Tumor immune microenvironment and clinical outcomes in stage IV urothelial cancer: YODO study.

BACKGROUND: Bladder cancer is the 10th most common cancer globally, with a growing incidence in Japan. Evaluation of molecular, genetic, and cellular biomarkers that predict treatment response and prognosis in patients with metastatic urothelial carcinoma (mUC) may help optimize sequential treatment strategies with chemotherapy and immune checkpoint inhibitors (ICIs). METHODS: This multicenter, retrospective cohort study, evaluated programmed death-ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and cancer-immune phenotype as predictive prognostic biomarkers following first-/second-line treatment in Japanese adult patients with mUC. The primary endpoint was prevalence of PD-L1 expression. Secondary endpoints were TMB, overall survival (OS), and progression-free survival (PFS) from initiation of first-line treatment, and exploratory endpoints were cancer-immune phenotype, OS, PFS, and treatment response according to potential biomarker status. RESULTS: Of the 143 patients included (mean age 71.7 years), PD-L1 expression was high in 29.4% of patients. Non-synonymous TMB was high in 33.6% and low in 66.4%. Cancer-immune phenotype was immune-desert in 62.9%, immune-excluded in 30.8%, and inflamed in 6.3%. Median OS and PFS following first-line treatment were 18.2 and 7.4 months, respectively. Overall response to second-line treatment was slightly better with high versus low/negative PD-L1 expression. PD-L1 expression and TMB were non-significant predictors of OS or PFS, whereas immune-excluded phenotype was associated with better OS in comparison with immune-desert phenotype. CONCLUSION: PD-L1 expression and TMB were non-significant predictors of prognosis after first-line treatment in Japanese patients with mUC, but cancer-immune phenotype may be an important prognostic factor in chemotherapy-ICI sequential treatment strategies. Clinical trial registration number UMIN000037727.

Inhibition of EGFR, HER2 and HER3 signaling with AZD8931 alone and in combination with paclitaxel: phase i study in Japanese patients with advanced solid malignancies and advanced breast cancer.

BACKGROUND: AZD8931 is an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), human EGFR 2 (HER2) and HER3. This two-part Japanese study (NCT01003158) assessed the safety/tolerability of AZD8931 monotherapy in patients with advanced solid tumors and in combination with paclitaxel in female patients with advanced breast cancer. METHODS: Monotherapy part: ascending doses of AZD8931 (40/60/80 mg twice daily [bid]) for 21 consecutive days. Combination part: AZD8931 40 mg bid and paclitaxel 90 mg/m(2) (on days 1, 8 and 15 of a 28-day cycle). RESULTS: Seventeen patients received AZD8931: 11 received AZD8931 monotherapy (40/60/80 mg [n = 3/4/4]) and six AZD8931 40 mg bid plus paclitaxel. No dose-limiting toxicities were observed for AZD8931 alone or combined with paclitaxel. The most frequent adverse events (AEs) were diarrhea, paronychia, pustular rash and dry skin (each n = 8) with AZD8931 monotherapy and diarrhea, stomatitis, rash, alopecia, epistaxis and neutropenia (each n = 4) with combination therapy. Grade ≥3 AEs were reported for one, two and four patients in the 40 mg, 60 mg and combination groups, respectively. AZD8931 was rapidly absorbed with a half-life of 12 h. There was no evidence of pharmacokinetic interaction between AZD8931 and paclitaxel. Two patients (one in each part) had unconfirmed and confirmed partial responses, with a duration of 42 and 172 days, respectively. CONCLUSION: Although maximum tolerated dose was not confirmed for AZD8931, based on overall incidence of rash and diarrhea AEs in the 80 mg group, doses up to 60 mg bid as monotherapy and 40 mg bid combined with paclitaxel are the feasible AZD8931 doses in Japanese patients.

