Stage III-IVB Research Articles

Real-world event-free survival (rwEFS) and overall survival (rwOS) in elderly patients with resected locoregionally advanced head and neck squamous cell carcinoma (LA HNSCC) in the US.

375 Background: Surgery followed by adjuvant radiotherapy (RT) ± systemic therapy (ST) is often recommended for patients (pts) with resectable LA HNSCC with curative intent. This study assessed rwEFS, rwOS, and the correlation between rwEFS and rwOS in elderly pts (≥66 years old at diagnosis) with resected LA HNSCC to better understand unmet needs and inform future clinical trial designs. Methods: This retrospective cohort study utilized linked SEER-Medicare data (2007–2019). Pts with newly diagnosed stage III-IVB (AJCC 6/7th) LA HNSCC (larynx, hypopharynx, oral cavity, or oropharynx) who underwent surgery as primary treatment within 4 months of diagnosis were included. Index date was defined as the primary treatment initiation date. rwEFS was defined as time from index date to first recurrence or death, whichever occurred first. rwOS was defined as time from index date to death. Baseline (12 months prior to index date) factors associated with rwEFS and rwOS were assessed using a Cox proportional hazards model. Correlation between rwEFS and rwOS was assessed using the normal scores rank correlation. Results: A total of 526 pts met the selection criteria (median follow-up: 24.3 months). The median (interquartile range) age at initial diagnosis was 72.6 (68.6-78.8) years, 63.9% were male, 79.5% were white, and 6.1% had stage IVb disease. HPV status and smoking status were not available. Over half of pts received adjuvant RT ± ST following resection. Median rwEFS and 5-year rwEFS were 8.0 months (95% CI: 6.4, 9.2) and 16.3%, respectively. Median rwOS was 32.6 months (95% CI: 26.2, 42.3), with a 5-year rwOS of 37.8%. Older age, primary hypopharynx disease (vs. oropharynx), and higher Charlson Comorbidity Index scores were associated with significantly shorter rwOS. Additionally, surgery followed by RT ± ST (vs. surgery only) and less advanced tumor stage were associated with significantly longer rwEFS and rwOS. The correlation between rwEFS and rwOS was moderate and significantly positive (r = 0.68 [95% CI: 0.62, 0.74], p<0.001). Conclusions: Real-world survival outcomes were modest among elderly pts with surgically managed LA HNSCC, highlighting a population with significant unmet need where more effective therapies are needed. rwEFS was found to have a significant, positive correlation with rwOS, supporting EFS as a predictor for OS in this patient population. Primary treatment and association with rwEFS and rwOS. 1,2,3 Treatment Pattern N (%) HR (95% CI) - rwEFS HR (95% CI) - rwOS Surgery Only 144 (27.4%) - - Surgery followed by RT 172 (32.7%) 0.60 (0.47, 0.78)* 0.77 (0.58, 1.03) Surgery followed by RT + ST 128 (24.3%) 0.49 (0.36, 0.66)* 0.50 (0.34, 0.72)* RT or RT+ST followed by surgery 66 (12.5%) 0.66 (0.47, 0.93)* 0.80 (0.55, 1.18) 1 Treatment modalities with N<11 were not reported. 2 *denotes p < 0.05. 3 denotes reference group.

The immunological milieu of oropharyngeal squamous cell carcinoma (OPC) according to HPV and smoking status and its influence on prognosis.

3147 Background: OPC exhibits distinct epidemiological, genetic, and clinical characteristics, significantly influenced by the presence of HPV. Despite multidisciplinary therapy, approximately 40% of OPC patients (pts) experience recurrence, and those who achieve cure often endure late and morbid sequelae of treatment. In this study, we comprehensively explored the composition and functional status of the tumor immune microenvironment (TIME) in a cohort of OPC pts treated with curative intent and investigated TIME differences based on HPV infection, smoking status, and clinical outcomes. Methods: Two tissue microarrays with baseline OPC tissues were stained with a previously validated panel containing 33 metal-tagged markers. Imaging mass cytometry was performed with the Fluidigm Helios CyTOF instrument, and analysis performed with Visiopharm software. HPV status was determined by p16 IHC and/or DNA testing. Comparison of cell types and markers densities among subgroups (HPV positive vs negative) were analyzed with Wilcoxon signed-rank test and its association with clinical outcomes (recurrence vs no-recurrence) with log-rank and Cox Proportional Hazards. Multiple comparisons were corrected by Benjamini Hochberg procedure. Results: A total of 99 samples from 61 pts from a single institution were included in this study. The majority of pts were male (N=47, 77%) and heavy smokers (N=55, 90%); 72% were HPV-negative. The median age was 61 years (range, 39 – 87 years), and 52% of cases were diagnosed with stages III-IVB (AJCC 8th edition). Most pts (57%) was treated with surgery (±RT). Thirty-three pts (54%) experienced recurrent disease. Smoking, stage III-IVB, and HPV-negative tumors were associated with higher recurrence rates (p <0.01). Regarding the OPC TIME, the most prevalent cell populations in the stroma were fibroblasts (22%), followed by T-cells (17%) and endothelial cells (10%). The stroma of HPV+ tumors exhibited higher densities of memory T cells (FDR < 0.01), B cells (FDR = 0.02), and T cells (FDR = 0.02) compared to HPV negative counterparts, which displayed an increased density of neutrophils (FDR = 0.04). The density of cancer stem cells was directly associated with smoking history (FDR<0.001), and an increased density of intra-tumoral B-cells was found in non-smokers (FDR=0.01). Higher intra-tumoral neutrophil density was linked to recurrent disease (FDR < 0.001). Conversely, higher densities of memory CD8+ T cells and non-M2 macrophages in the TIME were associated with a lower chance of recurrence (FDR < 0.1). Conclusions: The intricate analysis of the OPC TIME revealed significant differences according to HPV and smoking status and highlighted the prognostic role of neutrophils, memory CD8+ T cells, and non-M2 macrophages. These findings may guide the development of personalized therapeutic strategies for OPC.

