Treatment rationale and protocol design: an investigator-initiated phase II study of combination treatment of nivolumab and TM5614, a PAI-1 inhibitor for previously treated patients with non-small cell lung cancer.

Background: There is no established standard 3rd line treatment for patients with advanced non-small cell lung cancer (NSCLC). Although cytotoxic chemotherapeutic agents that are not used as 1st or 2nd line treatment are administrated as 3rd line treatment, their anti-tumor efficacy is insufficient. Anti-programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) treatment is more effective and less toxic than chemotherapy in anti-PD-L1/PD-1 treatment-naïve patients with NSCLC. Therefore, anti-PD-L1/PD-1 therapy is considered an appropriate 3rd line treatment. However, the anti-tumor efficacy is limited in patients previously treated with anti-PD-L1/PD-1 antibody. Today, new drugs are needed to increase the efficacy of anti-PD-L1/PD-1 antibodies. Methods: This open-label, single-arm, investigator-initiated phase II study is designed to evaluate combination treatment of nivolumab and TM5614, a plasminogen activator inhibitor (PAI-1) inhibitor as 3rd or more line treatment in NSCLC patients who underwent standard treatment. The primary endpoint is the objective response rate and the secondary endpoints are progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Recruitment began in September 2023 and is expected to continue for approximately three years. Discussion: Currently, there is no standard 3rd line treatment for advanced NSCLC, and we hope that the findings of this study will facilitate more effective treatments in this setting. Ethics and dissemination: the study protocol conformed to the ethical principles outlined in the Declaration of Helsinki. All patients will provide written informed consent prior to enrollment. Results will be published in a peer-reviewed publication. Trial Registration: This study is registered to Japan Registry of Clinical Trials with number: jRCT2061230039 (19/July/2023).

A Multicenter, Open-Label, Single-Arm Phase I Trial of Dual-Wield Parenchymal Transection: A New Technique of Liver Resection Using the Cavitron Ultrasonic Surgical Aspirator and Water-Jet Scalpel Simultaneously (HiSCO-14 Trial).

PURPOSE: This study evaluated the safety and feasibility of a technique of liver resection named dual-wield parenchymal transection technique (DWT), using cavitron ultrasonic surgical aspirator (CUSA) and water-jet scalpel simultaneously. METHODS: This multicenter, prospective, open-label, and single-arm phase I trial included patients aged 20 years or older with hepatic tumors indicated for surgical resection and scheduled for open radical resection. This study was conducted at two institutions affiliated with the Hiroshima Surgical Study Group of Clinical Oncology (HiSCO). The primary endpoint was the proportion of massive intraoperative blood loss (≥ 1000 mL). The secondary endpoints were the amount of blood loss, operative time, parenchymal transection speed, postoperative complications, and mortality. The safety endpoints were device failure and adverse events associated with devices. RESULTS: From June 2022 to May 2023, 20 patients were enrolled; one was excluded and 19 were included in the full analysis set (FAS). In the FAS, segmentectomy was performed in nine cases, sectionectomy in four cases, and hemihepatectomy in six cases. Radical resection was achieved in all patients. Intraoperative blood loss greater than 1000 mL was observed in five patients (26.3%). The median amount of blood loss was 545 mL (range, 180-4413), and blood transfusions were performed on two patients (10.5%). The median operative time was 346 minutes (range, 238-543) and the median parenchymal transection speed was 1.2 cm2/minute (range, 0.5-5.1). Postoperative complications of Clavien-Dindo classification ≥ Grade 3 occurred in four patients (21.1%). No mortalities occurred in this study. In the safety analysis, there were no device failures or adverse events associated with devices. CONCLUSIONS: This study demonstrated the safety and feasibility of DWT for liver resection. The efficacy of the DWT will be evaluated in future clinical trials.

Protection From Second Warm Ischemic Injury Using a Thermal Barrier Bag in Kidney Transplantation.

