ABSTRACT
BACKGROUND: Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM. METHODS: Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS). RESULTS: The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44-47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed. CONCLUSION: Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).
Subject(s)
Antineoplastic Agents, Alkylating , Liver Neoplasms , Melanoma , Melphalan , Uveal Neoplasms , Humans , Melanoma/drug therapy , Melanoma/pathology , Melanoma/secondary , Melanoma/mortality , Melphalan/administration & dosage , Male , Female , Middle Aged , Uveal Neoplasms/drug therapy , Uveal Neoplasms/pathology , Uveal Neoplasms/mortality , Aged , Adult , Survival Rate , Liver Neoplasms/secondary , Liver Neoplasms/drug therapy , Follow-Up Studies , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/therapeutic use , Prognosis , Aged, 80 and over , Drug Delivery SystemsABSTRACT
BACKGROUND: Radar-guided localization (RGL) offers a wire-free, nonradioactive surgical guidance method consisting of a small percutaneously-placed radar reflector and handheld probe. This study investigates the feasibility, timing, and outcomes of RGL for melanoma metastasectomy. METHODS: We retrospectively identified patients at our cancer center who underwent RGL resection of metastatic melanoma between December 2020-June 2023. Data pertaining to patients' melanoma history, management, reflector placement and retrieval, and follow-up was extracted from patient charts and analyzed using descriptive statistics. RESULTS: Twenty-three RGL cases were performed in patients with stage III-IV locoregional or oligometastatic disease, 10 of whom had reflectors placed prior to neoadjuvant therapy. Procedures included soft tissue nodule removals (8), index lymph node removals (13), and therapeutic lymph node dissections (2). Reflectors were located and retrieved intraoperatively in 96% of cases from a range of 2 to 282 days after placement; the last reflector was not able to be located during surgery via probe or intraoperative ultrasound. One retrieved reflector had migrated from the index lesion, thus overall success rate of reflector and associated index lesion removal was 21 of 23 (91%). All RGL-localized and retrieved index lesions that contained viable tumor (10) had microscopically negative margins. There were no complications attributable to reflector insertion and no unexpected complications of RGL surgery. CONCLUSION: In our practice, RGL is a safe and effective surgical localization method for soft tissue and nodal melanoma metastases. The inert nature of the reflector enables implantation prior to neoadjuvant therapy with utility in index lymph node removal.
There are a variety of tools available to localize melanoma that had spread to deep layers of the skin or lymph nodes that can guide surgeons to the cancer when the tumor cannot be felt. We evaluated a marker that reflects radar signals that has been studied in breast surgery but not in melanoma. The marker was placed in the tumor before surgery and was located during surgery using a handheld probe, guiding the surgeon to the correct location. An advantage of the radar-reflecting marker we studied is that since it is safe to stay in the body, it can be placed ahead of the use of cancer medications and can keep track of the tumor as it responds to treatment. In a review of 23 surgeries in which the radar-reflecting marker was used, there was one case where the marker migrated away from the tumor and one case where the marker was not able to be located. Monitoring or alternative definitive treatment was provided in each of these cases. Overall, we found the marker to be an effective tumor localization tool for surgeons and safe for patients. Other marker options available are unable or less suitable to be placed a long time in advance of surgery due to either technical or safety reasons, so the radar-reflecting marker is especially useful when it is placed in a tumor ahead of medical treatment leading up to planned surgical treatment.
Subject(s)
Melanoma , Humans , Retrospective Studies , Melanoma/surgery , Radar , Ultrasonography , Margins of ExcisionABSTRACT
BACKGROUND: Percutaneous Hepatic Perfusion (PHP) is a liver directed regional therapy recently FDA approved for metastatic uveal melanoma to the liver involving percutaneous isolation of liver, saturation of the entire liver with high-dose chemotherapy and filtration extracorporeally though in line filters and veno-venous bypass. The procedure is associated with hemodynamic shifts requiring hemodynamic support and blood product resuscitation due to coagulopathy. OBJECTIVE: To assess the cardiac safety and subsequent clinically significant sequalae of this therapy. METHODS: Consecutive PHP procedures done at our center between 2010-2022 were assessed retrospectively. Cardiac risk factors, post procedural cardiac enzymes, electrocardiograms, and transthoracic echocardiograms along with 90-day cardiac outcomes were reviewed. All data were reviewed by cardio-oncologists at our institution. RESULTS: Of 37 patients reviewed, mean age was 63 years and 57% were women. 132 procedures were performed with an average of 3.57 procedures per patient. 68.6% of patients had elevated troponin during at least 1 procedure. No patients were found to have acute coronary syndrome, heart failure, unstable arrhythmias, or cardiac death. No patients had notable echocardiographic changes. 10.8% of patients with positive troponin had asymptomatic transient electrocardiographic changes not meeting criteria for myocardial infarction. One patient had non-sustained ventricular tachycardiac intra-operatively which did not recur subsequently. Three patients died from non-cardiac causes within 90-days. There was no oncology treatment interruption, even in those with troponin elevation. In multivariable analysis, a history of hyperlipidemia was a predictor of postoperative troponin elevation. (P = .042). CONCLUSION: Percutaneous Hepatic Perfusion is safe and associated with a transient, asymptomatic troponin elevation peri-operatively without major adverse cardiac events at 90 days. The observed troponin elevation is likely secondary to coronary demand-supply mismatch related to procedural hemodynamic shifts, hypotension, and anemia.
