A Japanese prospective multi-institutional feasibility study on accelerated partial breast irradiation using multicatheter interstitial brachytherapy: clinical results with a median follow-up of 60 months.

BACKGROUND: We carried out the first multi-institutional prospective study on accelerated partial breast irradiation (APBI) via multicatheter interstitial brachytherapy in a shorter period for early breast cancer in Japan. METHODS: Patient eligibility criteria included positive hormone receptors, tumors ≤ 3 cm and TNM stage pN0M0. After breast-conserving surgery (Japanese cylindrical resection) and histological confirmation of negative surgical margins and the absence of lymph node metastasis, applicator implantation was performed either postoperatively or intraoperatively. High-dose-rate brachytherapy of 36 Gy in 6 fractions was delivered. RESULTS: Forty-six patients from six institutions received this treatment regimen, and the median follow-up time was 60 months (range 57-67 months). The median resected breast tissue volume was 81 cm3 (range 28-260 cm3). No Grade 4 late sequela, local recurrence nor death due to breast cancer were observed. Grade 2-3 sequelae such as rib fracture (2%), soft tissue necrosis (9%), fibrosis (20%), and breast pain (9%) were observed. The resected breast tissue volumes of the patients who had Grade ≥ 2 fibrosis and Grade < 2 fibrosis were 105.9 ± 32.3 cm3 and 76.3 ± 45.6 cm3, respectively, p = 0.02. The overall cosmetic outcome score of Excellent/Good was 74% at 60 months after APBI. Grade ≥ 1 fibrosis was observed in 44% and 92% of patients who scored Excellent/Good and Fair/Poor, respectively, p = 0.004. CONCLUSIONS: This study showed excellent local control and survival results with minimal late sequelae.

Non-invasive quantitative measures of qualitative grading effectiveness as the indices of acute radiation dermatitis in breast cancer patients.

BACKGROUND: Recent improvement of machinery evaluation for the skin changes in various therapies enabled us to evaluate fine changes quantitatively. In this study, we performed evaluation of the changes in radiation dermatitis (RD) using quantitative and qualitative methods, and verified the validity of the conventional qualitative assessment for clinical use. METHODS: Forty-three breast cancer patients received conventional fractionated radiotherapy to whole breast after breast-conserving surgery. Erythema, pigmentation and skin dryness were evaluated qualitatively, and biophysical parameters of RD were measured using a Multi-Display Device MDD4 with a Corneometer for capacitance, a Tewameter for transepidermal water loss (TEWL), a Mexameter for erythema index and melanin index. Measurements were performed periodically until 1 year. RESULTS: The quantitative manifestations developed serially from skin erythema followed by dryness and pigmentation. Quantitative measurements detected the effects of irradiation earlier than that of qualitative indices. However, the grades of the domains in RD by qualitative and quantitative assessment showed similar time courses and peak periods. However, no significant correlation was observed between the skin dryness grade and skin barrier function. In contrast to serial increase in pigmentation grades, melanin index showed initial decrease followed by marked increase with significant correlation with pigmentation grades. CONCLUSION: Subjectively and objectively measured results of RD were almost similar course and peak points through the study. Therefore, validity of the conventional qualitative scoring for RD is confirmed by the present quantitative assessments. Instrumental evaluations revealed the presence of modest inflammatory changes before radiotherapy and long-lasting skin dryness, suggesting indication of intervention for RD.

Results of a nationwide survey on Japanese clinical practice in breast-conserving radiotherapy for breast cancer.

The Breast Cancer Group of the Japanese Radiation Oncology Study Group conducted a nationwide questionnaire survey on the clinical practice of postoperative radiotherapy for breast-conserving treatment for breast cancer. This questionnaire consisted of 18 questions pertaining to the annual number of treated patients, planning method, contouring structure, field design, dose-fractionated regimen, application of hypofractionated radiotherapy, boost irradiation, radiotherapy for synchronously bilateral breast cancer, and accelerated partial breast irradiation. The web-based questionnaire had responses from 293 Japanese hospitals. The results indicated the following: treatment planning is performed using relatively similar field designs and delivery methods; the field-in-field technique is used at more than one-third of institutes; the commonest criteria for boost irradiation is based on the surgical margin width (≤5 mm) and the second commonest criteria was age (≤40 or ≤50 years), although some facilities applied a different age criterion (>70 years) for omitting a tumor bed boost; for conventional fractionation, almost all institutes delivered 50 Gy in 25 fractions to the conserved whole breast and 10 Gy in 5 fractions to the tumor bed. This survey revealed that 43% of hospitals offered hypofractionated radiotherapy, and the most common regimens were 42.56 Gy in 16 fractions for whole-breast irradiation and 10.64 Gy in 4 fractions for boost irradiation. Almost all of the facilities irradiated both breasts simultaneously for synchronously bilateral breast cancer, and accelerated partial breast irradiation was rarely offered in Japan. This survey provided an overview of the current clinical practice of radiotherapy for breast-conserving treatment of breast cancer in Japan.

