Gyorki, David E.

AbstractBackgroundIsolated limb infusion and perfusion (ILI/ILP) has been a mainstay treatment for unresectable melanoma in‐transit metastases (ITM), but increased use of immune checkpoint inhibitors (ICI) and intralesional therapy (talimogene laherparepvec [TVEC]) introduced several different management options. This study compares first‐line ILI/ILP, ICI, and TVEC.MethodsRetrospective review from 12 international institutions included patients treated from 1990 to 2022 with first‐line ILI/ILP, ICI, or TVEC for unresectable melanoma ITM.ResultsA total of 551 patients were treated, with ILI/ILP (n = 356), ICI (n = 125), and TVEC (n = 70) with median follow‐up of 5.5 years. Tumor burden was highest with ILI/ILP and lowest with TVEC (p = .002). Breslow thickness was lowest with TVEC (p = .007). TVEC was mostly used in stage IIIB disease versus IIIC for ILI/ILP and ICI (p = .01). Using ICI as the reference category, TVEC had the highest odds of a complete response (CR) (odds ratio, 1.96; p = .029) and a longer local progression‐free survival (PFS) (hazard ratio [HR], 0.40; p = .003). ILI/ILP had shorter local PFS (HR, 1.72; p = .012), PFS (HR, 1.79; p < .001), distant metastasis‐free survival (DMFS) (HR, 1.75; p = .014), overall survival (HR, 1.82; p = .009), and melanoma‐specific survival (HR, 2.29; p = .004). Stage IIIB disease had longer DMFS (HR, 0.24; p < .001) compared to IIIC/D.ConclusionsTVEC as first‐line therapy for unresectable melanoma ITM was associated with superior CR rates and local PFS. Notably, TVEC was used in patients with a lower Breslow thickness, disease stage, and tumor burden. Therefore, when compared to ILI/ILP and ICI, TVEC should be considered as first‐line therapy for unresectable stage IIIB melanoma ITM with minimal tumor burden and lower Breslow thickness.

9574 Background: Surgery remains the gold standard for resectable melanoma in-transit metastases (ITM). Unresectable ITM is a heterogenous disease with multiple treatment (tx) options including systemic therapies such as immune checkpoint inhibitors (ICI), regional therapies such as isolated limb infusion or perfusion (ILI/P), and intratumoral therapies such as talimogene laherparepvec (IT). Until now, there has been no direct comparison of these first-line tx for unresectable ITM. Methods: A retrospective chart review of patients (pts) with ITM treated first-line with IT, ILI/P, or ICI was performed at 11 institutions. Pts with unresectable ITM, synchronous nodal or distant metastatic disease were excluded. Results: 560 pts (54% women) were identified, 86 received IT, 353 received ILI/P, and 121 received ICI from 1990-2022. ICI pts were youngest, IT pts were oldest (p<0.001). Limb was the most common site of ITM. There was no difference in largest ITM size, but number of lesions (burden of disease (BOD)) was highest in ILI/P pts and lowest in IT pts (p=0.003). Toxicity (tox) requiring <90 days (p<0.001) or > 90 days (p=0.034) of pharmacologic tx as well as tox requiring hospitalization (p<0.001) was greatest in ICI pts. Lymphedema was more likely in ILI/P pts (p=0.016). Median follow-up was much longer for ILI/P pts at 8.0 yrs compared to 2.5 yrs for IT pts and 3.1 yrs for ICI pts. Overall response rate (ORR) was 82.2% in ILI/P pts, significantly higher than IT (72.1%, p=0.047) or ICI pts (63.6%, p<0.001). Overall survival was similar between modalities (p=0.167); however, ILI/P pts had worse progression-free survival (PFS) (p<0.0001) and melanoma-specific survival (MSS) (p=0.003). On multivariable analysis of MSS by number of ITM present, MSS remained worst if ILI/P was used for low BOD, ≤3 ITM (p=0.005), but no difference was seen between tx modalities for higher BOD, >3 ITM (p=0.211). Conclusions: ICI was used more often in younger pts with less BOD, IT in older pts with less BOD, and ILI/P in older pts with high BOD. Short and long-term tox was greater in ICI. ILI/P had the best ORR, but ICI and IT resulted in greater overall MSS. Multidisciplinary consideration of risks and benefits of each modality should guide ITM tx selection. [Table: see text]

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients.

9569 Background: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The aim of this study was to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international high‐volume melanoma centers. Methods: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c and N3c) and without distant disease (M0). Patients were treated with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). We assessed response rates, progression-free survival (PFS), melanoma-specific survival (MSS) and overall survival (OS). Results: A total of 287 patients from 21 institutions in 8 countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. Monotherapy with a PD-1 or CTLA-4 inhibitor was given in 233 (81%) and 23 (8%) patients respectively, while 31 (11%) received both in combination. Overall response rate was 56%, complete response (CR) rate 36% and progressive disease (PD) rate 32%. Median PFS was 10 months (95% CI 7.4-12.6 months) with a 1-, 2- and 5-year PFS rate of 48%, 33% and 18% respectively. Median MSS was not reached, and the 1-, 2- and 5-year MSS rates were 95%, 83% and 71% respectively. Conclusions: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the optimal role for systemic immunotherapy in the context of multimodality therapy including locoregional treatments such as surgery, intralesional therapy, and regional therapies.

