Yasuhiro Yanagita

Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial

BACKGROUND Palonosetron is a second-generation 5-hydroxytryptamine 3 (5-HT(3))-receptor antagonist that has shown better efficacy than ondansetron and dolasetron in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy, and similar efficacy to ondansetron in preventing CINV in patients receiving highly emetogenic chemotherapy. In this phase III, multicentre, randomised, double-blind, double-dummy, stratified, parallel-group, active-comparator trial, we assessed the efficacy and safety of palonosetron versus granisetron for chemotherapy-induced nausea and vomiting, both of which were administered with dexamethasone in patients receiving highly emetogenic chemotherapy. METHODS Between July 5, 2006, and May 31, 2007, 1143 patients with cancer who were receiving highly emetogenic chemotherapy (ie, cisplatin, or an anthracycline and cyclophosphamide combination [AC/EC]) were recruited from 75 institutions in Japan, and randomly assigned to either single-dose palonosetron (0.75 mg), or granisetron (40 microg/kg) 30 min before chemotherapy on day 1, both with dexamethasone (16 mg intravenously) on day 1 followed by additional doses (8 mg intravenously for patients receiving cisplatin or 4 mg orally for patients receiving AC/EC) on days 2 and 3. A non-deterministic minimisation method with a stochastic-biased coin was applied to the randomisation of patients. Covariates known to effect emetic risk, such as sex, age, and type of highly emetogenic chemotherapy, were used as stratification factors of minimisation to ensure balance between the treatment groups. Primary endpoints were the proportion of patients with a complete response (defined as no emetic episodes and no rescue medication) during the acute phase (0-24 h postchemotherapy; non-inferiority comparison with granisetron) and the proportion of patients with a complete response during the delayed phase (24-120 h postchemotherapy; superiority comparison with granisetron). The non-inferiority margin was predefined in the study protocol as a 10% difference between groups in the proportion of patients with complete response. The palonosetron dose of 0.75 mg was chosen on the basis of two dose-determining trials in Japanese patients. All patients who received study treatment and highly emetogenic chemotherapy were included in the efficacy analyses (modified intention to treat). This trial is registered with ClinicalTrials.gov, number NCT00359567. FINDINGS 1114 patients were included in the efficacy analyses: 555 patients in the palonosetron group and 559 patients in the granisetron group. 418 of 555 patients (75.3%) in the palonosetron group had complete response during the acute phase compared with 410 of 559 patients (73.3%) in the granisetron group (mean difference 2.9% [95% CI -2.70 to 7.27]). During the delayed phase, 315 of 555 patients (56.8%) had complete response in the palonosetron group compared with 249 of 559 patients (44.5%) in the granisetron group (p<0.0001). The main treatment-related adverse events were constipation (97 of 557 patients [17.4%] in the palonosetron group vs 88 of 562 [15.7%] in the granisetron group) and raised concentrations of serum aminotransferases (aspartate aminotransferase: 24 of 557 [4.3%] vs 34 of 562 [6.0%]; alanine aminotransferase: 16 of 557 [2.9%] vs 33 of 562 [5.9%]); no grade 4 main treatment-related adverse events were reported. INTERPRETATION When administered with dexamethasone before highly emetogenic chemotherapy, palonosetron exerts efficacy against chemotherapy-induced nausea and vomiting which is non-inferior to that of granisetron in the acute phase and better than that of granisetron in the delayed phase, with a comparable safety profile for the two treatments. FUNDING Taiho Pharmaceutical (Tokyo, Japan).

Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial

BACKGROUND Aromatase inhibitors have shown increased efficacy compared with tamoxifen in postmenopausal early breast cancer. We aimed to assess the efficacy and safety of anastrozole versus tamoxifen in premenopausal women receiving goserelin for early breast cancer in the neoadjuvant setting. METHODS In this phase 3, randomised, double-blind, parallel-group, multicentre study, we enrolled premenopausal women with oestrogen receptor (ER)-positive, HER2-negative, operable breast cancer with WHO performance status of 2 or lower. Patients were randomly assigned (1:1) to receive goserelin 3·6 mg/month plus either anastrozole 1 mg per day and tamoxifen placebo or tamoxifen 20 mg per day and anastrozole placebo for 24 weeks before surgery. Patients were randomised sequentially, stratified by centre, with randomisation codes. All study personnel were masked to study treatment. The primary endpoint was best overall tumour response (complete response or partial response), assessed by callipers, during the 24-week neoadjuvant treatment period for the intention-to-treat population. The primary endpoint was analysed for non-inferiority (with non-inferiority defined as the lower limit of the 95% CI for the difference in overall response rates between groups being 10% or less); in the event of non-inferiority, we assessed the superiority of the anastrozole group versus the tamoxifen group. We included all patients who received study medication at least once in the safety analysis set. We report the primary analysis; treatment will also continue in the adjuvant setting for 5 years. This trial is registered with ClinicalTrials.gov, number NCT00605267. FINDINGS Between Oct 2, 2007, and May 29, 2009, 204 patients were enrolled. 197 patients were randomly assigned to anastrozole (n=98) or tamoxifen (n=99), and 185 patients completed the 24-week neoadjuvant treatment period and had breast surgery (95 in the anastrazole group, 90 in the tamoxifen group). More patients in the anastrozole group had a complete or partial response than did those in the tamoxifen group during 24 weeks of neoadjuvant treatment (anastrozole 70·4% [69 of 98 patients] vs tamoxifen 50·5% [50 of 99 patients]; estimated difference between groups 19·9%, 95% CI 6·5-33·3; p=0·004). Two patients in the anastrozole group had treatment-related grade 3 adverse events (arthralgia and syncope) and so did one patient in the tamoxifen group (depression). One serious adverse event was reported in the anastrozole group (benign neoplasm, not related to treatment), compared with none in the tamoxifen group. INTERPRETATION Given its favourable risk-benefit profile, the combination of anastrozole plus goserelin could represent an alternative neoadjuvant treatment option for premenopausal women with early-stage breast cancer. FUNDING AstraZeneca.

