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Japanese Journal of Clinical Oncology

Japanese Journal of Clinical Oncology - RSS feed of current issue

Until recently, ovarian clear cell carcinoma was recognized by its unique morphology and unfavorable patient outcome primarily due to tumor chemoresistance. Recently, specific molecular characteristics of ovarian clear cell carcinoma, such as PI3CA mutation, ARID1a mutation and MET amplification, have been elucidated. In addition, an association between endometriosis and the tumor has also been a focus of research in recent years. The aim of this review is to discuss the specificity and importance of molecular changes and various intriguing points that are not solved until today. Finally, future aspects, including hopes for the development of novel therapies, are discussed.


Several ‘lines of therapy’ that utilize cytotoxic agents and are driven by platinum-free intervals are the current standard of care for patients with recurrent ovarian cancer. For patients with platinum-resistant disease, single agent chemotherapy (pegylated liposomal doxorubicin, topotecan, gemcitabine or weekly paclitaxel) is the standard of care. For patients with platinum-sensitive disease, combination chemotherapy (carboplatin plus paclitaxel, pegylated liposomal doxorubicin or gemcitabine) is the standard of care. In addition, antiangiogenic therapy using bevacizumab is an established option. Future directions could include ‘lines of therapy’ with biologic agents driven by specific biologic targets. Data from antiangiogenic agents (trebananib, pazopanib and cediranib), antifolate drugs (farletuzumab and vintafolide), poly(ADP-ribose) polymerase inhibitors (olaparib and veliparib), mTOR inhibitors (everolimus and temsirolimus) and immune editing agents (nivolumab) have been summarized in this review.


Objective

We investigated the prognostic importance of pre-operative Breast Imaging Reporting and Data System classification in ultrasound imaging.

Methods

Histopathological differences and disease-free survival were analyzed in Breast Imaging Reporting and Data System classification subgroups. Univariate and multivariate analyses were used to identify the prognostic factors.

Results

We identified 531 invasive breast cancer patients eligible for this study. Most patients classified as Breast Imaging Reporting and Data System 5 had large tumors and a higher rate of lymph node metastasis. However, hormonal receptor or HER-2 status did not differ according to Breast Imaging Reporting and Data System classification. During a median post-operative follow-up of 42.0 months, 43 patients were diagnosed with a disease-specific event. Disease-free survival was significantly lower in patients with Breast Imaging Reporting and Data System 5 than in patients with Breast Imaging Reporting and Data System 3–4. Subgroup analysis of patients with invasive breast cancer of Stage I showed that Breast Imaging Reporting and Data System 5 was an independent negative prognostic indicator of disease-free survival (hazard ratio 9.195; 95% confidence interval, 1.175–71.955; P = 0.035).

Conclusions

Breast Imaging Reporting and Data System classification might be considered as prognostic factors especially in Stage I breast cancer. Further confirmatory studies are needed.


Objective

Determination of human epidermal growth factor receptor-2 status in advanced gastric cancer is important in clinical decision making. In the trastuzumab for GC trial, trastuzumab-based therapy demonstrated a significant overall survival benefit in patients with human epidermal growth factor receptor-2-positive advanced gastric cancer. Human epidermal growth factor receptor-2 discordance in gastric cancer primary and its metastases has been long debated. The aim of the study was to evaluate the rate of human epidermal growth factor receptor-2 discordance and its effect on treatment decisions in advanced gastric cancer.

Methods

A total of 74 patients with advanced gastric cancer were included in the study. Both immunohistochemical staining and dual-color silver in situ hybridization were performed in all patients to evaluate the human epidermal growth factor receptor-2 status of the primary lesion and paired metastasis.

Results

The assessment of human epidermal growth factor receptor-2 status with the immunohistochemical staining method and dual-color silver in situ hybridization revealed a discordance rate of 9.5 and 16.2%, respectively. However, this discordance was clinically meaningful in only one patient leading to a change in treatment decision. While this patient had a human epidermal growth factor receptor-2-negative status in primary tumor (immunohistochemical = 0, dual-color silver in situ hybridization = negative), the human epidermal growth factor receptor-2 status was positive for liver metastasis (immunohistochemical = 2+, dual-color silver in situ hybridization = positive). Trastuzumab was added to the chemotherapy regimen.

Conclusions

In this study, we found a higher rate of human epidermal growth factor receptor-2 discordance between primary gastric tumor and metastatic lesions compared with the rates reported in previous studies. Detection of a human epidermal growth factor receptor-2-positive metastasis with a human epidermal growth factor receptor-2-negative primary tumor suggests that investigation of human epidermal growth factor receptor-2 is also required for the metastatic lesion and that trastuzumab could be administered in the case of a positive result.


