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Background: The aim of this study was to explore the clinical utility of serum HER2 extracellular domain (sHER2 ECD) using data from a clinical trial evaluating trastuzumab combined S-1 plus oxaliplatin (SOX) in HER2 positive gastric cancer., Methods: sHER2 ECD were prospectively measured at baseline and subsequent treatment courses. Based on each quantile point of baseline sHER2 ECD levels and its early changes, patients were divided into two groups and compared clinical outcomes., Results: 43 patients were enrolled, and 17 patients (39.5%) were positive for baseline sHER2 ECD. Higher baseline sHER2 ECD levels tended to have lower hazard ratios (HRs). When divided into two groups by baseline sHER2 ECD of 19.1 ng/ml, median progression-free survival (PFS) and overall survival (OS) was longer in the higher group (mPFS: 16.8 vs 8.7 months, p = 0.359. mOS: 35.5 vs 20.6 months, p = 0.270), respectively. After initiation of treatment, sHER2 ECD significantly decreased up until the third cycle. Higher reduction rates of sHER2 ECD within 3 cycles also tended to have lower HRs. When divided into two groups by reduction rate of 42.5%, mPFS and mOS was longer in the higher reduced group (mPFS: 17.2 vs 8.7 months, p = 0.095. mOS: 65.0 vs 17.8 months, p = 0.047), respectively. Furthermore, higher reduction rates could surrogate higher objective response rates (ORR) (ORR: 90% vs 63.2% for 29.5%, p = 0.065. 100% vs 70% for 42.5%, p = 0.085), respectively., Conclusions: Baseline sHER2 ECD levels and its early decline may be useful biomarkers for SOX plus trastuzumab efficacy in HER2 positive gastric cancer., (© 2024. The Author(s).)

Background: Three vascular endothelial growth factor (VEGF) inhibitors, Bevacizumab (BEV), ramucirumab (RAM), and aflibercept (AFL), are widely used for metastatic colorectal cancer (mCRC) patients who are treated with second-line chemotherapy. The difference in outcome between the three drugs has not been evaluated. In contrast to epidermal growth factor receptor inhibitors, VEGF inhibitors have few candidate predictors of efficacy., Methods: Consecutive mCRC patients who were treated with second-line chemotherapy were retrospectively enrolled. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were assessed. Subgroup analyses of prognostic and predictive efficacy markers were performed., Results: A total of 119 (41.2%), 107 (37.0%), and 63 patients (21.8%) were treated with FOLFIRI +BEV, RAM, or AFL, respectively. ORR, PFS, and OS showed no significant differences between three groups. However, the frequency of grade 3 or 4 adverse events (AEs) in the FOLFIRI +AFL group was significantly higher than that in the other groups (p < 0.001). Patients with grade 3 or 4 AEs, especially hypertension and neutropenia within the first four cycles of treatment had significantly longer PFS and OS than those without AEs, irrespective of treatment with VEGF inhibitors (p < 0.001). PFS in patients without prior BEV exposure was also significantly longer than that in patients with prior BEV exposure (p = 0.003)., Conclusions: Chemotherapeutic efficacy did not differ between the groups. Grade 3 or 4 AEs within the first four cycles of treatment and prior BEV exposure may be an effective predictor of treatment efficacy in mCRC patients administered VEGF inhibitors as second-line chemotherapy., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: This study aimed to evaluate the efficacy and the safety of polyethylene glycol conjugated granulocyte colony-stimulating factor (PEG-G-CSF) for preventing neutropenia in metastatic colorectal cancer (mCRC) patients that received fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab (Bev) in clinical practice., Methods: We retrospectively analyzed mCRC patients who received FOLFOXIRI plus Bev between December 2015 and December 2017. We evaluated the efficacy of PEG-G-CSF as preventing or treating grade 3 or 4 neutropenia, the overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival (PFS), overall survival (OS), and adverse events of FOLFOXIRI plus Bev based on the Common Terminology Criteria for Adverse Events version 4.0., Results: A total of 26 patients (median age 53.5 years) were included. The ORR rate was 65.3%, the median PFS was 9.6 months (7.2-16.9), and the median OS was 24.2 months (13.6-NA). Grade 3 or 4 neutropenia occurred in 53.8% of the patients, and febrile neutropenia occurred in 7.7%. PEG-G-CSF was given to 77.0% of the patients, including prophylactically (n = 9) and after the development of grade 3 or 4 neutropenia (n = 11). No patients experienced grade 3 or 4 neutropenia after the administration of PEG-G-CSF. In seven of the nine patients who received PEG-G-CSF prophylactically (77.8%), no dose adjustment was required., Conclusions: PEG-G-CSF is useful in preventing severe neutropenia in mCRC patients treated with FOLFOXIRI plus Bev.

