Shigemitsu Takashima

Zoledronic Acid Significantly Reduces Skeletal Complications Compared With Placebo in Japanese Women With Bone Metastases From Breast Cancer: A Randomized, Placebo-Controlled Trial

PURPOSE To investigate the efficacy and safety of zoledronic acid for the treatment of bone metastases from breast cancer. PATIENTS AND METHODS Women with bone metastases (N = 228) were randomly assigned to receive 4 mg zoledronic acid (n = 114) or placebo (n = 114) via 15-minute infusions every 4 weeks for 1 year. The primary efficacy end point was the skeletal-related event (SRE) rate ratio between treatment groups. An SRE was defined as pathologic fracture, spinal cord compression, and radiation or surgery to bone. Secondary end points included percentage of patients with at least one SRE, time-to-first SRE, and Andersen-Gill multiple-event analysis. RESULTS The SRE rate ratio at 1 year (excluding HCM and adjusted for prior fracture) was 0.61 (permutation test; P = .027), indicating that zoledronic acid reduced the rate of SRE by 39% compared with placebo. The percentage of patients with at least one SRE (excluding HCM) was significantly reduced by 20% by zoledronic acid (29.8% v 49.6% for placebo; P = .003). Zoledronic acid significantly delayed time-to-first SRE (median not reached v 364 days; Cox regression; P = .007) and reduced the risk of SREs by 41% in multiple event analysis (risk ratio = 0.59; P = .019) compared with placebo. Zoledronic acid was well tolerated with a safety profile similar to placebo. No patient treated with zoledronic acid had grade 3 or 4 serum creatinine increase. CONCLUSION Zoledronic acid significantly reduced skeletal complications compared with placebo across multiple end points in Japanese women with bone metastases from breast cancer.

Nationwide Survey on Complementary and Alternative Medicine in Cancer Patients in Japan

PURPOSE To determine the prevalence of use of complementary and alternative medicine (CAM) by patients with cancer in Japan, and to compare the characteristics of CAM users and CAM nonusers. PATIENTS AND METHODS A questionnaire on cancer CAM and the Hospital Anxiety and Depression Scale were delivered to 6,607 patients who were treated in 16 cancer centers and 40 palliative care units. RESULTS There were 3,461 available replies for a response rate of 52.4%. The prevalence of CAM use was 44.6% (1,382 of 3,100) in cancer patients and 25.5% (92 of 361) in noncancer patients with benign tumors. Multiple logistic regression analysis determined that history of chemotherapy, institute (palliative care units), higher education, an altered outlook on life after cancer diagnosis, primary cancer site, and younger age were strongly associated with CAM use in cancer patients. Most of the CAM users with cancer (96.2%) used products such as mushrooms, herbs, and shark cartilage. The motivation for most CAM use was recommendation from family members or friends (77.7%) rather than personal choice (23.3%). Positive effects were experienced by 24.3% of CAM users with cancer, although all of them received conventional cancer therapy concurrently. Adverse reactions were reported by 5.3% of cancer patients. CAM products were used without sufficient information by 57.3% of users with cancer and without a consultation with a doctor by 60.7% of users. CONCLUSION This survey revealed a high prevalence of CAM use among cancer patients, without sufficient information or consultation with their physicians. Oncologists should not ignore the CAM products used by their patients because of a lack of proven efficacy and safety.

Pulmonary Function After Lobectomy: Video- Assisted Thoracic Surgery Versus Thoracotomy

BACKGROUND Whether video-assisted thoracic surgery (VATS) improves postoperative pulmonary function is still controversial. We compared postoperative pulmonary function after VATS lobectomy and standard lobectomy. METHODS Eleven patients who had undergone standard lobectomy and 10 patients who had undergone VATS lobectomy were studied. Arterial blood gas analyses were performed on the 4th, 7th, and 14th postoperative days. Pulmonary function, including forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1.0), and peak flow rate (PFR) were measured on the 7th and 14th postoperative days (early phase), and approximately 1 year after surgery (late phase). RESULTS Pulmonary function, as assessed with arterial oxygen partial pressure (PaO2) (p = 0.054), arterial oxygen saturation (O2SAT) (p = 0.063), FVC (p = 0.10), and FEV1.0 (p = 0.08), was better after VATS lobectomy than after thoracotomy on the 7th postoperative day. PFR was significantly better after VATS on both the 7th and 14th postoperative days (p = 0.008 and p = 0.03, respectively). CONCLUSIONS VATS lobectomy had advantages on early postoperative pulmonary function. We conclude that VATS lobectomy is a beneficial alternative to standard thoracotomy, especially for patients with poor pulmonary reserve.