Second warm ischemic injury during vascular anastomosis not only adversely affects immediate posttransplant function but also affects long-term patient and graft survival. We developed a pouch-type thermal barrier bag (TBB) composed of a transparent, biocompatible insulation material suitably designed for kidneys and conducted the first-in-human clinical trial. Methods: A living-donor nephrectomy was performed using a minimum skin incision procedure. After back table preparation, the kidney graft was placed inside the TBB and preserved during vascular anastomosis. The graft surface temperature was measured before and after vascular anastomosis using a noncontact infrared thermometer. After completion of the anastomosis, the TBB was removed from the transplanted kidney before graft reperfusion. Clinical data, including patient characteristics and perioperative variables, were collected. The primary endpoint was safety, which was assessed by evaluating adverse events. The secondary endpoints were the feasibility, tolerability, and efficacy of the TBB in kidney transplant recipients. Results: Ten living-donor kidney transplant recipients with a median age of 56 y (range, 39-69 y) were enrolled in this study. No serious adverse events related to the TBB were observed. The median second warm ischemic time was 31 (27-39) min, and the median graft surface temperature at the end of anastomosis was 16.1 °C (12.8-18.7 °C). Conclusions: TBB can maintain transplanted kidneys at a low temperature during vascular anastomosis, which contributes to the functional preservation of transplanted kidneys and stable transplant outcomes.

Metastatic Metaplastic Breast Cancer Successfully Treated with Adriamycin and Cisplatin.

Metaplastic breast cancer (MBC) is characterized by the histological presence of a mixture of epithelial and mesenchymal-like elements. However, MBC responds poorly to chemotherapy. Due to its rarity, there is no well-defined treatment for MBC. Herein, we report the case of a 56-year-old woman who underwent a mastectomy and was diagnosed with MBC with osseous differentiation classified as pT4N0M1. After the operation, she was treated with adriamycin and cisplatin, which are standard osteosarcoma treatments, resulting in a partial response. However, to determine the proper chemotherapy treatment, knowledge of the metaplastic elements of the tumor is required.

Adoptive immunotherapy with natural killer cells from peripheral blood CD34+ stem cells to prevent hepatocellular carcinoma recurrence after curative hepatectomy: a study protocol for an open-label, single-arm phase I study.

INTRODUCTION: Hepatocellular carcinoma (HCC) remains a major clinical problem as more than half of these cases recur after radical resection. Natural killer (NK) cells are at the forefront of the innate immune system and attack microcarcinomas and circulating tumour cells. The objective of this study was to evaluate the feasibility and toxicity of peripheral blood CD34+ stem cell-derived NK cell infusion after radical hepatectomy for HCC. METHODS AND ANALYSIS: This is an open-label, single-arm, single-centre phase I study. Patients who have undergone initial hepatectomy for HCC with three or more risk factors for recurrence (≥10 ng/mL of Alpha fetoprotein (AFP), ≥360 mAU/mL of PIVKA-II, multiple tumours and ≥3 peripheral blood circulating tumour cells) will be enrolled and be treated with three peripheral blood CD34+ stem cell-derived NK cell infusions every 3 months. The primary endpoint will be safety assessment including the type and severity of adverse events, frequency of occurrence and duration of occurrence. The secondary endpoints will include survival, effect of immune response and clinical laboratory test results. ETHICS AND DISSEMINATION: Ethical approval of the trial was obtained from the Certified Committee for Regenerative Medicine Hiroshima University in Japan. The trial results will be shared with the scientific community at international conferences and by publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCTb060200020.

A Multicenter Study of Docetaxel at a Dose of 100 mg/m2 in Japanese Patients with Advanced or Recurrent Breast Cancer.