Background The effectiveness of reintroducing oxaliplatin for metastatic colorectal cancer (mCRC) refractory to both oxaliplatin and irinotecan was previously reported in a phase II study (RE-OPEN). We conducted a phase I study to determine the maximum tolerated dose of oxaliplatin plus trifluridine/tipiracil (FTD/TPI) in patients with refractory mCRC. Patients and Methods Three dosages of intravenous oxaliplatin (50, 65 and 85 mg/m 2 ) on days 1 and 15 and a fixed dose of FTD/TPI 35 mg/m 2 twice daily (bid) on days 1-5 and 15-19 every 4 weeks were investigated in patients with refractory mCRC using a 3 + 3 design. Eligible patients had received prior oxaliplatin-based treatment that achieved a response or stable disease followed by confirmed disease progression at least 6 months before entering the study. Results Twelve patients were enrolled in the study. Three of six patients in the oxaliplatin 85 mg/m 2 cohort had dose-limiting toxicities (DLTs) with treatment delays during the second cycle at ≥8 days due to grade ≥ 2 neutropenia or grade 2 AST/ALT increased. No DLTs were observed in the other cohorts. Grade ≥ 3 AEs were neutropenia (n = 3), thrombocytopenia (n = 1), anorexia (n = 1), and nausea (n = 1). There was no evidence of allergic reaction to oxaliplatin or severe peripheral sensory neuropathy. Conclusions A combination of FTD/TPI 35 mg/m 2 bid on days 1-5 and 15-19 and oxaliplatin 85 mg/m 2 on days 1 and 15 every 4 weeks could be a suitable regimen for the recommended dose of FTD/TPI plus oxaliplatin in patients with refractory mCRC.

Background: Trastuzumab with cisplatin and fluoropyrimidines improves overall survival (OS) in patients with HER2-positive advanced gastric cancer (AGC). S-1 plus oxaliplatin (SOX) is one of the standard regimens for HER2-negative AGC in Japan. However, few studies have evaluated trastuzumab combined with SOX in patients with HER2-positive AGC., Methods: This was a multicenter, phase II study conducted at 10 institutions in Japan. Patients with HER2-positive AGC received S-1 twice a day on days 1-14 and oxaliplatin and trastuzumab on day 1 of a 21-day cycle. The primary endpoint was the confirmed overall response rate (ORR), and the secondary endpoints were OS, progression-free survival (PFS), and safety. The sample size was 75 to have 90% power with an alpha error of 0.1 (one-sided), expecting an ORR of 65% and threshold of 50%., Results: From June 2015 to January 2018, 75 patients were enrolled. The ORR was 70.7% [95% confidence interval (CI) 59.0-80.6]. The median OS and PFS were estimated as 18.1 months (95% CI 15.6-26.5) and 8.8 months (95% CI 7.4-12.2), respectively. The major grade 3 or 4 adverse events were sensory neuropathy (16.0%) and neutropenia (10.7%)., Conclusions: Trastuzumab with SOX had promising activity with well-tolerated toxicities for patients with HER2-positive AGC., Clinical Trial Registration: UMIN000017602.