The prevalence of gene mutations in homologous recombination repair pathways in Japanese patients with metastatic castration-resistant prostate cancer in real-world clinical practice: The multi-institutional observational ZENSHIN study.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is a genetically heterogeneous disease with a poor prognosis. The prevalence of mutations in homologous recombination repair (HRR) pathway genes, including BRCA1/2, as well as treatment patterns and clinical outcomes, are not well characterized among Japanese men with mCRPC. METHODS: This multicenter, noninterventional cohort study enrolled Japanese men with mCRPC from 24 institutions between 2014 and 2018. Mutations in the 15 HRR-related genes were assessed using archival primary or metastatic tumor samples. Patterns of sequential therapies for mCRPC were investigated. Patients were followed up for survival evaluation including prostate-specific antigen progression-free survival (PSA-PFS) and overall survival (OS). RESULTS: Of the 143 patients analyzed, HRR-related mutations were detected in 51 patients (35.7%). The most frequently mutated genes were CDK12 (N = 19, 13.3%), followed by BRCA2 (N = 18, 12.6%), ATM (N = 8, 5.6%), and CHEK2 (N = 3, 2.1%). The most common type of first-line therapy for mCRPC was next-generation hormonal agents (NHA, 44.4%), followed by first-generation antiandrogens (FGA, 30.3%), and taxanes (22.5%). Commonly prescribed first-/second-line sequential regimens included FGA/NHA (17.6%), NHA/NHA (15.5%), and NHA/taxanes (14.1%). The median PSA-PFS and OS for the entire cohort were 5.6 and 26.1 months, respectively. Patients carrying BRCA1/2 mutations had numerically shorter PSA-PFS (median 3.3 vs. 5.9 months) and OS (median 20.7 vs. 27.3 months) than those without mutations. CONCLUSIONS: In conclusion, approximately one-third of Japanese patients with mCRPC carried mutations in HRR-related genes in this study. The real-world outcomes of mCRPC are poor with conventional therapy, warranting an expansion of treatment options based on genetic abnormalities of the disease.

Real-world outcomes of chemoradiotherapy for unresectable Stage III non-small cell lung cancer: The SOLUTION study.

There are limited real-world data on the treatment practices, outcomes, and safety of chemoradiotherapy (CRT) alone in potential candidates for immune checkpoint inhibitors (ICI) for unresectable non-small cell lung cancer (NSCLC). In this study, we analyzed the safety and efficacy of CRT in patients who underwent CRT and would satisfy the key eligibility criteria for maintenance therapy with durvalumab (eg, no progression after CRT) in real-world settings (m-sub) for unresectable Stage III NSCLC between 1 January 2013 and 31 December 2015 at 12 sites in Japan. The m-sub comprised 214 patients with a median follow-up of 31.6 months (range 1.9-65.8 months). Median overall survival (OS) and progression-free survival (PFS) from completing CRT were 36.4 months (95% confidence interval [CI] 28.1 months to not reached) and 9.5 months (95% CI 7.7-11.7 months), respectively. Consolidation chemotherapy did not influence OS or PFS. Median PFS was 16.9 vs 9.1 months in patients with vs without epidermal growth factor receptor (EGFR) mutations, with PFS rates of ~20% at 3-4 years. Pneumonitis was the most common adverse event (according to MedDRA version 21.0J), and about half of events were grade 1. Pneumonitis mostly occurred 10-24 weeks after starting CRT, peaking at 18-20 weeks. Esophagitis and dermatitis generally occurred from 0 to 4 weeks, peaking at 2-4 weeks after starting CRT. Pericarditis was rare and occurred sporadically. In conclusion, the results of the m-sub provide real-world insight into the outcomes of CRT, and will be useful for future evaluations of ICI maintenance therapy after CRT.

Phase 3, open-label, randomized study comparing 3-monthly with monthly goserelin in pre-menopausal women with estrogen receptor-positive advanced breast cancer.

