Real-world outcomes of third-line immune checkpoint inhibitors versus irinotecan-based chemotherapy in patients with advanced gastric cancer: a Korean, multicenter study (KCSG ST22-06).

BACKGROUND: Immune checkpoint inhibitor (ICI) or irinotecan-based chemotherapy is frequently used after failure of second-line paclitaxel plus ramucirumab treatment for patients with locally advanced unresectable or metastatic advanced gastric cancer (AGC). This study aimed to compare the efficacy between ICI and irinotecan-based chemotherapy as third-line treatment in patients with AGC. METHODS: We retrospectively reviewed patients with AGC, whose third-line treatment started between July 2019 and June 2021 at 17 institutions in Korea. The ICI group included patients who received nivolumab or pembrolizumab, and the irinotecan-based chemotherapy group included patients who received irinotecan or FOLFIRI (5-fluorouracil, leucovorin and irinotecan). RESULTS: A total of 363 patients [n = 129 (ICI) and n = 234 (irinotecan-based chemotherapy)] were analyzed. The median progression-free survival was 2.3 and 2.9 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.802). The median overall survival (OS) was 5.5 and 6.0 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.786). For all patients included in this study, multivariable analysis showed that weight loss, peritoneal metastasis, low serum sodium or albumin, and short duration of second-line treatment were associated with inferior OS (p < 0.05). ICI showed significantly longer OS than irinotecan-based chemotherapy in patients without peritoneal metastasis. Whereas ICI showed significantly shorter OS in patients without PD-L1 expression than irinotecan-based chemotherapy. CONCLUSIONS: No significant difference in survival outcome was observed between ICI and irinotecan-based chemotherapy as third-line treatment for AGC patients. ICI might be preferred for patients without peritoneal metastasis and irinotecan-based chemotherapy for patients with tumors without PD-L1 expression. TRIAL REGISTRATION: This study was registered in the Clinical Trial Registry of Korea ( https://cris.nih.go.kr : KCT 0007732).

Catastrophizing Maladaptive Coping Affects the Association Between Viral Anxiety and Fear of Progression in Cancer Patients During COVID-19 Pandemic.

OBJECTIVE: The aim of the present study was to explore whether or not cancer patients' viral anxiety and depression during the coronavirus-2019 (COVID-19) pandemic were associated with a fear of cancer progression. We also assessed whether coping strategies affected the relationship. METHODS: The present cross-sectional survey included cancer patients who visited Ulsan University Hospital in Ulsan, Korea. The participants' demographic information and responses to the following symptoms rating scales were collected: Stress and Anxiety to Viral Epidemic-6; Patient Health Questionnaire-9; Cognitive Emotion Regulation Questionnaire-short version; or Fear of Progression Questionnaire-short version. RESULTS: Of the 558 cancer patients surveyed, 25 (4.5%) reported that their treatment schedule was delayed during the COVID-19 pandemic. The patients' fear of progression was found to be related to age (ß=-0.08; p=0.011), viral anxiety (ß=0.40; p<0.001), depression (ß=0.26; p<0.001), and catastrophizing coping strategies (ß=0.15; p=0.004), for an overall adjusted R2 of 0.46 (F=66.8; p<0.001). Mediation analysis showed that viral anxiety and depression were directly associated with fear of progression, while catastrophizing mediated this relationship. CONCLUSION: Fear of progression in cancer patients was associated with viral anxiety, depression, and maladaptive coping techniques, such as catastrophizing, during the COVID-19 pandemic.

Development and pilot study of "Smart Cancer Care": a platform for managing side effects of chemotherapy.

BACKGROUND: As outpatient chemotherapy treatment increases, cancer patients receiving chemotherapy spend more time at home. In addition, since the types of chemotherapy are gradually expanding, it will be essential to prepare patient self-management strategies for various chemotherapy-related side effects. This study aimed to develop a platform (called Smart Cancer Care) to implement a chemotherapy side effect management program and to evaluate its feasibility. METHODS: Smart Cancer Care comprises an application for patients and a dashboard for medical staff. Thirty-two symptoms to be managed using Smart Cancer Care were summarized through a literature review and Delphi. Management guidelines were developed based on the severity of each symptom (3 stages), and installed in Smart Cancer Care according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 guidelines. To evaluate the feasibility of the developed application and medical dashboard, cancer patients and cancer treatment medical staff used Smart Cancer Care for 2 to 3 weeks and subsequently reported the experience of using them. RESULTS: The patient application provided a list of symptoms according to the cancer type and anticancer drug enabling presence and severity of each symptom to be evaluated. Patients received management guidelines for symptoms based on the symptom evaluation results. On the medical staff dashboard, administrators and authorized medical personnel could access and assess information regarding side effects and symptom severity submitted by the patient. The feasibility and usefulness of Smart Cancer Care were confirmed through a pilot test targeting 30 patients and 24 chemotherapy-related medical staff. For patients, the evaluation score for the "The program will be helpful when seeing medical staff" item was the highest. For medical staff, the score for the "By checking the patient's symptoms using the program, it helps to take appropriate measures for the patient" item was the highest. Although minor corrections were raised, most patients and medical staff expected that Smart Cancer Care would help their treatment. CONCLUSIONS: The configuration of the application and dashboard of Smart Cancer Care detailed in this study could be used for the development of a widely accepted platform to implement a chemotherapy side effect management program.

