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Preview: Japanese Journal of Clinical Oncology - current issue

Japanese Journal of Clinical Oncology Current Issue





Published: Fri, 23 Jun 2017 00:00:00 GMT

Last Build Date: Fri, 23 Jun 2017 06:44:51 GMT

 






IN THIS ISSUE

2017-06-23







Up-regulated microRNA-299 corrected with poor prognosis of glioblastoma multiforme patients by targeting ELL2

2017-05-20

Abstract
Background
An increasing understanding of the genes and molecular pathways of glioblastoma multiforme (GBM) can provide us a useful insight for the development of more effective targeted therapeutic.
Methods
To investigate the expression and clinical significance of miR-299 and its target genes in GBM, the expression levels of miR-299 and its target gene in human normal brain tissues and GBM were analyzed in silico using genes microarray and hierarchical clustering analysis followed by validation with quantitative RT-PCR.
Results
Our results show that miR-299 is up-regulated in GBM patients. Moreover, patients with low miR-299 expression had longer overall survival (OS) compared with those with high miR-299 expression. RNA polymerase II elongation factor, ELL2, was identified as a miR-299 direct target. High expression of ELL2 together with miR-299 down-regulation correlated with a shorter median OS.
Conclusions
Our results provide the first evidence that ELL2 is a direct target of miR-299 and increased ELL2 expression and down-regulation of miR-299 are associated with GBM progression and poor prognosis in patients, suggesting that ELL2 and miR-299 might have potential prognostic value and be used as tumor biomarkers for the diagnosis of patients with GBM.



Randomized phase III trial of adjuvant therapy with locoregional interferon beta versus surgery alone in stage II/III cutaneous melanoma: Japan Clinical Oncology Group Study (JCOG1309, J-FERON)

2017-05-09

Abstract
The Dermatologic Oncology Group of Japan Clinical Oncology Group has started a randomized phase III trial to confirm the superiority of adjuvant therapy with locoregional interferon beta in overall survival over surgery alone for patients with pathological stage II/III cutaneous melanoma (JCOG1309). Patients in the interferon beta arm receive intra- or subcutaneous injections of interferon beta directly into the surgical site at a flat dose of 3 million units once per day. Treatment is repeated for 10 consecutive days every 8 weeks for a total of 3 courses during the induction phase, then 1-day injection every 4 weeks for 2.5 years. A total of 240 patients will be accrued from 17 Japanese institutions within 6.5 years. Primary endpoint is overall survival. Secondary endpoints are relapse-free survival, distant metastasis-free survival, pattern of recurrence, and adverse events. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000017494 [http://www.umin.ac.jp/ctr/index.htm].



Efficacy and safety of osimertinib in a Japanese compassionate use program

2017-04-13

Abstract
Background
Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets the T790M mutation of EGFR. In 2016, AstraZeneca conducted a compassionate use program for osimertinib in Japan.
Methods
Eighteen consecutive patients with histologically proven non-small-cell lung cancer (NSCLC) and harboring the T790M EGFR mutation participated in the compassionate use program between 1 April and 25 May 2016, at the National Cancer Center Hospital. We examined the efficacy and safety of osimertinib in a compassionate use program.
Results
All patients had been previously treated with both cytotoxic chemotherapy and EGFR TKIs. Overall response rate was 62.5% (95% confidence interval (CI): 35.9–89.1%). Among the six patients pretreated with a third-generation EGFR TKI, two (33%) responded to osimertinib. On administration with osimertinib, median progression-free and overall survival rates at six months were 66.7% (95% CI: 44.9–88.5) and 88.9% (95% CI: 74.4–100), respectively. Although the toxicity of osimertinib was mild in most patients, three patients had severe adverse events: two developed interstitial lung disease (ILD) and one developed Grade 3 hepatotoxicity. Among these, two (33%) of the six patients who received osimertinib following nivolumab treatment developed severe adverse events, with one each developing Grade 3 hepatotoxicity and Grade 3 ILD. Only one patient visited our hospital seeking to participate in the compassionate program from another hospital.
Conclusion
Osimertinib demonstrated efficacy even in patients with heavily pretreated NSCLC harboring the T790M mutation. Some patients pretreated with another third-generation EGFR TKI also responded to osimertinib.