Background: S-1 monotherapy is one of the standard adjuvant treatments for patients with stage II and III gastric cancers. Early recurrence after S-1 adjuvant therapy has a poor prognosis. This study aimed to clarify the treatment outcomes of systemic chemotherapy and explore encouraging regimens., Methods: This was a multicenter retrospective study. Among gastric cancer patients who underwent curative gastrectomy followed by adjuvant S-1 monotherapy, patients who experienced a recurrence while receiving adjuvant therapy or within 6 months after completion and started systemic chemotherapy at four institutions between 2005 and 2015 were eligible., Results: A total of 112 patients were included. The main treatment regimens were weekly paclitaxel (n = 38, 34%), irinotecan plus cisplatin (n = 31, 28%), capecitabine plus cisplatin (n = 7, 6%), and irinotecan monotherapy (n = 6, 5%). For all patients, median progression-free survival and overall survival were 3.7 and 11.4 months, respectively. Among 77 patients with measurable lesions, the overall response and disease control rates were 24.7% and 62.3%, respectively. Multivariate analyses for overall survival showed that Eastern Cooperative Oncology Group performance status 2 [hazard ratio (HR) 3.71; 95% confidence interval (CI) 1.78-7.73] and undifferentiated histological type (HR 2.04; 95% CI 1.35-3.44) were independent prognostic factors, and treatment regimens were not prognostic. Exploratory comparisons did not show statistically significant differences between treatment regimens., Conclusions: This study of the largest number of patients with early recurrence after S-1 adjuvant monotherapy demonstrated that the prognosis for patients treated by all regimens was similar and poor.

Purpose: Few data of folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus ramucirumab (RAM) obtained in bevacizumab-naïve patients in clinical trials or routine clinical practice are available. The purpose of this retrospective study was to report the results of FOLFIRI plus RAM treatment as second-line chemotherapy for metastatic colorectal cancer (mCRC)., Methods: Seventy-four patients with mCRC who received second-line FOLFIRI + RAM mCRC therapy were stratified by previous first-line therapy to groups that had (PB) or had not (NPB) been given bevacizumab. The overall survival (OS), progression-free survival (PFS), and objective response were evaluated., Results: The overall median PFS was 6.2 months (95% CI 4.6-9.3) and median OS was 17.0 months (95% CI 11.6-NA). Median PFS was 8.0 months (95% CI 4.9-11.2) in NPB patients and 5.0 months (95% CI 3.1-7.3) in PB patients (hazard ratio = 0.72, 95% CI 0.40-1.30, p = 0.28). The response rates were 23% and 3% in NPB and PB patients, respectively. The disease control rates were 85% and 69% in NPB and PB patients, respectively., Conclusions: The effectiveness of FOLFIRI + RAM as a second-line chemotherapy in patients with mCRC was in line with that reported in the previous RAISE phase III trial. The response was better in bevacizumab-naïve patients than those with first-line treatment that had included bevacizumab.

