Immunotherapy and Biomarkers in Sarcoma.

OPINION STATEMENT: Sarcoma describes a rare and heterogeneous group of diseases. Current treatment options for metastatic sarcoma are quite limited. Conventional treatments with chemotherapy or anti-angiogenic agents result in a non-durable response and a survival rate of approximately 12 to 18 months. In addition, the benefits of such treatments remain limited in some sarcoma subtypes only. Immunotherapy is an emerging treatment for several cancer types with promising outcomes. Studies at the cellular level have shown a relatively high immunogenicity in some subtypes of sarcoma. It is therefore hypothesized that sarcoma may respond to immunotherapy. However, sarcoma is a heterogeneous disease and differences in terms of immunogenicity exist. A multitude of immune-based treatment approaches for sarcoma have been explored. This includes immune checkpoint inhibitors, therapeutic vaccines, and adoptive cell therapy. Single-agent immunotherapy has exhibited efficacy against some sarcoma subtypes, including alveolar soft-part sarcoma, angiosarcoma, and undifferentiated pleomorphic sarcoma. Combination immunotherapy appears superior to single-agent immunotherapy in terms of response, and several ongoing studies of immunotherapy using single/combination immune checkpoint inhibitors and combination with anti-angiogenesis have begun to report beneficial results. Predictive and prognostic biomarkers are also under active investigations, with particular interest in tumor-infiltrating lymphocytes or high tumor mutational burden levels. However, the information is still limited and further studies are needed.

Benefits of prophylactic percutaneous gastrostomy in patients with nasopharyngeal cancer receiving concurrent chemoradiotherapy: A multicenter analysis.

PURPOSE: Prophylactic percutaneous endoscopic gastrostomy (PPEG) is widely used for patients with head and neck cancer undergoing concurrent chemoradiation (CCRT). Nevertheless, the necessity of its use in patients with nasopharyngeal cancer (NPC) is uncertain. This study aimed to evaluate the benefits of PPEG on prevention of weight loss and treatment tolerance in patients with NPC receiving CCRT. MATERIALS AND METHODS: A retrospective multicenter chart review of 904 patients, 378 in the PPEG group and 526 in the non-PPEG group, was conducted. Baseline characteristics, weight loss, and treatment tolerance were analyzed and compared between the two groups. RESULTS: There was no significant difference in the mean baseline body mass index (BMI) between the groups. At the end of CCRT, no difference in weight loss was found between the 2 groups (non-PPEG group, 6.6%; PPEG group, 5.9%). Nonetheless, the subgroup analysis demonstrated that a baseline BMI < 18.5 kg/m2 (underweight) and non-intensity-modulated radiation therapy (IMRT) technique were independent factors associated with prevention of weight loss by PPEG. More patients in the PPEG group were able to complete planned cycles of chemotherapy (73.3% vs. 49.0%, P < .0001). CONCLUSION: Although the benefits of PPEG on prevention of weight loss were not observed for the entire cohort, we found a potentially protective effect of PPEG in some subgroups of patients. Additionally, PPEG significantly enhanced chemotherapy tolerance. Therefore, PPEG tube insertion should be strongly considered for patients with NPC receiving CCRT, particularly for underweight patients and those undergoing a non-IMRT technique.

Plasma extracellular vesicle microRNA-491-5p as diagnostic and prognostic marker for head and neck squamous cell carcinoma.

Poor survival of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is partly due to early diagnosis difficulties and the lack of reliable biomarkers for predicting treatment outcomes. In the discovery cohort, plasma-derived extracellular vesicles (EVs) from LA-HNSCC patients (n = 48) and healthy volunteers (n = 12) were used for profiling for microRNA (miRNA) expression by NanoString analysis. Ten EV-associated miRNAs were differentially expressed between LA-HNSCC patients and healthy volunteers. Subsequently, the results were validated in the individual discovery and additional cases (HNSCC, n = 73; control, n = 20) by quantitative RT-PCR. Among 10 EV-miRNAs, four (miR-27b-3p, miR-491-5p, miR-1910-5p, and miR-630) were significantly dysregulated in LA-HNSCC patients (n = 73) compared with healthy volunteers (n = 20). The miRNA prediction models were developed to discriminate HNSCC patients from healthy volunteers. The model using miR-491-5p was selected as a diagnostic biomarker for LA-HNSCC with a sensitivity and specificity of 46.6% and 100%, respectively (P < .001). The dynamic changes of miRNA model score (ΔmiRNAs) were determined using scores pre- and postdefinitive treatment to further investigate the prognostic value of miRNA prediction models. The univariate and multivariate analyses indicated that ΔmiR-491-5p was the most powerful and independent prognostic indicator for overall survival (hazard ratio [HR] 5.66, 95% confidence interval, 1.77-18.01; P = .003) and disease-free survival (HR 2.82, 95% CI, 1.13-7.05; P = .027) of HNSCC patients. In summary, the miR-491-5p prediction model could serve as a blood-based diagnostic marker for LA-HNSCC. Moreover, ΔmiR-491-5p could be a potential monitoring prognostic marker to reflect the survival of HNSCC patients.