Surgical resection for clinical-Stage I radiological pure-solid lung cancer that met the current high risk criteria

2017-04-13

Abstract
Objective
We assessed whether surgical resection is acceptable for radiological invasive non-small cell lung cancer (NSCLC) that met the current high-risk criteria.
Methods
We reviewed 500 clinical-Stage I NSCLCs with a radiological pure-solid appearance. High-risk criterion was defined as follows: (1) preoperative FEV1% ≤ 50% or DLco% ≤ 50%, (2) age > 75y with 50% < FEV1% < 60% or 50% < DLco% < 60%, and (3) three or more severe general comorbidities.
Results
The high-risk group comprised 184 (37%) patients. The percentages for elderly, male, smoker, non-adenocarcinoma histology were significantly higher than those of the normal-risk group (P < 0.001). Lobectomy was performed in 148 (80%) patients. Overall survival (OS) was significantly worse in the high-risk group (59.4% vs 73.1%, P = 0.004), however, a multivariate analysis revealed that high-risk was not associated with poor survival (P = 0.519). Furthermore, there were no significant differences between the high-risk and normal-risk groups regarding cancer-specific survival (74.5% vs 79.2%, P = 0.569). Postoperative morbidity rates were significantly different between the two study arms (45% vs 25%, P < 0.001), however, the 30-day and 90-day mortality rates for the high-risk group were 1.6% and 3.8%, respectively. In the high-risk patients, the difference in survival between lobectomy and sublobar resection was not significant (69.4% vs 78.6%, P = 0.716), and was also proven in the propensity-score matched patients (82.1% vs 76.0%, P = 0.623).
Conclusions
Conventional high-risk criteria are not always appropriate prognostic variables, and lung cancer specific survival or short-term mortalities for high-risk patients were fully acceptable. Surgical therapy including lobectomy should not be readily excluded from radical local management even when a patient meets the high-risk criteria.



Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup analysis from the CheckMate 025 study

2017-04-13

Abstract
Background
Nivolumab improved overall survival (OS) and objective response rate (ORR) versus everolimus in previously treated patients with advanced renal cell carcinoma in the phase III CheckMate 025 study (minimum follow-up: 14 months). We report efficacy and safety in the global and Japanese populations (minimum follow-up: 26 months).
Methods
Patients were randomized 1:1 to receive nivolumab 3 mg/kg intravenously every 2 weeks or everolimus 10-mg tablet orally once daily. Primary endpoint: OS, key secondary endpoints: ORR, progression-free survival and safety.
Results
Of 410 (nivolumab) and 411 (everolimus) patients, 37 (9%) and 26 (6%), respectively, were Japanese. Median OS for the global population was 26.0 months (nivolumab) and 19.7 months (everolimus; hazard ratio 0.73 [95% confidence interval [CI]: 0.61–0.88]; P = 0.0006), with medians not reached for Japanese patients. ORR for the global population was 26% (nivolumab) versus 5% (everolimus; odds ratio 6.13; 95% CI: 3.77–9.95); ORR for Japanese patients: 43% versus 8% (odds ratio 9.14; 95% CI: 1.76–88.33). In Japanese patients, any-grade treatment-related adverse events (AEs) occurred in 78% (Grade 3–4, 19%; most common, anemia [5%]) treated with nivolumab and 100% (Grade 3–4, 58%; most common, hypertriglyceridemia [12%]) treated with everolimus; the most common with nivolumab was diarrhea (19%) and with everolimus was stomatitis (77%). Quality of life was stable in the nivolumab arm.
Conclusions
With >2 years of follow-up, Japanese patients had a higher response rate with nivolumab versus everolimus that was more pronounced yet consistent with the global population, with median OS not reached, and a favorable safety profile.