Endostar combined with concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone for locoregionally advanced nasopharyngeal carcinoma (LA-NPC): A phase III, prospective, randomised-controlled, multicenter clinical trial.

6002 Background: Cisplatin-based concurrent chemoradiotherapy (CCRT) has long been regarded as standard treatment for LA-NPC. However, approximately 30% of patients still fail to obtain a satisfactory effect. Endostar (Rh-endostatin), an anti-angiogenesis inhibitor, is well-tolerated and has been reported as a promising complement to CCRT. This trial aimed to evaluate the efficacy and safety of adding Endostar to CCRT for LA-NPC. Methods: In this prospective, randomized phase III study, patients with LA-NPC (stage III-IVb, 7th edition) were enrolled at 6 centers in China, and randomly assigned (1:1) to receive Endostar plus CCRT (CCRT+E group, n=150) or CCRT alone (CCRT group, n=150). Endostar (7.5 mg/m2/day, days 1-10, 15 days/cycle) was given continuously intravenously for 5 cycles (3 concurrent from 5 days before radiotherapy, and 2 adjuvant from the first day after the completion of radiotherapy). The primary endpoint was the progress-free survival (PFS) rate. The secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), local-regional relapse-free survival (LRRFS), the rate of complete response (CR) at 3 months after RT, and safety. Results: Between November 2016 and July 2020, 300 patients with LA-NPC were randomized (CCRT+E group, 150; CCRT group, 150). As of the data cutoff (December 2023), the median follow-up was 66 months. Intention-to-treat analysis showed that patients in the CCRT+E group achieved better CR rate at 3 months after RT (90.0% vs 80.7%, P=0.022). The 3-year PFS was 84.8% in the CCRT+E group, and 75.1% in the CCRT group (HR, 0.544; 95% CI, 0.336-0.879; Plog-rank=0.011). The 3-year OS was 89.2% vs. 85.3% (HR, 0.595; 95% CI, 0.361-0.982; Plog-rank=0.039). The 3-year DMFS was 89.7% vs. 80.5% (HR, 0.468; 95% CI, 0.266-0.821; Plog-rank=0.007). The 3-year LRRFS was 91.5% vs. 90.8% (HR, 0.808; 95% CI, 0.407-1.604; Plog-rank=0.541). Patients in the CCRT+E group and in the CCRT group had similar Grade 3-4 acute and late toxicity profile (61.7% vs. 65.3%, p=0.519 and 8.0% vs.7.3%, p=0.815). Conclusions: The addition of Endostar to standard CCRT significantly improved the 3-year PFS of LA-NPC patients with good safety profile. Clinical trial information: NCT02907710 .

Analysis of PD-L1 expression in locally advanced head and neck squamous cell carcinoma and its correlation with the efficacy of neoadjuvant immunotherapy + chemotherapy: A retrospective real-world study.

6074 Background: The incidence rate of HNSCC in Hunan China are notably higher than in other regions, likely due to the high prevalence of betel nut chewing. Therefore, we conducted a study to examine the PD-L1 expression in newly diagnosed locally advanced (stage III-IVB) HNSCC patients. Methods: 1. We conducted a retrospective analysis of the PD-L1 expression (represented as CPS) in pre-treatment biopsy tissues from locally advanced HNSCC. 2. 57 patients received neoadjuvant treatment consisting of nab-paclitaxel+ cisplatin+ pembrolizumab. The efficacy of the treatment was evaluated using pathology assessments. Results: 1. A total of 373 patients were included. The top five primary sites of the tumors were the tongue(32.17%), Buccal oris (20.91%), oropharynx (10.19%), hypopharynx(9.92%), and gingiva(7.77%). The proportion of patients with PD-L1 CPS≥20 (55.23%) was significantly higher than the 43.20% reported in the KEYNOTE-048 study. Furthermore, the subgroup was even higher in the buccal oris (70.51%) and gingiva (72.41%). 2. A total of 57 patients were tested for PD-L1 CPS and received neoadjuvant treatment.After surgery, 22/57 (38.60%) achieved pathological complete response (pCR) or major pathological response (MPR), 29/57 (50.88%) achieved partial pathological response (pPR), resulting in an overall response rate (ORR) of 89.47%. In the PD-L1 CPS ≥20 group, the ORR was as high as 91.89% (34/37). 3. Among the 57 patients, 36 patients had lymph node metastasis. After treatment, 15/36 patients (41.67%) achieved pCR/MPR in lymph nodes, 7/36 patients (19.44%) achieved pPR, resulting in an ORR was 61.11% (22/36). Conclusions: 1. The oral cavity is the most common primary in HNSCC in Hunan,China. In the locally advanced , the proportion of PD-L1 CPS ≥20 is higher than reported in other studies. 2. Regardless of PD-L1 expression, neoadjuvant treatment with nab-paclitaxel+ cisplatin+ pembrolizumab has shown a high rate of local disease control in newly diagnosed HNSCC patients. Additionally, the use of neoadjuvant therapy has improved the delineation of surgical safety margins, leading to 100% R0 resections in all 57 patients. 3. The response of the primary lesion in patients treated with neoadjuvant therapy is better than that of the lymph node. Patients with a well-responding primary lesion but multiple lymph node metastases should be closely monitored for the possibility of short-term systemic metastasis. [Table: see text]

Real-world treatment patterns and overall survival (OS) in locoregionally advanced head and neck squamous cell carcinoma (LA HNSCC) in the U.S.

