An association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and better outcome after mastectomy and lung surgery for cancer has been recently suggested. In a retrospective ...analysis, we investigated the association between intraoperative NSAIDs use in conservative breast cancer surgery and breast cancer disease-free survival (DFS). Similarly, we also evaluated the association between breast cancer DFS and preoperative neutrophil:lymphocyte ratio (NLR).
A retrospective analysis of a single-centre cohort was performed in breast cancer patients (n=720) with uni- and multivariate analyses, using a Cox regression model.
In conservative breast cancer surgery, the intraoperative use of NSAIDs (ketorolac or diclofenac) was associated with an improved DFS {hazard ratio (HR)=0.57 95% confidence interval (CI): 0.37–0.89, P=0.01} and an improved overall survival (OS) HR=0.35 (95% CI: 0.17–0.70), P=0.03. In these patients, an NLR >3.3 (identified by a receiver-operating characteristic curve) was associated with a shorter DFS HR=1.99 (95% CI: 1.16–3.41), P=0.01 and OS HR=2.35 (95% CI: 1.02–5.43), P=0.046.
Intraoperative NSAIDs and higher preoperative NLR are associated with improved outcome in conservative breast cancer surgery. Prospective, randomized trials to evaluate if these associations are causal are warranted.
•This ESMO-EURACAN Clinical Practice Guideline provides key recommendations for managing nasopharyngeal cancer (NPC).•It covers screening, clinical and pathological diagnosis, staging and risk ...assessment, treatment and follow-up.•Treatment algorithms for locoregional and recurrent/metastatic NPC are provided.•Recommendations were compiled by the authors based on available scientific data and the authors' collective expert opinion.
Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab programmed death-ligand ...1 (PD-L1) antibody with or without tremelimumab cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, versus the EXTREME regimen in patients with R/M HNSCC.
Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2 : 1 : 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed.
Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively.
In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC.
•KESTREL assessed first-line durvalumab with or without tremelimumab versus the EXTREME regimen in patients with R/M HNSCC.•Durvalumab ± tremelimumab was not superior to the EXTREME regimen for OS in patients with PD-L1-high expression.•Durvalumab ± tremelimumab produced durable responses and fewer TRAEs versus EXTREME in patients with R/M HNSCC.•Subsequent immunotherapy use may have contributed to longer-than-expected OS in the EXTREME regimen arm.
•This special article provides updated treatment recommendations for nasopharyngeal carcinoma.•In high-risk locoregionally advanced NPC, adding metronomic or standard dose adjuvant capecitabine to ...CRT improves PFS.•Immunotherapy added to platinum and gemcitabine improves PFS as first-line metastatic treatment in endemic NPC areas.
In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and ...neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1.
Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes.
Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative 2.7 versus 1.6 months; HR 0.70 (95% CI 0.50–0.97),EGFR-amplified 2.8 versus 1.5 months; HR 0.53 (0.33–0.85), HER3-low 2.8 versus 1.8 months; HR 0.57 (0.37–0.88), and PTEN-high 1.6 versus 1.4 months; HR 0.55 (0.29–1.05) tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative andEGFR-amplified tumors 2.7 versus 1.5 months; HR 0.47 (0.28–0.80), and patients with p16-negative tumors who were EGFR therapy-naïve 4.0 versus 2.4 months; HR 0.55 (0.31–0.98). PFS was improved in afatinib-treated patients who were VeriStrat ‘Good’ versus ‘Poor’ 2.7 versus 1.5 months; HR 0.71 (0.49–0.94), but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35).
Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative,EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings.
NCT01345682.
This phase II study assessed the safety and efficacy of everolimus, an oral mammalian target of rapamycin inhibitor in advanced transitional carcinoma cell (TCC) after failure of platinum-based ...therapy.
Thirty-seven patients with advanced TCC received everolimus 10 mg/day until progressive disease (PD) or unacceptable toxicity. The primary end point was the disease control rate (DCR), defined as either stable disease (SD), partial response (PR), or complete response at 8 weeks. Angiogenesis-related proteins were detected in plasma and changes during everolimus treatment were analyzed. PTEN expression and PIK3CA mutations were correlated to disease control.
Two confirmed PR and eight SD were observed, resulting in a DCR of 27% at 8 weeks. Everolimus was well tolerated. Compared with patients with noncontrolled disease, we observed in patients with controlled disease a significant higher baseline level of angiopoietin-1 and a significant early plasma decrease in angiopoietin-1, endoglin, and platelet-derived growth factor-AB. PTEN loss was observed only in patients with PD.
