Phase II study of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as second-line treatment for metastatic colorectal cancer and exploratory analysis of associations between DNA methylation status and the efficacy of the anti-EGFR antibody: T-CORE1201.

Background: Little is known about the biweekly combined use of cetuximab and chemotherapy as second-line treatment of metastatic colorectal cancer (mCRC). Recently, DNA methylation status has been reported to be a new possible predictor of the efficacy from the anti-epidermal growth factor receptor (EGFR) antibody treatment. The purpose of this study was to examine the efficacy and safety of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as a second-line treatment for KRAS exon 2 wild-type mCRC. We also investigated the predictability of DNA methylation status on the efficacy of the EGFR antibody-containing treatment. Methods: Patients who were refractory or intolerant to the first-line chemotherapy were enrolled and received biweekly cetuximab plus mFOLFOX6 or mFOLFIRI. The primary endpoint was progression-free survival (PFS). Tumor evaluations were performed every 2 months using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. DNA methylation status of colorectal cancer cells was defined by a modified MethyLight assay. Results: Sixty-six cases were enrolled. The median PFS (mPFS) was 5.1 [95% confidence interval (CI), 3.8-7.6] months. The median overall survival (mOS) was 12.7 (95% CI, 7.5-15.3) months. Grade 3 or higher neutropenia occurred in 53.0% of patients, whereas skin disorders with a grade 3 or higher occurred in <15% of patients. In multivariate analysis, DNA methylation status could not be an independent predictor of PFS [hazard ratio (HR), 1.43; P=0.39] and OS (HR, 2.13; P=0.086). However, in RAS/BRAF wild-type patients, the mPFS and mOS in the low-methylated colorectal cancer (LMCC) group was numerically better than those in the highly-methylated colorectal cancer (HMCC) group, although the difference was not statistically significant [mPFS: 8.5 (95% CI, 6.1-10.9) vs. 3.3 (95% CI, 1.2-not reached) months, P=0.79; ΔmPFS, 5.2 months; mOS: 15.3 (95% CI, 11.9-23.5) vs. 6.5 (95% CI, 3.1-not reached) months, P=0.53; ΔmOS, 8.8 months]. Conclusions: Biweekly cetuximab plus mFOLFOX6 or mFOLFIRI is a useful second-line therapy for mCRC. DNA methylation status warrants further exploration as a predictive biomarker for anti-EGFR efficacy in mCRC.

Correlation between overall survival and quality of life in colon cancer patients with chemotherapy.

BACKGROUND: Patients presenting with inoperable colon cancer at first onset (ICF) or at time of relapse (ICR) are considered in unrecoverable. The therapeutic goal for unrecoverable cancer is to prolong overall survival (OS) and maintain a high quality of life (QOL). As data on objective indicators of QOL in cancer patients, such as length of hospitalisation (LOH), outpatient consultation times (OCT), and hospital-free survival (HFS), is limited, this study compared ICF and ICR with respect to OS and QOL over the entire clinical course. METHODS: We retrospectively evaluated 90 inoperable colon cancer patients with chemotherapy and compared ICF and ICR in terms of OS, LOH, OCT, and HFS. RESULTS: Patients with ICF had a worse OS than those with ICR. In patients with ICF and ICR, OS and LOH were not correlated but OS and OCT and OS and HFS were strongly correlated. In patients with ICF and ICR, OCT and HFS accounted for approximately 8% and 90% of their OS, respectively. CONCLUSIONS: The LOH, OCT, and HFS are important factors for evaluating objective QOL of patients with inoperable colon cancer and should be considered when making treatment decisions.

Cisplatin Plus Capecitabine After Adjuvant S-1 in Metastatic Gastric Cancer: A Phase II T-CORE1102 Trial.

BACKGROUND/AIM: This phase II study assessed the efficacy of capecitabine plus cisplatin in patients with advanced gastric cancer refractory to adjuvant S-1. PATIENTS AND METHODS: This single-arm, open-label, multicenter, phase II study was conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE) in Japan. Patients aged ≥20 years with advanced HER2-negative gastric cancer that was refractory to S-1 were enrolled. Patients received 80 mg/m2 cisplatin on day 1 intravenously and 1,000 mg/m2 capecitabine twice daily from day 1 to day 14, in 3-week cycles. The primary endpoint was progression-free survival (PFS). The threshold overall response rate (ORR) was estimated to be 15%. The secondary endpoints were overall survival (OS), time to treatment failure, ORR, and toxicities. RESULTS: In total, 21 patients were enrolled from seven hospitals. The median patient age was 63 years. Nineteen patients received the protocol treatment. Median PFS was 3.7 months [90% confidence interval (CI)=2.7-5.6 months], which did not reach the predefined threshold of 4.0 months. ORR was 5.9% (95%CI=0.0-17.1%). Median OS was 11.9 months (95% CI 6.3-19.4 months). Febrile neutropenia was observed in 5.3% of patients. The most frequently observed grade 3 non-hematologic toxicities were nausea (15.8%) and hyponatremia (15.8%). CONCLUSION: The addition of a fluoropyrimidine to a platinum agent after adjuvant therapy is not suitable for gastric cancer.

