Participants in a randomized controlled trial had longer overall survival than non-participants: a prospective cohort study.

PURPOSE: While some studies show improved outcomes in clinical trial participants as compared to non-participants, existence of such a trial effect has not been proved precisely. METHODS: This was a prospective cohort study to compare the prognoses for participants in the randomized controlled trial (SELECT BC) and non-participants. SELECT BC compared S-1 and taxane as first-line treatment for metastatic breast cancer. Non-participants were all patients who met the eligibility criteria of SELECT BC and who had been requested to participate in that trial by attending doctors and declined. The study aimed to compare the prognoses between participants and non-participants. The primary endpoint was median overall survival. RESULTS: The median OS in participants was significantly superior to that in non-participants with a statistically significant difference (36.8 months vs. 25.2 months. HR 1.48, p = 0.022). A similar result was obtained when only patients who received the same chemotherapy (S-1 or taxane) used in SELECT BC after declining participation were assumed as non-participants (36.8 months vs. 22.0 months. HR 2.03, p = 0.006). CONCLUSIONS: This study may suggest the existence of a trial effect, in which, for a given treatment, participation in a clinical trial is associated with a better outcome.

Anastrozole versus tamoxifen as adjuvant therapy for Japanese postmenopausal patients with hormone-responsive breast cancer: efficacy results of long-term follow-up data from the N-SAS BC 03 trial.

Aromatase inhibitors are superior to tamoxifen as adjuvant therapy in postmenopausal patients with hormone-responsive breast cancer. We report the follow-up efficacy results from the N-SAS BC 03 trial (UMIN CTRID: C000000056) where anastrozole was compared with tamoxifen as adjuvant therapy in postmenopausal Japanese patients with hormone-responsive early breast cancer. The full analysis set contained 696 patients (anastrozole arm, n = 345; tamoxifen arm, n = 351). The log-rank test was used to compare the two groups in terms of disease-free survival (DFS) and relapse-free survival (RFS); Kaplan-Meier estimates were calculated. The treatment effects were estimated by Cox's proportional hazards model. To examine time-varying effect of hazard ratios, we estimated time-varying hazard ratios at time t [HR(t)] using data from time t up to 12 months. After a median follow-up of 98.5 months, hazard ratios (95% CIs) were 0.90 (0.65-1.24; log-rank p = 0.526) for DFS and 0.83 (0.56-1.23; log-rank p = 0.344) for RFS. Hazard ratios (95% CIs) for DFS and RFS up to 36 months were 0.69 (0.40-1.17) and 0.54 (0.27-1.06) and those after 36 months were 1.06 (0.70-1.59) and 1.05 (0.64-1.73), respectively. Time-varying hazard ratios for both DFS and RFS showed that hazard ratios were initially in favor of anastrozole and approached 1.0 at around 36 months. Superior efficacy of anastrozole to tamoxifen suggested by the initial analysis was not confirmed in the present analysis after a long-term follow-up period. Advantage of anastrozole was the greatest immediately after switching from tamoxifen and then decreased thereafter.

[A case of complete response to multiple liver metastasis of gastric cancer after discontinuation of S-1 administration].

An 80-year-old man was diagnosed with advanced gastric cancer and underwent distal gastrectomy. Although the pathological Stage of the cancer was III A, he refused adjuvant chemotherapy. One year later, CT revealed multiple liver metastases. Therefore, he was started with S-1 administration and a complete response was obtained at 10 months after starting S-1 administration. He has maintained a complete response for 22 months after S-1 discontinuation.

Outcomes of Japanese breast cancer patients treated with pre-operative and post-operative anastrozole or tamoxifen.

