Neoadjuvant treatment for stage III and IV cutaneous melanoma.

BACKGROUND: Cutaneous melanoma is amongst the most aggressive of all skin cancers. Neoadjuvant treatment is a form of induction therapy, given to shrink a cancerous tumour prior to the main treatment (usually surgery). The purpose is to improve survival and surgical outcomes. This review systematically appraises the literature investigating the use of neoadjuvant treatment for stage III and IV cutaneous melanoma. OBJECTIVES: To assess the effects of neoadjuvant treatment in adults with stage III or stage IV melanoma according to the seventh edition American Joint Committee on Cancer (AJCC) staging system. SEARCH METHODS: We searched the following databases up to 10 August 2021 inclusive: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS and four trials registers, together with reference checking and contact with study authors to identify additional studies. We also handsearched proceedings from specific conferences from 2016 to 2020 inclusive. SELECTION CRITERIA: Randomised controlled trials (RCTs) of people with stage III and IV melanoma, comparing neoadjuvant treatment strategies (using targeted treatments, immunotherapies, radiotherapy, topical treatments or chemotherapy) with any of these agents or current standard of care (SOC), were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Primary outcomes were overall survival (OS) and adverse effects (AEs). Secondary outcomes included time to recurrence (TTR), quality of life (QOL), and overall response rate (ORR). We used GRADE to evaluate the certainty of the evidence. MAIN RESULTS: We included eight RCTs involving 402 participants. Studies enrolled adults, mostly with stage III melanoma, investigated immunotherapies, chemotherapy, or targeted treatments, and compared these with surgical excision with or without adjuvant treatment. Duration of follow-up and therapeutic regimens varied, which, combined with heterogeneity in the population and definitions of the endpoints, precluded meta-analysis of all identified studies. We performed a meta-analysis including three studies. We are very uncertain if neoadjuvant treatment increases OS when compared to no neoadjuvant treatment (hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.15 to 1.21; 2 studies, 171 participants; very low-certainty evidence). Neoadjuvant treatment may increase the rate of AEs, but the evidence is very uncertain (26% versus 16%, risk ratio (RR) 1.58, 95% CI 0.97 to 2.55; 2 studies, 162 participants; very low-certainty evidence). We are very uncertain if neoadjuvant treatment increases TTR (HR 0.51, 95% CI 0.22 to 1.17; 2 studies, 171 participants; very low-certainty evidence). Studies did not report ORR as a comparative outcome or measure QOL data. We are very uncertain whether neoadjuvant targeted treatment with dabrafenib and trametinib increases OS (HR 0.28, 95% CI 0.03 to 2.25; 1 study, 21 participants; very low-certainty evidence) or TTR (HR 0.02, 95% CI 0.00 to 0.22; 1 study, 21 participants; very low-certainty evidence) when compared to surgery. The study did not report comparative rates of AEs and overall response, and did not measure QOL. We are very uncertain if neoadjuvant immunotherapy with talimogene laherparepvec increases OS when compared to no neoadjuvant treatment (HR 0.49, 95% CI 0.15 to 1.64; 1 study, 150 participants, very low-certainty evidence). It may have a higher rate of AEs, but the evidence is very uncertain (16.5% versus 5.8%, RR 2.84, 95% CI 0.96 to 8.37; 1 study, 142 participants; very low-certainty evidence). We are very uncertain if it increases TTR (HR 0.75, 95% CI 0.31 to 1.79; 1 study, 150 participants; very low-certainty evidence). The study did not report comparative ORRs or measure QOL. OS was not reported for neoadjuvant immunotherapy (combined ipilimumab and nivolumab) when compared to the combination of ipilimumab and nivolumab as adjuvant treatment. There may be little or no difference in the rate of AEs between these treatments (9%, RR 1.0, 95% CI 0.75 to 1.34; 1 study, 20 participants; low-certainty evidence). The study did not report comparative ORRs or measure TTR and QOL. Neoadjuvant immunotherapy (combined ipilimumab and nivolumab) likely results in little to no difference in OS when compared to neoadjuvant nivolumab monotherapy (P = 0.18; 1 study, 23 participants; moderate-certainty evidence). It may increase the rate of AEs, but the certainty of this evidence is very low (72.8% versus 8.3%, RR 8.73, 95% CI 1.29 to 59; 1 study, 23 participants); this trial was halted early due to observation of disease progression preventing surgical resection in the monotherapy arm and the high rate of treatment-related AEs in the combination arm. Neoadjuvant combination treatment may lead to higher ORR, but the evidence is very uncertain (72.8% versus 25%, RR 2.91, 95% CI 1.02 to 8.27; 1 study, 23 participants; very low-certainty evidence). It likely results in little to no difference in TTR (P = 0.19; 1 study, 23 participants; low-certainty evidence). The study did not measure QOL. OS was not reported for neoadjuvant immunotherapy (combined ipilimumab and nivolumab) when compared to neoadjuvant sequential immunotherapy (ipilimumab then nivolumab). Only Grade 3 to 4 immune-related AEs were reported; fewer were reported with combination treatment, and the sequential treatment arm closed early due to a high incidence of severe AEs. The neoadjuvant combination likely results in a higher ORR compared to sequential neoadjuvant treatment (60.1% versus 42.3%, RR 1.42, 95% CI 0.87 to 2.32; 1 study, 86 participants; low-certainty evidence). The study did not measure TTR and QOL. No data were reported on OS, AEs, TTR, or QOL for the comparison of neoadjuvant interferon (HDI) plus chemotherapy versus neoadjuvant chemotherapy. Neoadjuvant HDI plus chemotherapy may have little to no effect on ORR, but the evidence is very uncertain (33% versus 22%, RR 1.75, 95% CI 0.62 to 4.95; 1 study, 36 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: We are uncertain if neoadjuvant treatment increases OS or TTR compared with no neoadjuvant treatment, and it may be associated with a slightly higher rate of AEs. There is insufficient evidence to support the use of neoadjuvant treatment in clinical practice. Priorities for research include the development of a core outcome set for neoadjuvant trials that are adequately powered, with validation of pathological and radiological responses as intermediate endpoints, to investigate the relative benefits of neoadjuvant treatment compared with adjuvant treatment with immunotherapies or targeted therapies.

