Locally Advanced Head And Neck Squamous Cell Carcinoma Research Articles

864P Clinical/biomarker data for neoadjuvant tislelizumab (TIS) plus chemotherapy (Chemo) in resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC): A single-arm, phase II trial

864P Clinical/biomarker data for neoadjuvant tislelizumab (TIS) plus chemotherapy (Chemo) in resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC): A single-arm, phase II trial

NMR-Based Metabolomics of Blood Serum in Predicting Response to Induction Chemotherapy in Head and Neck Cancer-A Preliminary Approach.

The role of induction chemotherapy (iCHT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is still to be established due to high toxicity and variable response rates. The aim of this retrospective study is to use NMR-based serum metabolomics to predict the response rates to iCHT from the pretreatment samples. The studied group consisted of 46 LA-HNSCC patients treated with iCHT. The response to the treatment was evaluated by the clinical, fiberoptic, and radiological examinations made before and after iCHT. The proton nuclear magnetic resonance (1H NMR) serum spectra of the samples collected before iCHT were acquired with a 400 MHz spectrometer and were analyzed using multivariate and univariate statistical methods. A significant multivariate model was obtained only for the male patients. The treatment-responsive men with >75% primary tumor regression after iCHT showed pretreatment elevated levels of isoleucine, alanine, glycine, tyrosine, N-acetylcysteine, and the lipid compounds, as well as decreased levels of acetate, glutamate, formate, and ketone bodies compared to those who did not respond (regression of the primary tumor <75%). The results indicate that the nutritional status, capacity of the immune system, and the efficiency of metabolism related to protein synthesis may be prognostic factors for the response to induction chemotherapy in male HNSCC patients. However, larger studies are required that would validate the findings and could contribute to the development of more personalized treatment protocols for HNSCC patients.

The application of induction chemotherapy in the treatment of locally advanced head and neck squamous cell carcinoma

Standard treatment for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) whose larynx could not be preserved surgically consists mainly of concurrent chemoradiotherapy (CCRT). Induction chemotherapy (ICT) followed by radiotherapy or chemoradiotherapy is also an alternative option. However, whether ICT could provide survival benefits for patients with LAHNSCC, besides its role in laryngeal preservation and selecting the treatment modality, is still controversial. The article summarizes the current position of ICT for LAHNSCC and discusses the standard regimen of ICT, its role in larynx preservation, its ability to predicting the result of chemoradiotherapy, clinical outcomes regarding the survival benefits after ICT, its role in the treatment deintensification for human papillomavirus-positive LAHNSCC and its application in the era of immunotherapy.

Meta-Analysis in Comparison between Cisplatin with Radiotherapy and Cetuximab with Radiotherapy in the Management of Locally Advanced Head and Neck Squamous Cell Carcinoma

Abstract Background Nowadays there is an increasing in the numbers of cases of head and neck squamous cell carcinoma (HNSCC) all over the world. Which affect upper aerodigestive tract including the nasopharynx, paranasal sinuses, oral cavity, oropharynx, hypopharynx and larynx. Objective To compare the using of radiotherapy (RT) with cisplatin versus cetuximab with RT in the treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC). The comparison between these two treatment regimens will be done in terms of overall survival rate and toxicity. Patients and Methods We performed this systematic review and meta-analysis in accordance to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) statement. PRISMA and MOOSE are reporting checklists for Authors, Editors, and Reviewers of Meta-analyses of interventional and observational studies. According to International committee of medical journal association (ICJME), reviewers must report their findings according to each of the items listed in those checklists. Results cetuximab with RT is associated with lower overall survival compared to cisplatin with RT in management of locally advanced head and neck squamous cell carcinoma, also patient treated with cetuximab were associated with higher rates of mortality compared to those treated with cisplatin Data Sources Medline databases (PubMed, Medscape, ScienceDirect. EMF-Portal) and all materials available in the Internet till 2020. Conclusion According to our study in the comparison between cisplatin with RT versus cetuximab with RT, cetuximab with RT is associated with lower overall survival compared to cisplatin with RT in management of locally advanced head and neck squamous cell carcinoma, also patient treated with cetuximab were associated with higher rates of mortality compared to those treated with cisplatin

Long-Term Update of a Phase 3 Randomized Study Comparing Once-a-Week Versus Once-Every-3-Weeks Cisplatin Along With Radiation in Head and Neck Cancer