BACKGROUND: Monthly goserelin 3.6 mg dosing suppresses estradiol (E2) production and has proven efficacy in pre-menopausal women with estrogen receptor (ER)-positive breast cancer. This non-inferiority study evaluated the efficacy and safety of 3-monthly goserelin 10.8 mg compared with monthly goserelin 3.6 mg. METHODS: This was a Phase 3, open-label, multicenter trial. Pre-menopausal women with ER-positive advanced breast cancer were randomized to 3-monthly goserelin 10.8 mg or monthly goserelin 3.6 mg; all patients received concomitant tamoxifen (20 mg daily). The primary endpoint was progression-free survival (PFS) rate at 24 weeks; non-inferiority was to be confirmed if the entire 95 % confidence interval (CI) for the treatment difference was above -17.5 %. Secondary endpoints included objective response rate (ORR), serum E2 levels, safety, and tolerability. RESULTS: In total, 222 patients were randomized (goserelin 10.8 mg, n = 109; goserelin 3.6 mg, n = 113). PFS rate at week 24 was 61.5 % (goserelin 10.8 mg) and 60.2 % (goserelin 3.6 mg); treatment difference (95 % CI) was 1.3 % (-11.4, 13.9), confirming non-inferiority of goserelin 10.8 mg compared with goserelin 3.6 mg. ORR was 23.9 % (goserelin 10.8 mg) and 26.9 % (goserelin 3.6 mg); treatment difference (95 % CI) was -3.0 % (-15.5, 9.7). At week 24, mean serum E2 concentrations were similar in the goserelin 10.8 mg and goserelin 3.6 mg groups (20.3 pg/mL and 24.8 pg/mL, respectively). CONCLUSION: A regimen of 3-monthly goserelin 10.8 mg demonstrated non-inferiority compared with monthly goserelin 3.6 mg for PFS rate at 24 weeks, with similar pharmacodynamic and safety profiles, in pre-menopausal women with ER-positive breast cancer.

Interim analysis of a phase II trial of cyclophosphamide, epirubicin and 5-fluorouracil (CEF) followed by docetaxel as preoperative chemotherapy for early stage breast carcinoma.

PURPOSE: A single-arm phase II multicenter trial of the combination of cyclophosphamide (C), epirubicin (E), and 5-fluorouracil (F) followed by docetaxel as neoadjuvant chemotherapy is being conducted by the Japan Breast Cancer Research Group. This report describes an interim analysis of the clinical response and safety of 79 patients who finished preoperative chemotherapy and surgery. PATIENTS AND METHODS: Patients with operable breast cancer received C at 500 mg/m2, E at 100 mg/m2, and F at 500 mg/m2 every 21 days for 4 cycles followed by docetaxel at 75 mg/m2 every 21 days for 4 cycles. RESULTS: Of the 79 patients evaluable for analysis the median age was 46 years (28-59), and 61 patients (77.2%) had T2 tumors. A total of 312 of 316 (98.7%) cycles of CEF and 296 of 312 (94.9%) cycles of docetaxel were administered. Average total cumulative dose was 92% and 95% for CEF and docetaxel, respectively. The rate and grade of edema, neuropathy, arthralgia and myalgia were higher with docetaxel than with CEF. The overall clinical response rate was 70.9%. Breast conserving surgery was performed in 31 of 42 patients (73.8%) with a base-line tumor size of more than 3 cm. CONCLUSIONS: Interim data suggest that CEF followed by docetaxel is an active and tolerable neoadjuvant chemotherapy regimen. A final analysis is planned for 2005.

Analysis of ipsilateral breast tumor recurrences after breast-conserving treatment based on the classification of true recurrences and new primary tumors.

