A Phase II Study About Efficacy and Safety of the Continuous IntraVenous Infusion of Ketamine as Adjuvant to Opioids in Terminally Ill Cancer Patients With Refractory Cancer Pain (CIVIK Trial).

BACKGROUND: Ketamine has been used to control refractory cancer pain as an adjuvant to opioids. We conducted a prospective phase II study to investigate the efficacy and safety of 5-day continuous intravenous infusion (CIVI) of Ketamine in terminally ill cancer patients with refractory cancer pain. METHODS: Hospitalized terminally ill cancer patients with refractory cancer pain were enrolled. Refractory cancer pain was indicated by requirements for 4 or more rescue opioids or pain intensity using numerical rating scale > personalized pain goal (PPG) despite of intravenous morphine equivalent daily dose (IV MEDD) ≥ 120 mg/day. The CIVI of ketamine was increased from .05 mg/kg/hour to .5 mg/kg/hour by .05 every 8 hours if pain intensity exceeded PPG or if number of rescue opioids ≥2 during prior 8 hours was required. The primary end-point was overall pain response rate, which indicates complete response (both rescue opioid ≤3/day and pain intensity ≤ PPG) plus partial response (rescue opioid ≤3/day), without unacceptable toxicities. RESULTS: Among 21 eligible patients enrolled between September 2019 and January 2023, 20 were analyzed. Most pain mechanisms were mixed type (n = 15, 75%), with neuropathic component (n = 17, 85%). The baseline background opioids were IV MEDD 186 mg/24hour (range, 124-592), number of rescue opioids was 6 (IQR, 5-9), and median PPG was 4 (IQR, 3-4). The overall pain response rate was 50% (n = 10) including 40% (n = 8) for complete pain response and 10% (n = 2) for partial pain response. CONCLUSION: This study showed efficacy of gradually increasing CIVI of ketamine for terminally ill cancer patients with refractory cancer pain. CIVI of ketamine could be a useful tool in these patients considering the limited treatment options. (NCT03362073, Initial Release: November 15, 2017).

Comparison of prophylactic effects for chemotherapy induced neutropenia between same-day versus next-day administration of pegteograstim (Neurapeg®) in patients treated with chemotherapy regimen composed of day 1 intensive myleosuppressive agent: A randomized phase III clinical trial.

BACKGROUND AND PURPOSE: Administration of pegylated granulocyte-colony-stimulating factor (peg-GCSF) 24 to 72 hours after chemotherapy is usually recommended. Next-day administration (after 24 hours) resulted in fewer duration of grade (Gr) 4 chemotherapy-induced neutropenia (CIN) and decreased severity of CIN than same-day (within 4 hours). However, patients sometimes receive same-day Peg-GCSF for the sake of convenience. In addition, a few prior studies showed that the same-day method is comparable or superior to the next-day method in preventing CIN, especially in chemotherapy regimens that include day 1 myelosuppressive agents. Thus, we aim to verify the hypothesis that same-day administration of pegteograstim, a new formulation of peg-GCSF, is non-inferior to next-day administration in terms of Gr4 CIN duration. METHODS: This study is a randomized, multicenter, open-label, investigator-initiated phase 3 study. Patients with adjuvant/neoadjuvant or first-line palliative chemotherapy comprising intensively myelosuppressive agents on day 1 (mFOLFIRINOX, ECb, EP, FOLFIRI, and FOLFOX) are enrolled. The patients are assigned to the same-day arm or the next-day arm in a 1:1 ratio. The randomizations are stratified according to number of patient CIN risk factors (1 vs ≥2), chemotherapy setting (perioperative vs palliative), and interval (2-week vs 3-week). In the same-day arm, pegteograstim 6 mg is subcutaneously injected within 4 hours after completion of chemotherapy. In the next-day arm, pegetograstim is injected at 24 to 36 hours post-chemotherapy. A complete blood count test is performed daily from day 5 to 9 during the cycle 1. The primary endpoint is duration of Gr4 CIN (cycle 1), and secondary endpoints include incidence of Gr 3 to 4 CIN (cycle 1), severity of CIN (cycle 1), time to recovery absolute neutrophil count 1000/µL (cycle 1), incidence of febrile neutropenia, incidence of CIN-related dose delay, and dose intensity. In order to verify non-inferiority of 0.6 days, we estimated a significance level of 5%, power of 80%, and drop-out rate of 15%. This results in the need for a total of 160 patients, 80 in each group.

Multidisciplinary Treatment Strategy for Early Colon Cancer: A Review-An English Version.