Erratum: Korean Practice Guidelines for Gastric Cancer 2022: An Evidence-based, Multidisciplinary Approach.

This corrects the article on p. 3 in vol. 23, PMID: 36750993.

Korean Practice Guidelines for Gastric Cancer 2022: An Evidence-based, Multidisciplinary Approach.

Gastric cancer is one of the most common cancers in Korea and the world. Since 2004, this is the 4th gastric cancer guideline published in Korea which is the revised version of previous evidence-based approach in 2018. Current guideline is a collaborative work of the interdisciplinary working group including experts in the field of gastric surgery, gastroenterology, endoscopy, medical oncology, abdominal radiology, pathology, nuclear medicine, radiation oncology and guideline development methodology. Total of 33 key questions were updated or proposed after a collaborative review by the working group and 40 statements were developed according to the systematic review using the MEDLINE, Embase, Cochrane Library and KoreaMed database. The level of evidence and the grading of recommendations were categorized according to the Grading of Recommendations, Assessment, Development and Evaluation proposition. Evidence level, benefit, harm, and clinical applicability was considered as the significant factors for recommendation. The working group reviewed recommendations and discussed for consensus. In the earlier part, general consideration discusses screening, diagnosis and staging of endoscopy, pathology, radiology, and nuclear medicine. Flowchart is depicted with statements which is supported by meta-analysis and references. Since clinical trial and systematic review was not suitable for postoperative oncologic and nutritional follow-up, working group agreed to conduct a nationwide survey investigating the clinical practice of all tertiary or general hospitals in Korea. The purpose of this survey was to provide baseline information on follow up. Herein we present a multidisciplinary-evidence based gastric cancer guideline.

Trastuzumab plus FOLFOX for HER2-positive biliary tract cancer refractory to gemcitabine and cisplatin: a multi-institutional phase 2 trial of the Korean Cancer Study Group (KCSG-HB19-14).

BACKGROUND: HER2 overexpression or amplification, which is present in 15% of all cases of biliary tract cancer, has been identified as a druggable molecular target by genomic profiling. In the phase 3 ABC-06 trial, the folinic acid, fluorouracil, and oxaliplatin (FOLFOX) regimen showed a survival benefit compared with active symptom control as second-line therapy for biliary tract cancer. We aimed to evaluate the clinical activity of FOLFOX plus anti-HER2 antibody trastuzumab as a second-line or third-line treatment for HER2-positive biliary tract cancer. METHODS: This study was an investigator-initiated, open-label, non-randomised, single-arm, multi institutional, phase 2 trial in participants aged 19 years or older with HER2-positive (defined as immunohistochemistry 3+ or immunohistochemistry 2+ and in-situ hybridisation positive or ERBB2 gene copy number ≥6·0 by next-generation sequencing) biliary tract cancer (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer) who progressed on chemotherapy containing gemcitabine and cisplatin (with one or two previous chemotherapy lines permitted). In cycle one, patients received intravenous trastuzumab-pkrb at 6 mg/kg on day 1, and FOLFOX (consisting of intravenous oxaliplatin [85 mg/m2], intravenous leucovorin [200 mg/m2], and fluorouracil [400 mg/m2 bolus] all on day 1, and fluorouracil [2400 mg/m2 infusion] on days 1-2. In cycle two onwards, participants were administered intravenous trastuzumab-pkrb at 4 mg/kg and FOLFOX, every 2 weeks, until unacceptable toxic effects or disease progression. The primary endpoint of the study was objective response rate based on RECIST version 1.1, assessed in the participants who completed at least one study cycle. The response rate threshold for a positive objective response rate was 25%. This trial is registered with ClinicalTrials.gov (NCT04722133) and is ongoing. FINDINGS: 34 participants were enrolled between June 26, 2020, and Sept 1, 2021. At the time of data cutoff on May 1, 2022, median follow-up was 13·0 months (IQR 11·0-16·9), with three participants remaining on treatment. Ten patients had a partial response and 17 had stable disease; the overall response rate was 29·4% (95% CI 16·7-46·3) and the disease control rate was 79·4% (95% CI 62·9-89·9). Median progression-free survival was 5·1 months (95% CI 3·6-6·7); median overall survival was 10·7 (95%CI 7·9-not reached). The most common treatment-related grade 3 or 4 adverse events were neutropenia (ten [29%] participants with grade 3 and nine [26%] with grade 4), grade 3 anaemia (five [15%] participants), and grade 3 peripheral sensory neuropathy (four [12%] participants). There were no treatment-related cardiac toxic effects or deaths. The overall health assessment (EuroQoL-VAS) score did not change significantly throughout the treatment. Sensory and motor neuropathy symptoms as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy twenty-item scale questionnaire did not change significantly over time. INTERPRETATION: For HER2-positive biliary tract cancer, second-line or third-line trastuzumab biosimilar plus FOLFOX exhibited promising activity with acceptable toxicity, warranting further investigation. FUNDING: Boryung Pharmaceutical, Celltrion, National Research Foundation of Korea, National R&D Program for Cancer Control through the National Cancer Center, Yonsei University College of Medicine.

