Interferon-gamma signature as prognostic and predictive marker in macroscopic stage III melanoma.

BACKGROUND: A substantial proportion of patients with macroscopic stage III melanoma do not benefit sufficiently from adjuvant anti-PD-1 therapy, as they either recur despite therapy or would never have recurred. To better inform adjuvant treatment selection, we have performed translational analyses to identify prognostic and predictive biomarkers. PATIENTS AND METHODS: Two cohorts of patients with macroscopic stage III melanoma from an ongoing biobank study were included. Clinical data were compared between an observation cohort (cohort 1) and an adjuvant intention cohort (cohort 2). RNA sequencing for translational analyses was performed and treatment subgroups (cohort 1A and cohort 2A) were compared for possible biomarkers, using a cut-off based on the treatment-naïve patients. In addition, two validation cohorts (Melanoma Institute Australia (MIA) and University Medical Centre Utrecht (UMCU)) were obtained. RESULTS: After a median follow-up of 26 months of the 98 patients in our discovery set, median recurrence-free survival (RFS) was significantly longer for the adjuvant intention cohort (cohort 2, n=49) versus the observation cohort (cohort 1, n=49). Median overall survival was not reached for either cohort, nor significantly different. In observation cohort 1A (n=24), RFS was significantly longer for patients with high interferon-gamma (IFNγ) score (p=0.002); for adjuvant patients of cohort 2A (n=24), a similar trend was observed (p=0.086). Patients with high B cell score had a longer RFS in cohort 1A, but no difference was seen in cohort 2A. The B cell score based on RNA correlated with CD20+ cells in tumor area but was not independent from the IFNγ score. In the MIA validation cohort (n=44), longer RFS was observed for patients with high IFNγ score compared with low IFNγ score (p=0.046), no difference in RFS was observed according to the B cell score. In both the observation (n=11) and the adjuvant (n=11) UMCU validation cohorts, no difference in RFS was seen for IFNγ and B cell. CONCLUSIONS: IFNγ has shown to be a prognostic marker in both patients who were and were not treated with adjuvant therapy. B cell score was prognostic but did not improve accuracy over IFNγ. Our study confirmed RFS benefit of adjuvant anti-PD-1 for patients with macroscopic stage III melanoma.

Is a History of Optimal Staging by Sentinel Lymph Node Biopsy in the Era Prior to Adjuvant Therapy Associated with Improved Outcome Once Melanoma Patients have Progressed to Advanced Disease?

INTRODUCTION: Sentinel lymph node biopsy (SLNB) is important for staging in patients with primary cutaneous melanoma. Did having previously undergone SLNB also affect outcomes in patients once they have progressed to metastatic melanoma in the era prior to adjuvant therapy? METHODS: Data were retrieved from the Dutch Melanoma Treatment Registry, a prospectively collected, nationwide database of patients with unresectable stage IIIC or IV (advanced) melanoma between 2012 and 2018. Melanoma-specific survival (MSS) was compared between patients with advanced cutaneous melanoma, previously treated with a wide local excision (WLE) or WLE combined with SLNB as initial treatment of their primary tumor. Cox regression analyses were used to analyze the influence of different variables on MSS. RESULTS: In total, 2581 patients were included, of whom 1412 were treated with a WLE of the primary tumor alone and 1169 in whom this was combined with SLNB. At a median follow-up of 44 months from diagnosis of advanced melanoma, MSS was significantly longer in patients who had previously undergone SLNB {median 23 months (95% confidence interval [CI] 19-29) vs. 18 months (95% CI 15-20) for patients treated with WLE alone; p = 0.002}. However, multivariate Cox regression did not identify SLNB as an independent favorable prognostic factor for MSS after diagnosis of advanced melanoma. CONCLUSION: Prior to the availability of adjuvant systemic therapy, once patients have unresectable stage IIIC or IV (advanced) melanoma, there was no difference in disease outcome for patients who were or were not previously staged with SLNB.

18F-FDG PET/CT During Neoadjuvant Targeted Therapy in Prior Unresectable Stage III Melanoma Patients: Can (Early) Metabolic Imaging Predict Histopathologic Response or Recurrence?

