Despite many advances in the treatment of melanoma, it still continues to be a disease that affects many people. Fortunately, there have been a multitude of randomized trials that have refined the treatment of this prevalent disease. From 1975 to 2000, there were 154 prospective randomized trials on the treatment of local, regional, and metastatic melanoma. From 2001 to now, additional randomized trials have focused on the role of surgery, adjuvants to surgery, and treatment of metastatic disease. The results of the practice-changing trials are summarized in this review.
Key points
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The results of trials have continued to demonstrate that more aggressive management of the regional lymph node basin is not associated with survival benefit.
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With the historical poor outcomes of chemotherapy in the treatment of melanoma, studies have focused on immunotherapy.
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The field of treatment of metastatic disease has been revolutionized by the advent of targeted therapies and checkpoint blockade, and for the first time, survival in Stage IV melanoma has improved.
Introduction
Despite many advances in the treatment of melanoma, it still continues to be a disease that affects many people. Fortunately, there have been a multitude of randomized trials that have refined the treatment of this prevalent disease. From 1975 to 2000, there were 154 prospective randomized trials on the treatment of local, regional, and metastatic melanoma. From 2001 to now, additional randomized trials have focused on the role of surgery, adjuvants to surgery, and treatment of metastatic disease. The results of the practice-changing trials are summarized in this review.
Introduction
Despite many advances in the treatment of melanoma, it still continues to be a disease that affects many people. Fortunately, there have been a multitude of randomized trials that have refined the treatment of this prevalent disease. From 1975 to 2000, there were 154 prospective randomized trials on the treatment of local, regional, and metastatic melanoma. From 2001 to now, additional randomized trials have focused on the role of surgery, adjuvants to surgery, and treatment of metastatic disease. The results of the practice-changing trials are summarized in this review.
Primary melanoma
Clinical trials on excision margins have failed to demonstrate a difference in survival with more aggressive surgery, and yet local recurrence is associated with a poor overall survival. Therefore, investigation into the appropriate margin has continued. Two recent trials addressed the impact of excision margins of the primary lesion on outcome in patients with melanoma. A large European multicentric Phase III study from 9 European centers investigated the difference between 2-cm and 5-cm excision margins for melanomas less than 2.1 mm thick. No significant difference was found in the number of recurrences, recurrence-free survival, or overall survival between the 2 excision margin groups. Another trial from the United Kingdom studied patients with melanomas 2 mm or greater in thickness randomized to either 1-cm or 3-cm margins. This trial did not demonstrate a significant difference in overall survival or melanoma-specific survival but did establish an increase in locoregional recurrence in the 1-cm margin group as compared with the 3-cm margin group (hazard ratio [HR] 1.26; P = .05). Patients in this trial did not have staging with sentinel lymph node biopsy, so it is not clear if the increased locoregional recurrence is a result of unbalanced groups. Taken collectively, the results of all the randomized trials on excision margins suggest that reasonable practice is still 1-cm margin for lesions less than 1 mm in thickness, and 2-cm margins for thicker lesions. Whether 1-cm margins may yield outcomes equivalent to 2-cm margins for lesions of 1 to 2 mm remains to be addressed specifically by the MelmarT trial. This trial randomizes to 1-cm versus 2-cm margins and is currently accruing patients ( https://clinicaltrials.gov/ct2/show/NCT02385214 ).
Regional metastatic disease
The results of trials have continued to demonstrate that more aggressive management of the regional lymph node basin is not associated with survival benefit. As shown in Tables 1 and 2 , elective lymph node dissection (ELND) did not improve survival in patients with melanoma. Only the long-term follow-up of the Intergroup trial suggested a survival benefit in patients with nonulcerated limb melanomas with thickness 1 to 2 mm. The sentinel lymph node (SLN) biopsy technique supplanted the need for further investigations into the merits of ELND and is the standard approach to evaluate clinically negative lymphatic basins. The Melanoma Selective Lymphadenectomy Trial (MSLT)-1 trial randomized patients with intermediate-thickness melanomas to either wide local excision (WLE) with nodal observation, or WLE in combination with SLN biopsy. Those patients with metastatic disease detected in the sentinel node underwent immediate completion lymph node dissection, whereas the patients in the observation arm underwent a therapeutic lymphadenectomy for clinically evident nodal disease. The study confirmed the prognostic value of the sentinel node status for patients with intermediate-thickness melanomas. MSLT-1 did not demonstrate any difference in melanoma-specific survival between the 2 groups, which was the primary endpoint of the trial. In a subset analysis of all patients with nodal metastases, however, there was a statistically significant improved 5-year survival rate in those patients who underwent SLN biopsy and immediate lymphadenectomy versus those who underwent delayed lymphadenectomy on clinically evident disease (72.3% vs 52.4%).