Perceptions of the meaning of life among Korean patients with advanced cancer: A mixed-methods study.

OBJECTIVE: This study aimed to explore perceptions of the meaning of life among Korean patients living with advanced cancer. METHOD: The study employed a mixed-methods design, and 16 participants were included in the analysis. Qualitative data gathered from in-depth interviews were analyzed using Colaizzi's phenomenological method. Quantitative survey data were analyzed using descriptive statistics, the Mann-Whitney U test, the Kruskal-Wallis test, and Spearman's ρ correlation. RESULTS: Participants experienced both the existence of meaning and the will to find meaning in terms of four categories: "interpersonal relationships based on attachment and cohesion" (three themes - family as the core meaning of one's life, supportive and dependent interconnectedness with significant others, and existential responsibility embedded in familism), "therapeutic relationships based on trust" (one theme - communication and trust between the patient and medical staff), "optimism" (two themes - positivity embodied through past experiences and a positive attitude toward the current situation), and "a sense of purpose with advanced cancer" (two themes - the will to survive and expectations for the near future). The meaning in life questionnaire (MLQ) and the purpose in life scale (PIL) showed a significant positive correlation tendency with the functional assessment of chronic illness therapy-spiritual well-being scale (FACIT-Sp). The patient health questionnaire (PHQ-9) showed significant negative correlation tendency with both the MLQ-presence of meaning (MLQ-PM) and PIL-Initiative (PIL-I) questionnaires. SIGNIFICANCE OF RESULTS: Finding meaning in life helps advanced cancer patients realize their will to live. It also acts as a coping mechanism that palliates negative experiences in the fight against the disease. In particular, among advanced cancer patients in the Korean culture, the dynamics of relationships with family and medical staff was a key axis that instilled optimism and will to live. These results suggest that considering the meaning of life in advanced cancer patients by reflecting Korean culture in the treatment process improves the quality of care.

The soluble VCAM-1 level is a potential biomarker predicting severe acute graft versus host disease after allogeneic hematopoietic cell transplantation.

BACKGROUND: Severe graft versus host disease (GVHD) is the main reason for non-relapse mortality following allogeneic hematopoietic cell transplantation (HCT). We investigated the serum protein profiles of patients who had undergone HCT to identify predictive biomarkers of severe acute GVHD (aGVHD). METHODS: Serum samples were collected for 30 patients from day - 7 to day + 14 of HCT. The serum levels of plasma beta2-microglobulin (ß2-MG), soluble vascular cell adhesion molecule-1 (sVCAM-1), platelet factor 4, and TNFSF-14 were measured by ELISA as potential biomarkers following 310 cytokine profiling array. RESULTS: The median age of the study patients was 53.5 years (range, 19-69). All grade and grade 2-4 aGVHD developed in 21 (70.0%) and 17 (56.7%) patients, respectively. Compared with their baseline levels on day - 7, ß2-MG and sVCAM-1 were significantly increased on day + 14 of the HCT procedure (P = 0.028 and P < 0.001, respectively). Patients with a grade 2-4 severe aGVHD showed a significantly higher sVCAM-1 level at baseline (day-7) and at day + 14, compared with the other group with a grade 1 aGVHD or no aGVHD (P = 0.028 and P = 0.035, respectively). CONCLUSION: Higher sVCAM- levels at baseline and on day + 14 in HCT patients could be a significant predictive biomarker of severe aGVHD.