BACKGROUND: Ipsilateral breast tumor recurrences (IBTR) after breast-conserving treatment include two different entities: true recurrence (TR) thought to occur when residual cancer cells grow gradually to detectable size and new primary (NP) thought to be de novo cancer independently arising in the preserved breast. The patients with ipsilateral breast tumor recurrence (IBTR) are potentially at high risk for subsequent distant metastasis, but many studies do not distinguish between these types of recurrence. The aim of this study is to clarify the biological difference between TR and NP, and to show the clinical significance of classifying IBTR into these two types of recurrence. PATIENTS AND METHODS: A total of 172 patients with IBTR after breast-conserving therapy from the cohort of a long-term large scale study (Research of cancer treatment from the Ministry of Health, Labor and Welfare of Japan (no.13-9)) were analyzed. We classified IBTRs as TR or NP based on tumor location and pathological findings. The characteristics of the primary tumors of TR and NP were compared. Survival rates and risk factors of each type of IBTR were examined by the Kaplan-Meier method. The results of salvage surgery were also analyzed. RESULTS: Of the 172 patients, 135 patients were classified as TR and 26 as NP. Eleven cases could not be categorized. The primary tumor of TR was characterized by a high rate of lymph node metastasis (37.8%) and short disease-free interval (mean DFI; 46.6 months) while that of NP showed a rather low lymph node positivity (8.7%) and longer DFI (62.1 months). The risk factors for TR were young age, positive surgical margin, omission of irradiation and positive lymph node metastasis. Those for NP were young age, omission of irradiation and contralateral breast cancer after the primary operation. The 5-year survival rates after IBTR were 71.0% in TR and 94.7% in NP (p=0.022). Salvage operation was performed in 136 IBTRs. Eighty-one patients underwent salvage mastectomy and 55 patients underwent repeat lumpectomy. Five-year survival rates after salvage operation were 75.7% for mastectomy and 84.2% for lumpectomy (N.S.). Twenty percent of patients who underwent repeat lumpectomy developed secondary local relapse within 5 years after salvage treatment. The risk factors for secondary local relapse were analyzed. Limited to cases of IBTR which received radiation therapy after the primary operation, NP was the only factor influencing secondary local relapse by univariate analysis. CONCLUSIONS: TR and NP show clinically quite different features; time to occurrence, characteristics of the original tumor, prognosis and risk factor profile for IBTR were all different. Classifying IBTR as TR or NP can provide clinically significant data for the management of IBTR.

Pharmacokinetic and pharmacodynamic study of IST-622, a novel synthetic derivative of chartreusin, by oral administration in a phase II study of patients with breast cancer.

The aim of this study was to analyze the pharmacokinetics and pharmacodynamics (PK/PD) of 6- O-(3-ethoxypropionyl)-3',4'- O-exo-benzylidene-chartreusin (IST-622) and its metabolites, and to develop limited sampling models (LSM). Based on the data from 18 patients with breast cancer who were treated orally with 280 or 525 mg/m(2) of IST-622 once daily after breakfast for five consecutive days, we analyzed the relationship between the area under the plasma concentration versus time curve (AUC) and toxicities using a sigmoid E-max model and logistic regression. Plasma concentrations of IST-622 and its metabolites, 3',4'- O-exo-benzylidene-chartreusin (A-132) and 3"-demethyl-3',4'- O-exo-benzylidene-chartreusin (A-132M), were measured at 1, 2, 4, 8 and 24 h after administration on day 1. The AUC was calculated using the trapezoidal method. We also developed a LSM using stepwise linear regression analysis. IST-622 was detected in very few patients, and its concentration was very low and could be disregarded. It was suggested that meals promoted absorption of IST-622. AUCs of A-132 plus A-132M showed a better correlation with the rates of decrease and nadir counts of leukocytes, neutrophils and platelets than the AUC of each metabolite separately. Patients with the sum of AUCs more than 70 microg.h/ml showed severe myelotoxicities. Moreover, logistic regression analysis showed that grade 4 myelotoxicities would be seen in 30% of patients at an AUC of 65 microg.h/ml. We also developed an unbiased and precise LSM: AUC_0-24h=C_8hx17.6-0.95, where C(8h) denotes the sum of plasma concentrations of A-132 and A-132M. Myelotoxicities showed a good correlation with AUC(0-24h), and based on the results, it was decided that the target AUC was 65 microg.h/ml. The LSM was very convenient for estimating AUC(0-24h) and sufficiently accurate. These results show the possibility of predicting toxicities and dose adaptation for interpatient variability using LSM.

Fulvestrant for the treatment of advanced breast cancer in postmenopausal women: a Japanese study.

