Immunogenicity and Optimal Timing of 13-Valent Pneumococcal Conjugate Vaccination during Adjuvant Chemotherapy in Gastric and Colorectal Cancer: A Randomized Controlled Trial

Purpose Pneumococcal vaccination (13-valent pneumococcal conjugate vaccine [PCV13]) is recommended to cancer patients undergoing systemic chemotherapy. However, the optimal time interval between vaccine administration and initiation of chemotherapy has been little studied in adult patients with solid malignancies. Materials and Methods We conducted a prospective randomized controlled trial to evaluate whether administering PCV13 on the first day of chemotherapy is non-inferior to vaccinating 2 weeks prior to chemotherapy initiation. Patients were randomly assigned to two study arms, and serum samples were collected at baseline and 4 weeks after vaccination to analyze the serologic response against Streptococcus pneumoniae using a multiplexed opsonophagocytic killing assay. Results Of the 92 patients who underwent randomization, 43 patients in arm A (vaccination 2 weeks before chemotherapy) and 44 patients in arm B (vaccination on the first day of chemotherapy) were analyzed. Immunogenicity was assessed by geometric mean and fold-increase of post-vaccination titers, seroprotection rates (percentage of patients with post-vaccination titers > 1:64), and seroconversion rates (percentage of patients with > 4-fold increase in post-vaccination titers). Serologic responses to PCV13 did not differ significantly between the two study arms according to all three types of assessments. Conclusion The overall antibody response to PCV13 is adequate in patients with gastric and colorectal cancer during adjuvant chemotherapy, and no significant difference was found when patients were vaccinated two weeks before or on the day of chemotherapy initiation.ope

Gefitinib-Induced Interstitial Lung Disease in Korean Lung Cancer Patients

PURPOSE: Interstitial lung disease (ILD) is a serious adverse effect of gefitinib. We examined the incidence and clinical characteristics of drug-induced ILD in Korean non-small cell lung carcinoma patients treated with gefitinib. MATERIALS AND METHODS: A retrospective cohort study was performed in non-small cell lung cancer (NSCLC) patients who started gefitinib treatment at Seoul National University Hospital from January 2002 through December 2011. Patients who developed new abnormal radiologic findings with respiratory symptoms after gefitinib treatment were defined as having possible adverse pulmonary reactions. The patients' medical records were reviewed independently by investigators to identify the causes of pulmonary toxicities. RESULTS: Among the 1,114 patients evaluated, 128 patients (11.5%) developed pulmonary adverse reactions after taking gefitinib. An infectious complication occurred in 98 patients (8.8%) and 15 patients (1.3%) developed ILD. Nine of the 15 patients (60.0%) with gefitinib-induced ILD experienced a fatal clinical course that met either the Common Terminology Criteria for Adverse Events grade 4 (n=3) or grade 5 (n=6). In the multivariate analysis, a lower serum albumin level (≤ 3.0 g/dL) at baseline was significantly associated with the development of gefitinib-induced ILD (odds ratio, 3.91; 95% confidence interval, 1.20 to 12.71). CONCLUSION: The incidence of gefitinib-induced ILD in Korean NSCLC patients was similar to that reported worldwide, but lower than values reported for Japanese population. ILD was usually a life-threatening adverse effect of gefitinib, and the development of ILD was significantly associated with a lower baseline serum albumin level.ope

Efficacy of Letrozole as First-Line Treatment of Postmenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer in Korea

Purpose: Letrozole showed efficacy and generally favorable toxicities, along with the convenience of oral administration in postmenopausal patients with hormone receptor (HR)-positive metastatic breast cancer (MBC). To the best of our knowledge, there have been no reports of the clinical outcomes in Korean patients, although letrozole is widely used in practice. Therefore, this studywas conducted to affirm the efficacy and toxicities of letrozole in Korean patients. Materials and methods: This study retrospectively analyzed 84 HR-positive MBC patients who had been treated with letrozole from January 2001 to December 2012. Clinicopathological characteristics and treatment history were extracted from medicalrecords. All patients received 2.5 mg letrozole once a day until there were disease progressions or unacceptable toxicity. Progression-free survival (PFS) was the primary endpoint, and secondary endpoints were overall survival (OS), objective response rate (ORR), and toxicity. Results: The median age of the subjects was 59.3 years. Letrozole treatment resulted in a median PFS of 16.8 months (95% confidence interval [CI], 9.8 to 23.8) and a median OS of 56.4 months (95% CI, 38.1 to 74.7). The ORR was 36.9% for the 84 patients with measurable lesions. Multivariate analysis revealed symptomatic visceral disease (hazard ratio, 3.437; 95% CI, 1.576 to 7.495; p=0.002) and a disease-free interval ≤ 2 years (hazard ratio, 2.697; 95% CI, 1.262 to 5.762; p=0.010) were independently associated with shorter PFS. However, sensitivity to adjuvant hormone treatment was not related to PFS. Letrozole was generally well tolerated. Conclusion: Letrozole showed considerable efficacy and tolerability as a first-line treatment in postmenopausal patients with HR-positive MBC.ope