Demographics, Changes in Treatment Patterns, and Outcomes of Bone and Soft Tissue Sarcomas in Korea-A Sarcoma-Specific, Institutional Registry-Based Analysis.

PURPOSE: Because of the heterogeneity of sarcomas, establishing a well-collected, sarcoma-specific database is important for sarcoma research. We analyzed the first histology-based, sarcoma-specific institutional registry in Korea, which collected 28 years of patient data according to a predefined data format. PATIENTS AND METHODS: Adult bone and soft tissue sarcoma patients who were treated from June 1989 to January 2017 were identified and analyzed, based on the ICD-O-3 codes. RESULTS: Among the 3420 patients included, soft tissue and bone sarcomas comprised 77.8% (n = 2661) and 22.2% (n = 759), respectively. Median age at diagnosis was 50 (range, 16-98) in soft tissue sarcomas and 37 (range, 16-85) in bone sarcomas. Males and females comprised 45.5% and 54.5% of soft tissue sarcomas and 52.7% and 47.3% of bone sarcomas, respectively. Among the 3407 patients with treatment data available, 90.5% of the patients with soft tissue sarcomas and 80.8% of the patients with bone sarcomas received surgery first, of which 57.8% and 71.7% did not receive any subsequent treatment, respectively. Overall, the proportion of patients who received surgery alone decreased from 85.7% to 60.5% from the pre-2000 period to the 2010-2017 period. However, the use of adjuvant chemotherapy increased in patients with soft tissue sarcomas (from 8.0% to 17.2% in the same period), and the use of perioperative radiotherapy also increased in both groups (from 1.4% to 22.7% in soft tissue sarcomas, and 0% to 14.5% in bone sarcomas in the same period). In both soft tissue and bone sarcomas, old age (≥65 years) and diagnosis in the early study period were associated with poorer survival. CONCLUSION: We presented a comprehensive summary of our sarcoma registry, including the demographics, changes in treatment patterns, and survival outcomes. This study will provide a framework for future studies.

Changes in decision-making process for life-sustaining treatment in patients with advanced cancer after the life-sustaining treatment decisions-making act.

BACKGROUND: Cancer is a leading cause of death in Korea. To protect the autonomy and dignity of terminally ill patients, the Life-Sustaining Treatment Decision-Making Act (LST-Act) came into full effect in Korea in February 2018. However, it is unclear whether the LST-Act influences decision- making process for life-sustaining treatment (LST) for terminally ill cancer patients. METHODS: This was a retrospective study conducted with a medical record review of cancer patients who died at Ulsan University Hospital between July 2015 and May 2020. Patients were divided into two groups: those who died in the period before the implementation of the LST-Act (from July 2015 to October 2017, Group 1) and after the implementation of the LST-Act (from February 2018 to May 2020, Group 2). We measured the self-determination rate and the timing of documentation of do-not-resuscitate (DNR) or Physician Orders for Life-Sustaining Treatment (POLST) in both groups. RESULTS: A total of 1,834 patients were included in the analysis (Group 1, n = 943; Group 2, n = 891). Documentation of DNR or POLST was completed by patients themselves in 1.5 and 63.5 % of patients in Groups 1 and 2, respectively (p < 0.001). The mean number of days between documentation of POLST or DNR and death was higher in Group 2 than in Group 1 (21.2 days vs. 14.4 days, p = 0.001). The rate of late decision, defined as documentation of DNR or POLST within 7 days prior to death, decreased significantly in Group 2 (56.1 % vs. 47.6 %, p < 0.001). In the multivariable analysis, female patients (odds ratio [OR] 0.71, p = 0.002) and patients with more than 12 years of education (OR 0.70, p = 0.019) were significantly related to a reduced rate of late decision. More than 12 years of education (OR 0.53, p = 0.018) and referral to hospice palliative care (OR 0.40, p < 0.001) were significantly related to self-determination. Enforcement of LST-Act was related to a reduced rate of surrogate decision-making (OR 0.01, p < 0.001) and late decision (OR 0.51, p < 0.001). However, physicians with clinical experience of less than 3 years had a higher rate of surrogate decision-making (OR 5.08, p = 0.030) and late decision (OR 2.47, p = 0.021). CONCLUSIONS: After the implementation of the LST-Act, the rate of self-determination increased and decisions for LST occurred earlier than in the era before the implementation of the LST-Act.