Patterns and outcomes of immune-related adverse events in solid tumor patients treated with immune checkpoint inhibitors in Thailand: a multicenter analysis.

BACKGROUND: Most immune-related adverse event (irAE) patterns and treatment guidelines are based on western clinical data. We evaluated the incidence and patterns of irAEs in patients treated with immune-checkpoint inhibitors (ICI) in Thailand. METHODS: All solid tumor patients treated with ICIs were retrospectively reviewed in a multicenter analysis. The study aims to evaluate the incidence of irAEs and their characteristics, treatments, outcomes, and impact on survival. All irAEs were graded using the CTCAE version 4.0. Characteristics of irAEs including time to onset, duration of irAEs, specific treatments, and outcomes of irAEs were reviewed. The Chi-square or Fisher's exact test was used to compare variables. Overall survival (OS) was estimated by the Kaplan-Meier method, and compared by the log-rank test. A p-value < 0.05 was considered statistically significant. RESULTS: irAEs of any grade were observed in 98 of 414 patients (24%), whereas grades 3-4 irAEs were observed in 5.6%. The majority of patients (78%) were treated with monotherapy ICI (anti-PD1/PD-L1 92%). The most common all-grade irAEs were hypothyroidism (7.5%), hepatitis (6.5%), and rash (4.8%). Median onset of overall irAEs was 63 days. Pancreatitis and pneumonitis had the earliest onset at 30 and 34 days, respectively. ICIs were rechallenged in 68 of 98 patients with irAE. Eleven of sixty-eight patients (11.2%) with initial irAE had reoccurrence after ICI rechallenge. Based on a multivariate analysis, pre-existing hypothyroidism, ICI used in a clinical trial setting, and combinations of ICI/ICI were independent factors predicting irAE occurrence. Patients with irAE had a statistically significant longer overall survival (OS) when compared to patients without irAE (p = 0.019). A multivariate analysis revealed that occurrence of irAE was an independent prognostic factor for OS (HR 0.70, 95% CI 0.51-0.96; p = 0.028). CONCLUSION: irAE was commonly observed in Thai cancer patients treated with ICIs. Most irAEs were low-grade and manageable. Re-occurrence of irAE after re-challenging ICI was not uncommonly observed. Patients who experienced irAEs might have significantly longer OS compared to patients without irAEs. However, OS in this study should be interpreted with caution since it might be affected by various tumor types, treatment settings, dosing schedule, and ICI combinations.

Discrepancy in p16 expression in patients with HPV-associated head and neck squamous cell carcinoma in Thailand: clinical characteristics and survival outcomes.

BACKGROUND: Lower prevalence HPV infection has been previously reported in Thai population when compared with Western countries. p16 expression indicates HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), but not non-OPSCC. We therefore evaluated the characteristic and association of p16 and HPV in Thai patients with HNSCC. METHODS: We used immunohistochemistry and qPCR, respectively, to detect p16 and HPV DNA in archrival formalin-fixed paraffin-embedded HNSCC tissues. Patient characteristics and survival were analyzed. RESULTS: p16 expression was detected in tumors of 72 of 662 (10.9%) patients with HNSCC and was significantly associated with higher-grade histology, advanced nodal stage, and oropharynx. p16 was expressed in 28 and 6.5% of patients with OPSCC or non-OPSCC, respectively, and HPV DNA was detected in 15.6 and 1% of patients, respectively. Using p16 as a surrogate for HPV status, sensitivities were 80 and 25% in OPSCC and non-OPSCC, respectively. Positive and negative predictive rates of OPSCC were 38 and 95%. Discordance rates between HPV and p16 were 23 and 7% in OPSCC and non-OPSCC, respectively. Overall survival (OS) were significantly longer in both p16-positive OPSCC (p = 0.049), and non-OPSCC (p = 0.003). CONCLUSIONS: Low prevalence of p16 and HPV associated OPSCC and non-OPSCC were confirmed in Thai patients. High discordance and low positive predictive rates of p16 were observed in HPV-associated OPSCC. p16 was a significant prognostic factor for OS for patients with OPSCC or non-OPSCC. Therefore, HPV testing should be performed to assess the association of HPV with HNSCC regardless of p16 expression.