Efficacy and safety of biweekly cetuximab plus irinotecan were evaluated to provide guidance for its use in Japan as third-line treatment for pretreated metastatic colorectal cancer (mCRC) patients harboring wild-type KRAS exon 2. Objective response rate (ORR) was used as primary endpoint based on an expected proportion of 0.23 with confidence width of 0.298 (95% CI, 0.105-0.403), which showed 35 to be the minimal participant number. Forty patients, refractory to first- and second-line chemotherapy containing irinotecan, oxaliplatin, and fluoropyrimidine, were enrolled. ORR and disease control rate were 25.0% (95% CI: 11.5-38.4) and 72.5% (95% CI: 56.8-86.4), respectively. Median progression-free survival (PFS), overall survival (OS), and number of courses were 5.70 months (95% CI: 2.7-7.9), 15.1 months (95% CI: 11.8-19.0), and 10.5 (range: 3.0-31.0), respectively. Grade 3 adverse events were skin toxicity (12.5%), diarrhea (10.0%), neutropenia (5.0%), febrile neutropenia (5.0%), nausea (5.0%), anorexia (5.0%), and fatigue (2.5%). C max mean was 723.2 μg/mL after first dose. High area under the curve (AUC) last variance was associated with t 1/2 range of 131.2-1209.6 hours (median, 174.4 hours). Early tumor shrinkage (ETS) and median depth of response were 25.0% and 13.0%, respectively. Mutation frequencies in KRAS exon 3 or 4, NRAS, BRAF, and PIK3CA were 5.5%, 2.7%, 8.3%, and 5.5%, respectively. Multivariate Cox regression analysis assessed whether any gene mutations and ETS are predictors for PFS, and whether performance status, synchronous metastasis, and ETS are predictors for OS. Importantly, the data provide guidance for a biweekly cetuximab plus irinotecan regimen in mCRC patients., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Although early tumor shrinkage (ETS) predictions of the efficacy and depth of response (DpR) reflects clinical outcomes in chemotherapy with epidermal growth factor receptor inhibitor regimens to treat metastatic colorectal cancer, their value in assessing treatments for advanced gastric cancer (AGC) is unclear. Here we evaluated relationships between ETS and DpR and clinical outcomes in AGC patients treated with first-line chemotherapy., Methods: We retrospectively enrolled 612 consecutive patients treated with first-line chemotherapy for AGC between January 2010 and June 2016. ETS and DpR were defined as changes from baseline in summed longest diameters in target lesions at 8 (±4) weeks for ETS and at the smallest observed volume for DpR., Results: Eligible patients were sorted into HER2 + (n = 100) and HER2 - (n = 186) groups. Median follow-up was 14.8 months. The overall response rate and disease control rates were 64 and 87% in the HER2 + group and 53.2 and 86.0% in the HER2 - group. Respective median PFS and OS were HER2 + : 7.9 and 20.8 months and HER2 - : 6.6 and 13.8 months. The respective ETS rate and median DpR were HER2 + : 70 and 44% and HER2 - : 57.5 and 24%. Clinical outcomes and ETS/DpR were correlated, especially in the HER2 + group (OS: P < 0.0001; PFS: P < 0.0001). In multivariate analysis, ETS was an independent predictor for OS in the HER2 + group and for PFS in both groups., Conclusion: These results indicate that ETS may be an early-on treatment predictor of the efficacy of HER2 + advanced gastric cancer treated with first-line chemotherapy that includes trastuzumab.

Background: Peritoneal cytology positive for carcinoma cells (CY+) is an independent poor prognostic factor in gastric cancer, and patients with CY+ are diagnosed with stage IV disease. However, there is no standard treatment strategy for CY+ gastric cancer, whereas combination chemotherapy with fluoropyrimidine and platinum has been established as the standard treatment for unresectable advanced gastric cancer or after R2 resection. Herein, we assessed whether adding cisplatin to S-1 (SP) could improve the outcome of CY+ gastric cancer patients, as compared to S-1 monotherapy., Methods: This retrospective study was conducted at a single Japanese institute between June 2005 and March 2014. Patients diagnosed with CY+ advanced gastric cancer and treated with S-1-based therapy were enrolled. Patients with incurable factors other than CY+ were excluded., Results: Forty-four patients were enrolled; 25 and 19 were administered S-1 and SP, respectively. The 2-year survival rates were 52.0% [95% confidence interval (CI), 31.2-69.2%] and 52.6% (28.7-71.9%) in the S-1 and SP groups, respectively. The median overall survival (OS) and progression-free survival (PFS) were 28.2 and 15.6 months in the S-1 group and 24.0 and 18.8 months in the SP group, respectively; they were not significantly different. The relative dose intensities were 0.79 (S-1) in the S-1 group and 0.69 (S-1)/0.70 (cisplatin) in the SP group., Conclusion: Adding cisplatin to long-term S-1 monotherapy did not significantly improve the outcome of CY+ advanced gastric cancer patients.

