Therapeutic implication of HER2 in advanced biliary tract cancer.

Currently, there is no validated therapeutic target for biliary tract cancer (BTC). This study aimed to investigate the pre-clinical and clinical implication of HER2 as a therapeutic target in BTC. We established two novel HER2-amplified BTC cell lines, SNU-2670 and SNU-2773, from gallbladder cancer patients. SNU-2670 and SNU-2773 cells were sensitive to trastuzumab, dacomitinib, and afatinib compared with nine HER2-negative BTC cell lines. Dacomitinib and afatinib led to G1 cell cycle arrest in SNU-2773 cells and apoptosis in SNU-2670 cells. Furthermore, dacomitinib, afatinib, and trastuzumab showed synergistic cytotoxicity when combined with some cytotoxic drugs including gemcitabine, cisplatin, paclitaxel, and 5-fluorouracil. In a SNU-2670 mouse xenograft model, trastuzumab demonstrated a good anti-tumor effect as a monotherapy and in combination with gemcitabine increasing apoptosis. In our clinical data, 13.0% of patients with advanced BTC were defined as HER2-positive. Of these, three patients completed HER2-targeted chemotherapy. Two of them demonstrated a partial response, and the other one showed stable disease for 18 weeks. In summary, these pre-clinical and clinical data suggest that HER2 could be a therapeutic target, and that a HER2-targeting strategy should be developed further in patients with HER2-positive advanced BTC.

Splenomegaly and Its Associations with Genetic Polymorphisms and Treatment Outcome in Colorectal Cancer Patients Treated with Adjuvant FOLFOX.

PURPOSE: Splenomegaly is a clinical surrogate of oxaliplatin-induced sinusoidal obstruction syndrome (SOS). We investigated development of splenomegaly and its association with treatment outcome and genetic polymorphisms following adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in colorectal cancer (CRC) patients. MATERIALS AND METHODS: Splenomegaly was determined by spleen volumetry using computed tomography images obtained before initiation of chemotherapy and after completion of adjuvant FOLFOX in CRC patients. Ten genetic polymorphisms in 4 SOS-related genes (VEGFA, MMP9, NOS3, and GSTP1) were analyzed using DNA from peripheral blood mononuclear cells. RESULTS: Of 124 patients included, increase in spleen size was observed in 109 (87.9%). Median change was 31% (range, -42% to 168%). Patients with splenomegaly had more severe thrombocytopenia compared to patients without splenomegaly during the chemotherapy period (p < 0.0001). The cumulative dose of oxaliplatin and the lowest platelet count during the chemotherapy period were clinical factors associated with splenomegaly. However, no significant associations were found between genetic polymorphisms and development of splenomegaly. Disease-free survival was similar regardless of the development of splenomegaly. CONCLUSION: Splenomegaly was frequently observed in patients receiving adjuvant FOLFOX and resulted in more severe thrombocytopenia but did not influence treatment outcome. Examined genetic polymorphisms did not predict development of splenomegaly.

Prognostic Significance of Nodal Ratio in Patients Undergoing Adjuvant Chemoradiotherapy After Curative Resection for Ampullary Cancer.

OBJECTIVES: To analyze the outcome of patients with ampullary cancer who had undergone curative surgery followed by adjuvant chemoradiotherapy and to identify the prognostic factors for these patients METHODS: : Between January 1991 and August 2006, 71 patients with ampullary cancer underwent curative resection followed by adjuvant radiotherapy. There were 38 males and 33 females, and median age was 56 years (range, 28 to 77 y). Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to 40 to 50 Gy at 2 Gy/fraction; 67 patients also received intravenous 5-fluorouracil as a radiosensitizer. Median follow-up duration was 72 months for survivors. RESULTS: There were 5 isolated locoregional recurrences, 20 isolated distant metastases, and 11 combined locoregional and distant relapses. The 5-year locoregional relapse-free and overall survival rates were 76.2% and 64.5%, respectively. On multivariate analysis, nodal ratio and histologic differentiation were significant prognostic factors for overall survival (P=0.0382 and 0.0331, respectively). CONCLUSIONS: Adjuvant chemoradiotherapy after curative resection can achieve a long-term survival rate in patients with ampullary cancer. Nodal ratio and histologic differentiation are independent prognostic factors for these patients.

