Hepatocellular carcinoma is the most common malignancy in liver, is also a global problem and is the fourth most commonly diagnosed cancers among men and the fourth leading causes of cancer death among both men and women in China. Liver resection or hepatic resection and radiofrequency ablation is widely accepted as a first-line surgical approach for hepatocellular carcinoma in China. However, the indications of radiofrequency ablation or hepatic resection are different and not unified in China. In this article, we review the current status of hepatic resection and radiofrequency ablation therapies in hepatocellular carcinoma management in China.
To compare the Ki-67 labeling index value obtained through immunohistochemistry analysis by human examiners to that obtained from computer-assisted image analysis, and to establish a cut-off value for Ki-67 labeling index for each method in luminal B breast carcinoma.
Immunohistochemistry analysis for Ki-67 was performed on the formalin-fixed, paraffin-embedded tissue samples from 403 patients with primary luminal breast cancers. Whole slide images were obtained using the NanoZoomer (Hamamatsu Photonics, Hamamatsu, Japan) and thoroughly analyzed using the Definiens Tissue Studio version 1.1 (Definiens AG, Munich, Germany) to detect the percentage of positively-stained nuclei of carcinoma cells.
Although a significant correlation was found between the Ki-67 labeling index obtained by manual assessment and computer-assisted image analysis (Spearman rank correlation coefficient, P < 0.01), the Ki-67 labeling index value obtained by manual assessment was significantly higher than that obtained by computer-assisted image analysis (Wilcoxon signed rank test, P < 0.0001). Disease-free survival was significantly lower in 403 patients with tumors having high Ki-67 labeling index values determined by automated analysis (cut-off value: 11.5%; P < 0.00001) and visual counting (cut-off value: 28.5%; P < 0.00001). Disease-free survival was also significantly lower in 288 patients who received adjuvant endocrine therapy alone having high Ki-67 labeling index values determined by automated analysis (cut-off value: 11.5%; P < 0.0001) and visual counting (cut-off value: 19.7%, P < 0. 0001).
The Ki-67 labeling index values determined by automated analysis and visual counting could equally predict disease-free survival in patients with luminal B breast carcinoma, including those who received endocrine therapy.
The primary objective of this study was to investigate the safety and tolerability and to confirm the recommended dose of the anti-vascular endothelial growth factor receptor 2 monoclonal antibody ramucirumab in combination with docetaxel in Japanese patients with metastatic/locally advanced breast cancer.
In this multicenter, single-arm, Phase Ib trial, eligibility criteria included: 20 years or older, Eastern Cooperative Oncology Group performance status of 0/1 and confirmed diagnosis of human epidermal growth factor receptor 2-negative metastatic/locally recurrent inoperable breast adenocarcinoma. Patients received docetaxel (75 mg/m2) followed by ramucirumab (10 mg/kg) on Day 1 of 21-day cycles. Recommended dose was defined as <33% dose-limiting toxicities in dose-limiting toxicity-evaluable patients in Cycle 1. The safety, pharmacokinetics, immunogenicity and antitumor activity were examined.
Seven patients were treated. Most adverse events were mild to moderate. Two patients during Cycle 1 experienced a dose-limiting toxicity; one patient each experienced Grade 3 febrile neutropenia and Grade 3 gingivitis. Both dose-limiting toxicities subsequently resolved. No patients discontinued study therapies during Cycle 1. Four serious adverse events were possibly related to ramucirumab in combination with docetaxel. Anti-ramucirumab antibodies were not detected. Pharmacokinetic analysis revealed low total body clearance and long apparent terminal elimination half-life (~7–12 days). Partial response was reported in four patients.
The combination of ramucirumab and docetaxel was tolerable in female Japanese patients with breast cancer. Ramucirumab 10 mg/kg in combination with docetaxel (75 mg/m2) was confirmed as the recommended dose among Japanese patients, supporting its use in future studies.
Phase I oncology trials have raised concerns that patients’ ‘unrealistic’ optimism could compromise the validity of informed consent, and that patients often participate in trials to conform to physicians’ or family members’ recommendations. We aimed to determine whether patients or families—given the same information of risk–benefit profile—are more likely to participate in Phase I trials than their physicians and whether people in family or physician situations are more likely to recommend trial participation to patients than they would want for themselves as patients.