BACKGROUND: Fulvestrant ('Faslodex') is a new type of oestrogen receptor (ER) antagonist that down-regulates the ER and has no known agonist effects. PATIENTS AND METHODS: In this open-label, Phase II trial, 30 postmenopausal Japanese women with hormone-sensitive advanced breast cancer, who had progressed on tamoxifen/toremifene following an initial response, received fulvestrant (250 mg; once-monthly intramuscular injection). Primary endpoints were objective tumour response rate (complete or partial response) and assessment of tolerability; secondary endpoints included clinical benefit (objective response, or stable disease > or = 24 weeks), duration of response and pharmacokinetic analysis. RESULTS: The objective response rate was 23.3% and 60.0% of patients experienced clinical benefit. Adverse events were generally mild; the most common were pharyngitis (26.7%), headache (23.3%) and nausea (20.0%). Pharmacokinetic data were similar to a Western study of postmenopausal patients. CONCLUSION: Fulvestrant 250 mg/month is effective and well-tolerated in Japanese patients who have relapsed after one prior endocrine treatment.

[Transdiaphragmatic radiofrequency ablation of malignant liver tumors].

The majority of patients with primary or metastatic liver tumors are not candidates for resection because of the size, location, or multifocality of their tumors, or because of inadequate hepatic function related to cirrhosis. Radiofrequency ablation (RFA) is an evolving technique for treating patients with unresectable primary or metastatic liver cancers. After obtaining the approval of our institutional review board for this study, 12 patients with HCC and 6 patients with metastatic liver tumors were treated using the LeVeen RF ablation system at the Department of Surgery of Osaka National Hospital between March 2000 and February 2002. Informed consent was obtained from all patients. Ultrasound-guided RFA was done during open surgery. In 12 patients, RFA was performed during laparotomy, while in 6 patients it was done transdiaphragmatically during thoracotomy. All treated tumors showed complete necrosis on imaging after the completion of RFA. After a median follow-up period of 288 days, the tumor had recurred in 5 out of 18 patients, and the median overall survival rate was 362 days. No deaths or major complications occurred in these 18 patients. Liver function tests (ALT, AST, GGT) that were elevated after RFA returned to baseline in most patients by day 7. In 5 patients who underwent RFA at laparotomy, bile leakage and liver abscess developed. There were no cases of bile duct injury or liver abscess in the patients receiving transdiaphragmatic RFA. In conclusion, transdiaphragmatic RFA during thoracotomy is a safe, well-tolerated, effective treatment for unresectable hepatic malignancies.

[A patient with diffuse peritoneal metastases of GIST who was administered STI571].

We report a patient with diffuse peritoneal metastases of GIST who was administered STI571 (a tyrosine kinase inhibitor). She was a 45-year-old woman who underwent surgery for a mass that was suspected to be an ovarian tumor. The postoperative diagnosis was GIST developing from the small intestine. Two years later, multiple peritoneal metastases were noted and a complete macroscopic resection was done. Six months after the second operation, she needed a third operation and complete macroscopic resection was repeated. Only 4 months after the third operation, she underwent a fourth operation. We resected massive peritoneal metastases, but diffuse metastases remained. Therefore, we started to administer STI571 at 400 mg/day. She has been free from peritoneal masses for 9 months after the fourth operation. We recommend STI571 for uncontrolled diffuse peritoneal metastases of GIST.

Phase II study of 4-weekly capecitabine monotherapy in advanced/metastatic breast cancer.

BACKGROUND: A multicenter, phase II study was conducted to evaluate the efficacy and safety of the Japanese intermittent 4-week regimen of capecitabine in patients with advanced/metastatic breast cancer. METHODS: Fifty patients who had received no more than one prior chemotherapy regimen for advanced/metastatic disease were enrolled from 23 centers and received at least two 4-weekly cycles of capecitabine (828 mg/m² orally twice daily for 3 weeks followed by a 1-week rest period). RESULTS: The overall response rate assessed by the Independent Review Committee (standard population, n = 46) was 28.3% (95% confidence interval 16.0-43.5%), including complete responses in 6.5%. Stable disease was observed in 20 patients and maintained for more than 6 months in 10 patients. The median duration of response in 13 evaluable responders was 5.3 months. Among evaluable patients (n = 47), median time to disease progression was 5.1 months. Median overall survival was 20.2 months. The most common treatment-related adverse events (all grades) were hand-foot syndrome (66%), nausea (26%), stomatitis (22%) and diarrhea (20%). Grade 3/4 treatment-related adverse events were seen in 23 patients (46%). The most common grade 3/4 adverse events were lymphocytopenia (22%), hand-foot syndrome (18%) and hyperbilirubinemia (10%). CONCLUSIONS: Although the target overall response rate was not reached, the Japanese intermittent 4-week regimen of capecitabine was shown to be an effective and well-tolerated first- or second-line therapy for advanced/metastatic breast cancer.