Risk and impact of delayed renal impairment in patients with locally advanced head and neck squamous cell carcinoma receiving chemoradiotherapy with cisplatin.

BACKGROUND: An incidence of cisplatin-induced acute kidney injury (AKI) of 34% has been reported in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, delayed cisplatin-induced nephrotoxicity and long-term renal outcomes remain poorly studied. METHODS: Patients with LA-HNSCC who underwent definitive or postoperative cisplatin-based chemoradiotherapy (CRT) were included. Acute kidney disease (AKD) was defined as newly developed estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 for < 3 months, ≥ 35% decrease in eGFR, or > 50% increase in serum creatinine for <3 months from baseline. RESULTS: A total of 509 patients were analyzed. AKD and AKI occurred in 27.9% and 13.4% of patients, respectively. Most patients had primary prophylactic feeding tube (95%) and definitive CRT (83%). More AKD patients had an ECOG status of 0 (p = 0.017), diabetes (p = 0.044), and hypertension (p < 0.001). AKI, but not AKD, was significantly associated with cumulative cisplatin dose, delay, dose reduction, termination, and hospitalization during CRT. GFR percentage in patients with AKD declined significantly during CRT (- 36%), worsened at 3 months (- 39%), and had not recovered to baseline at 12 months after CRT (- 29%). Multivariate analysis identified ECOG status 0 and hypertension as significantly associated with the development of AKD. CONCLUSION: Almost one third of LA-HNSCC patients who underwent CRT with cisplatin developed AKD, and their eGFR did not recover to baseline even after 1 year. ECOG 0 and hypertension were associated with AKD. These findings may have been due to the physician's awareness of AKD and underestimation of its potential complications in fit patients.

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study.

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response. METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031. FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], p<0·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group. INTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC. FUNDING: Merck Sharp & Dohme.

Optimal cumulative dose of cisplatin for concurrent chemoradiotherapy among patients with non-metastatic nasopharyngeal carcinoma: a multicenter analysis in Thailand.

BACKGROUND: Chemoradiotherapy (CRT) with high cumulative doses (CDs) of cisplatin has been considered the standard of care for non-metastatic nasopharyngeal carcinoma (NPC). However, given most patients' inability to tolerate high CDs due to cisplatin-related toxicities, the optimal CD of cisplatin during CRT remains undetermined. METHODS: Patients with non-metastatic NPC who received CRT with cisplatin between 2007 and 2017 were identified through the Thai head and neck cancer multicenter database and then categorized according to cisplatin CD (mg/m2) received. All complications and cisplatin-related toxicities during CRT were recorded. RESULTS: We identified 779 non-metastatic NPC patients receiving low (≤150; n = 97), intermediate (151-250; n = 411), and high (> 250; n = 271) CDs of cisplatin. Low CD patients had significantly lower mean actual radiation dose (p < 0.001) and more radiotherapy delay (p = 0.010), while intermediate CD patients had the least hospitalization (p < 0.001). Overall, 39.3% of the patients experienced cisplatin-related toxicity, which was associated with poor overall survival (OS) (p = 0.001). Acute kidney injury was observed in 7% in all patients, which was highest among low CD patients (15.5%; p = 0.002). Intermediate CD patients had significantly longer median OS than the low and high groups (64 vs. 49.8 vs. 53.2, respectively; p = 0.015). Univariate, but not multivariate, analysis showed that CD of cisplatin was significantly associated with OS. CONCLUSION: CD of cisplatin during CRT was not an independent prognostic factor for OS. An intermediate CD induced minimal toxicity without compromising survival and should be considered the optimal CD. Nonetheless, a randomized phase 3 study evaluating the optimal CD of cisplatin is warranted.

