Locoregionally Advanced Squamous Cell Carcinoma Of The Head And Neck Research Articles

Trilynx: A Phase 3 Trial of Xevinapant and Concurrent Chemoradiotherapy (CRT) for Locally Advanced Head and Neck Cancer

Purpose/Objective(s) Concurrent CRT is the standard of care for previously untreated patients with locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Xevinapant (Debio 1143) is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumor activity of platinum-based chemotherapy and radiotherapy. The radiosensitizing effect of xevinapant is mediated through caspase activation and TNF, IFNγ, and CD8 T cell-dependent pathways. Three-year follow-up results from a randomized Phase 2 study showed significant improvements for xevinapant versus placebo in addition to standard CRT for locoregional control (LRC) rate at 18 months, progression-free survival (PFS) and overall survival (OS). The addition of xevinapant was well tolerated, manageable and did not jeopardize backbone therapy [1, 2]. Materials/Methods TrilynX is a multinational, phase 3, double-blind, placebo-controlled, randomized clinical study assessing the efficacy of xevinapant in combination with concurrent CRT compared with placebo in combination with CRT for LA-SCCHN. Adult patients with newly diagnosed, pathologically proven, treatment-naive LA-SCCHN will be enrolled. Study population will include hypopharyngeal, laryngeal and p16-negative oropharyngeal. Other eligibility criteria: ECOG PS 0 or 1, AST and ALT ≤ 3.0 x ULN, total bilirubin ≤ 1.5 × ULN, and eligible for definitive CRT. Approximately 700 eligible patients will be randomly assigned to receive oral xevinapant at 200 mg per day on days 1 to 14 of 3-week cycles or placebo for three cycles in combination with cisplatin (100 mg/m², q3w) for three cycles, and concomitant standard fractionation intensity-modulated radiotherapy (70 Gy/7 weeks). The concurrent CRT period will be followed by a monotherapy period consisting of further three cycles of xevinapant or placebo. The primary endpoint is Event Free Survival (EFS) assessed by a Blinded Independent Radiological Committee (BIRC). An interim analysis will occur when 279 EFS events as assessed by the BIRC are observed. The primary analysis will occur once 429 EFS events are observed. TrilynX has ∼90% power to detect the expected hazard ratio benefit of 0.73. Secondary endpoints include OS, PFS, LRC, objective response rate, health-related quality of life, and safety. Patients will be followed up for a minimum of 60-months. PK sparse sampling will be performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. TrilynX started in August 2020 and is ongoing. Results TBD Conclusion TBD Concurrent CRT is the standard of care for previously untreated patients with locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Xevinapant (Debio 1143) is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumor activity of platinum-based chemotherapy and radiotherapy. The radiosensitizing effect of xevinapant is mediated through caspase activation and TNF, IFNγ, and CD8 T cell-dependent pathways. Three-year follow-up results from a randomized Phase 2 study showed significant improvements for xevinapant versus placebo in addition to standard CRT for locoregional control (LRC) rate at 18 months, progression-free survival (PFS) and overall survival (OS). The addition of xevinapant was well tolerated, manageable and did not jeopardize backbone therapy [1, 2]. TrilynX is a multinational, phase 3, double-blind, placebo-controlled, randomized clinical study assessing the efficacy of xevinapant in combination with concurrent CRT compared with placebo in combination with CRT for LA-SCCHN. Adult patients with newly diagnosed, pathologically proven, treatment-naive LA-SCCHN will be enrolled. Study population will include hypopharyngeal, laryngeal and p16-negative oropharyngeal. Other eligibility criteria: ECOG PS 0 or 1, AST and ALT ≤ 3.0 x ULN, total bilirubin ≤ 1.5 × ULN, and eligible for definitive CRT. Approximately 700 eligible patients will be randomly assigned to receive oral xevinapant at 200 mg per day on days 1 to 14 of 3-week cycles or placebo for three cycles in combination with cisplatin (100 mg/m², q3w) for three cycles, and concomitant standard fractionation intensity-modulated radiotherapy (70 Gy/7 weeks). The concurrent CRT period will be followed by a monotherapy period consisting of further three cycles of xevinapant or placebo. The primary endpoint is Event Free Survival (EFS) assessed by a Blinded Independent Radiological Committee (BIRC). An interim analysis will occur when 279 EFS events as assessed by the BIRC are observed. The primary analysis will occur once 429 EFS events are observed. TrilynX has ∼90% power to detect the expected hazard ratio benefit of 0.73. Secondary endpoints include OS, PFS, LRC, objective response rate, health-related quality of life, and safety. Patients will be followed up for a minimum of 60-months. PK sparse sampling will be performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. TrilynX started in August 2020 and is ongoing. TBD TBD