Objective This study examined the pharmacokinetics, safety and anti-tumor activity of docetaxel at a dose of 100 mg/m2 in Japanese patients with advanced or recurrent breast cancer. Methods Japanese patients with advanced or recurrent breast cancer received docetaxel at a dose of 100 mg/m2 intravenously every three weeks. The pharmacokinetics were assessed during the first cycle. The patients were allowed to receive supportive care drugs based on the indications and dosages in Japan. Results Six eligible patients aged 39-65 years old and 27 treatment cycles were analyzed. All patients experienced one or more adverse events (AEs). The common AEs were neutropenia, thrombocytopenia, alopecia, rash, diarrhea, neuropathy (sensory), fatigue, nausea, fever, hypoalbuminemia, alanine transaminase (ALT) increased, constipation, and taste alteration. Grade 3 or 4 AEs included neutropenia, leukopenia, anemia, lymphopenia, decreased appetite, γ-glutamyl transpeptidase (GTP) increased, aspartate transaminase (AST) increased, ALT increased, hypertension and cellulitis which were all reversible. There were no cases of febrile neutropenia, serious AEs or deaths. The median number of cycles was six. Dose reductions were not observed and most cycles were administered at their intended doses. No complete response and three partial responses were observed in four assessable patients with evaluable lesions. The maximum concentration and area under the blood concentration-time curve were 3,417.5 ng/mL and 4.35 µg・hr/mL (mean), respectively. Conclusion Docetaxel at a dose of 100 mg/m2 was tolerable with acceptable safety profiles and effective for Japanese patients with advanced or recurrent breast cancer with appropriate supportive therapies, and pharmacokinetic (PK) profiles which corresponded approximately with the findings of previous clinical studies.

Cryotherapy for the prevention of weekly paclitaxel-induced peripheral adverse events in breast cancer patients.

PURPOSE: This randomized phase II study was conducted to investigate the efficacy of cryotherapy in preventing peripheral neuropathy and dermatological adverse events in breast cancer patients treated with weekly paclitaxel. METHODS: Patients treated with 12 weekly doses of paclitaxel for breast cancer were randomized (1:1) into a cryotherapy or control group. The primary endpoint was the percentage of patients with a marked decrease in the Functional Assessment of Cancer Therapy-Neurotoxicity (FACT-NTX) score. The secondary endpoints were Patient Neurotoxicity Questionnaire (PNQ), Common Terminology Criteria for Adverse Event (CTCAE) for peripheral neuropathy, and FACT-Taxane score. RESULTS: Forty-four patients were randomly assigned to the cryotherapy (n = 22) or control groups (n = 22). The percentage of patients with a marked decrease in FACT-NTX scores was significantly lower in the cryotherapy group than in the control group (41 vs. 73%, p = 0.03). The incidence of CTCAE grade ≥ 2 sensory (p = 0.001) and motor peripheral neuropathy (p = 0.01), and PNQ grade D or higher for sensory peripheral neuropathy (p = 0.02), and decrease in the FACT-Taxane score (p = 0.02) were also significantly lower in the cryotherapy group than in the control group. There were no serious side effects associated with cryotherapy. CONCLUSION: Cryotherapy is an effective approach for prevention of peripheral neuropathy and dermatological adverse events in breast cancer patients treated with weekly paclitaxel.

Primary cardiac rhabdomyosarcoma successfully treated with eribulin: a case report.

Rhabdomyosarcoma is the most common soft tissue sarcoma that typically occurs in children and adolescents and is rare in adults. Furthermore, as cardiac tumor is rare, adult cardiac rhabdomyosarcoma is a very rare entity. Here, we report the case of a 68-year-old woman with cardiac rhabdomyosarcoma who was successfully treated with eribulin. She presented with sudden loss of consciousness, which was attributed to the cardiac tumor. The tumor was resected by emergency surgery and was diagnosed as embryonal rhabdomyosarcoma. Although surgical treatment alleviated her symptoms, the residual tumor increased in size after surgery and required multimodal treatment. First-line chemotherapy with the vincristine, actinomycin D, and cyclophosphamide regimen had to be discontinued owing to adverse events, and thus eribulin was used as a second-line treatment. Eribulin was better tolerated and helped maintain a stable disease status for >18 months. This reported case of cardiac rhabdomyosarcoma is the first case to be successfully treated with eribulin over a relatively long period. Eribulin therapy may thus be a viable treatment alternative for rhabdomyosarcoma.

