Effectiveness and safety of continuous low-molecular-weight heparin versus switching to direct oral anticoagulants in cancer-associated venous thrombosis.

Given the existing uncertainty regarding the effectiveness and safety of switching from low-molecular-weight heparin (LMWH) to direct oral anticoagulants (DOACs) in patients with cancer-associated venous thrombosis (CAT), we conducted a comprehensive population-based cohort study utilizing electronic health database in Hong Kong. A total of 4356 patients with CAT between 2010 and 2022 were included, with 1700 (39.0%) patients switching to DOAC treatment. Compared to continuous LMWH treatment, switching to DOACs was associated with a significantly lower risk of hospitalization due to venous thromboembolism (HR: 0.49 [95% CI = 0.35-0.68]) and all-cause mortality (HR: 0.67 [95% CI = 0.61-0.74]), with no significant difference in major bleeding (HR: 1.04 [95% CI = 0.83-1.31]) within six months. These findings provide reassurance regarding the effectiveness and safety of switching from LMWH to DOACs among patients with CAT, including vulnerable patient groups.

Using the genomic adjusted radiation dose (GARD) to personalize the radiation dose in nasopharyngeal cancer.

BACKGROUND: Locally advanced nasopharyngeal cancer (NPC) patients undergoing radiotherapy are at risk of treatment failure, particularly locoregional recurrence. To optimize the individual radiation dose, we hypothesize that the genomic adjusted radiation dose (GARD) can be used to correlate with locoregional control. METHODS: A total of 92 patients with American Joint Committee on Cancer / International Union Against Cancer stage III to stage IVB recruited in a randomized phase III trial were assessed (NPC-0501) (NCT00379262). Patients were treated with concurrent chemo-radiotherapy plus (neo) adjuvant chemotherapy. The primary endpoint is locoregional failure free rate (LRFFR). RESULTS: Despite the homogenous physical radiation dose prescribed (Median: 70 Gy, range 66-76 Gy), there was a wide range of GARD values (median: 50.7, range 31.1-67.8) in this cohort. In multivariable analysis, a GARD threshold (GARDT) of 45 was independently associated with LRFFR (p = 0.008). By evaluating the physical dose required to achieve the GARDT (RxRSI), three distinct clinical subgroups were identified: (1) radiosensitive tumors that RxRSI at dose < 66 Gy (N = 59, 64.1 %) (b) moderately radiosensitive tumors that RxRSI dose within the current standard of care range (66-74 Gy) (N = 20, 21.7 %), (c) radioresistant tumors that need a significant dose escalation above the current standard of care (>74 Gy) (N = 13, 14.1 %). CONCLUSION: GARD is independently associated with locoregional control in radiotherapy-treated NPC patients from a Phase 3 clinical trial. GARD may be a potential framework to personalize radiotherapy dose for NPC patients.

First-line maintenance therapy with niraparib in advanced platinum-sensitive ovarian cancer: two 'long responder' case reports and review of the current literature.

The standard of care for newly diagnosed advanced ovarian cancer is surgical cytoreduction plus platinum-based chemotherapy; however, recurrent disease frequently occurs after treatment. Poly(ADP-ribose) polymerase (PARP) inhibitors as first-line maintenance therapy have been demonstrated to significantly reduce the risk of disease progression or death in patients with advanced ovarian cancer who have a complete or partial response to first-line platinum-based chemotherapy. Niraparib is the only PARP inhibitor that offers a significant progression-free survival benefit compared with placebo in this patient population regardless of the homologous recombination status. However, predictive factors for treatment responses and approaches to dose optimization remain to be investigated. In this study, two Chinese patients with newly diagnosed advanced ovarian cancer exhibited long-term responses to niraparib treatment, and hematological toxicity was successfully managed by dose adjustment. The literature on clinical trials and real-world experience on the efficacy, tolerability, and dose individualization of niraparib treatment in Western and Chinese patients was also reviewed. Future research is warranted to identify the characteristics of 'long responders' to niraparib treatment.

Outcomes of Third-Line Trastuzumab Deruxtecan in a Patient with De Novo Stage 4 HER2-Positive Gastric Adenocarcinoma with Enteroblastic Differentiation: A Case Report.