The present study examined long-term efficacy outcomes in a subgroup of postmenopausal, estrogen receptor-positive Japanese breast cancer patients from the Pre-Operative "Arimidex" Compared with Tamoxifen trial, following pre-operative (3 months) and post-operative (5 years) adjuvant treatment with either anastrozole or tamoxifen. Patients with large, potentially operable, locally-advanced breast cancer were randomized to receive anastrozole (1 mg/day) plus tamoxifen placebo or tamoxifen (20 mg/day) plus anastrozole placebo pre-operatively. After surgery at 3 months, patients continued on the same study medication as adjuvant therapy for up to 5 years or until recurrence, intolerable toxicity or withdrawal of patient consent. Recurrence-free survival and overall survival were measured from the date of randomization to the date of recurrence or death, whichever occurred first. Patients were monitored for adverse events throughout the study period and up to 30 days following administration of the last study medication. During post-operative adjuvant therapy, 4/48 (8%) anastrozole and 25/49 (51%) tamoxifen patients experienced recurrence. There was a significant difference in recurrence-free survival between the two groups (hazard ratio 0.14; 95% confidence interval 0.05-0.41; P = 0.0003). There was a significant increase in overall survival with anastrozole (0.21; 0.05-0.96; P = 0.0436) and there were 2/48 (4%) and 10/49 (20%) deaths with anastrozole and tamoxifen, respectively. Most patients responding to pre-operative therapy remained recurrence-free. Sequential pre-operative/post-operative treatment with anastrozole resulted in lower recurrence and death rates, compared with tamoxifen.

(2-Amino-ethane-thiol-ato-κ(2)N,S)bis-[1,2-bis-(diphenyl-phosphan-yl)ethane-κ(2)P,P']ruthenium(II) hexa-fluoridophosphate.

In the crystal of the title compound, [Ru(C(2)H(6)NS)(C(26)H(24)P(2))(2)]PF(6), the Ru(II) atom is in a slightly distorted octa-hedral geometry, coordinated by one 2-amino-ethane-thiol-ate (aet) and two 1,2-bis-(diphenyl-phosphan-yl)ethane (dppe) ligands. The crystal consists of a pair of enanti-omers (Δ and Λ) of the compound. The Δ and Λ isomers have the λ and δ conformations for the aet chelate rings and the δ and λ conformations for the dppe chelate rings. The F atoms of the PF(6) (-) counter-anion are disordered over three positions, with site occupancies of 0.4, 0.3 and 0.3.

Significance of boost radiotherapy in early invasive ductal breast cancer with ductal carcinoma in situ component under negative surgical margins.

We hypothesize that there is a risk of ipsilateral breast tumor recurrence (IBTR) in surgical margin-free invasive ductal carcinoma (IDC) in the presence of ductal carcinoma in situ (DCIS) component affecting surgical margins in early stage. From 1990 to 2014, 343 patients with IDC in which the DCIS component constitute have received radiotherapy (RT) following breast-conserving surgery (BCS). All patients received whole breast irradiation with a prescribed dose of 50 Gy in 20 fractions (four times a week). This one-arm cohort with boost RT (253 patients) was compared for IBTR with a non-cohort group receiving no boost RT because of freedom from positive margins (90 patients). Median observation months were 98 (boost group) vs 119 (no boost group), respectively. The 15-year local recurrence-free survival (LRFS) rates were 98.5% and 85.6% in the boost and no boost groups, respectively (Cox proportional hazards model univariate analysis; p = 0.013, HR 0.13). Similarly, for other background factors, there was a significant difference in the LRFS between age groups. The 15-year LRFS rate was 91.8% in patients aged 45 years or younger and 94.6% in patients older than 46 years (p = 0.031, HR 0.21), respectively. Only these two factors were independently significant in Cox proportional hazards model multivariate analysis. IBTR risk in margin-free IDC with DCIS component was independently decreased by boost RT in the cohort setting. Tumor size, extensive intraductal component (EIC), boost dose, the presence of lymph node (LN) metastasis and hormonal therapy were not IBTR risk factors in this study.

Bis(bipyridine)ruthenium(II) complexes with an aliphatic sulfinato donor: synthesis, characterization, and properties.