The Appropriate First-Line Chemotherapy Regimen for Incurable Pancreatic Cancer in Clinical Practice: A Consideration of Patients' Overall Survival and Quality of Life.

Purpose: For incurable pancreatic cancer, the therapeutic goal is to prolong survival and maintain the quality of life (QOL). Unexpected outpatient consultation (OCT) and emergency hospitalization lead to QOL deterioration. The National Comprehensive Cancer Network (NCCN) guidelines recommend 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) and gemcitabine plus albumin-bound paclitaxel (nabPTX+GEM) as the preferred first-line regimens. Japanese clinical practice guidelines further recommend GEM and tegafur/gimeracil/oteracil potassium (S-1). Currently, no treatment strategy considers QOL at any stage during a patient's clinical course. Methods: In this study, hospital-free survival (HFS), defined as the period without hospitalization and OCT, was introduced as a new indicator of the qualitative aspect of overall survival (OS). We compared OS, length of hospitalization (LOH), OCT, and HFS for the four first-line chemotherapy groups. Results: No significant difference was observed in the median OS and HFS, nor was there a strong correlation between OS and LOH, based on the four first-line chemotherapy groups. In contrast, there were strong correlations between OS and OCT and between OS and HFS in all first-line chemotherapy groups. The ratio of OCT to OS was similar for mFOLFIRINOX and nabPTX+GEM. S-1 had the lowest OCT-to-OS ratio. The ratio of HFS to OS declined from highest to lowest in the order S-1, nabPTX+GEM, mFOLFIRINOX, and GEM. Conclusion: Our findings suggested existence of correlation differences between OS and HFS between first-line mFOLFIRINOX and first-line nabPTX+GEM. In addition, a good HFS was obtained with S-1 alone in some cases. In the future, clinical trials for chemotherapy should examine QOL during the entire clinical course.

Phase II Study of the Reuse of Trastuzumab with Docetaxel beyond Progression after First-Line Treatment in Second-Line Treatment for Unresectable, Metastatic Gastric Cancer (T-CORE1203).

Whether trastuzumab use beyond disease progression is beneficial in second-line treatment for patients with unresectable human epidermal growth factor receptor 2 (HER2)-positive gastric cancer remains to be elucidated. We conducted this phase II study to assess whether trastuzumab plus docetaxel was effective for patients with previously treated advanced HER2-positive gastric cancer. This trial was a single-arm, open-label, multicenter, phase II study, conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE). Patients aged 20 years or older who had advanced HER2-positive gastric cancer and were refractory to trastuzumab, fluoropyrimidine, and cisplatin were enrolled. Patients were treated with 6 mg/kg trastuzumab and 60 mg/m2 docetaxel every 3 weeks. The primary endpoint was the overall response rate. The threshold overall response rate was estimated to be at 15%. Secondary endpoints were progression-free survival, 6-month survival rate, overall survival, and toxicities. A total of 27 patients were enrolled from 7 hospitals. The median age was 67 years. Partial response was seen in 3 patients among the 26 evaluated patients. The overall response rate was at 11.5% (90% confidence interval 1.2%-21.8%). The median progression-free survival was 3.2 months, the 6-month survival rate was 85%, and the median overall survival was 11.6 months. Febrile neutropenia was observed in 14.8%. The most frequently observed grade 3 non-hematologic toxicity was anorexia (14.8%). The primary endpoint was not achieved. The results support a current consensus that the continuation of trastuzumab in second-line therapy for gastric cancer is not a recommended option.

Impact of palliative chemotherapy and best supportive care on overall survival and length of hospitalization in patients with incurable Cancer: a 4-year single institution experience in Japan.