| Trial | Thickness Melanoma | Margin | Comments |
|---|---|---|---|
| World Health Organization | <2 mm | 1 cm vs 3 cm | 1-cm margin safe for melanoma <1 mm, increased local recurrence with 1-cm excision in melanoma >1 mm |
| Intergroup | 1–4 mm | 2 cm vs 4 cm | 2-cm margin safe for intermediate-thickness melanoma |
| Swedish | 0.8–2 mm | 2 cm vs 5 cm | 2-cm margin safe |
| European phase III | <2.1 mm | 2 cm vs 5 cm | 2-cm safe |
| United Kingdom | >2 mm | 1 cm vs 3 cm | Increased locoregional recurrence rate with 1-cm excision, no sentinel lymph node biopsy performed |
| Study | n | Site | Thickness, mm | F/U, y | OS: WLE | OS: WLE + ELND | P |
|---|---|---|---|---|---|---|---|
| Sim et al, 1978 | 173 | Excluded midline trunk, head and neck | Any | NR | 85 | 85 | NS |
| Veronesi et al, 1982 | 553 | Extremity | Any | 8.2 | 72 | 74 | NS |
| Balch et al, 1996 (intergroup) | 740 | All | 1–4 | 7.4 | 82 | 86 | .25 |
| Intergroup f/u | 10 | 73 | 77 | .12 | |||
| Cascinelli et al, 1998 | 240 | Trunk | >1.5 | 11 | 51 | 62 | .09 |
The therapeutic value of completion lymph node (CLND) dissection for patients with a positive SLN biopsy is currently under investigation in the worldwide MSLT-II trial. This trial randomizes patients to CLND or observation with nodal ultrasound. In the meantime, a smaller replicate trial was performed in Germany, the DeCog trial. This trial did not demonstrate any evidence of difference in distant metastasis-free survival between groups.
The role of prophylactic regional hyperthermic isolated limb perfusion (ILP) for patients with high-risk melanomas was examined in a cooperative-group trial that randomized 832 patients to ILP with melphalan. No significant difference in survival was reported at the conclusion of the trial. Since 2001, the results of one additional randomized trial have been performed using ILP in the treatment of locally advanced melanoma (ACOSOG trial Z0020). This trial randomized patients with locally advanced melanoma to standard hyperthermic limb perfusion with either melphalan alone or melphalan in combination with tumor necrosis factor (TNF). The trial was stopped early because of an increase in grade 4 toxicities, including amputations, in the combined treatment arm. The survival data, with short follow-up, was not different between the 2 groups. TNF is currently not approved for use in the United States; however, continued use at high-volume European centers has demonstrated efficacy and safety of this drug.
Adjuvant treatment of high-risk melanoma
With the historically poor outcomes of chemotherapy in the treatment of melanoma, studies have focused on immunotherapy. Adjuvant immunotherapies aim to activate the host immune through vaccines, interferons, and other immune modulators, such as Bacillus Calmette-Guerin (BCG) and checkpoint blockade.
Interferon (IFN) is a protein that is produced by the immune system in response to viral infection and foreign proteins. Exogenous administration of this compound, therefore, is in an effort to stimulate the immune system to recognize melanoma antigens. The results of adjuvant IFN treatment, on the whole, fail to demonstrate a survival benefit, but do demonstrate a modest improvement in recurrence-free survival. Investigations have therefore continued to attempt to identify if there is a subset of patients and a dosing regimen that will improve outcomes. IFN-alpha-2b was approved by the Food and Drug Administration as adjuvant treatment for high-risk patients with deep primary melanomas or regional lymph node metastatic disease after the Eastern Cooperative Oncology Group (ECOG) trial E1684. This trial compared high-dose IFN-alpha-2b with observation, and found a significant improvement in disease-free and overall survival. The follow-up study compared observation, low-dose IFN-alpha-2b, and high-dose IFN-alpha-2b and found improved relapse-free survival but no overall survival difference.
