Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Beyond Progressive Disease: A Retrospective Analysis for Japanese Patients with Activating EGFR Mutations

IntroductionIt is not determined whether the continuous use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is reasonable for patients with activating EGFR mutations, who have progressed with the drug.MethodsWe retrospectively analyzed the data from 2002 to 2010 of consecutive patients who had advanced non–small-cell lung cancer (NSCLC) harboring activating EGFR mutations and showed radiological disease progression after EGFR-TKI treatment as the first-line or second-line setting. We classified them into two groups: continuous EGFR-TKI and switching to chemotherapy, and compared the clinical outcomes. Multivariate analysis for survival was performed including age, sex, Eastern Cooperative Oncology Group performance status (0–1/ 2–4), brain metastasis, EGFR mutations (deletions in exon 19 versus L858R), continuous EGFR-TKI (yes/no), and initiation of EGFR-TKI (first versus second).ResultsA total of 551 NSCLC patients were screened for EGFR mutations in the period, and 186 patients had activating EGFR mutations. To explore the potential use of EGFR-TKI beyond progressive disease (PD), 64 patients were selected and analyzed. There were 13 men and 51 women, and median age was 65.5 years (range, 42–86). Among them, 31 patients had deletions in exon 19, and 33 had point mutation of L858R in exon 21. Thirty-nine patients were continuing EGFR-TKI beyond PD; 25 patients were switched to cytotoxic chemotherapy alone. The median overall survival was 32.2 months in the patients continuing EGFR-TKI, and 23.0 months in the patients switching to chemotherapy, presenting a significant difference between the two groups (p = 0.005). Cox analysis showed that continuous EGFR-TKI after PD (hazards ratio 0.42, 95% confidence interval: 0.21–0.83, p = 0.013) was associated with improved survival.ConclusionContinuous use of EGFR-TKI beyond PD may prolong overall survival compared with switching to cytotoxic chemotherapy in patients with activating EGFR mutations. A prospective study will be needed to confirm our results

Distinguishing intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma using precontrast and gadoxetic acid-enhanced MRI

PURPOSEWe aimed to gain further insight in magnetic resonance imaging characteristics of mass-forming intrahepatic cholangiocarcinoma (mICC), its enhancement pattern with gadoxetic acid contrast agent, and distinction from poorly differentiated hepatocellular carcinoma (pHCC).METHODSFourteen mICC and 22 pHCC nodules were included in this study. Two observers recorded the tumor shape, intratumoral hemorrhage, fat on chemical shift imaging, signal intensity at the center of the tumor on T2-weighted image, fibrous capsule, enhancement pattern on arterial phase of dynamic study, late enhancement three minutes after contrast injection (dynamic late phase), contrast uptake on hepatobiliary phase, apparent diffusion coefficient, vascular invasion, and intrahepatic metastasis.RESULTSLate enhancement was more common in mICC (n=10, 71%) than in pHCC (n=3, 14%) (P < 0.001). A fat component was observed in 11 pHCC cases (50%) versus none of mICC cases (P = 0.002). Fibrous capsule was observed in 13 pHCC cases (59%) versus none of mICC cases (P < 0.001). On T2-weighted images a hypointense area was seen at the center of the tumor in 43% of mICC (6/14) and 9% of pHCC (2/22) cases (P = 0.018). Other parameters were not significantly different between the two types of nodules.CONCLUSIONThe absence of fat and fibrous capsule, and presence of enhancement at three minutes appear to be most characteristic for mICC and may help its differentiation from pHCC

Efficacy of preoperative transcatheter arterial chemoembolization combined with systemic chemotherapy for treatment of unresectable hepatoblastoma in children

Abstract Purpose The purpose of this study was to evaluate, retrospectively, the clinical efficacy of preoperative transcatheter arterial chemoembolization (TACE) combined with systemic chemotherapy for unresectable hepatoblastoma. Materials and methods Five boys and three girls (mean age 15.2 months) were treated with preoperative TACE combined with systemic chemotherapy for unresectable hepatoblastomas. Mean tumor diameter and mean alfafetoprotein (AFP) level were 11.8 cm and 549,386 ng/mL, respectively. Pretreatment, the extent of disease (PRE-TEXT) was: II, 1; III, 6; IV, 1. For all patients, preoperative systemic chemotherapy was administered before TACE. At each TACE, carboplatin and adriamycin mixed with iodized oil were infused into the feeding arteries. Tumor response and prognosis after treatment were evaluated. Results TACE resulted in few Grade 1 adverse effects (AEs), without G3 or more AEs, according to CTACAE 3.0. Mean tumor shrinkage was 60.9 %, and the mean AFP decrease from initial levels was 94.8 %. In all cases TACE combined with systemic chemotherapy enabled subsequent safe and complete surgical resection. After a mean followup of 59 months, tumor-free survival was 75 %. Conclusion Preoperative TACE combined with systemic chemotherapy was effective in inducing surgical resectability of unresectable hepatoblastoma

Potential of Photodynamic Therapy Based on Sugar-Conjugated Photosensitizers

In 2015, the Japanese health insurance approved the use of a second-generation photodynamic therapy (PDT) using talaporfin sodium (TS); however, its cancer cell selectivity and antitumor effects of TS PDT are not comprehensive. The Warburg effect describes the elevated rate of glycolysis in cancer cells, despite the presence of sufficient oxygen. Because cancer cells absorb considerable amounts of glucose, they are visible using positron emission tomography (PET). We developed a third-generation PDT based on the Warburg effect by synthesizing novel photosensitizers (PSs) in the form of sugar-conjugated chlorins. Glucose-conjugated (tetrafluorophenyl) chlorin (G-chlorin) PDT revealed significantly stronger antitumor effects than TS PDT and induced immunogenic cell death (ICD). ICD induced by PDT enhances cancer immunity, and a combination therapy of PDT and immune checkpoint blockers is expected to synergize antitumor effects. Mannose-conjugated (tetrafluorophenyl) chlorin (M-chlorin) PDT, which targets cancer cells and tumor-associated macrophages (TAMs), also shows strong antitumor effects. Finally, we synthesized a glucose-conjugated chlorin e6 (SC-N003HP) that showed 10,000–50,000 times stronger antitumor effects than TS (IC50) in vitro, and it was rapidly metabolized and excreted. In this review, we discuss the potential and the future of next-generation cancer cell-selective PDT and describe three types of sugar-conjugated PSs expected to be clinically developed in the future