Real-world evidence of lorlatinib therapy in Taiwanese patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer.

BACKGROUND: Lorlatinib is a brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) inhibitor indicated for ALK-positive metastatic non-small cell lung cancer (NSCLC). In a global phase II study, patients who experience disease progression despite prior treatment with ALK tyrosine kinase inhibitors (TKIs) was assessed. Herein, we report real-world clinical outcomes of lorlatinib-treated patients with ALK-positive advanced NSCLC who were heavily pretreated and progressed on first- and second-generation ALK-TKIs, in a Taiwanese population under the lorlatinib expanded access program (EAP). METHODS: This multicenter observational study examined the effectiveness and safety of ALK-positive advanced NSCLC patients that progressed from previous second-generation ALK-TKI therapy and received lorlatinib treatment subsequently. Patients who received lorlatinib treatment under EAP between Jul 2017 and Sep 2019 were eligible. Patients were followed for at least one year from the first lorlatinib treatment until study completion. RESULTS: Sixty-three patients were eligible for safety analysis (male: 46.0 %; median age: 52.8 [27.5-78.3] years; brain metastases: 81.0 %). Fifty-four patients with more than one-month lorlatinib treatment were included in the effectiveness analysis. Prior to lorlatinib treatment, 10 patients (18.5 %) received one ALK-TKI, 27 (50.0 %) received two ALK-TKIs, and 17 (31.5 %) received three or more ALK-TKIs. The overall median rwPFS was 9.2 months (95 % confidence interval: 5.3-21.1). The best overall response rate (n = 51) was 13.7 %, with a disease control rate of 80.4 %. CONCLUSION: Lorlatinib exhibits substantial activity and tolerability when used clinically in a later-line setting in a Taiwanese population with ALK-positive advanced NSCLC.

Comparing the effectiveness of different EGFR-TKIs in patients with EGFR mutant non-small-cell lung cancer: A retrospective cohort study in Taiwan.

The study was to compare the effectiveness of different epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced non-small-cell lung cancer (NSCLC) and received EGFR-TKIs as first-line therapy. This retrospective cohort study was conducted using data from real-world settings. Patients with stage IIIB and IV NSCLC and first received gefitinib, erlotinib, or afatinib between 2011 and 2015 were included. The date of the first claim for EGFR-TKIs was set as the index date. Study endpoints were all-cause death and treatment failure that was defined when patients added on or switched to chemotherapy or terminal care. A total of 5,940 patients, including 3,982 (67.0%) receiving gefitinib, 1,207 (20.3%) receiving erlotinib, and 751 (12.7%) receiving afatinib, were eligible for this study. The 1-year overall survival (OS) rates for gefitinib, erlotinib, and afatinib groups were 74% (95% confidence interval [CI]: 72-75%), 75% (95% CI: 73-77%), and 80% (95% CI: 77-83%), respectively. Compared to gefitinib, afatinib was associated with a lower risk of all-cause death (adjusted hazard ratio [aHR] = 0.82, 95% CI: 0.72-0.93) but not erlotinib (aHR = 0.95, 95% CI: 0.86-1.05). Similar results were also found regarding the effectiveness of treatment. All the three EGFR-TKIs showed no differences for both outcomes among patients with an Eastern Cooperative Oncology Group Performance Score of 2. The real-world data exhibited afatinib was more likely to be used for younger patients in a better condition than other EGFR inhibitors, and observed prolonged OS and treatment effectiveness compared to gefitinib after performing a multivariate Cox regression analysis.

Health-related quality of life associated with different cancer treatments in Chinese breast cancer survivors in Taiwan.

We assessed the quality of life (QoL) associated with patient's characteristics and different cancer treatments among Chinese breast cancer survivors in Taiwan. A cross-sectional survey was conducted in 2017 where 193 patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative metastatic breast cancer were recruited. Three QoL questionnaires were administered: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), its breast cancer supplementary measure (QLQ-BR23) and EQ-5D-5L. Multiple linear regression was performed to assess the association between QoL and cancer treatments, with adjustment for patient's characteristics. The mean age of study participants was 55.52 years. Simple linear regression showed that cancer stage and receiving chemotherapy were significantly associated with QoL scores (p < 0.05). Significant adverse effects of chemotherapy on QoL were found among early-stage cancer women (i.e., I or II), including poor cognitive and sexual functioning, and a higher symptom burden (i.e., dyspnoea, constipation, systematic therapy side effects). Multiple linear regression also revealed that receiving chemotherapy was significantly associated with poor QoL (e.g., lower functional health and higher symptom burden measured by the QLQ-BR23), compared to none chemotherapy (p < 0.05). Receiving chemotherapy was associated with poor QoL, especially among early-stage breast cancer patients.