Treatment for early colon cancer has progressed rapidly, with endoscopic resection and minimally invasive surgery. It is important to select patients without risk of lymph node metastasis before deciding on endoscopic resection for early colon cancer treatment. Pathological risk factors include histologic grade of cancer cell differentiation, lymphovascular invasion, perineural invasion, tumor budding, and deep submucosal invasion. These risk factors for predicting lymph node metastasis are crucial for determining the treatment strategy of endoscopic excision and radical resection for early colon cancer. A multidisciplinary approach is emphasized to establish a treatment strategy for early colon cancer to minimize the risk of complications and obtain excellent oncologic outcomes by selecting an appropriate treatment optimized for the patient's stage and condition. Therefore, we aimed to review the optimal multidisciplinary treatment strategies, including endoscopy and surgery, for early colon cancer.

Real-world experience of safety and effectiveness of regorafenib for treatment of metastatic colorectal cancer, advanced gastrointestinal stromal tumors, and hepatocellular carcinoma: a post-marketing surveillance study in Korea.

Purpose: This regulatory post-marketing surveillance (PMS) study was performed to evaluate the safety and effectiveness of regorafenib on Korean patients with colorectal cancer (CRC), gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma (HCC) in a real-world clinical setting. Methods: This PMS was conducted as a multi-center, prospective, observational study at 34 centers in Korea from August 2013 to August 2019. The primary objective was to evaluate the safety of regorafenib in real-world practice, with the secondary objective to investigate its effectiveness, including its overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: In total, 301 patients were included in the analysis (254 patients with CRC, 14 patients with GIST, and 33 patients with HCC). The incidence rates of adverse events (AEs) were 85.0%, 78.6%, and 81.8% in patients with CRC, GIST, and HCC, respectively. The most frequent AE related to regorafenib in the three cancer types was palmar-plantar erythrodysesthesia syndrome (PPES). The ORRs of patients with CRC, GIST, and HCC were 4.7%, 0%, and 41.4%, respectively. The median PFS and OS were 2.1 and 6.1 months for CRC, respectively; 9.2 and 16.4 months for GIST, respectively; and 5.5 months and not estimated (NE) for HCC, respectively. Patients who experienced a dose modification or discontinuation of regorafenib showed significantly shorter median PFS and OS (2.2 vs. 2.6 months, respectively, P = 0.0335 for PFS; 5.3 vs. 8.5 months, respectively, P = 0.0010 for OS). Conclusion: This PMS study, which is the largest surveillance study of CRC in Korea, found no newly identified safety concerns for patients who received regorafenib in the real-world setting. Additionally, the results of this study were consisted with those previously reported in phase III trials.

Efficacy and safety of atezolizumab plus bevacizumab in Korean patients with advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Atezolizumab plus bevacizumab (Ate/Bev) has demonstrated efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the phase III trial. Further evaluation is necessary to investigate the safety and efficacy of Ate/Bev in real settings. METHODS: This was a multicentre retrospective analysis. Between May 2020 and February 2021, 138 patients received Ate/Bev as first-line treatment for advanced HCC from 11 institutions. We excluded patients with Child-Pugh B or C and BCLC D stage, and the remaining 121 patients were included in this analysis. RESULTS: According to RECIST 1.1, the objective response and disease control rates were 24.0% and 76.0%. The median follow-up duration was 5.9 months (95% confidence interval [CI], 5.4-6.4), the median progression-free survival (PFS) was 6.5 months (95% CI, 4.1-9.0), and median overall survival (OS) was not reached (95% CI, not available). The most frequent grade 3-4 adverse event was aspartate aminotransferase elevation (10.7%). In the multivariate analyses, AFP increase (P = .037), baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 5 (P = .023), and best response to stable disease or progressive disease (P = .019) were significantly associated with worse PFS. Macrovascular invasion (P = .048) and baseline NLR ≥5 (P < .001) were significantly associated with worse OS. CONCLUSIONS: Ate/Bev showed real-life efficacy and safety in Korean patients with advanced HCC, in line with results from phase III trial. Considering unfavourable survival outcomes of Ate/Bev in patients with elevated NLR, careful assessment of treatment response needs to be performed in this group.

Verification of performance of a direct fluorescent assay for cell-free DNA quantification, stability according to pre-analytical storage conditions, and the effect of freeze-thawing.