Percutaneous hepatic perfusion using melphalan in patients with uveal melanoma and liver metastases carries no significant cardiac adverse events.
Subject(s)
Liver Neoplasms , Melanoma , Melphalan , Uveal Neoplasms , Humans , Female , Middle Aged , Male , Antineoplastic Agents, Alkylating , Retrospective Studies , Chemotherapy, Cancer, Regional Perfusion/methods , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Neoplasm Recurrence, Local/drug therapy , PerfusionABSTRACT
BACKGROUND AND OBJECTIVES: MSLT-2 and DECOG-SLT established that immediate complete axillary lymph node dissection (CLND) did not correlate with an increase in melanoma-specific survival when compared with active ultrasound observation in patients with sentinel lymph node (SLN)-positive disease. After those trials, there was a shift toward performing CLND only for clinically node-positive disease. With these changes, we sought to determine the role of level III axillary lymph nodes in bulky disease and how the use of neoadjuvant therapy may impact the rate of positivity in level III axillary nodes. METHODS: We performed a retrospective chart review on all patients who underwent axillary CLND for cutaneous melanoma by one surgeon at an academic center from 2014 to 2022. These patients underwent CLND based on either having SLN+ disease or having clinically palpable or radiographically bulky disease. RESULTS: Of 95 patients included, there were 7 (7.3%) patients with level III positivity. One was SLN+ (1.0%), while 3 (3.1%) had bulky disease and neoadjuvant therapy, and 3 (3.1%) had bulky disease without neoadjuvant therapy. No preoperative factors were identified that predicted level III involvement. After performing CLND, the patients who had clinically palpable or radiographically bulky disease and neoadjuvant therapy had higher percent necrosis of nodes in levels I and II but not III. At 5 years, overall survival and recurrence-free survival were improved in those without level III involvement (58% and 64%, respectively) when compared to those with level III involvement (41% and 50%), though this was not statistically significant. CONCLUSIONS: Further study may identify better prognostic factors for level III positivity, allowing for the possibility of dissecting only levels I and II or even replacing CLND with targeted node dissections.
Subject(s)
Axilla , Lymph Node Excision , Lymphatic Metastasis , Melanoma , Skin Neoplasms , Humans , Melanoma/surgery , Melanoma/pathology , Melanoma/secondary , Melanoma/mortality , Retrospective Studies , Female , Male , Middle Aged , Skin Neoplasms/pathology , Skin Neoplasms/surgery , Skin Neoplasms/mortality , Aged , Adult , Neoadjuvant Therapy , Sentinel Lymph Node Biopsy , Lymph Nodes/pathology , Lymph Nodes/surgery , Lymph Nodes/diagnostic imaging , Follow-Up StudiesABSTRACT
OBJECTIVE: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma. SUMMARY BACKGROUND DATA: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization. METHODS: We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics. RESULTS: Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients. CONCLUSIONS: There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation.