The continued inconsistency in results of IFN trials is demonstrated by 2 studies without significant results: the AIM HIGH Study and European Organisation for Research and Treatment of Cancer (EORTC) 18952. The AIM HIGH Study randomized patients to long-term low-dose IFN or observation after resection of stage IIB or III melanoma. In this trial, there was an initial benefit in recurrence-free survival that disappeared after 3 years of follow-up and was not significant. Fifteen percent of patients in the IFN group withdrew from the study and toxicities were modest. These results were similar to those of the EORTC 18952 trial, which randomized patients after resection with stage IIb or III melanoma to 13 months or 25 months of intermediate-dose IFN or observation. Recent results from the EORTC 18991, which randomized patients with stage III melanoma after resection to pegylated IFN or observation also demonstrated additional promise for this immunotherapy. The trial demonstrated a small (6% at 4 years) improvement in recurrence-free survival with the pegylated interferon, which is potentially best noted in the subgroup of patients with N1 disease. It is possible that long-term follow-up of pegylated IFN will continue to show an improvement in patients with early stage III disease, and therefore it may have a more definitive role in the adjuvant setting than standard IFN, because it is also better tolerated.
IFN has also been combined with other immunologic and chemotherapeutic agents. Garbe and colleagues randomized patients with stage III disease following surgery to adjuvant low-dose IFN with or without dacarbazine (DTIC) or to observation. Overall survival was significantly higher by multivariate analysis in patients with adjuvant low-dose IFN compared with surgery alone, but with the addition of dacarbazine, this survival benefit was lost. In another trial, high-dose IFN was compared with the ganglioside vaccine, GM2-KLH/QS-21, in patients with resected stage IIB and III melanomas. The trial was halted on an interim analysis due to a significant recurrence-free survival and overall survival benefit in the high-dose IFN arm. In 2007, Mitchell and colleagues reported on 604 patients who were randomized to 2 years of treatment with an allogeneic melanoma lysate and low-dose IFN or high-dose IFN. Overall and recurrence-free survival were the same between the 2 arms, providing another trial without any clear benefit to vaccine use in the adjuvant setting. Other immunotherapy trials have examined BCG in the adjuvant setting. Early trials reported improvements in disease-free survival with BCG use. To test this hypothesis, Agarwala and colleagues randomized 734 patients with stage I-III melanoma into 4 groups that were assembled into 22 cohorts: (1) BCG versus BCG plus DTIC and (2) BCG versus observation. There was no benefit to BCG or BCG plus DTIC with any patients in the stage I-III categories of patients with melanoma.
The Canvaxin vaccine consisted of allogeneic melanoma cells with high antigen expression. Much excitement was generated when phase II studies showed an improvement in survival when used as an adjuvant in stage III patients. Unfortunately, a multicenter randomized phase III trial failed to confirm these results, and this therapy is no longer used.
A recent adjuvant phase III trial (EORTC 18071) randomized patients with stage III disease, with 1 mm of tumor burden in the sentinel lymph node, to high-dose anti-CLA4 immunotherapy (ipilimumab at 10 mg/kg) versus placebo. The study demonstrated an improvement in recurrence-free survival, its primary endpoint, for the adjuvant ipilimumab group compared with control (40.8% vs 30.3% at 5 years, P <.001). Moreover, there was an improvement in overall survival observed at 5 years favoring the adjuvant immunotherapy group (65.4% vs 54.4%, P = .001). Notably, grade 3 or 4 immune-related adverse events occurred in 41.6% of patients in the adjuvant ipilimumab group, with 1.1% of patients in the treatment group having immune-related deaths.