e23275 Background: Multimodal therapy, including definitive radiotherapy (RT) with or without systemic therapy (ST) or surgery followed by adjuvant RT ± ST is typically recommended for patients (pts) with LA HNSCC treated with curative intent. Assessing real-world use of various treatment modalities and OS helps to better understand the unmet needs in this population. Methods: The linked SEER-Medicare data (2007–2019) was used in this retrospective cohort study. Pts with newly diagnosed stage III-IVB (AJCC 6/7th) LA HNSCC (larynx, hypopharynx, oral cavity, or oropharynx) who received primary treatment within 4 months after initial diagnosis were included. HPV status was not available. OS from index date, i.e., primary treatment initiation date, was described using the Kaplan-Meier method. Baseline (12 months prior to index date) factors associated with OS were assessed using a Cox proportional hazards model. Hazard ratios (HRs), 95% confidence intervals (CIs), and p values were reported. Results: In total, 1885 pts met the selection criteria (median follow-up: 24.8 months). The mean age at initial diagnosis was 74.3 years, 67.2% were male, and 81.6% were white. Less than 1/3rd of pts received primary surgery (resected). More than half of resected pts received RT±ST post-surgery. In unresected pts, nearly 2/3rds received definitive concurrent RT+ST. The median OS and 5-year OS were 32.7 months and 37.6%, respectively, for all pts and were comparable between resected and unresected pts. In the multivariable Cox models for both resected and unresected pts, older age, more advanced tumor stage, hypopharynx (vs. oropharynx), and higher Charlson comorbidity index scores were associated with significantly shorter survival. Additionally, surgery followed by RT+ST (vs. surgery only) (HR = 0.50, 95% CI = 0.34-0.72, p < 0.001) and definitive RT+ST (vs. definitive RT only) (HR = 0.69, 95% CI = 0.58-0.81, p < 0.001) were associated with significantly longer survival in resected and unresected pts, respectively. Conclusions: In elderly pts with LA HNSCC, surgery followed by RT and definitive RT+ST were the most common treatment modalities in resected and unresected pts, respectively. The suboptimal real-world survival across all pts with LA HNSCC regardless of treatment strategy highlights a significant unmet need. Studies focused on the novel application and sequencing of effective immunotherapies are needed. Table 1. Primary treatment and OS in LA HNSCC1 [Table: see text]

CTEP 10492, a phase 1/1b study of the AKT inhibitor ipatasertib with chemoradiation for locally advanced head and neck squamous cell carcinoma.

TPS6127 Background: Locally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with definitive chemoradiation therapy (CRT). However, locoregional recurrence rates of approximately 50% may occur in high risk patients. As such, there is an unmet need for up-front treatment intensification in this patient population. Preclinical evidence suggests that both radiation therapy (RT) and cisplatin activate the PI3K/AKT pathway, leading to treatment resistance through multiple processes, including increased DNA repair, decreased apoptosis, and modulation of the tumor microenvironment by promoting angiogenesis, immune escape and hypoxia. Furthermore, AKT inhibitors have been shown to sensitize a subset of HNSCC models to RT and platinum chemotherapy in vitro and in vivo. However, radiosensitization using a specific AKT inhibitor has not yet been studied in humans. This phase I studywill bethe first to establish safety and preliminary efficacy of ipatasertib combined with standard of care definitive CRT for HNSCC. Methods: The primary objective of this study is to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of ipatasertib in combination with definitive CRT in locally advanced HNSCC based on dose-limiting toxicities (DLTs). Secondary objectives include assessment of acute and late toxicities, long term swallowing function, and a preliminary assessment of efficacy. Eligible subjects must have pathologically confirmed, previously untreated, non-metastatic HNSCC that is either human papilloma virus (HPV)-negative clinical stage III-IVB, or HPV-positive clinical stage III. The study schema includes dose escalation and expansion cohorts. All subjects will receive RT for a standard 70 Gy in 7-week course, with concurrent weekly cisplatin. Two 28-day cycles of orally administered ipatasertib will be given concurrently with CRT. The four dose levels of ipatasertib range from 100-400 mg daily. Dose escalation of ipatasertib will follow a Time-to-Event Bayesian Optimal Interval (TITE-BOIN) design, with DLT window extending from the start of CRT, through 28 days after completion of RT. The expansion cohort will enroll an additional 10 subjects at the RP2D, and incorporate pharmacodynamic biopsies for each subject to evaluate whether the addition of ipatasertib to CRT will result in increased gamma-H2AX, consistent with radiosensitization, and also decreased pS6 and pPRAS40 to evaluate AKT pathway inhibition. Additional correlative studies include assessment of the pharmacokinetic profile of ipatasertib with CRT, as well as correlation of efficacy with tumor genotype, based on whole exome sequencing of pre-treatment biopsy specimens. Enrollment is currently at dose level 2 in the escalation phase, and is expected to complete accrual in 2025. Clinical trial information: NCT05172245 .

Novel approach of prophylactic radiation to reduce toxicities comparing 2-step 40 Gy with 56 Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck: A phase III trial (JCOG1912, NEW BRIDGE).

TPS6121 Background: Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN. Methods: This study is a multicenter, two-arm, open-label, randomized phase III trial. The main inclusion criteria are as follows: (i) Primary lesions are located in the oropharynx, hypopharynx, or larynx. (ii) Histologically proven SCC on biopsy specimens of the primary lesion. Immunohistochemistry reveals p16 negativity in patients with oropharyngeal cancer. (iii) Clinical stage of III, IVA, or IVB (excluding N3a) based on the 8th UICC-TNM classification. Patients are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m2 are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score.Patient accrual was started in May 2021 and the study is now open for accrual. A total of 186 patients have been enrolled as of January 2024. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100. Clinical trial information: jRCTs031210100 .

Neoadjuvant immunochemotherapy and new radiomic predictor for resectable locally advanced oral squamous cell carcinoma.

