Preview: Japanese Journal of Clinical Oncology - current issue
Japanese Journal of Clinical Oncology Current Issue
Published: Thu, 23 Mar 2017 00:00:00 GMT
Last Build Date: Fri, 24 Mar 2017 05:44:21 GMT
A phase 1 study of ramucirumab in Japanese patients with advanced solid tumors
ObjectiveRamucirumab is a recombinant human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. The aim of this phase 1 study was to evaluate the safety and tolerability of ramucirumab monotherapy in Japanese patients with advanced solid tumors.
MethodsPatients with solid tumors who had not responded to standard therapy or for whom no standard therapy was available received escalating doses of ramucirumab, administered once every 2 (Q2W) or 3 (Q3W) weeks. The primary objective was to establish the safety and pharmacokinetic profiles of ramucirumab. Secondary and exploratory objectives included assessment of immunogenicity and antitumor activity. ClinicalTrials.gov: NCT01005355.
ResultsFifteen patients were treated with ramucirumab at a dose of 6 mg/kg Q2W (N = 3), 8 mg/kg Q2W (N = 6) or 10 mg/kg Q3W (N = 6). There were no dose-limiting toxicities and the maximum tolerated dose was not reached. The most common ramucirumab-related adverse events were headache, pyrexia, hypertension and increased aspartate aminotransferase. Following single-dose administration of ramucirumab, there appeared to be a dose-proportional increase in maximum observed drug concentration but not in area under the curve. Treatment-emergent anti-ramucirumab antibodies were not detected in any patient.
ConclusionsRamucirumab monotherapy was well tolerated and feasible at the doses and schedules used in this study population of Japanese patients with advanced solid tumors.
Increased stathmin in serum as a potential tumor marker for lung adenocarcinoma
BackgroundStathmin has been found to be involved in malignant tumors; the aim of this study was to investigate the relationship between serum stathmin and clinico-pathological features of lung cancer.
MethodsIn three lung cancer cell lines, stathmin expression and its secretion level in the supernatant were examined by Western blot and enzyme-linked immunosorbent assay (ELISA). Expression of stathmin was examined by immunohistochemistry in 48 lung cancer tissues, and serum stathmin expression level was examined by ELISA in 96 patients with lung cancer and 82 normal individuals. Sensitivity and specificity of serum stathmin were determined by receiver operator characteristic curve (ROC).
ResultsIn the three cell lines and their supernatant, stathmin levels were higher than those in 16 HBE cell line. Lung cancer tissues expressed higher level stathmin more frequently than normal lung tissue (P < 0.05). Serum stathmin level was significantly higher in the patients with lung cancer than in normal individuals (P < 0.001). Increased stathmin level in cancer tissue and serum were significantly associated with adenocarcinoma histology, lymph node metastasis and advanced stage. The threshold level of serum stathmin for distinguishing lung cancer from normal individuals was 1.86 ng/ml. The sensitivity and specificity were 93.7% and 91.5%, respectively.
ConclusionsMeasurement of serum stathmin level could be a potential biomarker for lung cancer, especically those of adenocarcinoma, with lymph node metastasis and at advanced clinical stages.
Pemetrexed-related interstitial lung disease reported from post marketing surveillance (malignant pleural mesothelioma/non-small cell lung cancer)
BackgroundInterstitial lung disease (ILD) is important drug related toxicity because it commonly forced to discontinue the treatment.
MethodsTo characterize the prevalence and patterns of pemetrexed induced ILD, an independent ILD advisory board composed of external experts performed reassessment of ILD in two post marketing surveillance (PMS) studies for malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC).