Case report of a dose-volume histogram analysis of rib fracture after accelerated partial breast irradiation: interim analysis of a Japanese prospective multi-institutional feasibility study.

We initiated the first multi-institutional prospective study of accelerated partial breast irradiation for early breast cancer in Japan. Our early clinical results showed that the treatment methods were technically reproducible between institutions and showed excellent disease control at a median follow-up of 26 months in our previous report. At present, total 46 patients from six institutions underwent the treatment regimen from October 2009 to December 2011, and the median follow-up time was 60 months (range, 57-67 months). In 46 patients, we experienced one patient who had rib fracture as a late complication. The dose-volume histogram (DVH) result of this patient was analyzed. The D0.01cc, D0.1cc, and D1cc values of the patient were 913, 817, and 664 cGy per fraction, respectively. These values were the highest values in 46 patients. The average D0.01cc, D0.1cc, and D1cc values of the other 45 patients were 546, 500, and 419, respectively, cGy per fraction. From this result, DVH values showing high-dose irradiated volume (D0.01cc, D0.1cc, and D1cc) seem to be a good predictive factor of rib fracture for accelerated partial breast irradiation. However, further investigation is necessary because of the small number of patients investigated.

Development of Gentle Slope Light Guide Structure in a 3.4 µm Pixel Pitch Global Shutter CMOS Image Sensor with Multiple Accumulation Shutter Technology.

CMOS image sensors (CISs) with global shutter (GS) function are strongly required in order to avoid image degradation. However, CISs with GS function have generally been inferior to the rolling shutter (RS) CIS in performance, because they have more components. This problem is remarkable in small pixel pitch. The newly developed 3.4 µm pitch GS CIS solves this problem by using multiple accumulation shutter technology and the gentle slope light guide structure. As a result, the developed GS pixel achieves 1.8 e- temporal noise and 16,200 e- full well capacity with charge domain memory in 120 fps operation. The sensitivity and parasitic light sensitivity are 28,000 e-/lx·s and -89 dB, respectively. Moreover, the incident light angle dependence of sensitivity and parasitic light sensitivity are improved by the gentle slope light guide structure.

Uncertainty of cosmetic evaluation after accelerated partial breast irradiation: interim analysis of a Japanese prospective multi-institutional feasibility study.

PURPOSE: We conducted a multi-institutional prospective study on accelerated partial breast irradiation (APBI) using interstitial brachytherapy. The clinical results over a minimum follow-up period of 30 months are presented here. MATERIALS AND METHODS: Forty-six patients with breast cancer were treated with breast-conserving surgery and postoperative APBI. After confirmation of negative surgical margins and negative lymph nodes, a high-dose-rate brachytherapy protocol of 36 Gy/6 fractions was carried out. All clinical data were prospectively collected using the Common Terminology Criteria for Adverse Events ver. 3.0. RESULTS: No recurrence was observed. Cumulative rates of grade 2 or higher late sequelae were 25% for fibrosis, 2% for fractures, 9% for pain, and 9% for soft tissue necrosis. Rates of excellent or good cosmetic results as assessed by the physician and patient were 93 and 89% at the 12-month follow-up and 76 and 74% at the 30-month follow-up, respectively. Large volumes of resected tissue in small breasts were associated with fibrosis of grade 2 or higher. CONCLUSION: APBI in Japanese women provides satisfactory clinical results except for cosmetic outcomes. There is some difficulty with the assessment of fibrosis and cosmetic outcomes, especially in patients with small breasts. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000001677.

A Japanese prospective multi-institutional feasibility study on accelerated partial breast irradiation using interstitial brachytherapy: clinical results with a median follow-up of 26 months.