We conducted a hypothetical vignette study with a patient–caregiver–oncologist. Three groups—725 patient–caregiver pairs recruited by 134 oncologists—were asked to assume three different roles as patients, caregivers and physicians and provided a scenario of a hypothetical patient with treatment-resistant cancer. They were asked questions regarding their intention to participate in or to recommend a Phase I clinical trial.
Acceptance rates of the trial were as follows: (a) in the patients’ role: patients (54.1), caregivers (62.3) and physicians (63.4%); (b) in the caregivers’ role: 55.6, 64.7 and 70.9%; (c) in the physicians’ role: 66.1, 70.8 and 76.1%. Patients or caregivers were not more positive to the trial than physicians. All three groups showed more positive attitudes toward the clinical trial when they assumed the role of caregiver or physician than that of patient.
Patients and caregivers seem to make as reasonable decisions as physicians; patients seem to take family members’ or physicians’ recommendation as their legitimate roles rather than as undue pressure.
Early diagnosis and treatment of cancer may contribute substantially to complete cure, but it remains unknown whether treatment of early hepatocellular carcinoma can actually result in cure. This study was performed to clarify the cancer risk of the background liver after treating early hepatocellular carcinoma.
Early hepatocellular carcinoma is defined as very well-differentiated cancer containing Glisson's triad. The cumulative incidence of classical hepatocellular carcinoma, hypervascular liver cancer detected on imaging studies, after resection of early hepatocellular carcinoma positive for anti-hepatitis C antibody (early hepatocellular carcinoma group, n = 105) was compared with that in patients with chronic liver disease positive for anti-hepatitis C antibody (control group, n = 751) and propensity score-matched patients after resection of classical hepatocellular carcinoma (classical hepatocellular carcinoma group, n = 105).
After a median follow-up of 4.8 years (range, 0.3–15.0), the cumulative incidence of classical hepatocellular carcinoma at 5 years was 56.9% (95% confidence interval, 44.2–67.7%) in the early hepatocellular carcinoma group and 70.6% (52.5–81.8%) in the classical hepatocellular carcinoma group as compared with 4.6% (2.8–6.4%) in the control group. The risk of the development of classical hepatocellular carcinoma in the early hepatocellular carcinoma group was significantly higher than that in the control group (hazard ratio, 17.5; 95% confidence interval, 12.1–25.3; P < 0.001) and significantly lower than that in the classical hepatocellular carcinoma group (hazard ratio, 0.60; 0.41–0.89; P = 0.010). However, the cumulative incidence of second primary hepatocellular carcinoma in patients with one early hepatocellular carcinoma did not differ significantly from that in patients with two or more early hepatocellular carcinoma lesions (hazard ratio, 1.50; 0.85–2.65; P = 0.157).
Treatment of early hepatocellular carcinoma cannot provide complete cure due to the substantial risk of developing classical hepatocellular carcinoma.
Preoperative chemoradiotherapy has been established as a standard treatment for locally advanced rectal cancer. It is unclear whether preoperative chemoradiotherapy is truly beneficial in the elderly patients. Our aim was to assess the impact of age on the treatment tolerance and clinical outcomes.
We retrospectively analyzed 160 consecutive patients with clinical stage T3–4, and/or lymph node positive tumors who received preoperative chemoradiotherapy from May 2003 to December 2010 at a single hospital. Treatment tolerance and outcomes were compared between patients ≥70 years (N = 56) and <70 years (N = 104).
There was no disparity in the achievement of prescribed radiation dose and dose reduction of chemotherapy between two groups. Pathologic complete response rate (15.6% vs. 16.0%) and sphincter preservation rate (91.1% vs. 95.0%; P = 0.459) were not significantly different. The 3-year disease-free survival of older vs. younger patients was 77.8% vs. 92.3% and 5-year disease-free survival was 60.0% vs. 78.6%, respectively (P = 0.023). In multivariable analysis, age was significantly associated with disease-free survival (P = 0.033) but comorbidities were not (P = 0.092). However, both age (hazard ratio, 2.331; P = 0.028) and comorbidities (hazard ratio, 2.772; P = 0.031) were significantly associated with overall survival as well as clinical stage. Anemia was the only adverse effect more prominent in older patients.
Older patients showed non-inferior compliance and equivalent pathologic complete response rates without an increased incidence of treatment complications with preoperative chemoradiotherapy. More comprehensive consideration than age alone is warranted in the decision of applying preoperative chemoradiotherapy to elderly patients with rectal cancer.
