A randomized controlled trial of surgery and postoperative modified FOLFOX6 versus surgery and perioperative modified FOLFOX6 plus cetuximab in patients with KRAS wild-type resectable colorectal liver metastases: EXPERT study.

PURPOSE: To clarify the efficacy of perioperative chemotherapy for the patients with resectable colorectal liver metastases (CLM), we conducted a multicenter randomized phase III trial to compare surgery followed by postoperative FOLFOX regimen with perioperative FOLFOX regimen plus cetuximab in patients with KRAS wild-type resectable CLM. METHODS: Patients who had KRAS wild-type resectable CLM having one to eight liver nodules without extrahepatic disease were randomly assigned to the postoperative chemotherapy group, wherein up-front hepatectomy was performed followed by 12 cycles of postoperative modified FOLFOX6, and the perioperative chemotherapy group (experimental), wherein six cycles of preoperative modified FOLFOX6 plus cetuximab were performed followed by hepatectomy and six cycles of postoperative modified FOLFOX6 plus cetuximab. The primary endpoint was progression-free survival (PFS). RESULTS: There were 37 patients in postoperative chemotherapy group and 40 patients in the perioperative chemotherapy group who were analyzed. Baseline characteristics were well-balanced between groups. The PFS and overall survival (OS) showed no significant difference (PFS, hazard ratio 1.18 [95% confidence interval 0.69-2.01], P = 0.539: OS, 1.03 [0.46-2.29], P = 0.950). In the postoperative chemotherapy group, 35.1% had a 3-year PFS, and 86.5% had a 3-year OS. Meanwhile, in the perioperative chemotherapy group, 30.0% had a 3-year PFS, and 74.4% had a 3-year OS. CONCLUSION: There was no difference in survival found between the group of the perioperative chemotherapy plus cetuximab and that of the postoperative chemotherapy in the cohort of our study. The study was registered in the University Hospital Medical Information Network (UMIN000007787).

A multicenter phase II trial evaluating the efficacy of bevacizumab plus mFOLFOX6 for R0 surgical resection in advanced colorectal liver metastases harboring mutant-type KRAS: NEXTO-mt trial.

BACKGROUND: The effect of bevacizumab plus mFOLFOX6 on downsizing of liver metastases for curative resection has not been well assessed for patients with advanced colorectal liver metastases (CRLMs). This multicenter phase II trial aimed to examine the efficacy and safety of bevacizumab plus mFOLFOX6 for advanced CRLMs harboring mutant-type KRAS. METHODS: Patients with advanced CRLMs (tumor number of ≥5 and/or technically unresectable) harboring mutant-type KRAS were included. Surgical indication was evaluated every 4 cycles of bevacizumab plus mFOLFOX6. Liver resection was planned if the CRLMs were resectable. The primary endpoint was R0 resection rate. The secondary endpoints included overall survival (OS), recurrence-free survival, progression-free survival, and safety. RESULTS: Between 2013 and 2017, 29 patients from six centers were registered. The rates of complete and partial responses were 0% and 62.1%, respectively. R0 and R1 resections were performed in 19 and 1 patient, respectively (R0 resection rate: 65.5%). No mortality occurred. During the median follow-up of 30.7 months, the 3-year OS rate for all the patients was 64.4% with the median survival of 49.1 months. CONCLUSION: For advanced CRLMs harboring mutant-type KRAS, bevacizumab plus mFOLFOX6 achieved a high R0 resection rate, leading to favorable survival.

A Multicenter Phase 2 Trial to Evaluate the Efficacy of mFOLFOX6 + Cetuximab as Induction Chemotherapy to Achieve R0 Surgical Resection for Advanced Colorectal Liver Metastases (NEXTO Trial).