Registry of Genetic Alterations of Taiwan Non-Small Cell Lung Cancer by Comprehensive Next-Generation Sequencing: A Real-World Cohort Study-Taiwan Cooperative Oncology Group T1521.

PURPOSE: Tissue-based next-generation sequencing (NGS) analysis is highly recommended for patients with advanced/metastatic non-small cell lung cancer (NSCLC). We investigated a specific patient population with NSCLC that required tissue-based NGS analysis. MATERIALS AND METHODS: We enrolled 500 patients with advanced/metastatic (1) epidermal growth factor receptor (EGFR) mutations or anaplastic large-cell lymphoma kinase (ALK) rearrangement-positive NSCLC who had failed at minimum one line of tyrosine kinase inhibitor (TKI) therapy, (2) EGFR-/ALK-negative nonsquamous, and (3) non- or light-smoker patients with squamous NSCLC who were treatment-naïve or had failed at maximum two lines of systemic treatment. These patients were divided into five cohorts. Comprehensive tissue-based NGS testing (ACTOnco+) was conducted. RESULTS: Cohort 1: EGFR TKI-pretreated EGFR-mutated population (50.0%, n = 250), cohort 2: ALK inhibitor-pretreated ALK-positive population (1.6%, n = 8), cohort 3: treatment-naïve EGFR-/ALK-negative population (28.2%, n = 141), cohort 4: pretreated EGFR-/ALK-negative population (16.8%, n = 84), and cohort 5: squamous cell carcinoma (3.4%, n = 17). In cohort 1, 11.2% (28/250) of the patients had MET amplification, 32.4% (81/250) had been treated with osimertinib, and EGFR C797S was detected in 6.2% (5/81) of these patients. In cohort 2, resistance ALK mutation was detected in 37.5% (3/8) of the patients. In cohorts 3 and 4, targetable genetic alterations, including EGFR mutation (13.3%), ERBB2 mutation (9.3%), MET exon 14 skipping (5.3%), KRAS G12C mutation (4.4%), ROS1 fusion (2.7%), RET fusion (1.8%), and BRAF V600E mutation (1.3%), were detected. In cohort 5, MET exon 14 skipping was detected in 29.4% (5/17) of the patients. CONCLUSION: This multicenter registration study investigated tissue-based NGS for a specific patient population with NSCLC in Taiwan.

Cost-utility analysis of inotuzumab ozogamicin for relapsed or refractory B cell acute lymphoblastic leukemia from the perspective of Taiwan's health care system.

OBJECTIVES: We conduct a cost-utility analysis of inotuzumab ozogamicin (INO) versus chemotherapy as the standard of care (SOC) for adults with relapsed or refractory B cell acute lymphoblastic leukemia. METHODS: A Markov model incorporating transition probabilities between health states was applied to simulate disease progression. The model inputs, including overall survival, progression-free survival, and utility parameters, were obtained from the INO-VATE ALL trial and literatures. The Taiwan Cancer Registry Database and the Health and Welfare Database were utilized to identify the patient cohort and medical costs from the perspective of National Health Insurance Administration. The lifetime medical costs (in 2017 US dollars), quality-adjusted life years (QALYs) gained, and associated incremental cost-effectiveness ratio (ICER) were the main study outcomes. RESULTS: The lifetime medical costs for INO and SOC were $176,795 and $69,496, and the QALYs gained were 2.25 and 0.84, respectively. The ICER for INO versus SOC was $76,044 per QALY gained, which is slightly more than three times Taiwan's gross domestic product per capita (i.e., $73,224). Favorable economic results for INO versus SOC were found with an increased time horizon for model simulation, less discounting for the future benefit, and higher stem cell transplantation (SCT) rate after INO treatment; and among patients aged less than 55 years, with no SCT history, or in the first salvage treatment. CONCLUSIONS: INO versus SOC has higher costs but is more effective. The use of INO is favorable for patients in the early treatment course and when more future benefit associated with INO is considered.

Development and validation of a Taiwan version of the DN4-T questionnaire.