ResultsILD incidences were originally 1.6% and 2.6% in 903 MPM and 683 NSCLC patients in safety analyses, respectively. Based on the reassessment by the board, the incidence was 1.1% MPM and 1.8% NSCLC. Common possible risk factors of ILD in MPM and NSCLC patients were male gender, 60 years or older age, and pre-existing ILD. Asbestosis in MPM, and smoking history in NSCLC are also considered as risk, respectively. In terms of computed tomography (CT) pattern, 7 of 10 cases in MPM patients had acute interstitial pneumonia pattern, which four were fatal. Eight of the 12 NSCLC patients had diffuse grand glass opacity, which all had recovered. Onset of ILD in MPM varied between the first and the fifth courses of pemetrexed treatment, and the latest onset was 48 days after the last administration. For NSCLC, it was between the second and the ninth course, 7 and 56 days after the last administration.
ConclusionsThe risk of pemetrexed-related ILD is similar level as other anti-cancer drugs under clinical settings. Careful observations continuously during and at least for 2 months after the last administration of pemetrexed are advised.
Recovery from anemia and leukocytopenia after abstinence in Japanese alcoholic men and their genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2
BackgroundThe combination of the fast-metabolizing alcohol dehydrogenase-1B (ADH1B*2 allele) and inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) increases susceptibility to macrocytic anemia and leukocytopenia in alcoholics due to severe acetaldehydemia. More than half of Japanese drinkers with esophageal cancer have this genotype combination.
MethodsTo assess the recovery of hematologic abnormalities after drinking cessation, changes in blood erythrocyte indices and leukocyte count during 8-week hospital stay were evaluated in 925 Japanese alcoholic men. We used four categories in ascending order for high blood acetaldehyde exposure from drinking: A, ADH1B*1/*1 plus ALDH2*1/*1; B, ADH1B*2 plus ALDH2*1/*1; C, ADH1B*1/*1 plus ALDH2*1/*2; and D, ADH1B*2 plus ALDH2*1/*2.
ResultsMean values of hemoglobin and hematocrit were the lowest, and those of mean corpuscular volume (MCV) were markedly the highest in the D group on admission, and returning toward normal after abstinence, but the inter-group differences remained significant throughout the 8 weeks. The mean leukocyte count was the lowest in the D group on admission, but increased during 4-week abstinence when the inter-group differences were no longer significant. Frequencies of MCV ≥110 fl (50.5%), hemoglobin levels <11.5 g/dL (32.7%), hemoglobin levels <10.0 g/dL (9.9%) and leukocytopenia <4000/μL (22.8%) were the highest in the D group on the admission day and decreased at the 4-week abstinence (28.7%, 18.8%, 4.0% and 7.9%, respectively). The inter-group differences in frequencies of the severe anemia and leukocytopenia disappeared after 4-week abstinence.
ConclusionsDrinking cessation before surgery and/or chemoradiation treatment for esophageal cancer may be effective for recovery from anemia and leukocytopenia in drinkers belonging to the D group.
Sarcopenia is a novel poor prognostic factor in male patients with pathological Stage I non-small cell lung cancer
ObjectivesSarcopenia is the progressive loss of muscle mass and strength, and has a risk of adverse outcomes such as disability, poor quality of life and death. As prognosis depends not only on disease aggressiveness, but also on a patient's physical condition, sarcopenia can predict survival in patients with various cancer types. However, its effects on postoperative prognosis in patients with localized non-small cell lung cancers (NSCLC) have never been reported.
MethodsWe retrospectively investigated 215 male patients with pathological Stage I NSCLC. L3 muscle index is defined as the cross-section area of muscle at the third lumbar vertebra level, normalized for height, and is a clinical measurement of sarcopenia. We then investigated the effect of preoperative sarcopenia on their postoperative prognosis.
ResultsOur 215 subjects included 30 patients with sarcopenia. Sarcopenia was significantly associated with body mass index, nutritional condition, serum CYFRA 21-1 level and pathological stage, but not with preoperative respiratory function or performance status. Frequency of postoperative complications, length of postoperative hospital stay, thoracic drainage period or causes of death were not correlated with the presence of sarcopenia. The sarcopenia group had a significantly shorter median overall survival (32 months) than the no-sarcopenia group.