Preliminary result of accelerated partial breast irradiation after breast-conserving surgery.

PURPOSE: To investigate the feasibility of accelerated partial breast irradiation (APBI) for Japanese patients, we started high-dose-rate interstitial brachytherapy (HDR-ISBT) as monotherapy after breast-conserving surgery (BCS). METHODS: We implanted 45 Tis-2 breast cancer patients at National Hospital Organization Osaka National Hospital between June 2002 and June 2006. Our eligibility criteria were broader than the ones used previously in western countries. We included margin-positive cases and younger patients (median age: 44; range: 26-68) to adapt the criteria for Japanese women. Total prescribed doses were 36-42 Gy in six to seven fractions, and the volumes encompassed by 100% prescribed dose (V100) were 38.5-315.1 cc. Fifteen patients received chemotherapy. RESULTS: Treatment could be completed for all patients. Two local failures (4%) and two distant metastases were observed, while one patient died of liver metastasis. Seven wound complications, four with and three without infection, and two rib fractures occurred. The significant risk factors for wound complications were non-administration of prophylactic antibiotics during ISBT (P < 0.01), open cavity implant (P < 0.05), large V100 (P < 0.01), V150 (P < 0.05), and V200 (P < 0.05). CONCLUSION: APBI after BCS for Japanese women with relatively small breasts was well tolerated, but special care should be taken with treatment technique.

Phase I, dose escalation and pharmacokinetic study of cediranib (RECENTIN), a highly potent and selective VEGFR signaling inhibitor, in Japanese patients with advanced solid tumors.

PURPOSE: To evaluate safety and tolerability of cediranib, a highly potent and selective vascular endothelial growth factor signaling inhibitor, in Japanese patients with advanced solid tumors refractory to standard therapies. METHODS: In part A (n = 16), patients received once-daily oral cediranib (10-45 mg) to identify the maximum tolerated dose (MTD). In part B (n = 24), patients with non-small-cell lung cancer or colorectal cancer received multiple daily doses at the MTD. RESULTS: Cediranib 30 mg/day was considered the MTD since 50% of evaluable patients receiving 45 mg/day experienced dose-limiting toxicities in part A (proteinuria and diarrhea n = 1, proteinuria n = 1, thrombocytopenia n = 1). The most common adverse events were diarrhea (n = 34) and hypertension (n = 32). Pharmacokinetic analysis confirmed cediranib as suitable for once-daily oral dosing. Of 32 evaluable patients, two had partial RECIST responses and 24 had stable disease > or =8 weeks. CONCLUSIONS: Cediranib was generally well tolerated at < or =30 mg/day in these Japanese patients and showed encouraging antitumor activity.

Ipsilateral breast tumor recurrence (IBTR) after breast-conserving treatment for early breast cancer: risk factors and impact on distant metastases.