This case report describes the treatment of a patient diagnosed with de novo stage 4 human epidermal growth factor 2 (HER2)-positive gastric adenocarcinoma with enteroblastic differentiation (GAED), a rare and aggressive form of gastric cancer characterized by a tubulopapillary growth pattern and enteroblastic cell lineage markers such as GPC3, SALL4, and alpha fetoprotein. Given the patient's symptomatic, advanced-stage cancer, treatment objectives were focused on effectively deterring disease progression and ameliorating symptoms throughout the anticipated multiple lines of therapy. Subsequent to standard first- and second-line therapies for HER2-positive metastatic GC, third-line treatment using the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) for seven cycles resulted in satisfactory tumor control and well-preserved physical performance and quality of life, with minimal hematologic and pulmonary toxicities. The patient retained acceptable physical performance to receive subsequent lines of therapies, and still showed a tumor marker response to 5L trastuzumab-based chemotherapy. As the tumor was positive for both HER2 and programmed death-ligand 1 (PD-L1) expressions, the selection and sequencing of anti-HER2 and anti-PD-L1 therapies were discussed in relation to the latest U.S. Food and Drug Administration approvals and trial results.

Comparison of Clinical Outcomes, Pathologic Characteristics, and Immune-Related Features of Postradiation vs Sporadic Oral Cavity Squamous Cell Carcinoma.

Importance: Postradiation oral cavity squamous cell carcinoma (OCSCC) is a common secondary malignant neoplasm affecting survivors of head and neck cancer who underwent radiotherapy. The clinical, pathologic, and immune-related features of postradiation OCSCC are poorly characterized, and treatment options are limited because of surgical difficulty and high morbidity associated with reirradiation. Objective: To determine whether postradiation OCSCC has distinctive clinical, pathologic, and immune-related features compared with demographic-matched sporadic OCSCC. Design, Setting, and Participants: This retrospective matched cohort study was conducted at a single tertiary oncology center in Hong Kong. Participants included consecutive patients with OCSCC diagnosed between 2000 and 2020. Patients with postradiation OCSCC were matched with patients with sporadic OCSCC using age, year of diagnosis, sex, and anatomic subsites. Data analysis was performed from July to December 2022. Exposure: Head and neck irradiation involving the oral cavity before the diagnosis of OCSCC. Main Outcomes and Measures: The primary outcomes were relapse pattern, survival, and causes of death. Pathologic features; immunohistochemical staining for programmed death-ligand 1, PD-1, MSH6, PMS2, FOXP3, and Ki67; and mRNA expression of 31 immune-related genes were also analyzed. Results: A total of 173 patients, 60 with postradiation OCSCC (median [IQR] age, 63.8 [53.0-71.7] years; 43 men [71.7%]) and 113 with sporadic OCSCC (median [IQR] age, 64.4 [52.8-70.6] years; 83 men [73.5%]), were included. Patients with postradiation OCSCC had a higher proportion of N0 disease than those with sporadic OCSCC (50 patients [83.3%] vs 56 patients [49.6%]). With a median (IQR) follow-up of 10.2 (1.2-20.5) years, the 10-year relapse-free survival rates were lower in patients with postradiation OCSCC than sporadic OCSCC (29.6% [95% CI, 17.1%-43.2%] vs 52.4% [95% CI, 41.8%-62.0%]; P = .04), and the same was true for overall survival (30.5% [95% CI, 17.6%-44.4%] vs 52.3% [95% CI, 41.4%-62.1%]; P = .03). All relapses in patients with postradiation OCSCC were locoregional, whereas 35.2% of relapses (12 of 34 patients) in patients with sporadic OCSCC were distant. Despite similar 10-year disease-specific survival rates between the 2 groups (68.8% [95% CI, 55.8%-81.0%] vs 67.1% [95% CI, 57.5%-76.5%]; P = .91), patients with postradiation OCSCC had excess mortality due to pneumonia and cerebrovascular events. Postradiation OCSCC exhibited more adverse pathologic features (perineural invasion, worse pattern of invasion, and tumor budding), higher PD-1 expression, and higher gene expression of CD4 and TGF-ß compared with sporadic OCSCC. Conclusions and Relevance: This retrospective matched cohort study found distinctive pathologic characteristics and relapse patterns of postradiation OCSCC compared with sporadic OCSCC, which may be attributable to the lack of adjuvant radiotherapy, aggressive biologic phenotype, and different host immune response. Further exploration of the role of immune checkpoint therapy may be justified.

Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis.

BACKGROUND: The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis. METHODS: For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524. FINDINGS: The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2-13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59-0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69-0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75-1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%). INTERPRETATION: The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma. FUNDING: Institut National du Cancer and Ligue Nationale Contre le Cancer.

International recommendations for plasma Epstein-Barr virus DNA measurement in nasopharyngeal carcinoma in resource-constrained settings: lessons from the COVID-19 pandemic.

The effects of the COVID-19 pandemic continue to constrain health-care staff and resources worldwide, despite the availability of effective vaccines. Aerosol-generating procedures such as endoscopy, a common investigation tool for nasopharyngeal carcinoma, are recognised as a likely cause of SARS-CoV-2 spread in hospitals. Plasma Epstein-Barr virus (EBV) DNA is considered the most accurate biomarker for the routine management of nasopharyngeal carcinoma. A consensus statement on whether plasma EBV DNA can minimise the need for or replace aerosol-generating procedures, imaging methods, and face-to-face consultations in managing nasopharyngeal carcinoma is urgently needed amid the current pandemic and potentially for future highly contagious airborne diseases or natural disasters. We completed a modified Delphi consensus process of three rounds with 33 international experts in otorhinolaryngology or head and neck surgery, radiation oncology, medical oncology, and clinical oncology with vast experience in managing nasopharyngeal carcinoma, representing 51 international professional societies and national clinical trial groups. These consensus recommendations aim to enhance consistency in clinical practice, reduce ambiguity in delivering care, and offer advice for clinicians worldwide who work in endemic and non-endemic regions of nasopharyngeal carcinoma, in the context of COVID-19 and other airborne pandemics, and in future unexpected settings of severe resource constraints and insufficiency of personal protective equipment.

Epigenomic landscape study reveals molecular subtypes and EBV-associated regulatory epigenome reprogramming in nasopharyngeal carcinoma.

BACKGROUND: Epstein-Barr virus (EBV) latent infection is associated with genome-wide epigenomic changes in several malignancies, but its role in epigenetic dysregulation remains unclear in nasopharyngeal carcinoma (NPC). METHODS: To investigate EBV-associated epigenetic dysregulation, we performed a multi-omics study by integrating whole-genome bisulfite sequencing (WGBS), assay for transposase-accessible chromatin using sequencing (ATAC-Seq), whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-Seq) data. FINDINGS: In addition to the known global DNA hypermethylated subtype, we discovered a novel subtype with global hypomethylation in EBV + NPC. The consistent EBV-specific differentially methylated regions (EBV-DMRs) in the human genome were identified from both subtypes and associated with loss of CTCF binding (P < 2.2e-16). Importantly, CTCF is a master chromatin regulator and CTCF protein was reduced in 45% of NPC cases, especially in those with advanced NPC (Stage IV vs. others: 62% vs. 38%, P = 0.034). This result links EBV with chromatin changes. The ATAC-Seq data suggest regulatory epigenome reprogramming through chromatin accessibility changes in EBV + NPC with altered CTCF binding and the switch of transcription factor binding from differentiation-associated KLF/SP family to the innate and adaptive immunity-related NF-ĸB and IRF families. Detailed chromatin accessibility analysis identified a potential EBV target gene CD74, which mediated EBV-specific cell-cell communications in the tumor microenvironment (TME) and was strongly correlated with T cell exhaustion (r2 = 0.55). INTERPRETATION: Our study reveals the unexpected epigenetic heterogeneity, providing insights into NPC pathogenesis and highlighting the involvement of host factors in virus-associated epigenetic changes. EBV infection is associated with epigenome reprogramming and may promote immune evasion. FUNDING: This study was funded by the Hong Kong Research Grants Council grant (AoE/M-06/08) to MLL, General Research Fund (17103218 and 17102619) and seed funding for basic research (201611159158) to WD, and General Research Fund (17119618) to HC.