Minimal prognostic significance of sentinel lymph node metastasis in patients with cT1-2 and cN0 breast cancer.

BACKGROUND: The prognostic value of sentinel lymph node (SLN) metastases may be minimized by the limited disease burden of lymph node metastases and tailoring adjuvant therapy based on breast cancer biology. The aim of this study is to assess the prognostic significance of SLN metastasis in patients with cT1-2N0M0 breast cancer. PATIENTS AND METHODS: Between January 2006 and December 2015, 582 patients underwent SLN biopsy for cT1-2N0M0 breast cancers. cN0 was essentially diagnosed by ultrasound sonography. The prognostic values of SLN metastases were retrospectively evaluated. RESULTS: Among 582 patients with cT1-2N0M0 breast cancer, 111 patients (19.1%) were positive for SLN metastasis, including 39 cases (6.7%) of micrometastasis and 72 cases (12.4%) of macrometastases. The median size of SLN metastasis was 3.0 mm (range 0.2-16 mm, mean 4.1 mm). In log-rank test, presence of SLN metastasis was not associated with breast cancer recurrence (p = 0.21); 5-year and 10-year recurrence-free survival (RFS) were 93.0% and 96.5%, and 93.0% and 90.4% in the SLN-positive and SLN-negative groups, respectively. In the propensity score matching cohort (n = 178), there was no significant difference in RFS between the SLN-positive and SLN-negative groups (p = 0.90). In Cox regression analysis, a continuous value of Ki67 expression was a significant prognostic factor (HR 1.03; 95% CI 1.01-1.05, p = 0.017). CONCLUSION: SLN metastasis has a minimal impact on RFS for patients with cT1-2N0M0 breast cancer in the modern medical era. A proliferation marker is a better factor for poor prognosis than the presence of SLN metastases in this population.

Overexpression of topoisomerase II alpha protein is a factor for poor prognosis in patients with luminal B breast cancer.

BACKGROUND: The prognostic value and the best method of testing of topoisomerase II alpha (TOP2A) status have not been established in modern tailored therapy based on breast cancer subtype. RESULTS: The frequencies of TOP2A overexpression and TOP2A amplified were 55.8% and 9.5%, respectively. TOP2A overexpression correlated strongly with non-luminal A subtype (χ2-test, p < 0.001). TOP2A overexpression was significantly associated with relapse-free survival in luminal B breast cancer (n = 316; log rank test, p < 0.001) but not in other breast cancer subtypes. Cox regression analysis showed that TOP2A overexpression is a significant prognostic factor in luminal B breast cancer (hazard ratio (HR) 4.00, 95% confidence interval (CI) 1.65-9.54, p = 0.002). TOP2A amplified was recognized in HER2 positive breast cancer (p < 0.001). In HER2 positive breast cancer, TOP2A amplified (HR 0.30, 95% CI 0.085-1.07, p = 0.063) appeared to be a better prognostic factor. CONCLUSION: In modern tailored therapy, TOP2A overexpression can be a poor prognostic factor in luminal B breast cancer. In contrast, TOP2A amplified could be a better prognostic factor in HER2 positive breast cancer. MATERIALS AND METHODS: Between May 2005 and April 2015, a total of 643 consecutive non-metastatic invasive breast cancers were evaluated for TOP2A amplified using fluorescence in situ hybridization analysis (FISH) and for TOP2A overexpression using the immunohistochemistry assay. FISH ratios of 2 or higher were designated as TOP2A amplified, and TOP2A staining >10% was defined as TOP2A overexpression. The prognostic values of TOP2A amplified and TOP2A overexpression were retrospectively evaluated.

A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non-Small Cell Lung Cancer.

