Long-term efficacy and safety of CT-P6 versus trastuzumab in patients with HER2-positive early breast cancer: final results from a randomized phase III trial.

PURPOSE: Equivalent efficacy was demonstrated for the biosimilar CT-P6 and trastuzumab following neoadjuvant therapy for patients with human epidermal growth factor receptor-2 (HER2)-positive early breast cancer. Following adjuvant treatment, efficacy and safety were comparable between treatments. We report updated safety and efficacy data after up to 3 years' follow-up. METHODS: Following neoadjuvant chemotherapy with CT-P6/trastuzumab, patients underwent surgery and continued receiving adjuvant CT-P6/trastuzumab. The primary endpoint (previously reported) was pathological complete response. Time-to-event analyses (disease-free survival [DFS], progression-free survival [PFS], and overall survival [OS]), study drug-related and cardiac adverse events, and immunogenicity were assessed during post-treatment follow-up. RESULTS: Most patients entered the follow-up period (CT-P6: 259 [95.6%]; trastuzumab: 269 [96.8%]). After a median follow-up of 38.7 (CT-P6) and 39.6 (trastuzumab) months, medians were not reached for time-to-event parameters; estimated hazard ratios (HRs) and 3-year survival rates were similar between groups. Estimated HRs (95% confidence intervals) for CT-P6 versus trastuzumab were 1.23 (0.78-1.93) for DFS, 1.31 (0.86-2.01) for PFS, and 1.10 (0.57-2.13) for OS (intention-to-treat population). Safety findings were comparable between groups for the overall study and follow-up period, including study drug-related cardiac disorders (CT-P6: 22 [8.1%] patients; trastuzumab: 24 [8.6%] patients [overall]) and decreases in left ventricular ejection fraction. Immunogenicity was similar between groups. CONCLUSION: The similarity of the time-to-event analyses between CT-P6 and trastuzumab supports the equivalence in terms of efficacy established for the primary endpoint. CT-P6 was well tolerated, with comparable safety and immunogenicity to trastuzumab. ClinicalTrials.gov: NCT02162667 (registered June 13, 2014).

NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.

BACKGROUND: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. METHODS: Act.In.Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FINDINGS: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. INTERPRETATION: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FUNDING: Nanobiotix SA.

Challenges in the maintenance of an open hospital-based cancer registry system in a low-to-middle-income country (LMIC): 2017-2022 experience.

Hospital-based cancer registries (HBCRs) record data on all patients diagnosed and/or treated for cancer at healthcare facilities and evaluate the burden of the disease and the quality of healthcare services at that hospital, helping improve patient care, and providing an assessment of healthcare quality. The CARE PH app was created as a tool to facilitate a system of hospital-based cancer registries in the Philippines, a lower middle-income country. From 2017 to 2022, a total of 60,021 cancer registrants from 44 CARE PH hospitals were entered into the database. Breast cancer was the most common primary site, accounting for 17,660 cases (29.4%). This was followed by colorectal cancer at 11.1%, cervical cancer at 6.2%, head and neck cancer at 5.9%, and prostate and other male genital cancer at 5.1%.Among the 30 data fields collected, 17 exhibited 0-20% missing data, eight displayed 21%-90% missing data, while five depicted 91%-100% missing data. Most of the data fields with missing data are in the treatment and follow-up modules, which are stored in separate forms in a patient's record. Digital transformation of hospitals from paper-based charts to electronic medical records, and the integration of the HBCR to the EMR and hospital information system, will likely be the best solution for these limitations. It is recommended that the creation and maintenance of HBCRs nationwide must be harmonized, and embedded in all relevant national programs and legislations. The development of an information technology process that is based on a cancer patient's journey, should be built on an open system embedded in a well designed enterprise architecture, functioning under the guidance of a strong leadership and governance team. All these must be present in order to create and maintain a robust HBCR that is useful for furthering cancer registry and research in the country.

Second-line bevacizumab-containing therapy in patients with triple-negative breast cancer: subgroup analysis of the RIBBON-2 trial.