Palbociclib plus letrozole versus placebo plus letrozole in Asian postmenopausal women with oestrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Primary results from PALOMA-4.

BACKGROUND: The cyclin-dependent kinase 4/6 inhibitor palbociclib has demonstrated efficacy and a manageable safety profile in combination with endocrine therapy in women with oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) in international phase 3 trials. The phase 3 PALOMA-4 trial evaluated the efficacy and safety of palbociclib plus letrozole versus placebo plus letrozole in Asian women with ER+/HER2- ABC. METHODS: Postmenopausal women (n = 340) with no prior systemic treatment for advanced disease were randomised 1:1 to palbociclib (125 mg/d orally; 3 weeks on, 1 week off) plus letrozole (2.5 mg/d orally; continuously) or placebo plus letrozole. The primary end-point was investigator-assessed progression-free survival (PFS). Secondary end-points included tumour response and safety. RESULTS: Median (95% CI) PFS was 21.5 (16.6-24.9) months with palbociclib plus letrozole and 13.9 (13.7-16.6) months with placebo plus letrozole (hazard ratio, 0.68 [95% CI, 0.53-0.87]; P = 0.0012). Consistent with the established safety profile, the most common adverse events (AEs) with palbociclib plus letrozole were neutropenia, leukopenia, thrombocytopaenia, and anaemia. Grade 3/4 neutropenia was reported in 84.5% of patients in the palbociclib arm versus 1.2% in the placebo arm. One serious AE of febrile neutropenia in the palbociclib group was reported. CONCLUSIONS: Findings from PALOMA-4 support the efficacy and safety of first-line palbociclib plus letrozole in postmenopausal Asian women with ER+/HER2- ABC. No new safety concerns of palbociclib plus letrozole were identified. TRIAL REGISTRATION: Clinicaltrials. gov, NCT02297438.

Treatment Outcomes of Computer Tomography-Guided Brachytherapy in Cervical Cancer in Hong Kong: A Retrospective Review.

(1) Background: To report the long-term clinical outcomes of computer-tomography (CT)-guided brachytherapy (BT) for locally advanced cervical cancer. (2) Methods: A total of 135 patients with FIGO stage IB-IVA cervical cancer treated with definitive radiotherapy +/- chemotherapy with an IGABT boost at Queen Mary Hospital, Hong Kong, between November 2013 and December 2019 were included. Treatment included pelvic radiotherapy 40 Gy/20 Fr/4 weeks +/- chemotherapy then CT-guided BT (7 Gy × 4 Fr) and a sequential parametrial boost. The primary outcome was local control. Secondary outcomes were pelvic control, distant metastasis-free survival, overall survival (OS) and late toxicities. (3) Results: The median follow-up was 53.6 months (3.0-99.6 months). The five-year local control, pelvic control, distant metastasis-free survival and OS rates were 90.7%, 84.3%, 80.0% and 87.2%, respectively. The incidence of G3/4 long-term toxicities was 6.7%, including proctitis (2.2%), radiation cystitis (1.5%), bowel perforation (0.7%), ureteric stricture (0.7%) and vaginal stenosis and fistula (0.7%). Patients with adenocarcinomas had worse local control (HR 5.82, 95% CI 1.84-18.34, p = 0.003), pelvic control (HR 4.41, 95% CI 1.83-10.60, p = 0.001), distant metastasis-free survival (HR 2.83, 95% CI 1.17-6.84, p = 0.021) and OS (HR 4.38, 95% CI: 1.52-12.67, p = 0.003) rates. Distant metastasis-free survival was associated with HR-CTV volume ≥ 30 cm3 (HR 3.44, 95% CI 1.18-9.42, p = 0.025) and the presence of pelvic lymph node (HR 3.44, 95% CI 1.18-9.42, p = 0.025). OS was better in patients with concurrent chemotherapy (HR 4.33, 95% CI: 1.40-13.33, p = 0.011). (4) Conclusions: CT-guided BT for cervical cancer achieved excellent long-term local control and OS. Adenocarcinoma was associated with worse clinical outcomes. (4) Conclusion: CT-guided BT for cervical cancer achieved excellent long-term local control and OS. Adenocarcinoma was associated with worse clinical outcomes.