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.ope

First-in-human study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors

Preclinical models suggest anticancer activity of IM156, a novel biguanide mitochondrial protein complex 1 inhibitor of oxidative phosphorylation (OXPHOS). This first-in-human dose-escalation study enrolled patients with refractory advanced solid tumors to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Eligible patients received oral IM156 every other day (QOD) or daily (QD) and were assessed for safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary signals of efficacy. 22 patients with advanced cancers (gastric, n = 8; colorectal, n = 3; ovarian, n = 3; other, n = 8) received IM156 100 to 1,200 mg either QOD or QD. There were no DLTs. However, 1,200 mg QD was not well tolerated due to nausea; 800 mg QD was determined as the RP2D. The most frequent treatment-related AEs (TRAEs) were nausea (n = 15; 68%), diarrhea (n = 10; 46%), emesis (n = 9; 41%), fatigue (n = 4; 18%) and abdominal pain, constipation, and blood lactate increased (n = 2 each; 9%). Grade 3 nausea (n = 3; 14%) was the only grade ≥ 3 TRAE. Plasma exposures increased dose proportionally; mean Day 27 area under the curve (AUC0-24) values were higher following QD administration compared to the respective QOD regimen. Stable disease (SD), observed in 7 (32%) patients (confirmed in 2 [9%]), was the best response. To our knowledge, this is the first phase 1 study of an OXPHOS inhibitor that established a RP2D for further clinical development in cancer. Observed AEs of IM156 were manageable and SD was the best response.ope

Spontaneous rupture of hepatic metastasis from a thymoma: A case report

Bleeding resulting from spontaneous rupture of the liver is an infrequent but potentially life threatening complication that may be associated with an underlying liver disease. A hepatocellular carcinoma or hepatic adenoma is frequently reported is such cases. However, hemoperitoneum resulting from a hepatic metastatic thymoma is extremely rare. Here, we present a case of a 62-year-old man with hypovolemic shock induced by ruptured hepatic metastasis from a thymoma. At the first hospital admission, the patient had a 45-mm anterior mediastinal mass that was eventually diagnosed as a type A thymoma. The mass was excised, and the patient was disease-free for 6 years. He experienced sudden-onset right upper quadrant pain and was again admitted to our hospital. We noted large hemoperitoneum with a 10-cm encapsulated mass in S5/8 and a 2.3-cm nodular lesion in the right upper quadrant of the abdomen. He was diagnosed with hepatic metastasis from the thymoma, and he underwent chemotherapy and surgical excision.ope

Nationwide pharmacovigilance data for cetuximab-induced anaphylaxis and predictive model validation using prospective specific IgE detection

Background: Cetuximab (chimeric monoclonal antibody to human epidermal growth factor receptor) is used to treat colorectal and head and neck cancers. Due to cross-reactivity with galactose-α-1,3-galactose (alpha-gal), it can induce hypersensitivity even at first administration. We aimed to determine the incidence and clinical manifestation of cetuximab-induced anaphylaxis, and to establish a means of predicting its incidence in patients ahead of treatment. Methods: Nationwide and single-center pharmacovigilance data from 2010 to 2017 were collected from the Korea Institute of Drug Safety-Korea Adverse Event Reporting System and Severance Regional Pharmacovigilance Center. Patients scheduled for cetuximab administration were enrolled prospectively. A skin prick test was carried out and serum IgE specific to cetuximab and cross-reactive allergens were measured. Reactions were monitored after cetuximab infusion. Results: Over 8 years, there were 23 reports of anaphylaxis nationwide. In a single-center study, incidence of cetuximab-induced anaphylaxis was 1.1%. Most anaphylaxis occurred at first injection (93.3%), even under pretreatment with anti-allergic drugs. Four of 64 patients (6.3%) experienced severe anaphylaxis. The median cetuximab-specific IgE titer was 6.9 kUA/L in patients experiencing anaphylaxis and 0 kUA/L in those who did not (P < 0.001). The results of alpha-gal, beef sIgE, and cetuximab skin prick testing were similar to those of cetuximab sIgE. Patients who did not experience hypersensitivity were negative in all 4 allergy tests. Its positive and negative predictive values were 100%. Conclusions: Specific IgE detection of cetuximab or alpha-gal can accurately predict cetuximab-induced anaphylaxis prior to first administration.ope