Concurrent Chemoradiotherapy Versus Chemotherapy Alone for Unresectable Locally Advanced Pancreatic Cancer: A Retrospective Cohort Study.

PURPOSE: The optimal treatment strategy for locally advanced pancreatic cancer (LAPC), particularly the role of concurrent chemoradiotherapy (CCRT), remains debatable. We compared the clinical outcomes of CCRT and palliative chemotherapy alone (CA) in patients with unresectable LAPC. MATERIALS AND METHODS: Patients with LAPC who were consecutively treated between 2003 and 2010 were included. Resectability was evaluated according to National Comprehensive Cancer Network ver. 1.2012. The clinical outcomes for each treatment group (CCRT vs. CA) were evaluated retrospectively. RESULTS: Sixty-three patients (58.9%) and 44 patients (41.1%) were treated with CCRT and CA, respectively. The CCRT cohort included patients who were treated with CCRT with or without chemotherapy backbone (CCRT alone, induction chemotherapy-CCRT, CCRT-maintenance chemotherapy, and induction-CCRT-maintenance chemotherapy). Median progression-free survival (PFS) and overall survival (OS) of all patients were 7.2 months and 13.1 months. PFS of the CCRT and CA groups was 9.0 months and 4.4 months, respectively (p=0.020). OS of the CCRT and CA groups was 15.4 months and 9.3 months, respectively (p=0.011). In multivariate analysis, the adjusted hazard ratio of CCRT was 0.536 (p=0.003) for OS and 0.667 (p=0.078) for PFS. Although the pattern of failure was similar in the CCRT and CA groups, the times to both local and distant failure were significantly longer in the CCRT group. CONCLUSION: In patients with unresectable LAPC, those who underwent CCRT during their entire treatment courses had longer OS than patients treated with chemotherapy alone.

Prognostic influence of body mass index and body weight gain during adjuvant FOLFOX chemotherapy in Korean colorectal cancer patients.

BACKGROUND: Asian population has different body mass index (BMI) profile compared to Caucasian population. However, the effect of obesity and body weight gain in Asian colorectal cancer patients treated with adjuvant chemotherapy has not been studied thus far. METHODS: We have analyzed the association between disease-free survival (DFS) and obesity/body weight change during treatment in Korean stage III or high-risk stage II colorectal cancer patients treated with adjuvant 5-fluorouracil/ leucovorin/oxaliplatin. BMI was classified according to WHO Asia-Pacific classification. Weight change was calculated by comparing body weights measured at the last chemotherapy cycle and before surgery. RESULTS: Among a total of 522 patients, 35.7 % of patients were obese (BMI ≥ 25 kg/m(2)) and 29.1 % were overweight (BMI, 23-24.9 kg/m(2)) before surgery. 18.0 % of patients gained ≥ 5 kg and 26.1 % gained 2-4.9 kg during the adjuvant chemotherapy period. Baseline BMI or body weight change was not associated with DFS in the overall study population. However, body weight gain (≥5 kg) was associated with inferior DFS (adjusted hazard ratio 2.04, 95 % confidence interval 1.02-4.08, p = 0.043) in overweight and obese patients (BMI ≥ 23.0 kg/m(2)). CONCLUSION: In Korean colorectal cancer patients treated with adjuvant FOLFOX chemotherapy, body weight gain during the treatment period has a negative prognostic influence in overweight and obese patients.

KRAS mutation is associated with worse prognosis in stage III or high-risk stage II colon cancer patients treated with adjuvant FOLFOX.