Exploratory Study of NPC-0501 Trial: Optimal Cisplatin Dose of Concurrent and Induction/Adjuvant Chemotherapy for Locoregionally Advanced Nasopharyngeal Carcinoma.

PURPOSE: The current recommendation for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is cisplatin-based induction chemotherapy (IC) or adjuvant chemotherapy (AC) plus concurrent chemoradiotherapy (CRT). However, data on the optimal platinum doses for each phase of combined regimens are lacking. EXPERIMENTAL DESIGN: 742 patients with NPC in the NPC-0501 trial treated with CRT plus IC/AC and irradiated with intensity-modulated radiotherapy (IMRT) were analyzed. The optimal platinum dose to achieve the best overall survival (OS) in the concurrent and induction/adjuvant phases was studied. RESULTS: Evaluation of the whole series shows the optimal platinum dose was 160 mg/m2 in the concurrent and 260 mg/m2 in the induction/adjuvant phase. Repeating the analyses on 591 patients treated with cisplatin throughout (no replacement by carboplatin) confirmed the same results. The cohort with optimal platinum doses in both phases had better OS than the cohort suboptimal in both phases (stage III: 90% vs. 75%; stage IVA-B: 80% vs. 56%, at 5-year). Multivariable analyses confirmed optimal platinum doses in both phases versus suboptimal dose in each phase are significant independent factors for OS, with HR of 0.61 [95% confidence interval (CI), 0.41-0.91] and 0.67 (95% CI, 0.48-0.94), respectively. Treatment sequence was statistically insignificant after adjusting for platinum doses. CONCLUSIONS: Both concurrent and IC/AC are needed for locoregionally advanced NPC, even for patients irradiated by IMRT; the concurrent platinum dosage could be set at ≥160 mg/m2 when coupled with adequate induction/adjuvant dosage at ≥260 mg/m2 (or at least ≥240 mg/m2). To achieve these optimal dosages, IC-CRT at conventional fractionation is favored.

A comprehensive systematic review and network meta-analysis: the role of anti-angiogenic agents in advanced epithelial ovarian cancer.

The efficacy of anti-angiogenic agents (AAAs) in epithelial ovarian cancer (EOC) remains unclear. Therefore, we conducted a systematic review and network meta-analysis (NMA) to synthesize evidence of their comparative effectiveness for improving overall survival (OS) among EOC patients. We searched six databases for randomized controlled trials (RCTs) from their inception to February 2021. We performed an NMA with hazard ratios (HRs) and 95%-confidence intervals (CIs) to evaluate comparative effectiveness among different AAAs in chemotherapy-naïve and recurrent EOC. P-score was used to provide an effectiveness hierarchy ranking. Sensitivity NMA was carried out by focusing on studies that reported high-risk chemotherapy-naïve, platinum-resistant, and platinum-sensitive EOC. The primary outcome was OS. We identified 23 RCTs that assessed the effectiveness of AAAs. In recurrent EOC, concurrent use of trebananib (10 mg/kg) with chemotherapy was likely to be the best option (P-score: 0.88, HR 1.67, 95% CI 0.94; 2.94). The NMA indicated that bevacizumab plus chemotherapy followed by maintenance bevacizumab (P-score: 0.99) and pazopanib combined with chemotherapy (P-score: 0.79) both had the highest probability of being the best intervention for improving OS in high-risk chemotherapy-naïve and platinum-resistant EOC, respectively. AAAs may not play a significant clinical role in non-high-risk chemotherapy-naïve and platinum-sensitive EOC.

Meta-analysis of chemotherapy in nasopharynx carcinoma (MAC-NPC): An update on 26 trials and 7080 patients.