Phase II, multi-center, open-label, single-arm clinical trial evaluating the efficacy and safety of Mycophenolate Mofetil in patients with high-grade locally advanced or metastatic osteosarcoma (ESMMO): rationale and design of the ESMMO trial.

BACKGROUND: Clinical outcomes of patients with osteosarcoma remain unsatisfactory, with little improvement in a 5-year overall survival over the past three decades. There is a substantial need for further research and development to identify and develop more efficacious agents/regimens in order to improve clinical outcomes of patients for whom the prognosis is unfavorable. Recently, mycophenolate mofetil, a prodrug of mycophenolic acid, has been found to have anticancer activity against osteosarcoma in both in vitro and animal experiments, so that further investigation in humans is warranted. METHODS: A total of 27 patients with high-grade locally advanced or metastatic osteosarcoma will be enrolled into this phase II, multi-center, open-label, single-arm, two-stage clinical trial. The main objectives of this study are to determine the efficacy and safety of mycophenolate mofetil in the patients. The primary endpoint is progression-free survival at 16 weeks; the secondary endpoints include progression-free survival, overall survival, overall response rate, safety parameters, pharmacokinetic parameters, biomarkers, pain score, and quality of life. Mycophenolate mofetil at the initial dose of 5 g/day or lower will be administered for 4 cycles (28 days/cycle) or until disease progression or unacceptable toxicity. The dose of mycophenolate mofetil may be reduced by 1-2 g/day or withheld for some Grade 3 or Grade 4 toxicities whenever clinically needed. The duration of study participation is approximately 4-5 months, with a minimum of 12 study visits. If mycophenolate mofetil proves beneficial to some patients, as evidenced by stable disease or partial response at 16 weeks, administration of mycophenolate mofetil will continue in the extension period. DISCUSSION: This trial is the first step in the translation of therapeutic potential of mycophenolate mofetil emerging from in vitro and animal studies into the clinical domain. It is designed to assess the efficacy and safety of mycophenolate mofetil in patients with high-grade locally advanced or metastatic osteosarcoma. The results will provide important information about whether or not mycophenolate mofetil is worth further development. TRIAL REGISTRATION: This trial was prospectively registered on Thai Clinical Trials Registry (registration number: TCTR20190701001). The posted information will be updated as needed to reflect protocol amendments and study progress.

Oncoproteomic and gene expression analyses identify prognostic biomarkers for second primary malignancy in patients with head and neck squamous cell carcinoma.

Patients with head and neck squamous cell carcinoma are at increased risk of developing a second primary malignancy, which is associated with poor prognosis and early death. To help improve clinical outcome, we aimed to identify biomarkers for second primary malignancy risk prediction using the routinely obtained formalin-fixed paraffin-embedded tissues of the index head and neck cancer. Liquid chromatography-tandem mass spectrometry was initially performed for candidate biomarker discovery in 16 pairs of primary cancer tissues and their matched normal mucosal epithelia from head and neck squamous cell carcinoma patients with or without second primary malignancy. The 32 candidate proteins differentially expressed between head and neck cancers with and without second primary malignancy were identified. Among these, 30 selected candidates and seven more from literature review were further studied using NanoString nCounter gene expression assay in an independent cohort of 49 head and neck cancer patients. Focusing on the p16-negative cases, we showed that a multivariate logistic regression model comprising the expression levels of ITPR3, KMT2D, EMILIN1, and the patient's age can accurately predict second primary malignancy occurrence with 88% sensitivity and 75% specificity. Furthermore, using Cox proportional hazards regression analysis and survival analysis, high expression levels of ITPR3 and DSG3 were found to be significantly associated with shorter time to second primary malignancy development (log-rank test P = 0.017). In summary, we identified a set of genes whose expressions may serve as the prognostic biomarkers for second primary malignancy occurrence in head and neck squamous cell carcinomas. In combination with the histopathologic examination of index tumor, these biomarkers can be used to guide the optimum frequency of second primary malignancy surveillance, which may lead to early diagnosis and better survival outcome.

