Malignancies of the skin and soft tissue are among the most common cancers diagnosed in the United States.1 While the majority of these neoplasms are basal and squamous cell cancers with very low mortality, the incidence of malignant melanoma is increasing, and this potentially fatal malignancy was the fifth and seventh most common cancer in men and women, respectively, in 2015.2 Across the country, nearly 10,000 deaths will occur annually from this disease.
Treatment of melanoma has changed dramatically over the last several decades. Emphasis on early detection and diagnosis has led to more prompt identification of melanoma, with approximately half of new diagnoses being in situ disease.2 A series of studies initiated in the 1970s have documented the safety of smaller resection margins (1–2 cm vs. the historical 5 cm), sparing patients the accompanying morbidity and healthcare costs.3,4,5,6 A series of seminal articles have extended our understanding of nodal management, including the role of sentinel node biopsy, for early identification of nodal metastases without the morbidity of anatomic nodal dissection.7,8
Accompanying the changes in surgical management have been innovations in the systemic treatment of melanoma. Adjuvant interferon has been shown to reduce recurrences and improve survival, albeit modestly.9 The biggest changes in systemic treatment for metastatic melanoma have come with the introduction of targeted therapy (BRAF and MEK inhibition) and immunotherapy targeted at the CTLA-4 and PD-1 pathways. New research seeks to better understand how to incorporate these therapies with surgery, either as adjuvant therapy for high-risk stage II and III patients, or in combination with metastectomy in stage IV disease.
Soft tissue sarcoma represents a more rare, but important set of malignancies that the general surgeon will encounter. Almost 12,000 cases of sarcoma are identified in the United States every year with approximately 4870 deaths.2 Because of the relative rarity and heterogeneity of these malignancies, rigorous clinical trials have been more difficult to produce. However, beginning with the work at the National Cancer Institute in the 1970s and 1980s, the previous practice of amputation for soft tissue sarcoma of the extremities has been replaced with a limb-sparing approach, often in conjunction with radiotherapy. Knowledge gained from the management of extremity soft tissue sarcoma has been extrapolated to tumors arising in the retroperitoneum, which constitute about 12% of all sarcomas. Management of these tumors remains controversial, including the roles of aggressive resection of adjacent organs and the application of neoadjuvant radiation. Trials attempting to answer the latter have failed to accrue in the past, but a study is currently in progress under the guidance of the European Organization for Research and Treatment of Cancer that will hopefully add to our knowledge on this topic.
The treatment of soft-tissue sarcomas of the extremities: Prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy.
Rosenberg SA, Tepper J, Glatstein E, Costa J, Baker A, Brennan M, DeMoss EV, Seipp C, Sindelar WF, Sugarbaker P, Wesley R
Ann Surg. 1982;196(3):305–315.Takeaway Point: A limb-sparing approach (excision plus radiation) for soft tissue sarcoma of the extremity has equivalent survival to amputation.
Commentary: This study was the first rigorous comparison of limb-sparing surgery with radiation versus amputation for soft tissue sarcoma of the extremity. Forty-three patients were randomized between the two approaches. There were no significant differences in 5-year recurrence free (71% vs. 78%) or overall (83% and 88%) survival in the limb-sparing and amputation groups, respectively. The findings from this study dramatically changed the management of patients with extremity sarcomas, allowing limb preservation and better functional outcomes. This paradigm of organ preservation through more conservative surgery with adjuvant (or neoadjuvant) radiation has also been applied to other anatomic locations of sarcoma (eg, retroperitoneum, head, and neck) as well as to other malignancies (eg, breast, larynx).
Introduction: Soft tissue sarcomas represent a diverse group of pathologic tumors but share a tendency to local invasion along anatomic structures, resulting in high rates of local recurrence after surgical excision. Historically, this prompted radical excision with limb amputations to achieve local control. The combination of surgical excision with postoperative radiation has been suggested as a limb-sparing alternative. This is the first study to compare the two alternatives directly.
Objectives: To compare limb-sparing surgery with radiation to radical excision and amputation for soft tissue sarcomas of the extremity.
Trial Design: Prospective randomized controlled trial.
Inclusion Criteria: Patients with diagnosis of round cell or pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, synovial cell sarcoma, fibrosarcoma, neurofibrosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, or undifferentiated sarcoma distal to the shoulder or hip joints.
Exclusion Criteria: Metastatic disease, history of prior chemotherapy or radiation, other malignancy (other than basal cell), severe infection, concomitant severe disease, age <30 years with embryonal or alveolar rhabdomyosarcoma. Extensive tumor where local excision was not possible.