PurposeIn the weekly-3-weekly (W3W) study, cisplatin at 100 mg/m2 once-every-3-weeks led to superior locoregional control compared to cisplatin 30 mg/m2 once-a-week in combination with radical radiation for locally advanced head and neck squamous cell carcinoma (LAHNSCC). We report the updated analysis of the study. MethodsIn this phase III open label non-inferiority study conducted between 2013 and 2017, 300 patients with LAHNSCC were randomly assigned to receive cisplatin 100 mg/m2 once-in-3-weeks or cisplatin 30 mg/m2 once-a-week, concurrently with radiation. The primary endpoint was locoregional control (LRC). Secondary outcomes were overall survival (OS), progression free survival (PFS) and late adverse events. ResultsThe median follow-up was 6.91 years (95% CI, 6.12-7.36). The updated 2-year and 5-year LRC rates for the once-a-week cisplatin arm were 58.75% (95% CI, 51.08- 67.58) and 48.09% (95% CI, 40.26-57.43), while for the once-every-3-weeks cisplatin arm were 73.95% (95% CI, 66.93-81.70) and 56.76% (95% CI, 48.46-66.48), respectively; HR=1.44 (95% CI, 1.03-2.03), P=0.034. The 5-year OS was 43.60% (95% CI, 36.29-52.37) in the once-a-week cisplatin arm, and 50.55% (95% CI, 43.06-59.35) in the once-every-3-weeks cisplatin arm; P = 0.19. There was no difference in any grade or grade ≥ 3 late adverse events between the two arms, except for hearing dysfunction, which was significantly more common in patients who received high-dose cisplatin. ConclusionsLong term follow-up confirms that cisplatin at 100 mg/m2 administered once-every-3-weeks concurrently with radical radiation for LAHNSCC leads to superior locoregional control as compared to cisplatin 30 mg/m2 once-a-week and should remain one of the standard treatment options.

Epidermal growth factor receptor‑targeted antibody nimotuzumab combined with chemoradiotherapy improves survival in patients with locally advanced head and neck squamous cell carcinoma: a propensity score matching real-world study.

Patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) have poor survival outcomes. The real-world efficacy of nimotuzumab plus intensity modulated radiotherapy (IMRT)-based chemoradiotherapy in patients with LA-HNSCC remains unclear. A total of 25,442 HNSCC patients were screened, and 612 patients were matched by propensity score matching (PSM) (1:1). PSM was utilized to balance known confounding factors. Patients who completed at least five doses of nimotuzumab were identified as study group. The primary end point was 3-year overall survival (OS) rate. Log-rank test examined the difference between two survival curves and Cloglog transformation test was performed to compare survival at a fixed time point. The median follow-up time was 54.2 (95% confidence interval [CI]: 52.7-55.9) months. The study group was associated with improved OS (hazard ratio [HR]=0.75, 95% CI: 0.57-0.99, p=0.038) and progression-free survival (PFS) (HR=0.74, 95% CI: 0.58-0.96, p=0.021). Subgroup analysis revealed that aged 50-60 year, IV, N2, radiotherapy dose≥60Gy, without previous surgery, and neoadjuvant therapy have a trend of survival benefit with nimotuzumab. Nimotuzumab showed favorable safety, only 0.2% had nimotuzumab-related severe adverse events. Our study indicated the nimotuzumab plus chemoradiotherapy provides survival benefits and safety for LA-HNSCC patients in an IMRT era.

EVOLVE-HNSCC: A global phase 3 study of volrustomig as sequential therapy for unresected locally advanced head and neck squamous cell carcinoma (LA-HNSCC) following definitive concurrent chemoradiotherapy (cCRT).

TPS6120 Background: Currently there are no approved maintenance therapies for patients (pts) with unresected LA-HNSCC following definitive cCRT. The PD-1 inhibitors pembrolizumab and nivolumab are licensed for treatment of pts with recurrent or metastatic HNSCC who have progressed on or after a platinum-based therapy. Dual inhibition of CTLA-4 and PD-L1 is approved in solid tumors including renal cell carcinoma (RCC), NSCLC, and melanoma, and has shown a numerical trend towards improved survival in first-line pts with recurrent/metastatic HNSCC whose tumors express PD-L1. Volrustomig (MEDI5752) is a monovalent, PD-1/CTLA-4 bispecific, humanized IgG1 monoclonal antibody engineered to specifically inhibit PD-1, with increased CTLA-4 blockade on PD-1+ activated T cells compared to PD-1– resting peripheral T cells. In a first-in-human phase 1/2 study (NCT03530397), volrustomig monotherapy showed promising efficacy with acceptable tolerability in advanced clear cell RCC and in combination with chemotherapy in advanced NSCLC. The phase 3, randomized, open-label, multicenter, eVOLVE-HNSCC study will evaluate the efficacy and safety of sequential therapy with volrustomig compared with observation in pts with unresected LA-HNSCC who have not progressed after receiving definitive cCRT (NCT06129864). Methods: Key eligibility criteria include histologically or cytologically confirmed, unresected LA-HNSCC with no evidence of metastatic disease, i.e. AJCC 8th edition (TNM staging system) stage IVA/B cancers of the hypopharynx, oral cavity, larynx or HPV-negative oropharynx, or stage III HPV-positive oropharynx cancer; age ≥18 years; WHO/ECOG performance score of 0 or 1; and adequate organ and bone marrow function. Key exclusion criteria include requiring further treatment with curative intent after definitive cCRT, resected LA-HNSCC, recurrent/metastatic disease, and &gt;1 primary tumor. Following initial screening and definitive cCRT (cisplatin or carboplatin + paclitaxel or carboplatin + 5-FU, plus concomitant radiotherapy), approximately 1145 pts whose disease has not progressed within 12 weeks of the last dose of cCRT will be randomized 1:1 to Arm A or B. Arm A will receive volrustomig intravenously every 3 weeks for a maximum of 12 months or 18 cycles, or until RECIST v1.1-defined radiological progressive disease (PD) or unacceptable toxicity. Arm B will undergo observation for a maximum of 12 months or until PD. The primary endpoint is PFS in pts with PD-L1-expressing tumors. Secondary endpoints include PFS in all randomized pts, OS in pts with PD-L1-expressing tumors and in all randomized pts, PFS2, safety, patient-reported outcomes, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses will also be conducted. Enrollment began in December 2023. Clinical trial information: NCT06129864 .