6090 Background: The effectiveness of neoadjuvant immunochemotherapy (NAIC) in treating resectable locally advanced oral squamous cell carcinoma (LAOSCC) remains uncertain, with a notable lack of precise prognostic markers for NAIC outcomes. Methods: A single-arm prospective phase II trial was performed to assess the efficacy and safety of NAIC, consisting of 2 cycles of intravenous camrelizumab (200 mg), albumin paclitaxel (260 mg/m²), and cisplatin (75 mg/m²) administered every 3 weeks prior to radical surgery in LAOSCC patients. Adjuvant radiotherapy or chemoradiotherapy was determined by post-surgical pathology. Patients with previously untreated, stage III-IVB LAOSCC (the 8th edition of UICC/AJCC staging system), aged 18-75 years were enrolled. The primary endpoints were major pathological response (MPR, defined as ≤10% residual viable tumour (%RVT) cells) and safety, the second primary point was objective response rate (ORR) according to RECIST 1.1. To identify potential radiomic markers predictive of NAIC benefit, oscillating-gradient spin-echo (OGSE) magnetic resonance imaging sequences were obtained before and after NAIC. Results: From Feb 1, 2023 to Jan 1, 2024, 30 patients were enrolled, among which, 26 patients have received NAIC followed by surgery. The MPR rate was 65.4% (17/26), including a 34.6% (9/26) pathological complete response. Patients with PD-L1 (Combined Positive Score) ≥ 1 had higher MPR (80.0%, 16/20) than those with PD-L1 < 1 (16.7%, 1/6). NAIC was well-tolerated, without adverse effects on subsequent surgery, only two patients experienced grade 3 or 4 adverse events during NAIC, including one with grade 4 neutropenia (3.8%), and one with grade 3 thrombocytopenia (3.8%). The ORR was 80.8% (21/26), with 15.4% (4/26) complete response, 65.4% (17/26) partial response, and with no cases of progressive disease observed. The mean cell diameters of the whole tumor were calculated based on the OGSE sequences, twenty patients completed the OGSE scaning pre- and post-NAIC treatment. Pearson correlation analyses found that small post-NAIC mean cell diameter significantly related with fewer %RVT ( p = 0.026), supporting its potential as new radiomic predictors of NAIC efficacy. Among patients with MPR, the cell diameters were significantly decreased after NAIC, with a mean cell diameter of 18.87 ± 2.49 μm and 14.77 ± 1.85 μm for pre- and post-NAIC tumor, respectively ( p = 0.001). Conclusions: Camrelizumab combined with albumin paclitaxel/cisplatin as NAIC for LAOSCC demonstrates promising MPR and well safety. Mean cell diameter of tumor, derived from OGSE sequences, emerges as a potential new radiomic marker for predicting NAIC efficacy. Ongoing follow-ups on long-term survival and the development of a bio-radiomic prediction model integrating pathological features with OGSE data are underway. Clinical trial information: ChiCTR2200066119.

The use of adjuvant chemotherapy combined with concurrent chemoradiotherapy enhances survival rates in cases of locally advanced nasopharyngeal carcinoma.

This study aimed to evaluate the impact of adjuvant chemotherapy on survival rates, adverse events, and quality of life (QOL) in patients with locally advanced nasopharyngeal carcinoma (NPC). A retrospective cohort study was conducted, including patients with firstly histologically confirmed non-metastatic stage III-IVB NPC between February 2018 and February 2020, and with continuous follow-up data available, were chosen from the medical records of the affiliated hospital of Qingdao University and Zibo Central Hospital. There were 395 patients receiving concurrent chemoradiotherapy (CCRT) with adjuvant chemotherapy (adjuvant chemotherapy group) and 428 patients receiving CCRT alone (control group). The two groups were compared for treatment response, adverse events, and QOL scores. Besides, Kaplan-Meier plots, and multivariate COX analysis were conducted. The adjuvant chemotherapy group demonstrated a significantly higher overall survival and disease-free survival compared to the control group. The use of adjuvant chemotherapy was significantly correlated with improved overall survival and disease-free survival. Adjuvant chemotherapy was associated with reduced local recurrence and distant metastasis rates. However, higher rates of adverse events were observed in the adjuvant chemotherapy group. QOL scores for physical functioning, emotional functioning, and overall quality of life were higher in the adjuvant chemotherapy group. The findings of this study indicate that adjuvant chemotherapy in locally advanced NPC is associated with improved treatment response, extended overall and disease-free survivals, and better QOL, despite higher rates of adverse events.

Novel approach of prophylactic radiation to reduce toxicities comparing 2-step40 with 56-Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck, an intergroup phase III trial (JCOG1912, NEW BRIDGE)

BackgroundChemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN.MethodsThis study is a multicenter, two-arm, open-label, randomized phase III trial. Patients with LA-SCCHN excluding p16 positive oropharynx cancer are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m2 are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score.DiscussionIf the experimental arm is non-inferior to the standard arm in terms of TTF and superior on the safety endpoints, the 2-step40 procedure is the more useful treatment than SIB56 for definitive CRT.Trial registrationThis trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100 (https://jrct.niph.go.jp/latest-detail/jRCTs031210100). Date of Registration: May 2021.

Real-world study of patients with locally advanced HNSCC in the community oncology setting.

