Search

S-1 plus cisplatin is the standard chemotherapy for recurrent gastric cancer. While depression and delirium are frequent in cancer patients, hypomania during chemotherapy is rare. We describe a rare case of hypomania during S-1 plus cisplatin treatment for recurrent gastric cancer. A 66-year-old woman, with no previous psychiatric disorder, received S-1 plus cisplatin for recurrent gastric cancer. She showed peculiar behavior. Physical examination, urine, blood and imaging findings were normal. There was no gastric cancer progression. During psychiatric consultation, she behaved inappropriately. However, she behaved normally while performing daily activities. She manifested a persistently elevated, expansive or irritable mood, clearly different from her usual non-depressed state, meeting hypomania diagnostic criteria. Her condition did not require chemotherapy discontinuation or additional medication. During the second and subsequent S-1 plus cisplatin cycles, symptoms were stable. Cancer patients often have adjustment disorders, depression and delirium, but rarely hypomania. Our patient showed no significant changes in blood biochemistry and brain and whole body imaging. While S-1 plus cisplatin-induced hypomania cannot be excluded, hypomanic symptoms did not improve during the chemotherapy rest period, nor was there deterioration during subsequent cycles, suggesting drug-induced mania to be unlikely. Possible onset mechanisms include manic defense phenomena, common with stressful life events. There are no reports of recurrent gastric cancer patients experiencing hypomania during S-1 or S-1 plus cisplatin therapy, i.e. our patient represents a rare course. Clinicians should recognize psychosis or mood disorders during gastric cancer treatment. Further accumulation of such rare cases might elucidate pathological mechanisms underlying hypomania in cancer patients.

Dear Editor, The incidence of and mortality from pancreatic cancer are increasing in Japan. Pancreatic cancer remains one of the most serious malignancies.1 Although phase III studies in patients with advanced pancreatic cancer report that overall survival is prolonged by gemcitabine alone2 or gemcitabine plus nab-paclitaxel,3 investigations of new treatment options are essential. Intensive three-drug combination chemotherapy with fluorouracil, oxaliplatin and irinotecan (FOLFIRINOX) can dramatically prolong overall survival in pancreatic cancer.4 FOLFIRINOX was reported in this journal to have favorable efficacy and acceptable toxicity profiles in chemotherapy-naive Japanese patients with metastatic pancreatic cancer. However, a critical review of the article indicated that repeating FOLFIRINOX in the original dosage and treatment schedule is intolerable even in selected Japanese patients because the dose intensity of bolus fluorouracil was only 15.4%, and dose reduction and cycle delay were required by 88.9% of the patients.5 The authors should have stressed the need for dose reduction and prolongation of treatment interval. We suppose that the study by Okusaka et al. underestimated toxicity in Japanese patients for several reasons. First, the authors and sponsor of the study did not adequately evaluate the safety of FOLFIRINOX because they did not conduct any phase I dose-escalation studies to determine the optimal dosage of the three drugs. We have reported the results of a phase I study of FOLFOXIRI in patients with colorectal cancer, which used a similar three-drug combination regimen,6 and the recommended dosage was much lower than that in the study by Falcone et al.7 Second, the threshold criteria defining tolerability in the 10 patients were unrealistically higher than the conventional criteria used to define dose-limiting toxicity in phase I trials.6 Third, both the Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devises Agency strongly recommend that new drug applications in Japan should include the identical dosage and regimen used in global or bridging studies.8 Topotecan was approved for the treatment of ovarian cancer in Japan on the basis of a “public knowledge-based application”without conducting large clinical trials; in clinical practice, however, the approved dose is too toxic for Japanese patients with ovarian cancer.9 In conclusion, the dosage and treatment schedule of FOLFIRINOX combination chemotherapy should be more carefully evaluated in Japanese patients with pancreatic cancer treated in a clinical practice setting to avoid severe life-threatening toxic effects.