Subject(s)
Melanoma , Sentinel Lymph Node , Skin Neoplasms , Adult , Humans , Sentinel Lymph Node/surgery , Sentinel Lymph Node/pathology , Skin Neoplasms/surgery , Sentinel Lymph Node Biopsy , Cohort Studies , Melanoma/surgery , Melanoma/drug therapy , Lymph Node Excision , Retrospective StudiesABSTRACT
BACKGROUND: The purpose of this systematic review was to examine the timing and patterns of recurrence for patients with regionally metastatic melanoma on the basis of nodal management and receipt of adjuvant therapy. METHODS: We identified randomized controlled trials and non-randomized studies published between 2010 and 2020 that reported timing and/or patterns of recurrence. We evaluated recurrence-free survival (RFS), location of recurrence, and surveillance strategy on the basis of receipt of adjuvant systemic therapy and nodal management with observation versus completion dissection. We compared differences in patterns of recurrence across studies using RevMan. RFS was evaluated graphically using point estimates and confidence intervals. RESULTS: Among the 19 publications, there was wide variation in study populations, imaging surveillance regimens, and format of recurrence reporting. Patterns of disease recurrence did not differ between adjuvant and placebo/observation groups. A total of 11 studies reported RFS at variable time intervals, which ranged in adjuvant therapy groups (38-88% at 1 year, 29-67% at 2 years, 33-58% at 3 years, and 34-53% at 5 years) and placebo/observation groups (47-63% at 1 year, 39-47% at 2 years, 33-68% at 3 years, and 57% at 5 years). Anti-PD-1 immune therapy and BRAF/MEK inhibitor therapy were superior to placebo at year 1. DISCUSSION: We found that adjuvant treatment improved RFS but did not alter the patterns of disease recurrence compared with patients managed without adjuvant systemic treatment. Future studies should separately report sites of disease recurrence on the basis of specific adjuvant systemic treatment and surveillance practices to better advise patients about their patterns and risk of recurrence.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Neoplasm Recurrence, Local/therapy , Melanoma/drug therapy , Combined Modality Therapy , Skin Neoplasms/pathologyABSTRACT
BACKGROUND: The optimal time to initiate adjuvant immune checkpoint inhibitors (ICI) following resection remains undefined. Herein, we investigated the impact of time to adjuvant ICI on survival in patients with stage III melanoma. METHODS: Patients with resected stage III melanoma receiving adjuvant immune therapy were identified within a multi-institutional retrospective cohort. Patients were stratified by time to adjuvant ICI: within 6 weeks, 6-12 weeks, and greater than 12 weeks from surgery. Recurrence-free survival (RFS) was compared among time strata with Kaplan-Meier and Cox proportional hazards methods in the multi-institutional cohort. RESULTS: Altogether, 626 patients were identified within the multi-institutional cohort: 39% of patients initiated adjuvant ICI within 6 weeks, 42.2% within 6-12 weeks, and 18.8% greater than 12 weeks from surgery. In a multivariate Cox model, adjusting for histology, nodal tumor burden, and pathologic stage, we found that increased time to adjuvant ICI was associated with improved RFS. Patients who initiated adjuvant ICI within 6 weeks of surgery had worse RFS. These findings were preserved in a conditional landmark analysis and separate subgroups of patients with (1) new melanoma diagnoses, (2) occult stage III disease, and (3) those receiving anti-PD-1 monotherapy. CONCLUSIONS: Outcomes for patients with stage III melanoma are not compromised when adjuvant ICI is initiated beyond 6 weeks from resection. Additional work is needed to better understand the underlying mechanisms and implications of timing of adjuvant ICI on long-term outcomes.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Retrospective Studies , Melanoma/drug therapy , Melanoma/diagnosis , Skin Neoplasms/pathology , Immunotherapy/methods , Melanoma, Cutaneous MalignantABSTRACT
BACKGROUND: Atypical fibroxanthomas (AFX) are rare malignant cutaneous neoplasms. Unfortunately, limited clinicopathologic and outcomes data on this cancer exists. OBJECTIVE: We report the clinical, pathologic, and treatment characteristics, as well as oncologic outcomes in this single-institution retrospective analysis. METHODS: This retrospective cohort study compiled clinical, pathologic, treatment, and outcome data for all patients with AFX on definitive excision diagnosed, evaluated, and treated primarily by surgical resection at a single institution between 2000-2020. Descriptive statistics evaluated clinical and pathologic characteristics. Kaplan-Meier method and Cox proportional-hazards models were used to evaluate overall survival and recurrence-free survival. RESULTS: 78 patients with AFX were identified. The majority were elderly, immunocompetent, Caucasian men. 85% of tumors were located on the head and neck. 63% of patients were correctly diagnosed only after complete resection of the index lesion. The median surgical margin was 1.0 cm. Overall, only 1.3% (1/78) of patients developed a local recurrence (RFS). No patients died of disease. CONCLUSION: This study suggests that resection margins of 1 cm achieve excellent local control with close to 99% RFS and 100% disease-specific survival.