Treatment of metastatic melanoma
The field of treatment of metastatic disease has been revolutionized by the advent of targeted therapies and checkpoint blockade, and for the first time, survival in stage IV melanoma has improved. Immunotherapy with CTLA-4 or PD1 blockade has demonstrated survival benefits in multiple trials. Furthermore, blockade of the MAP kinase pathway in patients with a BRAF mutation have also resulted in survival benefit. Unfortunately, targeted therapy inhibition leads to resistance and now most patients receive combination BRAF/MEK inhibition. This section reviews the historical trials leading up to and including the practice of changing trials of targeted inhibition and immunotherapy.
The Dartmouth regimen (cisplatin, carmustine, DTIC, and tamoxifen) and its components were the most commonly studied regimen in several large prospective randomized controlled trials (RCTs). Activity was demonstrated in the 1992 study by Cocconi and colleagues that showed improved response rates and median survival with DTIC plus tamoxifen compared with DTIC alone. Chapman and colleagues then performed a study that showed no difference between the Dartmouth regimen and DTIC with regard to tumor response, toxicity, or survival. At that time, DTIC alone was thus felt to be the optimal treatment. Temozolomide also has been used to treat patients with metastatic melanoma, and DTIC was compared with temozolomide in a study by the Royal Marsden Hospital. Patients treated with temozolomide demonstrated equivalent progression-free survival (PFS), response rates, toxicity, and survival. Temozolomide also was studied in combination with cisplatin, with no benefit found in the combined regimen.
Investigators have combined treatments with biologic agents and chemotherapies in an effort to maximize activity against melanoma. Unfortunately, most of these studies have not improved survival. As reviewed in the prior chapter, studies comparing interleukin (IL)-2/IFN-alpha and chemotherapy with IL-2/IFN-alpha alone or IL-2 with IL-2/IFN-alpha showed no difference in overall survival. This review includes a biochemotherapy trial that is similar to other trials, such as EORTC 18951, in structure and outcomes, in that it compared cisplatin, vinblastine, and DTIC with cisplatin, vinblastine, dacarbazine, IL-2, and IFN-alpha and found no significant alteration in overall survival or durable responses. There were higher response rates and a longer median PFS rate with the biochemotherapy, but there were significant toxicities associated with these regimens. The conclusion from these trials is that biochemotherapy with IL-2 and IFN-alpha are not recommended for treating metastatic melanoma.
Immunotherapy with CTLA-4 blockade was the first to demonstrate a survival benefit, although modest, of 10% in heavily pretreated patients with metastatic melanoma. The durability of response with actual survivors alive at 10 years gave tremendous hope to the field. Blockade of PD1 was also then shown to be effective, with a response rate of 30%. The combination of CTLA-4 and PD1 blockade is now under investigation with initial response rates reported of more than 50%.
Furthermore, knowledge about the genomic drivers of melanoma have expanded. BRAFV600E mutation is found in approximately 50% of cutaneous melanomas, and blockade of the MAP kinase pathway in patients with a BRAF mutation have also resulted in survival benefit. Many of these patients develop resistance with single-agent blockade and now most patients receive combination BRAF/MEK inhibition. Imatinib mesylate also has been used in a phase II trial with 21 patients who had melanoma cells that expressed c-kit. At 400 mg twice a day, imatinib had little clinical efficacy, although it did have individual responders, suggesting a possible role for imatinib in patients with specific kit mutations.
Level Ia evidence in melanoma
Surgical Trials
Khayat D, Rixe O, Martin G, et al. French Group of Research on Malignant Melanoma. Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1-mm thick). Cancer 2003;97(8):1941–6.
Hypothesis
A smaller excision margin (2-cm) of the primary tumor for patients with melanomas less than 2.1 mm in thickness may yield similar outcomes with regard to disease recurrence and survival as a wider (5-cm) excision margin.
| No. Patients Randomized | Study Groups | Stratification | Significance Demonstrated | % Change Identified in Trial |
|---|---|---|---|---|
| 337 | 2-cm margins n = 161 | Histology | None equivalent | None |
| 5-cm margins n = 165 |
Published abstract
Background
This study addressed the question of whether limited surgery for primary malignant melanoma with a 2-cm margin is as good as a 5-cm margin. An update of a 16-year follow-up is provided.