Treatment of a thiolato-bridged Ru(II)Ag(I)Ru(II) trinuclear complex, [Ag{Ru(aet)(bpy)(2)}(2)](3+) (aet = 2-aminoethanthiolate; bpy = 2,2'-bipyridine), with NaI in aqueous ethanol under an aerobic condition afforded a mononuclear ruthenium(II) complex having an S-bonded sulfinato group, [1](+) ([Ru(aesi-N, S)(bpy)(2)](+) (aesi = 2-aminoethanesulfinate)). Similar treatment of optically active isomers of an analogous Ru(II)Ag(I)Ru(II) trinuclear complex, Δ(D)Δ(D)- and Λ(D)Λ(D)-[Ag{Ru(d-Hpen-O,S)(bpy)(2)}(2)](3+) (d-pen = d-penicillaminate), with NaI also produced mononuclear ruthenium(II) isomers with an S-bonded sulfinato group, Δ(D)- and Λ(D)-[2](+) ([Ru(d-Hpsi-O,S)(bpy)(2)](+) (d-psi = d-penicillaminesulfinate)), respectively, retaining the bidentate-O,S coordination mode of a d-Hpen ligand and the absolute configuration (Δ or Λ) about a Ru(II) center. On refluxing in water, the Δ(D) isomer of [2](+) underwent a linkage isomerization to form Δ(D)-[3] (+) ([Ru(d-Hpsi-N,S)(bpy)(2)](+)), in which a d-Hpsi ligand coordinates to a Ru(II) center in a bidentate-N,S mode. Complexes [1](+), Δ(D)- and Λ(D)-[2](+), and Δ(D)-[3](+) were fully characterized by electronic absorption, CD, NMR, and IR spectroscopies, together with single-crystal X-ray crystallography. The electrochemical properties of these complexes, which are highly dependent on the coordination mode of sulfinate ligands, are also described.

Phase III randomized adjuvant study of tamoxifen alone versus sequential tamoxifen and anastrozole in Japanese postmenopausal women with hormone-responsive breast cancer: N-SAS BC03 study.

Clinical trials conducted in Western countries have shown that aromatase inhibitors are associated with better disease-free survival (DFS) than tamoxifen in postmenopausal early breast cancer. Because pharmacogenetic differences in drug-metabolizing genes may cause ethnic differences, assessment of the efficacy and tolerability of aromatase inhibitors in non-white women is warranted. This open-label, randomized clinical trial included 706 postmenopausal Japanese women with hormone-receptor-positive breast cancer, who had received tamoxifen for 1 to 4 years as adjuvant therapy. This study was closed early after entry of approximately 28% of the initially planned patients. They were randomly assigned to either switch to anastrozole or to continue tamoxifen for total treatment duration of 5 years. Primary endpoints were DFS and adverse events. At a median follow-up of 42 months, the unadjusted hazard ratio was 0.69 (95% confidence interval, 0.42-1.14; P = 0.14) for DFS and 0.54 (95% CI, 0.29-1.02; P = 0.06) for relapse-free survival (RFS), both in favor of anastrozole. The incidence of thromboembolic events in the tamoxifen group and bone fractures in the anastrozole group was not excessively high. Switching from tamoxifen to anastrozole was likely to decrease disease recurrence in postmenopausal Japanese breast cancer patients. Ethnic differences in major adverse events may be attributable to a low baseline risk of these events in Japanese.

[Safety and tolerance of docetaxel (especially 75 mg/m2) with cyclophosphamide (TC therapy) as adjuvant chemotherapy for Japanese patients with operable breast cancer].

The safety and tolerance of docetaxel (especially 75 mg/m/2) plus cyclophosphamide (600 mg/m2) (TC therapy) as adjuvant chemotherapy for Japanese patients (n=47) with operable breast cancer was evaluated. Among 47 patients who received TC therapy, 38 patients (80.8%) were treated as scheduled for 4 courses every three weeks, and 6 patients (12.8%) were dose-reduced or the interval between courses was extended due to neutropenia or wound infection. Three patients (6.4%) quit TC therapy due to stomatitis or skin toxicities of grade 3. Although febrile neutropenia of grade 3 or 4 was observed in 2 patients (4.3%), TC therapy could be prescribed for these patients. Non-hematological side effects(such as edema, myalgia and arthralgia), occurred in relatively many cases, but were not remarkable. From these results, TC therapy (75/600 mg/m2) is considered to be a safe and tolerable regimen in Japanese patients operated for breast cancer.

Synthesis and linkage isomerization of thiolato-bridged Ru(II)Ag(I)Ru(II) trinuclear complex with D-penicillaminate.

