Adjuvant radiotherapy for melanoma metastatic to axillary and inguinal nodes : Regional tumor control and late effects

Background: Adjuvant radiotherapy reduces nodal recurrence in metastatic melanoma. The purpose of this study was to examine the effects of adjuvant radiotherapy on in-field nodal control of melanoma metastatic to axillary and inguinal lymph nodes. Methods: The medical records of patients who received adjuvant radiotherapy from January 1, 2003, through December 31, 2011, at Mayo Clinic were reviewed. Results: In the 20 patients identified, the rates of 2-year overall survival, nodal control, and freedom from distant metastases were 53%, 54%, and 44%, respectively. Intensity-modulated radiotherapy was used in 15 patients (75%) and 3-dimensional conformal radiotherapy in 5 (25%). Disease progression was documented in 13 patients, with a total of 10 distant metastases and 6 in-field nodal recurrences. Treatment complications occurred in 14 patients: lymphedema, 9; lymphedema and fibrosis, 1; lymphedema and wound dehiscence, 1; wound dehiscence, 1; lymphedema and seroma, 1; and lymphedema, seroma, and fibrosis, 1. Conclusion: Patients with axillary and inguinal nodal metastases from melanoma have poor overall survival. Surgery and adjuvant radiotherapy provided a 54% nodal control rate. No plexopathy or grade 3 lymphedema complications were seen; however, 20% developed wound dehiscence.

Radiotherapy is often not administered because of a belief that melanoma is radioresistant [12].Studies have suggested high-dose-per-fraction radiotherapy may render melanoma radioresponsive [13].However, this has not been confirmed by prospective clinical trials [14].The long-term sequelae of high-dose-per-fraction radiotherapy, especially intensity-modulated radiotherapy (IMRT), in patients with melanoma metastatic to axillary or inguinal lymph nodes have not been thoroughly characterized [7,12,14].The aim of this study was to examine the effects of adjuvant radiotherapy on in-field nodal control (NC) of melanoma metastatic to axillary and inguinal lymph nodes and to document treatment-related complications.
this study granted permission for their data to be used for research purposes.
Relapse was defined as any clinical or radiographic evidence of tumor recurrence.In-field NC was defined as non-recurrence of lymph node disease within the radiotherapy treatment volume.Out-of-field marginal recurrence was defined as recurrence of lymph node disease outside but adjacent to the radiotherapy treatment volume.Treatment-related lymphedema was retrospectively characterized according to the Common Terminology Criteria for Adverse Events version 4.0.Grade characterization required inference based on documented pertinent positive and negative physical examination findings.
Overall survival, freedom from relapse, freedom from distant metastasis, freedom from out-of-field marginal recurrence, and in-field NC were estimated using the Kaplan-Meier method and compared between subgroups using the log-rank test in univariate analysis.Because of small sample size, multivariate analysis was not performed.
Data were analyzed using JMP statistical software (version 9; SAS Institute Inc, Cary, North Carolina).Chisquared tests were used to examine associations between categorical variables.A P value of less than 0.05 was considered significant.The start of radiotherapy was used as time 0.

Patient characteristics
Twenty-four patients received radiotherapy after axillary or inguinal lymph node surgery for metastatic melanoma.Excluded were 4 patients treated palliatively for gross residual disease.A total of 20 patients (11 with axillary lymph node metastases, 9 with inguinal lymph node metastases) were studied.Patient and tumor characteristics at the time of initial melanoma diagnosis are listed in Table 1.

Treatment
Sixteen patients (80%) underwent axillary or inguinal lymph node surgery at the time of the initial diagnosis and surgery for the primary tumor and were found to be lymph node positive.The remaining 4 patients (20%) were observed and subsequently developed lymph node metastases.The time to delayed lymph node metastasis was 9 months, 17 months, 22 months, and 31 months.For the 17 patients in whom the size of the largest involved lymph node was documented, the median was 6.0 cm (range, 0.4-8.8cm).The median number of lymph nodes involved was 2 (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].Table 2 lists the nodal characteristics.Nodal staging according to the American Joint Committee on Cancer staging system (seventh edition) [15] was categorized at the time of surgery that preceded radiotherapy.None of the patients had local recurrence at the time of their delayed nodal recurrence.3.
In 1 of the 2 patients with marginal recurrences, the treatment failure occurred inferior to the target volume, which extended generously beyond the operative bed.In the other patient, the recurrence was inside the operative bed, which was not covered by the target volume.