A simple fluorescence-based cell-free DNA (CFD) assay has been previously developed that can directly measure nucleic acids without prior DNA extraction and amplification. However, studies on fluorescence-based CFD are lacking. In particular, there is no known information regarding the stability with regard to pre-analytical storage conditions in relation to time and temperature, or on the influence of freeze-thawing. Plasma was directly assayed to measure CFD using PicoGreen™ reagent. Standard linearity and accuracy were confirmed using salmon sperm DNA. Whole blood was left at room temperature (RT) and at 4˚C, and then plasma was separated. The CFD was also measured using thawed plasma after 1 week of freezing. As a correlation with a sperm DNA concentration, CFD demonstrated linearity over a wide range of concentrations, with a 0.998 correlation coefficient. The CFD level showed a change of up to 2.5 µg/ml according to pre-analytical storage time, and the changes were not consistent over time. The CFD values at RT after 1 h were similar to the baseline values, and the relative standard deviation was lowest under this condition. The CFD values between 4˚C and RT were similar over all time periods assessed. After freeze-thawing, the change in CFD value was reduced compared to that before freezing. The present study showed that CFD measurements using plasma processed within 1 h were optimal. Additionally, the effects of substantial changes according to storage conditions were reduced after freeze-thawing, and thus studies using stored samples is viable and relevant.

Safety and feasibility of 3-month interval access and flushing for maintenance of totally implantable central venous port system in colorectal cancer patients after completion of curative intended treatments.

ABSTRACT: Patients with colorectal cancer (CRC) treated with curative intent surgery undergo continuous fluorouracil (5-FU) infusion-based chemotherapy using totally implantable central venous port system (TICVPS) in cases with high risk of recurrence. Approximately 30% of patients relapse after therapy completion, especially within 2 years. Hence, many patients with high risk CRC keep the TICVPS for 6 to 24 months after treatment with regular intervals of TICVPS flushing. However, little is known about the proper interval duration of the port. The aim of this study is to investigate whether a 3 months extended interval is safe and if port maintenance is feasible.A retrospective cohort was compiled of patients with CRC who underwent curative intent surgery and perioperative chemotherapy using TICVPS between 2010 and 2017. The primary end point was TICVPS maintenance rate, including maintenance of TICVPS for at least 6 months, planned TICVPS removal after 6 months, and regaining the use of TICVPS at the time of recurrence.A total of 214 patients with CRC underwent curative intent treatments during the study period. Among them, 60 patients were excluded, including 6 patients for early recurrence within 3 months and 54 patients with violation of flushing interval. Finally, 154 patients were analyzed. Mean flushing interval was 98.4 days (95% confidence interval [CI], 96.2-100.6; range, 60-120). In December 2018, 35 patients kept the TICVPS, 92 patients had planned removal, 25 patients reused the TICVPS, and 2 patients had to unexpectedly remove the TICVPS due to site infection and pain. Thus, the functional TICVPS maintenance rate was 98.8% (152/154). Thirty-eight patients relapsed, and 30 patients were treated with intravenous chemotherapy. Among them, 25 patients (83.3%) reused the maintained TICVPS without a reinsertion procedures.Our study demonstrated that 3-month interval access and flushing is safe and feasible for maintaining TICVPS during surveillance of patients with CRC. An extended interval up to 3 months can be considered because it is compatible with CRC surveillance visit schedules.

Safety, Efficacy, and Patient Satisfaction with Initial Peripherally Inserted Central Catheters Compared with Usual Intravenous Access in Terminally Ill Cancer Patients: A Randomized Phase II Study.

PURPOSE: The purpose of this study was to investigate whether routine insertion of peripherally inserted central catheter (PICC) at admission to a hospice-palliative care (HPC) unit is acceptable in terms of safety and efficacy and whether it results in superior patient satisfaction compared to usual intravenous (IV) access. MATERIALS AND METHODS: Terminally ill cancer patients were randomly assigned to two arms: routine PICC access and usual IV access arm. The primary endpoint was IV maintenance success rate, defined as the rate of functional IV maintenance until the intended time (discharge, transfer, or death). RESULTS: A total of 66 terminally ill cancer patients were enrolled and randomized to study arms. Among them, 57 patients (routine PICC, 29; usual IV, 28) were analyzed. In the routine PICC arm, mean time to PICC was 0.84 days (range, 0 to 3 days), 27 patients maintained PICC with function until the intended time. In the usual IV arm, 11 patients maintained peripheral IV access until the intended time, and 15 patients underwent PICC insertion. The IV maintenance success rate in the routine PICC arm (27/29, 93.1%) was similar to that in the usual IV arm (26/28, 92.8%, p=0.958). Patient satisfaction at day 5 was better in the routine PICC arm (97%, 'a little comfort' or 'much comfort') compared with the usual IV arm (21%) (p <0.001). CONCLUSION: Routine PICC insertion in terminally ill cancer patients was comparable in safety and efficacy and resulted in superior satisfaction compared with usual IV access. Thus, routine PICC insertion could be considered at admission to the HPC unit.

