Joint Symposium of Korean Cancer Association & UICC-ARO-Cross-boundary cancer studies: cancer and Universal Health Coverage (UHC) in Asia.

On 16 June 2016, the Korean Cancer Association (KCA) and Union for International Cancer Control-Asia Regional Office (UICC-ARO) organized a joint symposium as part of the official program of the 42nd Annual Meeting of the Korean Cancer Association to discuss the topic 'Cross-boundary Cancer Studies: Cancer and Universal Health Coverage (UHC) in Asia.' Universal Health Coverage is included in the Sustainable Development Goals adopted by the United Nations as part of the 2030 Agenda for Sustainable Development. The objectives of UHC are to ensure that all people can receive high-quality medical services, are protected from public health risks, and are prevented from falling into poverty due to medical costs or loss of income arising from illness. The participants discussed the growing cost of cancer in the Asian region and the challenges that this poses to the establishment and deployment of UHC in the countries of Asia, all of which face budgetary and other systemic constraints in controlling cancer in the region. Representatives from Korea, Japan and Indonesia reported on the status of UHC in their countries and the challenges that are being faced, many of which are common to other countries in Asia. In addition to country-specific presentations about the progress of and challenges facing UHC, there were also presentations from WHO Kobe Centre concerning advancing UHC in non-communicable diseases and prospects for further collaboration and research on UHC. A presentation from the University of Tokyo also highlighted the need to focus on multidisciplinary studies in an age of globalization and digitization.

UICC International Session: What are the implications of sharing the concept of Universal Health Coverage for cancer in Asia?

The Japan National Committee for the Union for International Cancer Control (UICC) and UICC - Asia Regional Office organized an international session as part of the 74th Annual Meeting of the Japanese Cancer Association on the topic "What are the implications of sharing the concept of Universal Health Coverage for cancer in Asia?" Universal Health Coverage (UHC) is included in the United Nations' Sustainable Development Goals and aims to ensure that all people can receive high-quality medical services, are protected from public health risks, and are prevented from falling into poverty due to medical costs or loss of income arising from illness. The session discussed the growing cost of cancer and the challenges that this poses to the establishment and deployment of UHC in the Asian region, where countries face budgetary and other systemic constraints in tackling and controlling cancer. It was noted how sharing concepts on UHC will assist mutual learning among Asian countries and help in the formation of guidelines that can be adapted to national and regional realities. Presentations included a status report on UHC for cancer control in Thailand, and a report from the WHO Kobe Centre concerning prospects for collaborative research on UHC. Also discussed were the current status of cancer burden and control in China and Korea and Japan's progress in systemizing cost-effectiveness evaluation. The final presentation highlighted the importance of gathering social and economic data across Asia in order to build a picture of commonalities and differences in the region.

Leiomyosarcoma: investigation of prognostic factors for risk-stratification model.

BACKGROUND: We performed this study to define distinctive clinical features of leiomyosarcoma by assessing prognostic factors. METHODS: Between 1988 and 2011, 129 leiomyosarcoma patients who underwent surgical resection with curative intent were retrospectively reviewed. RESULTS: Of the 129 leiomyosarcoma patients, the distribution of anatomic locations was: extremity (n = 25), pelvis (n = 40), thoracic cavity (n = 11), intra-abdomen (n = 19), retroperitoneum (n = 23), and head/neck (n = 11). We classified the anatomic locations into two categories as abdominal (intra-abdomen and retroperitoneum, n = 42) and extra-abdominal (extremity, pelvis, thoracic cavity, and head/neck, n = 87). Prognosis was worse for the abdominal group than for the extra-abdominal group (median DFS 2.9 9.0 years, P = 0.04). Similarly, overall survival (OS) was also significantly worse for abdominal group (P = 0.027). Independent prognostic factors for survival were primary site (P = 0.041, hazard ratio (HR) 1.7; 95 % CI 1.2-2.8), tumor size (P = 0.038, HR 1.9; 95 % CI 1.13-3.38), margin status (P = 0.019, HR 2.1; 95 % CI 1.13-3.88), and histology grade (P = 0.01, HR 3.59; 95 % CI 1.64-7.87). We identified four different risk groups with different survival outcome: group 1 (n = 8), no adverse factors; groups 2 (n = 37) and 3 (n = 61) with one and two adverse factors, and group 4 (n = 23) with 3 or 4 adverse factors. CONCLUSION: Primary site, tumor size, resection margin, and histology subtype were independently associated with survival outcome. A prognostic model for leiomyosarcoma patients revealed four distinct groups of patients with good prognostic discrimination.