The prognosis of unresectable or metastatic gastric cancer is poor. One of the reasons for this is peritoneal dissemination, which is often observed in gastric cancer. Here, we discuss some new therapeutic strategies, especially chemotherapeutic strategies, for peritoneal dissemination of gastric cancer. Occasionally, in cases of peritoneal dissemination, patients have severe ascites or bowel obstruction. For those who have such complications, treatment via chemotherapy including S-1, capecitabine, or cisplatin is inappropriate. Therefore, methotrexate plus 5-fluorouracil(5-FU), 5-FU continuous infusion, 5- FU plus l-levofolinate, or paclitaxel are generally administered to such patients. To improve the efficacy of chemotherapy for such patients, an ongoing clinical trial(JCOG1108)is comparing triplet chemotherapy(FLTAX)including 5-FU plus l-levofolinate plus paclitaxel with chemotherapy including 5-FU plus l-levofolinate. For gastric cancer with positive lavage cytology, S-1 monotherapy or S-1 plus cisplatin therapy are often used. However, till date there has been no prospective clinical trial that has evaluated the efficacy of these therapies in gastric cancer with peritoneal dissemination. Therefore, further clinical trials are warranted to evaluate which chemotherapy is more suitable for patients with gastric cancer with peritoneal dissemination. Moreover, the use of conventional combination chemotherapy and intraperitoneal(IP)chemotherapy for patients with gastric cancer with peritoneal dissemination is now under evaluation. At the latest ASCOmeeting, the results of the "PHOENIX-GC trial" were reported. In this trial, patients receiving IP paclitaxel, intravenous(IV)paclitaxel, and S-1(experimental arm)and those receiving S-1 plus cisplatin(control arm)were compared. Longer survival was observed in the IP paclitaxel group compared with the other groups; however, this difference did not reach statistical significance. We hope that the evaluation of data from clinical trials would result in the identification of the optimal treatment strategy for patients with gastric cancer with peritoneal dissemination.

Purpose: Surgery is the only potentially curative strategy for patients who have Stage IV colorectal cancer (CRC) with resectable metastases, but relapse is common. Randomized trials of adjuvant 5-FU-based systemic chemotherapy have not demonstrated any benefit after resection of liver metastases. We evaluated the efficacy, safety, and tolerability of oxaliplatin-based adjuvant chemotherapy after curative resection of hepatic or extrahepatic metastases of CRC., Methods: We retrospectively studied data for 88 consecutive patients with Stage IV CRC who underwent curative resection of metastases followed by oxaliplatin-based adjuvant chemotherapy between March 2007 and June 2013., Results: The 3-year relapse-free survival (RFS) rate was 54.0 %. There was no significant difference in 3-year RFS between patients with metastases confined to the liver (52.7 %) and patients with extrahepatic metastases (57.2 %). Multivariate analysis revealed that the site of the primary tumor (right-sided colon or left-sided colon/rectum) and the number of metastases (solitary or multiple) were predictors of RFS. Scheduled courses were completed in 80.7 % of the patients. Except for neutropenia (47.7 %), severe adverse events were observed in <5 % of patients., Conclusions: Oxaliplatin-based adjuvant chemotherapy could be an effective option for selected patients with Stage IV CRC after curative resection of hepatic or extrahepatic metastases, and is both safe and tolerable.

Pericytes are crucial for angiogenesis. The impact of pericyte function to bevacizumab efficacy in mCRC treatment has not been comprehensively examined. This retrospective study investigated germline polymorphisms in genes related to early pericyte maturation to predict bevacizumab efficacy in 424 patients of two clinical trials treated first line with FOLFIRI+bevacizumab. Eight single-nucleotide polymorphisms (SNPs) were tested for potential biomarker value: RGS5 (regulator of G-protein signaling 5; rs1056515, rs2661280), PDGFR-β (platelet-derived growth factor receptor-β; rs2229562, rs2302273), CSPG4 (chondroitin sulfate proteoglycan NG2; rs8023621, rs1127648) and RALBP1 (RalA binding protein 1; rs10989, rs329007). For progression-free survival (PFS), PDGFR-β (rs2302273) was able to define significantly different patient cohorts in uni- and multivariate testing. RALPB1 (rs329007) showed predictive value for tumor response. The C allele in RGS5 (rs2661280) predicted longer overall survival and CSPG4 rs1127648 was associated with differences in PFS, but for both value was lost when multivariate analysis was applied. A comprehensive statistical analysis revealed that the biomarker value of the SNPs was dependent on primary tumor location. This is the first study to identify pericyte germline polymorphisms associated with clinical outcome in mCRC patients treated first line with FOLFIRI+bevacizumab. The differences seen with regard to primary tumor location may lead to further research to understand the clinical outcome differences seen in right- and left-sided colon cancer.

