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.

Heating properties of the re-entrant type cavity applicator for brain tumor with several resonant frequencies.

We have proposed the re-entrant resonant cavity applicator system for non-invasive brain tumor hyperthermia treatment. In this method, a human head is placed in the gap of the inner electrodes. A brain tumor is heated with the electromagnetic field stimulated in the cavity without contact between the human head and the applicator. We have already presented the effectiveness of the heating properties of this system with cylinder-type agar phantoms and by computer simulations. This paper discusses the heating properties of the developed system with the human head-type agar phantom for brain tumor hyperthermia treatment. First, in order to heat deep brain tumors, we tried to heat the human head-type agar phantom by using several electromagnetic field patterns of the resonant frequency. We found that the temperature distributions can be controlled inside the agar phantom by changing the resonant frequencies. Second, to heat local and deep areas of the agar phantom, we tried to achieve heating using the two different resonant frequencies. We found distinct heating properties by changing the electromagnetic field patterns of resonant frequencies. From these results, it was found that our developed heating system can be applied to hyperthermia treatments of deep-seated brain tumors. Further, by changing resonant frequency, treatment can very correspond to the size and the position of a tumor.

Improvement of the matching speed of AIMS for development of an automatic totally tuning system for hyperthermia treatment using a resonant cavity applicator.

In this paper, we discuss the improvement of the speed of AIMS (Automatic Impedance Matching System) to automatically make impedance matching for a re-entrant resonant cavity applicator for non-invasive deep brain tumors hyperthermia treatments. We have already discussed the effectiveness of the heating method using the AIMS, with experiments of heating agar phantoms. However, the operating time of AIMS was about 30 minutes. To develop the ATT System (Automatic Totally Tuning System) including the automatic frequency tuning system, we must improve this problem. Because, when using the ATTS, the AIMS is used repeatedly to find the resonant frequency. In order to improve the speed of impedance matching, we developed the new automatic impedance matching system program (AIMS2). In AIMS, the stepping motors were connected to the impedance matching unit's dials. These dials were turned to reduce the reflected power. AIMS consists of two phases: all range searching and detailed searching. We focused on the three factors affecting the operating speed and improved them. The first factor is the interval put between the turning of the motors and AD converter. The second factor is how the steps of the motor when operating all range searching. The third factor is the starting position of the motor when detail searching. We developed the simple ATT System (ATT-beta) based on the AIMS2. To evaluate the developed AIMS2 and ATT- beta, experiments with an agar phantom were performed. From these results, we found that the operating time of the AIMS2 is about 4 minutes, which was approximately 12% of AIMS. From ATT-beta results, it was shown that it is possible to tune frequency and automatically match impedance with the program based on the AIMS2.

Development of automatic impedance matching system for hyperthermia treatment using resonant cavity applicator.

In this paper, we discuss a new system to make impedance matching automatically for a re-entrant resonant cavity applicator for brain tumor hyperthermia treatment non-invasively. We have already discussed about the effectiveness of the heating method using manual type impedance matching controller, with experiments of heating an agar phantom and computer simulations. However, it becomes difficult to perform an accurate impedance matching as resonant frequency becomes high. Here, in order to make a more accurate impedance matching, we developed the automatic impedance matching system (AIMS). We noticed that the reflected power was generated when the impedance matching was not complete. In this system, therefore, to reduce the reflected power fed back, the stepping motor to turn the dial of variable capacitors is controlled by developed software. To evaluate the developed AIMS, the experiments of heating the agar phantom were performed. From these results, we found that the temperature rise of the agar phantom by using AIMS was about 180% of using manual type controller under the same heating condition. It was found that the proposed system was very effective for hyperthermia treatment using resonant cavity applicator even when the resonant frequency was high.

Heating properties of re-entrant resonant cavity applicator for brain tumor with simple head model.

We have already confirmed the effectiveness of the re-entrant resonant cavity applicator system with non-invasive experiments of heating cylindrical agar phantoms and computer simulations. This paper discusses the heating properties of the developed heating system with a human head model made of agar for brain tumor hyperthermia treatment. First, we present the results of heating a uniform agar head model with the developed heating system. In the experiments, the temperature rise at the center of the agar was about 8 degrees C, it was found that the center of the agar is heated to maximum temperature non-invasively. Second, we present the results of heating a non-uniform agar head model having an oral cavity and a nasal cavity. We found that the center of the agar can be heated to maximum temperature as well as uniform agar head model. From these results, it is confirmed that the possibility of effective hyperthermia for various types of deep-seated brain tumors.