The aim of the study was to establish a predictive model of survival period after bone metastasis from endometrial cancer.
A total of 28 patients with bone metastasis from uterine corpus cancer were included in the study. Data at the time of bone metastasis diagnosis, which included presence of extraskeletal metastasis, performance status, history of any previous radiation/chemotherapy and the number of bone metastases, were collected. Survival data were analyzed using Kaplan–Meier methods and Cox proportional hazard models.
The most common site of bone metastasis was the pelvis (50.0%), followed by lumbar spine (32.1%), thoracic spine (25.0%) and rib bone (17.9%). The median survival period after bone metastasis was 25 weeks. The overall rate of survival after bone metastasis of the entire cohort was 75.0% at 13 weeks, 46.4% at 26 weeks and 42.9% at 52 weeks. Performance status of 3–4 was confirmed as an independent prognostic factor (Hazard ratio, 3.5; 95% confidence interval, 1.41–8.70) and multiple bone metastases tended to be associated with poor prognosis (Hazard ratio, 2.4; 95% confidence interval, 0.95–5.97). A prognostic score was calculated by adding up the number of these two factors. The 26-week survival rates after bone metastasis were 88.9% for those with a score of 0, 45.5% for those with a score of 1 and 0% for those with a score of 2 (P = 0.0006).
This scoring system can be used to determine the optimal treatment for patients with bone metastasis from endometrial cancer.
Development of hand-foot syndrome symptoms, which is a common adverse effect of several cancer chemotherapy agents, can result in patient withdrawal from treatment. Its early identification allows appropriate modification of chemotherapy regimens and can avert treatment withdrawal by minimizing the impact on quality of life and duration of discontinued therapy. We sought to develop a simple home-based self-monitoring tool to facilitate reliable early identification of hand-foot syndrome, based on the self-administered quality of life questionnaire hand-foot syndrome-14.
We modified the hand-foot syndrome-14 to create a simple tool with binary responses (‘yes’ or ‘no’) for patients to self-evaluate subjective hand-foot syndrome symptoms daily. We evaluated this tool with 187 consecutive, consenting, eligible adult patients attending four centers and treated with capecitabine, sorafenib or sunitinib for various cancers. Univariate and multivariate logistic regression analyses were used to select the items with the greatest discrimination for detecting Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or 3 reactions, which indicate the need to modify the treatment regimen.
There were four items that were most strongly associated with Common Terminology Criteria for Adverse Events grade 2 or higher symptoms. ‘Pain associated with hand-foot syndrome’ was the most strongly associated with moderate hand-foot syndrome. For detecting moderate hand-foot syndrome symptoms, the sensitivity was 100.0%, specificity was 94.6%, positive predictive value was 82.6% and area under the curve was 0.98 by a sum of the scores of four-item self-monitoring tool with cut-off value.
We present a simple self-monitoring tool that can be used at home with high sensitivity and specificity for identifying grade 2 hand-foot syndrome. In addition, this tool might facilitate self-care.
Japan's first guidelines for parenteral fluid management for terminal cancer patients were issued in 2006. These guidelines focused on the fluid levels to administer to patients with a remaining life expectancy of 1–2 months. However, recent refinement of the concept of cachexia is prompting caregivers worldwide to rethink parenteral fluid management for terminal cancer patients.
Our objective was to develop guidelines for parenteral fluid management for terminal cancer patients with a remaining life expectancy of 1 month, a point when cachexia generally begins to severely adversely affect the body.
The Japanese Society for Palliative Medicine appointed a Guidelines Working Practitioner Group consisting of a multidisciplinary team of specialists. In response to 26 clinical questions on parenteral fluid management for terminal cancer patients, the Working Group used the Delphi method to reach consensus on the recommendability and evidence level of 89 relevant manuscripts identified through a systematic literature review. The Working Group then had an outside committee reviews the draft guidelines validity before authoring the final version.
The resulting clinically aligned guidelines contain specific recommendations (25 recommendations on physical suffering/remaining life expectancy, 10 nursing-related recommendations and 4 ethical recommendations) assessed using the Delphi method and by an outside committee.