Accessibility to surgical robot technology and prostate-cancer patient behavior for prostatectomy

2017-04-13

Abstract
Background
To examine how surgical robot emergence affects prostate-cancer patient behavior in seeking radical prostatectomy focusing on geographical accessibility.
Methods
In Japan, robotic surgery was approved in April 2012. Based on data in the Japanese Diagnosis Procedure Combination database between April 2012 and March 2014, distance to nearest surgical robot and interval days to radical prostatectomy (divided by mean interval in 2011: % interval days to radical prostatectomy) were calculated for individual radical prostatectomy cases at non-robotic hospitals. Caseload changes regarding distance to nearest surgical robot and robot introduction were investigated. Change in % interval days to radical prostatectomy was evaluated by multivariate analysis including distance to nearest surgical robot, age, comorbidity, hospital volume, operation type, hospital academic status, bed volume and temporal progress.
Results
% Interval days to radical prostatectomy became wider for distance to nearest surgical robot <30 km. When a surgical robot emerged within 30 and 10 km, the prostatectomy caseload in non-robot hospitals reduced by 13 and 18% within 6 months, respectively, while the robot hospitals gained +101% caseload (P < 0.01 for all) Multivariate analyses including 9759 open and 5052 non-robotic minimally invasive radical prostatectomies in 483 non-robot hospitals revealed a significant inverse association between distance to nearest surgical robot and % interval days to radical prostatectomy (B = −17.3% for distance to nearest surgical robot ≥30 km and −11.7% for 10–30 km versus distance to nearest surgical robot <10 km), while younger age, high-volume hospital, open-prostatectomy provider and temporal progress were other significant factors related to % interval days to radical prostatectomy widening (P < 0.05 for all).
Conclusions
Robotic surgery accessibility within 30 km would make patients less likely select conventional surgery. The nearer a robot was, the faster the caseload reduction was.



Phase II trial of neoadjuvant chemotherapy with S-1 and oxaliplatin plus bevacizumab for colorectal liver metastasis (N-SOG 05 trial)

2017-04-07

Abstract
Purpose
This Phase II trial evaluated the safety and efficacy of neoadjuvant chemotherapy (NAC) with S-1 and oxaliplatin (SOX) plus bevacizumab (Bev) in patients with colorectal liver metastasis (CRLM).
Methods
Patients with initially resectable CRLM received four cycles of SOX plus Bev as NAC. We adopted the R0 resection rate as the primary endpoint, and the threshold R0 resection rate was set at 80%.
Results
Between December 2010 and August 2014, 61 patients were enrolled in this study and all started NAC. The completion rate of NAC was 82.0%. Three patients (4.9%) developed severe liver dysfunction caused by NAC and one patient finally decided against resection. Three patients (4.9%) were judged as having progressive disease during or after NAC and did not undergo liver resection. Among 57 patients who underwent liver resection after NAC, three patients were diagnosed with CRLM by pre-treatment imaging modalities and received NAC although a final pathological diagnosis was another malignant disease or benign condition. Finally, 47 of the 54 patients (87.0%) with resected CRLM achieved R0 resection. The pathological complete response rate of the 54 patients was 13.0%, and 31.5% were judged as pathological responders. However, the R0 resection rate of 77.0% in the entire cohort did not meet the endpoint.
Conclusions
NAC with SOX plus Bev has an acceptable toxicity profile and achieved a satisfactory pathological response. However, accuracy of pre-operative diagnoses and liver dysfunction caused by NAC were serious problems. Easy introduction of NAC for initially resectable CRLM should not be performed.



Prognostic factors for patients with brain metastasis from gynecological cancer: a significance of treatment-free interval of more than 6 months

2017-04-07

Abstract
Objective
Treatment-free interval has been confirmed as a significant prognostic factor in recurrent gynecological cancers. However, treatment-free interval has not been evaluated in previous studies investigating brain metastasis from gynecological malignancies. The aim of the study was to establish a predictive model of survival period after brain metastasis from gynecological cancer.
Methods
Of a total of 2848 patients with gynecological cancer, patients with brain metastasis were included in the study. Data at the time of brain metastasis diagnosis, which included primary origin, presence of extracranial metastasis, the Eastern Cooperative Oncology Group (ECOG) performance status, the number of brain metastases, brain-metastasis free-interval, treatment-free interval and treatment for brain metastasis were collected. Survival data were analyzed using Kaplan–Meier methods and Cox proportional hazards models.
Results
Incidences of brain metastasis were 1.7% (47/2848). Median survival period after diagnosis of brain metastasis was 20 weeks (4–5 months). The 6-, 12- and 24-month survival rates after brain metastasis were 44.0%, 22.0% and 16.5%, respectively. Cox regression analysis showed that extracranial metastasis (hazard ratio [HR], 5.2; 95% confidence interval [CI]: 1.04–26.3), ECOG performance status of 3–4 (HR, 3.1; 95% CI: 1.20–7.91), treatment-free interval of <6 months (HR, 3.8; 95% CI: 1.09–13.1), and no anti-cancer treatment for brain metastasis (HR, 3.6; 95% CI: 1.34–9.41) were significantly and independently related to poor survival.
Conclusion
Treatment-free interval should be assessed in a future study to verify prognostic predictors of brain metastasis from gynecological cancer.



