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Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 7235-7236 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.2814
Merkel Cell Carcinoma: Improved Outcome With the Addition of Adjuvant TherapyDepartment of Radiation Oncology, Westmead Hospital and University of Sydney, Sydney, Australia To the Editor: I read with interest the article by Allen et al1 on Merkel cell carcinoma (MCC). They should be congratulated on analyzing such a large number of patients (n = 251) with MCC treated at Memorial Sloan-Kettering Cancer Center (MSKCC). They correctly highlight that previous studies have usually been small and retrospective with inherent biases. While correct in stating that the natural history of this disease entity is somewhat poorly defined, with reported variation in outcome data (locoregional recurrence and survival), most studies have concluded that MCC is an aggressive nonmelanoma skin cancer with high rates of locoregional relapse and cancer-specific mortality.2 Indeed, some series have documented almost 100% relapse rates. Meeuwissen et al3 from the Queensland Radium Institute reported a 100% relapse rate in 38 patients treated with surgery alone, compared with only 29% receiving adjuvant radiotherapy (50 Gy to primary site and draining lymph nodes). In all but two patients relapsing, after surgery, regional nodes were involved either alone or in association with local or distant relapse. Results from The University of Texas M.D. Anderson Cancer Center also strongly support the addition of adjuvant radiotherapy. In 37 patients treated with surgery alone, most (33 of 37; 89%) experienced either local (nine of 37), locoregional (seven of 37), or regional (17 of 37) recurrence. This compares to five of 12 patients recurring after surgery and radiotherapy (50 to 55 Gy), including one with a distant failure.4 The efficacy of adjuvant treatment in MCC is questioned by Allen et al and is reflected by the small number of patients receiving adjuvant radiotherapy or chemotherapy. Only a small minority (17%) of patients without distant disease treated at MSKCC received adjuvant radiotherapy, although relevant details of dose fractionation schedules and modality are lacking. A minority (12%) also received adjuvant chemotherapy, although again specific details of doses, sequencing and number of cycles are lacking. The 5-year relapse-free survival was 48% and almost half (n = 102; 43%) experienced a recurrent event, most often a nodal recurrence (n = 55; 55%). To illustrate the aggressive nature of this disease over a third of patients were either dead of disease (25%) or alive with disease (9%) at the time of last follow-up.
Local recurrence was low (8%) with most patients (94%) achieving negative surgical margins with a median tumor size of 15 mm. Interestingly with margins less than 1 v The treatment of regional nodes in all patients with MCC is essential. The data from MSKCC document a 23% rate of pathologically involved nodes (69% had one node involved) in clinically node-negative necks, but notably, a 44% rate of nodal recurrence in patients staged clinically node-negative and without nodal treatment. The reason for this discrepancy in the risk of occult disease in these two groups is unclear. All patients with clinical nodal disease were found to have pathologic nodes, with a mean number of four metastatic nodes (1 to 29). No comment is made on the incidence of extranodal spread. The authors analyzed all patients with pathologically involved nodes (n = 73) and reported no difference in nodal recurrence with the addition of adjuvant radiotherapy (13% v 14%; P = .83). However, it is more appropriate to compare nodal recurrence based on treatment in patients with clinical and pathological nodal disease noting that most had multiple involved nodes, possibly with extranodal spread present. In this setting the nodal recurrence was 13% with adjuvant radiotherapy, v 26% without radiotherapy (P = .13). Despite not reaching statistical significance the crude difference in recurrence is of clinical concern. I also report improved regional control (surgery alone 14% v surgery and radiotherapy 43%) in the setting of clinically involved metastatic nodes.6 This outcome is also supported by analogous data in the setting of another aggressive non melanoma skin cancer, that being metastatic cutaneous SCC to regional nodes of the head and neck, where patients had better regional control with combined treatment versus