PURPOSE: Chemotherapy, when added to radiotherapy, improves survival in locally advanced nasopharyngeal carcinoma (NPC). This article presents the second update of the Meta-Analysis of Chemotherapy in NPC. METHODS: Published or unpublished randomized trials assessing radiotherapy (±a second chemotherapy timing) with/without chemotherapy in non-metastatic NPC patients were identified. Updated data were sought for studies included in the previous rounds of the meta-analysis. The primary endpoint was overall survival. All trials were analyzed following the intent-to-treat principle using a fixed-effects model. Treatments were classified in five subsets according to chemotherapy timing. The statistical analysis plan was pre-specified. RESULTS: Eighteen new trials were identified. Individual patient data were available for seven. In total, the meta-analysis now included 26 trials and 7,080 patients. The addition of chemotherapy reduced the risk of death, with a hazard ratio (HR) of 0.79 (95% confidence interval (CI) [0.73; 0.85]), and an absolute survival increase at 5 and 10 years of 6.1% [+3.9; +8.3] and + 8.4% [+5.7; +11.1], respectively. The largest effect was observed for concomitant + adjuvant, induction (with concomitant in both arms) and concomitant chemotherapy, with respective HR [95%CI] of 0.68 [0.59; 0.79] (absolute survival increase at 5 years: 12.3% (7.0%;17.6%)), 0.73 [0.63; 0.86] (6.0% (2.5%;9.5%)) and 0.81 [0.70; 0.92] (5.2% (0.8%;9.6%)). The benefit of chemotherapy was also demonstrated by improvement in progression-free survival, cancer mortality, locoregional control and distant control. There was a significant interaction between patient age and chemotherapy effect. CONCLUSION: This updated meta-analysis confirms the benefit of concomitant chemotherapy and concomitant + adjuvant chemotherapy, and suggests that addition of induction or adjuvant chemotherapy to concomitant chemotherapy improves tumor control and survival. The benefit of chemotherapy decreases with increasing patient age.

Dose-Response Reduction in Risk of Nasopharyngeal Carcinoma From Smoking Cessation: A Multicenter Case-Control Study in Hong Kong, China.

BACKGROUND: Cigarette smoking is associated with nasopharyngeal cancer (NPC) risk. Whether quitting reduces the risk is unclear. We investigated the associations of NPC with duration of and age at quitting in an endemic region. METHODS: We investigated the associations between NPC and quitting in a multicenter case-control study in Hong Kong with 676 newly diagnosed NPC cases and 1,285 hospital controls between 2014 and 2017, using a computer-assisted self-administered questionnaire. Multivariable unconditional logistic regression yielded adjusted odds ratios (AORs) of NPC by quitting status, duration and age of quitting, combinations of duration and age of quitting, and quitting to smoking duration ratio, compared with current smoking. RESULTS: Quitting (AOR: 0.72; 95% CI: 0.53-0.98) and never smoking (0.73, 0.56-0.95) were associated with lower NPC risk. NPC risk decreased with (i) longer quitting duration (p < 0.01), reaching significance after 11-20 (0.62, 0.39-0.99) and 21+ years (0.54, 0.31-0.92) of quitting; (ii) younger quitting age (p = 0.01), reaching significance for quitting at <25 years (0.49, 0.24-0.97); and (iii) higher quitting to smoking duration ratio (p < 0.01), reaching significance when the ratio reached 1 (0.60, 0.39-0.93). Quitting younger (age <25) appeared to confer larger reductions (49% for ≤10 years of quitting, 50% for 11+ years) in NPC risk than quitting at older ages (25+) regardless of quitting duration (16% for ≤10 years, 39% for 11+ years). CONCLUSIONS: We have shown longer duration and younger age of quitting were associated with lower NPC risk, with dose-response relations. Our findings support including smoking as a cause of NPC. Stronger tobacco control measures and quitting services are needed to prevent NPC.

Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens.

PURPOSE: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein. METHODS: 621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1-14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety. RESULTS: 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity. CONCLUSION: Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted. CLINICAL TRIAL REGISTRATION: NCT01808573.

Using Risk Stratification to Optimize Mammography Screening in Chinese Women.