We want to review the value of 18-fluoro-deoxy-glucose positron emission tomography for response prediction of primary tumor in patients with esophageal cancer during or after neoadjuvant chemoradiotherapy.
Studies were searched in Pubmed, Embase and Cochrane Library with specific search strategy. The published articles were included according to the criteria established in advance. The included studies were divided into two groups according to the time of the repeat positron emission tomography: during (Group A) or after neoadjuvant chemoradiotherapy (Group B). The studies that performed the repeat positron emission tomography after neoadjuvant chemoradiotherapy were graded Quality Assessment of Diagnostic Accuracy Studies. The pooled sensitivity, specificity and diagnostic odds ratio were obtained for both groups on the basis of no-existing of threshold effect.
Fifteen studies were included in the present study. The threshold effect did not exist in both groups. The pooled sensitivity, specificity and diagnostic odds ratio were 85%, 59%, 6.82 with 95% confidence interval 76–91%, 48–69%, 2.25–20.72 in Group A. The equivalent values were 67%, 69%, 6.34 with 95% confidence interval 60–73%, 63–74%, 2.08–19.34 in Group B. The pooled sensitivity was 90% in four studies that enrolled patients with esophageal squamous cell carcinoma merely in Group B.
According to the present data, positron emission tomography should not be used routinely to guide treatment strategy in esophageal cancer patients. We speculated that positron emission tomography could be used as a tool to predict treatment response after neoadjuvant chemoradiotherapy in patients with esophageal squamous cell carcinoma.
This study is designed to evaluate the correlations of insulin-like growth factor I (IGF-I) and insulin-like growth factor I receptor (IGF-IR) expressions with the clinicopathological features and prognosis of patients with colon cancer.
From January 2010 to January 2009, tissue samples were collected from 121 colon cancer patients, 147 with colon adenoma and 63 patients with chronic diarrhea. Real-time quantitative polymerase chain reaction was used to analyze the mRNA expressions of IGF-I and IGF-IR. Immunohistochemistry was utilized to detect the protein expressions of IGF-I and IGF-IR.
The IGF-I and IGF-IR mRNA expressions in colon cancer tissues were higher than those in colon adenoma tissues and normal tissues. The positive protein expressions of IGF-I and IGF-IR in colon cancer tissues were also higher than those in colon adenoma tissues and normal tissues. The mRNA expressions of IGF-I and IGF-IR were associated with the degree of differentiation, tumor node metastasis stage and lymphatic metastasis of colon cancer. Tumor node metastasis stage, lymphatic metastasis, postoperative chemotherapy and IGF-IR protein expression were independent factors for the prognosis of colon cancer.
This study has demonstrated that overexpression of IGF-I and IGF-IR contributes to the development and progression of colon cancer.
The epidermal growth factor receptor (EGFR) T790M mutation is considered the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations. Although chemotherapy is commonly used for those patients under the condition without T790M-targeted therapy, the clinical outcomes are poorly defined. Therefore, we aimed to reveal the treatment patterns and clinical outcomes in patients with T790M-positive NSCLC.
We conducted a retrospective observational study at 23 sites in Japan, and 141 patients with T790M-positive advanced/recurrent NSCLC were identified from January 2008 to December 2014. Their records were studied to understand treatment patterns after detection of a T790M mutation and to assess the objective response rate (ORR) and median survival time (MST) to specific treatment modalities.
Of 141 patients, 24 had de novo T790M-positive tumors and 117 had acquired T790M-positive tumors, with MSTs (95% CI) of 21.4 (12.4–36.7) and 9.1 (6.4–13.9) months, respectively. The most common regimen was platinum-based doublet chemotherapy ± bevacizumab, which was associated with an ORR/MST of 25.0%/29.1 months, respectively, in patients with de novo T790M mutations, and 22.2%/15.3 months, respectively, in patients with acquired T790M mutations.
This study reveals the treatment patterns and outcomes of NSCLC patients in Japan after detection of the T790M mutation. The most common treatment following detection of the T790M mutation was platinum-based doublet chemotherapy ± bevacizumab. Platinum-based doublet chemotherapy ± bevacizumab was moderately effective, indicating the need for targeted therapies for patients with T790M mutation-positive NSCLC.