BACKGROUND: The effect of cetuximab plus mFOLFOX on downsizing of the tumors for curative resection has yet to be assessed for patients with advanced colorectal liver metastases (CRLMs). This study aimed to assess the oncologic benefit of cetuximab plus mFOLFOX for wild-type KRAS patients with advanced CRLMs. METHODS: In this multicenter phase 2 trial, patients with technically unresectable tumor and/or five or more CRLMs harboring wild-type KRAS were treated with mFOLFOX plus cetuximab. The patients were assessed for resectability after 4 treatments, and then every 2 months up to 12 treatments. Patients with resectable disease were offered surgery after a waiting period of 1 month. The primary end point of the study was the R0 resection rate. The secondary end points were safety, progression-free survival (PFS), and overall survival (OS). The study is registered with the University Hospital Medical Information Network-Clinical Trials Registry Clinical Trials Registry (no. C000007923). RESULTS: Between 2012 and 2015, 50 patients from 13 centers were enrolled in this trial. Two patients were excluded because they had not received induction therapy. The 48 patients had a complete response rate of 0% and a partial response rate of 64.6%. For 26 R0 resections (54.2%) and 5 R1 resections (10.4%), no mortality occurred. During a median follow-up period of 31 months, the median OS for all the patients was calculated to be 41 months (95% confidence interval, 28-not reached). The 3-year OS rate was 59%. CONCLUSION: For patients with advanced CRLMs harboring wild-type KRAS, cetuximab administered in combination with mFOLFOX yields high response rates, leading to significantly high R0 resection rates and favorable prognoses.

CD133 Expression at the Metastatic Site Predicts Patients' Outcome in Colorectal Cancer with Synchronous Liver Metastasis.

BACKGROUND: CD133 is a transmembrane protein that is proposed to be a stem cell marker of colorectal cancer (CRC); however, the correlation between CD133 expression and survival of CRC patients with liver metastasis has not been fully examined. METHODS: CD133 expression was evaluated immunohistochemically, both in primary tumors and synchronous liver metastases of 88 consecutive CRC patients, as well as recurrent lesions in the remnant liver of 27 of these 88 patients. The relationship between CD133 expression and clinicopathological characteristics, recurrence-free survival, and overall survival (OS) was analyzed. RESULTS: CD133 expression in liver metastases (mCD133) was detected in 50 of 88 patients (56.8 %), and had significant correlation with CD133 expression in primary lesions (pCD133) (p < 0.001). CD133 expression in liver recurrent lesions (recCD133) also had a significant correlation with mCD133 (p < 0.001). mCD133+ patients had significantly longer disease-free survival (p = 0.043) and OS (p = 0.014) than mCD133- patients. In addition, mCD133+ patients had a significantly lower rate of extrahepatic recurrence (p < 0.001). CONCLUSIONS: Patients without CD133 expression in liver metastasis had significantly shorter survival, perhaps because mCD133- patients had a significantly higher rate of extrahepatic recurrence.

Phase 1 study on S-1 and oxaliplatin therapy as an adjuvant after hepatectomy for colorectal liver metastases.

of Background Data The effectiveness of adjuvant chemotherapy in patients with stage II/III colorectal cancer has been confirmed in various studies. However, no adjuvant chemotherapy for colorectal liver metastasis (CLM) classified to stage IV has been established. Objectives We conducted a phase 1 study of S-1 and oxaliplatin to determine the recommended dose (RD) in patients with CLM as adjuvant therapy in two institutes. Methods S-1 and oxaliplatin were administered from day 1 to day 14 of a 3-week cycle as a 2-h infusion every 3 weeks, respectively. The initial doses of S-1 and oxaliplatin were fixed to 80 mg/m(2) and 100 mg/m(2), respectively (level 1). We scheduled in the protocol a dose change of S-1 and oxaliplatin to level 2 (S-1: 80 mg/m(2) and oxaliplatin: 130 mg/m(2)) or level 0 (S-1: 65 mg/m(2) and oxaliplatin: 100 mg/m(2)) depending on the incidence of dose-limiting toxicity (DLT) at level 1 in six patients. Results Because DLT occurred in one among the initial six patients at level 1, the doses were increased to level 2 in the next six patients. At level 2, grade 3 leukopenia and neutropenia occurred in one (16.7 %) and two (33.3 %) patients, respectively, in the absence of non-hematological event. Because no DLT occurred at level 2, we suggest that the RD can be set to the level 2 dose. The median number of cycles delivered at RD was 8. The mean relative dose intensity of S-1 and oxaliplatin at RD was 0.90 and 0.63, respectively. Conclusion In a patient undergoing hepatectomy for CLM, 80 mg/m(2) of S-1 and 130 mg/m(2) of oxaliplatin are recommended as adjuvant therapy. A further study is required to confirm the efficacy and safety of this regimen on a larger scale.