Objective

This single-arm Phase II trial was designed to assess the safety and efficacy of pegylated liposomal doxorubicin and carboplatin combination chemotherapy in patients with platinum-sensitive recurrent ovarian cancer.

Methods

Patients with a histological diagnosis of epithelial ovarian, fallopian tube or primary peritoneal carcinoma, who were relapse-free at least 6 months after completion of first-line platinum-based chemotherapy, and who had measurable disease and gave consent to participate in this study received infusions of pegylated liposomal doxorubicin (30 mg/m2) at 1 mg/min, followed by carboplatin (AUC 5 mg min/ml) over 30 min every 28 days.

Results

Thirty-three of 35 enrolled patients were eligible for efficacy analysis. One patient (3.0%) achieved a complete response, while 16 (48.5%) achieved a partial response, with an overall objective response rate of 51.5% (95% confidence interval, 34.5–68.6%). Among the 22 patients who had evaluable CA125 levels at entry, responses were observed in 18 patients, with a response rate of 81.8% (95% confidence interval, 65.3–98.3%). The median progression-free survival and overall survival rates for all 35 patients were 10.7 months (95% confidence interval, 8.1–13.2 months) and 38.8 months (95% confidence interval, 31.0–46.7 months), respectively. The most frequent Grade 3–4 toxicities, regardless of cause, were neutropenia (82.9%), thrombocytopenia (51.4%), leukopenia (45.7%) and anemia (17.1%).

Conclusions

The safety and efficacy of pegylated liposomal doxorubicin and carboplatin combination chemotherapy in patients with platinum-sensitive recurrent ovarian cancer were confirmed. Although there were concerns of severe hematological toxicity with this therapy, this potential complication was safely managed through adequate monitoring of bone marrow function.


Objective

The prognosis of differentiated thyroid carcinoma is generally favorable. However, some patients have negative radioiodine whole-body scans and detectable serum thyroglobulin with biochemical radioiodine-refractory carcinoma and are candidates for treatment with a multikinase inhibitor, such as sorafenib. The purpose of this study is to investigate the characteristics and prognosis of differentiated thyroid carcinoma patients who are thyroglobulin positive and scan negative.

Methods

We retrospectively classified 153 patients treated for 15 years by serum thyroglobulin level and radioiodine scan results and examined the relationship between clinical characteristics and prognosis.

Results

Overall, 27% of the patients were classified as thyroglobulin positive/scan negative (positive/negative) while 61% were thyroglobulin negative/scan negative (double negative). Compared with double-negative patients, positive/negative patients were significantly older, predominantly male, had a higher pT and pN, stage, and had higher pre-operative thyroglobulin values. Positive/negative patients showed worse prognosis in terms of overall survival, disease-specific survival and disease-free survival than double-negative patients (10-year overall survival, 85 vs. 93%, P = 0.001; 10-year disease-specific survival, 94 vs. 100%, P = 0.03, 10-year disease-free survival, 77 vs. 93%, P < 0.001). Multivariate analysis revealed that positive/negative status was the only factor associated with disease-free survival, including age and TNM stage (hazard ratio: 6.37, 95% confidence interval: 1.22–33.3). However, the median duration of disease-free period for positive/negative patients was 14.2 years.

Conclusions

Few patients among thyroglobulin-positive/scan-negative patients are candidates for sorafenib, despite the significant survival differences from double-negative patients.


Objective

We evaluated the clinical characteristics of a Dermatitis Control Program based on a moderately absorbent surgical pad for head and neck cancer patients undergoing (chemo)radiotherapy.

Methods

We retrospectively reviewed patients who underwent definitive radiotherapy or post-operative radiotherapy and were treated during radiotherapy with a Dermatitis Control Program using a moderately absorbent surgical pad from May 2011 through April 2012. The main protocol was the ‘Dermatitis Control Program’, a systematic program which consists of a three-step ladder. When radiation dermatitis reached Grade 2, the irradiated area was covered with a moderately absorbent surgical pad. All outpatients and their families were instructed on how to cover and moisten the irradiated area. Radiation dermatitis was evaluated by physicians or nurses at an outpatient clinic and reviewed from photographs.