Japanese Society for Palliative Medicine released a revised edition of the Guidelines for Parenteral Fluid Management for Terminal Cancer Patients, which are based on medical evidence and consider the pathologic features of cachexia. We recommend that caregivers carefully evaluate the clinical usefulness of the guidelines.
Guidelines for supportive care in cancer patients have recommended routine psychological screening in clinical practice, and a Japanese national project has recommended screening for depression using the Distress and Impact Thermometer. However, a previous study advocating the validity of the Distress and Impact Thermometer may have overestimated its effectiveness, as the study included already-treated patients who were not screening targets. This study re-evaluated the performance and usefulness of the Distress and Impact Thermometer using an adequate sample size and appropriate study design.
Patients were consecutively recruited at two highly specialized hospitals and three university hospitals in Japan. Inclusion criteria were (i) undergoing aggressive anti-cancer treatment, (ii) the Eastern Cooperative Oncology Group performance status score <3 and (iii) age >20 years. Patients who were receiving psychiatric treatment were excluded from the study. After completing the Distress and Impact Thermometer, patients were evaluated with the gold-standard Composite International Diagnostic Interview by researchers who were blinded to the patients’ Distress and Impact Thermometer scores.
Forty-four patients (9%) who were receiving psychiatric treatment were excluded. Of 468 subjects included in the final analysis, only 3 had current depression (0.6%). Using cutoff points recommended by the previous study, the positive and negative predictive values were 0.02 and 0.99, respectively.
Our data indicated that screening for untreated depression in cancer patients was not useful in the specific clinical settings that were studied, and such screening should be implemented in appropriate contexts. Since there are no evidence-based recommendations regarding contexts in which psychological screening is essential, further research is needed.
In clinical studies in Western countries, the recommended dose of combination ombrabulin a vascular disrupting agent, with cisplatin is 25 mg/m2 ombrabulin with 75 mg/m2 cisplatin every 3 weeks. Here, we report the first Phase 1 study of this treatment regimen in Japanese patients with advanced solid tumors.
This was an open-label, multicenter, sequential cohort, dose-escalation Phase 1 study of ombrabulin with cisplatin administered once every 3 weeks. The study used a 3 + 3 design without intrapatient dose escalation. The investigated dose levels of ombrabulin were 15.5 and 25 mg/m2 combined with cisplatin 75 mg/m2. The latter dose level was regarded as the maximum administered dose if more than one patient experienced dose-limiting toxicities.
Ten patients were treated, but no dose-limiting toxicity was observed at both dose levels. Ombrabulin 25 mg/m2 with cisplatin 75 mg/m2 was the maximum administered dose and regarded as the recommended dose in the combination regimen for Japanese patients with cancer. The most frequently reported drug-related adverse events were neutropenia, decreased appetite, constipation, nausea and fatigue. One partial response and five cases of stable disease were reported as the best overall responses. Pharmacokinetic parameters of ombrabulin and cisplatin were comparable with those in non-Japanese patients.
Ombrabulin 25 mg/m2 with cisplatin 75 mg/m2 once every 3 weeks was well tolerated and established as the recommended dose in Japanese patients with advanced solid tumors. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients.
To assess the feasibility of proton beam therapy for the patients with locally advanced non-small lung cancer.
The dosimetry was analyzed retrospectively to calculate the doses to organs at risk, such as the lung, heart, esophagus and spinal cord. A dosimetric comparison between proton beam therapy and dummy photon radiotherapy (three-dimensional conformal radiotherapy) plans was performed. Dummy intensity-modulated radiotherapy plans were also generated for the patients for whom curative three-dimensional conformal radiotherapy plans could not be generated.