Discrepancy between recurrence-free survival and overall survival in patients with resectable colorectal liver metastases: a potential surrogate endpoint for time to surgical failure.

BACKGROUND: Recurrence-free survival (RFS) may not be a surrogate for overall survival (OS) in patients with resectable colorectal liver metastases (CLM). We investigated whether a new composite tool-time to surgical failure (TSF)-is a suitable endpoint. METHODS: The medical records of consecutive patients who underwent curative resection for CLM at our center over a 17-year period were reviewed. Patients with liver-limited tumors (n = 371) who had not received previous treatment for metastasis were eligible for analysis. TSF was defined as the time until unresectable relapse or death. The correlations between TSF and OS, and between RFS and OS, were assessed for all the eligible patients. RESULTS: The median OS, TSF, and RFS were 5.7, 2.7, and 0.7 years, respectively, and the 5-year OS, TSF, and RFS rates were 52.6, 39.8, and 23.7 %, respectively, for all patients. The rates of first, second, and third relapse were 75.5, 77.6, and 70.8 %, respectively, and repeat resections were performed in 54.3 % (first relapses), 40.7 % (second relapses), and 47.1 % (third relapses) of patients. The concordance proportions of TSF and RFS for OS events were 0.83 and 0.65, respectively. The correlation between TSF and OS was stronger than that between RFS and OS in terms of the predicted probabilities. CONCLUSIONS: The correlation between TSF and OS was stronger than that between RFS and OS after curative hepatic resection. TSF could be a suitable endpoint for CLM overall management.

Surgical resection for local recurrence after radiofrequency ablation for colorectal liver metastasis is more extensive than primary resection.

OBJECTIVE: As a minimally invasive modality, radiofrequency ablation (RFA) has been increasingly applied not only for the treatment of hepatocellular carcinoma, but also for that of colorectal liver metastasis (CLM). However, RFA for CLM has been shown to be associated with a high local recurrence rate, and no optimal treatment for RFA failure has been established yet. The aim of this study was to evaluate the feasibility and outcome of surgical resection for local recurrence after RFA. MATERIAL AND METHODS: A retrospective study of 17 patients, who underwent surgery for local recurrence after RFA for resectable CLM, was carried out. The surgical procedures involved in the actual surgery were compared with those envisioned for the primary resection if RFA had not been selected. RESULTS: Surgical resection for RFA recurrence was more invasive than the envisioned surgical procedure in 10 cases (58%). In addition, the proportions of cases that required technically demanding procedures among the patients receiving surgery for RFA recurrence were higher than those in envisioned operations; major hepatectomy, eight cases [47%] versus two cases [12%] (p<0.0205); excision and/or reconstruction of the major hepatic veins, three cases [18%] versus zero case [0%] (p=0.035); excision of diaphragm: three cases [18%] versus zero case [0%] (p=0.035). The 1-, 3- and 5-year overall survival rates were 92%, 45% and 45%, respectively. CONCLUSIONS: Surgical resection for RFA recurrence for CLM required more invasive and technically demanding procedures. Thus, RFA for CLM should be limited to unresectable cases, and patients with resectable CLM should be thoroughly advised not to undergo RFA, but rather surgical resection.

Sequential therapy of portal vein embolization and systemic chemotherapy for locally advanced perihilar biliary tract cancer.