There is a need to understand the current treatment landscape for LA HNSCC in the real-world setting. This retrospective study assessed real-world outcomes and treatment patterns of 1,158 adult patients diagnosed with locally advanced (stage III-IVB) HNSCC initiating chemoradiotherapy (CRT) within the period January 2015 to December 2017 in a large network of US community oncology practices. Structured data were abstracted from electronic health records. Demographic, clinical and treatment characteristics were analyzed descriptively overall and stratified by index treatment (cisplatin + radiotherapy [RT], cisplatin + other chemotherapy + RT, or cetuximab + RT). Time to next treatment (TTNT) and overall survival (OS) were measured using the Kaplan-Meier method, and median duration of treatment was assessed. OS was compared across treatment cohorts using multinomial logistic regression with inverse probability treatment weighting. To identify covariates associated with OS, a multivariable adjusted Cox proportional hazard model was used. This study examined 22,782 records, of which 2124 had stage III to stage IVB and no other cancers, and 1158 met all eligibility criteria. Among the treatment cohorts analyzed (cisplatin + RT, cisplatin + other chemotherapy + RT, or cetuximab + RT), cisplatin + RT was the most common concurrent chemotherapy (65.8%). Among 1158 patients, 838 (72.4%) did not initiate subsequent treatment and 139 (12.0%) died. The median TTNT and median OS were only reached by the cetuximab + RT cohort. Among patients with oropharynx primary tumor location, patients with human papilloma virus (HPV) positive status had the longest time on treatment and highest survival at 60 months. Covariates associated with improved survival were never/former tobacco use, HPV positive status, and overweight or obese body mass index. Covariates associated with poorer survival were age of 60+ years, primary tumor location of hypopharynx or oral cavity and Eastern Cooperative Oncology Group performance status score of 2+. These data describe real-world treatment patterns in locally advanced head and neck squamous cell cancer and sets the baseline to assess outcomes for future studies on the community oncology population.

Reducing Target Volumes of Intensity Modulated Radiation Therapy After Induction Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: Long-Term Results of a Prospective, Multicenter, Randomized Trial

The objective of this study was to estimate the long-term survival, late toxicity profile, and quality of life of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated with combined induction chemotherapy (IC) and concurrent chemoradiotherapy from a clinical trial focused on reducing the target volume of intensity modulated radiation therapy (IMRT). This prospective, randomized clinical trial was conducted across 6 Chinese hospitals and included 212 patients with stage III-IVB NPC who were randomly allocated to a pre-IC or post-IC group. Eligible patients were treated with 2 cycles of IC+CCRT. All patients underwent radical IMRT. Gross tumor volumes of the nasopharynx were delineated according to pre-IC and post-IC tumor extent in the pre-IC and post-IC groups, respectively. After a median follow-up of 98.4 months, 32 of 97 (32.9%) and 33 of 115 (28.7%) patients experienced treatment failure or died in the pre-IC and post-IC groups, respectively. None of the patients developed grade 4 late toxicity. Late radiation-induced toxicity predominantly manifested as grade 1 to 2 subcutaneous fibrosis, hearing loss, tinnitus, and xerostomia, whereas grade 3 late toxicity included xerostomia and hearing loss. The 5-year estimated overall, progression-free, locoregional recurrence-free, and distant metastasis-free survival rates in the pre-IC and post-IC groups were 78.2% versus 83.3%, 72.0% versus 78.1%, 90.2% versus 93.5%, and 78.1% versus 82.1%, respectively. The pre-IC group had a significantly higher incidence of xerostomia and hearing damage than the post-IC group. In terms of quality of life, compared with the pre-IC group, the post-IC group showed significant improvement in cognitive function (P=.045) and symptoms including dry mouth (P=.004), sticky saliva (P=.047), and feeling ill (P=.041). After long-term follow-up, we confirmed that reducing the target volumes of IMRT after IC in locoregionally advanced NPC showed no inferiority in terms of the risk of locoregional relapse and potentially improved quality of life and alleviated late toxicity.

Tislelizumab plus chemotherapy as induction treatment followed by chemoradiotherapy or surgery in locally advanced hypopharyngeal squamous cell carcinoma: A single-arm, phase II trial.

6087 Background: Induction chemotherapy (ICT) followed by chemoradiotherapy (CRT) is the standard of care for locally advanced hypopharyngeal squamous cell carcinoma (LA HPSCC). We aimed to assess whether add immunotherapy to ICT further improving patient outcomes. Methods: In this phase II, single-arm study, eligible pts aged 18-70 yrs diagnosed with stage III-IVB (AJCC 8th) HPSCC received induction therapy with tislelizumab (200 mg), cisplatin (75 mg/m2) and nab-paclitaxel (260 mg/m2) Q3W for 3 cycles. After assessment by multidisciplinary team, pts received surgery or CRT. The primary endpoint was objective response rate (ORR). Secondary endpoints include major pathologic response (MPR) in surgery group, disease control rate (DCR), 2-yr PFS rate in CRT group and 2-yr DFS rate. Results: 29 pts were enrolled (median age, 61 y; 97% male; stage III/IVA/IVB, 7%/90%/3%) from May to Nov 2022. Median follow-up was 7.3 months, no disease progression occurred in all patients. For all pts, the post-induction ORR and DCR were 82% and 100%. In surgery group (n = 10), all pts achieved R0 resection, and 5 (50%) pts reached pathological complete response (pCR). A patient with stable disease underwent a total laryngectomy achieved pCR by postoperative pathologic evaluation. Grade 3 and 4 treatment-related adverse event (TRAE) reached 82.8%, and mainly come from chemotherapy-related neutropenia. There was no TRAE leading to treatment discontinuation. Conclusions: These early data suggested that tislelizumab plus chemotherapy as induction treatment followed by chemoradiotherapy or surgery was safe and had the potential to provide clinical benefits for patients in LA HPSCC. The inconsistency between radiographic and pathological evaluation needs further exploration. Further follow-up is needed to confirm the long-term efficacy. Clinical trial information: ChiCTR2200060094 .