Overall, 33 patients with stage III non-small cell lung cancer were treated with proton beam therapy between December 2011 and August 2014. The median age of the eligible patients was 67 years (range: 44–87 years). All the patients were treated with chemotherapy consisting of cisplatin/vinorelbine or carboplatin. The median prescribed dose was 60 GyE (range: 60–66 GyE). The mean normal lung V20 GyE was 23.6% (range: 14.9–32%), and the mean normal lung dose was 11.9 GyE (range: 6.0–19 GyE). The mean esophageal V50 GyE was 25.5% (range: 0.01–63.6%), the mean heart V40 GyE was 13.4% (range: 1.4–29.3%) and the mean maximum spinal cord dose was 40.7 GyE (range: 22.9–48 GyE). Based on dummy three-dimensional conformal radiotherapy planning, 12 patients were regarded as not being suitable for radical thoracic three-dimensional conformal radiotherapy. All the dose parameters of proton beam therapy, except for the esophageal dose, were lower than those for the dummy three-dimensional conformal radiotherapy plans. In comparison to the intensity-modulated radiotherapy plan, proton beam therapy also achieved dose reduction in the normal lung. None of the patients experienced grade 4 or worse non-hematological toxicities.
Proton beam therapy for patients with stage III non-small cell lung cancer was feasible and was superior to three-dimensional conformal radiotherapy for several dosimetric parameters.
Although the recent reclassification of histological subtypes of lung adenocarcinoma reflects disease prognosis better, the prognosis of papillary and acinar-predominant adenocarcinoma, which are highly prevalent, is heterogeneity. The present study aimed to identify the prognostic indicators for papillary and acinar-predominant adenocarcinoma.
This retrospective study included 315 consecutive patients with completely resected pathological N0 lung adenocarcinoma tumors ≤3 cm from two institutions. Tumors were classified according to histologically predominant subtypes as low-grade (adenocarcinoma in situ, minimally invasive adenocarcinoma or lepidic predominant), intermediate-grade (papillary or acinar predominant) or high-grade (solid or micropapillary predominant). Prognostic factors in intermediate-grade group were assessed among clinicopathological factors of age, gender, surgical procedure, tumor size, pleural, lymphatic and vascular invasion using Cox proportion hazards analyses.
There were 174 patients in the low-grade group, 109 in the intermediate-grade group and 32 in the high-grade group. The 3-year recurrence-free survival rates were 98.1%, 86.3% and 74.8% for these groups, respectively (P < 0.001). In the intermediate-grade group, the presence of vascular invasion was an independent prognostic factor on multivariate Cox regression analysis of recurrence-free survival (hazard ratio, 3.48; 95% confidence interval, 1.26–9.57, P = 0.01). Classification of intermediate-grade group based on vascular invasion revealed a clear division into favorable and unfavorable prognostic subgroups.
Consideration of the vascular invasion status in addition to the predominant subtype could provide a more accurate assessment of malignant aggressiveness and prognosis of patients with early-stage lung adenocarcinoma.
It has been proven that there is no survival advantage of surgery in clinical N2 non-small-cell lung cancer rather than chemoradiotherapy. Several decades ago, the results of thoracic radiotherapy for Clinical Stage III non-small-cell lung cancer were poor, and long-term survival rate was only 6%. Recent advances in combined therapy (radiotherapy and chemotherapy) have improved median survival to 15–20 months. In the Japanese registry of lung cancer surgery, the number of patients with Clinical Stage IIIA has decreased over the last decade because of the poor results of surgery alone for Clinical Stage III non-small-cell lung cancer. In contrast, survival of patients with Clinical Stage III non-small-cell lung cancer treated with surgery has improved gradually. This can be mainly attributed to the following: first, well-selected patients are treated with surgery; second, improved diagnostic imaging has produced a ‘Will Rogers phenomenon’. Similarly, concurrent chemoradiotherapy has also further improved and in recent clinical trials, the median survival time was 28–40 months. Unfortunately, recent randomized trials comparing induction chemotherapy followed by surgery, or induction chemoradiotherapy followed by surgery with chemoradiotherapy showed no significant survival advantage of surgery. Until appropriate patient selection for surgery can be shown in randomized control trials, chemoradiotherapy is the mainstream treatment for clinical N2 non-small-cell lung cancer in clinical practice.
The aim of this study was to evaluate the additional benefit of 3 Tesla magnetic resonance imaging for neurovascular bundle preservation in radical prostatectomy.