Whether microdosing studies can be used to evaluate the human pharmacokinetics of new anticancer drugs remains unclear. The disposition of docetaxel in cancer patients is linear in terms of dose proportionality. We examined whether the pharmacokinetics of docetaxel in a clinically relevant therapeutic dose could be predicted from the pharmacokinetics of a microdose of docetaxel in Japanese patients with cancer.A microdose of docetaxel (100 μg/patient) was given by 5-min intravenous infusion on day 1, followed by a therapeutic dose of docetaxel (60-75 mg m(-2)), given by 1-h intravenous infusion on day 8. Plasma docetaxel was analyzed by liquid chromatography-tandem mass spectrometry. A two-compartment pharmacokinetic model was used to calculate the area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf).Nine patients received both a microdose and therapeutic dose of docetaxel. The AUC0-inf after microdosing was 3640 ± 1150 ng h L(-1), while that after therapeutic dosing adjusted to 100 mg/patient was 2230 ± 757 µg h L(-1). The ratio of docetaxel clearance in therapeutic dose to that in microdose was 1.8 (P = 0.0041). Plasma α1-acid glycoprotein concentrations negatively correlated with docetaxel clearance at therapeutic dose, whereas the trend was weak at microdose.Docetaxel clearance showed marginal nonlinearity between microdose and therapeutic dose, presumably because of saturation of plasma protein binding; however, the magnitude was within twofold, allowing practically acceptable extrapolation.

610 Background: Systemic chemotherapies can convert irresectable liver metastases (LM) to resectable in some cases of metastatic colorectal cancer (mCRC). Secondary surgical resection is now considered to be a worthwhile therapeutic aim in mCRC with LM. There is a clear correlation between radiological response and secondary resection rate (SRR) (Jones RP et al. Eur J Cancer 2014). However, it remains unclear which monoclonal antibodies contribute the improvement of SRR, Bmab or anti-EGFRs. Methods: We performed a systematic review of literature published between Jan 1998 and Aug 2015 to analyze the relationship between SRR and antibodies in mCRC treated with 1st-line chemotherapy. Phase II or III trials which obtained the information of response rate (RR) and resection of LM were included in this analysis. The RR, SRR, and R0 SRR were compared between Bmab- and anti-EGFR (cetuximab or panitumumab)-containing regimen groups using Mann–Whitney U test. The correlation between RR and R0 SRR was assessed by Spearman's rank correlation coefficient. Results: A total of 40 studies were enrolled: 33 treatment arms from 16 trials for liver-limited disease (LLD) and 31 arms from 24 trials for non-LLD. The result is shown below. No difference was observed in SRR and R0 SRR between Bmab and anti-EGFR groups. In addition, a preliminary analysis showed that RR had significantly positive association with R0 SRR in anti-EGFR group (R2 0.74, P=0.027 for non-LLD; R2 0.88, P=0.018 for LLD) but not in Bmab group (P=0.27 for non-LLD, P=0.12 for LLD). Conclusions: The SRR and R0 SRR were comparable between Bmab and anti-EGFRs, even in mCRC with LLD, while RR correlated with R0 SSR in anti-EGFRs but not in Bmab. These findings warrant validation in ongoing trials to compare the targeted-agents. [Table: see text]

We report here a case of reversible posterior leukoencephalopathy syndrome(RPLS)induced by modified FOLFOX6(mFOLFOX6). The patient was a 43-year-old woman who had sigmoid colon cancer with multiple liver metastases. Treatment with mFOLFOX6 was started. Early in the morning of day 11, the patient was transported by ambulance to the hospital due to nausea with headache, disturbed consciousness, and visual disturbance. The patient experienced sudden, severe nausea and subsequently presented generalized tonic-chronic seizures. The seizures subsided after treatment. On the evening of day 11, another episode of generalized tonic-chronic seizures occurred. Status epilepticus developed and tracheal intubation was performed for airway protection. Cranial MRI showed increased signal intensity in both occipital lobes, centered on the boundary between the gray and white matter on FLAIR images. Her condition stabilized with no seizure recurrence following intubation. Although hypertension was present on admission to the emergency room, blood pressure gradually fell to within the normal range without antihypertensive treatment. She was extubated on day 18. There were no neurologic sequelae. Cranial MRI on day 40 showed that the increased intensity in both occipital lobes had almost disappeared. Because the patient's condition was characterized by a reversible central nervous system disorder, RPLS was diagnosed.

A 28-year-old man was referred to Hakodate Municipal Hospital for examination of multiple pulmonary nodules detected on a medical check-up. His chest CT demonstrated well-defined multiple nodules with random distribution. 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed abnormal uptake in the pulmonary nodules and the hilar, mediastinal lymph node. No other accumulation was observed outside the thorax. Transbronchial lung biopsy did not yield a diagnosis. Based on the high accumulation on FDG-PET, we suspected a malignant tumor and performed right S4 wedge resection under video assisted thoracoscopy. Considering the histologocal and immunohistological findings, we diagnosed pulmonary hyalinizing granuloma. No treatment was given and subsequently stable disease was obtained on chest radiography. The follow-up FDG-PET showed standardized uptake value reduction. Pulmonary hyalinizing granuloma is infrequent and benign, but has been reported to possibly progress to lymphoproliferative disease. Consequently, FDG-PET is valuable to evaluate the activity of the disease itself and the possibility of transition.