Oral capecitabine or tegafur/gimeracil/oteracil as induction and adjuvant/maintenance chemotherapy in the management of stage III-IVb nasopharyngeal carcinoma: A systematic-review and meta-analysis.

e18000 Background: According to practice guidelines, concurrent chemoradiotherapy or induction chemotherapy with subsequent chemoradiotherapy is the recommended regimen for Stage III-IV NPCA. Unfortunately, local and distant recurrence continue to be primary reasons for treatment failure. To improve existing treatment regimens, replacing infusional 5-fluorouracil with oral fluoropyrimidine equivalents was suggested due to lower hazard of death and progression. In this meta-analysis we will be investigating the use of oral fluoropyrimidines, namely capecitabine and tegafur/gimeracil/oteracil, to elucidate their efficacy and effectiveness in Nasopharyngeal Carcinoma (NPCA) compared to standard chemotherapy regimens. Methods: A literature search of PubMed, Cochrane CENTRAL, and ClinicalTrials.gov was done in compliance with the PRISMA-P guidelines. After screening 908 records and selecting 32 articles for full-text assessment, 29 articles were included in the systematic-review and 15 in the meta-analysis. Outcomes were assessed for quality of evidence using a modified GRADE criteria. Overall Survival (OS) was assessed as the primary endpoint. Secondary outcomes were Progression Free Survival (PFS), Disease Free Survival (DFS), Distant Metastasis Free Survival (DMFS) and Locoregional Recurrence Free Survival (LRFS). Risk Ratio (RR) was used as the measure of association for all outcomes. Significance was assessed using p-values and I2 for the presence of heterogeneity. All pooled outcomes were assessed with 95% confidence intervals (CI). Statistical analysis was done using Stata and Review Manager 5. Results: The PFS RR of the adjuvant/maintenance group and induction group, respectively, were 0.53 [95%CI 0.38, 0.72]; I2 = 41% (p < 0.001) and 0.59 [95%CI 0.37, 0.95]; I2 = 0% (p = 0.03). DFS, LRFS, and DMFS of the adjuvant/maintenance group were 0.61 [95%CI 0.44, 0.83]; I2 = 0% (p = 0.002), 0.48 [95%CI 0.28, 0.83]; I2 = 0% (p = 0.008) and 0.67 [95%CI 0.44, 1.01]; I2 = 0% (p = 0.06), respectively. The induction group's LRFS and DMFS, respectively, were 0.55 [95%CI 0.37, 0.82] (p = 0.004); I2 = 0% and 0.60 [95%CI 0.40, 0.91]; I2 = 25% (p = 0.02). The OS for the adjuvant and induction group were 0.51 [95%CI 0.38, 0.69]; I2 = 21% (p < 0.001) and 0.72 [95%CI 0.52, 1.00]; I2 = 14% (p = 0.05), respectively. Conclusions: Based on “Low to Moderate” levels of evidence, induction oral fluoropyrimidine-containing regimens are associated with significantly higher 2-3 year PFS and 3-5 year LRFS as well as DMFS with equivalent 2-5 year OS in previously-untreated Stage III-IVB NPCA. Meanwhile, adjuvant/maintenance oral fluoropyrimidine-containing regimens lead to significantly higher 2-5 year OS and 3-5 year PFS, DFS, DMFS and LRFS compared to induction CCRT alone in previously-untreated Stage III-IVB NPCA.

Treatment patterns and clinical outcomes of newly diagnosed locally advanced head and neck squamous cell carcinoma (LA HNSCC): A retrospective cohort analysis of national real-world data in England.

e18075 Background: LA HNSCC (stage III-IVb) is a potentially curable disease. However, many patients experience recurrence and metastasis, resulting in poorer prognoses. The multimodal approach to treating LA HNSCC makes the evaluation of treatment regimens difficult. This study aimed to describe the real-world treatment patterns, clinical outcomes and HCRU of LA HNSCC patients in England. Methods: This retrospective cohort study involved the use of data from the National Cancer Registration and Analysis Service databases (Cancer Registry, Systemic Anti-Cancer Therapy, Hospital Episode Statistics [HES], National Radiotherapy Dataset and Diagnostic Imaging Dataset). Adults with a first record of primary LA HNSCC between 01/01/2015 and 31/12/2018 were indexed. Treatment pathways and clinical outcomes were investigated over a maximum of 5-years follow-up period extending to 31st December 2020. Results: 12,790 patients were included within the cohort. 52.1% (n = 6,665) received chemotherapy at some point during follow-up as part of their combination treatment with surgery and/or radiotherapy. Within the chemotherapy receiving cohort, 21.2% (n = 1,413) received induction chemotherapy prior to surgery or radiotherapy, 92.2% (n = 6,145) received concurrent chemo-radiotherapy and 11.8% (n = 787) received chemotherapy following surgery or radiotherapy, suggesting palliative treatment. The majority of chemotherapy regimens used were platinum-based. Of those receiving surgery (n = 5,292), the most common type of surgery was transoral surgery, occurring in 51.3% of the resectable patients. 40.2% of the overall cohort received salvage surgery during follow-up. 50.1% and 12.4% of patients experienced locoregional or distant metastatic progression, respectively and 39.2% of the cohort died. The 5-year overall survival (OS) was ~59% and ~55% for resected and unresected patients respectively. For event free survival (EFS), the 5-year median survival time post event free state index for the overall cohort was 12.32 months. Median survival time for the different tumour sites ranged from 19.4 and 2.6 months, with the nasopharynx and ‘other’ site group representing these range ends respectively. The highest HCRU/costs were incurred within the first 3 months following diagnosis; mean number of HNSCC-related inpatient stays were 2.93 (SD = 4.05), costing a total of £57,781,497 (per patient: £4,855.18 [£5872.05], mean[SD]). Conclusions: This is the first real world study using the UK NCRAS datasets to assess the treatment pathway and outcomes of the LA HNSCC population in England. Survival outcomes varied across site of primary tumour and patients diagnosed at stage 4 experienced poorer outcomes, highlighting the need for improved treatment plans and clinical outcomes for this patient population.