ConclusionSarcopenia might not affect short-term outcomes in patients with early-stage lung cancer. Sarcopenia was a predictor of poor prognosis in male patients with Stage I NSCLC. As sarcopenic patients with NSCLC patients are at risk for significantly worse outcomes, their treatments require careful planning, even for those with Stage I disease.
Association between poorly differentiated clusters and efficacy of 5-fluorouracil-based adjuvant chemotherapy in stage III colorectal cancer
ObjectiveAlthough poorly differentiated cluster has been reported to be a useful grading system for predicting prognosis in colorectal cancer, its relationship to chemotherapy efficacy has not been demonstrated. We aimed to investigate the association between poorly differentiated cluster and the efficacy of 5-fluorouracil-based adjuvant chemotherapy in stage III colorectal cancer.
MethodsThis retrospective study enrolled 131 patients with stage III colorectal cancer who underwent curative resection: 72 received 5-fluorouracil-based adjuvant chemotherapy (chemotherapy group) and 59 did not (surgery-alone group). Poorly differentiated cluster was defined as a cancer cluster of ≥5 cancer cells without gland-like structure, and was classified into poorly differentiated cluster G1, G2 and G3 according to the number of clusters. The benefit of 5-fluorouracil-based adjuvant chemotherapy was evaluated based on poorly differentiated cluster grade.
ResultsThirty-nine, 40 and 52 patients were classified as poorly differentiated cluster G1, G2 and G3, respectively. Significant differences in the 5-year cumulative recurrence rate and relapse-free survival were observed between poorly differentiated cluster G1/G2 and G3 (26.7% vs. 47.5%, P = 0.010; 66.0% vs. 43.9%, P = 0.004). A comparison of cumulative recurrence rate and relapse-free survival between the chemotherapy and surgery-alone groups showed a significant benefit of adjuvant chemotherapy in poorly differentiated cluster G1/G2 patients (cumulative recurrence rate: 17.4% vs. 37.3%, P = 0.035; relapse-free survival: 79.5% vs. 51.9%, P = 0.002), but not in poorly differentiated cluster G3 patients (cumulative recurrence rate: 48.6% vs. 44.8%, P = 0.885; relapse-free survival: 51.4% vs. 32.7%, P = 0.068).
ConclusionsIn stage III colorectal cancer, poorly differentiated cluster G1/G2 predicts a significant benefit from 5-fluorouracil-based adjuvant chemotherapy, whereas poorly differentiated cluster G3 predicts a poor response to it.
Impact of microscopic orbital periosteum invasion in orbital preservation surgery
ObjectiveThe orbital periosteum is considered to be a barrier to tumor spread; however, it is difficult to evaluate microscopic tumor spread during surgery. This study aimed to assess the impact of pathological status in orbital preservation surgery.
MethodsWe retrospectively analyzed the 3-year local control rate and treatment outcomes of patients with malignant tumors invading the orbit who were treated between 2006 and 2012.
ResultsIn total, 27 patients were reviewed over a median follow-up period of 36 months. Pathologically, 19 had carcinomas and 8 had sarcomas. Treatment was by orbital exenteration in 6 patients and orbital preservation surgery in 21 patients. After orbital preservation surgery, poorer 3-year local control rates were significantly associated with positive surgical margins (negative vs. positive: 91% vs. 41%, P = 0.040) and microscopic orbital periosteum invasion (negative vs. positive: 90% vs. 39%, P = 0.010). These factors were independent risk factors in multivariate analysis. The locations of the positive margin were most common at the horizontal and vertical margins of the orbital periosteum and the posterior margin of the orbital apex. Moreover, in 24% of patients, invasion evaluation by preoperative imaging study was underestimated compared with postoperative microscopic evaluation.
ConclusionsThe positive surgical margin and microscopic orbital periosteum invasion were the risk factors of orbital recurrence. It is difficult to determine the indications for orbital preservation surgery by preoperative imaging studies because of the unpredictable accurate pathological status before surgery and the limitations of preoperative imaging evaluation.