BackgroundFor patients with sentinel lymph node (SLN)‐positive cutaneous melanoma, the Second Multicenter Selective Lymphadenectomy trial demonstrated equivalent disease‐specific survival (DSS) with active surveillance using nodal ultrasound versus completion lymph node dissection (CLND). Adoption and outcomes of active surveillance in clinical practice and in adjuvant therapy recipients are unknown.MethodsIn a retrospective cohort of SLN‐positive adults treated at 21 institutions in Australia, Europe, and the United States from June 2017 to November 2019, the authors evaluated the impact of active surveillance and adjuvant therapy on all‐site recurrence‐free survival (RFS), isolated nodal RFS, distant metastasis‐free survival (DMFS), and DSS using Kaplan‐Meier curves and Cox proportional hazard models.ResultsAmong 6347 SLN biopsies, 1154 (18%) were positive and had initial negative distant staging. In total, 965 patients (84%) received active surveillance, 189 (16%) underwent CLND. Four hundred thirty‐nine patients received adjuvant therapy (surveillance, 38%; CLND, 39%), with the majority (83%) receiving anti–PD‐1 immunotherapy. After a median follow‐up of 11 months, 220 patients developed recurrent disease (surveillance, 19%; CLND, 22%), and 24 died of melanoma (surveillance, 2%; CLND, 4%). Sixty‐eight patients had an isolated nodal recurrence (surveillance, 6%; CLND, 4%). In patients who received adjuvant treatment without undergoing prior CLND, all isolated nodal recurrences were resectable. On risk‐adjusted multivariable analyses, CLND was associated with improved isolated nodal RFS (hazard ratio [HR], 0.36; 95% CI, 0.15‐0.88), but not all‐site RFS (HR, 0.68; 95% CI, 0.45‐1.02). Adjuvant therapy improved all‐site RFS (HR, 0.52; 95% CI, 0.47‐0.57). DSS and DMFS did not differ by nodal management or adjuvant treatment.ConclusionsActive surveillance has been adopted for most SLN‐positive patients. At initial assessment, real‐world outcomes align with randomized trial findings, including in adjuvant therapy recipients.Lay Summary For patients with melanoma of the skin and microscopic spread to lymph nodes, monitoring with ultrasound is an alternative to surgically removing the remaining lymph nodes. The authors studied adoption and real‐world outcomes of ultrasound monitoring in over 1000 patients treated at 21 centers worldwide, finding that most patients now have ultrasounds instead of surgery. Although slightly more patients have cancer return in the lymph nodes with this strategy, typically, it can be removed with delayed surgery. Compared with up‐front surgery, ultrasound monitoring results in the same overall risk of melanoma coming back at any location or of dying from melanoma.

AbstractBackgroundPrimary mesenteric soft tissue sarcomas (STS) are rare and limited evidence is available to inform management. Surgical resection is challenging due to the proximity of vital structures and a need to preserve enteric function.ObjectivesTo determine the overall survival (OS) and recurrence‐free survival (RFS) for patients undergoing primary resection for mesenteric STS.MethodsThe Trans‐Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) is an intercontinental collaborative comprising specialist sarcoma centers. Data were collected retrospectively for all patients with mesenteric STS undergoing primary resection between 2000 and 2019.ResultsFifty‐six cases from 15 institutions were included. The spectrum of pathology was similar to the retroperitoneum, although of a higher grade. R0/R1 resection was achieved in 87%. Median OS was 56 months. OS was significantly shorter in higher‐grade tumors (p = .018) and extensive resection (p < .001). No significant association between OS and resection margin or tumor size was detected. Rates of local recurrence (LR) and distant metastases (DM) at 5 years were 60% and 41%, respectively. Liver metastases were common (60%), reflecting portal drainage of the mesentery.ConclusionPrimary mesenteric sarcoma is rare, with a modest survival rate. LR and DM are frequent events. Liver metastases are common, highlighting the need for surveillance imaging.

Abstract Background Schwannomas are rare tumours that pose a significant management challenge in the abdomen, retroperitoneum and pelvis. No data are available to inform management strategy. Methods A collaborative international cohort study, across specialist sarcoma units, was conducted to include adults presenting between 2000 and 2017 with histopathologically confirmed schwannomas within the abdomen, retroperitoneum or pelvis. Results Of 485 patients across 12 centres, 38 (7·8 per cent) were discharged without follow-up, 199 (41·0 per cent) underwent early resection and 248 (51·1 per cent) had radiological monitoring. Of these 248 patients, 96 (38·7 per cent) eventually had surgery, giving an overall resection rate of 60·8 per cent (295 of 485). At baseline, median tumour volume was 90·1 (i.q.r. 26·5–262·0) cm3. The estimated growth rate was 10·5 (95 per cent c.i. 9·4 to 11·6) per cent per year, and was consistent in the short term (within 2 years of diagnosis) and long term (beyond 2 years) (ρ = 0·405, P = 0·021). A decision to operate was more common in symptomatic patients (P &lt; 0·001) and for rapidly growing tumours (growth rate more than 20 per cent per year) (P = 0·025). R0/R1 resection was achieved in 91·6 per cent of patients (263 of 287). Kaplan–Meier long-term recurrence rates after R0/R1 resection were 2·3 and 6·7 per cent at 3 and 5 years respectively. Conclusion Specific recommendations include: indications for early surgery, prediction of growth from radiological monitoring, promotion of selective submacroscopic resection and cessation of postoperative imaging surveillance.