Results

A total of 116 head and neck cancer patients were treated by definitive or adjuvant (chemo)radiotherapy in our hospital from May 2011 through April 2012. Of these, 85 patients managed their dermatitis using a new device and they were reviewed. Fifty-five patients received chemoradiotherapy, of whom 22 received induction chemotherapy before chemoradiotherapy. Median radiation dose at the onset of Grade 2 dermatitis was 60.0 Gy (range 40–71.2 Gy). Median time to recover from the end of radiotherapy was 10.5 days (range 0–25 days). The rate of recovery from Grade 2 dermatitis within 2 weeks after the end of radiotherapy was 89.4%. The rate of Grade 3 dermatitis was 7.1, with 6.7% in radiotherapy and 7.3% in chemoradiotherapy.

Conclusions

This study suggests that the DeCoP protocol with a moderately absorbent surgical pad might be useful for the treatment of radiation dermatitis in clinical practice.


Objective

Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1–3. This analysis compared efficacy and safety of axitinib plus gemcitabine in patients with advanced pancreatic cancer from Japan, North America and the European Union, enrolled in a randomized Phase III study.

Methods

Patients (n = 632), stratified by disease extent, were randomly assigned (1:1) to receive axitinib/gemcitabine or placebo/gemcitabine. Axitinib was administered at a starting dose of 5 mg orally twice daily and gemcitabine at 1000 mg/m2 once weekly for 3 weeks in 4 week cycles. Primary endpoint was overall survival.

Results

Among Japanese patients, median overall survival was not estimable (95% confidence interval, 7.4 months—not estimable) with axitinib/gemcitabine (n = 58) and 9.9 months (95% confidence interval, 7.4–10.5) with placebo/gemcitabine (n = 56) (hazard ratio 1.093 [95% confidence interval, 0.525–2.274]). Median survival follow-up (range) was 5.1 months (0.02–12.3) with axitinib/gemcitabine vs. 5.4 months (1.8–10.5) with placebo/gemcitabine. Similarly, no difference was detected in overall survival between axitinib/gemcitabine and placebo/gemcitabine in patients from North America or the European Union. Common adverse events with axitinib/gemcitabine in Japanese patients were fatigue, anorexia, dysphonia, nausea and decreased platelet count. Axitinib safety profile was generally similar in patients from the three regions, although there were differences in incidence of some adverse events. An exploratory analysis did not show any correlation between axitinib/gemcitabine-related hypertension and overall survival.

Conclusions

Axitinib/gemcitabine, while tolerated, did not provide survival benefit over gemcitabine alone in patients with advanced pancreatic cancer from Japan or other regions.


Objective

In Japan, pazopanib has been made available to soft tissue sarcoma patients, also to patients histologically diagnosed as ineligible for the international Phase 3 study (PALETTE). However, clinical evidence for the use of pazopanib in PALETTE-ineligible patients is currently insufficient.

Methods

We retrospectively reviewed medical records of soft tissue sarcoma patients treated with pazopanib at our institute. By pathological review, the patients' eligibility for the PALETTE study was evaluated and the differences in their responses to pazopanib and incidences of adverse events were investigated.

Results

From November 2012 to August 2014, a total of 47 patients received pazopanib, 38 (81%) of whom were histologically eligible for the PALETTE study, and 9 of whom (19%) were not. The median follow-up time was 7.5 months (range 1.4–20.3 months). An objective response was observed in both groups, but the patients' survival tended to be longer in the PALETTE-eligible patients; median progression-free survival was 4.5 months vs. 2.9 months (P = 0.15) and overall survival was 10.7 months vs. 7.8 months (P = 0.55), though these differences were not statistically significant. There were no significant differences in the incidence of adverse events by PALETTE eligibility, but dose skipping or dose reduction was more likely to be observed in PALETTE-ineligible patients.

Conclusion

Pazopanib is tolerable to soft tissue sarcoma patients ineligible for the PALETTE study and some of them respond to pazopanib, but the prognoses of patients ineligible for the PALETTE study might be worse than those of PALETTE-eligible patients. The indication of pazopanib for soft tissue sarcoma patients with PALETTE-ineligible histologies should be decided carefully.


Objective

Although various factors thought to be correlated with anxiety in cancer patients, relative importance of each factors were unknown. We tested our hypothesis that personality traits and coping styles explain anxiety in lung cancer patients to a greater extent than other factors.

Methods

A total of 1334 consecutively recruited lung cancer patients were selected, and data on cancer-related variables, demographic characteristics, health behaviors, physical symptoms and psychological factors consisting of personality traits and coping styles were obtained. The participants were divided into groups with or without a significant anxiety using the Hospital Anxiety and Depression Scale-Anxiety, and a binary logistic regression analysis was used to identify factors correlated with significant anxiety using a multivariate model.