BACKGROUND: Although KRAS mutation has a predictive role in stage IV colorectal cancer (CRC) patients treated with anti-EGFR therapy, there have been controversies in the prognostic impact of KRAS mutation in stage II or III disease. The purpose of this study was to assess the prognostic impact of KRAS and BRAF mutation in patients treated with adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX). METHODS: KRAS exon 2 and BRAF codon 600 were analyzed in patients with stage II and III CRC who underwent curative resection followed by adjuvant FOLFOX. Clinicopathologic features and disease-free survival (DFS) were compared. RESULTS: Among a total of 437 patients, mutational data of KRAS and BRAF were available in 388 and 433 patients, respectively. KRAS mutation (codon 12 and 13) and BRAF V600E mutation was found in 26.5 and 3.7 % of patients. DFS was significantly worse in the KRAS mutant patients compared to KRAS wild type patients (3-year DFS 79 and 92 %, p = 0.006). Multivariate analysis revealed KRAS mutation as an independent negative prognostic factor for DFS (adjusted hazard ratio 2.30, 95 % confidence interval 1.23-4.32). Among the various subtypes of KRAS mutation, G13D (3-year DFS 76 %, p = 0.008) was significantly associated with poor DFS, while G12D was not associated with prognosis (3-year DFS 86 %, p = 0.61). There was no association between BRAF mutation and DFS. CONCLUSIONS: KRAS mutation has an adverse prognostic impact on stage II or III CRC treated with adjuvant FOLFOX.

Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial.

BACKGROUND: The CLASSIC trial was done to compare adjuvant capecitabine plus oxaliplatin versus observation after D2 gastrectomy for patients with stage II or III gastric cancer. The planned interim analysis of CLASSIC (median follow-up 34 months) showed that adjuvant capecitabine plus oxaliplatin significantly improved disease-free survival, the primary endpoint, compared with observation after D2 gastrectomy. We report the 5-year follow-up data from the trial. METHODS: CLASSIC was a phase 3, randomised, open-label study done at 35 cancer centres, medical centres, and hospitals in China, South Korea, and Taiwan. Patients with stage II-IIIB gastric cancer who underwent curative D2 gastrectomy were randomly assigned (1:1) after surgery to receive adjuvant chemotherapy with capecitabine and oxaliplatin (eight 3-week cycles of oral capecitabine 1000 mg/m(2) twice daily on days 1-14 plus intravenous oxaliplatin 130 mg/m(2) on day 1) for 6 months or observation alone. Randomisation was stratified by country and disease stage with a permuted block (size four) design. Neither patients nor investigators were masked to treatment assignment. The primary outcome was 3-year disease-free survival in the intention-to-treat population. This analysis presents the final preplanned assessment of outcomes after 5 years. The study is registered with ClinicalTrials.gov, NCT00411229. FINDINGS: We enrolled 1035 patients: 520 were randomly assigned to adjuvant capecitabine and oxaliplatin, and 515 to observation. Median follow-up for this analysis in the intention-to-treat population was 62·4 months (IQR 54-70). 139 (27%) patients had disease-free survival events in the adjuvant capecitabine and oxaliplatin group versus 203 (39%) patients in the observation group (stratified hazard ratio [HR] 0·58, 95% CI 0·47-0·72; p<0·0001). Estimated 5-year disease-free survival was 68% (95% CI 63-73) in the adjuvant capecitabine and oxaliplatin group versus 53% (47-58) in the observation alone group. By the clinical cutoff date, 103 patients (20%) had died in the adjuvant capecitabine and oxaliplatin group versus 141 patients (27%) in the observation group (stratified HR 0·66, 95% CI 0·51-0·85; p=0·0015). Estimated 5-year overall survival was 78% (95% CI 74-82) in the adjuvant capecitabine and oxaliplatin group versus 69% (64-73) in the observation group. Adverse event data were not collected after the primary analysis. INTERPRETATION: Adjuvant treatment with capecitabine plus oxaliplatin after D2 gastrectomy should be considered for patients with operable stage II or III gastric cancer. FUNDING: F Hoffmann La-Roche and Sanofi.

Chemoradiotherapy for extrahepatic bile duct cancer with gross residual disease after surgery.

BACKGROUND: The purpose of the present study was to analyze the outcome of chemoradiotherapy for extrahepatic bile duct (EHBD) cancer patients with gross residual disease after surgical resection. PATIENTS AND METHODS: We retrospectively analyzed 30 patients with EHBD adenocarcinoma who underwent chemoradiotherapy after palliative resection (R2 resection). Postoperative radiotherapy was delivered to the tumor bed including residual tumor and regional lymph nodes (range=40-55.8 Gy). Most patients underwent chemoradiotherapy concurrently with 5-fluorouracil (5-FU) or gemcitabine. RESULTS: The 2-year locoregional progression-free, distant metastasis-free and overall survival rates were 33.3%, 42.4% and 44.5%, respectively. High radiation dose≥50 Gy had a marginally significant impact on superior locoregional progression-free survival compared to 40 Gy (p=0.081). One patient developed grade 3 late gastrointestinal toxicity. CONCLUSION: Adjuvant chemoradiotherapy for EHBD cancer patients with gross residual disease after surgery was well-tolerated. There could be a chance for durable locoregional control and even long-term survival in selected patients.