BACKGROUND: A Japanese prospective multi-institutional feasibility study on accelerated partial breast irradiation using interstitial brachytherapy was performed. The first clinical results were reported with a median follow-up of 26 months. PATIENTS AND METHODS: Forty-six female breast cancer patients with positive hormone receptors and tumors ≤3 cm, pN0M0, completed the protocol treatment. After breast-conserving surgery and histological confirmation of negative surgical margins and pN0, brachytherapy applicators were implanted either postoperatively (n = 45) or intraoperatively (n = 1). High-dose-rate brachytherapy of 36 Gy/6 fractions was delivered. All clinical data were prospectively collected using case report forms and the Common Terminology Criteria for Adverse Events ver.3.0. RESULTS: At the median follow-up of 26 months, no breast cancer recurrence of any type was observed. Sequelae ≥G2 were dermatitis (G2, 7 %), fibrosis (G2, 11 %; G3, 4 %), fracture (G2, 2 %), pain (G2, 7 %; G3, 2 %), and soft tissue necrosis (G2, 6 %). Cosmetic outcomes evaluated by excellent/good scores were 100 % at pre-therapy (n = 46), 94 % at 12 months (n = 46), and 81 % at 24 months (n = 36), respectively. CONCLUSIONS: Disease control and sequelae were satisfactory due to the strict eligibility and protocol-defined treatment parameters. The cosmetic outcomes were comparable to those of previous Japanese breast-conserving therapy series.

A Japanese prospective multi-institutional feasibility study on accelerated partial breast irradiation using interstitial brachytherapy: treatment planning and quality assurance.

BACKGROUND: In Japan, breast-conserving surgery with closed cavity has generally been performed for breast cancer patients, and accelerated partial breast irradiation (APBI) is considered difficult because Asian females generally have smaller breast sizes than Western females. Therefore, common identification of target and treatment plan method in APBI is required. A prospective multicenter study was conducted in Japan to determine institutional compliance with APBI using high-dose-rate interstitial brachytherapy (ISBT) designed for Japanese female patients. METHODS: For this study, 46 patients were recruited at eight institutions from January 2009 to December 2011. The reproducibility of the ISBT-APBI plan was evaluated using three criteria: (1) minimum clinical target volume dose with a clip dose ≥ 6 Gy/fraction, (2) irradiated volume constraint of 40-150 cm(3), and (3) uniformity of dose distribution, expressed as the dose non-uniformity ratio (DNR, V150/V100) < 0.35. The ISBT-APBI plan for each patient was considered reproducible when all three criteria were met. When the number of non-reproducible patients was ≤ 4 at study completion, APBI at this institution was considered statistically reproducible. RESULTS: Half of the patients (52 %) had a small bra size (A/B cup). The mean values of the dose-constrained parameters were as follows: Vref, 117 cm(3) (range, 40-282), DNR, 0.30 (range, 0.22-0.51), and clip dose, 784 cGy (range, 469-3146). A total of 43/46 treatment plans were judged to be compliant and ISBT-APBI was concluded to be reproducible. CONCLUSIONS: This study showed that multi-institutional ISBT-APBI treatment plan was reproducible for small breast patient with closed cavity.

Final results from a multicenter prospective study ( JROSG 05-5) on postoperative radiotherapy for patients with ductal carcinoma in situ with an involved surgical margin or close margin widths of 1 mm or less.

This multicenter prospective study ( Japanese Radiation Oncology Study Group: JROSG 05-5) aimed to evaluate the effectiveness of postoperative radiotherapy (PORT) in patients with ductal carcinoma in situ (DCIS) with an involved surgical margin or close margin widths of ≤1 mm or less. PORT consisted of whole-breast irradiation (50 Gy in 25 fractions) followed by boost irradiation (10 Gy in 5 fractions). Eligibility criteria were as follows: (i) DCIS without an invasive carcinoma component, (ii) age between 20 and 80 years old, (iii) involved margin or close margin widths of ≤1 mm, (iv) refusal of re-resection, (v) performance status of 0-2, and (vi) written informed consent. The primary endpoint was ipsilateral breast tumor recurrence (IBTR), and secondary endpoints were overall survival (OS), relapse-free survival (RFS), recurrence patterns, and adverse events. A total of 37 patients from 12 institutions were enrolled from January 2007 to May 2009. The median follow-up time was 62 months (range, 28-85 months). The median pathological tumor size was 2.5 cm (range, 0.3-8.5 cm). Of the 37 patients, 21 had involved margins, and 16 had close margins. The 5-year IBTR, OS and RFS rates were 6% (95% confidence interval [CI]: 2-21), 97% (95% CI: 83-99) and 91% (95% CI: 77-97), respectively. Two patients developed local recurrence at the original site after 39 and 58 months. No severe adverse events were found. Our study suggests that this PORT regimen could be a treatment option for patients with DCIS with involved margin or close margin who don't desire re-resection.

