Immunotherapy in advanced cutaneous squamous cell carcinoma: Sydney west cancer network experience.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy in the Caucasian population. A minority of cases are inoperable at presentation, recur or develop metastatic disease with a historical 5-year overall survival of ~10%. Treatment options in this setting are generally palliative. Immunotherapy has emerged as a new paradigm in managing these patients. METHODS: Patients presenting to Sydney West Cancer Network with locally advanced or metastatic CSCC treated with the anti-PD1 agent cemiplimab were identified. Response to treatment was objectively assessed based on RECIST1.1 or PERCIST criteria. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), therapy toxicity, and predictors of treatment response. RESULTS: A total of 19 patients were identified with a median age of 76 (range 56-94) and 4 immunosuppressed. The longest follow up duration was 28 months. ORR, complete response (CR), and partial response (PR) were 68% (13/19), 53% (10/19), and 16% (3/19), respectively. Median PFS was 12 months (95% CI 9-14) whilst median OS was not reached by end of study. Responders (CR or PR) had significantly superior OS compared to those with no response (P < 0.01). A primary site of head and neck cancer was significantly associated with ORR (P = 0.04). A single patient experienced Grade 3 toxicity with the rest being Grades 0-1. CONCLUSION: This study confirms the clinical efficacy of cemiplimab in patients with advanced CSCC with many experiencing a durable response and an acceptable adverse effect profile.

Merkel cell carcinoma in situ: A systematic review of prognosis and management.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumour. While dermally invasive MCC is known to have a five-year survival of only 30-40%, the prognosis and management of MCC in situ (MCCis) is not widely reported. OBJECTIVE: We present a systematic review to elucidate the prognosis and management of MCCis. METHODS: We performed a systematic review, searching three databases to 01 June 2021. Case reports, cohort studies, clinical trials and literature reviews were considered for inclusion. RESULTS: We identified 26 cases of MCCis published in the literature with a median age of 74 years and involving 19 males and 7 females. Most cases were on the face and neck (n = 17), followed by upper limb (n = 8) and lower limb (n = 1). Sentinel lymph node biopsy was performed in three patients, and all were negative. One subject underwent adjuvant radiotherapy. No MCCis-associated deaths were reported. CONCLUSION: This review suggests that MCCis has an excellent prognosis with minimal, if any, risk of mortality and a very low risk of dermal invasion and recurrence when treated with wide local excision alone. Sentinel lymph node biopsy is unlikely to be useful for MCCis.

Immunotherapy in advanced Merkel cell carcinoma: Sydney west cancer network experience.

INTRODUCTION: Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with no survival benefit demonstrated using palliative cytotoxic chemotherapy in the setting of metastatic MCC. Recently, immune checkpoint inhibitors (anti-PD-L1/PD1) have been approved in this setting after durable clinical response was demonstrated in several clinical trials. In this series, we present a multicentre real-world experience in using anti-PD-L1/PD1 in advanced MCC. METHODS: A retrospective review was performed of all patients with metastatic MCC who were treated with at least one dose of anti-PD-L1/PD1 presenting to Sydney West Cancer Network (Westmead, Nepean and Blacktown hospitals) was performed between 2016 and 2020. Treatment response was assessed based on morphologic and/or metabolic changes of the disease on FDG-PET/CT scans. Primary end point investigated was objective response rate. Secondary outcomes included therapy toxicity, disease control and overall survival. RESULTS: Thirteen patients received anti-PD-L1/PD1 with a median age of 82 (range 62-89). Two patients had undergone prior palliative chemotherapy. The median follow-up time was 17 months (range 2-34). The overall, complete and partial response rates were 77% (10), 54% (7) and 23% (3), respectively. Treatment-related grade 1 or 2 toxicity was experienced by 69% with only 2 cases of greater severity. The median progression-free survival and overall survival were 18 months (95% CI 10-26 months) and 33 months (95% CI range 7.6-58.4 months), respectively. CONCLUSIONS: Consistent with clinical trial results, anti-PD-L1/PD1 therapy in this small series demonstrated efficacy and safety in patients with metastatic MCC.

Outcomes of patients with metastatic cutaneous squamous cell carcinoma to the axilla: a multicentre cohort study.