Trastuzumab emtansine (T-DM1), an anti-erb-b2 receptor tyrosine kinase 2 (HER2) antibody-drug conjugate, has been shown to significantly improve survival in HER2-positive breast cancer. We report a phase II trial of T-DM1 monotherapy in relapsed NSCLC with documented HER2 positivity (an immunohistochemistry [IHC] score of 3+, both an IHC score of 2+ and fluorescence in situ hybridization positivity, or exon 20 mutation). This study was terminated early because of limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: median age, 67 years; male sex, 47%; performance status of 0 to 1, 80%; HER2 status IHC 3+, 33%; HER status IHC 2+/fluorescence in situ hybridization-positive, 20%; and exon 20 mutation, 47%. The median number of delivered cycles was 3 (range 1-11). One patient achieved a partial response with an objective response rate of 6.7% (90% confidence interval: 0.2-32.0). With a median follow-up time of 9.2 months, the median progression-free survival time and median survival time were 2.0 and 10.9 months, respectively. Grade 3 or 4 adverse events included thrombocytopenia (40%) and hepatotoxicity (20%) without any treatment-related deaths. T-DM1 had a limited efficacy for HER2-positive NSCLC in our cohort. Applying the concept of precision medicine to tumors appears challenging; thus, additional molecular approaches are warranted.

A case report of locally advanced triple negative breast cancer showing pathological complete response to weekly paclitaxel with bevacizumab treatment following disease progression during anthracycline-based neoadjuvant chemotherapy.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced triple negative breast cancer, however, approximately 5% of cases show disease progression during NAC. Although downstaging is essential to create an opportunity for curative surgery and to improve the local control outcome in such a case, no additional line of chemotherapy has been established. CASE PRESENTATION: A 60-year-old woman was referred to our hospital for an axillary mass presenting three weeks ago and was diagnosed as having right locally advanced (T2N2M0, stage IIIA) triple negative breast cancer. After two courses of epirubicine and cyclophosphamide as NAC, disease progression was recognized and curative resection was considered impossible due to enlarged axillary lymph nodes showing invasion to surrounding tissue. As second-line chemotherapy, weekly paclitaxel with bevacizumab treatment was initiated and significant shrinkage was immediately obtained. A clinically complete response was diagnosed after four courses of weekly paclitaxel with bevacizumab and she underwent a right breast mastectomy with axillary lymph node dissection without major complications. Histopathological examination of surgical specimens showed no residual invasive or noninvasive disease and she was diagnosed as having a pathological complete response. CONCLUSIONS: Although the addition of bevacizumab to standard adjuvant chemotherapy is not recommended in unselected triple negative breast cancer, the potent effect on tumor shrinkage should be considered in the treatment of locally advanced triple negative breast cancer showing disease progression during standard NAC.

Primary cardiac rhabdomyosarcoma developed after receiving radiotherapy for left breast cancer 18 years prior.

The heart is an organ where primary malignant tumors rarely develop. In particular, the incidence of cardiac rhabdomyosarcoma (RMS) is extremely low. It has been reported that the risk of second malignant tumors in mediastinum is increased by radiotherapy in women with breast cancer. However, little is known about the association between irradiation to heart and cardiac RMS. Here, we report a case of a 68-year-old woman with primary cardiac RMS. She suddenly presented syncope at a workplace, and was taken to the emergency room at our hospital. Several imaging tests, including echocardiogram and cine magnetic resonance imaging, detected two tumors in the right ventricle (RV) and its outflow tract, which had almost obstructed the main trunk of the pulmonary artery (PA). To avoid sudden PA occlusion by the tumor, we emergently performed surgical excision of the tumors from the RV. Pathological analysis revealed that these tumors were embryonal type RMS. She had received radiotherapy after mastectomy for left breast cancer 18 years previously, and no recurrence of breast cancer had been detected. This cardiac RMS is considered as a second malignant tumor related to radiotherapy for breast cancer. .

Trastuzumab Emtansine in HER2+ Recurrent Metastatic Non-Small-Cell Lung Cancer: Study Protocol.

The treatment outcome has been unsatisfactory for patients with non-small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patients with HER2+ lung cancers. The major eligibility criteria are as follows: age ≥ 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer.

Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib.

BACKGROUND: Patients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs. METHODS: This study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples. RESULTS: The ORR was 6.7% (95% CI 1.4% to 18.3%), and the lower limit of 95% CI did not exceed the target of 5%. The median PFS (mPFS) and median OS (mOS) were 2.7 months (95% CI 1.4 to 4.2) and 18.0 months (95% CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4 months; mOS 20.7 vs 13.9 months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone. CONCLUSIONS: Although this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination. TRIAL REGISTRATION NUMBER: NCT01580735.

A Phase I Trial of 100 mg/m2 Docetaxel in Patients with Advanced or Recurrent Breast Cancer.

Docetaxel is a standard treatment for patients with advanced or recurrent breast cancer. The recommended dose is 60 to 100 mg/m2. Previous study have shown that the tumor response rates of patients who received docetaxel monotherapy at doses of 60, 75, and 100 mg/m2 were 22.1% , 23.3% , and 36.0% , respectively, and there was a significant relationship between the dose and response. In Europe and the United States, docetaxel is approved at a dose of 100 mg/m2, and Japanese guidelines also recommend a dose of 100 mg/m2. However, the approved dose in Japan is up to 75 mg/m2. We have launched a phase I trial evaluating 100 mg/m2 docetaxel in patients with advanced or relapsed breast cancer. The major eligibility criteria are as follows: age 20 years, pathologically diagnosed breast cancer, recurrent or advanced breast cancer, a good performance status, and HER2 [human epidermal growth factor receptor 2] negative. The primary endpoint is demonstrated safety of 100 mg/m2 docetaxel. This study will clarify whether 100mg/m2 docetaxel can be administrated safely in Japanese patients with advanced or recurrent breast cancer.

Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review.

BACKGROUND: In evaluation of the clinical benefit of a new targeted agent in a phase 3 trial enrolling molecularly selected patients with advanced non-small cell lung cancer (NSCLC), overall survival (OS) as an endpoint seems to be of limited use because of a high level of treatment crossover for ethical reasons. A more efficient and useful indicator for assessing efficacy is needed. METHODS AND FINDINGS: We identified 18 phase 3 trials in the literature investigating EGFR-tyrosine kinase inhibitor (TKIs) or ALK-TKIs, now approved for use to treat NSCLC, compared with standard cytotoxic chemotherapy (eight trials were performed in molecularly selected patients and ten using an "all-comer" design). Receiver operating characteristic analysis was used to identify the best threshold by which to divide the groups. Although trials enrolling molecularly selected patients and all-comer trials had similar OS-hazard ratios (OS-HRs) (0.99 vs. 1.04), the former exhibited greater progression-free survival-hazard ratios (PFS-HR) (mean, 0.40 vs. 1.01; P<0.01). A PFS-HR of 0.60 successfully distinguished between the two types of trials (sensitivity 100%, specificity 100%). The odds ratio for overall response was higher in trials with molecularly selected patients than in all-comer trials (mean: 6.10 vs. 1.64; P<0.01). An odds ratio of 3.40 for response afforded a sensitivity of 88% and a specificity of 90%. CONCLUSION: The notably enhanced PFS benefit was quite specific to trials with molecularly selected patients. A PFS-HR cutoff of ∼0.6 may help detect clinical benefit of molecular targeted agents in which OS is of limited use, although desired threshold might differ in an individual trial.

Use of Cox's Cure Model to Establish Clinical Determinants of Long-Term Disease-Free Survival in Neoadjuvant-Chemotherapy-Treated Breast Cancer Patients without Pathologic Complete Response.