PURPOSE: The aim of this study was to investigate whether 18F-FDG PET/CT can predict histopathological response or recurrence in BRAF-mutated unresectable locally advanced stage III melanoma treated with neoadjuvant BRAF/MEK inhibition followed by resection and the value of PET in detecting early recurrence after resection. PATIENTS AND METHODS: Twenty BRAF-mutated, unresectable stage III melanoma patients received BRAF/MEK inhibitors before surgery. 18F-FDG PET/CT was performed at baseline and 2 and 8 weeks after initiation of therapy. After resection, PET/CT was performed at specific time points during 5 years of follow-up. Pathological response was assessed on the dissection specimen. Response monitoring was measured with SUVmax, SUVpeak, MATV, and TLG and according to EORTC and PERCIST criteria. RESULTS: Pathological response was assessed in 18 patients. Nine patients (50%) had a pathologic complete or near-complete response, and 9 (50%) had a pathologic partial or no response. EORTC or PERCIST response measurements did not correspond with pathologic outcome. SUVmax, SUVpeak, MATV, and TLG at all time points and absolute or percentage change among the 3 initial time points did not differ between the groups.During follow-up, 8 of 17 patients with R0 resection developed a recurrence, 6 recurrences were detected with imaging only, 4 of which with PET/CT in less than 6 months after surgery. PET parameters before surgery did not predict recurrence. CONCLUSIONS: Baseline 18F-FDG PET or PET response in previous unresectable stage III melanoma patients seems not useful to predict pathologic response after neoadjuvant BRAF/MEK inhibitors treatment. However, PET/CT seems valuable in detecting recurrence early after R0 resection.

Postoperative radiotherapy in stage I-III Merkel cell carcinoma.

BACKGROUND: Postoperative radiotherapy (PORT) is currently recommended for the treatment of Merkel cell carcinoma. Nevertheless, deviations occur frequently due to the generally elderly and frail patient population. We aimed to evaluate the influence of PORT on survival in stage I-III MCC patients treated in the Netherlands. METHODS: Patients were included retrospectively between 2013 and 2018. Fine-Gray method was used for cumulative incidence of recurrence and MCC-related death, cox regression was performed for overall mortality. Analyses were performed in patients with clinical (sentinel node biopsy [SN] not performed) stage I/II (c-I/II-MCC), pathologic (SN negative) stage I/II (p-I/II-MCC) and stage III MCC (III-MCC), separately. Propensity score matching (PSM) was performed to assess confounding by indication. RESULTS: In total 182 patients were included, 35 had p-I/II-MCC, 69 had c-I/II-MCC and 78 had III-MCC. Median follow up time was 53.5 (IQR 33.4-67.4), 30.5 (13.0-43.6) and 29.3 (19.3-51.0) months, respectively. Multivariable analysis showed PORT to be associated with less recurrences and reduced overall mortality, but not with MCC-related mortality. In stage III-MCC, extracapsular extension (sub-distribution hazard [SDH] 4.09, p = 0.012) and PORT (SDH 0.45, p = 0.044) were associated with recurrence, and ≥ 4 positive lymph nodes (SDH 3.24, p = 0.024) were associated with MCC-related mortality. CONCLUSIONS: PORT was associated with less recurrences and reduced overall mortality in patients with stage I-III MCC, but not with MCC-related mortality. Trends in overall survival benefit are likely to be caused by selection bias suggesting further refinement of criteria for PORT is warranted, for instance by taking life expectancy into account.

Neoadjuvant Cytoreductive Treatment With BRAF/MEK Inhibition of Prior Unresectable Regionally Advanced Melanoma to Allow Complete Surgical Resection, REDUCTOR: A Prospective, Single-arm, Open-label Phase II Trial.

OBJECTIVE: To evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib (BRAF and MEK inhibitor) to allow for radical surgical resection in patients with unresectable locally advanced melanoma. SUMMARY BACKGROUND DATA: Approximately 5% of stage III melanoma patients presents with unresectable locally advanced disease, making standard of care with resection followed by adjuvant systemic therapy impossible. Although neoadjuvant targeted therapy has shown promising results in resectable stage III melanoma, its potency to enable surgical resection in patients with primarily unresectable locally advanced stage III melanoma is still unclear. METHODS: In this prospective, single-arm, phase II trial, patients with unresectable BRAF-mutated locally advanced stage IIIC or oligometastatic stage IV melanoma were included. After 8 weeks of treatment with dabrafenib and trametinib, evaluation by positron emission tomography/computed tomography and physical examination were used to assess sufficient downsizing of the tumor to enable resection. The primary objective was the percentage of patients who achieved a radical (R0) resection. RESULTS: Between August 2014 and March 2019, 21 patients (20/21 stage IIIC American Joint Committee on Cancer staging manual 7th edition) were included. Planned inclusion of 25 patients was not reached due to slow accrual and changing treatment landscape. Despite this, the predefined endpoint was successfully met. In 18/21 (86%) patients a resection was performed, of which 17 were R0 resections. At a median follow-up of 50 months (interquartile range 37.7-57.1 months), median recurrence-free survival was 9.9 months (95% confidence interval 7.52-not reached) in patients undergoing surgery. CONCLUSIONS: This prospective, single-arm, open-label phase II trial, shows neoadjuvant dabrafenib plus trametinib as a potent cytoreductive treatment, allowing radical resection of metastases in 17/21 (81%) patients with prior unresectable locally advanced melanoma.