Methods
Nine European centers, over a period of 5 years, prospectively randomized 337 patients with melanoma measuring less than 2.1 mm in thickness to undergo a local excision with either a 2-cm or a 5-cm margin. Three hundred twenty-six patients were eligible for statistical analysis. Excluded from the trial were patients older than 70 years; those with melanomas from the toe, nail, or finger; and those with acral-lentiginous melanoma. A separate randomization was performed to independently test an adjuvant treatment with a nonspecific immunostimulant, isoprinosine, compared with observation. The median follow-up time was 192 months (16 years) for the estimation of survival and disease recurrences.
Results
There were 22 tumor recurrences in the 2-cm arm and 33 in the 5-cm arm. The median time to disease recurrence was 43 months and 37.6 months, respectively. The 10-year disease-free survival rates were 85% for the group with a 2-cm margin and 83% for the group with a 5-cm margin. There was no difference in the 10-year overall survival rates (87% vs 86%). Isoprinosine did not demonstrate any activity in this setting.
Conclusions
The authors concluded that for melanoma less than 2.1-mm thick, a margin of excision of 2 cm is sufficient. A larger margin of 5 cm does not appear to have any impact on either the rate or the time to disease recurrence or on survival.
Editor’s summary and comments
This multicenter European trial investigated the role of surgical margins for melanoma lesions less than 2.1 mm in thickness by randomizing patients to either 2-cm or 5-cm excisional margins in patients (those older than 70 years and with acral lentiginous lesions were excluded). There was no difference in local tumor recurrence rates, disease-free survival or overall survival with a median follow-up of 16 years between the 2 excision margin groups. This study reinforces the results of the Swedish Melanoma Study group (2-cm vs 5-cm margin groups for 0.8 to 2-mm thickness lesions) and the prior WHO trial discussed above. As a secondary randomization, patients in each excisional margin arm were assigned to receive isoprinosine, shown to have immunostimulation properties toward natural killer cells against melanoma in vitro, or to observation. There was no difference seen in median overall survival or disease-free survival between the groups receiving adjuvant immunotherapy and those followed with observation alone using any subgroup analysis of tumor characteristics or surgery extent, although the numbers in each final randomized group were fairly small (76–89 patients).
Thomas JM, Newton-Bishop J, A’Hern R, et al. United Kingdom Melanoma Study Group; British Association of Plastic Surgeons; Scottish Cancer Therapy Network. Excision margins in high-risk malignant melanoma. N Engl J Med 2004;350(8):757–66.
Hypothesis
Narrow (1-cm) excision margins for high risk melanoma lesions (>2 mm) may be insufficient as compared with wider (3-cm) margins.
| No. Patients Randomized | Study Groups | Stratification | Significance Demonstrated | % Change Identified in Trial |
|---|---|---|---|---|
| 453 | 1-cm margin (n = 453) | Histology | Increase in loco-regional recurrence (LR) with 1-cm margin | HR 1.26 for LR in 1-cm vs 3-cm margin group ( P = .05) |
| 3-cm margin (n = 447) |
Published abstract
Background
Controversy exists concerning the necessary margin of excision for cutaneous melanoma 2 mm or greater in thickness.
Methods
We conducted a randomized clinical trial comparing 1-cm and 3-cm margins.
Results
Of the 900 patients who were enrolled, 453 were randomly assigned to undergo surgery with a 1-cm margin of excision and 447 with a 3-cm margin of excision; the median follow-up was 60 months. A 1-cm margin of excision was associated with a significantly increased risk of locoregional recurrence. There were 168 locoregional recurrences (as first events) in the group with 1-cm margins of excision, as compared with 142 in the group with 3-cm margins (hazard ratio, 1.26; 95% confidence interval, 1.00–1.59; P = .05). There were 128 deaths attributable to melanoma in the group with 1-cm margins, as compared with 105 in the group with 3-cm margins (hazard ratio, 1.24; 95% confidence interval, 0.96–1.61; P = .1); overall survival was similar in the two groups (hazard ratio for death, 1.07; 95% confidence interval, 0.85–1.36; P = .6).
Conclusions
A 1-cm margin of excision for melanoma with a poor prognosis (as defined by a tumor thickness of at least 2 mm) is associated with a significantly greater risk of regional recurrence than is a 3-cm margin, but with a similar overall survival rate.