We retrospectively evaluated patients who underwent 3 T magnetic resonance imaging followed by radical prostatectomy from April 2010 through February 2014 in our university. A total of 50 patients (100 prostate sides) were included in the study. The algorithm previously we described and magnetic resonance imaging findings were considered for the decision on neurovascular bundle preservation. A tumor adjacent to the neurovascular bundle or with extracapsular extension of a posterolateral lesion of the prostate on magnetic resonance imaging was considered a contraindication for nerve-sparing radical prostatectomy. Two experienced radiologists evaluated the magnetic resonance imaging findings. Patients who received neoadjuvant hormonal therapy were excluded. All patients underwent ultrasound-guided prostate biopsy with at least 10 cores.
Overall, 60 of the 100 neurovascular bundles were preserved according to an algorithm that consisted of the clinical stage, prostate specific antigen, Gleason score and a positive biopsy core in the apex of the prostate. Considering magnetic resonance imaging findings together with the algorithm, six neurovascular bundles were not preserved. The accuracy of predicting a positive surgical margin only by the algorithm was 56 of 60 neurovascular bundle (93.3%). When adding magnetic resonance imaging, the accuracy was 50 of 54 neurovascular bundle (92.3%).
3 T magnetic resonance imaging provided no additional benefit to our algorithm for neurovascular bundle preservation.
To conduct Japanese subgroup analyses of a randomized, global Phase II study of axitinib with and without dose titration in first-line metastatic renal cell carcinoma and to explore predictive factors for axitinib efficacy in first-line metastatic renal cell carcinoma.
The data included 44 Japanese and 169 non-Japanese treatment-naïve patients with metastatic renal cell carcinoma. Patients received twice-daily axitinib 5 mg during a 4-week lead-in period. Patients who met the pre-defined randomization criteria were stratified by Eastern Cooperative Oncology Group performance status and randomly assigned (1:1) to axitinib or placebo titration. The primary endpoint was objective response rate; secondary endpoints included progression-free survival and safety. Predictive factors were analyzed using data from all patients.
The objective response rate (95% confidence interval) was 66% (50–80%) vs. 44% (36–52%) in Japanese and non-Japanese patients, respectively. At the primary analysis, median progression-free survival could not be estimated for Japanese patients, and was 27.6 months (95% confidence interval: 16.6–33.2) in an updated analysis. Hypertension, diarrhea, hand–foot syndrome, dysphonia, hypothyroidism and proteinuria were common adverse events in Japanese patients. Due to a small number of randomized patients, effects of axitinib dose titration could not sufficiently be confirmed among Japanese patients. The multivariate analysis identified time from histopathological diagnosis to treatment and sum of the longest diameter for target lesion at baseline as independent predictive factors for progression-free survival.
Axitinib is effective and well tolerated as first-line metastatic renal cell carcinoma therapy in Japanese patients. Predictive factors for axitinib efficacy endpoints identified in this setting warrant further investigation.
In Japan, flutamide had been commonly used as second-line alternative antiandrogen hormonal therapy for metastatic castration-resistant prostate cancer that relapses after initial hormone therapy before new androgen pathway inhibitors became available. In this study, we attempted to identify predictive factors for efficacy of alternative antiandrogen as second-line hormone therapy.
We identified consecutive 65 patients with metastatic castration-resistant prostate cancer who were treated with alternative antiandrogen as second-line hormonal therapy (bicalutamide to flutamide). All patients were treated with combined androgen blockade initially. We analyzed correlations between progression-free survival of alternative antiandrogen and clinicopathological characteristics, including patients’ ages, initial prostate-specific antigen levels, prostate-specific antigen levels at flutamide induction, Gleason scores, T stage, N stage, extent of disease grades on bone scan and previous duration of prostate cancer response to combined androgen blockade.
In univariate analysis, T stage, N stage and previous duration of response to combined androgen blockade were correlated with shorter progression-free survival. We found four significant risk factors for shorter progression-free survival in multivariate analysis: initial prostate-specific antigen level, clinical N stage, extent of disease grades and previous duration of response to combined androgen blockade.
Initial prostate-specific antigen, N stage, extent of disease grades on bone scan and previous duration of response to combined androgen blockade were the significant predictors for efficacy of alternative antiandrogen as second-line hormone therapy in patients with metastatic castration-resistant prostate cancer. These findings might support that decision-making of when to start the new androgen receptor pathway inhibitors.