Bridging the gap between clinicians and systems biologists: from network biology to translational biomedical research.

With the wealth of data accumulated from completely sequenced genomes and other high-throughput experiments, global studies of biological systems, by simultaneously investigating multiple biological entities (e.g. genes, transcripts, proteins), has become a routine. Network representation is frequently used to capture the presence of these molecules as well as their relationship. Network biology has been widely used in molecular biology and genetics, where several network properties have been shown to be functionally important. Here, we discuss how such methodology can be useful to translational biomedical research, where scientists traditionally focus on one or a small set of genes, diseases, and drug candidates at any one time. We first give an overview of network representation frequently used in biology: what nodes and edges represent, and review its application in preclinical research to date. Using cancer as an example, we review how network biology can facilitate system-wide approaches to identify targeted small molecule inhibitors. These types of inhibitors have the potential to be more specific, resulting in high efficacy treatments with less side effects, compared to the conventional treatments such as chemotherapy. Global analysis may provide better insight into the overall picture of human diseases, as well as identify previously overlooked problems, leading to rapid advances in medicine. From the clinicians' point of view, it is necessary to bridge the gap between theoretical network biology and practical biomedical research, in order to improve the diagnosis, prevention, and treatment of the world's major diseases.

A phase I study of the histone deacetylase (HDAC) inhibitor entinostat, in combination with sorafenib in patients with advanced solid tumors.

Based on preclinical data demonstrating cytotoxic synergy between sorafenib and entinostat, a phase I study of this combination was conducted in patients with advanced solid tumors. Enrollment followed the traditional "3 + 3" dose escalation scheme. Entinostat was given orally once every 2 weeks, starting at a dose of 4 mg and escalating to 6 and 10 mg every 2 weeks. Sorafenib was administered as a continuous oral dose, escalating from 200 to 400 mg twice daily. A treatment cycle was 28 days. A total of 31 patients with advanced solid tumors were enrolled on the study. The three dose-limiting toxicities (DLTs) observed were grade 3 hand-foot syndrome, nausea/vomiting, and fatigue. MTD was not reached. The recommended phase II dose was defined as the full dose of the respective drugs administered individually. The most common grade 3-4 toxicities were muscle weakness (13 %), skin rash (10 %), fatigue (6 %), diarrhea (6 %), and hand-foot syndrome (3 %). One NSCLC patient achieved a partial response. Two patients (adenocarcinoma of GE junction and Hurthle cell carcinoma of the thyroid) were on the study for more than 9 months with stable disease. The combination of entinostat and sorafenib was well tolerated. Entinostat 10 mg orally once every 2 weeks in combination with sorafenib 400 mg orally twice daily, representing full single agent doses of each drug was identified as the recommended phase 2 dose (RP2D). These data support future clinical development of the combination of entinostat and sorafenib.

Early recurrence, time-to-recurrence, and recurrence patterns: Assessing their impact on survival outcomes in head and neck squamous cell carcinoma (R/M-HNSCC) patients treated with first line platinum-based chemotherapy.

BACKGROUND: R/M-HNSCC patients typically receive 1L platinum-based chemotherapy with pembrolizumab or cetuximab. However, the outcomes for patients with early recurrence (<6 months) remain unclear due to their exclusion from most 1L studies. This study aimed to assess the impact of time-to-recurrence intervals (TTRI) and recurrence patterns on the survival of R/M-HNSCC patients. METHODS: We identified non-curable R/M-HNSCC patients at our institution from 1/2008 through 6/2020. We analyzed the outcomes of early recurrent patients who received 1L systemic treatment, with different TTRIs and recurrence patterns. RESULTS: Our study included 234 eligible patients. The majority (47%) experienced early recurrence (<6 months), while 22%, 20%, and 11% had recurrences at 6-12 months, >12 months, and de novo metastasis, respectively. The platinum-based regimen was the most commonly used chemotherapy (86%), with cetuximab and immunotherapy utilized in 3% and 5% of cases, respectively. Significant differences in PFS and OS were observed among TTRI groups. For patients with early recurrence, both platinum-doublet and monotherapy treatments significantly improved OS. Locoregional recurrence (47%) was the most common, followed by distant metastasis (22%) and both (20%). Recurrence patterns were significantly associated with OS but not with PFS. In multivariate analysis, TTRI ≥12 months significantly correlated with improved PFS (HR 0.51; p = 0.004) and OS (HR 0.58; p = 0.009), whereas recurrent pattern did not. CONCLUSION: TTRI significantly influenced the survival, while recurrence patterns did not. In our study, the retrospective design limited our ability to definitively establish whether early recurrent R/M-HNSCC patients would benefit more from platinum-doublet. Despite poor prognosis, early recurrent patients benefited from 1L systemic treatments. Given the variation in prognoses, TTRI should be considered a stratification factor in future clinical trials.

