Treatment Option Overview
Merkel cell carcinoma (MCC) is an uncommon tumor. Most clinical management recommendations in the literature are based on case series that describe a relatively small number of patients who were not entered on formal clinical trials, evaluated with uniform clinical staging procedures, treated with uniform treatment protocols, or provided with regular, prescribed follow-up. These reports are also confounded by potential selection bias, referral bias, and short follow-up; and they are underpowered to detect modest differences in outcome.
In addition, outcomes of patients with American Joint Committee on Cancer stage IA, stage IB, and stage II are often reported together. In the absence of results from clinical trials with prescribed work-up, treatments, and follow-up, most MCC patients have been treated using institutional or practitioner preferences that consider the specifics of each case as well as patient preference.
Two competing philosophies underlie many of the controversies about the most appropriate method of treating MCC. In the first philosophy, MCC is treated like other nonmelanoma skin cancers, with an emphasis on treating local-regional disease with surgery and radiation as appropriate. In the second philosophy, MCC is treated according to its "biologic features." This would make it analogous to small cell lung cancer, which is assumed to be a systemic disease, and would lead to a more routine recommendation of systematic adjuvant chemotherapy.Surgery for the Primary Lesion
In a review of 18 case series, 279 of 926 patients (30.1%) developed local recurrence during follow-up, excluding those presenting with distant metastatic disease at presentation. These recurrences have been typically attributed to inadequate surgical margins or possibly a lack of adjuvant radiation therapy.[2,3]
Given the propensity of MCC to recur locally (sometimes with satellite lesions and/or in-transit metastases), wide local excision to reduce the risk of local recurrence has been recommended for patients with clinical stage I or stage II disease.
Recommendations about the optimal minimum width and depth of normal tissue margin that should be excised around the primary tumor differ among the various retrospective case series, but this question has not been studied systematically.[3-7][Level of evidence: 3iiiDiii] No definitive data suggest that extremely wide margins improve overall survival (OS), although some reports suggest that wider margins appear to improve local control.[Level of evidence: 3iiiDiii] Frozen-section evaluation of margins may be useful, especially when the tumor is in an anatomical site that is not amenable to wide margins.
Some authors have advocated the use of Mohs micrographic surgery as a tissue-sparing technique. The relapse rate has been reported to be similar to or better than that of wide excision, but comparatively few cases have been treated in this manner and none in randomized, controlled trials.[7-10][Level of evidence: 3iiiDiii]Regional Lymph Node Surgery
In some case series, local-regional recurrence rates are high when pathologic nodal staging is omitted. Surgical nodal staging in clinically negative patients has identified positive nodes in at least 25% to 35% of patients.[4,11,12][Level of evidence: 3iiiDiii] In one retrospective series of 213 patients who underwent surgical treatment of the primary tumor and evaluation of the draining nodes, nodal positivity was found in 2 of 54 patients with small tumors (e.g., ≤1.0 cm) and 51 of 159 patients with tumors greater than 1.0 cm.[Level of evidence: 3iiiDiii]
The role of elective lymph node dissection (ELND) in the absence of clinically positive nodes has not been studied in formal clinical trials. In small case series, ELND has been recommended for larger primary tumors, tumors with more than ten mitoses per high-power field, lymphatic or vascular invasion, and the small-cell histologic subtypes.[14-16][Level of evidence: 3iiiDiii]
Recently, sentinel lymph node (SLN) biopsy has been suggested as a preferred initial alternative to complete ELND for the proper staging of MCC. SLN biopsy has less morbidity than complete nodal dissection. Furthermore, for MCC sites with indeterminate lymphatic drainage, such as those on the back, SLN biopsy techniques can be used to identify the pertinent lymph node bed(s). If performed, SLN biopsy should be done at the time of the wide resection, when the local lymphatic channels are still intact.
- One meta-analysis of ten case series found that SLN positivity strongly predicted a high short-term risk of recurrence and that subsequent therapeutic lymph node dissection was effective in preventing short-term regional nodal recurrence.
- Another meta-analysis of 12 retrospective case series (only partially overlapping the collection of case series in the previous meta-analysis) found that:[Level of evidence: 3iiiDiii]
- SLN biopsy detected MCC spread in one-third of patients whose tumors would have otherwise been clinically and radiologically understaged.