BACKGROUND: Curative resection is the only potential treatment for cure in patients with perihilar biliary tract cancer (PBTC). However, post hepatectomy liver failure (PHLF) due to insufficient future liver remnant volume (FRLV) remains a lingering risk even after portal vein embolization (PVE). This study aimed to investigate the feasibility and efficacy of a sequential treatment strategy consisting of PVE followed by preoperative chemotherapy before surgery. METHODS: Between April 2019 and December 2021, 15 patients with locally advanced PBTC (LA-PBTC) underwent sequential treatment consisting of PVE followed by preoperative chemotherapy. The feasibility and efficacy, including resection rate, changes of FRLV, and chemotherapeutic effect, were investigated retrospectively. RESULTS: Thirteen of 15 patients (86.6%) underwent curative resection. The median duration time between PVE and surgery was 144 days. FRLV/TLV ratio was 31.3% at prePVE, 38.4%, at two weeks after PVE, and 45.7% before surgery, respectively. There was significant increase in FRLV/TLV ratio two weeks after PVE. Additional increase in FRLV/TLV ratio was significantly achieved before surgery. PHLF occurred in 5 patients (38.4%). Pathological complete response was found in 2 of 13 patients (15.3%). CONCLUSIONS: Sequential PVE and systemic chemotherapy contribute to the sufficient hypertrophy of FRLV without compromising resectability in patients with LA-PBTC.

Adjuvant chemotherapy can prolong recurrence-free survival but did not influence the type of recurrence or subsequent treatment in patients with colorectal liver metastases.

BACKGROUND: Although liver resection is the only potentially curative treatment for colorectal liver metastases, recurrence is frequent. We previously published the early results of a randomized controlled phase 3 trial showing that adjuvant therapy with uracil-tegafur and leucovorin significantly prolongs recurrence-free survival. This study sought to elucidate the impact of adjuvant chemotherapy on patient survival after an additional follow-up period, building upon the results of our previous study. METHODS: After resection for colorectal liver metastases, patients were randomly assigned in a 1:1 ratio to receive adjuvant uracil-tegafur and leucovorin or surgery alone. Patients assigned to the uracil-tegafur and leucovorin group received 5 cycles of uracil-tegafur and leucovorin within 8 weeks after surgery. RESULTS: Patients were assigned to an adjuvant uracil-tegafur and leucovorin (n = 90) or a surgery alone (n = 90) group; 3 patients were excluded because of protocol violations. After a median follow-up period of 7.36 years (95% confidence interval, 6.93-7.87), 60 (68.2%) patients in the uracil-tegafur and leucovorin group and 61 (68.5%) patients in the surgery alone group developed recurrences. The median recurrence-free survival was 1.45 years (95% confidence interval, 0.96-2.16) in the uracil-tegafur and leucovorin group and 0.70 years (95% confidence interval, 0.44-1.07) in the surgery alone group. The locations and treatments of the first recurrences did not differ between the groups, nor did the overall survival (hazard ratio, 0.86; 95% confidence interval, 0.54-1.38; P = .54). The overall survival was significantly longer in patients who underwent curative repeated resection than in patients who received non-surgical treatment (hazard ratio, 0.25; 95% confidence interval, 0.15-0.40; P < .0001). CONCLUSION: Adjuvant uracil-tegafur and leucovorin significantly prolonged the recurrence-free survival but not the overall survival. The repeated resection was the most important factor influencing overall survival.

Chemoprevention of glandular stomach carcinogenesis through duodenogastric reflux in rats by a COX-2 inhibitor.

Duodenogastric reflux (DGR) causes glandular stomach carcinogenesis in rats without carcinogens. We aimed to investigate how this carcinogenesis might be prevented by a selective COX-2 inhibitor, meloxicam. A series of 188 Fisher 344 rats underwent a surgical DGR procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other an experimental chow containing meloxicam [0.3 mg/kg bw/day] (meloxicam group). The animals were sequentially sacrificed at weeks 20, 30, 40, 50 and 60 after surgery. The stomachs were removed and examined for the presence of carcinoma, incidence of reflux-induced morphologic changes, COX-2 expression and its activity. Adenocarcinoma in the glandular stomach developed in 7 of 21 animals (33%) in the control group at week 60, but none of 20 (0%) in the meloxicam group (p < 0.01). Moreover, reflux-induced gastritis was definitely alleviated in the meloxicam group compared with the control group. COX-2 immunoreactivity was predominantly detected in stromal cells such as macrophages and fibroblasts. Compared with nonsurgical rats, RNA expression of COX-2 in the mucosa increased, reaching peak at an early phase of week 20 in both groups (p < 0.005). Expression of microsomal prostaglandin E synthase-1 was lower in the meloxicam group than in the control group. PGE(2) production was significantly suppressed throughout the experiment in the meloxicam group compared with the control group (p < 0.01). Gastric carcinogenesis via duodenal reflux was mediated by the COX-2 pathway in rats. Administration of meloxicam prevented this carcinogenesis by suppressing the inflammatory process.