Development and Internal Validation of a Prediction Model for Nasopharyngeal Carcinoma: Using BMI and Inflammatory Response for Deciding Sequence of Chemotherapy.

PURPOSE: Concurrent chemoradiotherapy followed by adjuvant chemotherapy (CRT-AC) and induction chemotherapy followed by concurrent chemoradiotherapy (IC-CRT) are among the best treatments in nasopharyngeal carcinoma (NPC). This study aimed to develop a model for deciding the sequence of chemotherapy in NPC. METHODS: Data were separated into two cohorts. The CRT-AC cohort had 295 patients, while the IC-CRT cohort had 112. The predictors were standard factors with BMI and neutrophil-lymphocyte ratio (NLR) to predict overall survival (OS). A flexible parametric survival model was used. RESULTS: A total of 132 (44.7%) and 72 patients (64.3%) died in the CRT-AC and IC-CRT cohorts, respectively. The predictors in the final models were age, sex, T, N, NLR, and BMI. The models of OS for CRT-AC and IC-CRT had concordance indices of 0.689 and 0.712, respectively, with good calibration curves. When changing the burden of disease along with NLR and BMI, we found that CRT-AC was not significantly different OS from IC-CRT when low NLR (<3) and high burden of disease (T3N3). By contrast, CRT-AC was remarkably more effective when there were high levels of NLR (≥3) and BMI (≥25) with any burden of disease (anyT anyN). CONCLUSION: With additional BMI and NLR in model, it could be easier to decide between CRT-AC and IC-CRT in countries with limited health care resources.

A Phase I Study of the CDK4/6 Inhibitor Palbociclib in Combination with Cetuximab and Radiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma.

PURPOSE: Palbociclib, a cyclin D kinase 4 (CDK4)/6 inhibitor, has shown radiosensitizing effects in preclinical studies. There is a strong rationale for adding palbociclib to cetuximab and radiotherapy in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), especially in p16-negative HNSCC. PATIENTS AND METHODS: We conducted a phase I dose-escalation study (NCT03024489) using a classical 3+3 design to determine safety, tolerability, and MTD of palbociclib, cetuximab, and intensity-modulated radiotherapy (IMRT) combination. At the recommended phase II dose (RP2D), additional p16-negative patients were enrolled. RESULTS: Twenty-seven patients with LA-HNSCC (13 in dose escalation, 14 in expansion) with oropharyngeal (41%) and hypopharyngeal (30%) cancers were enrolled. The MTD was not reached, and the RP2D of palbociclib was established at the full standard palbociclib dose of 125 mg/day for 21 days per cycle, administered for two cycles during IMRT. The most common grade 3-4 toxicities were mucositis (59%), radiation dermatitis (22%), and neutropenia (22%), with a febrile neutropenia rate of 7%. Common genomic alterations included mutations in TP53 (57%), GNAQ (35%), and PIK3CA (17%), and copy-number gains in CCND1 (22%), CCND2 (9%), and EGFR (9%). Overall, p16 expression was positive in 15% of patients. No correlation was observed between p16 status, genomic alterations, and preliminary efficacy. The objective response rate was 84%. The rates for 2-year locoregional control, event-free survival, and overall survival were 73%, 48%, and 71%, respectively. CONCLUSIONS: The palbociclib, cetuximab, and IMRT combination was well tolerated. The RP2D was established, while no MTD was determined. The regimen demonstrated promising preliminary efficacy, suggesting further investigation is warranted in patients with cisplatin-ineligible p16/human papilloma virus-unrelated LA-HNSCC.

Evolving role of novel radiosensitizers and immune checkpoint inhibitors in (chemo)radiotherapy of locally advanced head and neck squamous cell carcinoma.