BACKGROUND: Metastatic cutaneous squamous cell carcinoma to the axilla is uncommon, with limited data to guide management. We sought to assess the outcomes of patients with this condition after surgery and radiotherapy. METHODS: A retrospective cohort study of patients treated at two Australian hospitals from 1994 through 2016 was performed. RESULTS: A total of 74 patients were identified, including 48 treated curatively with surgery-plus-radiotherapy and 15 with surgery alone. Compared with patients treated with surgery alone, a higher proportion of patients treated with surgery-plus-radiotherapy had lymph nodes larger than 6 cm (53% versus 8%, P = 0.012) and multiple adverse histopathological features (75% versus 47%, P = 0.04). The groups had similar 5-year disease-free survival (45% versus 46%) and overall survival (51% versus 48%). Presence of multiple positive lymph nodes was associated with reduced disease-free survival (hazard ratio 4.57, P = 0.01) and overall survival (hazard ratio 3.53, P = 0.02). Regional recurrence was higher in patients treated with surgery alone (38% versus 22%, P = 0.22) and patients with lymph nodes larger than 6 cm (34% versus 10%, P = 0.03). All recurrences occurred within 2 years following treatment. CONCLUSION: Combined-modality therapy for metastatic cutaneous squamous cell carcinoma to the axilla is recommended for high-risk patients, although outcomes remain modest. The key period for recurrence is within 2 years following treatment.

Prognostic value of the 8th edition American Joint Commission Cancer nodal staging system for patients with head and neck cutaneous squamous cell carcinoma: A multi-institutional study.

BACKGROUND: The 8th edition American Joint Committee on Cancer staging manual (AJCC8) introduced a separate staging system for head and neck cutaneous squamous cell carcinoma (HNcSCC) which parallels mucosal SCC and incorporates extranodal extension (ENE). This study aims to evaluate its prognostic utility. METHODS: Univariate analysis of 1146 patients with metastatic HNcSCC from four Australian cancer centers was performed according to both AJCC 7th (AJCC7) and the 8th editions. RESULTS: AJCC8 increased classification of 924 (80.6%) patients to either pN2a or pN3b and 341 patients (29.8%) from stage III to IV compared to AJCC7. The disease-specific survival (DSS) was not significantly different between pN1, pN2 or pN3a categories per AJCC8. Estimates of model performance for the AJCC8 pN staging revealed modest predictive capacity (Harrell's C of 0.62 for DSS). CONCLUSIONS: The risk stratification according to pN classification of AJCC8 staging system performed poorly as a prognostic indicator.

Outcomes for elderly patients 75 years and older treated with curative intent radiotherapy for mucosal squamous cell carcinomas of the head and neck.

BACKGROUND: Elderly patients with mucosal squamous cell carcinomas of the head and neck (mHNSCC) represent a challenging clinical dilemma. METHODS: A retrospective review was performed of patients ≥75 years, treated with curative-intent radiotherapy for mHNSCC in two quaternary Sydney hospitals between 2007 and 2017. RESULTS: Ninety-five patients met inclusion criteria. The median age was 79 years (75-94). Patients received radiotherapy alone (n = 24), concurrent chemoradiotherapy (n = 22), surgery and adjuvant radiotherapy (n = 45), or surgery with adjuvant chemoradiotherapy (n = 4). Median follow-up was 4.5 years, median overall survival (OS) was 3.8 years, and 2-year and 5-year OS were 56% and 43%, respectively. Eastern Cooperative Oncology Group performance status of ≥2 (P < .001) was a statistically significant predictor of reduced OS. Thirty-four patients (36%) required hospitalization, 5 (5%) did not complete radiotherapy, and 9 (9%) were feeding tube dependent beyond 6 months. CONCLUSIONS: Appropriately selected elderly patients can achieve durable outcomes from curative intent radiotherapy with acceptable treatment toxicity.

Radiotherapy for early non-melanoma skin cancer.

This article reviews the important role of radiotherapy in the management of early non-melanoma skin cancer, in the definitive and adjuvant settings. Therapeutic considerations and appropriate patient selection will be discussed, as well as evidence for efficacy and potential side-effects. Additionally, we present some recent advances which may improve accessibility and quality of radiotherapy, such as more convenient dose-fractionation, wide-field treatments, electronic brachytherapy and 3D printed bolus.