Ingestion of thioproline suppresses rat esophageal adenocarcinogenesis caused by duodenogastroesophageal reflux.

Duodenogastroesophageal reflux causes esophageal adenocarcinoma in rats without the use of a carcinogen. This etiology is unclear, but may be associated with endogenous nitrosation in the gastrointestinal tract. Thioproline (TPRO) is an effective nitrite-trapping agent and blocks endogenous nitrosation. We investigated how ingested TPRO affected esophageal adenocarcinogenesis in rats with duodenogastroesophageal reflux (DGER) or gastroesophageal reflux (GER). A series of 200 male Fischer 344 rats received surgery to induce reflux of duodenogastric contents or gastric contents alone into the esophagus. The rats were separated into two divisions according to the surgical procedure employed (DGER or GER), and each division was further subdivided into two groups: one group was fed a special diet (CRF-1 containing 0.5% of TPRO); the other group was fed a standard diet (CRF-1). The rats were given no carcinogen and sacrificed at ten-week intervals from the 25th to the 45th week after surgery. Pathological examination was carried out using hematoxylin-eosin or immunohistochemical staining. Erosion, regenerative thickening, basal cell hyperplasia and columnar-lined epithelium (CLE) were found in both groups of the DGER rats. Adenocarcinoma (AC) appeared only in the DGER rats sacrificed at 35 and 45 weeks following surgery. The incidence of AC at the 45th week was significantly lower in the group of rats fed the diet containing TPRO, as compared to those fed the standard diet, whereas the incidences of CLE were the same for both groups. iNOS protein and nitrotyrosine protein were identified in the CLE and macrophages of the DGER group using immunohistochemical staining. There were no remarkable pathological changes in the esophagi of the rats which underwent the GER procedure. In conclustion, TPRO has an inhibitory effect on esophageal reflux-induced adenocarcinogenesis in rats in that it prevents the progression from CLE to AC.

[A case of adult neuroblastoma arising in the retroperitoneum following a poorly aggressive course].

A 69-year-old man complaining of enlarged cervical mass, appetite loss and lower abdominal pain was found to have abdominal tumors in heaps forming a large mass around the retroperitoneum. The biopsy specimen in the cervical mass showed undifferentiated carcinoma with neuroendocrine feature. This malignancy followed a poorly aggressive course and caused death in only 24 hospital days. The disease was diagnosed as undifferentiated neuroblastoma arising in the retroperitoneum by autopsy with appropriate immunohistochemical studies. Adult neuroblastoma in the peritoneum is rare and our case showed a aggressive behavior and unfortunate outcome.

Survival benefit of repeat resection of successive recurrences after the initial hepatic resection for colorectal liver metastases.

BACKGROUND: Relapse is common after the resection of colorectal liver metastases (CLM); however, the optimal treatment for such recurrent disease remains uncertain. We investigated whether repeat resections for successive recurrences of CLM provide survival benefit on the postrecurrence survival. METHODS: We reviewed patients who underwent upfront, curative resection for CLM at our center during a 15-year period. Of these, 263 patients who had not received any other perioperative treatment for the metastases were eligible for our analysis. The recurrence-free survival (RFS0) after the initial hepatic resection and after the first (n = 108), second (n = 43), and third (n = 15) repeat resections for recurrent disease were assessed (RFS1-3). The overall survival after the initial hepatic resection and the postrecurrence survival (n = 198) also was assessed. RESULTS: The median RFS0 was 0.8 years, and RFS1, RFS2, and RFS3 were 1.3, 1.1, and 2.0 years, respectively. The hazard ratio for RFS for the first, second, and third resections versus the initial hepatic resection was 0.9 (95% confidence interval [95% CI] 0.7-1.1; P = .34), 1.00 (95% CI 0.7-1.4; P = .97), and 0.7 (95% CI 0.4-1.3; P = .29). The 5-year and 10-year OS rates were 54.6% and 42.2%, and the 5-year and 10-year postrecurrence survival was 34.3% and 28.6%, respectively. CONCLUSION: Repeat resection in patients with recurrent disease after CLM resection is beneficial, offering the potential for cure in a small proportion of patients with recurrent disease.