surgery alone (15% v 77%).7 The authors suggest that patients at high-risk of nodal recurrence, and who would potentially benefit from adjuvant radiotherapy, need to be defined. I contend that the majority of patients with clinical (and usually pathological) nodes warrant adjuvant radiotherapy and are at high risk of regional relapse following surgery alone.2 To raise unsupported concerns about radiotherapy related toxicity shows a lack of appreciation of modern radiotherapy techniques and modalities. It is well-accepted dogma in clinical oncology that patients with a risk of recurrence more than 20% should be recommended adjuvant radiotherapy to improve disease-free survival and reduce the morbidity of recurrent regional disease. Recurrent disease is usually incurable and often portends to the development of distant relapse. Finally, MCC, similar with other small cell malignancies, is both a radiosensitive and chemosensitive disease. The authors commented on toxicity-related data from a recent landmark phase II trial undertaken by the Trans Tasman Radiation Oncology Group (TROG),8 but neglected to adequately present the outcome data from this trial.9 Patients received concurrent and adjuvant combination chemotherapy (etoposide/carboplatin) and radiotherapy (50 Gy). Eligible patients needed to have one or more unfavorable feature (< 10 mm primary, nodal disease, residual disease post surgery, surgical recurrence, or recurrence outside an irradiated field). The authors report an impressive 3-year overall survival, locoregional control and distant control rate of 76%, 75%, and 76%, respectively.8 Only 17% experienced locoregional recurrence. These findings in patients with poor prognostic features, particularly the presence of nodal metastases in 33 (62% stage III) patients, strongly suggest a benefit to the addition of combination chemotherapy in patients with unfavorable features. These results are unsurpassed by any other study. MCC is an incredibly aggressive primary cutaneous neuroendocrine carcinoma. The conclusion from this single-institution study that patients with MCC will not benefit from adjuvant radiotherapy or adjuvant chemotherapy is not necessarily supported by the evidence presented by my institution and that of others. Patients and clinicians should be aware of this important point. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Allen PJ, Bowne WB, Jaques DP, et al: Merkel cell carcinoma: Prognosis and treatment of patients from a single institution. J Clin Oncol 23:2300-2309, 2005 2. Veness MJ, Morgan GJ, Gebski V: Adjuvant locoregional radiotherapy as best practice in patients with Merkel cell carcinoma of the head and neck. Head Neck 27:208-216, 2005[CrossRef][Medline] 3. Meeuwissen JA, Bourne RG, Kearsley JH: The importance of postoperative radiation therapy in the treatment of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys 31:323-331, 1995 4. Morrison WH, Peters LJ, Silvia EG, et al: The essential role of radiation therapy in securing locoregional control of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys 19:583-591, 1990[Medline] 5. Medina-Franco H, Urist MM, Fiveash J, et al: Multimodality treatment of Merkel cell carcinoma: Case series and literature review of 1024 cases. Ann Surg Oncol 8:204-208, 2001[Medline] 6. Veness MJ, Perera L, McCourt J, et al: Merkel cell carcinoma: Improved regional control and survival with adjuvant radiotherapy. ANZ J Surg 75:275-281, 2005[Medline] 7. Veness MJ, Palme C, Smith M, et al: Metastatic cutaneous squamous cell carcinoma to cervical lymph (non-parotid): A better outcome with surgery and radiotherapy. Laryngoscope 11:1827-1833, 2003[CrossRef] 8. Poulsen M, Rischin D, Walpole E, et al: Analysis of toxicity of Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: A Trans-Tasman Radiation Oncology Group study. Int J Radiat Oncol Biol Phys 51:156-163, 2003
9. Poulsen M, Rischin D, Walpole E, et al: 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. J Clin Oncol 21, 4371-4376, 2003
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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1 cm no difference in local relapse was noted (9% v 10%; P = .83); not surprisingly adjuvant radiotherapy had no impact on local control. Despite this, in a review of 1,024 cases of MCC these authors identified 11 (n = 441) series that documented local relapse rates with, and without, adjuvant radiotherapy. The mean relapse rate reported with radiotherapy was 10% v 53% without (P = .00001).