BACKGROUND: This study aimed to analyze the determinants of patients' choice between palliative chemotherapy and best supportive care (BSC) and to investigate how this choice affects overall survival (OS) and length of hospitalization according to Eastern Cooperative Oncology Group (ECOG) performance status (PS). METHODS: An oncologist explained the palliative chemotherapy and BSC options to 129 patients with incurable cancer during their first consultation. Data on the ECOG PS, treatment decision, OS, and the length of hospitalization were retrospectively collected over 4 years. RESULTS: Patients with an ECOG PS of 0-2 chose palliative chemotherapy more often than those with an ECOG PS of 3-4 (P < 0.01). Patients with ≤70 years chose palliative chemotherapy more often than those with > 70 (P < 0.05). And patients with gastric cancer and colon cancer chose palliative chemotherapy more often than those with CUP (carcinoma of unknown primary) (P < 0.05, P < 0.05 respectively). Factors associated with a significantly poorer OS in an adjusted analysis included the ECOG PS and treatment decision (hazard ratios: 0.18 and 0.43; P < 0.001, P < 0.01 respectively). In patients with an ECOG PS of 0-2, palliative chemotherapy was not associated with a longer OS compared with BSC (median OS: 14.5 vs. 6.8 months, respectively; P = 0.144). In patients with an ECOG PS of 3-4, palliative chemotherapy resulted in a significant survival gain compared to with BSC (median OS: 3.8 vs. 1.4 months, respectively; P < 0.05). Strong positive correlations between OS and the length of hospitalization were observed in patients with an ECOG PS of 3-4 who underwent palliative chemotherapy (r2 = 0.683) and the length of hospitalization was approximately one-third of their OS. CONCLUSIONS: The determinants for treatment choice were age, ECOG PS and type of cancer, not sex difference. Oncologists should explain to patients that OS and the length of hospitalization vary according to the ECOG PS when selecting between palliative chemotherapy and BSC.

Patient perceptions of curability and physician-reported disclosures of incurability in Japanese patients with unresectable/recurrent cancer: a cross-sectional survey.

BACKGROUND: Although reports have described the perceptions of curability among patients with unresectable/recurrent cancer and the quality of death and dying, the association between patients' perceptions and physicians' disclosures of incurability remained unexplored. This survey aimed to evaluate the association between patients' perceptions of curability and physicians' disclosures of incurability. METHODS: In this cross-sectional, multicenter, observational study in Japan, we asked outpatients with unresectable/recurrent solid cancers about their perceptions of incurability. The patient inclusion criteria were unresectable/recurrent solid cancer, failure of first-line chemotherapy and an age ≥ 20 years. Additionally, we surveyed their primary responsible physicians regarding disclosures to patients regarding incurability. RESULTS: Although we estimated the necessary sample size as 250, we discontinued recruitment because the responsible researcher transferred to another hospital. Among the 135 included and surveyed patients, 39% responded that their cancer was incurable, 33% responded that their cancer was curable and 23% responded 'I don't know' or 'I don't wish to answer'. No significant association was observed between patients' perceptions of curability and physician-reported disclosures of incurability. CONCLUSION: In this Japanese population, 39% of patients with unresectable/recurrent solid cancers perceived that their cancers were incurable. However, such perceptions did not appear to be significantly affected by physician-reported disclosures. We recommend additional research to determine the best disclosure method to ensure that patients truly understand their disease status.

Intermittent Withdrawal of Oxaliplatin for Alleviating Neurotoxicity during Oxaliplatin-Based Chemotherapy for Japanese Patients with Inoperable or Metastatic Colorectal Cancer: A Phase 2 Multicenter Study.

Oxaliplatin-based chemotherapy is a well-established regimen for patients with inoperable and metastatic colorectal cancer. However, one of the major limitations of oxaliplatin-based chemotherapy is sensory neuropathy. It was previously reported that introduction of intermittent oxaliplatin treatment to an oxaliplatin-based regimen has a significant benefit on efficacy or safety. Here, we prospectively assessed whether efficacy and safety of first-line chemotherapy for advanced colorectal cancer are achieved by introduction of withdrawal of oxaliplatin treatment for a certain period (intermittent oxaliplatin treatment). The primary endpoint of the present study is to assess the progression free survival time on patients treated with chemotherapy (mFOLFOX6 (levofolinate, 5-fluorouracil and oxaliplatin combination therapy) plus bevacizumab or CapeOX (oxaliplatin and capecitabine combination therapy) plus bevacizumab) with intermittent oxaliplatin treatment. Bevacizumab is a humanized anti-vascular endothelial growth factor antibody. Median progression-free survival by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or the CapeOX plus bevacizumab with intermittent oxaliplatin treatment were 10.6 months (95% confidential interval [CI], 8.3-13.4 months) or 8.0 months (95% CI, 4.2-16.8 months), respectively. Overall response rate by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment was 55.1% or 42.1%, respectively. Grade 3 or 4 neuropathy was observed in 4.1% or 10.5% of patients treated with mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment, respectively. Introduction of intermittent oxaliplatin treatment has improved severe neuropathy in mFOLFOX6 plus bevacizumab regimen without reducing treatment efficacy.