Adjuvant Oral Uracil-Tegafur with Leucovorin for Colorectal Cancer Liver Metastases: A Randomized Controlled Trial.

BACKGROUND: The high recurrence rate after surgery for colorectal cancer liver metastasis (CLM) remains a crucial problem. The aim of this trial was to evaluate the efficacy of adjuvant therapy with uracil-tegafur and leucovorin (UFT/LV). METHODS: In the multicenter, open-label, phase III trial, patients undergoing curative resection of CLM were randomly assigned in a 1:1 ratio to either the UFT/LV group or surgery alone group. The UFT/LV group orally received 5 cycles of adjuvant UFT/LV (UFT 300mg/m2 and LV 75mg/day for 28 days followed by a 7-day rest per cycle). The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included overall survival (OS). RESULTS: Between February 2004 and December 2010, 180 patients (90 in each group) were enrolled into the study. Of these, 3 patients (2 in the UFT/LV group and 1 in the surgery alone group) were excluded from the efficacy analysis. Median follow-up was 4.76 (range, 0.15-9.84) years. The RFS rate at 3 years was higher in the UFT/LV group (38.6%, n = 88) than in the surgery alone group (32.3%, n = 89). The median RFS in the UFT/LV and surgery alone groups were 1.45 years and 0.70 years, respectively. UFT/LV significantly prolonged the RFS compared with surgery alone with the hazard ratio of 0.56 (95% confidence interval, 0.38-0.83; P = 0.003). The hazard ratio for death of the UFT/LV group against the surgery alone group was not significant (0.80; 95% confidence interval, 0.48-1.35; P = 0.409). CONCLUSION: Adjuvant therapy with UFT/LV effectively prolongs RFS after hepatic resection for CLM and can be recommended as an alternative choice. TRIAL REGISTRATION: UMIN Clinical Trials Registry C000000013.

Repeat resection leads to long-term survival: analysis of 10-year follow-up of patients with colorectal liver metastases.

BACKGROUND: Some reports have shown that a significant number of patients experience recurrence, even after 5 or more years after surgery for colorectal liver metastases (CLMs). This study aimed to determine the actual cure rate and identify clinical characteristics among long-term survivors. METHODS: A prospectively maintained database was used to retrospectively review patients who underwent liver resection for CLM between 1994 and 2001. RESULTS: A total of 130 patients underwent liver resection for CLM with a complete 10-year follow-up. The 10-year disease-specific survival rate was 31.1%, and the survival curve reached a plateau after 10 years from the time of hepatic resection. There were 35 actual 10-year survivors. Multivariate analysis revealed that female patients and those with negative surgical margins were independent prognostic factors for disease-specific survival. CONCLUSION: A 10-year survival following initial hepatectomy should be defined as cure.

Radiological Morphology of Colorectal Liver Metastases after Preoperative Chemotherapy Predicts Tumor Viability and Postoperative Outcomes.