Background: Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. We tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) pathways would significantly improve progression-free survival (PFS) by abrogating reciprocal signaling that promote drug resistance, Methods: This was a phase Ib/II study testing cixutumumab, combined with erlotinib and gemcitabine (G) in patients with untreated metastatic PC. The control arm was erlotinib plus G. The primary end point was PFS. Eligibility included performance status 0/1 and normal fasting blood glucose. Polymorphisms in genes involved in G metabolism and in the EGFR pathway were also studied, Results: The phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. In the RP2 portion (116 eligible patients; median age, 63), the median PFS and overall survival (OS) were 3.6 and 7.0 months, respectively, on the cixutumumab arm, and 3.6 and 6.7 months, respecively, on the control arm. Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12% and 6%, respectively; fatigue, 16% and 12%, respectively; gastrointestinal, 35% and 28%, respectively; neutropenia, 21% and 10%, respectively; and thrombocytopenia, 16% and 7%, respecively. Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (< 5%). No significant differences in PFS by genotype were seen for any of the polymorphisms., Conclusions: Adding the IGF-1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC., (© 2014 American Cancer Society.)

Purpose: The potential impact of different SNPs of VEGF/VEGFR pathway on the clinical outcome of mCRC patients receiving bev-containing regimens has been investigated in retrospective experiences with contrasting results. We previously reported the association of VEGFA rs833061 C/T variants with PFS in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab. The primary objective of this work was to prospectively validate that retrospective finding. A confirmatory analysis of other SNPs of VEGF/VEGFR pathway genes was included., Experimental Design: To detect a HR for PFS of 1.7 for VEGFA rs833061 T/T compared to C- variants in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab, setting two-sided α = 0.05 and β = 0.20, 199 events were required. VEGFA rs699946 A/G, rs699947 A/C, VEGFR1 rs9582036 A/C and rs7993418 A/G, VEGFR2 rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and EPAS1 rs4145836 A/G were also tested. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing., Results: Four-hundred-twenty-four pts were included. At the univariate analysis, no differences according to VEGFA rs833061 C/T variants were observed in PFS (p = 0.38) or OS (p = 0.95). Among analyzed SNPs, only VEGFR2 rs12505758 C- variants, compared to T/T, were associated to shorter PFS (HR: 1.36 [1.05-1.75], p = 0.015, dominant genetic model) and OS, with a trend toward significance (HR: 1.34 [0.95-1.88], p = 0.088). In the multivariate model, this association retained significance (HR: 1.405 [1.082-1.825], p = 0.012) in PFS, that was lost by applying multiple testing correction (p = 0.14)., Conclusion: This prospective experience failed to validate the hypothesized predictive impact of VEGFA rs833061 variants. Retrospective findings on different candidate SNPs were not confirmed. Only VEGFR2 rs12505758 variants, whose prognostic and not predictive impact was previously reported, correlated with PFS. Given the complexity of angiogenesis, it is rather unlike that a single germ-line SNP might be a good predictor of benefit from bevacizumab.

