastasis
 * N2 - in transit metastasis
 * defined as a tumor distinct from the primary tumor and either 1) between the primary and the nodal basin or 2) distal to the primary

Distant Metastases:
 * M0 - none
 * M1
 * M1a - metastasis to skin, subcutaneous tissues, or distant lymph nodes
 * M1b - metastasis to lung
 * M1c - metastasis to all other visceral sites

Stage Grouping:
 * IA - T1 pN0
 * IB - T1 cN0
 * IIA - T2-3 pN0
 * IIB - T2-3 cN0
 * IIC - T4 N0
 * IIIA - N1a
 * IIIB - cN1/N1b/N2 *(corrected in erratum)
 * IV - M1

Note: prognostically, pN0 is better than cN0 (without pathologically confirmed node negativity) and thus pN0 vs cN0 is incorporated into overall staging, as is N1a vs N1b


 * Erratum: AJCC 5th reprint page

Older staging systems
AJCC 6th Edition (2002) Was staged as a Non-melanoma skin cancer

Lymph Node Assessment

 * Michigan
 * 95 pts undergoing SLN biopsy for MCC.
 * 2011: PMID 21300936 -- "Features Predicting Sentinel Lymph Node Positivity in Merkel Cell Carcinoma." (Schwartz JL, J Clin Oncol. 2011 Mar 10;29(6):1036-1041.)
 * SLN identified in 93 of 97 primary tumors. SLN + associated with increasing clinical size, tumor thickness, mitotic rate, and infiltrative tumor growth pattern.
 * Conclusion: no subgroup of patients could be identified who had a < 15-20% likelihood of positive LN. SLN biopsy should be recommended in pts with localized disease.

Postoperative RT

 * SEER, 2007 (1973-2002) PMID 17369567 -- "Adjuvant radiation therapy is associated with improved survival in merkel cell carcinoma of the skin." (Mojica P, J Clin Oncol. 2007 Mar 20;25(9):1043-7.)
 * Retrospective. 1665 patients in SEER registry. Surgery in 89% cases, adjuvant RT 40%. Median F/U 40 months
 * Median survival: 49 months (surgery only 45 months vs. adjuvant RT 63 months)
 * RT benefit: for all patients, but highly significant if tumor size >2 cm (median OS 21 vs. 50 months). For tumors <1cm (48 months vs. 93 months), for tumors 1-2cm (52 months vs. 86 months)
 * Conclusion: "The use of adjuvant radiation therapy is associated with improved survival in patients with MCC."
 * Comment & author reply: PMID 17906216


 * Sydney; 2007 (Australia)(1992-2004) PMID 17356954 -- "Merkel cell carcinoma: assessing the effect of wide local excision, lymph node dissection, and radiotherapy on recurrence and survival in early-stage disease--results from a review of 82 consecutive cases diagnosed between 1992 and 2004." (Jabbour J, Ann Surg Oncol. 2007 Jun;14(6):1943-52.)
 * Retrospective. 82 patients with early-stage
 * Outcome: Recurrence rate 51%,
 * Predictors: LN+ status negative, lymphadenectomy prolonged DFS (28 months vs. 12 months, SS) but not OS. SM- not associated with better outcome. RT in 58%, improved DFS (24 months vs. 12 months); improved OS for both primary site (54 months vs. 46 months) and N+ (103 months vs. 34 months)
 * Conclusion: Adjuvant RT recommended for early-stage disease; involved regional LN should be treated


 * Brown University; 2006 PMID 16785371 -- "Adjuvant local irradiation for Merkel cell carcinoma." (Lewis KG, Arch Dermatol. 2006 Jun;142(6):693-700.)
 * Literature survey. 333 reports published between 1966-2004 reviewed
 * Outcome: With RT, local recurrence reduced HR 0.27 (SS); regional recurrence reduced HR 0.34 (SS). 1-year OS 87%, 5-year OS 49%; 1-year CSS 90%, 5-year CSS 62%. No difference in CSS or OS with RT, though if single patient case reports excluded, found CSS benefit (p=0.04) and OS benefit (p=0.02) for adjuvant RT
 * Conclusion: Surgery plus local adjuvant RT associated with lower local and regional recurrence