Adjuvant and neoadjuvant therapy for gastric cancer.

OPINION STATEMENT: To improve outcome of resectable gastric cancer, several treatment strategies have been evaluated. These include adjuvant chemotherapy, adjuvant chemoradiotherapy, and perioperative chemotherapy. The US Intergroup 0116 trial reported the benefit of postoperative chemoradiotherapy using 5-FU/leucovorin in a U.S. population. In this study, only 10 % of patients received D2 resection. For Korean patients after D2 resection, the ARTIST trial failed to show any benefit from adding radiotherapy to adjuvant chemotherapy in terms of 3-year disease-free survival. The MAGIC trial compared perioperative chemotherapy with surgery alone and reported a prolonged 5-year overall survival in the perioperative chemotherapy arm. In resectable gastric cancer, the benefit of adjuvant chemotherapy compared with surgery alone has been clearly demonstrated. After D2 dissection, S-1 adjuvant chemotherapy improved the overall survival (ACTS-GC trial) and capecitabine/oxaliplatin combination chemotherapy improved 3-year disease-free survival (CLASSIC trial). To date, for resectable gastric cancer, the use of chemotherapy in addition to surgery is beneficial for the reduction of recurrence and to improve overall survival. The optimal sequence of chemotherapy and surgery, as well as optimal chemotherapeutic agents, should be further studied. In D2-resected gastric cancer, the addition of radiotherapy to chemotherapy does not appear to provide any additional benefit.].

CD24 expression predicts distant metastasis in extrahepatic bile duct cancer.

AIM: To evaluate the prognostic significance of CD24 expression in patients undergoing adjuvant chemoradiotherapy for extrahepatic bile duct (EHBD) cancer. METHODS: Eighty-four patients with EHBD cancer who underwent curative resection followed by adjuvant chemoradiotherapy were enrolled in this study. Postoperative radiotherapy was delivered to the tumor bed and regional lymph nodes up to a median of 40 Gy (range: 40-56 Gy). All patients also received fluoropyrimidine chemotherapy for radiosensitization during radiotherapy. CD24 expression was assessed with immunohistochemical staining on tissue microarray. Clinicopathologic factors as well as CD24 expression were evaluated in multivariate analysis for clinical outcomes including loco-regional recurrence, distant metastasis-free and overall survival. RESULTS: CD24 was expressed in 36 patients (42.9%). CD24 expression was associated with distant metastasis, but not with loco-regional recurrence nor with overall survival. The 5-year distant metastasis-free survival rates were 55.1% and 29.0% in patients with negative and positive expression, respectively (P = 0.0100). On multivariate analysis incorporating N stage, histologic differentiation and CD24 expression, N stage was the only significant factor predicting distant metastasis-free survival (P = 0.0089), while CD24 expression had borderline significance (P = 0.0733). In subgroup analysis, CD24 expression was significantly associated with 5-year distant metastasis-free survival in node-positive patients (38.4% with negative expression vs 0% with positive expression, P = 0.0110), but not in node-negative patients (62.0% with negative expression vs 64.0% with positive expression, P = 0.8599). CONCLUSION: CD24 expression was a significant predictor of distant metastasis for patients undergoing curative resection followed by adjuvant chemoradiotherapy especially for node-positive EHBD cancer.

Pharmacogenetic analysis of adjuvant FOLFOX for Korean patients with colon cancer.