Patients with metastatic triple-negative breast cancer (TNBC) typically have a poor prognosis and limited treatment options. To determine the impact of combining bevacizumab with second-line chemotherapy in patients with metastatic TNBC, we performed an exploratory subgroup analysis of the randomized phase 3 RIBBON-2 trial. RIBBON-2 enrolled patients with metastatic breast cancer that had progressed on first-line non-bevacizumab-containing chemotherapy. After selection of chemotherapy (taxane, gemcitabine, capecitabine, or vinorelbine), patients were randomized 2:1 to receive chemotherapy with either bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Of 684 patients treated in RIBBON-2, 159 (23%) had TNBC. Baseline characteristics were reasonably balanced in the two treatment groups. The majority received taxane chemotherapy. The hazard ratio (HR) for PFS was 0.494 [95% confidence interval (CI) 0.33-0.74; P = 0.0006]. Median PFS was 6.0 months with bevacizumab-chemotherapy versus 2.7 months with chemotherapy alone. Median OS was 17.9 versus 12.6 months, respectively (HR 0.624, 95% CI 0.39-1.007; P = 0.0534). ORR was 41 versus 18%, respectively (P = 0.0078). The safety profile was consistent with the overall study population and previous phase 3 trials of bevacizumab. Patients with metastatic TNBC derived significant PFS and response benefits from the combination of bevacizumab with second-line chemotherapy. Despite the small sample size and immature data, there was a trend toward improved OS.

A machine learning-based SNP-set analysis approach for identifying disease-associated susceptibility loci.

Identifying disease-associated susceptibility loci is one of the most pressing and crucial challenges in modeling complex diseases. Existing approaches to biomarker discovery are subject to several limitations including underpowered detection, neglect for variant interactions, and restrictive dependence on prior biological knowledge. Addressing these challenges necessitates more ingenious ways of approaching the "missing heritability" problem. This study aims to discover disease-associated susceptibility loci by augmenting previous genome-wide association study (GWAS) using the integration of random forest and cluster analysis. The proposed integrated framework is applied to a hepatitis B virus surface antigen (HBsAg) seroclearance GWAS data. Multiple cluster analyses were performed on (1) single nucleotide polymorphisms (SNPs) considered significant by GWAS and (2) SNPs with the highest feature importance scores obtained using random forest. The resulting SNP-sets from the cluster analyses were subsequently tested for trait-association. Three susceptibility loci possibly associated with HBsAg seroclearance were identified: (1) SNP rs2399971, (2) gene LINC00578, and (3) locus 11p15. SNP rs2399971 is a biomarker reported in the literature to be significantly associated with HBsAg seroclearance in patients who had received antiviral treatment. The latter two loci are linked with diseases influenced by the presence of hepatitis B virus infection. These findings demonstrate the potential of the proposed integrated framework in identifying disease-associated susceptibility loci. With further validation, results herein could aid in better understanding complex disease etiologies and provide inputs for a more advanced disease risk assessment for patients.

Final Safety and Health-Related Quality of LIfe Results of the Phase 2/3 Act.In.Sarc Study With Preoperative NBTXR3 Plus Radiation Therapy Versus Radiation Therapy in Locally Advanced Soft-Tissue Sarcoma.

PURPOSE: Act.In.Sarc (NCT02379845) demonstrated that the first-in-class radioenhancer NBTXR3, activated by preoperative radiation therapy (RT), doubled the rate of pathologic complete response after resection compared with preoperative RT alone in adult patients with locally advanced soft tissue sarcoma of the extremity or trunk wall (16.1% vs 7.9%, P = .045), and more patients achieved R0 resections (77.0% vs 64.0%, P = .042). These are the toxicity and health-related quality of life (HRQoL) results. METHODS AND MATERIALS: Act.In.Sarc randomized eligible patients 1:1 to either NBTXR3 (single intratumoral injection, volume equivalent to 10% of baseline tumor volume, at 53.3 g/L) activated by external-beam RT (arm A) or external-beam RT alone (arm B) (50 Gy in 25 fractions), followed by surgery in both arms. Here, we report the safety analyses in the all-treated population with a long-term follow-up of at least 2 years, and HRQoL in the intention-to-treat full analysis set. RESULTS: During the on-treatment period, serious adverse events (SAEs) of all grades related to NBTXR3 occurred in 10.1% (9/89) of patients (arm A), and SAEs related to RT occurred in 5.6% (5/89) (arm A) versus 5.6% (5/90) (arm B); postsurgery hospitalization owing to SAEs occurred in 15.7% (14/89) (arm A) versus 24.4% (22/90) (arm B). During the follow-up period, posttreatment SAEs (regardless of relationship) occurred in 13.5% (12/89) (arm A) versus 24.4% (22/90) (arm B). NBTXR3 did not negatively affect HRQoL; during the follow-up period, there was an improvement in most mean Toronto extremity salvage, EuroQoL 5-dimension (EQ-5D), EQ5D02-EQ visual analog scale, reintegration to normal living index, and musculoskeletal tumor rating scale scores. CONCLUSIONS: NBTXR3 did not negatively affect safety or HRQoL. Long-term safety results reinforce the favorable benefit-risk ratio of NBTXR3 plus RT.

Artificial intelligence on COVID-19 pneumonia detection using chest xray images.