Safety and feasibility of adjuvant chemotherapy with S-1 in Japanese breast cancer patients after primary systemic chemotherapy: a feasibility study.

BACKGROUND: Advanced breast cancer patients have a higher risk of postoperative recurrence than early-stage breast cancer patients. Recurrence is believed to be caused by the increase in micrometases, which were not eradicated by preoperative or postoperative chemotherapy. Therefore, a new therapeutic strategy that can improve treatment efficacy is mandatory for advanced breast cancer. S-1 was shown to be effective and safe in Japanese metastatic breast cancer patients treated with previous chemotherapy, including anthracyclines. Thus, in this study, we evaluated S-1 as adjuvant chemotherapy in breast cancer patients after standard primary systemic chemotherapy. METHODS: The treatment consisted of 18 courses (a 2-week administration and a 1-week withdrawal; one year) administered at 80-120 mg/body/day. In cases judged to require postoperative radiotherapy, it was concurrently initiated on Day 1 of the study. If the estrogen receptor and/or human epidermal growth factor receptor 2 were positive, endocrine therapy and/or trastuzumab were permitted, concurrently. RESULTS: Of the 45 patients enrolled between September 2007 and September 2009 from 3 institutions, 43 patients were eligible. Thirty-two of the 43 (74.4%) patients received concurrent radiotherapy. Twenty-two of the 43 (51.2%) patients completed the scheduled courses of chemotherapy. The most common reasons for withdrawal of treatment were subjective symptoms, such as nausea, anorexia, or general fatigue during the first 9 courses of treatment in 9/43 (20.9%) patients, recurrence in 7/43 (16.3%) patients, and adverse events in 5/43 (11.6%) patients. The cumulative percentage of administration for 365 days was 66.4% (95% confidence interval: 50.8-79.1%). Although grade 3 neutropenia (9.3%), leukopenia (4.7%), and diarrhea (4.7%) were observed, they were manageable. No grade 4 adverse effects were observed. CONCLUSIONS: The percentage of Japanese breast cancer patients completing the 18-course treatment and the cumulative percentage of administration for 365 days using S-1 after standard primary systemic chemotherapy were similar with the results of another study of adjuvant chemotherapy for the Japanese gastric cancer patients with no severe adverse effects. A phase III trial investigating the usefulness of adjuvant S-1 is now ongoing in Japan, and it is expected that S-1 will have a significant survival benefit in breast cancer patients. UMIN000013469.

[CyberKnife radiotherapy for head and neck cancer].

Locoregional failure after radiation therapy is a significant problem in the management of head and neck cancer. Reirradiation is rarely used in conventional radiation therapy because of concerns about treatment-related toxicity and lack of efficacy. However, stereotactic radiotherapy, which was made possible by the advancement in therapeutic devices enables reirradiation. The CyberKnife system is one of the best devices for stereotactic radiotherapy. We discuss salvage treatment, including reirradiation using the CyberKnife system, in patients with locally recurrent head and neck cancer patients.

A comparison of the respiratory signals acquired by different respiratory monitoring systems used in respiratory gated radiotherapy.