Results

Among the recruited patients, 440 (33.0%) had significant anxiety. The binary logistic regression analysis revealed a coefficient of determination (overall R2) of 39.0%, and the explanation for psychological factors was much higher (30.7%) than those for cancer-related variables (1.1%), demographic characteristics (2.1%), health behaviors (0.8%) and physical symptoms (4.3%). Four specific factors remained significant in a multivariate model. A neurotic personality trait, a coping style of helplessness/hopelessness, and a female sex were positively correlated with significant anxiety, while a coping style of fatalism was negatively correlated.

Conclusions

Our hypothesis was supported, and anxiety was strongly linked with personality trait and coping style. As a clinical implication, the use of screening instruments to identify these factors and intervention for psychological crisis may be needed.


Objective

The incidence of brain metastases greatly varies in patients with non-small-cell lung cancer, and molecular markers are considered to predict brain metastases. Therefore, this study sought to identify the predictive value and potential mechanisms of miRNA-328 and miRNA-378 for brain metastases in non-small-cell lung cancer.

Methods

Patients who received a curable surgery for their lung cancer were screened according to our criteria. Formalin-fixed paraffin-embedded samples from the patients were examined for the expression of miRNA-328 and miRNA-378 using real-time polymerase chain reaction and the expression of N-cadherin, E-cadherin, vascular endothelial growth factor, protein kinase Cα and S100B were investigated using immunohistochemical staining.

Results

In total, 86 patients were screened for this study and 23 patients were diagnosed with brain metastases during the follow-up period. Comparing patients with and without brain metastases, the expression of miRNA-328 and miRNA-378 in tumor tissues were significantly different (P = 6.2 x 10–5 and P = 2.8 x 10–5, respectively). For the patients with brain metastases, the expression of miRNA-328 and miRNA-378 in tumor tissues compared with para-carcinoma tissues were also significantly different (P = 2.2 x 10–5 and P = 1.6 x 10–5, respectively). For patients with brain metastases, the association between miRNA-328 and protein kinase Cα was significant (r = 0.591, P = 0.003), but that between miRNA-378 and protein kinase Cα was not significant (r = 0.259, P = 0.232).

Conclusions

The expression of miRNA-328 and miRNA-378 in tumor tissues can be used to predict brain metastases in patients with non-small-cell lung cancer. miRNA-328 might promote brain metastases by regulating the expression of protein kinase Cα. However, the mechanisms of miRNA-378 to promote brain metastases should be studied in the future.


Objective

Recent reports strongly suggest the profound role of miRNAs in cancer therapeutic response and progression, including invasion and metastasis. The sensitivity to therapy and invasion is the major obstacle for successful treatment in prostate cancer. We aimed to investigate the regulative effect of miR-128/zinc-finger E-box-binding homeobox 1 axis on prostate cancer cell chemosensitivity and invasion.

Methods

The miR-128 expression pattern of prostate cancer cell lines and tissues was detected by real-time reverse transcriptase-polymerase chain reaction, while the mRNA and protein expression levels of zinc-finger E-box-binding homeobox 1 were measured by real-time reverse transcriptase-polymerase chain reaction and western blot assay, respectively. Dual-luciferase reporter gene assay was used to find the direct target of miR-128. Furthermore, prostate cancer cells were treated with miR-128 mimic or zinc-finger E-box-binding homeobox 1-siRNA, and then the cells' chemosensitivity and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and transwell assay, respectively.

Results

We found miR-128 expression obviously decreased in prostate cancer tissues compared with paired normal tissues. Restored miR-128 expression sensitized prostate cancer cells to cisplatin and inhibited the invasion. Furthermore, there was an inverse expression pattern between miR-128 and zinc-finger E-box-binding homeobox 1 in prostate cancer cells and tissues, and zinc-finger E-box-binding homeobox 1 was identified as a direct target of miR-128 in prostate cancer. Knockdown of zinc-finger E-box-binding homeobox 1 expression efficiently sensitized prostate cancer cells to cisplatin and inhibited the invasion. However, ectopic zinc-finger E-box-binding homeobox 1 expression impaired the effects of miR-128 on chemosensitivity and invasion in prostate cancer cells.

Conclusions

miR-128 functions as a potential cancer suppressor in prostate cancer progression and rational therapeutic strategies for prostate cancer would be developed based on miR-128/zinc-finger E-box-binding homeobox 1 axis.


Objective

Previous reports on the risk of stroke after androgen deprivation therapy for prostate cancer were largely based on Caucasians. We investigated the risk of ischemic stroke after androgen deprivation therapy for prostate cancer in the Chinese population.