Vascular soft-tissue sarcomas: a prognostic model from a retrospective single-center study.

BACKGROUND: Vascular soft-tissue sarcomas are a rare form of sarcoma. Malignant subtypes exhibit a variety of biological behaviors. We describe the clinicopathological characteristics and patient survival outcomes of malignant vascular soft-tissue sarcomas. METHODS: We conducted a retrospective study on a cohort of 84 patients diagnosed with vascular tumors by histological examination at the Yonsei University College of Medicine between April 1987 and August 2011. The primary end point was overall survival (OS). RESULTS: The angiosarcoma patients had a significantly shorter OS than the patients with other subtypes of sarcomas (59.0 and 142.7 months, respectively; p < 0.001). Upon multivariate analysis of survival in patients who underwent surgical resection, the following independent prognostic factors were identified: primary site (trunk, p = 0.001), age (older than 65 years, p < 0.001), pathology (angiosarcoma, p = 0.006) and R2 resection (p = 0.002). CONCLUSION: The independent prognostic factors for shorter survival are the trunk as the primary site, malignant angiosarcoma and age (>65 years). Complete excision should be attempted for providing a survival advantage in the patients with localized disease. In addition, bleeding episodes are much more frequent in patients with a poor survival outcome.

Union for International Cancer Control International Session: healthcare economics: the significance of the UN Summit non-communicable diseases political declaration in Asia.

The Japan National Committee for the Union for International Cancer Control (UICC) and UICC-Asia Regional Office (ARO) organized an international session as part of the official program of the 71st Annual Meeting of the Japanese Cancer Association to discuss the topic "Healthcare Economics: The Significance of the UN Summit non-communicable diseases (NCDs) Political Declaration in Asia." The presenters and participants discussed the growing cost of cancer in the Asian region and the challenges that are faced by the countries of Asia, all of which face budgetary and other systemic constraints in tackling and controlling cancer in the region. The session benefited from the participation of various stakeholders, including cancer researchers and representatives of the pharmaceutical industry. They discussed the significance of the UN Political Declaration on the prevention and control of NCDs (2011) as a means of boosting awareness of cancer in the Asian region and also addressed the ways in which stakeholders can cooperate to improve cancer control and treatment. Other issues that were covered included challenges relating to pharmaceutical trials in Asia and how to link knowledge and research outcomes. The session concluded with the recognition that with the onset of a super-aged society in most countries in Asia and an increasing focus on quality of life rather than quantity of life, it is more important than ever for all stakeholders to continue to share information and promote policy dialogue on cancer control and treatment.

Prognostic value of mucinous histology depends on microsatellite instability status in patients with stage III colon cancer treated with adjuvant FOLFOX chemotherapy: a retrospective cohort study.

BACKGROUND: The close association between mucinous histology and microsatellite instability (MSI) may have hindered the evaluation of prognostic significance of mucinous histology. The aim of this retrospective study was to investigate whether mucinous histology was associated with a worse prognosis, independent of MSI status, compared to nonmucinous histology in patients with stage III colon cancer. METHODS: This study enrolled 394 consecutive patients with stage III colorectal cancer treated with adjuvant FOLFOX after curative resection (R0). Clinicopathological information was retrospectively reviewed. Tumors were analyzed for MSI by polymerase chain reaction to determine MSI status. Kaplan-Meier method, log-rank test, and Cox proportional hazard regression models were used. RESULTS: The estimated rate of 3-year disease-free survival (DFS) in patients with nonmucinous adenocarcinoma (NMA 79.2 %) was significantly greater than that in patients with mucinous adenocarcinoma (MA) and adenocarcinoma with mucinous component (MC) (56.9 %; log-rank, P = 0.002). In univariate analysis, histology (NMA vs. MA/MC), American Joint Committee on Cancer stage (IIIA, IIIB, and IIIC), and lymphovascular invasion (present vs. absent) were significantly associated with DFS. In multivariate analysis, mucinous histology (MA/MC) was associated with decreased DFS in all patients (hazard ratio 1.82, 95 % confidence interval 1.03-3.23, P = 0.0403). In patients with MA/MC, no difference in DFS was observed between MSI and microsatellite stability (log-rank, P = 0.732). CONCLUSIONS: Mucinous histology is an independent poor prognostic factor for DFS in patients with stage III colon cancer after adjuvant FOLFOX chemotherapy.