- The recurrence rate was three times higher in patients with a positive SLN biopsy than in those with a negative SLN biopsy (P= .03).
- Between 2006 and 2010, a large, retrospective, single-institutional series of 95 patients (with a total of 97 primary tumors) identified a SLN in 93 instances, and nodal tumor was seen in 42 patients. Immunohistochemical techniques were used to assess node positivity. Various models of tumor and patient characteristics were studied to predict node positivity. There was no subgroup of patients predicted to have lower than 15% to 20% likelihood of SLN positivity, suggesting that SLN biopsy may be considered for all curative patients with clinically negative nodes and no distant metastases.[Level of evidence: 3iiiDiii]
- From 1996 to 2010, another retrospective, single-institutional study of 153 patients with localized MCC who underwent SLN biopsy analyzed factors associated with SLN positivity. The best predictors of SLN biopsy positivity were tumor size and lymphovascular invasion.[22,23][Level of evidence: 3iiiDiii]
- Should every positive SLN biopsy be followed routinely by completion nodal surgery and/or radiation therapy?
- Are outcomes demonstrably improved by routinely adding radiation if node surgery reveals tumor in multiple nodes and/or extracapsular extension and/or lymphovascular invasion?
- Should patients with MCCs smaller than 1 cm routinely undergo sentinel lymph node dissection (SLND)?
- Should patients with negative or omitted nodal work-up routinely undergo local or local-regional radiation therapy?
- Should immunohistochemical staining techniques be used to identify micrometastases in nodes, and is micrometastatic disease in nodes clinically relevant?
At present, the primary role of lymph node surgery is for staging and guiding additional treatment.
Based on a small number of retrospective studies, therapeutic dissection of the regional nodes after a positive SLND appears to minimize but not totally eliminate the risk of subsequent regional node recurrence and in-transit metastases.[4,21,24][Level of evidence: 3iiiDiii] There are no data from prospective randomized trials demonstrating that definitive regional nodal treatment with surgery improves survival.Radiation Therapy
Because of the aggressive nature of MCC, its apparent radiosensitivity, and the high incidence of local and regional recurrences (including in-transit metastases after surgery alone to the primary tumor bed), some clinicians have recommended adjuvant radiation therapy to the primary site and nodal basin. Nodal basin radiation in contiguity with radiation to the primary site has been considered, especially for patients with larger tumors, locally unresectable tumors, close or positive excision margins that cannot be improved by additional surgery, and those with positive regional nodes, especially after SLND (stage II).[10,11,14,15,25][Level of evidence: 3iiiDiii] Several small, retrospective series have shown that radiation plus adequate surgery improves local-regional control compared to surgery alone, [2,5,26-29] whereas other series did not show the same results.[4,8][Level of evidence: 3iiiDiii]
- Should every positive SLN biopsy be followed routinely by completion nodal surgery and/or radiation therapy?
- Are outcomes demonstrably improved by routinely adding radiation only if nodal surgery reveals tumor in multiple nodes and/or extracapsular extension and/or lymphovascular invasion?
- Should all or just certain patients with negative or omitted nodal work-up receive local or local-regional radiation routinely?
Because of the small size of these nonrandomized, retrospective series, the precise benefit from radiation therapy remains unproven.
When recommended, the radiation dose given has been at least 50 Gy to the surgical bed with margins and to the draining regional lymphatics, delivered in 2 Gy fractions. For patients with unresected tumors or tumors with microscopic evidence of spread beyond resected margins, higher doses of 56 Gy to 65 Gy to the primary site have been recommended.[5,10,11,14,15,27,31,35][Level of evidence: 3iiiDiii] These doses have not been studied prospectively in clinical trials.