Background: The cost-effectiveness of mammography screening among Chinese women remains contentious. Here, we characterized breast cancer (BC) epidemiology in Hong Kong and evaluated the cost-effectiveness of personalized risk-based screening. Methods: We used the Hong Kong Breast Cancer Study (a case-control study with 3501 cases and 3610 controls) and Hong Kong Cancer Registry to develop a risk stratification model based on well-documented risk factors. We used the Shanghai Breast Cancer Study to validate the model. We considered risk-based programs with different screening age ranges and risk thresholds under which women were eligible to join if their remaining BC risk at the starting age exceeded the threshold. Results: The lifetime risk (15-99 years) of BC ranged from 1.8% to 26.6% with a mean of 6.8%. Biennial screening was most cost-effective when the starting age was 44 years, and screening from age 44 to 69 years would reduce breast cancer mortality by 25.4% (95% credible interval [CrI] = 20.5%-29.4%) for all risk strata. If the risk threshold for this screening program was 8.4% (the average remaining BC risk among US women at their recommended starting age of 50 years), the coverage was 25.8%, and the incremental cost-effectiveness ratio (ICER) was US$18 151 (95% CrI = $10 408-$27 663) per quality-of-life-year (QALY) compared with no screening. The ICER of universal screening was $34 953 (95% CrI = $22 820-$50 268) and $48 303 (95% CrI = $32 210-$68 000) per QALY compared with no screening and risk-based screening with 8.4% threshold, respectively. Conclusion: Organized BC screening in Chinese women should commence as risk-based programs. Outcome data (e.g., QALY loss because of false-positive mammograms) should be systemically collected for optimizing the risk threshold.

Low vitamin D exposure and risk of nasopharyngeal carcinoma: Observational and genetic evidence from a multicenter case-control study.

BACKGROUND & AIMS: Little is known about the risk of nasopharyngeal carcinoma (NPC) in relation to vitamin D exposure. The aim of this study was to examine the associations of NPC risk with serum level of 25-hydroxyvitamin D (25OHD) and genetic predicted 25OHD, and potential effect modification by several putative risk factors of NPC. METHODS: Our multicenter case-control study in Hong Kong recruited 815 NPC cases and 1502 frequency-matched (by sex and age) hospital controls from five major regional hospitals, and recruited 299 healthy subjects from blood donation centers (2014-2017). Circulating level of 25-hydroxyvitamin D (25OHD) and genetic predicted 25OHD (rs12785878, rs11234027, rs12794714, rs4588 and rs6013897) were measured by validated enzyme immunoassay and the iPLEX assay on the MassARRAY System, respectively. Data were also collected on demographics, lifestyle factors, ultraviolet radiation exposure, and potential confounders using a computer-assisted, self-administered questionnaire with satisfactory test-retest reliability. Unconditional logistic regression models were used to estimate ORs and 95% CIs. RESULTS: Despite no significant association of NPC risk with circulating 25OHD and genetic predicted 25OHD, there was evidence for an inverse association in participants with normal body mass index (between 18.5 and 27.5) across categories of 25OHD (Ptrend = 0.003), and a positive association in those with low socioeconomic status across categories based on the genetic score (Ptrend = 0.005). In addition, risk of NPC diagnosed at an early stage was higher for genetically lower 25OHD level (adjusted OR = 3.09, 95% CI = 1.04-9.21, Ptrend = 0.022). CONCLUSIONS: Findings of this first comprehensive study to investigate the positive association of NPC risk with vitamin D deficiency need to be confirmed and be best interpreted with results of further similar studies. Our findings may inform possible etiological mechanisms of the associations with several putative risk/protective factors of NPC.

Phase II, Randomized Study of Spartalizumab (PDR001), an Anti-PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer.