Surgery for Unresectable Stage IIIC and IV Melanoma in the Era of New Systemic Therapy.

Opportunities for surgical treatment in metastatic melanoma patients have re-emerged due to the development of novel systemic therapeutics over the past decade. The aim of this study is to present data on outcomes of surgery in patients with unresectable stage IIIC and IV melanoma, who have previously been treated with immunotherapy or targeted therapy. Data was extracted from the Dutch Melanoma Treatment Registry (DMTR) on 154 patients obtaining disease control to systemic therapy and undergoing subsequent surgery. Disease control was defined as a complete response (CR), which was seen in 3.2% of patients; a partial response (PR), seen in 46.1% of patients; or stable disease (SD), seen in 44.2% of patients. At a median follow-up of 10.0 months (interquartile range 4-22) after surgery, the median overall survival (OS) had not been reached in our cohort and median progression-free survival (PFS) was 9.0 months (95% CI 6.3-11.7). A CR or PR at first follow-up after surgery was associated with both a better OS and PFS compared to stable or progressive disease (p < 0.001). We conclude that selected patients can benefit from surgery after achieving disease control with systemic therapy.

Primary Melanoma: from History to Actual Debates.

PURPOSE OF REVIEW: This review describes the long scientific background followed to design guidelines and everyday clinical practice applied to melanoma patients. Surgery is the first option to cure melanoma patients (PTS) at initial diagnosis, since primary cutaneous lesions are usually easily resectable. An excisional biopsy of the lesion, with minimal clear margins, can be obtained in the vast majority of cases. Punch biopsies may be proposed only in case of large lesions located on specific cosmetic or functional areas like the face, extremities, or genitals where a mutilating complete resection would not be performed without prior histological diagnosis. RECENT FINDINGS: After the histologic confirmation of melanoma, definite surgical excision of the scar and surrounding tissue is planned, to obtain microsatellite free margins. The width of these margins has been identified following the results of several clinical trials and it is either 1 or 2 cm, depending on the Breslow thickness of the primary tumor. Following the latest staging system proposed by the American Joint Cancer commission (AJCC), a sentinel node biopsy (SNB) is usually performed in case of a primary lesion > 0.8 mm thickness or for high-risk thinner lesions, if no evidence of nodal involvement has been identified clinically or radiographically. Surgical management of primary melanoma is well established. There is debate on the optimal surgical margins for 1-2 mm melanomas. There are specific considerations for special primaries (bulky, extremity, mucosal). Sentinel node (SN) evaluation does not improve survival, but is routinely used as staging.

Surgery for Metastatic Melanoma: an Evolving Concept.

PURPOSE OF REVIEW: This review describes the evolving role of surgery in stage III and IV melanoma. RECENT FINDINGS: Surgery has been the first option to cure melanoma patients at initial diagnosis of metastatic spread: a complete surgical excision of the disease either in stage III or IV has been the gold standard for decades. A positive sentinel node biopsy (SNB) has been followed by a complete lymph node dissection (CLND) since the early stages of modern surgical oncology. However, since two randomized trials have indicated that a CLND does not improve survival in patients with a positive SNB, a CLND is no longer considered mandatory. A therapeutic lymph node dissection (TLND) is still offered to patients with macroscopic nodal disease and in highly selected cases, patients with distant melanoma metastases can be treated surgically as well. Also the availability of adjuvant, and in the future possibly neoadjuvant, systemic therapy have shifted the landscape to less extensive surgery in metastatic melanoma. With the development of new systemic options, surgery in metastatic melanoma has become more and more part of a multidisciplinary treatment: surgical indications are moving from previous standards to a new role.

Adjuvant systemic therapy in high-risk melanoma.

In resected high-risk melanoma (stage IIB/C-III) the risk of locoregional and/or distant recurrence is substantial and so far adjuvant therapies have been fairly unsuccessful. Interferon showed slight improvements in recurrence-free survival (RFS) but failed to convincingly improve overall survival (OS). In these patients, adjuvant therapy with treatments that show promising results in stage IV disease is arising. Studies using immune checkpoint blockade with anti-CTLA-4 and anti-PD-1 agents reveal convincing RFS benefits. OS rates, however, are not mature yet in most studies. Only ipilimumab has shown an OS benefit but at a high cost of toxicity. Also in studies with adjuvant targeted therapy using BRAF and MEK inhibitors, ensuring results are reported regarding RFS. As possible toxicity cannot be ignored, it is crucial to identify patients who would benefit most from these adjuvant therapies. In patients with clinically detectable lymph node metastases, studies using neoadjuvant schedules of immunotherapy and targeted therapy have been performed. In phase I and II studies the most optimal schedule of combination immunotherapy was identified and further research on this front will follow in the coming years. Concluding, after decades of scarce options for patients with high-risk melanoma, recent developments in adjuvant therapy have changed the standard of care for these patients.