Subject(s)
Skin Neoplasms , Male , Humans , Aged , Retrospective Studies , Skin Neoplasms/pathology , Margins of Excision , Neoplasm Recurrence, Local/pathologyABSTRACT
BACKGROUND AND OBJECTIVES: Primary cutaneous leiomyosarcoma (cLMS), a rare, typically intradermal tumor, has previously been reported to exhibit an indolent course of disease with zero-to-low risk of local recurrence or distant metastasis. This study seeks to evaluate recurrence and survival of cLMS patients through study of its clinicopathologic and treatment characteristics. METHODS: All patients included underwent resection of primary cLMS at this institution between 2006 and 2019. A retrospective cohort study analysis of clinicopathologic characteristics, treatment, recurrence, and overall survival was performed. Data was assessed through descriptive statistics and outcome measures assessed by Cox proportional models and log-rank tests. RESULTS: Eighty-eight patients with cLMS were evaluated. The majority were men (n = 68, 77%) and Caucasian (n = 85, 97%), with median age at diagnosis of 66 years (range 20-96). 65% of tumors were located on the extremities, with a median size of 1.3 cm (range .3-15). Assessment revealed low (n = 41, 47%), intermediate (n = 29, 33%), and high (n = 18, 20%) grade tumors, demonstrating extension into subcutaneous tissue in 38/60 (60%), with 3 patients exhibiting extension into muscle (3%). All underwent resection as primary treatment with median 1 cm margins (range .5-2). With median follow-up of 27.5 months (IQR 8-51; range 1-131), no low-grade cases had recurrence or death while there was a recurrence rate of 19.1% (9/47) and death rate of 8.5% (4/47) in intermediate- to high-grade cases. CONCLUSIONS: Primary tumor resection of cLMS provides excellent local control for low-grade tumors as no low-grade cases experienced recurrence. For patients with intermediate- to high-grade tumors, there is potential for local recurrence, distant metastasis, and death, and therefore surveillance following treatment is encouraged.
Subject(s)
Leiomyosarcoma , Skin Neoplasms , Male , Humans , Female , Young Adult , Adult , Middle Aged , Aged , Aged, 80 and over , Leiomyosarcoma/surgery , Leiomyosarcoma/pathology , Retrospective Studies , Skin Neoplasms/surgery , Skin Neoplasms/pathology , Proportional Hazards Models , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/pathology , PrognosisABSTRACT
BACKGROUND: Technetium-99m-labeled Tilmanocept, a multivalent mannose, is readily internalized by the CD206 surface receptor on macrophages and dendritic cells which are abundantly present in lymph nodes. We want to examine the drainage patterns of Technetium-99m-labeled Tilmanocept to sentinel lymph nodes (SLNs) in melanoma patients following the 10% rule. METHODS: Multi-center retrospective review of patients with cutaneous melanoma undergoing SLN biopsy using Technetium-99m-labeled Tilmanocept between 2008 and 2014 was conducted. Statistical methods were used for data analyses. RESULTS: Of the 564 patients (mean age of 60.3 and 62% male) with preoperative lymphoscintigraphy showing at least one SLN, several primary tumor sites were included: 27% head/neck, 33% trunk, 21% upper extremity and 19% lower extremity. For the head/neck primary site, 36.5% of patients had multiple draining basins; for the trunk site, 36.4% of patients; for the upper extremity site, 13% of patients; and for the lower extremity, 27.4% of patients. A median of 3 (range 1-18) SLNs were identified and resected. Overall, 78% of patients had >1 SLN identified by Technetium-99m-labeled Tilmanocept. In a multivariate model, patients with >1 SLN were significantly associated with age, Breslow depth, tumor location and higher AJCC tumor stage. A total of 17.7% of patients (100/564) had a positive SLN identified. A total of 145 positive SLNs were identified out of 1,812 SLNs with a positive SLN rate of 8%. Positive SLN status was significantly associated with younger age, greater Breslow depth, mitosis rate, higher AJCC tumor stage, presence of ulceration and angiolymphatic invasion. CONCLUSIONS: Using the 10% rule, Technetium-99m-labeled Tilmanocept detects multiple SLNs in most melanoma patients.
