ABSTRACT: The use of radiation as adjuvant therapy for patients with cutaneous malignant melanoma has been hindered by the unsubstantiated belief that melanoma cells are radioresistant. An abundance of literature has now demonstrated that locoregional relapse of melanoma is common after surgery alone when certain clinicopathologic features are present. Features associated with a high risk of primary tumor recurrence include desmoplastic subtype, positive microscopic margins, recurrent disease, and thick primary lesions with ulceration or satellitosis. Features associated with a high risk of nodal relapse include extracapsular extension, involvement of four or more lymph nodes, lymph nodes measuring at least 3 cm, cervical lymph node location, and recurrent disease. Numerous studies support the efficacy of adjuvant irradiation in these clinical situations. Although data in the literature remain sparse, evidence also indicates that elective irradiation is effective in eradicating subclinical nodal metastases after removal of the primary melanoma. Consequently, there may be an opportunity to integrate radiotherapy into the multimodality treatment of patients at high risk of subclinical nodal disease, particularly those with an involved sentinel lymph node. Such patients are known to have a low rate of additional lymph node involvement, and thus in this group, a short course of radiotherapy may be an adequate substitute for regional lymph node dissection. This will be the topic of future research.
Because of improved public awareness, most cases of cutaneous malignant melanoma are diagnosed at an early stage and can be cured by simple surgical resection. Local recurrence after wide local excision of primary disease is rare, and with few exceptions, the role of adjuvant local therapy in primary melanoma is limited. As the thickness of the primary melanoma increases, however, so does the risk of lymphatic spread. Surgical resection of clinically documented regional disease results in satisfactory regional control, but for certain patients adjuvant regional irradiation is indicated to prevent potentially morbid regional relapse.
For patients without clinically apparent lymphatic involvement, the risk of subclinical nodal disease may be predicted from clinicopathologic features of the primary lesion. In patients with a high risk of subclinical regional disease, approaches have included observation of the nodal basin (with delayed dissection as needed), elective lymph node dissection, and, less frequently, elective lymph node irradiation.
Although elective treatment results in lower rates of nodal recurrence, findings in the four randomized trials investigating the effect of elective dissection on overall survival were negative.[ 1-4] Despite these results, recent developments in sentinel lymph node biopsy techniques have renewed interest in regional lymph node dissection. Patients with an involved sentinel lymph node generally undergo completion dissection. The role of ra diotherapy after sentinel lymph node biopsy remains largely undefined.
In this article we review the rationale and indications for radiotherapy in cutaneous malignant melanoma. We focus first on adjuvant irradiation of the primary tumor site or regional lymph node basins after surgical excision of the primary tumor or dissection of lymph nodes. We then turn to the evolving role of elective nodal irradiation for patients with clinically node-negative disease but a high risk of subclinical nodal involvement. Finally, we discuss the implications of recent developments in sentinel lymph node biopsy for the use of elective lymph node treatment.
Adjuvant Irradiation of the Primary Site
Surgical resection remains the primary mode of therapy for cutaneous malignant melanoma. In general, local recurrence after adequate wide local excision of primary tumors is rare, occurring in fewer than 5% of cases. As detailed in Table 1, the rate of local recurrence is higher when primary lesions are thicker than 4 mm, are located on the head or neck, or are associated with ulceration or satellitosis.[2,5-17]
Even when these factors are present, however, the rate of local recurrence is generally less than 15%, although combinations of these factors- such as thickness greater than 4 mm with ulceration or head and neck location-most likely further increase the risk of local recurrence.[ 6,14] Desmoplastic melanoma, a rare variant of cutaneous melanoma, is associated with a clearly increased local recurrence rate.[18-23] These tumors typically present in elderly patients, have a predilection for head and neck sites, and are associated with perineural invasion. Recurrence rates as high as 50% have been reported after ostensibly adequate wide local excision of desmoplastic melanomas (Table 1).
Adjuvant Radiotherapy Data
Few series have examined the use of adjuvant irradiation of the primary tumor site in the presence of high-risk clinicopathologic features. The first report of this approach was that of Dickson, who analyzed outcomes in a series of 234 patients according to primary treatment. Treatment consisted of local excision alone (71 patients), radical surgery alone (42 patients), or surgery followed by adjuvant radiotherapy (121 patients). In the adjuvant radiotherapy group, surgery usually involved only simple excision or electrocautery. Radium (surface molds or teleradium therapy) or orthovoltage x-rays were used with almost equal frequency-the latter to deliver a dose of 5,000 cGy in 10 days to the primary tumor site. Although the result in terms of local disease control was not reported, overall survival after simple excision and radio- therapy was similar to that after wide local excision and skin grafting.
Johanson et al reported on a group of 54 patients who underwent surgery and radiotherapy for nodular melanoma to a total dose of 24 Gy in three fractions delivered on days 0, 7, and 21. Of the nine patients who received radiotherapy to the primary tumor site for gross or microscopic residual disease, only one developed progressive local disease.
Although prospective studies are lacking, the available data support a strategy of adjuvant irradiation when local recurrence is of concern. Indications for irradiation of the primary tumor site are detailed in Table 2 and include desmoplastic melanoma, but primary thick primary tumors with associated ulceration or satellitosis, close or positive resection margins where re-resection might compromise cosmesis, and locally recurrent disease are also associated with an increased local failure rate and adjuvant irradiation may be warranted. The primary tumor site may also be irradiated when features of the primary tumor by themselves do not indicate the need for local adjuvant irradiation but regional nodal irradiation is indicated (see below).