PURPOSE: No standard treatment exists for platinum-refractory, recurrent/metastatic nasopharyngeal cancer (NPC). This phase II study (NCT02605967) evaluated progression-free survival (PFS) of spartalizumab, an antiprogrammed cell death protein-1 (PD-1) monoclonal antibody, versus chemotherapy, in NPC. PATIENTS AND METHODS: Patients with nonkeratinizing recurrent/metastatic NPC who progressed on/after platinum-based chemotherapy were enrolled. Spartalizumab was dosed 400 mg once every 4 weeks, and chemotherapy was received per investigator's choice. RESULTS: Patients were randomized to receive either spartalizumab (82 patients) or chemotherapy (40 patients). The most common spartalizumab treatment-related adverse events were fatigue (10.3%) and pruritus (9.3%). Median PFS in the spartalizumab arm was 1.9 months versus 6.6 months in the chemotherapy arm (P = 0.915). The overall response rate in the spartalizumab arm was 17.1% versus 35.0% in the chemotherapy arm. Median duration of response was 10.2 versus 5.7 months in the spartalizumab versus chemotherapy arms, respectively. Median overall survival was 25.2 and 15.5 months in the spartalizumab and chemotherapy arms, respectively. Tumor RNA sequencing showed a correlation between response to spartalizumab and IFNγ, LAG-3, and TIM-3 gene expression. CONCLUSIONS: Spartalizumab demonstrated a safety profile consistent with other anti-PD-1 antibodies. The primary endpoint of median PFS was not met; however, median overall survival and median duration of response were longer with spartalizumab compared with chemotherapy.

Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.

PURPOSE: In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT. EXPERIMENTAL DESIGN: Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated. RESULTS: Four hundred and seven patients were included in the serum analysis set (lenvatinib n = 279, sorafenib n = 128); 58 patients were included in the gene-expression analysis set (lenvatinib n = 34, sorafenib n = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, P = 0.014; FGF23: 48.4% vs. 16.4%, P = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33-0.85; P-interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16-0.91; P = 0.0253). CONCLUSIONS: Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.

Dietary fiber intake from fresh and preserved food and risk of nasopharyngeal carcinoma: observational evidence from a Chinese population.

BACKGROUND: The role of dietary fiber intake on risk of nasopharyngeal carcinoma (NPC) remains unclear. We examined the associations of dietary fiber intake on the risk of NPC adjusting for a comprehensive list of potential confounders. METHODS: Using data from a multicenter case-control study, we included 815 histologically confirmed NPC incident cases and 1502 controls in Hong Kong, China recruited in 2014-2017. Odds ratios (ORs) of NPC (cases vs controls) for dietary fiber intake from different sources at different life periods (age 13-18, age 19-30, and 10 years before recruitment) were evaluated using unconditional logistic regression, adjusting for sex, age, socioeconomic status, smoking and drinking status, occupational hazards, family history of cancer, salted fish, and total energy intake in Model 1, Epstein-Barr virus viral capsid antigen serological status in Model 2, and duration of sun exposure and circulating 25-hydroxyvitamin D in Model 3. RESULTS: Higher intake of total dietary fiber 10 years before recruitment was significantly associated with decreased NPC risk, with demonstrable dose-response relationship (P-values for trend = 0.001, 0.020 and 0.024 in Models 1-3, respectively). The adjusted ORs (95% CI) in the highest versus the lowest quartile were 0.51 (0.38-0.69) in Model 1, 0.48 (0.33-0.69) in Model 2, and 0.48 (0.33-0.70) in Model 3. However, the association was less clear after adjustment of other potential confounders (e.g. EBV) in the two younger periods (age of 13-18 and 19-30 years). Risks of NPC were significantly lower for dietary fiber intake from fresh vegetables and fruits and soybean products over all three periods, with dose-response relationships observed in all Models (P-values for trend for age 13-18, age 19-30 and 10 years before recruitment were, respectively, 0.002, 0.009 and 0.001 for Model1; 0.020, 0.031 and 0.003 for Model 2; and 0.022, 0.037 and 0.004 for Model 3). No clear association of NPC risk with dietary fiber intake from preserved vegetables, fruits and condiments was observed. CONCLUSION: Our study has shown the protective role of dietary fiber from fresh food items in NPC risk, but no association for total dietary fiber intake was observed, probably because total intake also included intake of preserved food. Further studies with detailed dietary information and in prospective settings are needed to confirm this finding, and to explore the possible underlying biological mechanisms.