Application of the adjuvant! Online model to Korean breast cancer patients: an assessment of prognostic accuracy and development of an alternative prognostic tool.

BACKGROUND: Adjuvant! Online (AOL) is a Web-accessible risk-assessment model that predicts the mortality and the benefits of adjuvant therapy for breast cancer. METHODS: Using the Yonsei Tumor Registry database, patients with T1-3, N0-3, M0 breast cancer who were treated at the Yonsei Cancer Center between 1986 and 1999 were entered into AOL version 8.0 to calculate survival. RESULTS: The median age of the study population was 45 years (range, 23-76 years) and the median follow-up duration was 10.8 years (range, 0.1-25.9 years) for all 699 patients. AOL significantly overestimated overall survival (OS) (by 11.1 %, P < 0.001), breast cancer-specific survival (BCSS) (by 11.6 %, P < 0.001), and event free-free survival (EFS) (by 9.25 %, P < 0.001) in Korean patients. Therefore, we developed a Korean version of AOL (KAOL), which is a new model for prognosis based on AOL's parameters. The observed 10-year OS (61.4 %), BCSS (62.3 %), and EFS (59.1 %) and the KAOL predicted OS (61.5 %), BCSS (63.5 %) and EFS (57.6 %) were not different (P = 0.976, P = 0.771, and P = 0.674, respectively). CONCLUSIONS: AOL was not found to be suitable in Korean patients with breast cancer. The newly developed KAOL accurately predicted 10-year outcomes in Korean breast cancer patients.

Circulating vascular endothelial growth factor receptor 2/pAkt-positive cells as a functional pharmacodynamic marker in metastatic colorectal cancers treated with antiangiogenic agent.

OBJECTIVE: The anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has received considerable attention as a first-line treatment of advanced colorectal cancers. Difficulties associated with effectively monitoring the activity of this drug have prompted us to seek a pharmacodynamic marker suitable for defining the optimum biological dose and schedule of bevacizumab administration against colon cancer in early clinical trials. METHODS: We evaluated inhibitory effects of bevacizumab on VEGF signaling and tumor growth in vitro and in vivo, and assessed phosphorylation of VEGF receptor 2 (VEGFR2) and downstream signaling in endothelial cells as pharmacodynamic markers using phospho-flow cytometry. We also validated markers in patients with metastatic colorectal cancer (mCRC) treated with bevacizumab-based chemotherapy. RESULTS: In in vitro studies, bevacizumab inhibited proliferation of human umbilical vein endothelial cells in association with reduced VEGF signaling. Notably, bevacizumab inhibited VEGF-induced phosphorylation of VEGFR-2, Akt, and extracellular signal-regulated kinase (ERK). In vivo, treatment with bevacizumab inhibited growth of xenografted tumors and attenuated VEGF-induced phosphorylation of Akt and ERK. The median percentages of VEGFR2 + pAkt + and VEGFR2 + pERK + cells, determined by phospho-flow cytometry, were approximately 3-fold higher in mCRC patients than in healthy controls. Bevacizumab treatment decreased VEGFR2 + pAkt + cells in 18 of 24 patients on day 3. CONCLUSION: Bevacizumab combined with chemotherapy decreased the number of VEGFR2 + pAkt + cells, reflecting impaired VEGFR2 signaling. Together, these data suggest that changes in the proportion of circulating VEGFR2 + pAkt + cells may be a potential pharmacodynamic marker of the efficacy of antiangiogenic agents, and could prove valuable in determining drug dosage and administration schedule.

Estimating the adjuvant chemotherapy effect in elderly stage II and III colon cancer patients in an observational study.