Frailty as a predictor of adverse outcomes in head and neck reconstruction: A systematic review.

BACKGROUND: Frailty has been shown to adversely impact outcomes in a number of surgical disciplines. In head and neck reconstructive surgery, frailty may represent a significant risk factor in predicting post-operative outcomes due to the common characteristics of the patient population undergoing these procedures. OBJECTIVES: To summarize the available evidence about frailty as a predictor of post-operative complications, length of hospital stay and quality of life in patients undergoing head and neck reconstructive surgery. STUDY DESIGN: Systematic Review. METHODS: The study protocol was registered with PROSPERO, registration CRD42022302899. Methodology was in keeping with the PRISMA Guidelines for Systematic Reviews. MEDLINE, SCOPUS, EMBASE, Web of Science and CENTRAL were the databases searched. Qualitative synthesis of the included studies was carried out, and quality assessment was performed. RESULTS: Nine studies that reported data on 10,457 patients undergoing reconstruction of the head and neck were included in the review. A number of different tools were used to assess frailty, with the modified frailty index being the most frequently used. In total, 8 studies reported increased rates of complications in patients with increased levels of frailty, irrespective of the frailty tool used, with varied levels of statistical significance across the studies. CONCLUSION: An association is observed between increased rates of perioperative complications and increased levels of frailty in patients undergoing head and neck reconstruction. Frailty tools may represent a useful method to risk stratify patients undergoing reconstructive head and neck surgery.

Analysis of Outcomes of Pharyngo-laryngo-esophagectomy and Reconstruction with Longitudinal Comparison in a Single Institution.

Advanced hypopharyngeal tumours present complex clinical challenges, and where resection is attempted, there is a requirement for major reconstruction. Despite advances in surgical technique, outcomes remain poor for this patient group, and optimum treatment has yet to be established. We aimed to assess the treatment and outcomes of patients in our institution in the context of previous studies. All patients from 2008 to 2018 who underwent surgical management for hypopharyngeal tumours with pharyngo-laryngo-esophagectomy and flap-based reconstruction were included in the study. Demographic and outcome data were collected, and patient-reported outcomes were solicited from surviving patients using the EORTC QLQ H&N 43 questionnaire. Thirty patients were assessed, in which 12 had gastric pull-ups, 16 had free jejunum flaps, and 2 had free anterolateral thigh flaps. There was a 38% five-year survival rate. Overall, the rates of stricture (10.7%) and fistula (7.1%) were low. The majority of patients (53.6%) returned to a normal diet within three months with a soft or puree diet in 35.7% of patients. Some form of speech was possible in 92.9% of patients. The average questionnaire score for surviving patients was 87.3, with good outcomes related to eating and swallowing, but poorer outcomes for speech and communication. This study showed that outcomes for patients receiving complex reconstruction following hypopharyngeal tumour resection are improving over time. There is still scope for improvement of patient outcomes and refinement of optimum surgical management strategies.