Surgery and imatinib therapy for liver oligometastasis of GIST: a study of Japanese Study Group on GIST
AbstractWe conducted a multicenter prospective study to clarify the efficacy and safety of surgery and imatinib for liver oligometastasis of gastrointestinal stromal tumors. Eligible gastrointestinal stromal tumor patients were enrolled in the surgery trial or the imatinib trial. Primary endpoints were recurrence-free survival and progression-free survival, respectively. The trials were prematurely terminated due to amendment of guidelines for adjuvant imatinib therapy and low patient accrual. In the surgery trial, all the six patients showed hepatic recurrence: median recurrence-free survival was 145 days (range: 62–1366 days). Of the five patients receiving salvage imatinib therapy, two showed progressive disease although no death was observed. Of the five patients enrolled in the imatinib trial, one died of pneumonia after progressive disease, and four had not shown progressive disease as of last visit. The results suggest that liver oligometastasis of gastrointestinal stromal tumor may not be controllable by surgery alone and require concomitant imatinib therapy.
Predictive factors of gastroduodenal bleeding after postoperative radiotherapy in biliary tract cancer
ObjectiveTo identify predictive factors for gastroduodenal bleeding after postoperative radiation therapy in patients with biliary tract cancer.
MethodsWe identified 186 patients with biliary tract cancer who completed scheduled postoperative radiation therapy from March 2000 to August 2013. To isolate the effects of radiation on gastroduodenal bleeding, patients with pylorus-preserving pancreaticoduodenectomy, pylorus-resecting pancreaticoduodenectomy or Whipple surgery (n = 67) were excluded from this analysis. Postoperative radiation therapy was started at a median 5 weeks (range: 4–12 weeks) after surgery with a median dose of 44 Gy (range: 44–54), and chemotherapy was also concurrently administered to 102 patients.
ResultsThe median age of the patients was 59 years (range: 36–76 years). Of the 119 patients, 26 had intrahepatic cholangiocarcinoma, 29 had hilar cholangiocarcinoma, while 64 had extrahepatic tumors (gallbladder cancer, n = 53; proximal bile duct cancer, n = 10; choledochal cyst cancer, n = 1). Of all, 11 patients (9%) developed gastroduodenal bleeding. In univariate analyses, hepatic artery resection and gastroduodenal wall thickening on postoperative radiation therapy simulation computed tomography were statistically significant factors for gastroduodenal bleeding. Multivariate analysis by a logistic regression model using those two variables revealed that both parameters were independent predictors for gastroduodenal bleeding.
ConclusionsConcomitant hepatic artery resection and presence of gastroduodenal wall thickening on postoperative radiation therapy simulation computed tomography were predictive factors for gastroduodenal bleeding after postoperative radiation therapy in biliary tract cancer. In such cases, patients should be informed of the high risk of gastroduodenal bleeding, and should be closely observed during and after postoperative radiation therapy.
A histological positive margin after surgery is correlated with high local re-recurrence rate in patients with recurrent myxofibrosarcoma
ObjectiveMyxofibrosarcoma has high frequency of local recurrence after surgery. To determine an optimal treatment for recurrent tumors, clinical features of recurrent cases should be characterized.
MethodsWe performed a retrospective analysis of 30 patients with recurrent myxofibrosarcoma who underwent surgery between 1999 and 2008.
ResultsA negative margin after surgery was achieved in only 12 patients (40.0%). The 5-year re-recurrence free-survival rate was 31.7%. The 5-year re-recurrence free survival for those with positive histological margin and those with negative margin were 9.8% and 62.3%, respectively, which indicated that a positive margin was the significant predictor of poor prognosis (P = 0.006). In 21 patients with recurrent myxofibrosarcoma in the extremities, 10 patients (47.6%) ultimately underwent amputation in the follow-up period and the 5-year amputation-free survival rate was 62.5%. The 5-year metastasis-free survival rates and the 5-year overall survival rates were 84.8% and 83.6%, respectively.