Recent studies show the potential of artificial intelligence (AI) as a screening tool to detect COVID-19 pneumonia based on chest x-ray (CXR) images. However, issues on the datasets and study designs from medical and technical perspectives, as well as questions on the vulnerability and robustness of AI algorithms have emerged. In this study, we address these issues with a more realistic development of AI-driven COVID-19 pneumonia detection models by generating our own data through a retrospective clinical study to augment the dataset aggregated from external sources. We optimized five deep learning architectures, implemented development strategies by manipulating data distribution to quantitatively compare study designs, and introduced several detection scenarios to evaluate the robustness and diagnostic performance of the models. At the current level of data availability, the performance of the detection model depends on the hyperparameter tuning and has less dependency on the quantity of data. InceptionV3 attained the highest performance in distinguishing pneumonia from normal CXR in two-class detection scenario with sensitivity (Sn), specificity (Sp), and positive predictive value (PPV) of 96%. The models attained higher general performance of 91-96% Sn, 94-98% Sp, and 90-96% PPV in three-class compared to four-class detection scenario. InceptionV3 has the highest general performance with accuracy, F1-score, and g-mean of 96% in the three-class detection scenario. For COVID-19 pneumonia detection, InceptionV3 attained the highest performance with 86% Sn, 99% Sp, and 91% PPV with an AUC of 0.99 in distinguishing pneumonia from normal CXR. Its capability of differentiating COVID-19 pneumonia from normal and non-COVID-19 pneumonia attained 0.98 AUC and a micro-average of 0.99 for other classes.

Early experience with COVID-19 patients in a private tertiary hospital in the Philippines: Implications on surge capacity, healthcare systems response, and clinical care.

BACKGROUND: Our healthcare institution was one of the first to see SARS CoV-2 cases in the country. We describe the early COVID-19 experience of a private hospital in the Philippines and discuss the healthcare system response in the setting of surge capacity. METHODS: We reviewed the medical records of adult COVID-19 hospitalized patients admitted in March 2020. We reported their demographic and clinical characteristics using descriptive statistics. RESULTS: Of 40 patients admitted, 23 (57.5%) were male and 19 (47.5%) were aged <60 years. Most (n = 27, 67.5%) had moderate-risk, 9 (22.5%) had high-risk, and 4 (10%) had low-risk COVID-19. SARS-CoV-2 testing took 5.5 (range 1-10) days. Overall mortality rate was 6/40 (15.0%). Clinical cure was documented in all low-risk patients, 25 (92.6%) moderate-risk patients, and only 1 (11.1%) high-risk patient. In response to the surge, the hospital rapidly introduced one-way traffic systems, dedicated screening, triage and Emergency Department areas for COVID-19, a clinical pathway, engineering controls, patient cohorting, and strict infection prevention and control measures. CONCLUSION: Majority of patients recovered from COVID-19. Older age and high-risk pneumonia were associated with poor outcomes. Adaptations to hospital structure and staff were quickly made in response to surge capacity, although our response was hampered by prolonged time to COVID-19 confirmation. Our study underscores the urgent need for rapid adaptive response by the healthcare system to address the surge of cases.

Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial.

OBJECTIVES: LUME-Lung 2 investigated the efficacy/safety of nintedanib plus pemetrexed in patients with pretreated non-squamous non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with stage IIIB/IV or recurrent non-squamous NSCLC who had received one prior chemotherapy regimen were randomized (1:1 stratified by histology [adenocarcinoma/non-adenocarcinoma], prior bevacizumab, Eastern Cooperative Oncology Group performance status and presence of brain metastases) to receive intravenous pemetrexed 500mg/m2 on Day 1 plus nintedanib 200mg orally twice daily or matching placebo on Days 2-21, every 3 weeks until progression/unacceptable toxicity. Progression-free survival (PFS) by independent central review was the primary endpoint. Overall survival (OS) was the key secondary endpoint. RESULTS: Based on the pre-planned futility analysis of investigator-assessed PFS, conducted by an independent data monitoring committee, recruitment was halted on 18 June 2011 after 713 (n=353 nintedanib/pemetrexed; n=360 placebo/pemetrexed)/1300 planned patients had enrolled. There were no safety concerns. Subsequent analysis demonstrated a significant improvement in PFS favoring nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months vs 3.6 months; hazard ratio [HR]=0.83, 95% confidence interval [CI] 0.70-0.99, p=0.0435). There was no significant difference in OS (median 12.0 months vs 12.7 months; HR=1.01, 95% CI 0.85-1.21, p=0.8940) after 514 deaths. Nintedanib/pemetrexed resulted in a higher incidence of grade ≥3 elevated alanine aminotransferase (23.3% vs 7.3%), elevated aspartate aminotransferase (12.1% vs 1.7%) and diarrhea (3.5% vs 1.1%) compared with placebo/pemetrexed, but no difference in hypertension, bleeding or thrombosis. CONCLUSION: Although recruitment stopped prematurely, combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced non-squamous NSCLC after first-line chemotherapy, with a manageable safety profile.