PURPOSE: Adjuvant chemotherapy has been known as a standard treatment for patients with resected colon cancer. However, in elderly colon cancer patients, the characteristics of patients are heterogeneous with regard to life expectancy and comorbidities. Thus, with regard to the effectiveness of adjuvant chemotherapy for colon cancer, it is difficult to extrapolate data of clinical trials from the younger into the older general population. METHODS: Data for 382 elderly colon cancer patients were analyzed: 217 in Stage II and 165 in Stage III. The efficacy of adjuvant chemotherapy was evaluated in elderly colon cancer patients after a match by the propensity score method. RESULTS: For matched patients with Stage II colon cancer, there was no significant efficacy of adjuvant chemotherapy in the risk of death during all follow-up periods (P-value, 0.06-0.37). Though there was a tendency that the adjuvant chemotherapy reduces the death rate during the follow-up periods, it was not statistically significant. In the case of Stage III, the adjuvant chemotherapy was significantly effective in matched patients for 5-year (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.30-0.90) and overall survival (HR, 0.56; 95% CI, 0.34-0.94). CONCLUSIONS: Adjuvant chemotherapy for elderly patients with Stage II colon cancer is not effective, whereas elderly patients with Stage III with adjuvant chemotherapy appear to have a better survival rate in the general population.

Randomized controlled trial of standardized education and telemonitoring for pain in outpatients with advanced solid tumors.

PURPOSE: Previous studies have not defined the role of telemonitoring with educational tools in outpatients with advanced cancers. We tested the effectiveness of standardized education and telemonitoring for improving pain, distress, anxiety, depression, quality of life (QoL), and performance in outpatients with advanced cancers. METHODS: A total of 108 patients were randomly assigned to receive pain education alone (control arm) or pain education plus telemonitoring (experimental arm). Nursing specialists provided video-assisted educational material in both arms and daily telemonitoring for the first week in the experimental arm. Assessment was performed at baseline and 1 week and included evaluations of pain (Brief Pain Inventory, BPI), distress (Distress Thermometer, DT), anxiety, and depression (Hospital Anxiety and Depression Scale, HADS), QoL (QLQ-C30), and a Karnofsky score. RESULTS: Overall (n = 108), pain intensity was significantly improved at 1 week, including worst pain (7.3 to 5.7, P < 0.01) and average pain (4.6 to 3.8, P < 0.01). Additionally, anxiety (HADS score ≥ 11, 75% to 56%, P < 0.01), depression (HADS score ≥ 11, 73% to 51%, P < 0.01), QoL (fatigue and insomnia), and the Karnofsky score (32 to 66, P < 0.01) were also significantly improved at 1 week. However, the level of distress did not improve. The telemonitoring plus standardized education group showed more significant improvement in portion of pain >4 on VAS scale (35% vs. 19%, P = 0.02). CONCLUSIONS: Standardized pain education using nursing specialists is an efficient way to improve not only pain itself but also anxiety, depression, performance, and QoL. The addition of telemonitoring helps to improve pain management in the outpatient setting.

Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.

BACKGROUND: We investigated the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer and sought associations between the mutation status of the KRAS gene in tumors and clinical response to cetuximab. METHODS: We randomly assigned patients with epidermal growth factor receptor-positive colorectal cancer with unresectable metastases to receive FOLFIRI either alone or in combination with cetuximab. The primary end point was progression-free survival. RESULTS: A total of 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone. The hazard ratio for progression-free survival in the cetuximab-FOLFIRI group as compared with the FOLFIRI group was 0.85 (95% confidence interval [CI], 0.72 to 0.99; P=0.048). There was no significant difference in the overall survival between the two treatment groups (hazard ratio, 0.93; 95% CI, 0.81 to 1.07; P=0.31). There was a significant interaction between treatment group and KRAS mutation status for tumor response (P=0.03) but not for progression-free survival (P=0.07) or overall survival (P=0.44). The hazard ratio for progression-free survival among patients with wild-type-KRAS tumors was 0.68 (95% CI, 0.50 to 0.94), in favor of the cetuximab-FOLFIRI group. The following grade 3 or 4 adverse events were more frequent with cetuximab plus FOLFIRI than with FOLFIRI alone: skin reactions (which were grade 3 only) (in 19.7% vs. 0.2% of patients, P<0.001), infusion-related reactions (in 2.5% vs. 0%, P<0.001), and diarrhea (in 15.7% vs. 10.5%, P=0.008). CONCLUSIONS: First-line treatment with cetuximab plus FOLFIRI, as compared with FOLFIRI alone, reduced the risk of progression of metastatic colorectal cancer. The benefit of cetuximab was limited to patients with KRAS wild-type tumors. (ClinicalTrials.gov number, NCT00154102.)

A phase I pharmacokinetic study of TSU-68 (a multiple tyrosine kinase inhibitor of VEGFR-2, FGF and PDFG) in combination with S-1 and oxaliplatin in metastatic colorectal cancer patients previously treated with chemotherapy.