Adjuvant Irradiation of the Regional Lymph Nodes
For patients who present with documented nodal disease or nodal recurrence after local excision of primary melanoma, therapeutic nodal dissection results in regional control in more than 85% of patients overall. However, several features (Table 3) substantially decrease this satisfactory nodal control rate and indicate a need for adjuvant radiotherapy to avoid uncontrolled regional recurrence. In most series, the presence of any one of these high-risk features results in a 30% to 50% rate of subsequent nodal recurrence after surgery alone.
Although these high-risk features also predict for increased rates of hematogenous metastases, the importance of maintaining regional control and avoiding unmanageable regional recurrence should not be underestimated. The most consistently reported high-risk feature is extracapsular extension, but other factors must also be considered when patients are evaluated for adjuvant therapy.
• Extracapsular Extension—In an early surgical series from M. D. Anderson Cancer Center that included 1,001 patients with nodal metastasis, the nodal failure rate after surgery alone was significantly higher when lymph nodes were described as matted (eg, gross extracapsular extension).[ 26] Investigators from Roswell Park Cancer Institute also reported a significantly elevated regional failure rate in the presence of extracapsular extension. In their series of 338 patients, the nodal failure rate was 63% when extracapsular extension was noted microscopically. This association remained significant on multivariate analysis. In another series, from the John Wayne Cancer Institute, extracapsular extension was the single most important predictor of subsequent regional failure after surgery alone. Reported rates of regional failure after surgery alone for nodal metastases with associated extracapsular extension range from 31% to 63% (Table 3).[26-29]
• Number of Involved Nodes—Another factor associated with an increased risk of regional recurrence is a high number of involved lymph nodes. Lee and colleagues reported regional recurrence rates of 25% when 1 to 3 nodes were involved, 46% for 4 to 10 involved nodes, and 63% for more than 10 involved nodes (P = .0001). Two additional series also revealed an increasing risk of regional recurrence with an increasing number of involved lymph nodes.[28,30] Reported rates of regional failure increase rapidly when four or more lymph nodes are involved, ranging from 22% to 63% (Table 3). Although not specifically addressed in most studies, it is reasonable to predict a high correlation between a high number of positive nodes and the presence of extracapsular extension.
• Size of Lymph Nodes—Lymph node size has less frequently been cor- related with the rate of recurrence, but Lee and colleagues did report higher regional recurrence rates with larger lymph nodes: 25% when lymph nodes were smaller than 3 cm, 42% when they were 3 to 6 cm, and 80% when they were larger than 6 cm (P < .001). This finding is not surprising, as the probability of extracapsular extension generally increases with increasing nodal size.
• Clinical Factors—Finally, clinical factors may also predict an increased rate of regional recurrence. At least two series have reported that nodal recurrence rates are higher for cervical nodal disease than for disease in the axillary or inguinal basins.[ 27,31] Also, some series have suggested that the risk of regional recurrence is higher in patients who undergo therapeutic dissection for clinically apparent disease than in patients who have subclinical nodal metastases discovered at the time of elective dissection.
Specifically, in an M. D. Anderson series including patients with cervical lymph node metastases treated with therapeutic modified neck dissection, the regional recurrence rate was 50% for patients with multiple positive lymph nodes as compared with a regional recurrence rate of only 17% when dissection was performed electively but lymph nodes were found to be involved. Other series, including patients with disease in any nodal basin, have reported regional recurrence rates ranging from 20% to 50% when dissection is performed therapeutically (Table 3).[14,27,28]
Adjuvant Radiotherapy Data
Data from several retrospective series are now available suggesting significant improvements in regional control when adjuvant nodal irradiation is delivered (Table 4).[32-38] In an analysis from M. D. Anderson, the regional recurrence rate in patients treated with adjuvant radiotherapy for axillary nodal metastases was only 13%, despite the fact that the majority of patients presented with one or more of the high-risk features outlined in Table 3. In a separate analysis, we reviewed the records of 160 patients with cervical lymph node metastases and a high risk of regional recurrence and found a 6% 10-year recurrence rate after adjuvant radiotherapy. These findings are consistent with those of other adjuvant radiotherapy series in which regional recurrence rates are consistently below what has been reported after surgery alone despite the presence of adverse clinicopathologic risk factors (compare Tables 3 and 4).
Review of published series, therefore, suggests a clear association between the risk of regional recurrence and the presence of extracapsular ex-tension, the number of involved lymph nodes, size of the lymph nodes, and the site of disease. Although no series has directly analyzed regional recurrence rates according to disease presentation (ie, recurrence after prior lymph node dissection vs primary presentation), recurrent disease is a wellaccepted risk factor for subsequent relapse and indicates the need for radiotherapy. Although therapeutic (vs elective) dissection was associated with an increased risk of nodal recurrence in several retrospective series, at M. D. Anderson we have reserved adjuvant irradiation of lymph node basins for patients who have combinations of therapeutic dissection and other high-risk features. Indications for adjuvant regional radiotherapy are summarized in Table 2.