PURPOSE: Ethnic diversity of genetic polymorphism can result in individual differences in the efficacy and toxicity of cancer chemotherapy. METHODS: We analyzed 20 germline polymorphisms in 10 genes (TS, MTHFR, ERCC1, XPD, XRCC1, ABCC2, AGXT, GSTP1, GSTT1 and GSTM1) from prospectively enrolled 292 Korean patients treated with adjuvant oxaliplatin plus leucovorin plus 5-fluorouracil (FOLFOX) for colon cancer. RESULTS: In contrast to previous studies in Caucasians, neutropenia (grade 3-4, 60.5 %) was frequently observed, whereas only 16.4 % experienced grade 2 or more sensory neuropathy. Neutropenia was more frequent in MTHFR 677TT [adjusted odds ratio (OR) 2.32, 95 % confidence interval (CI) 1.19-4.55] and ERCC1 19007TT (adjusted OR 4.58, 95 % CI 1.20-17.40) genotypes. Patients harboring XRCC1 23885GG experienced less grade 2-4 neuropathy [adjusted OR 0.52, 95 % CI 0.27-0.99]. MTHFR 677TT (p = 0.002) and XRCC1 23885GG (p = 0.146) genotypes were also more prevalent in Koreans compared to Caucasians. TS 'low' genotype (adjusted HR 1.83, 95 % CI 1.003-3.34) was significantly related to shorter disease-free survival. Overall survival was not significantly different according to the polymorphisms. CONCLUSIONS: Polymorphisms in MTHFR, XRCC1 and TS are related to toxicities and disease-free survival in patients with colon cancer. The ethnic differences in frequencies of genotypes may explain the ethnic difference in toxicity profile following adjuvant FOLFOX chemotherapy.

Methylation and microsatellite status and recurrence following adjuvant FOLFOX in colorectal cancer.

The prognostic impact of CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) on the treatment outcome of colon cancer patients receiving adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) is unclear. We investigated CIMP and MSI status in colorectal cancer patients treated with adjuvant FOLFOX. Stages II and III sporadic colorectal cancer patients who underwent curative resection followed by adjuvant FOLFOX were included. Eight CpG island loci (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, CDKN2A (p16), RUNX3 and SOCS1) and five microsatellite markers were examined. Disease-free survival (DFS) was analyzed according to CIMP and MSI status. A total of 322 patients were included: male/female 192/130, median age 61 years (range 30-78), proximal/distal location 118/204 and Stages II/III 43/279. CIMP status was high in 25 patients (7.8%) and 21 patients (6.5%) had MSI-high tumor. CIMP/MSI status was not significantly associated with DFS: 3-year DFS 100% in CIMP(-)/MSI(+), 84% in CIMP(-)/MSI(-), 82% in CIMP(+)/MSI(-) and 75% in CIMP(+)/MSI(+) (p = 0.33). Results of exploratory analysis showed that concurrent methylation at NEUROG1 and CDKN2A (p16) was associated with shorter DFS: 3-year DFS 69% in NEUROG1(+)/CDKN2A (p16)(+) versus 87% in NEUROG1(-)/CDKN2A (p16)(-) (p = 0.006). In conclusion, concurrent methylation of NEUROG1 and CDKN2A (p16) is associated with recurrence following adjuvant FOLFOX in Stages II/III colorectal cancer.

Prognostic significance of tumour location after adjuvant chemoradiotherapy for periampullary adenocarcinoma.

PURPOSE: To analyse the outcome of adjuvant chemoradiotherapy for periampullary adenocarcinoma and the impact of tumour location as a prognosticator. METHODS AND MATERIALS: Between January 1991 and December 2002, 147 patients with periampullary cancer underwent adjuvant chemoradiotherapy after pancreaticoduodenectomy. Postoperative radiotherapy was delivered to tumour bed and regional lymph nodes up to 40 Gy at 2 Gy/fraction with a two-week planned rest. Intravenous 5-fluorouracil (500 mg/m(2)/day) was given on days 1-3 of each split course. The median follow-up period was 82 months in survivors. RESULTS: Tumour >2 cm and margin-positivity were more common in patients with pancreatic cancer than nonpancreatic periampullary cancers (p<0.0001 and 0.0780, respectively). According to the tumour location, 5-year overall survival rates of ampulla of Vater, distal common bile duct, duodenal and pancreatic head cancers were 53.0%, 50.3%, 37.5%, and 13.0%, respectively (p<0.0001). On multivariate analysis, pancreatic location (p<0.0001) and nodal involvement (p=0.0123) were associated with inferior overall survival. CONCLUSION: Regardless of its advanced histologic features, pancreatic location itself was an adverse prognostic factor affecting overall survival.

Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial.

BACKGROUND: D2 gastrectomy is recommended in US and European guidelines, and is preferred in east Asia, for patients with resectable gastric cancer. Adjuvant chemotherapy improves patient outcomes after surgery, but the benefits after a D2 resection have not been extensively investigated in large-scale trials. We investigated the effect on disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared with D2 gastrectomy only in patients with stage II-IIIB gastric cancer. METHODS: The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study was an open-label, parallel-group, phase 3, randomised controlled trial undertaken in 37 centres in South Korea, China, and Taiwan. Patients with stage II-IIIB gastric cancer who had had curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1000 mg/m(2) twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m(2) on day 1 of each cycle) for 6 months or surgery only. Block randomisation was done by a central interactive computerised system, stratified by country and disease stage. Patients, and investigators giving interventions, assessing outcomes, and analysing data were not masked. The primary endpoint was 3 year disease-free survival, analysed by intention to treat. This study reports a prespecified interim efficacy analysis, after which the trial was stopped after a recommendation by the data monitoring committee. The trial is registered at ClinicalTrials.gov (NCT00411229). FINDINGS: 1035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up was 34·2 months (25·4-41·7) in the chemotherapy and surgery group and 34·3 months (25·6-41·9) in the surgery only group. 3 year disease-free survival was 74% (95% CI 69-79) in the chemotherapy and surgery group and 59% (53-64) in the surgery only group (hazard ratio 0·56, 95% CI 0·44-0·72; p<0·0001). Grade 3 or 4 adverse events were reported in 279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only group. The most common adverse events in the intervention group were nausea (n=326), neutropenia (n=300), and decreased appetite (n=294). INTERPRETATION: Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer. FUNDING: F Hoffmann-La Roche and Sanofi-Aventis.

Role of adjuvant chemoradiotherapy for duodenal cancer: a single center experience.

OBJECTIVES: To compare the treatment outcome of surgery alone with that of surgery followed by adjuvant chemoradiotherapy (CRT) for duodenal cancer. METHODS: Between January 1991 and December 2002, 24 patients with duodenal cancer underwent pancreaticoduodenectomy. There were 14 males and 10 females, and median age was 61 years (range, 33-75). Nine patients received adjuvant CRT, and 15 did not. Postoperative radiotherapy was delivered up to 40 Gy at 2 Gy/fraction with a 2-week planned rest. Intravenous 5-fluorouracil (500 mg/m/d) was given on days 1 to 3 of each split course. Median follow-up period was 32 months (range, 5-170). RESULTS: Nodal stage and stage group were more advanced in CRT (+) group (P=0.0894 and 0.0361, respectively). However, other patient and tumor characteristics were similar in each group. Five-year overall survival rates of CRT (-) and CRT (+) group were 47% and 30%, respectively (P=0.3799). Five-year locoregional relapse-free survival rates of CRT (-) and CRT (+) group were 64% and 80%, respectively (P=0.4188). On multivariate analysis, patients treated with adjuvant CRT had better locoregional relapse-free survival with borderline significance (P=0.0750). No patient suffered grade 3 or higher toxicity during CRT. CONCLUSIONS: Adjuvant CRT is feasible and may enhance locoregional control in advanced-staged duodenal cancer after curative resection.

Adjuvant chemoradiotherapy after curative resection for extrahepatic bile duct cancer: a long-term single center experience.