Prospective study of thoracoscopic limited resection for ground-glass opacity selected by computed tomography

BACKGROUND With recent advances in low-dose helical computed tomography (CT), detection of ground-glass opacity (GGO) has increased. The aim of this study was to correlate high-resolution CT (HRCT) findings with pathologic features and to evaluate the efficacy of thoracoscopic limited resection for focal GGO, which were selected based on HRCT findings. METHODS Focal GGO lesions were classified into two subtypes based on HRCT findings: pure type and mixed type. Ninety-six patients with persistent GGO 2 cm or less in diameter underwent pulmonary resection from January 1997 to December 2001. Among these, thoracoscopic wedge resection was performed prospectively between June 2000 and December 2001 in 33 patients with pure GGO lesions that were 1 cm or less. RESULTS Thoracoscopic wedge resection was completed with complete safety. The histologic diagnoses of these 33 lesions were adenocarcinoma in 1, bronchioloalveolar carcinoma (BAC) in 23, and atypical adenomatous hyperplasia (AAH) in 9. No patients have had any evidence of tumor recurrence to date. Of the total 96 GGO lesions, 93.0% (53/57) of pure GGO 1 cm or less were BAC or AAH, whereas 38.5% (15/39) of pure GGO larger than 1 cm or mixed GGO were adenocarcinoma. CONCLUSIONS Pure GGO 1 cm or less was characteristic of noninvasive lesions. Thoracoscopic limited resection for small GGO lesions selected by HRCT was valid.

Relation between cancer cellularity and apparent diffusion coefficient values using diffusion-weighted magnetic resonance imaging in breast cancer

PurposeThe purpose of this study was to examine the relation between cancer cellularity and the apparent diffusion coefficient (ADC) value using diffusion-weighted magnetic resonance imaging in breast cancer.Materials and methodsThe subjects were 27 women who had undergone operation for breast cancer. There were 27 breast cancer lesions, 24 of which were invasive ductal carcinoma (IDC) and 3 of which were noninvasive ductal carcinoma (NIDC).ResultsThe mean ADC values of IDC, NIDC, and normal breasts were 1.07 ± 0.19 ·10−3, 1.42 ± 0.17 ·10−3, and 1.96 ± 0.21 ·10−3 mm2/s, respectively. The mean ADC values of IDC and NIDC were signifi cantly different from that of normal breasts (P < 0.001 each). The mean ADC values were also signifi cantly different between IDC and NIDC (P < 0.001). There was no correlation between the ADC value and cancer cellularity.ConclusionThe mean ADC values for breast cancer were significantly different from that of normal breasts. The mean ADC value for breast cancer did not significantly correlate with cancer cellularity but did correlate with histological types.

Construction and validation of a practical prognostic index for patients with metastatic breast cancer.

PURPOSE To identify the readily available prognostic factors most helpful in predicting survival and to construct and validate a prognostic index for metastatic breast cancer (MBC) patients. PATIENTS AND METHODS Data from 233 MBC patients, accrued on a multiinstitutional randomized phase III trial (Japan Clinical Oncology Group [JCOG] study 8808), were analyzed to identify significant prognostic factors and a prognostic index was constructed by incorporating these prognostic factors. For validation of the prognostic index, another data set from 315 consecutive MBC patients, who had been treated with standard anthracycline-containing regimens, was analyzed. RESULTS In multivariate regression analyses, history of adjuvant chemotherapy (ADJCT) (P = .0005), presence of distant lymph nodes (DLNs) (P = .0117) and liver (HEP) (P = .0099) metastases, elevation of serum lactate dehydrogenase (LDH) (P < .0001), and shorter disease-free interval (DFI) (P < .0001) significantly contributed to poorer survival. The prognostic index was constructed as follows: Prognostic Index = ADJCT (not received = 0, received = 1) + DLNs (absent = 0, present = 1) + HEP (absent = 0, present = 1) + LDH (< or = one times normal = 0, > one times normal = 1) + DFI (> or = 24 months = 0, < 24 months = 2). With this prognostic index, patients could be stratified into three risk groups. The median survival times (MSTs) of low-, intermediate- and high-risk groups were 45.5, 24.6, and 10.6 months, respectively (P < .0001). This prognostic index was applied to the validation patients. The respective MSTs for each risk group were 49.6,22.8, and 10.0 months (P < .0001). CONCLUSION ADJCT, DLNs, HEP, LDH, and DFI were important prognostic factors for MBC patients. The prognostic index readily enables MBC patients to be stratified into three risk groups and is worth considering for future clinical trials.

Patients' understanding of their own disease and survival potential in patients with metastatic breast cancer.

Purpose: To investigate the effect of understanding their own disease by patients with metastatic breast cancer on their survival potential after being informed by their physician.Patientsandmethods: Two hundred and fourteen women with metastatic breast cancer who participated in a multi-institutional, randomized phase III trial (Japan Clinical Oncology Group (JCOG) Study 8808) were asked whether they understood their own disease after being given information about the clinical trial. They were classified into two groups on the basis of whether they understood or not. We estimated their survival after the time of registration and derived relative hazard ratios from Coxs proportional hazards model.Results: There were 190 patients in the ‘better understanding’ group and 24 in the ‘poor understanding’ group. Median survival times after registration were 28.3 and 16.1 months, respectively. The ‘better understanding’ group showed a significant difference from the ‘poor understanding’ group (p=0.016). In multivariate regression analysis, patients who did not understand still showed poorer survival than those who understood (hazard ratio = 2.09; 95% confidence interval (CI) 1.16–3.78; p=0.014)

A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer.

