Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial.

BACKGROUND: Pembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). PATIENTS AND METHODS: KEYNOTE-629 was a global, open-label, nonrandomized, phase II trial of patients with locally advanced (LA) or R/M cSCC conducted at 59 centers. Eligible patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary endpoint was objective response rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR), by blinded independent central review as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included duration of response (DOR), disease control rate, progression-free survival, overall survival, and safety and tolerability. Efficacy and safety were analyzed in patients who were treated with at least one dose of pembrolizumab. RESULTS: Between 29 November 2017 and 25 September 2019, 159 patients were enrolled and treated with pembrolizumab (LA cohort, n = 54; R/M cohort, n = 105). The median time from the first dose to data cut-off date (29 July 2020) was 14.9 [interquartile range (IQR), 12.6-17.2] months for the LA cohort and 27.2 (IQR, 25.6-29.2) months for the R/M cohort. In the LA cohort, ORR was 50.0% [95% confidence interval (CI), 36.1% to 63.9%], including 16.7% of patients with a CR and 33.3% with a PR. In the R/M cohort, ORR was 35.2% (95% CI, 26.2% to 45.2%), including 10.5% of patients with a CR and 24.8% with a PR. Median DOR was not reached in either cohort. Grade 3-5 treatment-related adverse events occurred in 11.9% of patients. CONCLUSIONS: The robust antitumor activity of pembrolizumab in both LA and R/M cSCC was confirmed and demonstrated to be durable without unexpected safety signals. Our findings establish pembrolizumab as a promising treatment option for cSCC.

Development of a core outcome set for cutaneous squamous cell carcinoma trials: identification of core domains and outcomes.

BACKGROUND: The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment effectiveness across trials. OBJECTIVES: To develop a core outcome set (COS), a minimum set of agreed-upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC. METHODS: One hundred and nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, in two rounds of Delphi exercises. Outcomes scored 'critically important' (score of 7, 8 or 9) by ≥ 70% of patients and ≥ 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants. RESULTS: A core set of seven outcomes was finalized at the consensus meeting: (i) serious or persistent adverse events, (ii) patient-reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence-free survival, (vi) progression-free survival and (vii) disease-specific survival. CONCLUSIONS: In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes.

Validation of an updated evidence-based protocol for proactive gastrostomy tube insertion in patients with head and neck cancer.

BACKGROUND/OBJECTIVES: Evidence-based practice guidelines are available to assist in the decision making for nutrition interventions in patients with head and neck cancer. Re-assessment of guideline recommendations is important with changing demographics, new treatment regimens, advancing radiotherapy techniques, such as helical intensity-modulated radiotherapy, and the emergence of new literature. The aim of this study was to validate the updated high-risk category definition in our local hospital protocol for the swallowing and nutrition management of patients with head and neck cancer to determine the ongoing predictive ability for identifying proactive gastrostomy requirement in a new cohort. SUBJECTS/METHODS: Patients attending a major tertiary hospital for head and neck cancer treatment from 2010 to 2011 were included (n=270). Data were collected on patient demographics (age and gender), clinical factors (tumour site, staging and treatment), nutrition outcome measures (weight, enteral feeding) and protocol adherence. Sensitivity and specificity were calculated and compared with the original validation study. RESULTS: Proactive gastrostomy tubes were inserted in 86 patients. Overall protocol adherence was 93%. Sensitivity improved to 72% (increase of 18%) and specificity improved to 96% (increase of 3%) compared with the original validation study where patients received three-dimensional (3-D) conformal radiotherapy. CONCLUSIONS: The results of this study confirm that the updated high-risk category in the protocol for the swallowing and nutrition management of patients with head and neck cancer remains valid to predict proactive gastrostomy in a mixed population receiving helical intensity-modulated radiotherapy and 3-D conformal radiotherapy. The protocol has an improved sensitivity and specificity and hence remains just as relevant for advanced techniques of radiation treatment delivery.

A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial.

BACKGROUND: We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. PATIENTS AND METHODS: Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point. RESULTS: Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79-1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82-1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. CONCLUSION: The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further. CLINICAL TRIALS NUMBER: Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.

New radiotherapy techniques do not reduce the need for nutrition intervention in patients with head and neck cancer.