Subject(s)
Melanoma , Sentinel Lymph Node , Skin Neoplasms , Humans , Male , Middle Aged , Female , Sentinel Lymph Node/diagnostic imaging , Sentinel Lymph Node/surgery , Sentinel Lymph Node/pathology , Lymphoscintigraphy/methods , Melanoma/diagnostic imaging , Melanoma/surgery , Melanoma/pathology , Sentinel Lymph Node Biopsy/methods , Radiopharmaceuticals , Technetium Tc 99m Pentetate , Technetium , Lymphatic Metastasis/pathology , Skin Neoplasms/diagnostic imaging , Skin Neoplasms/surgery , Skin Neoplasms/pathology , Lymph Nodes/diagnostic imaging , Lymph Nodes/surgery , Lymph Nodes/pathologyABSTRACT
BACKGROUND: Sentinel lymph node biopsy is not routinely recommended for T1a cutaneous melanoma due to the overall low risk of positivity. Prognostic factors for positive sentinel lymph node (SLN+) in this population are poorly characterized. OBJECTIVE: To determine factors associated with SLN+ in patients with T1a melanoma. METHODS: Patients with pathologic T1a (<0.80 mm, nonulcerated) cutaneous melanoma from 5 high-volume melanoma centers from 2001 to 2020 who underwent wide local excision with sentinel lymph node biopsy were included in the study. Patient and tumor characteristics associated with SLN+ were analyzed by univariate and multivariable logistic regression analyses. Age was dichotomized into ≤42 (25% quartile cutoff) and >42 years. RESULTS: Of the 965 patients identified, the overall SLN+ was 4.4% (N = 43). Factors associated with SLN+ were age ≤42 years (7.5% vs 3.7%; odds ratio [OR], 2.14; P = .03), head/neck primary tumor location (9.2% vs 4%; OR, 2.75; P = .04), lymphovascular invasion (21.4% vs 4.2%; OR, 5.64; P = .01), and ≥2 mitoses/mm2 (8.2% vs 3.4%; OR, 2.31; P = .03). Patients <42 years with ≥2 mitoses/mm2 (N = 38) had a SLN+ rate of 18.4%. LIMITATIONS: Retrospective study. CONCLUSION: SLN+ is low in patients with T1a melanomas, but younger age, lymphovascular invasion, mitogenicity, and head/neck primary site appear to confer a higher risk of SLN+.
Subject(s)
Melanoma , Sentinel Lymph Node , Skin Neoplasms , Humans , Adult , Sentinel Lymph Node Biopsy , Melanoma/surgery , Melanoma/pathology , Skin Neoplasms/surgery , Skin Neoplasms/pathology , Retrospective Studies , Lymphatic Metastasis/pathology , Sentinel Lymph Node/pathology , Prognosis , Lymph Node Excision , Melanoma, Cutaneous MalignantABSTRACT
BACKGROUND: We present a case of RCM evaluation of ALM surgical margins demonstrating intracorneal melanocytic bodies overlying subsequently confirmed melanoma in situ by histopathology. CASE PRESENTATION: A 73-year-old male with a history of acral lentiginous melanoma (ALM) of the right great toe presented to our clinic for evaluation of positive surgical margins. The positive margin was localized for examination and subsequent biopsy with reflectance confocal microscopy (RCM) which allowed targeted re-resection of the area of concern. Three punch biopsies were obtained in the area of concern, which confirmed residual melanoma in situ. Immunostains confirmed the cellular remnants in the stratum corneum were melanocytic. To correlate the intra stratum corneum findings seen with confocal to the histopathology, a 3D rendering of a stack of images was used to demonstrate the location. DISCUSSION: Typically, acral surfaces are challenging to examine with RCM due to the limited ability of light to penetrate thickened stratum corneum; however, we observed unique cellular features with confocal. Scattered hyper-reflective pleomorphic cells consistent with melanocytes were observed in the stratum corneum, although the visualized underlying epidermis appeared normal. Confocal microscopy may aid in diagnosis and management of ALM, especially in the context of positive surgical margins.
Subject(s)
Melanoma , Skin Neoplasms , Male , Humans , Aged , Margins of Excision , Skin Neoplasms/diagnostic imaging , Skin Neoplasms/surgery , Skin Neoplasms/pathology , Melanoma/diagnostic imaging , Melanoma/surgery , Melanocytes/pathology , Epidermis/pathology , Microscopy, Confocal/methods , Melanoma, Cutaneous MalignantABSTRACT
BACKGROUND: The standard of care when treating melanoma in situ (MMIS) is an excision with at least 5 mm surgical margins.1 Some studies have suggested up to 9 mm margins to maximize local recurrence-free survival.2 This retrospective review aims to assess the efficacy of imiquimod as a topical treatment for persistently positive MMIS at the margins of prior excisions or where surgery is not an option. METHODS: Retrospective study conducted at Moffitt Cancer Center between 2019 and 2021 with patients aged > 18 years with MMIS at the margins of excision of an invasive melanoma or MMIS. Included patients were not ideal candidates for primary or additional surgical resection due to non-feasibility of surgery because of comorbidity or cosmetically sensitive location and/or the need for repeated skin grafting, or due to patient's refusal. Patients received imiquimod on protocol for 16 weeks and were monitored for treatment response and side effects. Following completion of the treatment, scouting biopsies were performed to assess histological response, and dermoscopy was used to determine the clinical disease status. RESULTS: Ten patients completed 16 weeks of imiquimod. Seven (75%) had a median of 2 surgical resections, and 3 refused surgery despite discussion that surgery was standard of care. Seven were deemed free of disease on post-imiquimod treatment scouting biopsies, while 2 were found to be clinically free of disease following confocal microscopy, indicating a tumor clearance rate of 90% with imiquimod treatment. One patient was found to have persistent residual disease following 2 rounds of imiquimod and was taken for an additional surgical excision after which they were deemed free of disease. Median follow-up duration from the onset of imiquimod therapy to the last clinic visit was 18 months, without any recurrences to date. CONCLUSION: Imiquimod appears to demonstrate an encouraging tumor clearance among patients with persistent MMIS after surgery where further surgical resection may not be feasible. Although long-term durability has not been demonstrated in this study, a 90% tumor clearance rate is promising. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.6987.