Purpose: We investigated the relationship between the p53-dependent apoptotic pathway and the survival of patients with gastric cancer, retrospectively, to elucidate new biomarkers of uracil/tegafur (UFT) chemotherapy., Methods: We examined the expression of p53, p21, Bax, and myeloid cell leukemia 1 (Mcl-1) proteins immunohistochemically in 105 patients who underwent curative gastrectomy for gastric cancer invading the serosa. Postoperative oral UFT was prescribed for 1 year. Kaplan-Meier survival curves were compared with the two-sided log-rank test., Results: Positive staining for p53, p21, Bax, and Mcl-1 proteins was found in 63.8, 52.4, 39.0, and 72.4% of the subjects, respectively. Survival time did not differ significantly between the patients with and those without p53, p21, and Bax expression. However, patients with Mcl-1- tumors survived longer than those with Mcl-1+ tumors. Postoperative UFT treatment did not improve survival; however, adjuvant UFT significantly prolonged the survival of patients with p53-, p21-), Bax+, or Mcl-1+ tumors, but not of patients with p53+, p21+, Bax-, or Mcl-1- tumors., Conclusions: The efficacy of adjuvant chemotherapy for gastric cancer may be affected by the status of apoptosis-related proteins such as p53, p21, Bax, and Mcl-1. However, because susceptibility to apoptosis did not explain the sensitivity of chemotherapeutic agents, further investigation of the mutual interaction between apoptosis-related proteins is required.

Intrahepatic cholangiocarcinoma (ICC) is a relatively rare and highly fatal neoplasm that arises from the biliary epithelium. Prognosis is generally poor and survival is limited to a few months. Here we present a case of advanced ICC successfully treated by chemosensitivity test-guided systemic chemotherapy combining S-1 and cisplatin (CDDP). A 65-year-old woman with a liver tumor was referred to our hospital on November 21, 2007. Abdominal ultrasonography and computed tomography (CT) showed low-density masses of 50 and 15 mm in diameter, respectively in segment VIII of the liver and in the enlarged lymph node in the para-aorta. Ultrasonography-guided fine needle biopsy diagnosed the tumors as ICC. Since the patient was inoperable for lymph node metastasis, she underwent systemic chemotherapy with gemcitabine. Six months after initiation of chemotherapy, CT revealed ICC progression in the liver and pleural dissemination with pleural effusion. The patient was admitted to our hospital for anticancer drug sensitivity testing on June 9, 2008. Based on the sensitivity test results, we elected to administer systemic chemotherapy combining S-1 and CDDP. Two months into the second chemotherapy treatment, CT revealed a reduction of the tumors in the liver and lymph node and a decrease in pleural effusion. After eight cycles of the second chemotherapy, 17 mo after ICC diagnosis, she is alive and well with no sign of recurrence. We conclude that chemosensitivity testing may effectively determine the appropriate chemotherapy regimen for advanced ICC., (2009 The WJG Press and Baishideng. All rights reserved.)

We report a case of breast cancer with spinal and vertebral lesions. A 49-year-old premenopausal woman with a left breast tumor was admitted to our hospital for acute weakness of the lower limbs and dysuria. She could neither stand nor walk. The tumor in the left breast was 5.0 cm in diameter with skin ulcer, and it was diagnosed as breast cancer. Magnetic resonance (MR) image showed multiple vertebral and spinal metastases from breast cancer. Chemotherapy, consisting of cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) was initiated. Her symptoms dramatically changed for the better. She became able to walk and urinate. We performed palliative mastectomy after 3 cycles of CAF therapy. Histopathological findings of breast tumor showed scirrhous carcinoma. Although the estrogen and progesterone receptor status of primary tumor was negative, chemo-endocrine therapy, consisting of medroxyprogesterone acetate (MPA) and doxifluridine (5'-DFUR) was given as daily therapy, and vertebral and spinal lesions were reduced. Her condition has remained stable for 4 years. For patients with metastatic breast cancer, complete remission is uncommon, and disease stabilization is a reasonable goal of successful therapy. In this respect, therapy with CAF, followed by MPA and 5'-DFUR, was successful in the patient.