Idiopathic Carpal Spasm (Trousseau's Sign) After Intraoperative Arm Tourniquet Inflation in an Intubated Patient.

We present a case of a 38-year-old male who sustained a laceration from a knife to the volar aspect of his left index and middle fingers. He had clinical injury to his flexor digitorum profundus tendons to both digits. He underwent operative exploration and repair of the tendons under general anaesthetic. An arm tourniquet was inflated to allow for haemostasis in the operative field. A few minutes after inflation, the patient's hand went into carpal spasm. The tourniquet was deflated and the spasm resolved. Intraoperative serum calcium and carbon dioxide levels were normal. The operation proceeded with the tourniquet deflated. Postoperatively serum calcium and magnesium levels were within normal limits, as was serum vitamin D and parathyroid hormone levels. It has been reported that carpal spasm can occur with tourniquet use in the anxious patient due to hyperventilation and resultant metabolic alkalosis. This however is the first reported case of carpal spasm in the setting of tourniquet use and normal serum electrolytes and respiratory parameters in an intubated patient.

Microvascular free tissue transfer in elderly patients: the Toronto experience.

BACKGROUND: Microvascular free tissue transfer has become an accepted and versatile method of reconstruction in the head and neck region, offering a one-stage procedure and thus reducing the number and length of hospital stays. Many of the patients requiring head and neck free flaps are elderly, with concomitant medical problems, including respiratory and cardiovascular compromise, and are therefore potentially at higher risk of adverse outcomes. In addition, they frequently have a history of heavy alcohol and cigarette consumption, which can compound the risks. METHODS: We analyzed a series of 288 intraoral free flap reconstructions and arbitrarily divided them into four groups depending on age: <50, 51-60, 61-70, >70. These reconstructions were all performed for malignant lesions. Preoperative medical problems, including ischemic heart disease, hypertension, chronic obstructive pulmonary disease, peripheral vascular disease, and diabetes, were assessed and compared among the different age groups. CONCLUSIONS: Our results suggest that free flap surgery is a safe technique in elderly patients with comparable surgical complications to a younger patient population. As a result of concomitant medical problems, however, postoperative medical complications are more frequent in the older age groups, with a resultant increase in length of hospital stay.

Role of thrombolysis in free-flap salvage.

Approximately 5 percent of microvascular free-tissue transfers fail; often this is due to microvascular or peri-anastomotic thrombosis. Various reports have advocated the use of thrombolytics for salvage of these flaps, although clinical evidence supporting this approach is sparse. The authors attempted to review their own and other published results and present an algorithm for the use of thrombolytics in the management of failing free flaps. A retrospective review of 590 free flaps, revealed 71 (12 percent) requiring re-exploration for impending flap failure, determined by standard clinical indicators. Forty-four (62 percent) were found to have pedicle thrombosis and 20 (28 percent) received thrombolysis with streptokinase or urokinase. All 44 flaps were grouped by final outcome and thrombolytic use for comparison. In 24 (55 percent) of the flaps with evidence of thrombosis, the use of thrombolytics was felt to be inappropriate or unnecessary; 13 (54 percent) of these were salvaged. Twenty flaps, however, did receive thrombolysis and 6 (30 percent) of these were salvaged. There was no statistically significant difference among groups with respect to preoperative risk factors, age, gender, flap type, and site of anastomotic thrombosis. There was a twofold higher use of vein grafts in the failed vs. salvaged flaps (36 percent vs. 15.7 percent), and no flaps with vessel grafts were salvaged with thrombolytics. Despite the fact that all flaps were re-explored within 3 hr of a problem being detected, the mean time from the initial operation to re-exploration was significantly higher in flaps that did not respond to thrombolytics (63. 8 vs. 32.8 hr, respectively, p=0.0457). Also, the mean time to re-exploration was significantly higher in the salvaged flaps receiving thrombolysis vs. those that did not (32.8 vs. 22.3 hr, respectively, p=0.0264). While early detection and re-exploration are crucial for salvaging failing free flaps, those flaps unresponsive to other standard interventions may benefit from the selective use of thrombolytics.