A late phase II clinical trial of RP56976 (docetaxel), derived from Taxus baccata was performed to evaluate anti-tumour activity, time to progression and clinical toxicity in patients with advanced or recurrent breast cancer. The patients, between 15 and 80 years old with performance status (PS) of 0-2, received at least two cycles of docetaxel 60 mg m-2 intravenously at 3-4 week intervals. Of the 81 patients enrolled, the 72 eligible for the study were given a total of 327 cycles, with a median of four cycles each. Five patients obtained a complete response (CR) and 27 a partial response (PR); the response rate (RR) was 44.4% (95% confidence interval 32.7-56.6%). A relatively high RR of 9/28 (32.1%) was observed in patients who had received prior chemotherapy involving anthracyclines. The dose-limiting toxicity was grade 3-4 leucocytopenia or neutropenia, found in 78.9% and 85.9% patients respectively. Other severe (grade > 3) toxicities included alopecia (38%), anorexia (18.3%), nausea/vomiting (11.3%), and fatigue (9.9%). Hypersensitivity reactions, oedema and skin toxicity were not severe and were reversible. One therapy-related death occurred 10 days after the initial dose was given. These findings indicate that docetaxel has potent activity against metastatic breast cancer, and that the dose of 60 mg m-2 is safe.

Tumor‐infiltrating endothelial cells and endothelial precursor cells in inflammatory breast cancer

Inflammatory breast cancer (IBC) is a specific type of breast tumor that generally has a poor prognosis, in spite of recent advances in treatment. In the present study, semiquantitative reverse transcriptase polymerase chain reaction examination of resected specimens showed that angiogenic factors, not lymphangiogenic factors, are overexpressed in IBC tumors, compared with non‐IBC tumors. Immunohistochemical analysis of the specimens revealed a significantly higher population of tumor‐infiltrating (TI) endothelial cells (ECs) or endothelial precursor cells (EPCs) in tumor‐associated stroma of IBC specimens than in non‐IBC specimens. In a previous study, we examined the phenotype of host cells in response to transplanted IBC cells, using an established human IBC xenograft model (WIBC‐9) (Shirakawa et al., Cancer Res 2001;61:445–51). The data obtained in that study are consistent with the findings of the present study. To explore the therapeutic potential of blocking vascular endothelial growth factor (VEGF) and angiopoietin (Ang) pathways in IBC, established vectors encoding soluble Flt‐1 (sFlt‐1) and soluble Tie2 (sTie2) were injected directly into WIBC‐9. Both vectors produced growth inhibition ratios of WIBC‐9 that were significantly higher than those of a non‐IBC xenograft (MC‐5). Also, both vectors suppressed WIBC‐9 lung metastases. The efficacy correlated with the number of TI ECs/EPCs, which was determined by fluorescence‐activated cell sorting. These ECs/EPCs incorporated acetylated lipoprotein and were integrated within a HUVEC monolayer in vitro culture on day 5.

A Phase II Study of S-1 in Patients with Metastatic Breast Cancer : A Japanese Trial by the S-1 Cooperative Study Group, Breast Cancer Working Group

BackgroundS-l is a newly developed novel oral dihydrouracil dehydrogenase inhibiting fluoro-pyrimidine drug consisting of 1 M tegafur (FT), 0.4 M 5-chloro-2, 4-dihydroxypyrimidine (gimeracil), and 1 M potassium oxonate (oteracil), with efficient antitumor activity and low gastrointestinal toxicity which is widely used in Japan against advanced gastric, head and neck cancers. We investigated its clinical efficacy against metastatic breast cancer.MethodsA non-blind phase II study was carried out to evaluate the efficacy and toxicity in metastatic breast cancer patients. Patients with measurable metastasis foci (n = 111) were enrolled, and 108 patients were regarded as eligible. S-l was administered orally at a standard dose of 80 mg/m2/day b.i.d. One course consisted of 28 consecutive days of administration followed by a 14-day rest, and courses were repeated up to six times.ResultsAmong the eligible patients, 10 had a complete response and 35 had a partial response, with an overall response rate (CRplus PR) of 41.7% (95% confidence interval: CI, 32.3–51.5%). The incidences of toxicity (≧ grade 3) were neutropenia 9.1%, anemia 0.9%, anorexia 3.6%, stomatitis 1.8%, nausea/vomiting 1.8%, diarrhea 0.9%, and fatigue 2.7%, however no treatment-related deaths were observed. The median survival time was 872 days (95% CI, 572-1,110 days). There was no difference in response rate or toxicity between the under 65-year-old group and the older group.ConclusionS-l was demonstrated to have high efficacy with low gastrointestinal toxicity even in older patients and will be a promising new chemotherapy drug for metastatic breast cancer.