Neutropenia following intravenous immunoglobulin therapy in adult patients with immune thrombocytopenic purpura: A single center experience and literature review.

The purpose of this study was to evaluate neutropenia following intravenous immunoglobulin (IVIG) therapy in adults with immune thrombocytopenic purpura (ITP).Our analysis included 88 patients with ITP, who received IVIG from January 2006 to March 2016, at Pusan National University Hospital in Korea. Their white blood cell (WBC) count and absolute neutrophil count (ANC) before and after IVIG treatment were analyzed.Of 88 patients, 24 patients (27.3%) were male, and 64 patients (72.7%) were female. Neutropenia developed in 8 patients (18.7%) after IVIG treatment. In patients with a decrease in WBC count and ANC compared to baseline, median WBC count decreased from 6280/µL to 4530/µL after IVIG therapy, and median ANC decreased from 3840/µL to 2840/µL after IVIG therapy. The neutropenia induced by IVIG had resolved spontaneously after several days, and the mean recovery time was 8.72 days after the completion of the IVIG treatment. During the neutropenic episodes, only one patient developed neutropenic fever, which subsided soon without any treatment.The results of this study suggest that IVIG may cause neutropenia commonly in adults with ITP, and it seems to be transient and self-limited. This study is meaningful as the first report that not only pediatric ITP patients may develop neutropenia post IVIG administration, but also adult patients suffering ITP.

Retrospective evaluation of the efficacy and safety of rivaroxaban in patients with cancer-associated venous thromboembolism: A single-center study.

ABSTRCT: The purpose of this study was to evaluate the efficacy and safety of rivaroxaban for the treatment of cancer-associated venous thromboembolism (VTE).We performed a retrospective chart review of cancer patients with a pulmonary embolism, deep vein thrombosis, or both. Our analysis included all patients who received rivaroxaban from March 2013 to June 2016 at the Hemato-Oncology Division at the Pusan National University Hospital in Korea.Preliminary results identified 123 patients with a history of cancer that were treated with rivaroxaban. The average duration of rivaroxaban therapy was 95.25 days. While 35 patients had resolved VTE after the initiation of rivaroxaban, only one patient had it recur on rivaroxaban treatment. Major bleeding was observed in 6 (4.9%) patients and minor bleeding in 12 (9.8%) patients. The majority of bleeding events occurred spontaneously and most incidences of bleeding could be treated conservatively. Recurrence and major bleeding events on rivaroxaban were relatively low despite the fact that many patients had metastatic disease. Among 52 patient deaths (42.3%), none were due to VTE or bleeding complications; the cause of death in the majority of cases was cancer progression.Rivaroxaban is effective and safe for the treatment of cancer-associated VTE.

Feasibility of Early Application of an Advance Directive at the Time of First-Line Palliative Chemotherapy in Patients With Incurable Cancer: A Prospective Study.

CONTEXT: This study aimed to evaluate the feasibility of an advance directive (AD) at the time of starting first-line palliative chemotherapy. We investigated changes in emotional distress, quality of life (QoL), and attitudes toward anticancer treatments between before and after AD. METHODS: Patients with advanced cancer who had just started palliative chemotherapy were prospectively enrolled. We assessed attitudes toward chemotherapy, Hospital Anxiety and Depression Scale (HADS), and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ) before conducting the AD and subsequently performed the AD after the first cycle of chemotherapy. Follow-up evaluations using same parameters were performed in the next cycle visit. RESULTS: During the study period, 104 patients started palliative chemotherapy. Among them, 41 patients (11 with cognitive impairment at baseline, 14 with clinical deteriorations after the first cycle of chemotherapy, 6 with follow-up loss, 7 without proxy, 3 with protocol violations) were excluded, and the AD were recommended in the remaining 64 patients (proportion of AD recommendation: 62%). Among the 64 patients, 44 agreed to conduct the AD (proportion of AD consent: 69%). There were no significant changes before and after AD in terms of HADS and EORTC-QLQ. Attitudes regarding chemotherapy were also unchanged (P = .773). A total of 36 (82%) patients followed physician's recommendations, with the exception of 8 patients who terminated chemotherapy due to refusal or loss to follow-up. CONCLUSIONS: Considering our results showing no significant changes in depression and anxiety scores, QoL, and attitudes toward anticancer treatments after the AD, early integration of the AD at initiation of first-line palliative chemotherapy might be feasible.