Sentinel lymph node biopsy in clinically node-negative Merkel cell carcinoma: the Westmead Hospital experience.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy with a propensity to metastasize to regional lymph nodes. Sentinel lymph node biopsy (SLNB) in patients with clinically node-negative MCC has been utilized to identify patients with subclinical nodal metastases. This study aims to review the accuracy of SLNB in MCC and to evaluate the impact of SLNB on management. METHODS: Patients with clinically node-negative MCC who underwent SLNB were identified from a prospective database of patients treated at the Westmead Hospital, Sydney, between 1998 and 2017. Data from these patients were reviewed and analysed. RESULTS: Forty-one patients were identified: 28 men and 13 women, median age 70 years. Median duration of follow-up was 27 months. Sixteen (39%) patients had a positive SLNB and all underwent nodal treatment which consisted of radiotherapy (n = 13), completion lymphadenectomy and adjuvant radiotherapy (n = 2), and completion lymphadenectomy alone (n = 1). Following negative SLNB, 24 of 25 patients did not undergo further nodal treatment. The false-negative rate was 16% as three patients developed in-field nodal recurrence subsequent to a negative SLNB. At last follow-up, 29 patients had no evidence of disease, six were alive with disease and three had died from other causes. Three SLN-positive patients have died of MCC. CONCLUSION: SLNB has a high rate of positivity and can improve the accuracy of staging and prognostication in MCC, and guide management. The relatively low risk of a false-negative SLNB justifies close observation in SLNB-negative patients.

The role of radiotherapy in the management of non-melanoma skin cancer.

The global incidence of non-melanoma skin cancer continues to increase as the global population ages with the highest incidence in the world occurring in Australian and New Zealand patients. There are numerous treatment options available for non-melanoma skin cancer patients of which radiotherapy is an efficacious and versatile tissue preserving non-surgical (or medical) option. In patients where excision may not be an option (medically/technically inoperable) or considered less ideal (e.g. cosmetic outcome), radiotherapy offers an excellent option. Following surgery, adjuvant radiotherapy in patients with unfavourable pathology can decrease the risk of recurrence and associated morbidity. Elderly and co-morbid patients with poor performance status can benefit from short-course hypofractionated radiotherapy in the setting where surgery is not an option. As with any modality, radiotherapy has advantages and disadvantages and it is therefore important for clinicians to appreciate these. We aim to present an update for clinicians that manage patients with non-melanoma skin cancer on the role of radiotherapy.

Systematic review of sentinel lymph node biopsy in Merkel cell carcinoma of the head and neck.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine tumor arising on the head and neck in 40%-50% of patients. Between 20% and 40% will harbor subclinical nodal metastasis. METHODS: Using search terms 'Merkel AND sentinel', MEDLINE, PUMED, and EMBASE databases were systematically reviewed for publications regarding sentinel lymph node biopsy (SLNB) in classification I and II MCC of the head and neck. RESULTS: Twenty-nine publications encompassing 136 patients were included. The SLNB finding was positive in 42 patients (30.9%). Primary MCC was located on the malar/zygomatic (34.4%), forehead/frontal (13.5%), and nasal (13.5%) regions. Recurrence in an SLNB negative nodal basin result occurred in 10 patients (false negative rate of 19.2%). Site of primary MCC was not associated with a false-negative SLNB result; however, there was a non-statistically significant trend for increased frequency among midline lesions. CONCLUSIONS: Sentinel lymph node biopsy (SLNB) is recommended for eligible patients with classification I and II head and neck MCC.

Efficacy of hypofractionated radiotherapy in patients with non-melanoma skin cancer: Results of a systematic review.

Radiation oncologists are increasingly tasked with the management of elderly patients with non-melanoma skin cancer, unsuitable for surgical intervention due to inoperable lesions and/or poor performance status. In this cohort, hypofractionated radiotherapy, delivered either daily, alternative daily or once weekly is highly effective. A systematic literature search was conducted of PUBMED, MEDLINE and EMBASE databases using the algorithm ('radiotherapy' OR 'radiation therapy' OR 'brachytherapy') AND ('hypofraction' OR 'hypofractionated' OR 'hypofractionation') AND ('skin neoplasms' OR 'carcinoma' OR 'malignancy') AND ('skin' OR 'epidermis' OR 'epidermal' OR 'cutaneous'). Forty relevant publications (1983-2017) encompassing 12,337 irradiated lesions were retrieved. Studies documented a mean age of 71.73 years and male predilection (54.5%). Both external beam radiotherapy and brachytherapy were utilized. Tumour subtype was squamous cell carcinoma (23.5%), basal cell carcinoma (75.2%) or others (1.3%). Irradiated lesions were primary (or denovo) (92.6%), located on the head and neck (95.7%) and received definitive therapy (96.5%). Analysis demonstrated a mean weighted total radiotherapy dose (38.15 Gy), dose per fraction (7.95 Gy) and treatments per week (2.98). Despite significant heterogeneity in the study population, the radiotherapy delivered and follow-up, local recurrence rate (crude or Kaplan-Meier analysis) did not exceed 7.9% in all but three of the 36 publications providing these data. Twenty-nine publications documented local control exceeding 90%. There is a body of evidence documenting the efficacy of hypofractionated radiotherapy as an option that confers no obvious disadvantage in local control when compared to traditional more protracted radiotherapy schedules.