Local and/or regional control of MCC with radiation alone has been reported in small, highly selected, nonrandomized case series of patients with diverse clinical characteristics.[29,36] Typically, these patients have had inoperable primary tumors and/or nodes or were considered medically inappropriate for surgery.[29,36][Level of evidence: 3iiiDiii]
Retrospective Surveillance, Epidemiology and End Results Program data suggest a survival value for adding radiation to surgery, but the conclusions are complicated by incomplete patient data, no protocol for evaluation and treatment, and potential sampling bias. Prospective randomized clinical trials will be required to assess whether combining surgery with radiation therapy affects survival.[33,34][Level of evidence: 3iiiDiii]Chemotherapy
A variety of chemotherapy regimens have been used for patients with MCC in the settings of adjuvant, advanced, and recurrent therapy.[5,34,37,38] [Level of evidence: 3iiiDiii] Even though no phase III clinical trials have been conducted to demonstrate that adjuvant chemotherapy produces improvements in OS, some clinicians recommend its use in most cases because of the following:
- A biologic analogy is made between MCC and the histologically similar small cell carcinoma of the lung, which is considered a systemic disease.
- The risk of metastases and progression with MCC is high.
- Good initial clinical response rates have been noted with some chemotherapy regimens.
When possible, patients should be encouraged to participate in clinical trials.
From 1997 to 2001, the Trans-Tasman Radiation Oncology Group performed a phase II evaluation of 53 MCC patients with high-risk, local-regional disease. High risk was defined as recurrence after initial therapy, involved lymph nodes, primary tumor greater than 1 cm, gross residual disease after surgery, or occult primary with positive nodes. Therapy included local-regional radiation (50 Gy in 25 fractions), synchronous carboplatin (area under the curve [auc] 4.5), and intravenous etoposide (89 mg/m2 on days 1–3 in weeks 1, 4, 7, and 10). Surgery was not standardized for either the primary or the nodes, and 12 patients had close margins, positive margins, or gross residual disease. Twenty-eight patients had undissected nodal beds, and the remainder had a variety of nodal surgeries. With a median follow-up of 48 months, 3-year OS, local-regional control, and distant control were 76%, 75% and 76%, respectively. Radiation reactions in the skin and febrile neutropenia were significant clinical acute toxicities. Given the heterogeneity of the population and the nonstandardized surgery, it is difficult to infer a clear treatment benefit from the chemotherapy.[Level of evidence: 3iiiA]
In a subsequent report, the same investigators evaluated a subset of these protocol patients (n = 40, after excluding patients with unknown primaries) and compared them with 61 historical controls who received no chemotherapy, were treated at the same institutions, were diagnosed before 1997, and underwent no routine imaging staging studies. Radiation was given to 50 patients. There was no significant survival benefit seen for chemotherapy patients.
In a subsequent, pilot, clinical trial of 18 patients from 2004 to 2006, the same investigators attempted to reduce the skin and hematological toxicity seen in Study 96-07. The drug schedule was changed to carboplatin (auc = 2) administered weekly during radiation beginning day 1 for a maximum of five doses, followed by three cycles of carboplatin (auc 4.5, and IV etoposide 80 mg/m2 on days 1–3 beginning 3 weeks after radiation and repeated every 3 weeks for three cycles). The radiation was similar to the earlier trial. Early results suggest less toxicity, but other clinical outcomes have not yet been reported.
Use of chemotherapy has also been reported in selected patients with locally advanced and metastatic disease. In one retrospective study of 107 patients, 57% of patients with metastatic disease and 69% with locally advanced disease responded to initial chemotherapy. Median OS was 9 months for patients with metastatic disease and 24 months for patients with locally advanced disease. At 3 years, OS was projected to be 17% and 35%, respectively. Toxicity was significant, however, and without clear benefit, particularly in older patients.[Level of evidence: 3iiiDiii]Follow-up
The most appropriate follow-up techniques and frequency for patients treated for MCC have not been prospectively studied. Given the propensity for local and regional recurrence, clinicians should perform at least a thorough physical examination of the site of initial disease and the regional nodes. Imaging studies may be ordered to evaluate signs and symptoms of concern, or they may be performed to identify distant metastases early; but, there are no data suggesting that early detection and treatment of new distant metastases results in improved survival.
In one series of 237 patients presenting with local or regional disease, the median time-to-recurrence was 9 months (range, 2 months–70 months). Ninety-one percent of recurrences occurred within 2 years of diagnosis. It has been suggested that the intensity of follow-up can be gradually diminished after 2 to 3 years as the majority of recurrences are likely to have occurred in this time frame.Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with neuroendocrine carcinoma of the skin. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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