Adjuvant androgen deprivation therapy is a common treatment option for prostate cancer after radical prostatectomy, especially in Asia. However, no study has investigated the oncological outcome after cessation of long-term adjuvant androgen deprivation therapy with favorable prostate-specific antigen control.
Among 855 patients undergoing radical prostatectomy at our institution between 2000 and 2012, we identified 56 men with pT2–4N0–1M0 prostate cancer who had received long-term (>2 years) adjuvant androgen deprivation therapy after radical prostatectomy and subsequently stopped it under a condition of continued prostate-specific antigen values <0.1 ng/mL. The oncological outcome was evaluated using biochemical recurrence, defined as two consecutive prostate-specific antigen values ≥0.2 ng/mL, as the primary endpoint. Cox proportional hazards model was used for multivariate analysis. Age at androgen deprivation therapy cessation was dichotomized as <68 years and ≥68 years, based on the most discriminatory cutoff.
Median duration of adjuvant androgen deprivation therapy was 70 months. Overall, 13 of 56 (23%) patients developed biochemical recurrence with a median follow-up period of 41 months after androgen deprivation therapy cessation. Multivariate analysis identified age at androgen deprivation therapy cessation <68 years and pN1 as independent predictors of biochemical recurrence. Predisposition of younger age to poorer survival may be related to more frequent testosterone recovery in younger men (73 vs 33%, P = 0.0299). One patient had evidence of clinical metastasis and no one died of prostate cancer.
Androgen deprivation therapy cessation would be feasible in most men who received long-term adjuvant androgen deprivation therapy after radical prostatectomy with favorable prostate-specific antigen control. Risk factors of biochemical recurrence after androgen deprivation therapy cessation included younger age at androgen deprivation therapy cessation and pN1.
We investigated chronological changes in the outcomes of patients with upper urinary tract urothelial carcinoma treated in the past two decades, during which there was an important change in treatment paradigm.
A retrospective review was conducted of 1180 urinary tract urothelial carcinoma patients who underwent radical nephroureterectomy in multicenter collaborative institutions between 1996 and 2015. The patients were divided into four groups according to the year when radical nephroureterectomy was performed, as follows: 1996–2000 (period 1; P1), 2001–05 (P2), 2006–10 (P3) and 2011–15 (P4). Variables including tumor grade, T and N categories, administration of perioperative chemotherapy and treatment outcomes were compared among the four groups.
There were 146 (12%), 312 (27%), 459 (39%) and 263 (22%) patients in the P1, P2, P3 and P4 groups, respectively. The proportion of patients harboring pT2/3 and Grade 3 tumors increased gradually from 42% (P1) to 58% (P4) and from 49% (P1) to 65% (P4), respectively. The 5-year disease-free survival rates were 74%, 74%, 73% and 75%, and the 5-year overall survival rates were 74%, 65%, 67% and 72% for the P1, P2, P3, and P4 groups, respectively. Multivariate analysis with adjustment for possible confounding factors revealed no significant differences in disease-specific survival, overall survival or intravesical recurrence-free survival among the four groups.
Despite advances in diagnostic instruments, surgery and systemic chemotherapy, the clinical outcome of urinary tract urothelial carcinoma after radical surgery has not significantly improved over the last two decades, and further research is therefore required.
Active surveillance has emerged as an alternative to immediate treatment in men with favorable-risk prostate cancer; however, consensus about defining the appropriate candidates is still lacking. To examine the factors predicting unfavorable pathology among active surveillance candidates, we assessed low-risk radical prostatectomy specimens.
This retrospective study included 1753 men who had undergone radical prostatectomy at six independent institutions in Japan from 2005 to 2011. Patients who met the active surveillance criteria were categorized depending on the pathological features of the radical prostatectomy specimens. ‘Reclassification’ was defined as upstaging (≥pT3) or upgrading (radical prostatectomy Gleason score ≥7), and ‘adverse pathology’ was defined as pathological stage ≥pT3 or radical prostatectomy Gleason score ≥4 + 3. Multivariate analysis was used to analyze the preoperative factors for reclassification and adverse pathology. The rates of reclassification and adverse pathology were evaluated by classifying patients according to biopsy core numbers.