The reaction of [Ru(solvent)(2)(bpy)(2)](2+) (bpy = 2,2'-bipyridine) with D-H(2)pen (D-penicillamine) in ethanol/water in the presence of Ag(+) gave a thiolato-bridged Ru(II)Ag(I)Ru(II) trinuclear complex, [Ag{Ru(D-Hpen)(bpy)(2)}(2)](3+) ([1](3+)), in which two octahedral [Ru(II)(D-Hpen)(bpy)(2)](+) units are linked by a linear Ag(I) ion. Of three possible isomers (Delta(D)Delta(D), Delta(D)Lambda(D), and Lambda(D)Lambda(D)), [1](3+) formed the Delta(D)Delta(D) and Lambda(D)Lambda(D) isomers that were separately isolated by fractional crystallization with the use of [Sb(2)(R,R-tartrato)(2)](2-). In [1](3+), each D-Hpen ligand chelates to a Ru(II) center through thiolate and carboxylate groups, while an amine group of D-Hpen is protonated and does not participate in the coordination. On refluxing in ethanol/water, the Delta(D)Delta(D) isomer of [1](3+) was converted to Delta(D)Delta(D)-[2](3+), in which each D-Hpen ligand chelates to a Ru(II) center through thiolate and amine groups with a non-coordinating carboxyl group. On the other hand, a similar thermal linkage isomerization was not noticed for the Lambda(D)Lambda(D) isomer of [1](3+) under the same conditions. The isolated Delta(D)Delta(D)-[1](3+), Lambda(D)Lambda(D)-[1](3+), and Delta(D)Delta(D)-[2](3+) were fully characterized by electronic absorption, CD, and NMR spectroscopies, along with single-crystal X-ray crystallography for Lambda(D)Lambda(D)-[1](3+) and Delta(D)Delta(D)-[2](3+).

[Efficacy and toxicity of combination treatment with epirubicin (EPI) plus docetaxel (DOC) in advanced breast cancer].

Thirty women (mean age 50.4 years, range 31-63) with primary advanced breast cancer were given EPI 40-60 mg/m(2) and DOC 50-60 mg/m(2) intravenously every three weeks. The efficacy was evaluated after 4 cycle treatments. There were 5 complete responses (CR) and 14 partial responses (PR), giving an overall response rate of 63.3%. There were 2 pathological CR (8%) which showed complete disappearance of cancer cells. The high dose group showed a better response than the low-dose group. The most common grade 3/4 adverse events were neutropenia (26.7%) and general fatigue (6.7%). The simultaneous combination treatment of EPI and DOC is effective for primary chemotherapy and can be performed safely even for outpatients.

Examination of breast conserving therapy in lobular carcinoma.

BACKGROUND: Experience with conserving surgery for lobular carcinoma has grown as more breast conserving surgeries have been performed. We examined the results of breast conserving therapy in lobular carcinoma. PATIENTS AND METHODS: We examined the postoperative positive margin rate, presence or absence of additional surgery, presence or absence of local or systemic recurrence and role of breast helical CT in 25 cases of breast conserving surgery performed at this department from 1991 through June 2003. RESULTS: Among the 303 cases of all breast conserving surgeries, there were 63 case with positive margins (20.8%), but there were 15 of 25 positive margin cases (60.0%) among the lobular carcinoma cases. In 8 of the 15 positive margin cases the technique was changed to mastectomy. One case of recurrence in the breast has been observed thus far. Although the positive margin rate and positive margin rate in infiltrating carcinoma cases tended to decline after the introduction of breast helical CT, the rates remained high. CONCLUSIONS: Since the positive margin rate was significantly high at the time of breast conserving surgery for lobular carcinoma, careful selection of technique based on imaging studies such as breast helical CT and MRI along with careful follow-up is considered necessary.

Metastatic breast cancer of HER2 scored 2+ by IHC and HER2 gene amplification assayed by FISH has a good response to single agent therapy with trastuzumab: a case report.