INTRODUCTION: The computed tomography (CT) morphology after chemotherapy is reportedly correlated with the histopathologic response to chemotherapy and a better surgical outcome in patients with colorectal liver metastases (CLM). However, the true prognostic advantage of CT morphology remains uncertain. METHODS: The prognostic advantage of CT morphology was validated in 86 patients who underwent surgical resection for CLM after undergoing a 5-fluorouracil-based chemotherapy regimen with or without bevacizumab. RESULTS: An optimal morphologic response was observed in 18 (22.8%) patients, and a strong correlation between the CT morphology and tumor viability was confirmed (P < 0.001). A multivariate analysis revealed that bevacizumab (odds ratio [OR], 6.8; P = 0.03) and chemotherapy cycles ≥6 (OR, 3.6; P = 0.04) were associated with an optimal morphologic response. Overall survival (OS) and recurrence-free survival (RFS) were also predicted by CT morphology with a higher sensitivity. Particularly, a group 1 morphology was associated with a higher OS rate (3-year OS 100%) and RFS rate (3-year RFS, 57.0%), and a multivariate analysis confirmed that group 2 and group 3 tumor morphology was a significant predictive factor for tumor recurrence (hazard ratio [HR], 2.5; P = 0.03 and HR, 3.2; P < 0.01, respectively). CONCLUSION: The CT morphology of CLM predicts tumor viability and long-term surgical outcomes after chemotherapy.

Cetuximab treatment for metastatic colorectal cancer with KRAS p.G13D mutations improves progression-free survival.

A number of previous studies have reported that 30-50% of patients with colorectal cancer (CRC) harbor Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, which is a major predictive biomarker of resistance to epidermal growth factor (EGFR)-targeted therapy. Treatment with an anti-EGFR inhibitor is recommended for patients with KRAS wild-type metastatic colorectal cancer (mCRC). A recent retrospective study of cetuximab reported that patients with KRAS p.G13D mutations had better outcomes compared with those with other mutations. The aim of this retrospective study was to assess the prevalence of KRAS p.G13D mutations and evaluate the effectiveness of cetuximab in mCRC patients with KRAS p.G13D or other KRAS mutations. We reviewed the clinical records of 98 mCRC patients with KRAS mutations who were treated between August, 2004 and January, 2011 in four hospitals located in Tokyo and Kyushu Island. We also investigated KRAS mutation subtypes and patient characteristics. In the patients who received cetuximab, univariate and multivariate analyses were performed to assess the effect of KRAS p.G13D mutations on progression-free survival (PFS) and overall survival (OS). Of the 98 patients, 23 (23.5%) had KRAS p.G13D-mutated tumors, whereas 75 (76.5%) had tumors harboring other mutations. Of the 31 patients who received cetuximab, 9 (29.0%) had KRAS p.G13D mutations and 22 (71.0%) had other mutations. There were no significant differences in age, gender, primary site, pathological type, history of chemotherapy, or the combined use of irinotecan between either of the patient subgroups. The univariate analysis revealed no significant difference in PFS or OS between the patients with KRAS p.G13D mutations and those with other mutations (median PFS, 4.5 vs. 2.8 months, respectively; P=0.65; and median OS, 15.3 vs. 8.9 months, respectively; P=0.51). However, the multivariate analysis revealed a trend toward better PFS among patients harboring p.G13D mutations (PFS: HR=0.29; 95% CI: 0.08-1.10; P=0.07; OS: HR=0.23; 95% CI: 0.04-1.54; P=0.13). In conclusion, treatment with cetuximab may be more clinically beneficial in mCRC patients with a KRAS p.G13D mutation, compared with those harboring other mutations. However, further investigation is required to clearly determine the benefits of cetuximab treatment in patients with KRAS p.G13D mutation-positive mCRC.

Evaluation of the safety and efficacy of simultaneous resection of primary colorectal cancer and synchronous colorectal liver metastases.

BACKGROUND: It remains unclear whether primary colorectal cancer and synchronous liver metastases (SLMs) should be resected simultaneously or with a staged procedure. METHODS: We reviewed the short-term outcomes of 127 patients who underwent simultaneous resection of primary colorectal cancer and SLM at our institution from January 1993 to December 2011. RESULTS: The proportion of simultaneous resections was 84.7% (127 of 150 patients). There was no postoperative mortality, and the postoperative complication rate was 61.4%. Major complications occurred in 23 (18.2%) patients, and anastomotic failure occurred in 2 (1.6%). The 3-, 5-, and 10-year overall survival rates were 74%, 64%, and 52%, respectively. The median recurrence-free survival period was 7.0 months (95% confidence interval, 4.5-9.5 months) and the 5-year recurrence-free survival rate was 17%. CONCLUSION: Simultaneous resection can be performed safely in patients with colorectal cancer and SLM.