BACKGROUND: Neuropathic pain (NeP) is often under-recognized, resulting in poor pain management. Therefore, a Taiwan version of the 10-item Douleur Neuropathique 4 (DN4-T) questionnaire was developed to identify patients with NeP from a mixed population of patients with pain. METHODS: A prospective, nonrandomized, multicenter study was conducted in the Neurology Departments of four Taiwanese medical centers, to develop and validate the DN4-T questionnaire as a diagnostic tool for identifying patients with NeP. Patients who experienced pain for >30 days were classified as having neuropathic, nociceptive, or mixed pain. Patients and physicians also completed the DN4-T questionnaire. The DN4-T scores were assessed with the optimal cut-off score calculated using a receiver operating characteristics (ROC) curve, and sensitivity and specificity assessed and reliability determined statistically using the Cronbach alpha coefficient. RESULTS: Of the 318 patients who completed the DN4-T questionnaire, 189 patients were diagnosed with NeP, seven patients with mixed pain, and 122 patients with nociceptive pain. For statistical analysis, patients were categorized as having NeP (those with neuropathic pain and mixed pain) or non-neuropathic (nociceptive) pain (non-NeP). Using an optimum DN4-T cut-off score of ≥3 (ranging from 0 to 10, determined by a maximum c index value of 1.54), DN4-T scores provided a sensitivity of 0.77 and specificity of 0.78, for predicting NeP. The predictive power of DN4-T in diagnosing NeP was 0.83 (as determined by area under the curve of the ROC curve), and was significantly predictive of pain type (p < 0.0001) with a concordance of 0.785, a discordance of 0.129, and a Cronbach alpha coefficient of 0.7, suggesting that the DN4-T questionnaire is a useful predictive tool for diagnosing NeP. CONCLUSION: The DN4-T questionnaire has been reliably translated into Mandarin Chinese and can be used as a diagnostic tool for NeP in conjunction with clinical evaluation.

Development and validation of a Taiwan version of the ID Pain questionnaire (ID Pain-T).

BACKGROUND: Neuropathic pain (NeP) is distinct from nociceptive pain and has different underlying mechanisms requiring specific treatment strategies. To aid diagnosis, self-administered screening questionnaires (such as ID Pain) have been developed to help physicians identify patients with NeP. The aim of this study was to develop and validate a translated ID Pain questionnaire for Taiwanese subjects (ID Pain-T). METHODS: ID Pain, a 6-item self-administered questionnaire, score ranged from -1 to 5, was translated from English into Mandarin Chinese using local terms and back-translated by an expert panel. A prospective, non-randomized, multi-center study was performed in four medical centers in Taiwan. Patients aged over 18 years with pain other than headache for more than 30 days in either neurology or pain clinic were prospectively recruited. They completed the ID Pain-T questionnaire themselves. The study investigators, blinded to the subjects' ID Pain-T scores, examined subjects using a standardized clinical and neurological diagnostic procedure. The ID Pain-T questionnaire scores were verified and validated. RESULTS: A total of 317 patients completed the study. Clinical diagnosis of NeP was given for 189 (60%) patients, mixed pain diagnosed in 7 (2%) patients, and nociceptive pain in 121 (38%) patients. The reliability and consistency of the ID Pain-T were acceptable, with a Cronbach's alpha value of 0.6. Statistical analysis of the ID Pain-T questionnaire calculated an optimal cut-off score of ≥2 for determining NeP with 77% sensitivity and 74% specificity for predicting NeP. Ordinary least squares regression analysis showed significant predictive accuracy of the ID Pain-T questionnaire for NeP (P < 0.0001). These results are comparable to other studies that have translated the ID Pain questionnaire into other languages. CONCLUSION: This study provides evidence that the ID Pain-T questionnaire is a valid and reliable self-administered screening tool to identify NeP in Taiwanese patients.

Is final TNM staging a predictor for survival in locally advanced rectal cancer after preoperative chemoradiation therapy?

BACKGROUND: Neoadjuvant chemoradiation therapy has improved the local control rate and overall survival in locally advanced rectal cancers. The purpose of this retrospective study is to evaluate the correlation between the final pathologic stage and survival in these patients. METHODS: Patients with biopsy-proven rectal carcinoma, pretreatment staging by magnetic resonance imaging such as T3 or T4 tumors, or node-positive disease were treated with preoperative concomitant 5-fluorouracil-based chemotherapy and radiation, followed by radical surgical resection. Clinical outcome with survival, disease-free survival, recurrence rate, and local recurrence rate were compared with each T and N findings using the American Joint Committee on Cancer Tumor-Node-Metastasis (TNM) staging system. RESULTS: A total of 248 patients were enrolled in this study. Overall survival and disease-free survival at 1, 3, and 5 years were 97.1, 92, and 89.9% and 87.5, 71.1, and 69.5%, respectively. Thirty-six patients (14.5%) had a pathologic complete response after neoadjuvant therapy. The recurrence rate was significantly different between the pathologic complete response group and residual group (5.6 vs 31.1%; P = .002). Five-year disease-free survival was significantly better in the complete response group than the residual tumor group (93 vs 66%; P = .0045). There was no statistical difference in survival or locoregional recurrence rate between these two groups. CONCLUSIONS: Posttreatment pathologic TNM stage is correlated to disease-free survival and tumor recurrence rate in locally advanced rectal cancer after preoperative chemoradiation. Also, pathologic complete response to neoadjuvant treatment has its oncologic benefit in both overall recurrence and disease-free survival.