Cutaneous squamous cell carcinoma and the emerging role of sentinel lymph node biopsy.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and is usually associated with a favorable prognosis in most patients. However, a small minority of patients will be diagnosed with a high-risk cSCC (HRcSCC) and a proportion will have a poor outcome, in some cases causing death. HRcSCC is characterized by an increase in aggressiveness manifested as local recurrence, the development of lymph node metastases, and occasionally death. The utility of sentinel lymph node biopsy (SLNB) in this group of patients is unclear without high-level evidence or clear-cut recommendations. If clinicians accept as a cut-off threshold of a >10% of risk of harboring occult nodal metastasis, then selected HRcSCC patients may benefit from SLNB and/or additional investigations. Herein, we performed a review of the current evidence regarding SLNB in HRcSCC. We believe that SLNB may be considered in selected HRcSCC patients to potentially better predict prognosis and influence management. However larger prospective studies are needed to better define the subset of patients that may benefit from SLNB and if early detection of occult nodal metastases is associated with an improved outcome.

Immunocompromised patients with metastatic cutaneous nodal squamous cell carcinoma of the head and neck: Poor outcome unrelated to the index lesion.

BACKGROUND: Immunocompromised patients with metastatic cutaneous nodal head and neck squamous cell carcinoma (HNSCC) have worse outcomes compared to the immunocompetent. The purpose of this study was to investigate the characteristics of the primary cutaneous squamous cell carcinoma (SCC), nodal pathology, and outcome between these 2 groups. METHODS: Analysis of a prospective database was performed. A 2:1 pooled analysis selected 46 immunocompetent patients matched with 23 immunocompromised patients. Overall survival (OS) and relapse-free survival (RFS) were calculated using the Kaplan-Meier method. RESULTS: No significant difference was found in the primary tumor characteristics between the 2 groups. In the immunocompromised group, RFS (hazard ratio [HR] 2.70; P = .01) and OS (HR 2.32; P = .04) were significantly worse. Extracapsular spread was present in 100% of the immunocompromised patients. CONCLUSION: No significant difference was identified in the primary cutaneous SCC between the immunocompetent and immunocompromised patients. Immunosuppression predicted worse outcome.

Definitive radiotherapy for Merkel cell carcinoma confers clinically meaningful in-field locoregional control: A review and analysis of the literature.

BACKGROUND: Merkel cell carcinoma (MCC) is an uncommon radiosensitive, neuroendocrine malignancy. Treatment often involves surgery; however, older, sicker patients may not be candidates for an operation. Institutions have published data favoring the role of definitive radiotherapy for macroscopic locoregional disease. OBJECTIVE: Our objective was to report the outcome of patients treated with definitive radiotherapy. METHODS: We performed a systematic review of Medline, PubMed, and Embase databases for reported cases or series of definitive radiotherapy for macroscopic locoregional MCC. RESULTS: The mean radiation dose did not significantly differ between primary and regional sites (48.7 ± 13.2 vs 49.4 ± 10.1 Gy, P = .74). The rate of recurrence was calculated on the basis of the site of disease (11.7%) and per patient (14.3%). Recurrence was significantly more likely to occur at regional than at primary irradiated sites (16.3% vs 7.6%, P = .02). There was no association between radiotherapy dose and incidence of recurrence or nonrecurrence; primary (42.7 ± 23 vs 49.3 ± 11.8 Gy, P = .197) and regional (48.6 ± 10 vs 49.5 ± 10.3 Gy, P = .77). LIMITATIONS: A limitation of this report is that most publications were retrospective; heterogeneity was present in the size of MCC and in radiotherapy details. CONCLUSIONS: Definitive radiotherapy for locoregional macroscopic MCC was found to confer clinically meaningful local and regional in-field control.

Important prognostic significance of lymph node density in patients with node positive oral tongue cancer.