[Tips on the use of granulocyte colony-stimulating factors in cancer patients predisposed to chemotherapy - induced febrile neutropenia].

Chemotherapy-induced febrile neutropenia(FN)is a major risk factor for severe infections, with a dose-limiting toxicity that necessitates dose reductions and/or delays in scheduled chemotherapy sessions. Therefore, the use of granulocyte colony- stimulating factors(G-CSF)is recommended in cancer patients at a risk of chemotherapy-induced FN. Three types of GCSF, filgrastim, lenograstim, and nartograstim, have been available thus far. The differences in potency and efficacy among these G-CSF needs to be thoroughly understood. Prophylactic G-CSF is recommended in patients receiving a chemotherapy regimen associated with a high risk(>20%)of FN. A chemotherapy regimen associated with intermediate risk(10-20%)of FN, requires particular attention to the neutrophil count and observation of symptoms of infection after chemotherapy. Prophylactic G-CSF could be included in subsequent chemotherapy regimens, if needed.

Safety verification trials of mFOLFIRI and sequential IRIS + bevacizumab as first- or second-line therapies for metastatic colorectal cancer in Japanese patients.

OBJECTIVE: S-1 is effective in sequential combination with irinotecan (IRIS) in treating metastatic colorectal cancer. We conducted a randomized phase II trial of modified leucovorin, fluorouracil and irinotecan (mFOLFIRI) + bevacizumab and sequential IRIS + bevacizumab as first- or second-line therapies. METHODS: Sixty metastatic colorectal cancer patients were randomly assigned to receive mFOLFIRI + bevacizumab or sequential IRIS + bevacizumab (7.5 mg/kg of bevacizumab and 150 mg/m(2) of irinitecan, and 80 mg/m(2)/day of S-1 orally from day 3 until day 16 as a 3-week course). The primary endpoint was the safety of each method until week 12, with the secondary endpoint being the comparison of the safety and efficacy of the two methods. RESULTS: The safety of the two treatments was comparable, except that G3 anorexia and diarrhoea were less frequent with sequential IRIS + bevacizumab. The overall response rate was 62% [95% confidence interval (CI) 40.1-79.8] versus 72% (95% CI 50.6-86.2), and progression-free survival was 324 days (95% CI 247-475) versus 345 days (95% CI 312-594) with mFOLFIRI + bevacizumab versus IRIS + bevacizumab, respectively. CONCLUSION: Sequential IRIS + bevacizumab is a safe and effective method of systemic chemotherapy against metastatic colorectal cancer and is compatible with mFOLFIRI + bevacizumab.

Understanding the concept of a 'good death' in Japan: differences in the views of doctors, palliative and non-palliative ward nurses.

AIM: Achieving a 'good death' is the ultimate goal for medical staff caring for terminally ill cancer patients, but the exact definition of a 'good death' is subject to interpretation. This exploratory study investigates the differences in how Japanese cancer care staff perceive a 'good death' by using factor analysis. METHOD: Participants included doctors, palliative and non-palliative ward nurses working in Miyagi Cancer Center, Natori, Japan. The various components of a 'good death' for cancer patients have been identified in a previous Japanese study. In the present study, respondents were asked to state the percentages of patients for which the component had been achieved, the extent to which the respondent contributed to achieving the component, and the concrete means they would use to ensure that patients were free from psychological distress and prepared for dying. RESULTS: Medical staff had largely similar views on the percentage of patients for which a component of 'good death' was achieved. All the achievement ratings determined in the present study were considerably lower than the necessity ratings given by non-medical staff in a previous study. There were differences among medical staff with respect to their contribution to achieving a component of 'good death' and the concrete means they would use to achieve a 'good death'.

[Clinical characteristics of cancer of unknown primary (CUP)--a summary of 22 cases].

Cancer of unknown primary site (CUP) is not a rare entity and accounts for 3-5% of all malignant neoplasias. CUPs are diagnosed with metastatic lesion so they are all in the advanced stage. Systemic chemotherapy is applied in many cases, but the ideal therapeutic strategy has not yet been determined. CUP shows much histological and therapeutic heterogeneity. Histologically, half of CUPs are adenocarcinoma and the rest are undifferentiated carcinomas. We analyzed the clinical and therapeutic characteristics 22 cases of CUP patients. Most CUP patients are found from lymph node swelling. There is no significant tendency as to the site of lymph node metastasis. Bone metastases are frequently encountered. It seems undifferentiated carcinomas are more responsive to chemotherapy. Chemo-sensitive patients are likely to have a longer life expectancy. In our experience all of the chemo-responsive cases are treated with platinum-based chemotherapy. Today several platinum-based combination chemotherapies are reported, but there is no large-scale randomized study. Because of its variety, individualized therapy may be ideal for CUP.