Intervention: Either amputation or limb-sparing resection (removal of all gross disease) followed by radiation therapy, randomization stratified by histology, grade, time from initial diagnosis, and proximal or distal lesion.
Primary Endpoint: Disease-free and overall survival.
Secondary Endpoint: Quality of life.
Sample Size: 43 patients enrolled between 1975 and 1981, with 16 in the amputation arm and 27 in the limb-sparing plus radiation arm.
Statistical Analysis: Mantel–Haenszel test, Kaplan–Meier curves, Fisher exact test.
Baseline Data: There were no significant differences in gender, race, site, histology, or grade between the groups. Patients randomized to amputation tended to be younger.
Outcomes: Four of the 27 limb-sparing patients had positive resection margins, versus zero in the amputation group. Median follow-up was 4 years and 8 months. In that time, three amputation patients and six limb-sparing patients experienced recurrence. There was no significant difference in time to recurrence between the groups. Five-year disease-free survival (75% amputation, 71% limb-sparing) and overall survival (88% vs. 83%) were similar between the groups. There was a trend toward higher local recurrence in the limb-sparing group (p 0.06). There was no significant difference in quality-of-life parameters between the two groups.
Conclusion: There is no difference in disease-free or overall survival between amputation and limb-sparing surgery plus radiation for soft tissue sarcoma of the extremity.
Limitations: The same cohort was also enrolled in a study of adjuvant chemotherapy. This may account for the overall improvement in outcomes compared with prior studies of extremity soft tissue sarcomas.
Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm.
Veronesi U, Cascinelli N, Adamus J, Balch C, Bandiera D, Barchuk A, Bufalino R, Craig P, Marsillac JD, Durand JC, van Geel AN, Holmstrom H, Hunter JA, Horgensen OG, Kiss B, Kroon B, Lacour J, Lejeune F, MacKie R, Mechl Z, Mitrov G, Morabito A, Nosek H, Panizzon R, Prade M, Santi Pierluigi, Slooten EV, Tomin R, Trapeznikov N, Tsanov T, Urist M, Wozniak KD
NEJM. 1988;318(18):1159–1162.Takeaway Point: For melanomas less than 2 mm thick, 1-cm margins are as effective as 3-cm margins in obtaining local control and are associated with equivalent survival.
Commentary: This article presents the results of a large, multicenter randomized trial organized by the World Health Organization Melanoma Group of excision margins in early-stage melanoma. 610 patients with melanomas less than 2 mm Breslow thickness were randomly assigned to 1- or 3-cm margins of excision around the biopsy site. After a mean follow-up of 55 months, there was no significant difference in 5-year survival between the groups. The locoregional recurrence rates were extremely low in both groups. The results from this study helped usher in an era of more conservative resection of primary melanoma. Prior to this study, margins of 3–5 cm or even wider were advocated, leading to a great deal of local morbidity, including necessity for skin grafts and complex flap reconstructions. After these findings were published, 1-cm margins became the standard for thin melanoma.
Introduction: Prior to this study, the standard of care for excision of primary melanoma consisted of wide local excision with 3–5-cm margins. Breslow first reported favorable outcomes of narrow margins in 1977, but no randomized trial had yet compared the two approaches.
Objectives: To determine whether an excision with a 1-cm skin margin was adequate and safe in patients with cutaneous melanomas ≤2 mm thick.
Trial Design: Randomized controlled trial.
Inclusion Criteria: Patients with clinical stage I melanoma (≤2 mm thick).
Exclusion Criteria: Facial or digit melanomas, excisional biopsy > 6 weeks prior to randomization, age >65, satellite nodules, multiple primary melanomas, or history of additional cancer.
Intervention: All patients had excisional biopsy to verify thickness <2 mm, and were then randomized to excision with either 3- or 1-cm margins surrounding the scar. All participating sites had a standard protocol for management of recurrent disease during follow-up.
Primary Endpoint: Recurrence rate.
Secondary Endpoints: Disease-free and overall survival.
Sample Size: 612 patients enrolled between 1980 and 1985, 305 were randomized to 1-cm margins and 307 to 3-cm margins.
Statistical Analysis: χ2 test, Kaplan–Meier curves.
Baseline Data: The two groups were similar in gender, age, and location of the primary tumor. Mean thickness was 0.99 mm in the 1-cm excision group and 1.2 mm in the 3-cm excision group (p > 0.05).
Outcomes: At 55 months’ follow-up, survival was 96.8% in the 1-cm excision group and 96% in the 3-cm excision group (p 0.58). Disease-free survival was also similar between the groups (p 0.66). There was no difference in rates of regional or distant nodal metastases.
Conclusion: More conservative surgical excision (1 cm lateral margins) is as effective as the traditional 3 cm margins in patients with cutaneous melanoma ≤2 mm.