OBJECTIVES: To analyze the outcome of adjuvant chemoradiotherapy for patients with extrahepatic bile duct (EHBD) cancer, and to identify the prognostic factors for these patients. METHODS: Between January 1995 and December 2002, 86 patients with adenocarcinoma of EHBD underwent curative resection followed by adjuvant chemoradiotherapy. There were 59 male and 27 female patients, and median age was 59 years (range, 34 to 73 y). Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to 40 Gy at 2 Gy/fraction with a 2-week planned rest. Intravenous 5-fluorouracil (500 mg/m(2)/d) was given on day 1 to 3 of each split course. The median follow-up period was 83 months for survivors. RESULTS: Forty-eight patients failed the treatment: locoregional recurrence in 20, distant metastasis in 38, and both locoregional and distant relapses in 10 patients. Five-year locoregional relapse-free survival rate was 70.3%. On multivariate analysis, resection margin status was the only significant prognosticator (P=0.0299). Five-year distant metastasis-free survival rate was 53.6%. Three or more involved lymph nodes had an adverse impact on distant metastasis-free survival (P=0.0334). Five-year overall survival rate was 44.7%, and poorly differentiated tumor was associated with inferior overall survival (P=0.0297). CONCLUSIONS: Adjuvant chemoradiotherapy after curative resection can achieve a long-term survival in patients with EHBD cancer. Resection margin status, number of involved lymph nodes, and histologic differentiation are associated with locoregional relapse, distant metastasis, and overall survival, respectively. Distant metastasis was the major pattern of failure, possibly due to the increased locoregional control by use of adjuvant chemoradiotherapy. Intensification of systemic treatment is warranted.

Evaluation of the antitumor effects and mechanisms of PF00299804, a pan-HER inhibitor, alone or in combination with chemotherapy or targeted agents in gastric cancer.

Recently, HER2-directed treatment, such as trastuzumab, has shown clinical benefit in HER2-amplified gastric cancer. On the basis of recent studies about epidermal growth factor receptor (EGFR) or HER2-targeting agents (including gefitinib, lapatinib, and trastuzumab) in gastric cancer, the potent effects of pan-HER inhibitors targeting the HER family are anticipated. In this study, we evaluated the activity and mechanisms of PF00299804, an irreversible pan-HER inhibitor, in gastric cancer in vitro and in vivo models. PF00299804 showed significant growth-inhibitory effects in HER2-amplified gastric cancer cells (SNU216, N87), and it had lower 50% inhibitory concentration values compared with other EGFR tyrosine kinase inhibitors, including gefitinib, lapatinib, BIBW-2992, and CI-1033. PF00299804 induced apoptosis and G(1) arrest and inhibited phosphorylation of receptors in the HER family and downstream signaling pathways including STAT3, AKT, and extracellular signal-regulated kinases (ERK) in HER2-amplified gastric cancer cells. PF00299804 also blocked EGFR/HER2, HER2/HER3, and HER3/HER4 heterodimer formation as well as the association of HER3 with p85α in SNU216 cells. The combination of PF00299804 with clinically relevant chemotherapeutic agents or molecular-targeted agents including trastuzumab (an anti-HER2 monoclonal antibody), CP751871 (an IGF1R inhibitor), PD0325901 (an ERK1/2 inhibitor), and PF04691502 (a PI3K/mTOR inhibitor) produced synergistic effects. These findings indicate that PF00299804 can be used as a targeted therapy for the treatment of HER2-amplified gastric cancer through inhibition of HER family heterodimer formation and may augment antitumor efficacy of chemotherapeutic and/or molecular-targeted agents.

Concurrent versus sequential administration of CMF chemotherapy and radiotherapy after breast-conserving surgery in early breast cancer.

AIMS AND BACKGROUND: To compare the outcome of concurrent versus sequential administration of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy and radiotherapy after breast-conserving surgery in early breast cancer. METHODS: From February 1992 to January 2002, 156 patients underwent CMF chemotherapy and radiotherapy, either concurrently (CCRT group, 88 patients) or sequentially (SCRT group, 68 patients). There was a predilection of patients with a larger tumor (P = 0.0035), with more frequent nodal involvement (P = 0.0686), and younger age (P = 0.0776) in the CCRT group. RESULTS: The planned radiotherapy was completed in every patient. No grade 3 or 4 late treatment-related toxicity was observed in the CCRT or SCRT group. Compliance to the treatment as well as cosmetic outcome of the two groups were comparable. Despite more adverse factors for local-regional recurrence in the CCRT group, the 5-year local-regional control rate of the CCRT group was similar to that of the SCRT group (97.7% vs 93.8%, respectively, P = 0.1688). On multivariate analysis, concomitant administration of chemotherapy and radiotherapy was associated with improved local-regional control (P = 0.0463). CONCLUSIONS: Concurrent administration of CMF chemotherapy and radiotherapy resulted in improved local-regional control over sequential administration without an increase in significant toxicity. Concurrent CMF chemoradiotherapy may serve as a viable option for patients at high-risk of local-regional relapse not suitable for anthracycline or taxane-based chemotherapy.