Prognostic factor analysis and long-term results of the TAX 323 (EORTC 24971) study in unresectable head and neck cancer patients

BackgroundIn the TAX 323 (EORTC 24971) phase III trial enrolling patients with unresectable locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), the addition of docetaxel (T) to cisplatin and 5-fluorouracil (PF)-based induction chemotherapy prior to definite radiotherapy significantly improved progression-free survival (PFS) and overall survival (OS). MethodsThe data were updated for PFS, OS and treatment-related long-term side-effects. Baseline clinical and laboratory data of 17 variables were collected and subjected to univariate and multivariate prognostic factor analyses for OS. ResultsAll 358 patients randomised between 1999 and 2002 were included in the long-term analysis with a median follow-up of 8.6 years. The primary end-point of PFS remained significantly improved with TPF compared with PF (adjusted hazard ratio [HR], 0.70; 95% CI, 0.56–0.88, p = 0.002), translating into a persisting benefit in OS (adjusted HR, 0.75; 95% CI, 0.60–0.95, p = 0.015). Long-term side-effects in the TPF/PF arms comprised tracheostomy (7%/5%), feeding tube dependency (3%/6%) and gastrostomy (11%/11%). Second malignancy occurred in 8%/3%, respectively. Out of 177 patients randomised to the TPF arm, 160 were included in the multivariate analysis. Grade 2 or more dysphagia (p = 0.002) and grade 2 or more pain (p = 0.004) at baseline were identified as independent negative prognostic factors. In addition, OS differed across primary tumour sites (p = 0.027) and was worse in patients with a higher N-stage (p = 0.025). ConclusionsIn LA-SCCHN patients treated with sequential chemoradiotherapy, TPF induction chemotherapy demonstrated long-lasting efficacy, superior to the PF regimen. Higher-grade dysphagia and pain are unfavourable prognosticators.

3-weekly or weekly cisplatin concurrently with radiotherapy for patients with squamous cell carcinoma of the head and neck \u2013 a multicentre, retrospective analysis

BackgroundConcurrent chemoradiotherapy with cisplatin is standard for patients (pts) with loco-regionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) and for patients with resected SCCHN with high-risk features. The standard regimen includes 3-weekly cisplatin, but weekly regimens are often used to lower toxicity. Reaching a cumulative dose of ≥200 mg/m2 cisplatin was shown being associated with improved outcome. We herein investigated cumulative dose reached and toxicities between the 3-weekly and weekly cisplatin regimens with concurrent radiotherapy.MethodsMulticentre, retrospective analysis of all patients undergoing combined RCT with cisplatin treated at 3 centres in Switzerland between 06/2008 and 12/2015.ResultsThree hundred fourteen pts. were included (3-weekly, N = 127; weekly, N = 187). Median cumulative cisplatin dose was 200 mg/m2 (IQR 150–300) for pts. treated with a 3-weekly schedule and 160 mg/m2 (120–240) for the weekly schedule, consequently more pts. treated with a 3-weekly schedule reached a cumulative dose ≥200 mg/m2 (75.6% vs. 47.1%, p < 0.001). This association was also observed in multivariable analysis adjusted for age and sex (OR 3.46, 95% confidence interval [CI], 2.1–5.7). The 3-weekly regimen led to a higher rate of acute renal toxicity (33.1% vs. 20.9%, p = 0.022). In the landmark analysis, we could not confirm that a cisplatin dose ≥200 mg/m2 is associated with better survival (HR 1.3, 95% CI 0.8–1.9).ConclusionsSignificantly more patients receive a cumulative cisplatin dose of ≥200 mg/m2, when treated with a 3-weekly schedule compared to weekly dosing. The previously reported association between a cumulative cisplatin dose ≥200 mg/m2 and improved outcome could not be shown in our study.

Outcomes of chemoradiation (CRT) for locoregionally advanced (LRA)squamous cell carcinoma of the head and neck (SCCHN): Outcomes with weekly cisplatin (WC) in an academic community based hospital.

e18081Background: CRT is a component of treatment (tx) for LRA SCCHN. High dose cisplatin (HDC) on weeks 1, 4, 7 is a standard but toxic regimen. Additionally, many cases of SCCHN are now attributa...