Adjuvant capecitabine for breast cancer after preoperative chemotherapy

BACKGROUND Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)‐negative breast cancer have poor prognoses. The benefit of adjuvant chemotherapy in these patients remains unclear. METHODS We randomly assigned 910 patients with HER2‐negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease‐free survival. Secondary end points included overall survival. RESULTS The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease‐free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval [CI], 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple‐negative disease, the rate of disease‐free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand‐foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group. CONCLUSIONS After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease‐free survival and overall survival among patients with HER2‐negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE‐X UMIN Clinical Trials Registry number, UMIN000000843.)

Tuberculosis of axillary lymph nodes with primary breast cancer.

A rare case of tuberculosis of axillary lymph nodes occurring with primary breast cancer is presented. A 78-year-old woman with no history of pulmonary tuberculosis was admitted to our hospital to undergo examination for a lump in her right breast. The tumor was in the upper outer quadrant of the right breast. On palpation, the tumor was 1.2 cm in diameter and axillary lymph node swelling was noted. Mammography disclosed a spiculated mass and swelling and calcification of the axillary lymph nodes. Sonography showed an irregular hypoechoic mass in the right breast and lymph node swelling in the right axilla, indicating breast cancer with axillary lymph nodes metastases. Chest X-ray showed clustered calcifications in the right axilla and a granular shadow in the right upper lobe. Breast conserving therapy was carried out. Invasive papillotubular carcinoma of the right breast and granulomas with calcification of lymph nodes, compatible with tuberculosis, was diagnosed. Tubercle bacillis were detected by culture of lymph nodes. This case suggests that X-ray is useful for diagnosing lymph node tuberculosis. Lymph node tuberculosis should be suspected when lymph node swelling is noted and X-ray shows clustered calcifications in axillary lymph nodes.

Clinicopathological significance of decreased galectin-3 expression and the long-term prognosis in patients with breast cancer

PurposeGalectin-3 expression is modulated in cancer cells, and that finding has led to the recognition of galectin-3 as a diagnostic or prognostic marker for various cancers, including breast cancer. This study investigated the correlation between galectin-3 expression and the clinicopathological features in patients with breast cancer, in order to determine the relevance and role of galectin-3 in breast cancer progression.MethodsGalectin-3 expression was investigated immunohistochemically in 116 patients with breast cancer, and a statistical analysis was performed.ResultsGalectin-3 expression in breast cancer was significantly associated with tumor vascular invasion. However, galectin-3 expression was not associated with Ki-67 expression, which reflects tumor proliferation. Disease-free survival and long-term overall survival were significantly shorter for patients with reduced galectin-3 expression.ConclusionsThis study demonstrated that the galectin-3 expression was associated with tumor vascular invasion and metastasis, suggesting that galectin-3 plays a critical role in tumor progression via an invasive mechanism but not via proliferation in breast cancer. Furthermore, reduced expression of galectin-3 is useful for predicting a long-term poor prognosis in patients with breast cancer.

Analysis of Ki-67 expression with neoadjuvant anastrozole or tamoxifen in patients receiving goserelin for premenopausal breast cancer

The increasing costs associated with large‐scale adjuvant trials mean that the prognostic value of biologic markers is increasingly important. The expression of nuclear antigen Ki‐67, a marker of cell proliferation, has been correlated with treatment efficacy and is being investigated for its value as a predictive marker of therapeutic response. In the current study, the authors explored correlations between Ki‐67 expression and tumor response, estrogen receptor (ER) status, progesterone receptor (PgR) status, and histopathologic response from the STAGE study (S_tudy of T_amoxifen or A_rimidex, combined with G_oserelin acetate to compare E_fficacy and safety).