Neoadjuvant adebrelimab plus dalpiciclib in HPV-negative locally advanced head and neck squamous cell carcinoma: A phase II clinical trial.

TPS6129 Background: The efficacy and safety of neoadjuvant immunotherapy (NAI) for treating resectable locally advanced head and neck squamous cell carcinoma (LAHNSCC) remain uncertain, and the comprehensive protocol of NAI needs further explored. The tumor suppressor gene CDKN2A plays a pivotal role in cell cycle regulation by modulating cyclin-dependent kinase (CDK) activity. Mutations in CDKN2A lead to continuous activation of CDK4/6, resulting in uncontrolled cell proliferation and tumor growth. Approximately 35.7% of HNSCC patients exhibit CDKN2A mutations, with the incidence rising to 58% among HPV-negative LAHNSCC patients. Studies have shown that combining immunotherapy with a CDK4/6 inhibitor produces a synergistic anti-tumor effect. This study aims to assess the efficacy and safety of combining anti-PD-L1 (adebrelimab) with a CDK4/6 inhibitor (dalpiciclib) as NAI in resectable LAHNSCC patients. Methods: This open-label, single-arm, prospective phase II trial will enroll LAHNSCC patients eligible for surgery. Inclusion criteria include: being 18 to 75 years old at study entry; pathologically confirmed HPV-negative HNSCC (oral, laryngeal, hypopharyngeal, and HPV-negative oropharyngeal carcinoma), determined via p16 immunohistochemistry or HPV DNA tests; with CDKN2A mutation; resectable LAHNSCC, staged III-IVB according to the UICC/AJCC 8th edition TNM system; an ECOG Performance Status score of 0 or 1; no prior relevant anti-tumor treatments; intent for curative treatment; and adequate organ function. Key exclusion criteria are active autoimmune diseases, use of immunosuppressive drugs, or systemic corticosteroids. Eligible patients receive 3 cycles of adebrelimab (1200 mg intravenously every 3 weeks, Day 1, 22 and 43) and 2 cycles of dalpiciclib (150 mg, po, every 4 weeks, day 1-21 and 29-49) before surgery. Dose adjustments are allowed based on toxicity. Surgery will follow 2-4 weeks post-NAI, with subsequent adjuvant radiotherapy or chemoradiotherapy based on risk factors after surgery. The primary endpoints are 1-year disease-free survival (defined as the time from surgical resection to local recurrence) and major pathological response (MPR, defined as ≤10% residual viable tumor cells), with secondary endpoints focusing on safety and predictive biomarkers. Clinical trial information: NCT06199271 .

TTCC-2022-01: Niraparib and dostarlimab in locally-advanced head and neck squamous cell carcinoma treated with (chemo) radiotherapy (RADIAN).