In prognostic studies for breast cancer patients treated with neoadjuvant chemotherapy (NAC), the ordinary Cox proportional-hazards (PH) model has been often used to identify prognostic factors for disease-free survival (DFS). This model assumes that all patients eventually experience relapse or death. However, a subset of NAC-treated breast cancer patients never experience these events during long-term follow-up (>10 years) and may be considered clinically "cured." Clinical factors associated with cure have not been studied adequately. Because the ordinary Cox PH model cannot be used to identify such clinical factors, we used the Cox PH cure model, a recently developed statistical method. This model includes both a logistic regression component for the cure rate and a Cox regression component for the hazard for uncured patients. The purpose of this study was to identify the clinical factors associated with cure and the variables associated with the time to recurrence or death in NAC-treated breast cancer patients without a pathologic complete response, by using the Cox PH cure model. We found that hormone receptor status, clinical response, human epidermal growth factor receptor 2 status, histological grade, and the number of lymph node metastases were associated with cure.

Content analysis of oncology-related pharmaceutical advertising in a peer-reviewed medical journal.

BACKGROUND: The oncology market represents one of the largest pharmaceutical markets in any medical field, and printed advertising in medical journals is an important channel by which pharmaceutical companies communicate with healthcare professionals. The aim of the present study was to analyze the volume and content of and trends and changes in oncology-related advertising intended for healthcare professionals in a peer-reviewed medical journal. Information that could be included in advertisements to promote drug development and improve treatment strategies for cancer patients is discussed on the basis of the results of the analysis. METHODS/PRINCIPAL FINDINGS: Overall, 6,720 advertisements covering 13,039 pages in a leading oncology medical journal published (by the American Society of Clinical Oncology) between January 2005 and December 2009 were analyzed. The advertisements targeting pharmaceuticals and clinical trials, in particular, were reviewed. A total of 6,720 advertisements covering 13,039 pages were included in the analysis. For the years 2005-2009, the percentages of total journal pages dedicated to advertising were 24.0%, 45.7%, 49.8%, 46.8%, and 49.8%, respectively. Package insert information and efficacy and safety explanations appeared in more than 80% of advertisements intended for pharmaceutical promotion. From 2005 to 2009, the overall quantity of drug advertisements decreased by approximately 13%, whereas advertisements calling for the enrollment of patients into registration trials increased by approximately 11%. CONCLUSION/SIGNIFICANCE: Throughout the study period, oncology-related pharmaceutical advertisements occupied a considerable number of pages relative to other journal content. The proportion of advertisements on ongoing clinical trials increased progressively throughout the study period.

A phase I study of BMS-690514 in Japanese patients with advanced or metastatic solid tumors.

PURPOSE: BMS-690514 is a novel oral tyrosine kinase inhibitor of ErbB and vascular endothelial growth factor receptor. This open-label phase I dose-escalation study (ClinicalTrials.gov Identifier: NCT00516451) aimed to assess the safety, preliminary efficacy, pharmacokinetics, and pharmacodynamics of BMS-690514 in Japanese patients with advanced or metastatic solid tumors. METHODS: Patients with advanced or metastatic solid tumors received oral BMS-690514 once daily continuously until disease progression or intolerable toxicity occurred. Dose-limiting toxicity (DLT) was evaluated from the first dose to Day 29. Dose levels at 100 and 200 mg were investigated. Assessments included adverse events, tumor response, pharmacokinetics, pharmacodynamics, 2 [18F] fluoro-2-deoxyglucose positron-emitting tomography, and epidermal growth factor receptor and K-ras mutations. RESULTS: BMS-690514 at the dose of 100 mg (n = 3) or 200 mg (n = 3) was administered once daily to totally nine patients and was well tolerated up to 200 mg. No treatment-related serious adverse events or DLTs were reported. Frequently observed treatment-related AEs were acne, diarrhea, dry skin, hypertension, stomatitis, blood fibrinogen increased, hemoglobin decreased, pruritus, and hypoalbuminemia. These were generally reported as Grade 1 and 2. Five of 9 patients (56 %) had stable disease. Plasma concentrations of BMS-690514 reached Cmax within 3 h and declined with an effective half-life of approximately 10 and 12 h at 100 and 200 mg, respectively. CONCLUSIONS: Oral BMS-690514 was well tolerated in Japanese patients with advanced or metastatic solid tumors up to 200 mg.