Subject(s)
Antineoplastic Agents , Melanoma , Skin Neoplasms , Humans , Imiquimod/adverse effects , Antineoplastic Agents/adverse effects , Retrospective Studies , Melanoma/drug therapy , Melanoma/surgery , Melanoma/pathology , Skin Neoplasms/drug therapy , Skin Neoplasms/surgery , Skin Neoplasms/pathology , Aminoquinolines/adverse effects , Treatment Outcome , Melanoma, Cutaneous MalignantABSTRACT
BACKGROUND: The significance of tumor-infiltrating lymphocytes (TILs) in melanoma is debated. This article presents a multicenter, retrospective study assessing the predictive and prognostic value of TILs. METHODS: The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with known TIL data. TILs were categorized as absent or present, which included nonbrisk (NB), brisk (B), and present but unspecified TIL levels. Clinicopathologic factors were correlated with TILs, sentinel lymph node (SLN) status, and melanoma-specific survival (MSS). RESULTS: Overall, 3203 patients were included. The median thickness was 1.5 mm, and 469 cases had SLN metastases. TILs were present in 2458 cases (76.7%), with NB, B, and unspecified TILs seen in 1691 (68.8%), 691 (28.1%), and 76 (3.1%), respectively. Multivariable analysis showed that the presence of TILs significantly predicted a negative SLN biopsy (P < .05). The median follow-up was 25.2 months. MSS was significantly better for cases with TILs than cases without TILs (P < .001). According to multivariable analysis, age, gender, thickness, mitotic rate, ulceration, lymphovascular invasion, and SLN status were significantly prognostic of MSS (all P values < .05). Although TILs were not prognostic of MSS, when multiple imputation was used and the SLN status was excluded, the presence of TILs was significantly prognostic of improved MSS (hazard ratio, 0.78; 95% confidence interval, 0.64-0.95; P = .0154). CONCLUSIONS: TILs are a favorable marker because their presence significantly predicts a negative SLN, and the absence of TILs may be a prognostic marker of worse survival in patients with a positive SLN but not a negative SLN. TILs may also serve as a prognostic marker of survival when the SLN status is not considered.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Lymphocytes, Tumor-Infiltrating , Melanoma/pathology , Prognosis , Retrospective Studies , Sentinel Lymph Node Biopsy , Skin Neoplasms/pathologyABSTRACT
PURPOSE: Talimogene Laherparepvec (T-VEC) is a modified herpes simplex virus type-1 used as intralesional immunotherapy in stage IIIB-IVM1a melanoma patients. Recently, Stahlie et al. published a predictive model for complete response (CR) to T-VEC. This study was designed to validate this model externally in an independent, American patient cohort. METHODS: In total, 71 stage IIIB-IVM1a melanoma patients treated with T-VEC at Moffitt Cancer Center were included. A second nomogram was built incorporating the same predictive factors: tumor size (diameter of largest metastasis), type of metastases (cutaneous, subcutaneous and nodal), and number of metastases (cutoff: < 20 and > 20). Predictive accuracy was assessed through calculation of overall performance, discriminative ability, and calibration. RESULTS: The two cohorts were similar in many clinicopathologic factors and only differing in tumor mutational status and use of systemic therapy prior to T-VEC. In the validation cohort, 37 (52%) patients showed CR, 22 (31%) partial response (PR), 2 (5.6%) stable disease (SD), and 10 (15%) progressive disease (PD). Of those who demonstrated a CR, 16 (43%) recurred. Overall performance was good (0.164), and discriminative power resulted in fair discriminative ability (0.827). The calibration curve showed slight underestimation for predicted probabilities > 0.15 and slight overestimation <0.15. CONCLUSIONS: The original model as well as the validation model show comparable and good predictive accuracy. The validation model reinforces the conclusion that for the best response to T-VEC, it should be used early on in the course of the disease, when the tumor burden is cutaneous with smaller diameter and fewer of metastases.