Editor’s summary and comments
This well-designed randomized trial addresses the important question as to whether 1-cm margins are adequate for higher risk melanoma lesions greater than 2 mm in thickness. Interestingly, the comparison arm to the 1-cm margin is a 3-cm margin and not 2-cm, which is the standard margin size routinely performed for intermediate-thickness lesions (adapted largely from the results of the Intergroup trial). The study design does directly complement the design of the WHO trial though, which compared 1-cm to 3-cm margins for lesions less than 2 mm. The investigators found a decrease in the incidence of loco-regional recurrence (which included local, in transit or regional nodal recurrences) favoring the 3-cm margin group. This did not however translate into a statistically different disease-free survival or overall survival though between the 2 randomized arms, although there was a trend toward increased disease-specific mortality associated with the narrow margin (HR 1.24, P = .1), a trend that continued in long-term follow-up. It should be noted that patients in the study did not undergo SLN biopsy, and it remains unclear how the use of this technique, which is routinely performed in this patient population, would have impacted the results.
Morton DL, Thompson JF, Cochran AJ, et al, MSLT Group. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006;355(13):1307–17, and 10-year follow-up N Engl J Med 2014;377:7.
Hypothesis
Patients with intermediate-thickness melanomas undergoing SLN biopsy for staging with immediate lymphadenectomy for SLN metastases would have an improved survival as compared with patients with simple excision of their primary lesion and therapeutic lymphadenectomy on detection of clinically evident regional nodal disease.
| No. Patients Randomized | Study Groups | Stratification | Significance Demonstrated | % Change Identified in Trial |
|---|---|---|---|---|
| 1347 | Nodal observation with therapeutic lymphadenectomy for clinically evident disease (n = 500) | Tumor thickness Tumor site | None | None a Melanoma-specific survival at 10 y 78.3% vs 81.4 ( P = .18) |
| SLN biopsy and immediate lymphadenectomy for SLN metastases (n = 769) |
Published abstract
Background
We evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma.
Methods
Patients with a primary cutaneous melanoma were randomly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred, or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy.
Results
Among 1269 patients with an intermediate-thickness primary melanoma, the mean (±SE) estimated 5-year disease-free survival rate for the population was 78.3% ± 1.6% in the biopsy group and 73.1% ± 2.1% in the observation group (hazard ratio for recurrence[corrected], 0.74; 95% confidence interval [CI], 0.59–0.93; P = .009). Five-year melanoma-specific survival rates were similar in the 2 groups (87.1% ± 1.3% and 86.6% ± 1.6%, respectively). In the biopsy group, the presence of metastases in the sentinel node was the most important prognostic factor; the 5-year survival rate was 72.3% ± 4.6% among patients with tumor-positive sentinel nodes and 90.2% ± 1.3% among those with tumor-negative sentinel nodes (hazard ratio for death, 2.48; 95% CI, 1.54–3.98; P <.001). The incidence of sentinel-node micrometastases was 16.0% (122 of 764 patients), and the rate of nodal relapse in the observation group was 15.6% (78 of 500 patients). The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group ( P <.001), indicating disease progression during observation. Among patients with nodal metastases, the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed (72.3% ± 4.6% vs 52.4% ± 5.9%; hazard ratio for death, 0.51; 95% CI, 0.32–0.81; P = .004). This held up in the 10-year follow-up of patients with a 62.1% survival for the SLN biopsy group compared with 45.5% in the nodal recurrence group ( P = .006).
Conclusions
The staging of intermediate-thickness (1.2–3.5 mm) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy.