The active surveillance criteria were met by 284 cases. Reclassification was identified in 154 (54.2%) cases, while adverse pathology in 60 (21.1%) cases. Prostate-specific antigen density and percentage of positive cores were independently associated with reclassification and adverse pathology. The rates of reclassification and adverse pathology were significantly higher among patients with <10 biopsy cores than among others. Thus, focusing on 149 patients with ≥10 biopsy cores, prostate-specific antigen density was the only independent predictor of unfavorable pathological features. The receiver operating characteristic curve analysis determines an optimal cut-off value of prostate-specific antigen density as 0.15 ng/ml2.
Prostate-specific antigen density is the most important predictor of unfavorable pathological features in active surveillance candidates.
To assess the prognostic value of perioperative changes in the neutrophil–lymphocyte ratio in patients with bladder cancer undergoing radical cystectomy.
We performed a retrospective analysis of 323 patients who had undergone radical cystectomy at our institutions. Overall survival was assessed with the Kaplan–Meier method and Cox regression analysis.
Preoperative and postoperative neutrophil–lymphocyte ratios were significantly correlated with overall survival (both P = 0.0001). Changes in perioperative neutrophil–lymphocyte ratio stratified the patients into two groups, designated favorable- and poor-risk groups, with significantly different 5-year overall survival rates (75.1% and 41.4%, respectively; P < 0.0001). Multivariate Cox regression analyses showed that the perioperative change in neutrophil–lymphocyte ratio was an independent prognostic factor for overall survival (hazard ratio 2.56, 95% confidence interval 1.75–3.73; P < 0.001). Moreover, a decrease in neutrophil–lymphocyte ratio after adjuvant chemotherapy was associated with favorable overall survival in patients with high postoperative neutrophil–lymphocyte ratio (P < 0.001), indicating that neutrophil–lymphocyte ratio may be a predictive factor for the efficacy of adjuvant chemotherapy.
Perioperative changes in neutrophil–lymphocyte ratio are significantly associated with overall survival in patients with bladder cancer undergoing radical cystectomy. Follow-up of the neutrophil–lymphocyte ratio change may be useful for the clinical management of patients after surgery.
The optimal management of clinical N2 Stage IIIA non–small cell lung cancer is still controversial. For a cure of locally advanced IIIA/N2 non–small cell lung cancer, the control of both local regions and possible distant micrometastases is crucial. Chemotherapy is generally expected to prevent distant recurrence. For local tumor control, radiotherapy or surgery has been adopted singly or in combination. If a complete resection can be safely performed, surgery remains the strongest modality for ‘eradicating’ local disease. Many retrospective studies have reported a possible survival benefit of induction treatment followed by surgery in selected patients with IIIA/N2 non–small cell lung cancer; however, randomized Phase III trials have failed to demonstrate the superiority of induction treatment followed by surgery over chemoradiotherapy, mainly because of the heterogeneity of the N2 status. IIIA/N2 non–small cell lung cancer consists of a heterogeneous group of disease ranging from microscopically single station to radiologically bulky ipsilateral multi-station mediastinal lymph node involvement. A recent definition proposed by the American College of Chest Physicians classified non–small cell lung cancer based on the N2 status, such as discrete or infiltrative type, and recommendations were made according to this N2 status, with definitive chemoradiotherapy recommended for infiltrative clinical N2 and definitive chemoradiotherapy or induction treatment followed by surgery recommended for other cases. Thus, the introduction of a multimodality treatment strategy seems to be necessary for the improved prognosis of non–small cell lung cancer patients with IIIA/N2 disease. In this review, we discuss the role of surgery and the optimal surgical management for patients with IIIA/N2 non–small cell lung cancer.
A number of promising new approaches for both local and systemic control of locally advanced non–small cell lung cancer have been examined in clinical trials, aimed at improving the patient survival. Development of better systemic therapies by adopting newer agents (such as epidermal growth factor receptor-tyrosine kinase inhibitors and immune checkpoint inhibitors) from advanced non–small cell lung cancer is mandatory. As for radiotherapy, adaptive radiotherapy and proton therapy are under investigation after the RTOG 0617 trial unexpectedly failed to show the efficacy of high-dose radiotherapy for Stage III disease. To date, no Phase III trial has clearly shown the benefit of adding surgery as a part of multimodality therapy for locally advanced non–small cell lung cancer. Such poor progress in the development of effective treatments for Stage III non–small cell lung cancer is considered to be attributable to the existence of heterogeneities in the disease characteristics, including the biological and anatomic characteristics. Constant effort via well-designed and well-conducted clinical trials is needed to decipher the heterogeneity of Stage III non–small cell lung cancer.