Impact of lymph node dissection on clinical outcomes during nephroureterectomy in patients with clinically node-negative upper urinary tract urothelial cancer: subanalysis of a multi-institutional nationwide case series of the Japanese Urological Association

2017-04-07

Abstract
Objective
To evaluate the impact of lymph node dissection (LND) on the clinical outcomes during radical nephroureterectomy (RNU) in patients with clinically node-negative upper urinary tract urothelial cancer (UTUC).
Methods
Within the nationwide case series of the Japanese Urological Association, which comprises 1509 patients with UTUC diagnosed in 2005, we identified 823 patients with clinically node-negative UTUC who underwent RNU. The extent of limited LND was defined as the renal hilar region only for renal pelvic cancer and as either the pelvic region or para-aortic/paracaval region only for ureteral cancer, while the extent of wider LND was defined as at least one perilesional LND region in addition to limited LND. Multivariate analysis with a Cox regression hazard model was used to evaluate the survival benefit.
Results
Among the 823 patients, LND was performed in 197 (23.9%) patients, and 26 (13.2%) of them had pathologically node-positive disease. Of 197 patients who underwent LND, limited and wider LND was performed in 119 (60.4%) and 78 (39.6%) patients, respectively. Patients with node-positive disease showed significantly shorter overall survival than those with node-negative disease. No LND-associated survival improvement was observed in a direct comparison between patients with and without LND. In addition, limited or wider LND was not associated with overall survival or cancer-specific survival.
Conclusions
The therapeutic benefit obtained by LND remains unclear regardless of the extent of LND, although LND has diagnostic value with respect to the prediction of a poor prognosis especially in patients with clinically muscle-invasive disease.



Survival after failure of first-line chemotherapy in advanced gastric cancer patients: differences between Japan and the rest of the world

2017-04-07

Abstract
In this review, we focus on post-progression survival after first-line chemotherapy of advanced gastric cancer, and particularly the differences between Japan and the rest of the world. We reviewed 15 recent phase III trials of which 4 were solely recruited from Japanese and 11 from rest of the world. The patient characteristics age, performance status, previous gastrectomy and the number of metastatic sites were similar in Japan and rest of the world. However, the diffuse histological type was more common in Japan. While overall survival was longer in Japan (10.5–14.1 vs. 7.9–12.2 months), progression-free survival tended to be shorter in Japan (3.6–6.0 vs. 3.1–7.4 months). Post-progression survival calculated as the difference between median overall survival and progression-free survival was clearly longer in Japan (6.9–8.6 vs. 2.4–6.2 months). The proportion of patients receiving second-line chemotherapy (%2nd-CX) was quite different in Japan and rest of the world (69–85% vs. 11–59%). Correlations between %2nd-CX and post-progression survival were strong (Spearman's rank correlation coefficient; ρ = 0.86, P < 0.001). Correlations between %2nd-CX and ratio of post-progression survival to total overall survival were also strong (ρ = 0.84, P < 0.001). Because a survival benefit of second-CX was documented in several phase III trials, it can be concluded that higher %2nd-CX partly contributed to extended post-progression survival. However, considering that second-CX increased survival only by ~1.5 months at median, other factors such as third-line chemotherapy may have some influences to prolonged post-progression survival.