Evaluation of hematological reconstitution potential of autologous peripheral blood progenitor cells cryopreserved by a simple controlled-rate freezing method.

A novel and simple procedure for the controlled-rate cryopreservation of peripheral blood progenitor cells (PBPCs) was introduced. A freezing bag housed in a protective aluminum canister was placed on top of a styrene foam box in the -85 degrees C electric freezer. A second set of samples was kept in cryotubes placed in a double styrene foam box in the same electric freezer. Measurement of the freezing rate in the PB bags and cryotubes demonstrated that this simple method for PBPC cryopreservation provided optimal conditions for both large-scale and small-scale cryopreservation. Within several days after autologous peripheral blood stem cell transplantation, we thawed the cells in the small sample tubes and evaluated the cell viability, the cell recovery, and the recovery rates of hematopoietic progenitor cells (HPCs), such as CD34+ cells and colony-forming unit-granulocyte/macrophage (CFU-GM) colonies. The median duration of cryopreservation was 59 days (range, 14-365 days). According to our analysis, infusions of more than 2 x 10(6) CD34+ cells/kg body weight and 0.5 x 10(6) CFU-GM colonies/kg body weight after thawing had favorable influences on the neutrophil engraftment. We have therefore established a simple freezing method for cryopreservation of human PBPCs, which ensures the transplantability of hematopoietic progenitors even after thawing. In vitro HPC assay after thawing is important to evaluate the quality of cryopreservation procedures.

A novel germline mutation of the LKB1 gene in a patient with Peutz-Jeghers syndrome with early-onset gastric cancer.

The gene responsible for Peutz-Jeghers syndrome (PJS), LKB1 (also called STK11) was mapped to chromosome 19p13.3 and was found to encode a putative serine/threonine protein kinase, LKB1. As only a limited number (approximately 100) of germline mutations of the gene have been reported, and because the protein function is still unclear, information about LKB1 mutations and their expression should be accumulated to understand the phenotype-genotype correlation of this disease. Here we report a patient with sporadic PJS with early-onset gastric cancer. We found a novel germline frameshift mutation (757-758insT) in the LKB1 gene and a marked reduction in LKB1 protein expression in the carcinoma cells, suggesting that the loss of LKB1 function may have led to the carcinogenesis of the gastric cancer.

The absolute number of peripheral blood CD34+ cells predicts a timing for apheresis and progenitor cell yield in patients with hematologic malignancies and solid tumors.

Retrospective analysis was conducted in 51 autologous peripheral blood progenitor cell (PBPC) collections using the Spectra AutoPBSC System from patients with hematologic malignancies and solid tumors to study the predictive value of CD34+ cell counts in the peripheral blood for the yield of CD34+ cells in the apheresis product. The correlation coefficients for CD34+ cells microL(-1) of peripheral blood with CD34+ cell yield (x 10(6) kg(-1) of body weight and x 10(5) kg(-1) of body weight L(-1) of blood processed) were 0.903 and 0.778 (n=51 collections), respectively. Products collected from patients with CD34+ cell counts below 15 microL(-1) in the peripheral blood contained a median of 0.49 x 10(6) CD34+ cells kg(-1) (range: 0.05-2.55), whereas those with CD34+ cell counts more than 15 microL(-1) contained a median of 3.72 x 10(6) CD34+ cells kg(-1) (range: 1.06-37.57). From these results, a number of at least 15 CD34+ cells microL(-1) in the peripheral blood ensured a minimum yield of 1 x 10(6) CD34+ cells kg(-1) as obtained by a single apheresis procedure. The number of CD34+ cells in the peripheral blood can be used as a good predictor for timing of apheresis and estimating PBPC yield. With regard to our results, apheresis with a possibly poor efficiency should be avoided because the collection procedure is time-consuming and expensive.

Alpha-FP normalization as a prognostic factor for mediastinal origin embryonal carcinoma: report of five cases.

It is well known that a subgroup of germ cell tumors, embryonal carcinoma of extra-gonadal origin have a poor prognosis. We have encountered five cases of mediastinal embryonal carcinoma treated with high-dose chemotherapy (HD-CT) supported by auto-PBSCT in four, and resection in three. Our cases indicated that normalization of the alpha-FP tumor marker level during standard chemotherapy is a very important factor for cure, and the resection of the residual mass after chemotherapy is indicated due to the great risk of remnant malignant cells despite HD-CT.