Therapeutic decision-making in elderly patients with acute myeloid leukemia: conventional intensive chemotherapy versus hypomethylating agent therapy.

Standards of care for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy remain undefined. We aimed to compare outcomes of hypomethylating agent (HMA) therapy and intensive chemotherapy (IC) in elderly AML patients and identify the subgroup of patients who are eligible for HMA therapy. We reviewed data on the outcomes of 86 AML patients aged ≥ 65 years, who had undergone treatment between 2010 and 2015. These treatments included IC (25 patients, 29.1%) or therapy using HMA including azacitidine or decitabine (61 patients, 70.9%). The overall response rates were 32 and 19.7%, respectively. Median overall survival (OS) (8 vs. 8 months) and progression-free survival (PFS) (6 vs. 7 months) durations were similar in the two groups. Patients in the HMA group with less than 10% peripheral blood (PB) blasts achieved significantly better OS duration than patients in the IC group (P = 0.043). Patients in the IC group with PB blasts and bone marrow blast of ≥ 10 and ≥ 50%, respectively, achieved better PFS durations than the corresponding patients in the HMA group (P = 0.038). Multivariate analysis identified the hematologic improvement-platelet (HI-P) as an independent prognostic factor for survival in the HMA group (P = 0.005). Our results showed that HMA therapy and IC were associated with similar survival duration in elderly AML patients. This study was noteworthy because it assessed prognostic factors that would help to select elderly patients who could expect actual benefits from undergoing the different therapeutic options available, especially HMA therapy.

Clinical significance of standardized uptake value and maximum tumor diameter in patients with primary extranodal diffuse large B cell lymphoma.

BACKGROUND: Maximum standardized uptake value (SUVmax) and maximum tumor diameter (MTD) have been shown to reflect survival outcome in diffuse large B cell lymphoma (DLBCL). However, applying these values to primary extranodal DLBCL is difficult because they are separate nosological entities with differences in genetic origin. We therefore decided to evaluate whether SUVmax and MTD on 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (18-FDG) positron emission tomography (PET) would affect the survival outcome in primary extranodal DLBCL. METHODS: From October 2005 to November 2010, 76 primary extranodal DLBCL patients receiving R-CHOP therapy were analyzed. All patients had undergone an initial 18-FDG PET/CT and conventional computed tomography (CT) of the neck, chest, abdomen, and pelvis for staging. Median follow-up period was 35 months. RESULTS: The SUVmax and MTD cut-off values were 11.0 and 7.5 cm, respectively. SUVmax≥11.0 predicted a short progression free survival (PFS, P=0.002) and overall survival (OS, P=0.002). MTD≥7.5 cm was associated with poor PFS (P=0.003) and OS (P=0.003). High International Prognostic Index (IPI) was also associated with the survival outcome (PFS, P=0.046; OS, P=0.030). Multivariate analysis revealed that SUVmax≥11.0 (PFS, hazard ratio [HR]=10.813, P=0.024; OS, HR=6.312, P=0.015); MTD≥7.5 cm (PFS, HR=5.631, P=0.008; OS, HR=4.072, P=0.008); and high IPI (PFS, P=0.027; OS, P=0.046) were independent prognostic factors. CONCLUSION: It appears that both MTD and SUVmax can be independent prognostic factors in primary extranodal DLBCL.

Thyrotoxic periodic paralysis associated with transient thyrotoxicosis due to painless thyroiditis.

Thyrotoxic periodic paralysis (TPP) is a rare manifestation of hyperthyroidism characterized by muscle weakness and hypokalemia. All ethnicities can be affected, but TPP typically presents in men of Asian descent. The most common cause of TPP in thyrotoxicosis is Graves' disease. However, TPP can occur with any form of thyrotoxicosis. Up to our knowledge, very few cases ever reported the relationship between TPP and painless thyroiditis. We herein report a 25-yr-old Korean man who suffered from flaccid paralysis of the lower extremities and numbness of hands. The patient was subsequently diagnosed as having TPP associated with transient thyrotoxicosis due to painless thyroiditis. The paralytic attack did not recur after improving the thyroid function. Therefore, it is necessary that early diagnosis of TPP due to transient thyrotoxicosis is made to administer definite treatment and prevent recurrent paralysis.