TPS6125 Background: The prognosis of locally-advanced head and neck squamous cell carcinoma (LA-HNSCC) remains poor, with a 60% 5-year overall survival (OS) rate despite curative-intent therapies. Treatment intensification strategies with antiPD-(L)1 agents given concurrently to (chemo)radiotherapy (CRT) have failed to improve survival. New radiosensitizing agents such as PARP inhibitors have shown encouraging results in early studies, and are of special interest in cisplatin-unfit patients (pts) (Moutafi et al. 2021). Beyond radiation sensitization, PARP inhibition is predicted to trigger immune responses via STING pathway activation, and synergize with anti-PD-(L)1 agents (Sen T et al., 2019). We hypothesize that niraparib will enhance antitumor immune responses when combined with dostarlimab before and after definitive CRT and will boost RT response ultimately leading to higher disease-free survival (DFS). Methods: Trial design: RADIAN is an investigator-initiated, multi-center, non-randomized two-cohort phase 1b study of niraparib and dostarlimab in LA-HNSCC pts candidates for CRT (cohort A) or RT alone (cohort B – cisplatin unfit). Dostarlimab 500mg is given intravenously 3 weeks(w) before RT and then q/3w starting w4 post-RT for up to 14 cycles. Niraparib 200 or 300mg is given orally once daily 1w after dostarlimab until start of CRT (cohort A) or continuously until last dose of RT (Cohort B) and then continuously in 3w cycles from w4 post-RT for up to a year (14 cycles). Intensity-modulated RT (70 Grays:2Gray/fraction) and high-dose cisplatin are given as per standard-of-care. Study procedures include collection of baseline archival or fresh tumor sample for molecular profiling, PD-L1 expression and immunophenotyping; serial blood samples for circulating tumor (ct) DNA and clinical/endoscopic photographs of the tumor (baseline, pre-niraparib, pre-RT, 12w post-RT, end-of treatment, and at progression). Imaging and follow-up procedures are conducted as per standard-of-care. Key eligibility criteria: untreated, stage III to IVB laryngeal, hypopharyngeal, HPV-negative oropharyngeal SCC (stage III only if HPV-positive), and stage IVB oral cavity SCC as per TNM 8th edition;adequate organ function; no autoimmune disorders; no immunosuppressive therapy. Study objectives: primary objective is to evaluate 1-year disease free survival. Secondary objectives: safety/tolerability including RT delay/completion; locoregional and distant control, event-free survival, OS and ctDNA dynamics correlation with efficacy endpoints. Sample size: 32 evaluable pts for correlative studies are planned for enrollment (16/cohort). It is expected that experimental treatment will provide an increase of efficacy of 0.64 in terms of HR (1-year DFS of 75.9 % in cohort A and 68.2% in cohort B). Study activation: Nov 11th 2023, with 2 pts enrolled as of Feb 6th 2024. Clinical trial information: NCT05784012 .

Anti‑epidermal growth factor receptor monoclonal antibody therapy in locally advanced head and neck cancer: A systematic review of phase III clinical trials.

The present systematic review evaluated the effectiveness of anti-EGFR therapy in combination with radiotherapy (RT) or with chemoradiation compared with the existing standard of care for the treatment of locally advanced head and neck squamous cell carcinoma (LAHNSCC). The PubMed, SCOPUS, EMBASE and COCHRANE databases were searched and 12 phase III randomized controlled trials were included. The effectiveness of the anti-EGFR monoclonal antibody cetuximab was evaluated in nine trials. Nimotuzumab (one trial), zalutumumab (one trial) and panitumumab (one trial) were the monoclonal antibodies evaluated in the remaining three trials. One study tested the effectiveness of adding cetuximab to radical RT and found that patients with LAHNSCC exhibited improvement in locoregional control (LRC), overall survival (OS) and progression-free survival (PFS) compared with those of patients treated with RT alone. A total of three studies tested the effectiveness of adding an anti-EGFR agent to chemoradiation. Of these, a single institution study in which patients received cisplatin at 30 mg/m2 weekly, instead of the standard doses of 100 mg/m2 every 3 weeks or 40 mg/m2 every week, reported significant improvement in PFS with the addition of nimotuzumab to chemoradiotherapy without an improvement in overall survival. However, the other two studies indicated that, when added to standard chemoradiation, the anti-EGFR monoclonal antibodies cetuximab or zalutumumab did not improve survival outcomes. Two phase III trials evaluated RT plus an anti-EGFR agent compared with chemoradiation alone. Of these, one study reported inferior outcomes with cetuximab-RT in terms of OS and LRC, whereas the other study with panitumumab plus RT failed to prove the non-inferiority. Two trials evaluated induction chemotherapy followed by cetuximab-RT compared with chemoradiotherapy and reported no benefits in terms of OS or PFS. Furthermore, one study evaluated induction chemotherapy followed by cetuximab-RT compared with induction chemotherapy followed by chemoradiotherapy and found no improvement in OS or PFS. Finally, three phase III trials tested the effectiveness of cetuximab plus RT in the treatment of human papillomavirus-positive oropharyngeal carcinoma, and found it to be inferior compared with cisplatin-RT in terms of OS, PFS and failure-free survival. Based on the aforementioned findings, it is difficult to conclude that anti-EGFR therapy in any form has an advantage over conventional chemoradiation in the treatment of LAHNSCC.

Efficacy and Safety of Paclitaxel versus Cisplatin with Concurrent Radiotherapy in Central India Patients with Locally Advanced Head-and-neck Cancers: A Randomized, Open-label Study