Subject(s)
Herpesvirus 1, Human , Melanoma , Oncolytic Virotherapy , Skin Neoplasms , Biological Products , Humans , Melanoma/drug therapy , Neoplasm Recurrence, Local , Nomograms , Skin Neoplasms/drug therapy , United StatesABSTRACT
BACKGROUND: The relationship between tumor-infiltrating lymphocytes (TILs) and regression in melanoma is unknown. This report describes a large multicenter study assessing the association between TILs and regression. METHODS: The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with TILs and regression data. Clinicopathologic factors were correlated with regression and TIL status, sentinel lymph node (SLN) status, and overall survival (OS). RESULTS: The study enrolled 2450 patients. In 1811 cases, TILs (73.9%) were present, with regression present in 328 of these 1811 (18.1%) cases and in 49 (7.7%) of 639 cases without TILs. The presence of TILs was significantly associated with regression (p < 0.0001) as well as a negative SLN (p < 0.05). However, when TILs were stratified by regression status, only absence or presence of both TILs and regression were significantly associated with SLN metastases (p = 0.038). Although the presence of TILs was associated with OS (p < 0.05), regression status by itself was not (p = 0.2058 and 0.252, respectively). Furthermore, when TILs were stratified by regression status, only the presence of TILs with or without regression was significantly associated with improved OS (p = 0.0081 and 0.0137, respectively) versus the absence of both TILs and regression, with regression status not significantly affecting OS for patients with or without TILs (p = 0.2314 and 0.65, respectively). CONCLUSIONS: Regression is highly correlated with TILs, but only TILs are significantly associated with SLN metastasis and OS in melanoma patients, whereas regression is not. The impact of regression on outcomes ultimately appears dependent upon the absence or presence of TILs.
Subject(s)
Lymphadenopathy , Melanoma , Skin Neoplasms , Humans , Lymphatic Metastasis/pathology , Lymphocytes, Tumor-Infiltrating/pathology , Melanoma/pathology , Prognosis , Sentinel Lymph Node Biopsy , Skin Neoplasms/pathologyABSTRACT
BACKGROUND: Patients presenting with early-stage melanoma (AJCC pT1b-pT2a) reportedly have a relatively low risk of a positive SNB (~5-10%). Those patients are usually found to have low-volume metastatic disease after SNB, typically reclassified to AJCC stage IIIA, with an excellent prognosis of ~90% 5-year survival. Currently, adjuvant systemic therapy is not routinely recommended for most patients with AJCC stage IIIA melanoma. The purpose was to assess the SN-positivity rate in early-stage melanoma and to identify primary tumor characteristics associated with high-risk nodal disease eligible for adjuvant systemic therapy METHODS: An international, multicenter retrospective cohort study from 7 large-volume cancer centers identified 3,610 patients with early primary cutaneous melanomas 0.8-2.0 mm in Breslow thickness (pT1b-pT2a; AJCC 8th edition). Patient demographics, primary tumor characteristics, and SNB status/details were analyzed. RESULTS: The overall SNB-positivity rate was 11.4% (412/3610). Virtually all SNB-positive patients (409/412; 99.3%) were reclassified to AJCC stage IIIA. Multivariate analysis identified age, T-stage, mitotic rate, primary site and subtype, and lymphovascular invasion as independent predictors of sentinel node status. A mitotic rate of >1/mm2 was associated with a significantly increased SN-positivity rate and was the only significant independent predictor of high-risk SNB metastases (>1 mm maximum diameter). CONCLUSIONS: The new treatment paradigm brings into question the role of SNB for patients with early-stage melanoma. The results of this large international cohort study suggest that a reevaluation of the indications for SNB for some patients with early-stage melanoma is required.