Chemoradiotherapy (CRT) remains the standard treatment for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), based on numerous randomized controlled trials and meta-analyses demonstrating that CRT improved locoregional control and overall survival. Achieving locoregional control is a crucial outcome for the treatment of HNSCC, as it directly affects patient quality of life and survival. Cisplatin is the recommended standard-of-care radiosensitizing agent for LA-HNSCC patients undergoing CRT, whereas cetuximab-radiotherapy is reserved for cisplatin-ineligible patients. Immune checkpoint inhibitors (ICIs) have shown promise in the treatment of recurrent or metastatic HNSCC. However, the combination of ICIs with standard-of-care radiotherapy or chemoradiotherapy in LA-HNSCC has not demonstrated significant improvement in survivals. Over the past few decades, significant advancements in radiotherapy techniques have allowed for more precise and effective radiation delivery while minimizing toxicity to surrounding normal tissues. These advances have led to improved treatment outcomes and quality of life for patients with LA-HNSCC. Despite these advancements, the development of novel radiosensitizing agents remains an unmet need. This review discusses the mechanism of radiotherapy and its impact on the immune system. We summarize the latest clinical development of novel radiosensitizing agents, such as SMAC mimetics, DDR pathway inhibitors, and CDK4/6 inhibitor. We also elucidate the emerging evidence of combining ICIs with radiotherapy or chemoradiotherapy in curative settings for LA-HNSCC, using both concurrent and sequential approaches. Lastly, we discuss the future direction of systemic therapy in combination with radiotherapy in treatment for LA-HNSCC.

Predictive Factors for the Survival Outcomes of Preoperative Chemotherapy in Patients with Resectable and Borderline Resectable Colorectal Cancer with Liver Metastasis.

BACKGROUND: Preoperative chemotherapy increases resectability in borderline resectable colorectal liver metastasis (CRLM) patients who undergo curative liver surgery. Most clinical risk scores and other predictive factors for survival have been extensively studied in patients who undergo upfront liver surgery. However, predictive factors of CRLM patients who received preoperative chemotherapy remains controversial. METHODS: CRLM patients who received preoperative systemic therapy followed by curative liver surgery at our institution between 1/2012 and 12/2018 were included. This study aimed to investigate factors that predicted the outcomes of preoperative systemic treatment, optimal dose/duration, and toxicity in patients with CRLM. OUTCOMES: Ninety-eight patients were eligible for analysis. Most patients received oxaliplatin-based chemotherapy (72.7%), while 15.9% received both oxaliplatin and irinotecan. Biologic agents were administered in 48.9% of patients. Overall, chemotherapy-induced liver injury was observed in 38.5%. The median disease-free survival (DFS) and overall survival (OS) were 8.7 months and 3.6 years, respectively. Baseline, pre-surgery, and increased Fong scores after preoperative chemotherapy were significantly associated with DFS and OS. In multivariate analysis, a high Fong score at baseline (p=0.018) was significantly associated with shorter DFS, whereas male sex (p=0.040) and liver surgery (p=0.044) were related to longer OS. CONCLUSION: In our study, Fong clinical risk scores, female sex, and liver surgery as a part of liver-directed therapy were independent prognostic factors for survival in CRLM patients who received preoperative chemotherapy. These clinical factors should be considered as an option to guide physicians' decisions in selecting patients with CRLM who may benefit most from curative liver-directed therapy.

Real-world evidence of cisplatin versus carboplatin in patients with locally advanced nasopharyngeal carcinoma receiving concurrent chemoradiotherapy: A multicenter analysis.

