While the incidence of melanoma continues to rise, the mortality of the disease appears to have stabilized. This may, in part, be due to the development and application of immune checkpoint ...inhibitors as standard of care in advanced melanoma. However, many patients do not respond to these therapies alone. Combining immune checkpoint inhibitors with other classes of therapeutics appears to be a promising direction to improve response and survival in advanced melanoma.
This review article aims to discuss phase 1 and 2 clinical trials examining immune checkpoint inhibitors in combination therapy for the treatment of advanced, unresectable melanoma. In particular, these regimens include various kinase inhibitors, tumor-infiltrating lymphocytes, toll-like receptor agonists, cytokines, and oncolytic viral therapies. The combinations under discussion include both systemic and combination systemic/local therapies.
Drug combinations discussed here appear to be promising therapeutic regimens for advanced melanoma. Improved understanding of the mechanisms of primary, adaptive, and acquired resistance to immune checkpoint inhibitors may guide the development of future combination regimens.
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.
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.
To assess the cardiac safety and subsequent clinically significant sequalae of this therapy.
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.
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. (
= .042).
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.
Background
Talimogene laherparepvec (TVEC) is an oncolytic herpes virus used as intralesional therapy for patients with unresectable stage IIIB through IV melanoma. We reviewed the standard of care ...treatment of TVEC at a single institution.
Methods
All patients treated with TVEC for advanced melanoma were retrospectively evaluated from 2015 to 2018. Patient demographics, clinicopathologic characteristics, treatment response, and toxicity were reviewed.
Results
Twenty-seven patients underwent therapy with TVEC. Median age was 75 years, and 63% of patients were female. Seventeen (63.0%) patients underwent injections on the lower extremity, four (14.8%) on the upper extremity, four (14.8%) on the head and neck, and two (7.4%) on the trunk. Median number of injections was five. Median follow-up was 8.6 months. Of the 27 patients, 23 patients met the criteria for response analysis with at least 8 weeks follow-up. Ten (43.5%) patients experienced a complete response (CR), three (13.1%) experienced a partial response (PR), and five (21.7%) had stable disease (SD) for an overall response rate of 56.5% (CR + PR) and a disease control rate of 78.3% (CR + PR + SD). Adverse events were mostly limited to mild constitutional symptoms within 48 h of injection. Two patients developed cellulitis treated with oral antibiotics, and one patient underwent excision of a lesion for ulceration and bleeding during therapy.
Discussion
TVEC is an effective and well-tolerated intralesional therapy for patients with unresectable stage IIIB through IV melanoma. A CR was achieved in almost half of patients treated. Disease control is seen in the vast majority.
Purpose
To update the American Society of Clinical Oncology (ASCO)-Society of Surgical Oncology (SSO) guideline for sentinel lymph node (SLN) biopsy in melanoma.
Methods
An ASCO-SSO panel was formed, ...and a systematic review of the literature was conducted regarding SLN biopsy and completion lymph node dissection (CLND) after a positive sentinel node in patients with melanoma.
Results
Nine new observational studies, two systematic reviews and an updated randomized controlled trial (RCT) of SLN biopsy, as well as two randomized controlled trials of CLND after positive SLN biopsy, were included.
Recommendations
Routine SLN biopsy is not recommended for patients with thin melanomas that are T1a (non-ulcerated lesions < 0.8 mm in Breslow thickness). SLN biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or <0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure. SLN biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of >1.0 to 4.0 mm). SLN biopsy may be recommended for patients with thick melanomas (T4; > 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm. In the case of a positive SLN biopsy, CLND or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathological factors. For higher risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND. Important qualifying statements outlining relevant clinicopathological factors, and details of the reference patient populations are included within the guideline.
Melanoma is an aggressive cutaneous malignancy with rapidly rising incidence. Diagnosis of controversial melanocytic lesions, correct prognostication of patients, selection of appropriate adjuvant ...and systemic therapies, and prediction of response to a given therapy remain very real challenges. Despite these challenges, multiple high throughput, nucleic-acid based biomarkers have been developed that can be assayed from histologic tissue specimens. FISH, CGH, Decision-Dx, and other multi-marker assays have been combined to improve overall predictability. This review discusses some of the most promising nucleic acid based assays that can be obtained from tissue specimens to assist with diagnosis, prognostication, and prediction of treatment response.
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