 * Cologne; 2002 (1990-2000) PMID 11823697 -- "Role of postoperative radiotherapy in the management of Merkel cell carcinoma." (Eich HT, Am J Clin Oncol. 2002 Feb;25(1):50-6.)
 * Retrospective. 31 patients, 13 H&N, 13 limbs, 5 trunk. Stage I 26, Stage II 4, Stage III 1. Surgery alone 14/31, adjuvant RT 16/31, definitive RT 1/31
 * Outcome: median OS 2.7 years; local recurrence 20%, regional LN mets 30%, DM 23%. RT decreased locoregional reccurence from 36% to 6%
 * Negative predictive factors: H&N location, lack of post-op RT
 * Conclusion: Post-op RT to primary tumor and regional lymphatics effective


 * MD Anderson; 2001 (1945-95) - PMID 11177031 &mdash; "Merkel cell carcinoma of the head and neck: effect of surgical excision and radiation on recurrence and survival." Gillenwater AM et al. Arch Otolaryngol Head Neck Surg. 2001 Feb;127(2):149-54.
 * Retrospective. 66 pts. No difference in local relapse for surgical margins <1 vs 1-2cm vs >2cm. Improved local recurrence (12% vs 44%) and regional recurrence (27% vs 85%) rate for addition of RT. No difference in OS. Distant disease developed in 36% of pts regardless of treatment.


 * Queensland Radium Institute; 1995 (1981-91) - PMID 7836086 &mdash; "The importance of postoperative radiation therapy in the treatment of Merkel cell carcinoma." Meeuwissen JA et al. Int J Radiat Oncol Biol Phys. 1995 Jan 15;31(2):325-31.
 * Retrospective. 80 pts. 38 of 38 pts treated with surgery alone relapsed, versus 10 of 34 pts with S+RT.

Chemotherapy + RT

 * Queensland Radium Institute / TROG; 2006 PMID 16125873 &mdash; "Does chemotherapy improve survival in high-risk stage I and II Merkel cell carcinoma of the skin?" Poulsen MG et al. Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):114-9.
 * Retrospective. Compared 53 pts from TROG 96:07 (chemo + RT) to 144 pts treated at Queensland from 1988-96 (RT only).
 * Chemotherapy does not improve survival.


 * TROG 96:07 (1996-2001)
 * Phase II. Pts with disease limited to the primary and nodes with at least 1 risk factor: recurrence after initial therapy, involved nodes, size > 1 cm, gross residual disease, or occult primary with nodes. N+ in 62%. 50 Gy in 25 fx with concurrent carboplatin/etoposide on days 1-3 on weeks 1, 4, 7, and 10.
 * 2001 PMID 11516865 &mdash; "Analysis of toxicity of Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group study." Poulsen M et al. Int J Radiat Oncol Biol Phys. 2001 Sep 1;51(1):156-63. Median F/U 1.8 years
 * Toxicity: Grade 3-4 skin 63%; neutropenia 40%
 * Conclusion: Toxicity acceptable. No outcome measures reported
 * 2003 PMID 14645427 -- "High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group Study--TROG 96:07." (Poulsen M, J Clin Oncol. 2003 Dec 1;21(23):4371-6.). Median F/U 4 years
 * 3-year outcome: OS 76%, LR control 75%, DM control 76%
 * Conclusion: Addition of chemo to RT resulted in high control

Reviews

 * New Zealand; 2008 PMID 18391627 -- "Management of Merkel tumours: an evidence-based review." (Henness S, Curr Opin Oncol. 2008 May;20(3):280-6.)
 * High propensity for recurrence post treatment. 5-year OS 23-80%
 * Addition of RT can confer significant benefit in reducing local and regional recurrence rates, and prolonging DFS. Current literature does not support role of chemotherapy
 * Stage-specific treatment regimens outlined


 * U. Michigan; 2007 PMID 17520670 -- "Merkel cell carcinoma: critical review with guidelines for multidisciplinary management." (Bichakjian CK, Cancer. 2007 Jul 1;110(1):1-12.)


 * NCCN; 2006 - PMID 16884673 &mdash; "Role of radiotherapy in the management of merkel cell carcinoma of the skin." Decker RH and Wilson LD.  J Natl Compr Canc Netw. 2006 Aug 4;(7):713-8.