ABSTRACT Background: In India, majority of the patients with head-and-neck cancers are diagnosed in the locally advanced stage. The aim of this study was to compare the efficacy and safety of paclitaxel versus cisplatin with concurrent radiotherapy (RT) in patients with locally advanced head-and-neck squamous cell carcinomas (LAHNSCCs). Materials and Methods: This was an open-label, randomized study involving 100 patients with LAHNSCC who were randomly divided into two groups: the first group received paclitaxel (Tax, n = 50, 30 mg/m2/week for 7 weeks) and the second group received cisplatin (Cis, n = 50; 40 mg/m2/week for 7 weeks). Both the groups received concurrent RT in a total dose of 66.6 Gy in 37 fractions of 5 days/week over a period of 7.5 weeks. Results: The complete (46% vs. 36%) and partial (40% vs. 50%) response rates in the Tax + RT group and Cis + RT group were not significantly different (both P &gt; 0.05). Cis + RT resulted in significantly greater Grade I adverse events (AEs) (P &lt; 0.05). While, Grade II, III, and IV AEs were significantly greater with Tax + RT (all P &lt; 0.05). Overall analysis revealed that the use of Cis + RT was associated with a significantly greater number of patients who were free from AEs (P &lt; 0.05). Conclusions Tax + RT and Cis + RT were equi-efficacious in patients with LAHNSCC. However, Cis + RT had a better safety profile.

Standard versus fractionated high-dose cisplatin plus radiation for locally advanced head and neck cancer: Results of the CisFRad (GORTEC 2015-02) randomized phase II trial

BackgroundChemoradiotherapy with high-dose cisplatin (HD-Cis: 100 mg/m2 q3w for three cycles) is the standard of care (SOC) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Cumulative delivered dose of cisplatin is prognostic of survival, even beyond 200 mg/m2 but high toxicity compromises its delivery. AimCisplatin fractionation may allow, by decreasing the peak serum concentration, to decrease toxicity. To date, no direct comparison was done of HD-Cis versus fractionated high dose cisplatin (FHD-Cis). MethodsThis is a multi-institutional randomized phase II trial, stratified on postoperative or definitive chemoradiotherapy, comparing HD-Cis to FHD-Cis (25 mg/m2/d d1-4 q3w for 3 cycles) in patients with LA-HNSCC. The primary endpoint was the cumulative delivered cisplatin dose. ResultsBetween December 2015 and April 2018, 124 patients were randomized. Median cisplatin cumulative delivered dose was 291 mg/m2 (IQR: 251;298) in the FHD-Cis arm and 274 mg/m2 (IQR: 198;295) in the HD-Cis arm (P = 0.054). The proportion of patients receiving a third cycle of cisplatin was higher, with a lower proportion of grade 3–4 acute AEs in the FHD-Cis arm compared to the HD-Cis arm: 81 % vs. 64 % (P = 0.04) and 10 % vs. 17 % (P = 0.002), respectively.With a median follow-up of 48 months (IQR: 41;55), locoregional failure rate, PFS and OS were similar between the two arms. ConclusionAlthough the primary endpoint was not met, FHD-Cis allowed more cycles of cisplatin to be delivered with lower toxicity, when compared to SOC. FHD-Cis concurrently with RT is a treatment option which deserves further consideration.

Multimodal detection of molecular residual disease in high-risk locally advanced squamous cell carcinoma of the head and neck.

Up to 30% of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) relapse. Molecular residual disease (MRD) detection using multiple assays after definitive therapy has not been reported. In this study, we included patients with LA-HNSCC (stage III Human Papilloma virus (HPV)-positive, III-IVB HPV-negative) treated with curative intent. Plasma was collected pre-treatment, at 4-6 weeks (FU1) and 8-12 weeks (FU2) post-treatment. Circulating tumor DNA (ctDNA) was analyzed using a tumor-informed (RaDaR®) and a tumor-naïve (CAPP-seq) assay. HPV DNA was measured using HPV-sequencing (HPV-seq) and digital PCR (dPCR). A total of 86 plasma samples from 32 patients were analyzed; all patients with at least 1 follow-up sample. Most patients were stage III HPV-positive (50%) and received chemoradiation (78%). No patients had radiological residual disease at FU2. With a median follow-up of 25 months, there were 7 clinical relapses. ctDNA at baseline was detected in 15/17 (88%) by RaDaR and was not associated with recurrence free survival (RFS). Two patients relapsed within a year after definitive therapy and showed MRD at FU2 using RaDaR; detection of ctDNA during follow-up was associated with shorter RFS (p < 0.001). ctDNA detection by CAPP-seq pre-treatment and during follow-up was not associated with RFS (p = 0.09). HPV DNA using HPV-seq or dPCR during follow-up was associated with shorter RFS (p < 0.001). Sensitivity and specificity for MRD at FU2 using RaDaR was 40% and 100% versus 20 and 90.5% using CAPP-seq. Sensitivity and specificity for MRD during follow-up using HPV-seq was 100% and 91.7% versus 50% and 100% using dPCR. In conclusion, HPV DNA and ctDNA can be detected in LA-HNSCC before definitive therapy. The RaDaR assay but not CAPP-seq may detect MRD in patients who relapse within 1 year. HPV-seq may be more sensitive than dPCR for MRD detection.