Clinical outcomes of liposomal irinotecan plus fluorouracil/leucovorin for metastatic pancreatic adenocarcinoma in patients previously treated with conventional irinotecan-containing chemotherapy.

INTRODUCTION: Liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has shown clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on gemcitabine-based chemotherapy. However, its role in patients with mPAC previously treated with conventional irinotecan-containing chemotherapy has not been appropriately investigated. METHODS: In this retrospective analysis, patients with mPAC who received nal-IRI plus 5-FU/LV after conventional irinotecan-containing regimen between January 2017 and March 2020, were identified from two referral cancer centers in South Korea. The ratio of time to progression (TTP) with nal-IRI plus 5-FU/LV to TTP with conventional irinotecan (TTPr) was analyzed with respect to the duration and cumulative dose of conventional irinotecan treatment. RESULTS: In total, 35 patients treated with nal-IRI plus 5-FU/LV after the irinotecan-containing regimen were analyzed. The median age was 58 years and 16 (46%) patients were male. The median duration of conventional irinotecan therapy was 4.6 months at a median cumulative dose of 1230 mg. The objective response rate of nal-IRI plus 5-FU/LV was 2.9%, and stable disease was achieved in 11 (31.4%) patients. During the median follow-up of 9.2 [95% confidence interval (CI): 7.8-10.5] months, the median progression-free survival (PFS) and overall survival (OS) were 2.0 (95% CI: 1.4-2.6) months and 4.4 (95% CI: 3.6-5.7) months, respectively. The 6-month PFS and OS rates were 16.3% and 37.5%, respectively. The median TTPr was 0.41 (range, 0.07-2.07), showing a negative correlation with the cumulative dose of prior irinotecan therapy (R = -0.37, p = 0.041). A tentative negative correlation between TTPr and duration of prior irinotecan therapy was observed (R = -0.35, p = 0.062). The most common grade 3-4 toxicities were neutropenia (20%) and fatigue (8.6%). CONCLUSION: Nal-IRI plus 5-FU/LV showed modest effectiveness and manageable toxicities for patients with mPAC previously treated with conventional irinotecan-containing chemotherapy. The cumulative dose of prior conventional irinotecan therapy may be inversely correlated with the effectiveness of nal-IRI plus 5-FU/LV.

Unmet needs related to the quality of life of advanced cancer patients in Korea: a qualitative study.

BACKGROUND: It has recently been emphasized that the unmet needs of cancer patients should be evaluated more holistically, for example, by exploring caregivers' perspectives and cross cultural differences. This study explored additional domains or items of unmet needs among Korean cancer patients in reference to the Sheffield Profile for Assessment and Referral to Care (SPARC). METHODS: We conducted four focus group discussions (FGDs) with 15 cancer patients, following a semi-structured format to elicit participants' health perceptions, comments on SPARC, and opinions on the roles of medical professionals to improve the health-related quality of life of cancer patients. We analyzed the verbatim transcripts using a content analysis method. RESULTS: The following themes were derived: living as a cancer patient, striving to overcome cancer, changing attitudes toward life after the cancer diagnosis, and ways to live a better life as a cancer patient. The participants asserted the significance of providing adequate treatment information that is easily understood by cancer patients during the conversation between patients and medical professionals. Besides the physical symptoms identified by SPARC, the participants struggled with numbness in their hands and feet and hair loss. Korean cancer patients prominently wished to avoid burdening their family or others in their daily life. They considered the improvement of health behaviors, such as diet and exercise, as part of the treatment, which was not limited to drugs. Furthermore, it was essential to evaluate the value of cancer patients' lives, as they desired to be helpful members of their families and society. CONCLUSIONS: This study identified additional domains and items of unmet needs of Korean cancer patients and broadened the understanding of unmet needs among cancer patients.

Use of Gemcitabine plus Carboplatin is Associated with Poor Outcomes in Urothelial Carcinoma Patients with Chronic Kidney Disease Stage 4-5.