Subject(s)
Melanoma , Skin Neoplasms , Adjuvants, Immunologic , Cohort Studies , Humans , Melanoma/pathology , Neoplasm Staging , Retrospective Studies , Sentinel Lymph Node Biopsy/methods , Skin Neoplasms/drug therapy , Skin Neoplasms/surgery , Melanoma, Cutaneous MalignantABSTRACT
BACKGROUND: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy for which factors predictive of disease-specific survival (DSS) are poorly defined. METHODS: Patients from six centers (2005-2020) with clinical stage I-II MCC who underwent sentinel lymph node (SLN) biopsy were included. Factors associated with DSS were identified using competing-risks regression analysis. Risk-score modeling was established using competing-risks regression on a training dataset and internally validated by point assignment to variables. RESULTS: Of 604 patients, 474 (78.5%) and 128 (21.2%) patients had clinical stage I and II disease, respectively, and 189 (31.3%) had SLN metastases. The 5-year DSS rate was 81.8% with a median follow-up of 31 months. Prognostic factors associated with worse DSS included increasing age (hazard ratio [HR] 1.03, p = 0.046), male sex (HR 3.21, p = 0.021), immune compromise (HR 2.46, p = 0.013), presence of microsatellites (HR 2.65, p = 0.041), and regional nodal involvement (1 node: HR 2.48, p = 0.039; ≥2 nodes: HR 2.95, p = 0.026). An internally validated, risk-score model incorporating all of these factors was developed with good performance (AUC 0.738). Patients with ≤ 4.00 and > 4.00 points had 5-year DSS rates of 89.4% and 67.2%, respectively. Five-year DSS for pathologic stage I/II patients with > 4.00 points (n = 49) was 79.8% and for pathologic stage III patients with ≤ 4.00 points (n = 62) was 90.3%. CONCLUSIONS: A risk-score model, including patient and tumor factors, based on DSS improves prognostic assessment of patients with clinically localized MCC. This may inform surveillance strategies and patient selection for adjuvant therapy trials.
Subject(s)
Carcinoma, Merkel Cell , Skin Neoplasms , Carcinoma, Merkel Cell/pathology , Humans , Lymphatic Metastasis , Male , Prognosis , Sentinel Lymph Node Biopsy , Skin Neoplasms/pathologyABSTRACT
BACKGROUND: Talimogene laherparepvec (T-VEC) is an oncolytic virus approved for the treatment of unresectable, recurrent melanoma. The role of T-VEC after progression on systemic immunotherapy (IO) remains undefined. The goal of this study was to characterize the efficacy of T-VEC after failure of IO in patients with unresectable metastatic melanoma. METHODS: An international, multi-institutional review of AJCC version 8 stage IIIB-IV melanoma patients treated with T-VEC after failure of IO was performed at six centers from October 2015-December 2020. Primary outcome was in-field response; secondary outcomes included analyses of in-field and overall progression-free survival (PFS) and in-field and overall disease-free survival (DFS) after a complete response. Subset analysis of T-VEC initiation sequentially after or concurrently with IO was performed. RESULTS: Of 112 patients, median age at T-VEC initiation was 69 years (range 21-93); 65 (58%) were male. Before T-VEC, 57% patients received one IO regimen, 42% received two or more, with most patients (n = 74, 66%) receiving T-VEC sequential to IO. Most were stage 3C (n = 51, 46%) at T-VEC initiation, 29 (26%) received injections to nodal disease. Over median follow-up of 14 months, in-field response at final T-VEC injection was 37% complete (CR), 14% partial (PR). T-VEC initiation sequentially or concurrently did not significantly affect in-field response (p = 0.26). Median in-field PFS was 15 months (95% confidence interval 4.6-NE). Median overall DFS after CR was 32 months (95% confidence interval 17-NE). CONCLUSIONS: T-VEC after failure of IO is effective in unresectable, metastatic stage IIIB-IV melanoma. T-VEC initiation sequentially or concurrently did not significantly affect in-field response.
Subject(s)
Melanoma , Oncolytic Virotherapy , Skin Neoplasms , Adult , Aged , Aged, 80 and over , Biological Products , Herpesvirus 1, Human , Humans , Immunotherapy , Male , Melanoma/therapy , Middle Aged , Neoplasm Recurrence, Local/therapy , Skin Neoplasms/therapy , Young AdultABSTRACT
Exciting advances in melanoma systemic therapies have presented the opportunity for surgical oncologists and their multidisciplinary colleagues to test the neoadjuvant systemic treatment approach in high-risk, resectable metastatic melanomas. Here we describe the state of the science of neoadjuvant systemic therapy (NAST) for melanoma, focusing on the surgical aspects and the key role of the surgical oncologist in this treatment paradigm. This paper summarizes the past decade of developments in melanoma treatment and the current evidence for NAST in stage III melanoma specifically. Issues of surgical relevance are discussed, including the risk of progression on NAST prior to surgery. Technical aspects, such as the definition of resectability for melanoma and the extent and scope of routine surgery are presented. Other important issues, such as the utility of radiographic response evaluation and method of pathologic response evaluation, are addressed. Surgical complications and perioperative management of NAST related adverse events are considered. The International Neoadjuvant Melanoma Consortium has the goal of harmonizing NAST trials in melanoma to facilitate rapid advances with new approaches, and facilitating the comparison of results across trials evaluating different treatment regimens. Our ultimate goals are to provide definitive proof of the safety and efficacy of NAST in melanoma, sufficient for NAST to become an acceptable standard of care, and to leverage this platform to allow more personalized, biomarker-driven, tailored approaches to subsequent treatment and surveillance.