Chromosomal aberrations among Filipino health workers at the chemotherapy oncology wards/clinics of a tertiary government hospital

INTRODUCTION: Chromosomal mutations are casual events in neoplasia development. Biomarker cytogenetic assays can determine exposure to mutagenic agents in occupational settings. This study assessed early biological marker chromosomal aberrations among health workers in the chemotheraphy oncology wards/ clinics, exploring its association to the subjects' occupational, environmental and baseline profile.METHODS: This was an IRB approved cross-sectional exploratory study among hospital personnel working in the chemotherapy oncology facility of a tertiary government hospital, who underwent structured interview and blood extraction for cytogenetic assay after informed consent. Study funds only permitted assay of 44 specimens of 144 planned sample size, hence, Stata 6.0 only analyzed data from 44 subjects.RESULTS: All 44 subjects had varying exposure to chemotherapy drug infusions. Of these, 79% had 1.0 breaks per cell (hypersensitive). Predominantly chromatid breaks (CTB), chromatid gaps (CTG), sister chromatid exhanges (SCE) were seen. No significant association was shown between mutagenic sensitivity and baseline characteristics, but with small sample size.CONCLUSION: 21% borderline to hypersensitive mutagenic sensitivity among oncology workers at the tertiary government hospital is relatively significant, despite small sample size, connoting a must preventive promotive practice of chemotherapy administration in the workplace.

Induction chemotherapy followed by concurrent chemoradiotherapy vs concurrent chemoradiotherapy followed by chemotherapy in the treatment of patients with advanced nasopharyngeal carcinoma

Background: The standard treatment of patients with advanced nasopharyngeal carcinoma is concurrent chemoradiotherapy followed by chemotherapy. The voluminous number of patients with this disease and the constraints of limited facilities to accommodate such number of patients in our institution have brought about treatment modifications. This pilot study compared the 3-year progression-free survival (PFS) and overall survival (OS) of patients with advanced nasopharyngeal cancer who received concurrent chemoradiotherapy as induct ion fol lowed by chemotherapy ver sus chemotherapy fol lowed by concurrent chemoradiotherapy. Patients and Methods: From 2005 to 2007, 30 patients with biopsy-proven stage III to IV-B nasopharyngeal cancer seen at the Medical Oncology Outpatient/Inpatient unit of the Philippine General Hospital were randomized to receive cisplatin (25 mg/m2 D1-4) on weeks 1, 4 and 7 of radiotherapy (70 Gy for 7 weeks) followed by cisplatin (20 mg/m2 D1-4) and 5-fluorouracil (1000 mg/m2 D1-4) on weeks 11, 15 and 19 (standard arm) or to receive cisplatin (20 mg/m2) on D1-4 and 5-fluorouracil (1000 mg/ m2 on D1-4) on weeks 1, 5 and 9 followed by concurrent chemoradiotherapy. started after 4 weeks of the 3rd cycle of chemotherapy (week 13) with cisplatin (25 mg/ m2 on D1-4) given on weeks 13, 16 and 19 of treatment every 3 weeks dur ing radiotherapy (investigative arm).Treatment modifications were done based on creatinine clearance and toxicities. Carboplatin (AUC 5) was substituted for cisplatin for creatinine clearance < 30 ml/min or grade 3 hearing impairment. Results: Baseline characteristics were comparable except for age and histology. Median PFS was 19.6 months (standard arm) versus 25.7 months (investigative arm). 3-year PFS rates were 25% and 63%, respectively with hazard ratio 2.64 (p= 0.176). Median OS were 17.5 months and 21.5 months, respectively. 3-year survival rates were 36% and 25.4%, respectively with hazard ratio 0.92 (p= 0.889). The complete response rate was 18.7% (standard arm) versus 28.5% (investigative arm), partial response rate was 31.2% vs 21.4% and progressive disease was 31.2% and 28.5% respectively. Anemia, anorexia, nausea, vomiting and xerostomia were the most frequent grade 3 adverse events. Conclusion: Induct ion chemotherapy fol lowed by concur rent chemoradiotherapy appears to be comparable to the standard of concurrent chemoradiotherapy followed by chemotherapy in terms of PFS and OS. However, no final conclusion can be drawn due to the small sample size and poor follow-up.