3088^ Background: Dovitinib is a tyrosine kinase inhibitor with demonstrated inhibitory activity against FGFRs, VEGFRs, and PDGFRs in vivo. Based on responses observed in renal cell carcinoma, breast cancer, AML, melanoma, and multiple myeloma in clinical studies in the West, we investigated dovitinib in Japanese patients (pts). Methods: This multicenter phase I study determined the maximum tolerated dose (MTD) of dovitinib based on the occurrence of dose-limiting toxicity (DLT) in Japanese pts with advanced solid tumors. Following a 2-day pharmacokinetic (PK) run-in period, dovitinib was administered orally once daily on a 5-days-on/2-days-off schedule in 28-day cycles until disease progression or withdrawal. The planned dose range was 100-600 mg/day. A 2-parameter Bayesian logistic regression model based on the principle of escalation with overdose control was used to estimate the MTD. Results: In total, 28 pts received dovitinib: 100 mg (n = 3), 200 mg (n = 3), 300 mg (n = 7), 400 mg (n = 9), and 500 mg (n = 6). The median age was 58.5 years (range, 30-76); 16 of 28 pts (57%) were male. All pts had stage IV disease, with an ECOG performance status of 0 or 1. Pts completed a median of 3 cycles. One pt is currently ongoing in the study (peritoneal adenocarcinoma, 400-mg cohort, cycle 19), 23 discontinued due to disease progression, and 4 discontinued due to adverse events (AEs). All DLTs were grade 3: anorexia (n = 1; 300 mg), nausea/vomiting (n = 1; 400 mg), liver function disorder (n = 1; 400 mg), and increased alanine transaminase (n = 1; 500 mg). The most common grade 3/4 AEs (occurring in >10% of pts) suspected to be related to study drug were lymphopenia (18%), neutropenia (14%), abnormal hepatic function (14%), decreased white blood cell count (14%), decreased appetite (14%), and hypertension (14%). Best responses were confirmed partial response in 1 pt (4%; peritoneal adenocarcinoma, 400-mg cohort), stable disease in 9 pts (32%), and progressive disease in 10 pts (36%). No treatment-related deaths have been reported. Safety and PK parameters were comparable to those of non-Japanese pts in the global study. Conclusions: The study has completed enrollment. Dovitinib was found to be tolerable at doses up to 500 mg, which was declared as the MTD in Japanese pts.

There is currently no standard method for the detection of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status in colorectal tumors. In the present study, we compared the KRAS mutation detection ability of four methods: direct sequencing, Scorpion-ARMS assaying, pyrosequencing and multi-analyte profiling (Luminex xMAP). We evaluated 73 cases of metastatic colorectal cancer (mCRC) resistant to irinotecan, oxaliplatin and fluoropyrimidine that were enrolled in an all-case study of cetuximab. The KRAS mutation detection capacity of the four analytical methods was compared using DNA samples extracted from tumor tissue, and the detection success rate and concordance of the detection results were evaluated. KRAS mutations were detected by direct sequencing, Scorpion-ARMS assays, pyrosequencing and Luminex xMAP at success rates of 93.2%, 97.3%, 95.9% and 94.5%, respectively. The concordance rates of the detection results by Scorpion-ARMS, pyrosequencing and Luminex xMAP with those of direct sequencing were 0.897, 0.923 and 0.900 (κ statistics), respectively. The direct sequencing method could not determine KRAS mutation status in five DNA samples. Of these, Scorpion-ARMS, pyrosequencing and Luminex xMAP successfully detected three, two and one KRAS mutation statuses, respectively. Three cases demonstrated inconsistent results, whereby Luminex xMAP detected mutated KRAS in two samples while wild-type KRAS was detected by the other methods. In the remaining case, direct sequencing detected wild-type KRAS, which was identified as mutated KRAS by the other methods. In conclusion, we confirmed that Scorpion-ARMS, pyrosequencing and Luminex xMAP were equally reliable in detecting KRAS mutation status in mCRC. However, in rare cases, the KRAS status was differentially diagnosed using these methods.