Effect of Standard Radiotherapy With Cisplatin vs Accelerated Radiotherapy With Panitumumab in Locoregionally Advanced Squamous Cell Head and Neck Carcinoma

The Canadian Cancer Trials Group study HN.6 is the largest randomized clinical trial to date comparing the concurrent administration of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies with radiotherapy (RT) to standard chemoradiotherapy in locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). To compare progression-free survival (PFS) in patients with LA-SCCHN treated with standard-fractionation RT plus high-dose cisplatin vs accelerated-fractionation RT plus the anti-EGFR antibody panitumumab. A randomized phase 3 clinical trial in 17 Canadian centers. A total of 320 patients were randomized between December 2008 and November 2011. Patients with TanyN+M0 or T3-4N0M0 LA-SCCHN were randomized 1:1 to receive standard-fractionation RT (70 Gy/35 over 7 weeks) plus cisplatin at 100 mg/m2 intravenous for 3 doses (arm A) vs accelerated-fractionation RT (70 Gy/35 over 6 weeks) plus panitumumab at 9 mg/kg intravenous for 3 doses (arm B). Primary end point was PFS. Due to an observed declining event rate, the protocol was amended to a time-based analysis. Secondary end points included overall survival, local and regional PFS, distant metastasis-free survival, quality of life, adverse events, and safety. Of 320 patients randomized (268 [84%] male; median age, 56 years), 156 received arm A and 159 arm B. A total of 93 PFS events occurred. By intention-to-treat, 2-year PFS was 73% (95% CI, 65%-79%) in arm A and 76% (95% CI, 68%-82%) in arm B (hazard ratio [HR], 0.95; 95% CI, 0.60-1.50; P = .83). The upper bound of the HR 95% CI exceeded the prespecified noninferiority margin. Two-year overall survival was 85% (95% CI, 78%-90%) in arm A and 88% (95% CI, 82%-92%) in arm B (HR, 0.89; 95% CI, 0.54-1.48; P = .66). Incidence of any grade 3 to 5 nonhematologic adverse event was 88% in arm A and 92% in arm B (P = .25). With a median follow-up of 46 months, the PFS of panitumumab plus accelerated-fractionation RT was not superior to cisplatin plus standard-fractionation RT in LA-SCCHN and noninferiority was not proven. Despite having negative results, HN.6 has contributed important data regarding disease control and toxic effects of these treatment strategies. clinicaltrials.gov Identifier: NCT00820248.

2817 12-year Follow-up (FU) Data and late local toxicity Of Two Cohorts of patients with locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) treated with Concomitant Chemoradiation (CCRT) With Or Without Induction Chemotherapy (ICT)

2817 12-year Follow-up (FU) Data and late local toxicity Of Two Cohorts of patients with locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) treated with Concomitant Chemoradiation (CCRT) With Or Without Induction Chemotherapy (ICT)

Phase III randomized trial of standard fractionation radiotherapy (SFX) with concurrent cisplatin (CIS) versus accelerated fractionation radiotherapy (AFX) with panitumumab (PMab) in patients (pts) with locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN): NCIC Clinical Trials Group HN.6 trial.

6000 Background: Concurrent administration of anti-EGFR monoclonal antibody with radiotherapy (RT) increases survival compared to RT alone in pts with LA-SCCHN. No prospective data are available co...

Quality of life (QOL) in a phase III randomized trial of standard fractionation radiotherapy (SFX) with concurrent cisplatin (CIS) versus accelerated fractionation radiotherapy (AFX) with panitumumab (PMab) in patients (pts) with locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN): NCIC Clinical Trials Group HN.6 (NCT00820248).

6053 Background: Addition of concurrent anti-EGFR monoclonal antibody to radiotherapy alone did not worsen QOL (Curran 2007). We compared standard chemoradiotherapy (cRT) to bioradiotherapy (bRT). ...

Outcome and prognostic factors of 125 loco-regionally advanced head and neck squamous cell carcinoma treated with multi-modality treatment

To investigate the treatment outcome of loco-regionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) after been treated with multi-modality approach since 2005 in our hospital and to explore the prognostic factors for treatment outcomes. Clinical data of 125 postoperative LA-SCCHN patients treated in our department with radiotherapy/chemoradiotherapy from May 2005 to December 2011 were collected and reviewed in this study. The radiotherapy technique was intensity-modulated radiotherapy (IMRT) (93.6%) and a minority of patients received 3D-conformal radiotherapy (3D-CRT). Up to January 6th, 2013, 124 patients were followed up with a median follow-up duration of 25 months. The 3-year overall survival (OS), disease-free survival (DFS), loco-regional control (LRC), distant metastasis-free survival (DMFS) were 69.7%, 56.1%, 80.8%, and 73.1%, respectively. A total of 37 patients died during the follow-up period. Among the 43 patients presented with treatment failure, 13 patients had loco-regional relapse, 20 patients had distant metastasis and 10 patients presented with both loco-regional and distant relapses. Distant metastasis accounted for the predominant cause of death. Lung and mediastinal lymph nodes are the most common sites involved by distant metastasis.Univariate analysis indicated that patients who underwent non-radical surgery, with larger size of invaded lymph nodes, higher N stage (N2b and above) and vascular tumor embolism had a lower OS (P = 0.001, 0.000, 0.032, 0.007, respectively). Patients who underwent neck dissection only, or those with higher N stage (N2b and above) or higher TNM stage or vascular tumor thrombi had higher distant metastasis rates (P = 0.017, 0.002, 0.008, 0.001, respectively). The multivariate analysis showed that non-radical surgery was an independent prognostic factor for OS (P = 0.001), larger size of invaded lymph nodes was an independent prognostic factor for poorer LRC (P = 0.001); higher N stage (N2b and above) or T4 stage and vascular tumor thrombi were independent prognostic factors for poorer distant metastasis-free survival (P = 0.035, 0.008 and 0.050, respectively). Our results indicate that multi-modality treatment for LA-SCCHN has achieved better outcome than before. Distant metastasis has become the predominant pattern of failure as well as the primary cause of death instead of loco-regional relapse as a result of improved local control modality. More efforts should be made to decrease the rate of distant metastasis in the future.