A bioconvergence study on platinum-free concurrent chemoradiotherapy for the treatment of HPV-negative head and neck carcinoma

Locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is characterized by high rate of recurrence, resulting in a poor survival. Standard treatments are associated with significant toxicities that impact the patient’s quality of life, highlighting the urgent need for novel therapies to improve patient outcomes. On this regard, noble metal nanoparticles (NPs) are emerging as promising agents as both drug carriers and radiosensitizers. On the other hand, co-treatments based on NPs are still at the preclinical stage because of the associated metal-persistence. In this bioconvergence study, we introduce a novel strategy to exploit tumour chorioallantoic membrane models (CAMs) in radio-investigations within clinical equipment and evaluate the performance of non-persistent nanoarchitectures (NAs) in combination with radiotherapy with respect to the standard concurrent chemoradiotherapy for the treatment of HPV-negative HNSCCs. A comparable effect has been observed between the tested approaches, suggesting NAs as a potential platinum-free agent in concurrent chemoradiotherapy for HNSCCs. On a broader basis, our bioconvergence approach provides an advance for the translation of Pt-free radiosensitizer to the clinical practice, positively shifting the therapeutic vs. side effects equilibrium for the management of HNSCCs.

Role of primary tumor volume and metastatic lymph node volume in response to curative effect of definitive radiotherapy for locally advanced head and neck cancer

BackgroundStudies have shown mixed results concerning the role of primary tumor volume (TV) and metastatic lymph node (NV) volume in response to the curative effect of definitive radiotherapy for locally advanced head and neck squamous cell carcinoma (LAHNSCC).ObjectiveWe aimed to evaluate the impact of TV and NV on the efficacy of radical radiotherapy in LAHNSCC patients, with the goal of guiding individualized therapy.Patients and methodsPatients with LAHNSCC who received radical radiation therapy and were reexamined within 6 months post-therapy from January 2012 to December 2021 were selected. The volumes of the primary tumors and metastatic lymph nodes were calculated by software and then were divided into a large TV group vs small TV group and a large NV group vs small NV group according to the relationship with the median. Additionally, patients who received concurrent chemoradiotherapy (CCRT) or not were divided into the CCRT group and the radiotherapy (RT) group. Patients with lymph node metastasis were divided into node concurrent chemotherapy (N-CCRT) group and a node metastatic chemotherapy (N-RT) group according to whether they received concurrent chemotherapy or not. The volume shrinkage rate (VSR), objective response rate (ORR), local control rate (LCR) and overall survival (OS) were recorded and analyzed.Results96 patients were included in the primary tumor volume group, and 73 patients were included in the metastatic lymph node group. Receiver operating characteristic (ROC) curves were constructed for objective remission (OR) endpoints, and a volume threshold was defined for TV and NV patients. The threshold primary tumor volume was 32.45 cm3, and the threshold metastatic lymph node volume was 6.05 cm3.The primary TV shrinkage rates of the small TV and the large TV groups were basically the same, P = 0.801. Similarly, the ORR and LCR were not significantly different between the small TV group and the large TV group (PORR = 0.118, PLCR = 0.315). Additionally, the TV shrinkage rate did not significantly differ between the CCRT group and the RT group, P = 0.133. Additionally, there was no significant difference in ORR or LCR in CCRT group (PORR = 0.057, PLCR = 0.088). However, the metastatic lymph node volume shrinkage rate in the small NV group was significantly greater than that in the large NV group (P = 0.001). The ORR and LCR of the small NV subgroup were significantly greater than those of the large NV subgroup (PORR = 0.002, PLCR = 0.037). Moreover, compared with that of the N-RT group, the NV shrinkage rate of the N-CCRT group was 84.10 ± s3.11%, and the shrinkage rate was 70.76 ± s5.77% (P = 0.047). For the ORR and LCR, the N-CCRT group and N-RT group were significantly different (PORR = 0.030, PLCR = 0.037). The median OS of the whole group was 26 months. However, neither TV/NV nor concurrent chemotherapy seemed to influence OS.ConclusionPrimary tumor volume is not a prognostic factor for the response to curative effect radiotherapy in LAHNSCC patients. Nevertheless, metastatic lymph nodes are a prognostic factor for the response to curative effect radiotherapy in LAHNSCC patients. Patients with smaller lymph nodes have better local control.

Clinical decision pathway and management of locally advanced head and neck squamous cell carcinoma: A multidisciplinary consensus in Asia-Pacific