PURPOSE: Respiratory monitoring systems are used to detect the respiratory phase of patients during the planning and administration of respiratory gated radiotherapy by using four-dimensional computed tomography (4DCT) or 4D positron-emission tomography/CT (4DPET/CT) and the linear accelerator (linac), respectively. Generally, identical respiratory monitoring systems are used for 4DCT, 4DPET/CT, and linac. However, different systems are sometimes used in combination because the accessibility of the respiratory monitoring systems may differ by manufacturer. The combined use of different respiratory monitoring systems in phase-based gating is of concern because the differences in the timing of tags (end-respiration signals algorithmically determined by the respiratory monitoring system), defined by the two systems, may result in phase differences, The purpose of this study is to estimate this difference and evaluate its effect on 4DCT data. METHODS: Ten patients (seven men and three women) with a median age of 75 yr (range: 57-84 yr) were treated by gated stereotactic body radiation therapy between April and December 2009. Two types of respiratory monitoring systems--RPM (Varian Medical Systems) and AZ-733V (Anzai MEDICAL)--were placed on the abdominal surface of the patients, and the respiratory signals were acquired by both systems. The relationship between the amplitude peak and the tag obtained by each respiratory system was analyzed for each patient. Further, the 4DCT images were reconstructed by using the signals obtained from both the RPM and the AZ-733V systems, and the tumor volumes and the tumor centroid positions in the craniocaudal plane were analyzed for each patient. RESULTS: The correlation factor between the respiratory signals from the RPM system and AZ-733V system was 0.990 (range: 0.940-0.994). The amplitude peak of the RPM system corresponded well with that of the AZ-733V system. The median +/- standard deviation of the phase difference for all the patients ranged from -4.3 +/- 7.1% to 3.5 +/- 2.2%. In the case of some patients, differences were noted between the two systems in the estimation of the tumor centroid position and tumor shape. CONCLUSIONS: The estimation of the position of the tumor centroid and tumor shape may vary with the use of different respiratory monitoring systems. This implies that it is preferable to use the same respiratory monitoring system with 4DCT, 4DPET-CT, and linac.

Inhibition of poly (ADP-ribose) polymerase as a protective effect of nicaraven in ionizing radiation- and ara-C-induced cell death.

BACKGROUND: Nicaraven is a drug used for patients with a subarachnoid hemorrhage. It crosses the blood-brain barrier and has potent antivasospastic and brain-protective effects. While nicaraven scavenges the hydroxyl radical, the mechanism of its protection remains obscure. In addition to the hydroxyl radical scavenging effect, nicaraven also exhibits inhibitory action on poly (ADP-ribose) polymerase (PARP). The mechanism of the pharmacological action of nicaraven has not yet been clarified. MATERIALS AND METHODS: Human myeloid HL-525 cells were exposed to ionizing radiation or hydrogen peroxide and the effect of nicaraven on the activation of the Egr-1 promoter was measured. Next, the action of the drug on DNA fragmentation and inhibition of thymidine uptake caused by the genotoxic stimulation of ionizing radiation or cytosine B-D-arabinofuranoside (ara-C) were assessed. Finally, direct inhibition of the PARP enzyme by nicaraven was measured. RESULTS: Nicaraven did not inhibit the activation of the Egr-1 promoter caused by H2O2 and the activation caused by ionizing radiation. However, the drug repressed DNA fragmentation and increased thymidine uptake dose-dependently. Nicaraven had a direct inhibitory effect on PARP. DISCUSSION: The effect of nicaraven on the Egr-1 promoter was different from that of another free-radical scavenger, N-acetyl cysteine. Nicaraven demonstrated similar protection of the PARP inhibitors including 3-aminobenzamide. Since nicaraven directly inhibits the PARP enzyme, the drug might be useful in oncology as well as in studying tissue-damaging conditions characterized by increased PARP activity.

Long-term, irradiation-induced effects on thermoregulation in the skin after thermal stimulation.

PURPOSE: The morphological effect of radiation on the skin has been adequately analyzed, but the functional effect has received little attention. The purpose of this study was to examine the long-term effects of radiation on the skin from the viewpoint of function. MATERIALS AND METHODS: Physiological changes in the irradiated skin of patients who had undergone breast-conserving therapy for the treatment of breast cancer were examined throughout the follow-up period. Thermal stimulation was applied to both breasts, and changes in skin temperature and sweating reactivity of irradiated and non-irradiated skin were measured. RESULTS: From three weeks to the end of radiotherapy, the resting skin temperature of the irradiated region was significantly elevated, while the rate of sweating was lower. More than two years after radiotherapy, the elevated resting skin temperature of the irradiated region had returned to within the range observed for non-irradiated skin, although an abnormally high increase in skin temperature after thermal stimulation continued to be observed for more than two years after radiotherapy. At the same time, sweating after thermal stimulation continued to be suppressed. CONCLUSION: Present observations suggest that functional effects, such as the skin temperature and sweating ability of irradiated skin, persist longer than readily visible morphological changes.