PURPOSE: This study aimed to investigate the clinical outcomes with gemcitabine-carboplatin (GCb), the standard treatment for patients with advanced urothelial carcinoma (UC) who are ineligible for cisplatin-based regimens, in advanced UC patients with a glomerular filtration rate (GFR) < 30 mL/min. MATERIALS AND METHODS: A retrospective cohort study involving GCb-treated advanced UC patients with GFR < 60 mL/min (n=89) was performed. Clinical outcomes were compared between subgroups with GFR < 30 mL/min and GFR ≥ 30 mL/min but < 60 mL/min. RESULTS: Most baseline characteristics were comparable between the two subgroups. Patients with GFR < 30 mL/min had a significantly lower objective response rate (12.5%) compared to those with higher GFR levels (56.7%) (p=0.004). The number of GCb cycles was significantly lower in patients with GFR < 30 mL/min (median 2 cycles) than in those with higher GFR levels (median 6 cycles) (p=0.002). Compared to those with GFR ≥ 30 mL/min but < 60 mL/min, patients with GFR < 30 mL/min showed significantly worse progression-free survival (PFS) and overall survival (OS) (p < 0.001 for both). Further stratification of patient subgroups according to their GFR (i.e., GFR ≥ 45 mL/min but < 60 mL/min vs. GFR ≥ 30 mL/min but < 45 mL/min vs. GFR < 30 mL/min) revealed significantly different PFS and OS (p < 0.001 for both). CONCLUSION: The use of GCb is discouraged in advanced UC patients with GFR < 30 mL/min. Alternative therapeutic approaches with better efficacy are warranted for these patients.

Pegteograstim prophylaxis for chemotherapy-induced neutropenia and febrile neutropenia: a prospective, observational, postmarketing surveillance study in Korea.

PURPOSE: This observational study aimed to evaluate the safety and efficacy of pegteograstim prophylaxis in patients with lymphoma and solid malignancies. METHODS: This study was conducted at 18 sites in Korea between November 2015 and August 2018. RESULTS: In total, 611 patients (female, 61.2%) with a median age of 58 (range, 18-88) years were included. Most patients had lymphomas (n = 371, 60.7%) and breast cancer (n = 230, 37.6%) and were administered R-CHOP21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone per 21 days) (n = 284, 46.5%) and AC (doxorubicin and cyclophosphamide) (n = 177, 29.0%). The total pegteograstim dose in the 611 patients was 14,970 mg (2495 doses), with each patient receiving an average daily dose of 6.0 mg. Neutropenia grade 4 occurred in 97 patients (15.9%), and febrile neutropenia (FN) occurred in 31 patients (5.1%). Among the 611 patients, 267 patients (43.7%) developed 882 adverse events (AEs), and 11 patients (1.8%) experienced 18 adverse drug reactions (ADRs). There were 62 patients (10.2%) who experienced 81 cases of serious adverse events (SAEs), with FN and pneumonia being the most frequent at 14 and 13 episodes, respectively, in 13 patients (2.1%). Meanwhile, 1 patient (0.2%) developed 2 episodes of serious ADRs (grade 1 and grade 2 hypotension). No safety concerns in the elderly and patients with liver and/or renal disease were identified. CONCLUSION: The prophylactic use of pegteograstim might have good overall safety and efficacy in patients with lymphomas and solid malignancies in routine clinical practice, even in those who are elderly and have liver and renal diseases.

Analysis of clinical outcomes and prognostic factors in patients treated with definitive chemoradiotherapy for oesophageal squamous cell carcinoma.

As patients receiving definitive chemoradiotherapy (dCRT) for oesophageal squamous cell carcinoma (ESCC) are heterogeneous, we aimed to identify prognostic factors and failure patterns after dCRT. From 2006 to 2015, 327 patients who received dCRT for ESCC were reviewed. Treatment response to dCRT was evaluated based on EORTC-PET criteria with endoscopy and CT results. After dCRT, 296 patients (90.5%) achieved disease stabilisation, with 132 cases of complete response (CR) (40.4%), 158 of partial response (PR) (48.3%) and 6 of stable disease (SD) (1.8%); 31 patients (9.5%) had progressive disease (PD). Median overall survival (OS) from response evaluation was 24.0 months in the overall population. Post-treatment clinical response was the most significant prognostic factor for OS in the multivariate analysis (median OS, 65.0 months for CR, 17.3 months for PR, 4.4 months for SD and 4.0 months for PD; p < 0.0001). Median progression-free survival (PFS) in 296 patients who achieved disease stabilisation was 13.1 months, and only clinical response was a significant factor in the multivariate analysis. The median PFS of CR, PR and SD patients were 36.9, 9.2 and 2.8 months, respectively (p < 0.0001). The clinical response was also significantly associated with the predominant failure pattern (locoregional failure [81.6%] in the initial non-PD group vs. distant metastasis [87.1%] in the initial PD group [p < 0.0001]). In conclusion, definitive chemoradiotherapy-treated ESCC patients showed highly different prognoses after treatment especially according to the clinical response to chemoradiotherapy.