BACKGROUND: Lymph node density (LND) has been described as a prognostic factor for survival in patients with head and neck squamous cell carcinoma, particularly of the oral cavity. The aim of this study was to determine the prognostic significance of LND in patients with node positive oral tongue squamous cell carcinoma (OTSCC). METHODS: Patients with pathological node positive OTSCC were identified in a retrospective review of prospectively collected data. The optimal cut-point for LND was determined using the minimum P-value method and the log-rank test. The impact of this LND cut-point on time to disease progression and overall survival was determined. RESULTS: In 72 patients with OTSCC, an LND of 14.3% was found to have the greatest separation using the log-rank test (P < 0.001). LND ≤14.3% was predicted for longer time to disease progression with a median time of 73 months compared to 9.4 months in patients with an LND >14.3% (hazard ratio: 3.43; 95% confidence interval: 1.76-6.70; P < 0.001). LND was also a significant predictor of overall survival with a median overall survival with LND ≤14.3% of 82.3 months, compared with 14.7 months in patients with an LND >14.3% (hazard ratio: 3.28; 95% confidence interval: 1.61-6.68; P = 0.001). Patients with an LND >14.3% experienced a higher rate of regional recurrence. CONCLUSION: Our findings confirm the prognostic significance of LND in patients with node positive OTSCC, with a similar LND cut-point value to other published series. Improving regional control in these high-risk patients may improve outcome.

Prognostic Significance of Lymph Node Ratio in Metastatic Cutaneous Squamous Cell Carcinoma of the Head and Neck.

BACKGROUND: The prognostic variables in patients with metastatic cutaneous nodal squamous cell carcinoma (SCC) are well documented; however, the relationship between lymph node ratio (LNR) and outcome is not well researched. LNR represents the ratio of positive lymph nodes to total excised lymph nodes. We analyzed the correlation between LNR and outcome in patients who have undergone surgery for metastatic cutaneous nodal SCC of the head and neck. METHODS: Analysis was performed on retrospectively collected data, identifying patients who underwent surgery at Westmead Hospital, Sydney. Pathology reports were reviewed to ascertain LNR. A log-rank test identified a specific LNR value to compare time to disease progression (TTDP) and overall survival (OS). Multivariate proportional hazard regression models were used to review outcome. RESULTS: In total, 193 males and 45 females with a median of age 68 years were identified, with a mean recorded LNR of 0.15. On multivariate analysis, an LNR cutpoint of 0.21 was a significant predictor of decreased TTDP [hazard ratio (HR) 2.34, 95 % confidence interval (CI) 4.40-0.49; p = 0.009] and OS (HR 2.75, 95 % CI 1.57-4.82; p < 0.001). Forty-nine of 238 patients (21 %) developed recurrence, with most recurrences being regional (29 of 49; 59 %). A total of 17 % of patients with an LNR ≤0.21 recurred compared with 40 % for patients with an LNR >0.21. CONCLUSIONS: LNR is potentially an independent predictor of outcome in patients with metastatic cutaneous nodal SCC. The clinical relevance of this finding requires further validation.

Merkel cell carcinoma: A case of palliative upper limb amputation in a patient with refractory in-transit metastases.

We report an unusual case of Merkel cell carcinoma in a 70-year-old woman with the rapid development of left upper limb in-transit and hepatic metastases. The patient had a preceding history of left-sided breast cancer. Palliative chemotherapy with carboplatin and etoposide produced a minimal response. The in-transit metastases rapidly progressed and were refractory to chemotherapy and a single fraction of palliative radiotherapy, leading to a marked impact on her quality of life, secondary to sepsis and bleeding. After lengthy discussion, she consented to an above-elbow amputation resulting in a marked improvement in her well-being. In this case, we believe that palliative amputation of the involved arm was justified and beneficial to the patient.

Nonmelanoma Cutaneous Head and Neck Cancer and Merkel Cell Carcinoma: Current Concepts, Advances, and Controversies.

Nonmelanoma skin cancer (NMSC) is the most common cancer worldwide and the most frequently observed malignancy in whites. Approximately 75% to 80% are basal cell carcinomas and 20% to 25% are squamous cell carcinomas. Incidence is increasing, partly reflecting an ageing population, and NMSC is more commonly seen in men. The predominant causative agent is ultraviolet solar radiation exposure, with the majority of cases occurring on the head and neck. Surgical excision is typically the treatment of choice, providing histopathologic information, high cure rates, and acceptable cosmetic and functional outcomes. Radiation therapy is reserved for cases where surgery is not the preferred choice or for high-risk cases where adjuvant therapy is recommended. Although overall mortality rates are low, patients with complex cases such as those with immunosuppression should be considered for management within multidisciplinary tumor boards. In contrast, Merkel cell carcinoma is a rare and aggressive malignancy, frequently arising on the head and neck in older whites, with a poorer prognosis. This article focuses on the current evidence guiding practice, recent advances, and areas of controversy in NMSC and Merkel cell carcinoma of the head and neck.