Postoperative intraportal anti-cancer chemotherapy was used for 51 patients with curatively resected colorectal cancer who were selected in the randomized controlled study to evaluate its inhibitory effect on liver metastasis from colo-rectal cancer. In cases of intraportal chemotherapy, 30 mg of Mitomycin-C (in 3 doses) and 5 mg/kg (B.W.)/day (1985-1986) or 3 mg/kg/day (1987-1988) of 5-FU was injected through the catheter inserted into the portal vein during postoperative 14 days. In cases of the control group (58 patients), the same doses of the drugs were injected into the peripheral vein during the same term. Six patients with recurrences were observed in the intraportal chemotherapy group, and 3 of them had liver metastases. In the control group, more liver metastases were observed (5 of 7 recurrences were liver metastases). Intraportally injected 5 mg/kg/day of 5-FU slightly disturbed the liver function. The averages of the serum GOT, GPT and gamma-GTP level of these cases were higher than those of the control cases. Three mg/kg/day of intraportally injected 5-FU had no influence on the liver function. There were no differences in the incidence of leukocytopenia or thrombocytopenia between the two groups.

Fifty-four patients with unresectable malignant liver tumors (14 of hepatocellular carcinoma, 40 of metastasis to the liver from gastric or colo-rectal cancer) were treated with intra-hepato-arterial (IHA) injections of cis-diamminedichloroplatinum (II) (CDDP) plus 5-fluorouracil (5-FU). In 32 of the patients, the liver tumors were detected synchronously with the diagnosis of the primary cancers, which were resected palliatively. Therapeutic schedules consisted of bolus injections of CDDP (50 mg/body/week) and 5-FU (250 mg/body/day) [Regimen I], and CDDP (50 mg/body/10-14 days) and 5-FU (100 mg/body/day) [Regimen II]. In 48 patients treated with IHA chemotherapy only, a partial response (PR) was obtained in 6 of 14 (43%) evaluable patients for Regimen I and in 11 of 30 (37%) patients for Regimen II. The dose-limiting factor for treatment with CDDP was bone marrow toxicity, but this toxicity was remarkably alleviated in Regimen II without any decrease in antitumor effectiveness. In 13 patients, other modalities, such as total-body hyperthermia (4 patients), radiofrequency capacitive local hyperthermia (5), and temporary arterial embolization (4), were combined with IHA chemotherapy. PR was obtained in 7 of 13 (54%) patients with the combined therapy. This combined therapy was efficacious in 7 patients in whom no desired results were obtained by IHA chemotherapy only. The survival rate was 50% at 12 months. IHA chemotherapy with CDDP plus 5-FU, especially when according to Regimen II, appears to be a strongly recommended strategy for treatment of unresected primary or metastatic liver tumor. Further, addition of the hyperthermia or the arterial embolization might enhance the antitumor effect of IHA chemotherapy.

Eight hepatocellular cancer patients and eighteen metastatic liver cancer patients were treated with intrahepato-arterial infusion of CDDP (cis-diamminedichloro-platinum II) plus 5-FU (5-fluorouracil); CDDP (0.8-1.0 mg/kg) was given once every 7 or 10-14 days, while 5-FU (250-100 mg/day) was infused daily. A partial response was obtained in 5 of 8 patients with primary liver cancer and in 9 of 14 evaluable patients with metastatic liver cancer. However, severe complications due to bone marrow suppression were observed in 4 patients, 3 of whom died of septicemia and one of enterocolitis. This combined intra-hepato-arterial chemotherapy exerts a synergistic anticancer effect on malignant liver tumors, although the bone marrow suppression associated with it remains to be overcome.

Four hepatocellular cancer patients and 11 metastatic liver cancer patients were treated with intra-hepato-arterial infusions of cis-diamminedichloroplatinum (II) plus 5-fluorouracil. Cis-diamminedichloroplatinum (II) (25-35 mg/m2) was given once a week, 5-fluorouracil (150-180 mg/m2) was infused daily. A partial response was obtained in 3 of 4 patients with primary cancer and in 5 of 9 evaluable metastatic cancer patients; the mean response durations were 27+ weeks in the former and 47+ weeks in the latter. However, severe bone marrow suppression occurred in 4 patients; 3 died of septicemia (2 cases) and massive intra-tracheal bleeding, respectively. This combined intra-hepato-arterial chemotherapy exerts a synergistic anticancer effect on malignant liver tumors, however, the related bone marrow suppression remains to be overcome.