Neoadjuvant camrelizumab plus chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: A single-arm, phase II trial.

e18057 Background: Anti-programmed death receptor-1 (PD-1) agents improve survival in patients with recurrent or metastatic nasopharyngeal carcinoma (NPC), but have not been studied well in patients with locoregionally advanced NPC. In this study, we investigated the efficacy and safety of the PD-1 inhibitor camrelizumab combined with gemcitabine and cisplatin as neoadjuvant therapy in patients with locoregionally advanced NPC. Methods: This was a single-arm, single-center, phase II trial done at the First Affiliated Hospital of University of Science and Technology of China. Patients with previously untreated, stage III-IVB (except T3N0-1; AJCC 8th) NPC, aged 18-70 years without severe comorbidities were enrolled. Eligible patients received neoadjuvant therapy with camrelizumab 200 mg on day 1, cisplatin 80 mg/m2 on day 1, and gemcitabine 1,000 mg/m2 on days 1 and 8 of each 21-day cycle for three cycles. The primary endpoints were overall response rate(ORR) per RECIST version 1.1 and safety. Biomarker analysis included programmed death-ligand 1 (PD-L1) expression using the tumor proportion score (TPS) and combined positive score (CPS; Dako 22C3 pharmDx assay). Results: Between January 2022 and January 2023, 14 patients were enrolled and treated. The median age was 55 years (range, 33-68), and 11 (78.6%) patients were males. Thirteen (92.9%) patients had baseline PD-L1 data: TPS ranged from 2% to 80% and CPS ranged from 5 to 90. Eight patients (61.5%) had PD-L1 TPS of higher than 20% and seven patients (53.8%) had PD-L1 CPS of higher than 50. The ORR was 92.9% (13 of 14), including one (7.14%) patient with complete response and 12 (85.7%) patients with partial response. The most common grade 3 treatment-related adverse events (TRAEs; Common Terminology Criteria for Adverse Events, version 5.0) during neoadjuvant treatment were anorexia (two of 14;16.7%) and nausea (two, 9.5%), and no grade 4 or 5 TRAEs occurred. The most common immune-related AEs were endocrinopathies (all grade 1; 50%). Conclusions: Neoadjuvant camrelizumab plus chemotherapy showed promising activity with a manageable safety profile for patients with locoregionally advanced NPC. Longer follow-up and larger studies are needed to further confirm the efficacy of this combination in this population. This trial was approved by the Ethics Office of the First Affiliated Hospital of the University of Science and Technology of China (2021 no98), and registered in the Chinese Clinical Trial Registry. Clinical trial information: ChiCTR2200057745 .

Weekly Adaptive Radiotherapy vs Standard Intensity-Modulated Radiotherapy for Improving Salivary Function in Patients With Head and Neck Cancer

Xerostomia is a major toxic effect associated with intensity-modulated radiotherapy (IMRT) for oropharyngeal cancers. To assess whether adaptive radiotherapy (ART) improves salivary function compared with IMRT in patients with head and neck cancer. This phase 3 randomized clinical trial was conducted in 11 French centers. Patients aged 18 to 75 years with stage III-IVB squamous cell oropharyngeal cancer treated with chemoradiotherapy were enrolled between July 5, 2013, and October 1, 2018. Data were analyzed from November 2021 to May 2022. The patients were randomly assigned (1:1) to receive standard IMRT (without replanning) or ART (systematic weekly replanning). The primary end point was the frequency of xerostomia, measured by stimulating salivary flow with paraffin. Secondary end points included salivary gland excretory function measured using technetium-99m pertechnetate scintigraphy, patient-reported outcomes (Eisbruch xerostomia-specific questionnaire and the MD Anderson Symptom Inventory for Head and Neck Cancer questionnaire), early and late toxic effects, disease control, and overall and cancer-specific survival. A total of 132 patients were randomized, and after 1 exclusion in the ART arm, 131 were analyzed: 66 in the ART arm (mean [SD] age at inclusion, 60 [8] years; 57 [86.4%] male) and 65 in the standard IMRT arm (mean [SD] age at inclusion, 60 [8] years; 57 [87.7%] male). The median follow-up was 26.4 months (IQR, 1.2-31.3 months). The mean (SD) salivary flow (paraffin) at 12 months was 630 (450) mg/min in the ART arm and 584 (464) mg/min in the standard arm (P = .64). The mean (SD) excretory function of the parotid gland at 12 months, measured by scintigraphy, improved in the ART arm (48% [17%]) compared with the standard arm (41% [17%]) (P = .02). The 2-year-overall survival was 76.9% (95% CI, 64.7%-85.4%) in both arms. This randomized clinical trial did not demonstrate a benefit of ART in decreasing xerostomia compared with standard IMRT. No significant differences were found in secondary end points except for parotid gland excretory function, as assessed by scintigraphy, or in survival rates. ClinicalTrials.gov Identifier: NCT01874587.

Postchemoradiotherapy systemic inflammation response index predicts treatment response and overall survival for patients with locally advanced nasopharyngeal cancer

To explore the clinical utility of the systemic inflammation response index (SIRI) in the prediction of patients with poor treatment response to concurrent chemoradiotherapy (CCRT) in locally advanced nasopharyngeal cancer (NPC). A total of 167 stage III-IVB (AJCC 7th edition) nasopharyngeal cancer patients who received CCRT were retrospectively collected. The SIRI was calculated using the following formula: SIRI=neutrophil count×monocyte count/lymphocyte count (109/L). The optimal cutoff values of the SIRI for noncomplete response were determined by receiver operating characteristic curve analysis. Logistic regression analyses were performed to identify factors predictive of treatment response. We used Cox proportional hazards models to identify predictors of survival. Multivariate logistic regression showed that only the posttreatment SIRI was independently associated with treatment response in locally advanced NPC. A posttreatment SIRI≥1.15 was a risk factor for developing an incomplete response after CCRT (odds ratio 3.10, 95% confidence interval (CI): 1.22-9.08, p=0.025). A posttreatment SIRI≥1.15 was also an independent negative predictor of progression-free survival (hazard ratio 2.38, 95% CI: 1.35-4.20, p=0.003) and overall survival (hazard ratio 2.13, 95% CI: 1.15-3.96, p=0.017). The posttreatment SIRI could be used to predict the treatment response and prognosis of locally advanced NPC.