Treatment-related complications
Treatment-related complications were documented in 14 patients (70%) (Table 6).Nine patients experienced only lymphedema.Of these, 5 patients had grade 1 lymphedema.Two patients had grade 1 lymphedema before the start of radiation without subsequent progression of symptoms.One patient initially had grade 1 lymphedema, which progressed to elbow contracture with a second course of radiotherapy.Another patient had an initial diagnosis of grade 1 lymphedema, which progressed to a "recalcitrant" state.One patient had grade 1 lymphedema before the start of radiation, but fibrosis developed.All patients experiencing lymphedema were treated with a compression garment.Abbreviations: IMRT = intensity-modulated radiotherapy; RT = radiotherapy; 3-D = 3-dimensional; a = Values are number (percentage).
One patient had grade 1 lymphedema and an inguinal wound dehiscence.The wound was treated with a freeflap reconstruction (grade 3 complication).One patient had an axillary and shoulder wound dehiscence attributed to radiation recall, initiation of multidrug chemotherapy after radiotherapy, and infection with methicillin-sensitive Staphylococcus aureus.The wound was managed with multiple débridements and 2 free-flap closures (grade 3 complication).
One patient had grade 1 lymphedema and a seroma after initial inguinal lymph node surgery and continued to experience these complications through radiotherapy.This patient had a prior lymph node dissection.After radiotherapy, the lymphedema worsened to the point of "limited mobility," and the seroma remained unresolved (grade 3 complication).One patient had grade 2 lymphedema documented as "erythema and induration"; however, it was unclear whether the findings were from the lymphedema or from the lymphedema and concurrent inguinal seroma and recurrent cellulitis.This patient had 3 prior inguinal dissections, and fibrosis also developed in this patient.
Interestingly, 3 patients received a prophylactic lymphedema compression stocking but did not have lymphedema documented.There was no brachial or lumbosacral plexopathy.The median time interval between surgery and the start of postoperative radiotherapy did not differ in patients who did and did not have complications: 5.0 weeks (range, 3.3-10.5weeks) compared with 5.6 weeks (range, 3.0-6.7 weeks respectively).