BACKGROUND/OBJECTIVES: Since 2007, our institution has used validated guidelines for the insertion of proactive gastrostomy feeding tubes in patients with head and neck cancer. Helical intensity-modulated radiotherapy (H-IMRT) delivered by Tomotherapy, is an advanced radiotherapy technique introduced at our centre in 2010. This form of therapy reduces long-term treatment-related toxicity to normal tissues. The aim of this study is to compare weight change and need for tube feeding following H-IMRT (n=53) with patients that would have previously been treated with three-dimensional conformal radiotherapy (n=134). SUBJECTS/METHODS: Patients with head and neck cancer assessed as high nutritional risk with recommendation for proactive gastrostomy were identified from cohorts from 2007 to 2008 and 2010 to 2011. Retrospective data were collected on clinical factors, weight change from baseline to completion of treatment, incidence of severe weight loss (⩾ 10%) and tube feeding. Statistical analyses to compare outcomes between the two treatments included χ(2)-test, Fisher's exact and two-sample Wilcoxon tests (P<0.05). RESULTS: The H-IMRT cohort had higher proportions of patients with definitive chemoradiotherapy (P=0.032) and more advanced N stage (P<0.001). Nutrition outcomes were not significantly different between H-IMRT and conformal radiotherapy, respectively: need for proactive gastrostomy (n=49, 92% versus n=115, 86%, P=0.213), median percentage weight change (-7.2% versus -7.3%, P=0.573) and severe weight loss incidence (28% versus 27%, P=0.843). CONCLUSIONS: Both groups had median weight loss >5% and high incidences of tube feeding and severe weight loss. Nutrition intervention remains critical in this patient population, despite advances in radiotherapy techniques, and no changes to current management are recommended.

Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma.

BACKGROUND: Although advanced cutaneous squamous cell carcinoma (CSCC) is quite common, there are few prospective trials regarding its optimal management. This study evaluated the efficacy and safety of single-agent panitumumab in the treatment of patients with CSCC not suitable for local therapy. PATIENTS AND METHODS: Sixteen patients received single-agent panitumumab at a dose of 6 mg/kg repeated every 2 weeks for a minimum of three cycles and continued until progression, a maximum of nine cycles or dose-limiting toxicity. The primary end point was the best overall response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) criteria. Secondary end points included evaluation of safety, toxicity and progression-free survival (PFS). RESULTS: Between May 2010 and May 2012, 16 patients were recruited. Fourteen patients were male and the median age was 68 years. Fifteen patients had locoregionally advanced or recurrent disease with 14 patients receiving previous radiotherapy and 7 receiving previous cytotoxic chemotherapy. The best ORR [partial (PR) or complete response (CR)] was 31% (3/16 PR, 2/16 CR) with a further 6 of 16 patients achieving SD. The median PFS and overall survival were 8 and 11 months respectively. Grade 3 or 4 events were observed in five patients (four being skin toxicity) with one patient ceasing due to skin toxicity. With a median follow-up of 24 months, 10 patients died due to progressive disease, 6 are alive, one patient with no evidence of disease at the time of analysis. CONCLUSIONS: Single-agent panitumumab is safe and effective in the management of patients with advanced CSCC even in a previously extensively pre-treated cohort.

Quality-of-life among head and neck cancer survivors at one year after treatment--a systematic review.

BACKGROUND: The importance of quality-of-life (QoL) research has been recognised over the past two decades in patients with head and neck (H&N) cancer. The aims of this systematic review are to evaluate the QoL status of H&N cancer survivors one year after treatment and to identify the determinants affecting their QoL. METHODS: Pubmed, Medline, Scopus, Sciencedirect and CINAHL (2000-2011) were searched for relevant studies, and two of the present authors assessed their methodological quality. The characteristics and main findings of the studies were extracted and reported. RESULTS: Thirty-seven studies met the inclusion criteria, and the methodological quality of the majority was moderate to high. While patients of the group in question recover their global QoL by 12 months after treatment, a number of outstanding issues persist - deterioration in physical functioning, fatigue, xerostomia and sticky saliva. Age, cancer site, stage of disease, social support, smoking, feeding tube placement and alcohol consumption are the significant determinants of QoL at 12 months, while gender has little or no influence. CONCLUSIONS: Regular assessments should be carried out to monitor physical functioning, degree of fatigue, xerostomia and sticky saliva. Further research is required to develop appropriate and effective interventions to deal with these issues, and thus to promote the patients' QoL.