ObjectivesTo develop consensus on patient characteristics and disease-related factors considered in deciding treatment approaches for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) based on real-world treatment patterns in 4 territories in Asia-Pacific. MethodsA three-round modified Delphi involving a multidisciplinary panel of HN surgeons, medical oncologists, and radiation oncologists was used. Of 41 panelists recruited, responses of 26 from Australia, Japan, Singapore, and Taiwan were analyzed. All panelists had ≥five years’ experience managing LA-HNSCC patients and treated ≥15 patients with LA-HNSCC annually. ResultsAll statements on definitions of LA-HNSCC, treatment intolerance and cisplatin dosing reached consensus. 4 of 7 statements on unresectability, 2 of 4 on adjuvant chemoradiotherapy, 7 of 13 on induction chemotherapy, 1 of 8 on absolute contraindications and 7 of 11 on relative contraindications to high-dose cisplatin did not reach consensus. In all territories except Taiwan, high-dose cisplatin was preferred in definitive and adjuvant settings for patients with no contraindications to cisplatin; weekly cisplatin (40 mg/m2) preferred for patients with relative contraindications to high-dose cisplatin. For Taiwan, the main treatment option was weekly cisplatin. For patients with absolute contraindications to cisplatin, carboplatin ± 5-fluorouracil or radiotherapy alone were preferred alternatives in both definitive and adjuvant settings. ConclusionThis multidisciplinary consensus provides insights into management of LA-HNSCC in Asia-Pacific based on patient- and disease-related factors that guide selection of treatment modality and systemic treatment. Despite strong consensus on use of cisplatin-based regimens, areas of non-consensus showed that variability in practice exists where there is limited evidence.

Treatment outcomes of radiotherapy with concurrent weekly cisplatin in older patients with locally advanced head and neck squamous cell carcinoma

BackgroundTri-weekly cisplatin and radiotherapy (CDDP + RT) is a standard of care for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) but is sometimes challenging to complete in older patients. Weekly CDDP + RT has shown mild toxicity compared to tri-weekly CDDP + RT for LA-HNSCC and is a promising option for older adults. We aimed to report the treatment outcomes and prognostic factors in patients with LA-HNSCC treated with weekly CDDP + RT.MethodsWe analyzed patients aged ≥ 70 years who started weekly CDDP + RT for LA-HNSCC between July 2006 and October 2022. LA-HNSCC includes cancer in the oropharynx, hypopharynx, or larynx with a clinical stage of 3 or 4 without distant metastases based on the Union for International Cancer Control staging system 8th edition. The radiation dose of 70 Gy was delivered in 35 fractions by 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, or proton beam therapy. The primary endpoint was the 3-year overall survival (OS), and the secondary endpoints were the 3-year progression-free survival (PFS) and 3-year cause-specific survival (CSS). The Kaplan–Meier method was used to calculate survival rates, and the log-rank test was used to evaluate statistical significance. A Cox proportional hazards model was used for the multivariate analysis of prognostic factors.ResultsThe median age of the 49 patients was 72 (range: 70–78) years. The median CDDP dose was 200 (40–280) mg/ m2, and 47 patients completed scheduled radiotherapy. Forty-eight patients (98.0%) had a performance status of ≥ 1 at the initial visit. The 3-year OS, PFS, and CSS were 80.9% (95% confidence interval [CI]: 64.8–90.7), 58.9% (95%CI: 42.7–73.3), and 85.0% (95%CI: 68.7–93.4), respectively. In the multivariate analysis, the cumulative CDDP dose (< 200 or ≥ 200 mg/m2) was a significant factor for OS (hazard ratio: 0.29 [95% CI 0.08–0.97], p = 0.044). There was one case of early mortality. Grade 3 or higher late adverse events were observed in four patients (8.2%).ConclusionsWeekly CDDP + RT in older patients led to good survival outcomes with an acceptable rate of adverse events. CDDP should be administered at a dose of at least 200 mg/m2 in older patients.Trial registration Retrospectively registered

Effectiveness of Head-and-Neck Molecular Imaging Reporting and Data System Criterion in Head-and-Neck Squamous Cell Carcinoma PostConcurrent Chemoradiotherapy.

Postconcurrent chemoradiotherapy (CRT) response assessment has been challenging in locally advanced head-and-neck squamous cell carcinoma (LA-HNSCC) due to prevailing postradiation changes. Molecular response methods have been encouraging, although further clarifications and validations were needed. We tested the effectiveness of a proposed semi-quantitative molecular response criterion in these patients. Two subspecialty-trained physicians evaluated 18F-fluorodeoxyglucose positron emission tomography/computed tomography of LA-HNSCC patients (n = 83) post 3 months CRT using a five points Head and Neck Molecular Imaging-Reporting and Data System (HAN-MI-RADS) criterion. Where available, histopathology examination with clinical and imaging interpretation was taken as a reference for the disease. A diagnostic accuracy comparison was done with the existing Hopkins score. Further effectiveness was analyzed with disease-free survival (DFI) and overall survival (OS). Metastasis was developed in 11/83 patients at 3 months of evaluation. Of 72 patients, 39, 2, and 31 patients had a complete response, equivocal response, and partial response as per HAN-MI-RADS. Per patient sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for predicting loco-regional disease up to 1 and 2 years was 93.3%, 92.5%, 90.3%, 94.9%, 92.9%, and 84.9%, 91.9%, 90.3%, 87.2%, and 88.6% respectively. One year and two years DFI for each HAN-MI-RADS score showed a statistically significant difference while it was not for OS. The receiver operating characteristic curve analysis showed significantly better outcome predictability of HAN-MI-RADS (area under the curve [AUC] 0.884) than Hopkins (AUC 0.699). A five points HAN-MI-RADS criterion was found promising for response assessment with less equivocal results and statistically significant higher AUC than Hopkins for loco-regional recurrence prediction.