Discussion
Although melanoma has traditionally been regarded as a radioresistant disease, a contemporary study has shown NC is significantly improved in selected patients treated with adjuvant radiotherapy [5].We report a 2-year NC rate of 54% for the entire group, with a rate of 54% for patients with axillary metastases and 67% for patients with inguinal metastases.Though our reported time frame for outcomes is different than 5-year published reports, we still see that our NC rate is less than reported NC rates of 81% to 89% for all nodal metastases, 88% to 91% for axillary metastases, and 69% to 77% for inguinal metastases at 5 years (Table 7) [1,7,15].The intergroup randomized Trans-Tasman Radiation Oncology Group (TROG) trial reported that 20 of 109 patients who received adjuvant radiotherapy experienced a recurrence within the lymph node field compared with 34 of 108 observational patients [5].The 3-year reported cumulative incidence of lymph node relapse was 19% in the radiotherapy group and 31% in the observational group [5].The higher risk of lymph node field relapse in the observational group was also similar on analysis for axillary and inguinal nodal sites [5].Therefore, our NC rate of 54% is also less than that in both arms of the TROG trial.The lower NC rate in our study might be a reflection of our cohort's characteristics.Only 4 of our patients met the eligibility criteria for the TROG study.Three of the patients were treated with adjuvant radiotherapy after 2 or more nodal recurrences.Further, we also reported subsequent nodal recurrences even after distant metastases were documented.
With regard to treatment-related complications, there was no plexopathy.Lymphedema was mainly grade 1 and managed by referral to the lymphedema clinic and use of compression garments.Moreover, none of the lymphedema cases were severe enough to cause skin folds.The 2 patients with the poor inguinal, axillary and shoulder wound healing were successfully treated with reconstructive surgery.There was no difference in the time interval between surgery and the start of postoperative radiotherapy between patients who had no complications and those in whom wound dehiscence developed, suggesting there is no relationship between wound-healing issues and the interval between surgery and the onset of radiotherapy in our study.
Nevertheless, the pattern of lymphedema-prominent treatment-related complications in our study is similar to that previously reported, with the greater part of complications being lymphedema and the vast majority of lymphedema being low grade and manageable medically [1,2,6,7,16].In the TROG trial, the most common adverse event related to radiotherapy in the axilla and groin was dermatitis, and the most common adverse events related to surgery were seroma formation and wound infection [5].This relatively small magnitude of severe radiotherapy-induced lymphedema is most likely a reflection of improved radiotherapy and lymphedema management techniques in the modern era.Interestingly, 3 patients in our study received prophylactic compression stockings, and lymphedema did not develop in these patients, suggesting investigation is warranted into whether prophylactic use of compression stockings reduces the incidence and severity of lymphedema.
Although adjuvant radiotherapy has been shown to improve NC in selected patients in a prospective trial, the optimal technique and schedule remain controversial.This study specifically reports outcomes for IMRT.
IMRT is more expensive than 3-dimensional conformal radiotherapy and subsequently may be thought of as placing a greater financial burden on the patient and society.However, IMRT allows for more conformal dose to the tumor volume while sparing critical structures such as the brachial plexus in the axilla and the small bowel, bladder, rectum, external genitalia, and hip when treating the inguinal region.However, the higher charge per treatment can be mitigated by the use of hypofractionation with fewer treatments.
With regard to optimal radiotherapy dose and fractionation, there is no single standard.Hypofractionated regimens have been favored by some on the basis of radiobiological data suggesting melanoma may be more responsive to higher-dose-per-fraction regimens, although this has not been confirmed clinically [12].The TROG trial used 48 Gy in 20 fractions.Retrospective studies have generally analyzed outcomes for hypofractionated regimens and have documented impressive NC rates [2,7,9,[16][17][18].A hypofractionated regimen is more convenient for patients and also less costly.Future studies could compare 48 Gy in 20 fractions to a more hypofractionated regimen.
Although surgery and adjuvant radiotherapy may satisfactorily control nodal disease, the risk of distant metastases and melanoma-related death was relatively high in the patients reported in this study.We report a 2-year overall survival rate of 53% and freedom from distant relapse rate of 27%.This is less than the 5-year overall survival and freedom from distant relapse rates of 51% and 46% to 49%, respectively, reported by others [7,16].As noted above, our higher rates are probably a reflection of selection bias (our referral pattern and/ or patient population).The introduction of ipilimumab into the multidisciplinary management of metastatic melanoma has significantly improved survival outcomes [19].Nevertheless, distant metastasis remains a high risk in patients with advanced disease requiring further improvements in systemic therapy and further investigations into outcomes of combined systemic and local therapies.

Conclusion
Our results show outcomes could be improved in patients with melanoma metastatic to axillary or inguinal lymph nodes who receive adjuvant radiotherapy.We recommend evaluating earlier intervention with postoperative adjuvant radiotherapy and hypofractionated treatment protocols.More effective therapeutics that may be safely combined with radiotherapy are also needed.We acknowledge this study has limitations.It was a small cohort with short median follow-up.Additionally, the retrospective nature of this review inherently creates bias and incomplete data.However, this study reports recurrence and treatment-related outcomes specific for hypofractionated IMRT.

Table 1
Patient and tumor characteristics at initial melanoma diagnosis (N=20) a

Table 2
Lymph node characteristics at time of surgery preceding postoperative radiotherapy (N=20) a second documented lymph node recurrence after initial lymph node surgery, and 1 patient received radiotherapy on the third documented lymph node recurrence.One patient received systemic therapy for the initial lymph node metastasis and then received surgery and radiotherapy on lymph node progression.Patient nodal characteristics, treatment course, outcomes, and complications are summarized in Table for lymph node recurrence or progression after initial lymph node surgery or after initial systemic therapy.Four of 7 patients received radiotherapy on the first nodal recurrence or progression after lymph node surgery or systemic therapy, whereas 1 patient received radiotherapy on the

Table 5
Site of disease progression after radiotherapy (N=20) a

Table 6
Treatment-related complications by nodal site, RT technique, and RT dose (N=20) a

Table 7
Studies of melanoma metastatic to axillary and/or inguinal lymph nodes.