Interpretation of magnetic resonance imaging for locally advanced rectal carcinoma after preoperative chemoradiation therapy.

PURPOSE: Neoadjuvant concomitant chemoradiotherapy has been used in cases of locally advanced rectal cancer to preserve sphincter function, decrease local recurrence, and improve survival. Preoperative staging is essential for planning and providing optimal therapy. The purpose of this study is to determine the accuracy of staging with magnetic resonance imaging and to define any factors that interfere in interpretation of images obtained after preoperative chemoradiation therapy. METHODS: Thirty-six patients with biopsy-proven, locally advanced rectal cancer were treated with preoperative concomitant 5-fluorouracil-based chemotherapy and radiation, followed six to eight weeks later by radical surgery. Preoperative magnetic resonance images were reinterpreted by one radiologist and the results compared with histopathologic staging. RESULTS: T-level downstaging occurred in 10 of 36 patients (28 percent), and N-level downstaging occurred in 29 of 36 patients (80 percent) after completion of chemoradiation therapy. Pathologic complete remission after chemoradiotherapy occurred in five patients (12 percent). Of the 36 patients, 17 (47 percent) were overstaged and 2 (6 percent) were understaged in T-level, whereas 10 patients (28 percent) were overstaged and 3 patients (8 percent) were understaged in N-level. The accuracy of magnetic resonance imaging for determining depth of wall invasion was 47 percent, with 64 percent accuracy for nodal staging. CONCLUSIONS: Magnetic resonance imaging is commonly used in staging of pelvic malignancies because of its fine resolution, but chemoradiotherapy may decrease its accuracy. Thickening of the rectal wall after radiation by marked fibrosis, and peritumoral infiltration of inflammatory cells and vascular proliferation may contribute to overestimation of stage. By contrast, pathologic residual cancer beneath normal mural structure after chemoradiation therapy may result in understaging of rectal cancer.

Unexpectedly frequent hepatitis B reactivation by chemoradiation in postgastrectomy patients.

BACKGROUND: Postgastrectomy patients undergoing chemoradiation risk chemoradiation-induced liver disease (CRILD). The objectives of this study were to investigate dosimetric implications and assess biologic susceptibility to CRILD in these patients. METHODS: Sixty-two patients with Stage IB-IV gastric/gastroesophageal adenocarcinoma without metastases underwent radical total/subtotal gastrectomy; regional lymph node dissection; and postoperative, adjuvant, concomitant chemoradiotherapy (CCRT). Among these, 8 patients developed CRILD (defined as Grade 3-4 liver toxicity), and 11 patients were chronic hepatitis B virus (HBV) carriers (HBV+). Chemotherapy consisted of 1 cycle of etoposide, leucovorin, and 5-fluorouracil (ELF); followed by 5 weekly high doses of 5-fluorouracil (2000-2600 mg/m2) and leucovorin concurrent with radiotherapy (median dose, 45 grays [Gy] to the tumor bed/regional lymphatics); followed by 3 cycles of ELF separated by a 21-day interval. Patients were followed for > or = 4 months after CCRT. Patient-related and dosimetric factors were correlated with CRILD. RESULTS: HBV+ status was the only independent factor associated with CRILD. HBV+ patients had a higher CRILD incidence (6 of 11 patients vs. 2 of 51 patients; P < 0.001). HBV-negative patients with CRILD were recipients of a higher mean liver dose (MLD) (23.8 Gy vs. 15.2 Gy; P = 0.009) and a higher volume fraction of liver that received > 30 Gy (36.5% vs. 19.7%; P = 0.009) compared with noncarriers without CRILD, but no MLD difference was found between HBV+ patients with or without CRILD. Moreover, in four of six carriers with CRILD, HBV infection was reactivated during CRILD. Two of the toxicities were fatal. CONCLUSIONS: HBV carriers had a higher incidence of CRILD after postgastrectomy CCRT, probably related to HBV reactivation. Dosimetric parameters modulated the risk of CRILD in noncarriers, but not in carriers. These factors deserve attention in CRILD/HBV+ patients, and the underlying pathogenesis warrants investigation.