TSU-68 is a novel multiple tyrosine kinase inhibitor that inhibits VEGFR-2, FGF and PDGF receptors. We conducted a phase I study to evaluate the safety and pharmacokinetic of TSU-68 when used with S-1 and oxaliplatin (SOX) in metastatic colorectal cancer (mCRC) patients. Patients with mCRC were treated with TSU-68 200 mg (Level 1) or 400 mg (Level 2) b.i.d. daily, S-1 35 mg/m(2) b.i.d. on Days 1-14 and oxaliplatin 130 mg/m(2) i.v. on Day 1 repeatedly every 3 weeks. Of eleven patients enrolled, two patients were excluded from dose limiting toxicity (DLT) assessment. Six patients at Level 1 experienced no DLT. Of three patients at Level 2, two patients experienced DLTs (one patient: grade 3 hiccup and palmar-plantar erythrodysaesthesia syndrome, another one: grade 2 neutropenia which prevented the initiation of next cycle within 14 days). The maximal tolerated dose (MTD) and recommended dose (RD) of TSU-68 was 200 mg b.i.d. C(max) and AUC(0-t) of TSU-68 at Level 2 were higher than those at Level 1, but doubling the dose of TSU-68 increased C(max) and AUC(0-t) less than two-fold. There was no appreciable difference in the PK of S-1 components (FT, CDHP and Oxo), 5-FU and oxaliplatin-derived platinum between Levels 1 and 2. A significant decrease in PDGF after TSU-68 treatment was identified and it might serve as pharmacodynamic marker of TSU-68. Administration of TSU-68 in combination with SOX is generally well tolerated. The MTD and RD of TSU-68 in this study was 200 mg b.i.d. daily.

A Phase Ib pharmacokinetic study of the anti-angiogenic agent CKD-732 used in combination with capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer patients who progressed on irinotecan-based chemotherapy.

BACKGROUND: We conducted a Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics (PK) of CKD-732 [6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate] in combination with capecitabine and oxaliplatin (XELOX) in nine metastatic colorectal cancer patients who had progressed on irinotecan-based chemotherapy. METHODS: Using a dose-escalation schedule, CKD-732 doses of 2, 5, or 10 mg/m(2)/d were administered twice weekly for 2 weeks, followed by a 1-week rest. Oxaliplatin (130 mg/m(2)) was administered on day 1, and capecitabine (1,000 mg/m(2) twice a day) was orally administered for 14 days of a 3-week cycle. RESULTS: In the group given the 10 mg/m(2)/d dose, two patients experienced dose limiting toxicities (one had grade 3 nausea, insomnia, and fatigue; the other had grade 3 insomnia). The maximum tolerated dose was 10 mg/m(2)/d, and the clinically recommended dose was 5 mg/m(2)/d for CKD-732 in combination with XELOX. Frequently encountered non-hematological grade 3/4 adverse events included insomnia (22.2%), fatigue (11.1%), sensory neuropathy (11.1%), hyperbilirubinemia (11.1%), and dyspnea (11.1%). The area under the concentration-time curve and maximum concentration of CKD-732 increased in a dose-dependent manner. There were no notable effects of CKD-732 on the PK of capecitabine and oxaliplatin-derived platinum. CONCLUSION: The Phase II recommended dose of CKD-732 was determined to be 5 mg/m(2)/d, and this dose was safely combined with a conventional dose of capecitabine and oxaliplatin in this patient population. Further studies on the effects of CKD-732 in combination with XELOX and other chemotherapies using a larger study population are warranted.

Application of the Western-based adjuvant online model to Korean colon cancer patients; a single institution experience.

BACKGROUND: Adjuvant Online (AOL) is web-accessible risk-assessment model that predicts the mortality and the benefits of adjuvant therapy (http://www.newadjuvantonline.com). AOL has never been validated for Asian colon cancer patients. METHODS: Using the Yonsei Tumor Registry database, patients who were treated within the Yonsei University Health System between 1990 and 2005 for T1-4, N0-2, and M0 colon cancer were included in the calculations for survival. Observed and predicted 5-year overall survival was compared for each patient. RESULTS: The median age of the study population of 1431 patients was 60 years (range, 15-87 years), and the median follow-up duration was 7.9 years (range, 0.06-19.8 years). The predicted 5-year overall survival rate (77.7%) and observed survival (79.5%) was not statistically different (95% Confidential interval, 76.3-81.5) in all patients. Predicted outcomes were within 95% confidential interval of observed survival in both stage II and III disease, including most demographic and pathologic subgroups. Moreover, AOL more accurately predicted OS for patients with stage II than stage III. CONCLUSIONS: AOL tended to offer reliable prediction for 5-year overall survival and could be used as a decision making tool for adjuvant treatment in Korean colon cancer patients whose prognosis is similar to other Asian patients.