BACKGROUND: Though concurrent chemoradiotherapy (CCRT) with cisplatin remains a standard of care for patients with locally advanced nasopharyngeal carcinoma (LA-NPC), carboplatin has alternatively been used without sufficient supportive evidences. Thus, we evaluated an efficacy and tolerability of carboplatin CCRT compared with cisplatin in LA-NPC patients. METHODS: Patients with LA-NPC treated with CCRT were identified through the Thai multicenter head and neck cancer database. Patient tolerability and survival were analyzed and compared between regimens. Survivals were calculated by using the Kaplan-Meier method, and compared by the log-rank test. A p-value of <0.05 was considered statistically significant. RESULTS: A total of 135 of 980 patients (13.8%) were treated with carboplatin. Patients treated with carboplatin were significantly associated with older age (p < 0.001), smoking (p = 0.003), more comorbidity (p = 0.014), kidney disease (p = 0.016), and lower baseline creatinine clearance (p < 0.001). Intensity-modulated radiation therapy was used significantly more in the cisplatin group than carboplatin group (p < 0.001). Patients who received carboplatin were associated with delay (p = 0.049) and hospitalization (p = 0.006), whereas cisplatin CCRT had more dose reduction (p = 0.001). Patients treated with cisplatin had CCRT interruption from grade 3-4 mucositis (p = 0.019) more than carboplatin, whereas carboplatin had more grade 3-4 thrombocytopenia (p < 0.001). The 5-year overall survival (OS) of patients treated with cisplatin and carboplatin was 59% and 49%, respectively (p = 0.128). Cisplatin or carboplatin CCRT was not a significant predictor for OS and locoregional recurrence-free survival in multivariate analysis. CONCLUSIONS: Carboplatin CCRT provided acceptable efficacy and tolerability profiles in real-world practice. Carboplatin should be considered as an alternative regimen, particularly in cisplatin-ineligible patients with LA-NPC treated with CCRT.

Six-MicroRNA Prognostic Signature in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma.

PURPOSE: MicroRNAs (miRNAs) have been evaluated as biomarkers in cancers. Therefore, we aimed to identify a prognostic miRNA signature from The Cancer Genome Atlas (TCGA) database and validate it in the Ramathibodi (RA) locally advanced head and neck squamous cell carcinoma (LA-HNSCC) cohort. METHODS: The correlation between candidate miRNAs and the survival of patients with LA-HNSCC in TCGA database was analyzed. A prognostic miRNA signature model was generated that classified patients into high-risk and low-risk groups. This candidate miRNA signature was further validated in the independent RA cohort using droplet-digital polymerase chain reaction. RESULTS: In TCGA database, we compared the expression of 277 miRNAs between 519 head and neck squamous cell carcinoma tissues and 44 normal tissues. The expression of hsa-miR-10b, hsa-miR-148b, hsa-miR-99a, hsa-miR-127, hsa-miR-370, and hsa-miR-500a was independently associated with overall survival (OS). Thus, we established the miRNA signature risk score from these six miRNAs and categorized patients into low-risk and high-risk groups. The median OS of TCGA patients was significantly shorter in the low-risk group than in the high-risk group (P < .001). The six-miRNA signature was further validated in the RA cohort (N = 87). The median OS of the low-risk group was significantly shorter compared with the high-risk group (P = .03). In multivariate analysis, the six-miRNA signature was an independent prognostic factor for OS in the RA cohort (HR, 1.958; 95% CI, 1.006 to 3.812; P = .048). CONCLUSION: We identified a prognostic six-miRNA signature for patients with LA-HNSCC from TCGA cohort and validated it in our independent cohort. However, larger studies are warranted to confirm these results.

Unusual manifestation of gastric adenocarcinoma presenting with lymphedema, chylothorax, and chylous ascites.

A 62-year-old Thai man with a 2-year history of bilateral lymphedema and an unprovoked left axillary vein thrombosis presented with progressive leg, scrotal, and abdominal swelling, and shortness of breath. He denied any gastrointestinal symptoms. His lymphedema had initially been diagnosed as chronic filariasis due to positive blood tests for anti-filarial antibodies; however, treatment with anti-filarial drugs failed to improve his symptoms. Subsequently, he underwent surgical lymphaticovenular anastomosis with scrotal reduction, which proved to be of limited symptomatic relief. Later investigations revealed bilateral chylothorax and chylous ascites, with the presence of metastatic adenocarcinoma. Histopathological examination of the patient's skin and scrotum biopsy from his previous surgery revealed invasion of the lymphatics by neoplastic cells with signet ring cell formation. Gastroscopy uncovered a gastric mass, and biopsy confirmed the diagnosis of stage IV gastric adenocarcinoma with signet ring cell. He later received palliative chemotherapy. For the management of chyle leakage, he was prescribed a very low-fat diet and supplemented with parenteral nutrition. Despite treatment, he developed cutaneous metastasis and was transitioned to best supportive care. The patient passed away 14 months after diagnosis.