Pre-treatment risk factors to predict early cisplatin-related nephrotoxicity in locally advanced head and neck cancer patients treated with chemoradiation: A single Institution experience

ObjectivesCisplatin is essential in the curative treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC) patients. The assessment of risk factors to predict an early cisplatin-induced nephrotoxicity could help in better managing one of the most relevant cisplatin-related dose-limiting factors. Material and methodsWe retrospectively collected data of LA-HNSCC patients treated at our Institution from 2008 to 2019. Patients received cisplatin in a curative setting concurrently with radiation. Acute Kidney Injury (AKI) was assessed as a dichotomous variable (CreaIncr) based on pre-treatment values, and values recorded at days 6–20 post-first cycle of cisplatin. Univariable logistic regression models were performed to investigate associations between CreaIncr and clinical characteristics. A multivariable logistic model on a priori selected putative covariates was performed. ResultsOf the 350 LA-HNSCC treated patients, 204 were analyzed. Ninety (44 %) suffered from any grade AKI (grade I 51.1 %): out of them, 84.4 % received high-dose cisplatin (100 mg/m2 q21). On the univariable logistic regression model, male sex, age, serum uric acid, creatinine, concomitant drugs, and cisplatin schedule were significantly associated with a higher rate of AKI. At multivariable model, age (p = 0.034), baseline creatinine (p = 0.027), concomitant drugs (p = 0.043), and cisplatin schedule (one-day bolus or fractionated high-dose vs. weekly; p = 0.001) maintained their significant association. ConclusionsIdentifying pre-treatment risk factors in LA-HNSCC patients may improve decision-making in a setting where cisplatin has a curative significance. A strict monitoring of AKI could avoid cisplatin dose adjustments, interruptions, and treatment delays, thus limiting a negative impact on outcomes.

Phase 3 randomized study for evaluation of physician choice Rx and triple metronomic as second-line therapy in head and neck cancer (CRSF 2021-HN-001).

LBA6004 Background: There are multiple options of treatment in second-line therapy in locally advanced head and neck squamous cell carcinoma (LAHNSCC) with recurrent or metastatic disease. However triple metronomic chemotherapy is oral, affordable, and requires minimal resources. Hence in this study, we compared NCCN-recommended physician choice of standard systemic therapy versus triple metronomic therapy in the second-line treatment of head and neck cancer. Methods: This was a phase 3, multicentric (16 sites), randomized study with a superiority design that was approved by the institutional ethics committees and registered with CTRI (CTRI/2021/08/036002) conducted in India under the aegis of Cancer Research Statistics Foundation. The study recruited LAHNSCC with a recurrent and metastatic disease that either was platinum-refractory or was planned for second-line chemotherapy. The key inclusion criteria were: Age ≥18 years, ECOG PS 0-2, and the presence of normal hematological and biochemical parameters. These patients underwent 1:1 central stratified randomization (Stratification - site of disease &amp; ECOG PS) to either triple metronomic chemotherapy (methotrexate 9 mg/m2 PO weekly, celecoxib 200 mg PO twice daily and erlotinib 150 mg PO once daily) or physician choice therapy ( nivolumab or pembrolizumab or cetuximab or taxane or afatinib or 5-FU or capecitabine). The study drugs were administered either till disease progression or the development of intolerable side effects. The primary endpoint of the study is overall survival (OS). The secondary endpoints are adverse events (CTCAE version 5.0), progression-free survival (PFS), and quality of life (EORTC). The sample size required was 114. The OS and PFS were estimated using Kaplan-Meier method and were compared using the log-rank test. Cox proportional hazard model was constructed for the calculation of the hazard ratio. The adverse events were compared using Fisher's test. A p-value of 0.05 was considered significant. Results: At a median follow-up of 258 (95% CI 209-306) days.The median overall survival of the triple metronomic chemotherapy was 181 days (95%CI 142.7-219.2) versus 123 days (95%CI 94-152) in the physician choice therapy arm (P=.0.002). The corresponding hazard ratio of death was 0.58 (95%CI 0.33-0.79, P=0.003). The 6-month OS was 52.9% (95%CI 36.9-65.1) versus 14.8% (95%CI 6.4-26.4). The median progression-free survival was 120 days (95%CI 89.2-150.8) versus 70 days (95% CI 58.2-81.8) in metronomic chemotherapy and in the physician choice therapy arms respectively (P=0.000). The corresponding hazard ratio of progression was 0.5 (95%CI 0.33-0.74, P=0.001). Conclusions: In this phase 3 multicentric study, triple metronomic chemotherapy as second-line therapy had an overall survival and progression-free survival advantage over NCCN-recommended physician choice therapy. Clinical trial information: CTRI/2021/08/036002 .