The eighth Asia cancer forum: seeking to advance the outcomes of the UN summit: 'global health as the key to a new paradigm in cancer research'.

To date, the Asia Cancer Forum has focused its efforts on creating a common concept for collaborative efforts in international cancer research with a focus on Asia, where cancer incidence is rising dramatically, and also sharing information and knowledge among cancer specialists about the importance of cancer as a global health agenda issue. The Eighth Asia Cancer Forum was held following the historic outcome of the High-level Meeting of the United Nations General Assembly on the Prevention and Control of Non-communicable Diseases held in New York in September 2011, at which cancer was duly recognized as a global health agenda issue. Despite this significant development, however, the issue of cancer, one of the most intractable of all non-communicable diseases, still faces a variety of challenges if it is to be addressed on the global level. The Eighth Asia Cancer Forum sought to address these various issues, seeking ways to capitalize on the outcomes of the UN Meeting and take global collaborative studies and alliances in the field of cancer further. It was recognized that one of the main challenges for the Asia Cancer Forum is to formulate a proposal that demonstrates how middle-income countries can provide a good level of care using only their own limited medical resources. Given that the Asia Cancer Forum is one of the organizations that can provide assistance in working to further boost awareness about cancer research and the situation relating to cancer in Asian countries, discussion also focused on how to concretize activities in the future.

Methylation status of lamin A/C in gastric cancer cell lines.

BACKGROUND/AIMS: Epigenetic regulations play a role in the development and progression of cancer. Therefore, discovering novel epigenetically regulated genes could provide useful information in understanding cancer. Lamin A/C is an intermediate filament protein whose expression is reported to be suppressed in tissues of gastro-intestinal malignancies. We examined expression of lamin A/C in gastric and colorectal cancer cell lines and its association with DNA methylation. METHODOLOGY: The methylation status of CpG island in 19 gastric, 5 colorectal cancer cells and 1 normal colon cell line were examined with methylation-specific PCR using paired methylated and unmethylated primers. The level of mRNA expression of lamin A/C was detected using RT-PCR. RESULTS: Eighteen gastric cancer cell lines showed 95% unmethylation of lamin A/C and 1 cell line showed partial methylation. In colorectal cancer, only 1 out of 5 cancer cell lines (20%) was partially methylated and the remaining cell lines, including 1 normal colon cell line was unmethylated. With RT-PCR, all cell lines demonstrated mRNA expression of lamin A/C regardless of methylation status. CONCLUSIONS: We observed that the expression of lamin A/C was not suppressed in gastrointestinal cancer cell lines different from hematologic malignant cells and it is not regulated through DNA methylation.

Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study.

BACKGROUND: Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting. METHODS: Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT00148798. FINDINGS: KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17·5 months [95% CI 11·7-23·4] vs 8·5 months [7·1-10·8], hazard ratio [HR] 0·52 [0·32-0·84], p=0·0063; chemotherapy alone: 23·8 months [15·2-not reached] vs 10·0 months [8·7-11·0], HR 0·35 [0·21-0·59], p<0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11·4 months [8·6-13·6] vs 6·8 months [5·9-12·7], HR 0·80 [0·55-1·16], p=0·24; chemotherapy alone: 11·0 months [9·2-12·6] vs 9·3 months [7·6-11·9], HR 0·77 [0·54-1·10], p=0·16). INTERPRETATION: The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed. FUNDING: Merck KGaA.

Phase II trial of S-1 monotherapy in elderly or frail patients with metastatic colorectal cancer.