Methods

All Chinese prostate cancer patients who were treated primarily with radical prostatectomy or radiotherapy, with (androgen deprivation therapy group) or without (non-androgen deprivation therapy group) further androgen deprivation therapy, at our hospital from year 2000–09 were reviewed. Potential risk factors of ischemic stroke including age, baseline prostate-specific antigen, Gleason score, clinical T stage, hypertension, diabetes mellitus, hyperlipidemia, ischemic heart disease, history of stroke, use of androgen deprivation therapy and duration of androgen deprivation therapy were reviewed. The risk of ischemic stroke after androgen deprivation therapy was analyzed with Kaplan–Meier and multivariate Cox regression analyses.

Results

A total of 452 patients were included, consisting of 200 patients in the non-androgen deprivation therapy group and 252 patients in the androgen deprivation therapy group. The androgen deprivation therapy group appeared to have increased risk of ischemic stroke when compared with the non-androgen deprivation therapy group (P = 0.063) upon Kaplan–Meier analysis. Upon multivariate Cox regression analyses, older age (hazard ratio 1.13, 95% confidence interval 1.04–1.22, P = 0.003), hyperlipidemia (hazard ratio 4.61, 95% confidence interval 2.01–10.54, P < 0.001) and the use of androgen deprivation therapy (hazard ratio 3.32, 95% confidence interval 1.14–9.67, P = 0.028) were associated with increased risk of ischemic stroke.

Conclusions

There was increased risk of ischemic stroke after androgen deprivation therapy for prostate cancer in the Chinese population. The risk of ischemic stroke should be considered while deciding on androgen deprivation therapy, especially in older patients with known history of hyperlipidemia.


Objective

Patients with upper urinary tract urothelial carcinoma (UUT-UC) without a history of bladder cancer have a different natural history of intravesical recurrence after nephroureterectomy compared with those with a history of bladder cancer. The aim of this study was to identify predictive factors for post-operative intravesical recurrence in patients with non-metastatic upper urinary tract-localized urothelial carcinoma without a history of bladder cancer and who were not taking medication during the perioperative period.

Methods

This retrospective study included 133 patients who were treated between 1995 and 2012. Univariate and multivariate analyses were used to evaluate the clinical and pathological factors associated with the cumulative incidence of bladder cancer.

Results

Of the 133 patients, 51 (38.3%) developed intravesical recurrence during a median follow-up of 71 months (range, 0.8–210.8). In the multivariate analysis, multifocality (P = 0.03) and high tumour grade (P = 0.007) were significantly associated with the cumulative incidence of bladder cancer. We constructed a prediction classification model on the basis of the total number of risk factors. The 2-year cumulative incidence rates were 5.6, 34.8 and 50.0% in individuals with no, one and two risk factors, respectively. There was a significant difference between patients with no risk factors and those with two risk factors (P = 0.01).

Conclusions

Although this retrospective study had several limitations, tumour multifocality and tumour grade were found to be potential risk factors for intravesical recurrence in our cases.


Chemotherapy with cisplatin plus fluorouracil is the current standard treatment for metastatic or recurrent esophageal cancer. We have developed a 2-weekly docetaxel combined with CF regimen and conducted a Phase I/II trial for metastatic or recurrent esophageal cancer (JCOG0807). Promising efficacy and safety were shown in JCOG0807, and we have commenced a Phase III trial in September 2014 to confirm the superiority of 2-weekly DCF to CF for patients with metastatic or recurrent esophageal cancer. A total of 240 patients will be accrued from 41 Japanese institutions over a period of 4 years. The primary end point is overall survival. The secondary end points are progression-free survival, response rate and proportion of adverse events. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000015107 (http://www.umin.ac.jp/ctr/index.htm).


Post-operative adjuvant chemotherapy has been considered an effective strategy to reduce cancer recurrence and improve survival for resected non-small-cell lung cancer. The Japan Clinical Oncology Group has completed patient accrual for a randomized Phase III study (JCOG0707), which compares the survival benefit of UFT and S-1 for completely resected pathological Stage I (T1 >2 cm and T2 in TNM classification version 6) non-small-cell lung cancer. However, there is a growing concern that those who participated in clinical trials are highly selected patients and do not represent the ‘real-world’ population. This multicenter observational cohort study aims to analyze the backgrounds, pattern of care and outcomes of the patients who were excluded from the JCOG0707 study during the accrual period. The results of this cohort study will be useful for external validity of the results of clinical trial such as JCOG0707.