Genome-wide and size-based cell-free DNA indices as predictive biomarkers for locally advanced esophageal squamous cell carcinoma treated with preoperative or definitive chemoradiotherapy.

For locally advanced esophageal cancer, concurrent chemoradiotherapy (CRT) followed by surgery has been a standard treatment, while clinical studies showed comparable survival outcomes between definitive CRT and neoadjuvant CRT followed by surgery in patients responding to CRT. Thus, biomarkers are required to predict treatment outcomes and benefit of adding surgery after CRT. This prospective biomarker study examined the role of cell-free DNA (cfDNA) fragmentation profiles and genomic copy number variations (CNVs) in predicting treatment outcomes in esophageal squamous cell carcinoma patients treated with neoadjuvant or definitive CRT. The clinical response was evaluated after induction chemotherapy and after CRT. Fragment Ratio (FR)-score and I-score were calculated from plasma cfDNA reflecting fragment lengths and CNV of cfDNA, respectively. The association between indices of cfDNA (cfDNA concentration, FR-score, and I-score) and treatment outcomes (clinical response, time to progression [TTP], and overall survival [OS]) were evaluated. Sixty-one patients were included. Thirty patients received neoadjuvant CRT followed by surgery, whereas 31 received definitive CRT. Low baseline, post-induction chemotherapy, and post-CRT FR-scores and low post-induction I-score were significantly associated with improved treatment response (P < 0.05). Additionally, patients with surgery after CRT showed significantly longer survival than patients without surgery in the FR-score-high group (median TTP, 12.7 vs 3.4 months; P = 0.011; OS, not reached vs 12.9 months; P = 0.02), while there was no survival benefit with surgery in the FR-score-low group. FR-score may be a new biomarker to predict treatment response, residual tumor burden after CRT, and consequently, survival benefit of adding morbid surgery after CRT. FR-score has strength in a relatively simple and inexpensive methodology compared to deep sequencing, resulting in high availability and accessibility, despite limited sensitivity.

Rivaroxaban Versus Low-molecular-weight Heparin for Venous Thromboembolism in Advanced Upper Gastrointestinal Tract and Hepatopancreatobiliary Cancer.

BACKGROUND/AIM: The aim of this study was to examine the efficacy and safety of direct oral anticoagulants for cancer-associated venous thromboembolism (VTE) in patients with active cancer. PATIENTS AND METHODS: This study included patients with advanced unresectable/metastatic upper gastrointestinal (GI) or hepatopancreatobiliary (HPB) cancers with high risks of VTE and bleeding. RESULTS: No significant differences were noted in potential bleeding factors between the rivaroxaban (n=105) and low-molecular-weight heparin (LMWH) (n=69) groups. Rivaroxaban exhibited similar risk of recurrent/aggravated VTE compared with LMWH (p=0.625) but increased risk of major bleeding (17.4% vs. 7.6%; p=0.072), clinically relevant bleeding (31.9% vs. 14.3%; p=0.019), and total bleeding (40.6% vs. 19%; p=0.010). The multivariate analysis regarded rivaroxaban as a significant factor for major bleeding (p=0.043) and clinically relevant bleeding (p=0.043). CONCLUSION: Rivaroxaban exhibits comparable efficacy but increases bleeding risks compared with LMWH in patients with active unresectable/metastatic upper GI tract or HPB cancers, requiring extra caution of higher major bleeding risks.

Real-world efficacy and safety of liposomal irinotecan plus fluorouracil/leucovorin in patients with metastatic pancreatic adenocarcinoma: a study by the Korean Cancer Study Group.

BACKGROUND: Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) was effective and well-tolerated in patients with metastatic pancreatic adenocarcinoma (mPAC) that progressed on gemcitabine-based therapy in the global NAPOLI-1 trial. Real-world data may further clarify the outcomes and safety profile of nal-IRI + 5-FU/LV in clinical practice. METHODS: This retrospective analysis included patients with mPAC who received nal-IRI + 5-FU/LV following gemcitabine-based therapy under a Managed Access Program in Korea. RESULTS: From January 2017 to April 2018, 86 patients across 10 institutions received nal-IRI + 5-FU/LV (median age, 61 years; 60% male; ECOG performance status, 0-1). A total of 35 (41%) and 51 (59%) patients had received less than two and two or more lines of chemotherapy before inclusion, respectively. At a median follow up of 6.4 months, median overall survival (OS) was 9.4 months (95% confidence interval [CI] 7.4-11.4) and median progression-free survival (PFS) was 3.5 months (95% CI 1.3-5.7). Six-month OS and PFS rates were 65.1% and 37.5%, respectively. Objective response and disease control rates were 10% and 55%, respectively. Most common grade 3-4 toxicities were neutropenia (37.2%), nausea (10.5%), vomiting (9.3%), anorexia (8.1%) and diarrhoea (4.7%). CONCLUSION: Real-life data for Korean patients indicate that, consistent with NAPOLI-1, nal-IRI + 5-FU/LV is effective and well-tolerated in patients with mPAC that progressed on gemcitabine-based therapy.