Abstract 1005: LINE-1 hypomethylation is associated with poor outcomes in locoregionally advanced oropharyngeal cancer

Abstract Background: Currently, human papillomavirus (HPV) positivity represents a strong prognostic factor for both reduced risk of relapse and improved survival in patients with oropharyngeal squamous cell carcinoma (OPSCC). However, a subset of HPV-positive OPSCC patients still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse, are still lacking suitable prognostic biomarkers for clinical outcome. Here, we evaluated the prognostic value of LINE-1 methylation level in OPSCC patients, and further addressed the relationship between LINE-1 methylation status and p53 protein expression as well as genome-wide/gene-specific DNA methylation. Results: In this study, DNA was extracted from 163 formalin-fixed paraffin-embedded tissue samples retrospectively collected from stage III-IVB OPSCC patients managed with curative intent with up-front treatment. Quantitative methylation-specific PCR revealed that LINE-1 hypomethylation was directly associated with poor prognosis (5-year overall survival - OS: 28.1% for LINE-1 methylation<35% versus 69.1% for ≥55%; p<0.0001). When LINE-1 methylation was dichotomized as <55% vs. ≥55%, interaction with HPV16 emerged: compared with hypermethylated HPV-16 positive patients, subjects with hypomethylated HPV16-negative OPSCC reported an adjusted higher risk of death (HR: 4.83, 95% CI: 2.24-10.38) and progression (HR: 4.54, 95% CI: 2.18-9.48). Tumor protein p53 (TP53) gene is often mutated and overexpressed in HPV-negative OPSCC. Since p53 has been reported to repress LINE-1 promoter, we then analyzed the association between p53 protein expression and LINE-1 methylation levels. Following p53 immunohistochemistry, results indicated that among HPV16-negative patients with p53≥50%, LINE-1 methylation levels declined and remained stable at approximately 43%; any HPV16-positive patient reported p53≥50%. Finally, DNA methylation analysis demonstrated that genome-wide average methylation level at cytosine-phosphate-guanine sites was significantly lower in HPV16-negative OPSCC patients who relapsed within two years. The subsequent integrative analysis of gene expression and DNA methylation identified 20 up-regulated/hypomethylated genes in relapsed patients, and most of them contained LINE-1 elements in their promoter sequences. Conclusions: Evaluation of the methylation level of LINE-1 may help in identifying the subset of OPSCC patients with bad prognosis regardless of their HPV status. Aberrant LINE-1 hypomethylation might occur along with TP53 mutations, and lead to altered gene expression in OPSCC. Citation Format: Mariateresa Casarotto, Valentina Lupato, Giorgio Giurato, Roberto Guerrieri, Sandro Sulfaro, Annamaria Salvati, Elisa D'Angelo, Carlo Furlan, Anna Menegaldo, Lorena Baboci, Barbara Montico, Irene Turturici, Riccardo Dolcetti, Salvatore Romeo, Vittorio Baggio, Stefania Corrado, Gianluca Businello, Maria Guido, Alessandro Weisz, Vittorio Giacomarra, Giovanni Franchin, Agostino Steffan, Luca Sigalotti, Emanuela Vaccher, Paolo Boscolo-Rizzo, Jerry Polesel, Giuseppe Fanetti, Elisabetta Fratta. LINE-1 hypomethylation is associated with poor outcomes in locoregionally advanced oropharyngeal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1005.

Role of Sentinel Lymph Node Drainage Mapping for Localization of Contralateral Lymph Node Metastasis in Locally Advanced Oral Squamous Cell Carcinoma - A Prospective Pilot Study.

Sentinel lymph node biopsy (SLNB) has become the standard of care for nodal staging in early-stage oral squamous cell carcinoma (OSCC) as an alternative to elective neck dissection. However, the role of sentinel lymph node (SLN) and lymphatic drainage mapping with image-guided surgery has not been studied in locally advanced OSCC. Therefore, this study was undertaken to evaluate the role of lymphatic drainage mapping in the identification of contralateral cervical lymph node metastasis in locally advanced OSCC (Stage III-IVb). We have prospectively analyzed treatment-naïve patients of locally advanced, lateralized OSCC (n = 20). All patients underwent SLN imaging using peritumoral injection 0.5-1.0 mCi of 99 mTc-Sulfur colloid (Filtered) and intraoperative identification of contralateral neck nodes using a handheld gamma probe (Crystal Photonics). A total of 20 patients (18 males and 2 females) with a median age of 52.5 (33-70 years) were included. Ipsilateral SLN was localized in 18 (90%) patients. Bilateral cervical nodes were visualized only in 7 (35%) patients on lymphoscintigraphy (LSG). Out of the seven patients, 5 patients underwent bilateral neck dissection and 2 patients had unilateral neck dissection with LSG-guided exploration of contralateral cervical node and intraoperative frozen section examination. Six out of these seven patients had one or other risk factor for contralateral metastasis (patients had either primary in the tongue, involvement of floor of mouth, or tumor thickness >3.75 mm). On postoperative HPE, only 1/20 (5%) patient showed metastasis in the contralateral cervical lymph node. Correct identification of metastatic disease in contralateral neck directly influences clinical management, as it can reduce contralateral neck failure rate and limit the morbidity associated with unnecessary contralateral neck dissection, and it is also crucial in radiotherapy planning in locally advanced OSCC. In the current study, lymphatic drainage mapping showed a metastatic rate of 5% in the contralateral neck nodes in locally advanced, lateralized OSCC. However, the role of SLNB and lymphatic drainage mapping in this subgroup of OSCC needs to be studied in larger population to validate these findings.