We conducted the present study to elucidate the clinical presentation, treatment outcomes and risk factors for the development of metachronous brain metastasis at a single progressive disease site, the so-called isolated brain metastasis, in patients with testicular germ cell tumors.
To identify metachronous brain metastasis in a timely manner, brain imaging was performed when the re-elevation of tumor markers was observed during chemotherapy, even in patients who were free from central nervous system symptoms. The medical records of 147 patients with metastatic germ cell tumors who were treated between 1991 and 2015 were retrospectively reviewed.
Eight (5.4%) of the 147 patients presented synchronous brain metastasis. Of these, five patients suffered from metachronous brain metastasis relapse. An additional nine patients developed metachronous brain metastasis during or after chemotherapy. Ten of the 14 patients with metachronous brain metastasis did not have central nervous system symptoms. Eight (57%) patients had isolated brain metastasis. Ten patients underwent multimodal treatments, predominantly chemotherapy and radiotherapy. The 3-year overall survival of all 14 patients was 34.6%, but that of the patients with isolated brain metastasis was high as 66.7%. The development of metachronous brain metastasis was associated with a choriocarcinoma element at the primary site and an human chorionic gonadotropin level of >50 000 IU/L and brain metastasis at the initial diagnosis.
In our series, we identified isolated brain metastasis in 57% of the metachronous brain metastasis patients. The monitoring of tumor markers and appropriate brain imaging are mandatory for the diagnosis of isolated brain relapse, which is associated with a higher rate of long-term survival.
The Japanese government introduced endoscopic screening for gastric cancer in 2015 as a public policy based on the Japanese guidelines on gastric cancer screening. To provide appropriate endoscopic screening for gastric cancer in Japanese communities, we developed a quality assurance manual of endoscopic screening and recommend 10 strategies with their brief descriptions as follows: (i) Formulation of a committee responsible for implementing and managing endoscopic screening, and for deciding the suitable implementation methods in consideration of the local context; (ii) Development of an interpretation system that leads to a final judgement to standardize endoscopic examination and improve its accuracy; (iii) Preparation of management and reporting systems for adverse effects by the committee for safety management; (iv) Obtaining informed consent before operation following adequate explanations regarding the benefits and harms of endoscopic screening; (v) Avoidance of frequent screenings to reduce false-positive results and overdiagnosis. As a reference, the target age group is ≥50 years, and the screening interval is 2 years; (vi) Keeping the biopsy rate within 10% as post-biopsy bleeding may occur. Before endoscopic screening, any history of antithrombotic drug usage should be checked; (vii) Nonadministration of sedation in endoscopic screening for safety management; (viii) Adherence to proper endoscopic cleaning and disinfection to reduce infection; (ix) Use of a checklist to achieve optimal program preparation when municipal governments introduce endoscopic screening; (x) Identification of the aims and roles by referring to a checklist if primary care physicians decide to participate in endoscopic screening.
The incidence of gastric cancer and the number of gastric cancer patients that a surgeon treats annually are so vastly different between countries and regions that it is not easy to define which type of gastric cancer surgery should be considered the global standard. Nevertheless, a consensus that D2 dissection is the most appropriate way to treat resectable advanced gastric cancer has arguably been reached after long-term follow-up and flexible interpretation of the Dutch D1 versus D2 trial and evidence from the Japan Clinical Oncology Group 9501 study which denied survival benefit of more extensive lymphadenectomy. After the Japan Clinical Oncology Group 9501 trial, surgeons gradually lost interest in attempting to improve survival through extended resection and instead began to expend greater resources on establishing and standardizing the technique of minimally invasive surgery and proving its oncological non-inferiority compared with the conventional approach. Laparoscopic distal gastrectomy has become an option in daily clinical practice in the Far East, and more demanding procedures such as laparoscopic total gastrectomy and laparoscopic surgery for advanced gastric cancer are currently being explored in clinical trials from the viewpoint of both safety and oncological feasibility. In addition, the high proportion of early-stage cancer in the Far East prompted surgeons to develop limited surgery such as proximal gastrectomy and pylorus-preserving gastrectomy, which warrant further evaluation regarding benefits in terms of postoperative nutritional state and/or quality of life measurements to convince the rest of the world.