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: 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) 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: 17906216 Sydney; 2007 (Australia)(1992-2004) 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 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) 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) - 11177031 — "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) - 7836086 — "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 16125873 — "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 11516865 — "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 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 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 17520670 -- "Merkel cell carcinoma: critical review with guidelines for multidisciplinary management." (Bichakjian CK, Cancer. 2007 Jul 1;110(1):1-12.) NCCN; 2006 - 16884673 — "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. External links http://www.merkelcell.org - run by Seattle Cancer Care Alliance Resource for physicians + patients. General info. Useful photographs and contains a few good publications in PDF format