A phase II study was conducted to evaluate S-1 monotherapy in previously untreated elderly or frail metastatic colorectal cancer patients. A total of 48 elderly (70-85 years old) and frail [Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 and 65-69 years old] patients were eligible for first-line S-1 of 35 mg/m(2) given twice daily for 2 weeks followed by 1 week of rest. The overall response rate (ORR) for all patients was 19%. Similarly, the ORR for frail and elderly patients was 22% and 18%, respectively. Median progression-free survival (PFS) and overall survival (OS) for all patients were 3.9 months (95% CI, 3.0-4.8) and 11.3 months (95% CI, 7.4-15.2), respectively. For frail patients, PFS was 1.4 (95% CI, 0.8-2.0) vs. 4.3 months (95% CI, 3.0-5.4) for the elderly (P = 0.016). OS was significantly longer for elderly patients than for frail patients (13.1 months, 95% CI, 9.5-16.7) vs. (4.1 months, 95% CI, 3.2-5.0; P = 0.01). Toxicity was mild to moderate, as only 29% of patients experienced grade 3 toxicity. Grade 4 toxicity and febrile neutropenia did not occur; however, two frail patients died from grade 5 treatment-related infections. Generally, S-1 monotherapy was well-tolerated and efficacious in the elderly patient group, but not in the frail patient group. Considering performance status and co-morbidities in patients >70 years old, S-1 monotherapy may be a first-line therapeutic option for elderly mCRC patients.

Comparison of long-term outcome between doublet and triplet neoadjuvant chemotherapy in non-metastatic osteosarcoma of the extremity.

OBJECTIVE: This study compared outcomes between doublet (AP) and triplet (IAP) neoadjuvant chemotherapy for nonmetastatic osteosarcoma of the extremity. METHODS: A total of 124 patients were enrolled. In the AP group, a doublet regimen of intraarterial cisplatin and intravenous doxorubicin was given to 77 patients from 1991 to 1999. In the IAP group, a triplet regimen of additional intravenous ifosfamide was given to 47 patients from 2000 to 2007. After completion of 3 cycles of chemotherapy, patients underwent surgery. We assessed tumor response according to pathologic tumor necrosis, and treated patients with further adjuvant chemotherapy. RESULTS: The overall pathologic response was excellent with more than 90% tumor necrosis in 74.8% of patients. Total necrosis of tumors was also found in 46 (37.4%) patients. There was no difference between the 2 groups in pathologic response (75.3 vs. 72.3%; p = 0.52) or other clinicopathologic parameters. There was no difference between the 2 groups in recurrence rate (31.2 vs. 31.9%; p = 0.17) or lung metastasis (28.6 vs. 23.4%; p = 0.53). Moreover, there were no statistical differences in median disease-free survival and overall survival between the groups. There was more hematologic toxicity in the IAP group (neutropenia, p = 0.002; thrombocytopenia, p = 0.001; febrile neutropenia, p < 0.001). CONCLUSIONS: The addition of ifosfamide to doxorubicin and cisplatin in neoadjuvant chemotherapy did not show improved outcomes in this study. Further trials are required to elucidate optimal neoadjuvant chemotherapy and effective salvage regimens.

Predictive values of 5-fluorouracil pathway genes for S-1 treatment in patients with advanced gastric cancer.

Determination of significant associations between gene expression and predefined endpoints might improve treatment tailoring for advanced gastric cancer. We investigated the mRNA expression of 5-fluorouracil (5-FU) pathway genes in prechemotherapeutic tumor samples of primary gastric cancer to try to predict the treatment outcome of S-1 monotherapy. 5-FU pathway genes, dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), and thymidine phosphorylase (TP), were analyzed using quantitative real-time PCR of RNA extracted from archived formalin-fixed paraffin-embedded tissues. We selected the median value for each gene as a cutoff to separate patients into high and low gene expression groups. High OPRT gene expression was significantly associated with tumor response (P = 0.014). In a combined analysis including OPRT, patients with high OPRT and TP showed a higher overall response rate than did the remaining patients (40 vs. 10%, respectively; P = 0.002). For survival, patients with high OPRT and low TS levels showed prolonged survival in both progression-free survival (3.4 vs. 2.4 months, P = 0.024) and overall survival (11.0 vs. 8.2 months, P = 0.007). In a multivariate analysis, the combinations of OPRT and TP for response and OPRT and TS for both progression-free survival and overall survival were independent variables. To conclude, mRNA expression levels of molecular markers in formalin-fixed paraffin-embedded specimens of primary gastric tumors can be useful for identifying patients with advanced gastric cancer who would most likely benefit from S-1 treatment.