A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer

Concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with unresectable, nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN). This randomized, open-label, phase III clinical trial compared the efficacy between standard CCRT and two different induction chemotherapy (ICT) regimens followed by CCRT. Patients with untreated LASCCHN were randomly assigned to ICT (three cycles), with either docetaxel (Taxotere), cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CCRT [7 weeks of radiotherapy (RT) with cisplatin 100 mg/m(2) on days 1, 22 and 43]; or 7 weeks of CCRT alone. The primary end points were progression-free survival (PFS) and time-to-treatment failure (TTF). In the intention-to-treat (ITT) population (n = 439), the median PFS times were 14.6 (95% CI, 11.6-20.4), 14.3 (95% CI, 11.8-19.3) and 13.8 months (95% CI, 11.0-17.5) at TPF-CCRT, PF-CCRT and CCRT arms, respectively (log-rank P = 0.56). The median TTF were 7.9 (95% CI, 5.9-11.8), 7.9 (95% CI, 6.5-11.8) and 8.2 months (95% CI, 6.7-12.6) for TPF-CCRT, PF-CCRT and CCRT alone, respectively (log-rank P = 0.90). There were no statistically significant differences for overall survival (OS). Toxic effects from ICT-CCRT were manageable. Overall, this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN.

Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival

Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximab-induced rash and survival. Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6-7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m(2) initial dose, followed by seven weekly doses at 250 mg/m(2). Randomisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter. The trial is registered at www.ClinicalTrials.gov, number NCT00004227. Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months (95% CI 32.8-69.5) versus 29.3 months (20.6-41.4) in the radiotherapy-alone group (hazard ratio [HR] 0.73, 95% CI 0.56-0.95; p=0.018). 5-year overall survival was 45.6% in the cetuximab-plus-radiotherapy group and 36.4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0.49, 0.34-0.72; p=0.002). For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash. ImClone Systems, Merck KGaA, and Bristol-Myers Squibb.

A non-randomized comparison of gemcitabine-based chemoradiation with or without induction chemotherapy for locally advanced squamous cell carcinoma of the head and neck

BackgroundConcomitant chemotherapy and radiotherapy (chemoradiation; CRT) is the standard treatment for locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). CRT improves local control and overall survival (OS) when compared to radiotherapy (RT) alone. Induction chemotherapy (IC) reduces the risk of distant metastases (DM) and improves OS by 5% with the use of cisplatin/infusional 5 fluorouracil (PF) in meta-analysis. Adding a taxane to PF in the IC regimen confers a better outcome. Sequential treatment (ST) of IC followed by CRT is therefore under active investigation in multiple phase III trials.MethodsWe compared the outcome of two cohorts of patients (pts) with LA-SCCHN treated at our institution with CRT (n = 27) or ST (n = 31), respectively. CRT consisted of GEM 100 mg/m2 weekly + conventional RT (70 Gy); ST consisted of the same CRT preceded by platinum-based IC.ResultsResponse to IC: complete 8 (26%), partial 20 (65%), stable 1, progressive 1, not evaluable 1. Median follow up of the surviving pts: for CRT 73 months, for ST 51 months. Median time to distant metastasis (TDM) was for CRT 23.6 months, for ST not reached. Median OS was for CRT 20.2 months, for ST 40.2 months. Cox regression analysis, taking into account age, T and N stage and tumor site, showed a hazard ratio with ST of 1.190 for time to locoregional failure (p = 0.712), 0.162 for TDM (p = 0.002), and 0.441 for overall survival (OS) (p = 0.026).ConclusionTDM and OS were found significantly longer in the ST cohort without a reduced locoregional control. Notwithstanding the limitations of a non-randomized single-center comparison, the results are in line with very preliminary data of randomized comparisons suggesting an improved outcome with ST.