Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

[Histopathological and autoradiographical studies of experimental brain tumors after continuous local chemotherapy--acute stage in rat models].

Continuous local chemotherapy has been evaluated as being an effective administration method and as a possible adjuvant therapy in the sensitivity aspect of the cell cycle for malignant glioma. However, neurotoxicity of anti-cancer agents in the normal brain and non-effective methods for the deeper part of the tumor seem to be the most serious problems. This study was initiated to evaluate histological findings, the uptake distribution, and neurotoxicity of the continuous local administration of isotope labeled anti-cancer agents in the brain tumor of rats. The experimental brain tumor of rats and the method of continuous local chemotherapy were as follows. The tumor was produced by intracerebral inoculation of cultured cells derived from rat brain tumor induced by Rous sarcoma virus (Kumanishi et al. strain). One week later Fluorouracil (5-6-3H) (17.7 Ci/m mol) and methotrexate (L-glutamyl 3-4-3H) (41.0 Ci/m mol) were administered into the brain tumors of rats utilizing a mini osmotic pump (Alzet Model 2001), respectively. We used five rats of various groups. The rats were sacrificed at various time intervals (6 hrs, 12 hrs, 24 hrs, 48 hrs, 72 hrs and 7 days). The tumor tissues for light microscopic autoradiography were fixed in 10% formalin for 24 hours. Sections for the light microscopic autoradiography were cut at 4 mu thick and coated with Sakura NR-M2 drips. Following exposure for one week at 4 degrees C, the sections were stained with Konidol X. Six hours after administration, slight radioactivity was distributed in the subarachnoid space and subpial brain tissue in the vicinity of the inserted tube. Twenty-four hours after administration, high radioactivity was clearly present in many tumor cells and phagocytes at the tube tip, but no radioactivity was observed in the deeper part of the tumor or normal brain tissue. In the vicinity of necrosis foci, acute toxic inflammation was also observed. In conclusion, this experimental study shows that these anti-cancer agents are capable of direct penetration into the neoplastic cells of an intracerebral tumor following continuous local administration. However, necrotic foci were small in size. The most serious side effect seemed to be the presence of acute toxic inflammation in the vicinity of the necrotic foci.

[Hypothalamic and pituitary function in brain death].

Hypothalamic and pituitary hormone levels were measured in 56 patients meeting the criteria of brain death proposed by the Japanese Ministry of Welfare. Pituitary hormone releasing tests were carried out in 39 patients. In addition, cerebral angiography and transcranial Doppler (TCD) were performed in 13 and six patients, respectively, just after hormone measurements. Serum hypothalamic and pituitary hormone levels were inconsistently high based on the half life time in the presumed absence of cerebral blood flow shown by angiography. The responses to releasing hormones were normal in 16 patients. TCD detected cerebral blood flow in the middle cerebral artery or ophthalmic artery in three patients who showed non-filling on angiography. Postmortem microscopic examination of the hypothalamus and anterior pituitary lobe revealed normal structure and cells intermingled with lytic changes and necrosis. This series suggests that some part of the hypothalamus and hypophysis may still be alive after brain death, although the function of these regions may be clinically insignificant.

[Studies on hyperthermia by the use of a thermosensitizing drug].

Hyperthermic treatment using ACNU combined with a thermosensitizing drug, methylglyoxal-bis-guanylhydrazone (MGBG), was studied in human gastric cancer xenotransplanted into nude mice. In order to increase the intra-cellular MGBG content, intraperitoneal injection of alpha-difluoromethylornithine(DFMO) 1000 mg/kg was performed twice with an interval of 6 hours and 50 mg/kg of MGBG was given at the time of the second administration of DFMO. After 6 hours of MGBG administration, ACNU 20 mg/kg was given intraperitoneally and, subsequently a 23-minute hyperthermia was carried out in a water bath at 43.5 degrees C. After 48 hours a second hyperthermia was performed by the same method. Tumor weight was estimated using Battelle's Columbus Institute protocol and the inoculated tumors, which were extirpated 60 minutes after 3H-thymidine injection at a prescribed interval after cessation of hyperthermia, were assayed biochemically for the determination of DNA biosynthesis. In mice given ACNU, DFMO, MGBG plus heat, considerably superior results were obtained. Although the DFMO plus MGBG group was inferior in antitumor activity to the ACNU only or heat only group, the DFMO, MGBG plus heat group showed much the same antitumor effects, compared to the ACNU plus heat group. These data suggest that the thermosensitizing efficacy of MGBG may be applicable for clinical use.

[A case of thalamic germinoma with crossed aphasia in a dextral (author's transl)].

We present a rare case of thalamic germinoma with crossed aphasia in a dextral. A patient, 17-year-old righat-handed male, was admitted to Nippon Medical School Hospital with chief complaints of headache, abnormality of visual field and speech disturbance. There were pigmentations on the back of hand, foot and the perineum. Neurological examination revealed left homonymous hemianopsia, right slight degree of ptosis, left facial palsy, a mild paresis of the left upper extremity and motor aphasia. Right carotid angiography showed marked unrolling and midline shift of right anterior cerebral artery. CT scan revealed ring-like high density area in the right thalamic region, which was enhanced after constant infusion. Brain scintigraphy also showed an abnormal accumulation at the same site. The hen-egg sized tumor of 40 g. weight was almost totally removed by the right fronto-parietal craniotomy. The tumor was characterized histologically by the so-called two cell pattern with teratomatous components. As postoperative treatment local injection of adriamycine, irradiation and immunotherapy with picibanil were performed, and then left hemiparesis was markedly improved without sign of recurrence. Language evaluation was performed after operation. There were dysarthria, remarkable word amnesia, paraphasia and perseveration. Repetition was also impaired. His speech function was concluded to be a mixed type aphasia mainly composed of Broca's aphasia. The speech function of thalamus and crossed aphasia with dextrales were discussed.