BACKGROUND: The clinical features of ipsilateral breast tumor recurrence (IBTR) after breast conserving therapy (BCT) for early stage breast cancer were analyzed from long-term follow-up of BCT in Japan. The purpose of this study was to clarify risk factors of IBTR and the impact of IBTR on development of distant metastases in this ethnic group. METHODS: Patients (N = 1901)with unilateral breast cancer < or = 3 cm in diameter who underwent BCT at 18 Japanese major breast cancer treatment institutes from 1986 to 1993 were registered in this study. Survival rates, the incidences of IBTR and distant metastases, and annual rates of IBTR and distant metastases after primary operation were calculated by the Kaplan-Meier method. A Cox proportional hazards model was used to estimate the risks of IBTR and distant metastases. A Cox model was also used to estimate the risks of distant metastases after IBTR in the group of IBTR. RESULTS: At a median follow-up time of 107 months, the 10-year overall and disease-free survival rates were 83.9% and 77.8%, respectively. The 10-year cumulative rates of IBTR were 8.5% in the patients with postoperative irradiation and 17.2% in the patients without irradiation. The 10-year cumulative distant metastasis rate was 10.9%. On multivariate analysis, young age, positive surgical margin, and omission of radiation therapy were significant predictors of IBTR. In addition, IBTR significantly correlated with subsequent distant metastases (hazard ratio, 3.93; 95% confidence interval, 2.676-5.771; P < 0.0001). Among patients who developed IBTR, initial lymph node metastases and short interval to IBTR were significant risk factors for subsequent distant metastasis. CONCLUSIONS: Young age, positive surgical margin, and omission of radiation therapy seemed to be important factors in relation to local control. The authors' results also indicated that IBTR is significantly associated with subsequent distant metastasis. Patients with positive nodal status at primary operation or with short interval from primary operation to IBTR are at especially high risk of distant metastasis. It remains unclear, however, whether IBTR is an indicator or a cause of subsequent distant metastases.

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.

Phase II study of weekly paclitaxel for docetaxel-resistant metastatic breast cancer in Japan.

The purpose of the study was to evaluate the efficacy of weekly paclitaxel (PTX) against metastatic breast cancer (MBC) that was resistant to docetaxel (DTX) given every 3 weeks. A multicenter phase II study was performed. Women with MBC resistant to DTX were eligible for enrollment. DTX resistance was defined as no tumor response to DTX and stable disease, partial response, or complete response to DTX preceding disease progression. PTX 80 mg/m(2) was administered over 1 hour once a week for 3 weeks per 4-week cycle. Among 47 enrolled patients, 46 patients were assessable for response and toxicity. The overall objective response rate (complete responses [CRs] and partial responses [PRs]) was 17.4% and overall clinical benefit rate (CRs, PRs, and stable disease >or=24 weeks) was 26.1%. The median time to progression was 11 weeks. There were a few severe hematologic toxicities related to the therapy, with grade 4 neutropenia (4.3%) and thrombocytopenia (2.2%). Grade 3 anaphylaxis and grade 3 neuropathy were observed in one patient (2.2%) each. The median delivered dose intensity was 77.6 mg/m(2)/week, 97.1% of the planned dose intensity. Weekly PTX has activity in patients with MBC resistant to DTX every 3 weeks.

Long-term results of breast-conserving treatment for early-stage breast cancer in Japanese women from multicenter investigation.

BACKGROUND: Although many clinical data regarding breast-conserving treatment have already been reported from European and North American countries, few clinical data with long-term follow-up have been reported from Japan. METHOD: We collected information on therapeutic and possible or developed prognostic factors and follow-up data for Japanese women who had received breast-conserving treatment consisting of wide excision of the primary tumor, axillary dissection and radiotherapy for unilateral breast cancer considered suitable for breast-conserving treatment from 18 Japanese major breast cancer treating hospitals; 1561 patients were registered. RESULTS: The median follow-up period was 77 months. Five-year disease-free and overall survival rates were 89.4 and 95.9%, respectively. The 5-year local recurrence-free rate was 96.3%. The patients with histologically positive margins (P < 0.0001) or estrogen receptor negative tumor (P = 0.0340) or younger than 40 years old (P < 0.0001) developed statistically significantly more local recurrences. Adjuvant endocrine therapy was essential for the estrogen receptor positive patients to have a lower local recurrence rate. Endocrine therapy did not change the local recurrence rate among estrogen receptor negative patients at all. Multivariate analysis showed histological margin status and the combination of estrogen receptor status and endocrine therapy were independent prognostic factors for local recurrence. CONCLUSION: The 5-year local recurrence rate of Japanese breast cancer patients who were treated with breast-conserving treatment using radiotherapy was 3.7%. Independent prognostic factors for local recurrence were histological margin status and the combination of estrogen receptor status and adjuvant endocrine therapy.