We report that single agent therapy with trastuzumab had a significant effect on metastatic breast cancer, which was confirmed to be HER2 positive by Herceptest showing 2+staining, and gene amplification positively detected by FISH analysis. A 48-year-old woman underwent extended radical mastectomy (T2N0M0 stage II). Three years after the operation supraclavicular lymph node metastasis was noted. Bone scintigraphy showed metastases to the left ribs 5 years after operation. She was treated with chemo-endocrine therapy, but nonetheless could not bear the back pain caused by the bone metastases. Another chemotherapy course could not be permitted because of leukopenia. Immunohistochemistry (IHC) analysis with Herceptest showed 2+staining for HER2 and FISH analysis showed gene amplification of HER2. We started single agent therapy with trastuzumab and she subsequently had remarkably improved back pain. Physical examination and ultrasonography showed disappearance of the previous palpable supraclaviclar lymph nodes. Serum tumor markers were also reduced after the first administration of trastuzumab. The patient is currently alive, with no further progression of the lymph node or bone metastases.

A bis-bipyridine osmium(II) complex with an N,S-chelating 2-aminoethanesulfinate: photoinduced conversion of an amine to an imine donor group by air oxidation.

Treatment of [Os(bpy)(2)Cl(2)] (bpy = 2,2'-bipyridine) with 2-aminoethanethiolate was accompanied by air oxidation to give [Os(2-aminoethanesulfinato-N,S)(bpy)(2)](+) ([1](+)), which was further oxidized by air to be converted into [Os(2-iminoethanesulfinato-N,S)(bpy)(2)](+) ([2](+)) under photoirradiation. Complex [2](+) was reverted back to [1](+) by treatment with BH(4)(-).

Thiolato-bridged RuIIAgIRuII trinuclear complex composed of bis(bipyridine)ruthenium(II) units with chelating 2-aminoethanethiolate: conversion to a disulfide-bridged RuIIRuII dinuclear complex.

The reaction of [Ru(solvent)2(bpy)2]2+ (bpy = 2,2'-bipyridine) with Haet (2-aminoethanethiol) in ethanol/water in the presence of Ag+ gave a thiolato-bridged RuIIAgIRuII trinuclear complex, [Ag{Ru(aet)(bpy)2}2]3+, in which two [RuII(aet)(bpy)2]+ units are linked by an AgI atom. When this complex was treated with HCl in acetonitrile/water, a disulfide-bridged RuIIRuII dinuclear complex, [Ru2(cysta)(bpy)4]4+ (cysta = cystamine), was produced as a result of the removal of an AgI atom and the autoxidation of thiolato groups. It was found that the dinuclear structure in [Ru2(cysta)(bpy)4]4+ is reverted back to [Ag{Ru(aet)(bpy)2}2]3+ by treatment with Ag+ assisted by Zn reduction.

Late phase II clinical study of vinorelbine monotherapy in advanced or recurrent breast cancer previously treated with anthracyclines and taxanes.

BACKGROUND: At present, it is one of the most important issues for the treatment of breast cancer to develop the standard therapy for patients previously treated with anthracyclines and taxanes. With the objective of determining the usefulness of vinorelbine monotherapy in patients with advanced or recurrent breast cancer after standard therapy, we evaluated the efficacy and safety of vinorelbine in patients previously treated with anthracyclines and taxanes. METHODS: Vinorelbine was administered at a dose level of 25 mg/m(2) intravenously on days 1 and 8 of a 3 week cycle. Patients were given three or more cycles in the absence of tumor progression. A maximum of nine cycles were administered. RESULTS: The response rate in 50 evaluable patients was 20.0% (10 out of 50; 95% confidence interval, 10.0-33.7%). Responders plus those who had minor response (MR) or no change (NC) accounted for 58.0% [10 partial responses (PRs) + one MR + 18 NCs out of 50]. The Kaplan-Meier estimate (50% point) of time to progression (TTP) was 115.0 days. The response rate in the visceral organs was 17.3% (nine PRs out of 52). The major toxicity was myelosuppression, which was reversible and did not require discontinuation of treatment. CONCLUSION: The results of this study show that vinorelbine monotherapy is useful in patients with advanced or recurrent breast cancer previously exposed to both anthracyclines and taxanes.