Usefulness of a visceral mini-retractor accessible without trocar port during laparoscopic surgery

During endoscopic surgery, all surgical manipulation should be performed through a limited number of fixed ports, which contributes to the difficulty associated with laparoscopic surgery. Especially in colorectal resection, many bowel clamps have been required to hold the large intestine [1]. Therefore, we developed a new retractor that is sufficiently fine to allow it to enter without any trocar port. The use of this mini-retractor was evaluated during laparoscopic surgery. Materials and methods The mini-retractor consists of a stainless-steel catheter (2 mm in diameter, 15 cm long), an inner needle, and a wire loop (Fig. 1). The catheter is insulated with a contractive tube. When visceral retraction was required, a inner needle was set to the catheter and the abdominal wall was punctured at an appropriate site under videoscopic guidance. After removing inner needle, a loop wire was inserted in the steel catheter. The wall of bowel or gallbladder was snared with the loop, which was fixed by a clamp. The intestine and gallbladder were manipulated by this instrument during laparoscopic surgery (Fig. 2). Results and discussion The needle-type retractor was used during seven endoscopic surgical procedures (four cholecystectomies and three colectomies). No complication associated with the miniretractor were observed in any of the patients. Laparoscopic assisted colectomy and cholecystectomy could be performed by using only two or three conventional trocars assisted with several mini-retractors and a fine probe of electric cautery [2]. The position of insertion could be altered according to the operating field. No bleeding or air leakage was observed at the puncture site during and after surgery. The puncture wound was closed without any sutures and scar formation was not induced. Based on these results, the mini-retractor reduces the number of ports required for instruments during video-assisted surgery, thus improving the cost performance and minimal invasiveness of endolaparoscopic surgery.

Videoscopic thyroidectomy with fine needle-type apparatuses: an approach that does not leave a scar on the neck or anterior chest.

A total videoscopic operation with constant CO2 gas insufflation is ideal for performing a scarless thyroidectomy because the skin incisions at the surgical ports are made far from the neck in the axillar area. However, there are many difficulties associated with the performance of a videoscopic thyroidectomy when approaching pneumo-subcutaneously from distant ports, because the instruments are inserted tangentially toward the thyroid gland from a distant port and their range of manipulation is limited. The devices and surgical techniques used for a videoscopic thyroidectomy that does not leave a scar on the anterior chest or neck were developed. Fine needle-type cautery and forceps that could access directly to the thyroid gland from the neck were used to support the forceps. A CO2 reservoir bag connected to the CO2 insufflation tube contributed to the safer manipulation by the creation of a stable operation space during emitting smoke from coagulation device. A silicon ring stopper was useful to prevent dislodging of the ports. In conclusion, videoscopic neck surgery would be easier using these new devices and techniques and would produce better cosmetic results than video-assisted and conventional neck surgeries.

Clinicopathological Study of Unilateral Multiple Breast Cancer

BackgroundThe tendency for breast cancer to form multiple lesions is important to consider when planning breast-conserving surgery. However, many unknowns remain regarding the pathology and prognosis of multiple breast cancer, and therefore it is clinically significant to investigate its clinicopathological properties.MethodsOver the past 25 years, in the period between April 1972 and March 1997, we investigated the clinicopathological findings including the 5-year and 10-year survival rates of 66 patients treated for unilateral multiple breast cancer.ResultsOf the total of 1,334 female patients with unilateral breast cancer who underwent curative surgery at our hospital, we identified 66 (5.0%) patients with unilateral multiple cancer. The incidence of such cancer has been higher in recent years. Of the 66 patients, 50 (75.8%) were premenopausal, and the remaining patients were postmenopausal, but multiple cancer among postmenopausal women is a recent phenomenon. The ER positivity rate of the main lesion in patients with multiple breast cancer was 69.2% and that of PgR was 50.0%. The 5-and 10-year overall survival rate in all 66 patients with multiple breast cancer was 90.8% and 79.7%, respectively.ConclusionIn the past, multiple breast cancer was frequently identified in premenopausal women. However, the current findings indicate that its incidence among postmenopausal women has increased in recent years. In addition, prognoses were comparable for patients with multiple or solitary breast cancer, a relevant finding in the planning of breast-conserving surgery.

A new fine probe for electric cautery during endoscopic surgery

Abstract. The present paper introduces a new fine probe for electric cautery (1.65 mm in diameter, 22 cm long) that can be connected to a conventional cylindrical hand-controlled cautery holder, which is monopolar and widely used in general surgery. When cautery was required, a 14-gauge intravenous catheter was inserted at an appropriate site under the guidance of a videoscope. After removing the steel inner needle, the extra tube was used as the fine surgical port for the cautery probe. The position of insertion could be altered according to the operating field. Cautery was performed by conventional methods. There was no bleeding or air leakage at the site of puncture during or after surgery. The puncture wound was closed without any sutures. Based on these results, the new fine probe for cautery can reduce the number of surgical ports required for instruments during video-assisted surgery, thus improving the ease and safety of endoscopic surgery.