Clinical features and KRAS mutation in colorectal cancer with bone metastasis

Bone metastasis is known as a poor prognostic factor in colorectal cancer (CRC), but its clinical manifestations and outcomes are uncertain. CRC with bone metastasis was searched from January 2006 to April 2016. Of 11,551 CRC patients, 321 (2.7%) patients had bone metastasis. Bone-only metastasis was found in only 8.7% of patients. Synchronous bone metastasis was present in 147 (45.8%) patients. In patients with metachronous bone metastasis, the median time from CRC diagnosis to bone metastasis (TTB) was 27.2 months. KRAS mutation status was a marginally significant factor affecting TTB (median TTB, KRAS wild-type or mutation: 29 or 25.8 months, respectively, P = 0.068). Skeletal-related events (SREs) were noted in 200 (62.3%) patients. Median overall survival (OS) from diagnosis of bone metastasis was 8.0 months. On multivariate analysis, multi-organ metastasis, peritoneal metastasis, neutrophil-to-lymphocyte ratio (NLR) ≥ 2.7, and alkaline phosphatase (ALP) ≥ 123 were independent factors for OS. Palliative chemotherapy prolonged survival in CRC patients with bone metastasis (HR 0.25, 95% CI 0.2-0.33). In conclusion, bone metastasis of CRC is rare, but it is related to SREs. Most patients have other organ metastasis and survival is 8.0 months. Attention should be paid to bone metastasis in CRC patients.ope

A New Practical Desensitization Protocol for Oxaliplatin-Induced Immediate Hypersensitivity Reactions: A Necessary and Useful Approach

BACKGROUND AND OBJECTIVE: Desensitization protocols for patients with immediate hypersensitivity reactions (IHSRs) have proven to be effective, but they are not widely used in clinical practice because of impracticalities such as high cost, long procedure duration, and a lack of trained personnel. We aimed to determine the clinical characteristics of oxaliplatin-induced IHSRs and assess measures to protect against these reactions and to validate a new practical desensitization protocol. METHODS: We retrospectively reviewed 2640 cases of oxaliplatin IHSRs in 271 oxaliplatin users and prospectively used a newly designed desensitization protocol 32 times in 12 patients with hypersensitivity to platinum-based chemotherapy. The protocol consisted of increases in infusion rate every 15 minutes, regardless of the concentration of the chemotherapy agent in the infusion bags. RESULTS: Of the 271 patients administered oxaliplatin, 45 (16.6%) experienced IHSRs. Of 39 patients who experienced an IHSR but needed to continue oxaliplatin, 6 (15.4%) stopped treatment due to the reaction, and 33 (84.6%) continued despite the risk of further reactions. The new desensitization protocol was successfully completed in 12 patients (100%), but it was ineffective in 3 patients (all with a negative skin prick test), who experienced fever without urticaria. CONCLUSIONS: Many patients who experience oxaliplatin-induced IHSRs are required to stop first-line oxaliplatin-based chemotherapy or to continue without desensitization, with the associated risks. Our new desensitization protocol is practical and easy to use in clinical practice.ope

Phase 2 study of TAS-117, an allosteric akt inhibitor in advanced solid tumors harboring phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog gene mutations

TAS-117 is a potent and selective allosteric pan-v-akt murine thymoma viral oncogene homolog (Akt) inhibitor. We conducted a single-arm single-center phase 2 study of TAS-117 in heavily treated patients with tumors refractory to systemic chemotherapy and harboring phosphatidylinositol 3-kinase (PI3K)/Akt mutations. Patients with gastrointestinal (GI) cancers were orally administered 16 mg TAS-117 daily, and those with non-GI tumors were administered 24 mg on a 4 days on/3 days off schedule. The primary endpoint was overall response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), PFS ratio, safety, and tolerability. Thirteen patients were enrolled: eight with non-GI (breast, ovarian, endometrial, and non-small cell lung) and five with GI (colon, rectal, gastric, and gallbladder) cancers. Ten patients were treated with TAS-117 after ≥ 4 lines of therapy. Twelve patients showed PIK3 catalytic subunit alpha (PIK3CA) mutations; one harbored an Akt1E17K mutation. The median treatment duration was 1.4 months; the median number of treatment cycles was 2. The ORR was 8 %, and DCR was 23 %. The median PFS and OS were 1.4 and 4.8 months, respectively. Grade 3-4 treatment-related adverse events were anorexia (grade 3, 8 %) and hyperglycemia (grade 3, 8 %; grade 4, 8 %).Grade 3-4 treatment-related adverse events occurred in 27 % of grade 3 anorexia (9 %) and hyperglycemia (grade 3, 8 %; grade 4, 9\%). TAS-117 showed limited antitumor activity and manageable toxicity. Clinical efficacy was observed in patients with ovarian cancer harboring PIK3CA E545K mutations and in patients with breast cancer harboring PIK3CA H1047R and Akt1E17K mutations.Trial registration: This study was retrospectively registered with ClinicalTrial.gov (NCT03017521 on January 11, 2017).ope