Ceritinib in patients with advanced, crizotinib-treated, anaplastic lymphoma kinase-rearranged NSCLC: Japanese subset

2017-03-28

Abstract
Introduction
Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer is sensitive to tyrosine kinase inhibitors; however, resistance can develop. Data are presented from the phase II trial (ASCEND-2) evaluating efficacy and safety in a subset of Japanese patients with ALK-rearranged non-small cell lung cancer previously treated with platinum-based chemotherapy, who experienced disease progression on crizotinib.
Methods
Patients with advanced ALK-rearranged non-small cell lung cancer, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/day. Whole-body and intracranial responses were assessed by investigator and Blinded Independent Review Committee (RECIST v1.1). Safety and tolerability were also investigated.
Results
All 24 Japanese patients had received ≥2 previous treatment regimens, with crizotinib the last therapy received prior to ceritinib. Median duration of ceritinib exposure was 8.1 (range: 0.2–12.5) months. Overall response rate was 45.8% (95% confidence interval: 25.6–67.2). Other efficacy endpoints included disease control rate (79.2% [95% confidence interval: 57.8–92.9]), time to response (median 1.9 months [range: 1.7–3.5]), duration of response (median 9.2 months [95% confidence interval: 4.0–not estimable]) and progression-free survival (median 6.6 months [95% confidence interval: 3.7–9.3]). Of the four patients with active baseline target brain lesions, two achieved an intracranial partial response (50%). The most commonly reported adverse events (majority grade 1/2) were nausea (91.7%), diarrhea (83.3%) and vomiting (83.3%).
Conclusions
This study demonstrates the clinical activity and manageable tolerability of ceritinib in a Japanese subset of chemotherapy- and crizotinib-pretreated patients with ALK-rearranged non-small cell lung cancer who progressed on crizotinib, as was shown in the whole ASCEND-2 study population.ClinicalTrials.gov identifier: NCT01685060



Providing written information increases patient satisfaction: a web-based questionnaire survey of Japanese cancer survivors

2017-03-23

Abstract
Purpose
The Institute of Medicine (IOM) of the United States recommends that all cancer survivors be provided with a survivorship care plan (SCP), which includes a patient treatment summary and a follow-up care plan. However, SCPs have not been widely adopted in Japan. To provide basic data necessary for implementing SCPs in Japan, we aimed to investigate the forms of clinical and survivorship-related information that Japanese cancer survivors receive from their healthcare providers, and to examine whether written information increases their satisfaction.
Methods
We performed a cross-sectional online survey of cancer survivors who underwent acute cancer treatment and had at least one follow-up with a physician in the past year. Cancer survivors provided the elements and forms (verbally and/or written) of information they received, as well as the degree of satisfaction with the information provided.
Results
Responses were obtained from 545 cancer survivors. Information elements such as surgical procedure (98.3%), surgical outcome (98.1%), and names of administered chemotherapy agents (97.8%) were commonly provided, whereas mental care resources and providers (29.7%), effects on marital relationship and sexual health (35.7%), and effects on fertility (43.4%) were less common. A large proportion of cancer survivors received verbal information only. For 18 of 20 elements, except for effects on fertility and duration of hormonal therapy, satisfaction was significantly higher when both forms of information were provided (P < 0.05).
Conclusions
Providing written and verbal explanations of clinical and survivorship-related information can better meet the needs of Japanese cancer survivors.



Epidemiological analysis of childhood cancer in Japan based on population-based cancer registries, 1993–2009

2017-03-17

Abstract
Background
There are few recent data on trends in childhood cancer incidence using population-based cancer registries in Japan.
Methods
This study comprised 6110 reported cases of patients aged 0–14 years who were diagnosed as having primary cancer between 1993 and 2009. We chose cancer registries of seven prefectures, according to the international cancer registry standard of fewer than 10% death certificate only cases among cancer registries in Japan. We analyzed population-based cancer registration data in the seven prefectures between 1993 and 2009. We calculated childhood cancer incidence, age-specific incidence, crude incidence rate, age-adjusted incidence rate, confidence intervals and annual change for each prefecture and classified the data into 12 diagnostic groups, according to the International Classification of Childhood Cancer (ICCC).
Results
According to sex-specific incidence, males accounted for slightly more cases than females. Children 0–3 years old accounted for 41.1% of patients. Leukemia accounted for 36.0% of cancers, followed by central nervous system tumors with 15.0%, according to the ICCC. The crude incidence rate did not change substantially, remaining at an average 8–11 per 100 000 population. In addition, the age-adjusted incidence rate remained constant with an average 2 per 100 000 population.
Conclusions
Using population-based cancer registry data, age-specific incidence and 12 diagnostic groups according to the ICCC showed characteristics of childhood cancers. The incidence rate of childhood cancers has been nearly stable in Japan over the past 15 years.