Editor’s summary and comments
This trial randomizes patients with intermediate-thickness melanomas to either SLN biopsy and immediate lymphadenectomy for those patients with metastatic disease in the SLNs versus observation and therapeutic lymphadenectomy for patients who develop clinically evident nodal disease. Several important conclusions can be drawn from this well-designed study requiring tremendous international efforts for its implementation. First, the study confirms the prognostic role of SLN status in patients with intermediate-thickness melanomas. On Cox multivariate analysis, SLN status conferred an HR (positive vs negative) of 3.04 ( P <.001) for disease recurrence and 2.48 for melanoma-specific mortality ( P <.001). Second, the incidence of SLN positivity and clinically evident disease in the observation group were almost identical (16% vs 15.6% respectively), suggesting the patients randomized in the 2 groups shared similar characteristics and that the natural progression of SLN positivity would be the development of clinically evident nodal disease. Finally, although the study showed no difference in melanoma-specific survival between the 2 randomized arms (primary endpoint), in a subset analysis focusing on patients with nodal metastases, those patients with positive SLN biopsy who underwent immediate lymphadenectomy demonstrated an improved melanoma-specific survival when compared with patients in the observation group with clinically evident nodal disease who underwent a therapeutic lymphadenectomy. This observation strongly held up in the 10-year survival analysis as well. Although the staging information of an SLN biopsy remain well accepted, the survival of subset analysis has been the subject of ongoing controversy regarding the possible therapeutic value of an SLN biopsy.
Leiter U, Stadler R, Mauch C, et al, German Dermatologic Cooperative Oncology Group (DeCOG). Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicenter, randomized, phase 3 trial. Lancet Oncol 2016;17(6):757–67.
| No. Patients Randomized | Study Groups | Stratification | Outcome | % Change Identified in Trial |
|---|---|---|---|---|
| 483 | Completion lymph node dissection vs nodal observation with ultrasound | 1:1 | Distant metastasis-free survival | None, at 3 y DMM 74.9% vs 77% |
Hypothesis
Completion lymph node dissection is equivalent to nodal observation in patients with melanoma.
Published abstract
Background
Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation.
Methods
In this multicenter, randomized, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centers. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumor thickness, ulceration of primary tumor, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analyzed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov , number NCT02434107 . Follow-up is ongoing, but the trial no longer recruiting patients.
Findings
Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomization into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. A total of 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analyzed in the observation group and 240 patients were analyzed in the complete lymph node dissection group, as the intention-to-treat population. A total of 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (interquartile range 20–54). Distant metastasis-free survival at 3 years was 77.0% (90% CI 71.9–82.1; 55 events) in the observation group and 74.9% (69.5–80.3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph edema (grade 3 in 7 patients, grade 4 in 13 patients), lymph fistula (grade 3 in 1 patient, grade 4 in 2 patients), seroma (grade 3 in 3 patients, no grade 4), infection (grade 3 in 3 patients, no grade 4), and delayed wound healing (grade 3 in 1 patient, grade 4 in 4 patients); no serious adverse events were reported.
Interpretation
Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller.
Editor’s note
This trial (DeCOG-SLT) accrued patients from 41 skin centers in Germany comparing completion lymph node dissection versus observation in patients with micrometastasis in the regional nodes identified by SLN biopsy. There is no difference in distant metastasis-free survival at 3 years between the 2 groups. In the completion lymphadenectomy group, grade 3 and 4 complications occurred in 14% of patients. Notable limitations of this study included relatively short follow-up (35 months) and exclusion of patients with head and neck primaries. Moreover, due to the difficulty in trial accrual, the study was felt to be underpowered. Interestingly, patients were more likely to withdraw from the trial if randomized to the surgery arm as compared with the observation arm (36 patients in surgery arm vs 3 in observation arm). Results from 2 additional investigations are eagerly awaited, the MSLT2 randomized trial and the EORTC 1208 (Minitub) prospective registry study, to help direct the optimal surgical management of patients with melanoma micrometastases identified in the sentinel lymph nodes.
Adjuvant Treatment
Prospective Randomized Trial of Interferon Alfa-2b and Interleukin-2 as Adjuvant Treatment for Resected Intermediate- and High-Risk Primary Melanoma Without Clinically Detectable Node Metastasis.
Hauschild A, Weichenthal M, Balda BR, et al. Prospective randomized trial of interferon alfa-2b and interleukin-2 as adjuvant treatment for resected intermediate- and high-risk primary melanoma without clinically detectable node metastasis. J Clin Oncol 2003;21:2883–8.
Hypothesis
The addition of low-dose IL-2 to adjuvant low-dose IFN-alpha-2b will improve survival.
| No. Patients Randomized | Study Groups | Stratification | Significance Demonstrated | % Change Identified in Trial |
|---|---|---|---|---|
| 225 | Surgery, low-dose IFN-alpha, low-dose IL-2 | None | None | |
| Surgery, observation |
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