Efficacy of infusional 5-fluorouracil, doxorubicin, and mitomycin-C (iFAM) in the treatment of patients with gemcitabine-pretreated pancreatic cancer and analysis of prognostic factors in a salvage setting.

PURPOSE: In gemcitabine-pretreated pancreatic cancer, salvage chemotherapy has not been established, and the prognostic factors are not completely known. The purpose of this study was to determine the efficacy and safety of infusional 5-fluorouracil (5-FU), doxorubicin, and mitomycin-C (iFAM) in patients with gemcitabine-pretreated pancreatic cancer and to elucidate the prognostic factors. METHODS: Study eligibility was as follows: (1) 18-75 years of age; (2) relapse within 6 months after adjuvant gemcitabine-based chemotherapy (GBC) or previously treated with palliative GBC; and (3) an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2. iFAM consisted of a 5-FU (800 mg/m(2)) infusion over 10 h on days 1-5, doxorubicin (30 mg/m(2)) on day 1, and mitomycin-C (8 mg/m(2)) on day 1 every 4 weeks. RESULTS: Sixty patients were enrolled. The responses to iFAM included a partial response in 6 patients (10.0%) and stable disease in 8 patients (13.3%). The median progression-free survival (PFS) and overall survival (OS) were 2.4 months (95% confidence interval [CI], 2.0-2.8 months) and 6.1 months (95% CI, 4.2-8.0 months), respectively. The 6- and 12-month survival rates were 50.4 and 26.4%, respectively. Grade 3/4 hematologic toxicities included neutropenia (3.3%) and thrombocytopenia (3.3%). The ECOG PS was a significant prognostic factor for PFS (P < 0.001) and OS (P = 0.022). An elevated CA 19-9 at the time of initiating iFAM (P = 0.011) was a poor prognostic factor for OS. CONCLUSIONS: iFAM is an effective and well-tolerated in patients with gemcitabine-pretreated pancreatic cancer, even patients with an ECOG PS of 2. ECOG PS and CA 19-9 were shown to be significant prognostic factors in this salvage setting.

Increasing nodal ratio is a poor prognostic factor for survival in stage III-IV (M0) gastric cancer patients who received curative surgery followed by adjuvant chemotherapy: a retrospective study.

OBJECTIVE: The aim of this study is to evaluate the efficacy of adjuvant chemotherapy with 5-fluorouracil and cisplatin in gastric cancer patients and to assess prognostic factors affecting relapse and survival. METHODS: We retrospectively reviewed the data of 153 patients with Stage III-IV (M0) gastric cancer. The patients were given adjuvant 5-fluorouracil/cisplatin chemotherapy after curative gastric resection with D2 dissection from November 1995 to November 2003. Chemotherapy consisted of cisplatin (60 mg/m(2) as 15 min i.v. infusion) and 5-fluorouracil (1200 mg/m(2) as 12 h continuous i.v. infusion for 4 days) in every 21 days up to six cycles. RESULTS: During a median follow-up period of 72.9 months (range: 2.0-135.0 months), a total of 105 patients relapsed (locoregional 19.0% vs. systemic 81.0%). The median disease-free survival and overall survival were 19.8 and 32.2 months, respectively. Univariate analysis revealed T stage, TNM stage and lymph node ratio as prognostic factors for survival (P = 0.002, <0.0001 and <0.0001, respectively). After stepwise selection of the factors, multivariate analysis confirmed the impact of the lymph node ratio and T stage on overall survival and disease-free survival. CONCLUSIONS: In patients with Stage III-IV (M0) gastric cancer, adjuvant 5-fluorouracil/cisplatin chemotherapy was tolerable, but did not seem to confer survival advantage. And the lymph node ratio was found as an independent prognostic factor in this population. This evidence suggests that the clinical trial using more active chemotherapeutic agents is mandatory.