Limitations: No multivariate analysis was performed. Follow-up was at 55 months; this may not be long enough (especially given the very high survival rate) to demonstrate the true difference in approaches.
Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial EST 1684.
Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH
J Clin Oncol. 1996;14(1):7–17.Takeaway Point: Interferon alfa-2b (IFNα-2b) prolongs the relapse-free interval and overall survival following resection of high-risk (T4 or N1) melanoma.
Commentary: IFNα-2b had previously been found to have antitumor activity against metastatic melanoma. Patients with deep primary tumors or lymph node metastases have a high risk of relapse and mortality. Prior adjuvant therapies had not impacted relapse-free or overall survival. This study evaluated the use of IFNα-2b as adjuvant therapy in high-risk patients, and found that IFN prolongs both relapse-free interval and overall survival following resection. This was the first study to demonstrate the success of an adjuvant treatment for this population. IFN treatment was associated with significant toxicity, with the majority of patients requiring dose adjustments, and the risk–benefit analysis of when to use this treatment continues to be an individualized decision.
Introduction: IFNα-2b has shown antitumor activity in metastatic melanoma. In this study, it was evaluated as adjuvant therapy following resection in high-risk patients.
Objectives: To evaluate the efficacy of IFNα-2b as adjuvant therapy following resection of deep primary (T4) or regionally metastatic (N1) melanoma.
Trial Design: Phase 3, multicenter, blinded, randomized controlled trial.
Inclusion Criteria: Patients with histologically proven primary cutaneous melanoma. Patients were grouped into four categories based on extent of disease: (1) deep (>4 mm) primary melanomas (T4, N0, M0), (2) primary melanomas of any stage with occult lymph node metastasis discovered at elective lymph node dissection (Tp, N1, M0), (3) clinically detected regional lymph node involvement with synchronous primary melanoma (TcN1M0), and (4) regional lymph node recurrence after primary surgery. Groups 1–3 were required to enter the study within 56 days of first biopsy; group 4 was required to enter within 42 days of lymphadenectomy.
Exclusion Criteria: Those with staging errors; failure to perform lymphadenectomy; unknown primary site. Prior systemic therapy, distant metastatic disease, or significant comorbidities.
Intervention: Patients were randomized to either IFNα-2b at maximum tolerated doses of 20 MU/m per day IV for 5 days per week for 4 weeks, then 3 times weekly at 10 MU/m per day subcutaneously (SC) for 48 weeks, or clinical observation.
Primary Endpoint: Relapse-free survival; overall survival.
Secondary Endpoints: Relapse-free survival stratified by stage; association of patient characteristics (age, sex, performance status, Clark level, Breslow thickness, time to randomization, ulceration, excisional biopsy performed) with survival.
Sample Size: 280 patients enrolled between 1984 and 1990, block-randomized according to tumor stage, 143 to receive IFN, 137 to observation alone.
Statistical Analysis: Kaplan–Meier survival curves; estimated hazard plots for overall survival smoothed with a simple kernel technique; Fisher’s exact test; Cox’s proportional-hazards regression; stratified log-rank test; Cox model.
Baseline Data: Patients largely well matched across baseline characteristics. Nonsignificant trend toward thicker primary in the observation group.
Primary: Median relapse-free survival time for patients who received IFN was 1.72 years, versus 0.98 years for observation alone (p 0.0023). Overall median survival time was 3.82 years for IFN patients and 2.78 years for observation (p 0.0237).
Secondary: The estimated 5-year relapse-free survival rate was 37% for IFN versus 26% for observation. The estimated 5-year survival rate was 46% for IFN and 37% for observation. There was a marked suppression of relapse and death with IFN treatment across all node-positive groups. In patients with nonpalpable but pathologically detected lymph node metastases, there was a reduction of the estimated hazard of relapse from 60% to 25% during the first year of treatment. The reduction in hazard of relapse for those with clinically palpable nodes was even more prominent. In the multivariate analysis, treatment with IFN, age, time from diagnosis or first recurrence to study entry, and tumor ulceration were all significantly associated with both relapse-free and overall survival (p < 0.05). Dosing delays or dose reductions were required for 50% of patients during the IV treatment phase and for 48% of patients during the SC treatment phase due to side effects. These were primarily constitutional and neuropsychiatric symptoms, as well as myelosuppression and hepatotoxicity and included two deaths from hepatic failure. Overall 74% of patients were able to continue treatment until 1 year.
Conclusion: IFNα-2b prolongs the relapse-free interval and overall survival following resection of deep primary (T4) or regionally metastatic (N1) melanoma. Toxicity is significant, and requires dose adjustments in the majority of patients.
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