ConclusionsIn this study, the majority of recurrent cases could not achieve negative margins; notably, a positive margin is a significant poor prognostic indicator of local re-recurrence in patients with recurrent myxofibrosarcoma. To control local recurrence of myxofibrosarcoma was extremely difficult and amputation is often needed in the extremity cases.
Retrospective analysis of survival in patients with leptomeningeal carcinomatosis from lung adenocarcinoma treated with erlotinib and gefitinib
BackgroundLeptomeningeal carcinomatosis is a relatively rare metastatic form of non-small cell lung cancer, which can impact prognosis. There is an increasing need for selecting suitable epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors among those currently included in standard care for EGFR mutation-positive patients. We compared the efficacy of gefitinib and erlotinib in survival of patients with leptomeningeal carcinomatosis.
Patients and methodsThe medical records of 269 patients who received tyrosine kinase inhibitors at a single center were retrospectively reviewed. Overall, 22 patients (8.2%) were treated with tyrosine kinase inhibitors for leptomeningeal carcinomatosis from non-small cell lung cancer with EGFR mutation between 2006 and 2016. Time to death from leptomeningeal carcinomatosis diagnosis was compared between the gefitinib and erlotinib groups.
ResultsGefitinib and erlotinib were administrated to 5 and 17 patients, respectively. Median progression-free survival was longer in the erlotinib group than in the gefitinib group (6.60 vs 2.12 months, P = 0.07). Overall survival was more than twice as long in the erlotinib arm compared with that in the gefitinib arm (7.20 vs 2.99 months, P = 0.32). Response in patients with exon 19 deletion was better than in those with exon 21 mutation (overall survival, 7.20 and 5.62 months, respectively, P = 0.12).
ConclusionsErlotinib seemed more effective than gefitinib in prolonging survival in leptomeningeal carcinomatosis from EGFR mutation-positive non-small cell lung cancer and may be particularly beneficial in patients with EGFR exon 19 mutations, warranting further studies.
Epidemiology and treatment of hepatocellular carcinoma in Thailand
AbstractHepatocellular carcinoma (HCC) is the most frequent type of malignant liver tumor in Thailand. The high incidence rate of HCC reflects from chronic HBV infection in this endemic area. Some patients are asymptomatic at presentation whereas many of them presented at advanced stage of HCC with limited treatment options and grave outcome. The Barcelona Clinic Liver Cancer (BCLC) staging system and management allocation for HCC is widely accepted and used in many international guidelines including Thailand. Curative treatment is expected in early stage of HCC while palliative treatment, combination treatment and best supportive care are offered to advanced stage of HCC. The most effective strategy to prevent the development of HCC is prevention of HBV vertical transmission and treatment HBV or HCV infection. The purpose of this article is to update information of HCC in Thailand including epidemiology, diagnosis, clinical manifestation, and treatment.
A review of prognostic scores after liver resection in hepatocellular carcinoma: the MSKCC, SLICER and SSCLIP scores
AbstractPredicting prognosis in hepatocellular carcinoma (HCC) aids clinical decision-making and stratifies patient follow-up plans. There are currently three prognostic scores specific to liver resection of HCC published in the literature: the MSKCC, SLICER and SSCLIP scores. In this review, we highlight the methodology employed in the construction of these scores and discuss the strengths and weaknesses of each. Current limitations to prognostic scores include the inability to differentiate between early and late recurrences of HCC, the failure to account for the impact of aetiology of HCC and the assumption that ethnicity has no impact on disease process. Further scientific discoveries in these areas will allow for improvement in prognostication. The SLICER score is currently the most comprehensive. External validation of each score in cohorts of patients with different baseline demographics and clinical characteristics will be required to examine their stability and reliability.