Everolimus showed clinical activity in advanced TCC. The profile of the plasma angiogenesis-related proteins suggested a role of the everolimus antiangiogenic properties in disease control. PTEN loss might be associated with everolimus resistance.
Background: Treatment options for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are limited with response rates to cytotoxic chemotherapy of ∼30% and median survival of 6 ...months.
Patients and methods: In a multicentre phase II study, 32 patients with recurrent or metastatic HNSCC received 3-AP Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), an inhibitor of ribonucleotide reductase, 96 mg/m2, daily for 4 days every 14 days (one cycle). Eligibility criteria required Eastern Cooperative Oncology Group performance status (ECOG PS) of zero to two with a life expectancy of >3 months; one prior chemotherapy regimen was allowed.
Results: Thirty patients were assessable for response and toxicity. Median age was 57 years (range 36–79) and median ECOG PS was one (range 0–2). Thirteen patients had previously been treated with chemotherapy. A total of 130 cycles were administered with a median number of cycles of 3.5 (range 1–8). Mild anaemia (40%), nausea (22%) and fatigue (22%) were commonly reported with G3 and G4 neutropenia documented in 22% and 22%, respectively. Overall response rate was 5.9% (95% confidence interval 0.2% to 28.7%). One patient achieved a partial response, eight had stable disease and 21 progressive disease. Median time to disease progression was 3.9 months.
Conclusions: 3-AP Triapine as a single agent, at this dose and schedule, is well tolerated but has only minor activity in the treatment of advanced HNSCC.
The molecular landscape of squamous cell carcinoma of the head and the neck (SCCHN) has been characterized and actionable or targetable genomic alterations have been identified. However, targeted ...therapies have very limited activity in unselected SCCHN, and the current treatment strategy is still based on tumor location and disease stage and not on tumor biology. Trying to select upfront the patients who will benefit from a specific treatment might be a way to improve patients’ outcome. With the objective of optimizing the activity of targeted therapies and immunotherapy, we have designed an umbrella biomarker-driven study dedicated to recurrent and/or metastatic SCCHN patients (EORTC-1559-HNCG, NCT03088059). In this article, we review not only the different trial designs for biomarker-driven studies with their respective advantages and opportunities but also the potential pitfalls that led to the design of the EORTC-1559-HNCG protocol. We also discuss the scientific and logistic challenges of biomarker-driven trials.
Forty to fifty percent of patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) relapse despite multimodal treatment. Circulating tumor DNA (ctDNA) has the potential ...to detect minimal residual disease (MRD) after curative-intent therapy and to identify earlier which patients will progress. We developed a tumor-agnostic plasma ctDNA assay to detect MRD in unselected LA SCCHN with the aim of predicting progression-free survival (PFS) and overall survival without the need for tumor sequencing.
A 26-gene next-generation sequencing panel was constructed that included the most frequently mutated genes in SCCHN and two HPV-16 genes. MRD was assessed in each patient through an in-house informatic workflow informed by somatic mutations identified in the corresponding pre-treatment plasma sample. The presence of MRD was defined as the detection of ctDNA in one plasma sample collected within 1-12 weeks of the end of curative treatment. The primary endpoint was the PFS rate at 2 years. At least 32 patients were planned for inclusion with the hypothesis that PFS at 2 years was >80% in MRD-negative patients and <30% in MRD-positive patients (α = 0.05, β = 0.9).
We sequenced DNA from 116 plasma samples derived from 53 LA SCCHN patients who underwent curative-intent treatment. ctDNA was detected in 41/53 (77%) patients in the pre-treatment samples. Out of these 41 patients, 17 (41%) were MRD positive after treatment. The 2-year PFS rate was 23.53% (9.9% to 55.4%) and 86.6% (73.4% to 100%) in MRD-positive and MRD-negative patients, respectively (P < 0.05). Median survival was 28.37 months (14.30 months-not estimable) for MRD-positive patients and was not reached for the MRD-negative cohort (P = 0.011).
Our ctDNA assay detects MRD in LA SCCHN and predicts disease progression and survival without the need for tumor sequencing, making this approach easily applicable in daily practice.
•ctDNA may detect MRD after curative-intent therapy and allow the early identification of patients likely to progress.•A tumor-agnostic ctDNA assay was designed for LA SCCHN.•The assay detects MRD in LA SCCHN and predicts PFS and survival without the need for tumor sequencing.•This tumor-agnostic approach has the potential to be used broadly, and further studies are warranted.
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