Genome-wide copy number alteration and VEGFA amplification of circulating cell-free DNA as a biomarker in advanced hepatocellular carcinoma patients treated with Sorafenib.

BACKGROUND: Although sorafenib is the global standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), it does not have reliable predictive or prognostic biomarkers. Circulating cell-free DNA (cfDNA) has shown promise as a biomarker for various cancers. We investigated the use of cfDNA to predict clinical outcomes in HCC patients treated with sorafenib. METHODS: This prospective biomarker study analyzed plasma cfDNA from 151 HCC patients who received first-line sorafenib and 14 healthy controls. The concentration and VEGFA-to-EIF2C1 ratios (the VEGFA ratio) of cfDNA were measured. Low depth whole-genome sequencing of cfDNA was used to identify genome-wide copy number alteration (CNA), and the I-score was developed to express genomic instability. The I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. The primary aim of this study was to develop cfDNA biomarkers predicting treatment outcomes of sorafenib, and the primary study outcome was the association between biomarkers with treatment efficacy including disease control rate (DCR), time to progression (TTP) and overall survival (OS) in these patients. RESULTS: The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/µL; P < 0.0001). Patients who did not achieve disease control with sorafenib had significantly higher cfDNA levels (0.82 vs. 0.63 ng/µL; P = 0.006) and I-scores (3405 vs. 1024; P = 0.0017) than those achieving disease control. The cfDNA-high group had significantly worse TTP (2.2 vs. 4.1 months; HR = 1.71; P = 0.002) and OS (4.1 vs. 14.8 months; HR = 3.50; P < 0.0001) than the cfDNA-low group. The I-score-high group had poorer TTP (2.2 vs. 4.1 months; HR = 2.09; P < 0.0001) and OS (4.6 vs. 14.8 months; HR = 3.35; P < 0.0001). In the multivariable analyses, the cfDNA remained an independent prognostic factor for OS (P < 0.0001), and the I-score for both TTP (P = 0.011) and OS (P = 0.010). The VEGFA ratio was not significantly associated with treatment outcomes. CONCLUSION: Pretreatment cfDNA concentration and genome-wide CNA in cfDNA are potential biomarkers predicting outcomes in advanced HCC patients receiving first-line sorafenib.

HSP90 inhibitor, AUY922, debilitates intrinsic and acquired lapatinib-resistant HER2-positive gastric cancer cells.

Human epidermal growth factor receptor 2 (HER2) inhibitors, such as trastuzumab and lapatinib are used to treat HER2-positive breast and gastric cancers. However, as with other targeted therapies, intrinsic or acquired resistance to HER2 inhibitors presents unresolved therapeutic problems for HER2-positive gastric cancer. The present study describes investigations with AUY922, a heat shock protein 90 (HSP90) inhibitor, in primary lapatinib-resistant (ESO26 and OE33) and lapatinib-sensitive gastric cancer cells (OE19, N87, and SNU-216) harboring HER2 amplification/over-expression. In order to investigate whether AUY922 could overcome intrinsic and acquired resistance to HER2 inhibitors in HER2-positive gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (OE19/LR and N87/LR) by continuous exposure to lapatinib in vitro. We found that activation of HER2 and protein kinase B (AKT) were key factors in inducing intrinsic and acquired lapatinib-resistant gastric cancer cell lines, and that AUY922 effectively suppressed activation of both HER2 and AKT in acquired lapatinib-resistant gastric cancer cell lines. In conclusion, AUY922 showed a synergistic anti-cancer effect with lapatinib and sensitized gastric cancer cells with intrinsic resistance to lapatinib. Dual inhibition of the HSP90 and HER2 signaling pathways could represent a potent therapeutic strategy to treat HER2-positive gastric cancer with intrinsic and acquired resistance to lapatinib. [BMB Reports 2018; 51(12): 660-665].