Ramucirumab plus FOLFIRI as second-line treatment for patients with RAS wild-type metastatic colorectal cancer previously treated with anti-EGFR antibody: JACCRO CC-16.

BACKGROUND: Chemotherapy in combination with anti-epidermal growth factor receptor (EGFR) antibody is considered a first-line treatment regimen for RAS wild-type and left-sided metastatic colorectal cancer (mCRC), whereas second-line treatment regimens have not yet been established. Few studies have prospectively evaluated second-line treatment with anti-vascular endothelial growth factor antibody after first-line anti-EGFR antibody therapy for RAS wild-type mCRC. PATIENTS AND METHODS: This non-randomized phase II trial investigated the clinical outcomes of second-line ramucirumab (RAM) plus fluorouracil, levofolinate, and irinotecan (FOLFIRI) after first-line anti-EGFR antibody in combination with doublet or triplet regimen in patients with RAS wild-type mCRC. The primary endpoint was the 6-month progression-free survival (PFS) rate. The secondary endpoints were PFS, overall survival (OS), objective response rate (ORR), rate of early tumor shrinkage (ETS), and safety. We hypothesized a threshold 6-month PFS rate of 30% and an expected 6-month PFS rate of 45%. Treatment was considered effective if the lower limit of the 90% confidence interval (CI) of the 6-month PFS rate was >0.30. RESULTS: Ninety-two patients were enrolled in the study. The primary tumor was located on the left side in 86 (95.6%) patients. Twenty (22.0%) patients had received triplet plus cetuximab as previous therapy. Six-month PFS rate was 58.2% (90% CI 49.3% to 66.2%) with a median PFS of 7.0 months (95% CI 5.7-7.6 months). Median OS was 23.6 months (95% CI 16.5-26.3 months). The ORR and ETS rate were 10.7% and 16.9%, respectively, in 83 patients with measurable lesions. The 6-month PFS rate was comparable between patients previously treated with doublet and triplet regimens; however, median PFS was longer for the doublet regimen (7.4 versus 6.4 months, P = 0.036). CONCLUSIONS: Our study demonstrated prospectively that RAM plus FOLFIRI is an effective second-line treatment after anti-EGFR antibody-containing first-line therapy in RAS wild-type and left-sided mCRC. Furthermore, the results were similar for patients who were previously treated with triplet regimen.

Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy.

BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

Phase II study of trifluridine/tipiracil plus bevacizumab by RAS mutation status in patients with metastatic colorectal cancer refractory to standard therapies: JFMC51-1702-C7.

BACKGROUND: Although the efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) against metastatic colorectal cancer (mCRC) has been demonstrated, little is known about its effectiveness upon disease stratification by RAS mutations. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to RAS mutation status. PATIENTS AND METHODS: Eligible patients were mCRC refractory or intolerant to all standard therapies other than FTD/TPI and regorafenib. Patients received 4-week cycles of treatment with FTD/TPI (35 mg/m2, twice daily, days 1-5 and 8-12) and bevacizumab (5 mg/kg, days 1 and 15). The primary endpoint was disease control rate (DCR). The null hypothesis of DCR in both RAS wild-type (WT) and mutant (MUT) cohorts was 44%, assuming a one-sided significance level of 5.0%. The necessary sample size was estimated to be 49 patients (target sample size: 50 patients) for each cohort. RESULTS: Between January and September 2018, 102 patients were enrolled, and 97 patients fulfilled the eligibility criteria (48 in the RAS WT cohort and 49 in the RAS MUT cohort). DCRs in the RAS WT and MUT cohort were 66.7% [90% confidence interval (CI), 53.9%-77.8%, P = 0.0013] and 55.1% (90% CI, 42.4%-67.3%, P = 0.0780), respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.8 and 9.3 months, respectively, in the RAS WT cohort and 3.5 and 8.4 months, respectively, in the RAS MUT cohort. The most common grade 3 or higher adverse event in both cohorts was neutropenia (46% in the RAS WT cohort and 62% in the RAS MUT cohort), without unexpected safety signals. CONCLUSIONS: FTD/TPI plus bevacizumab showed promising activity with an acceptable safety profile for pretreated mCRC, regardless of RAS mutation status, although the efficacy outcomes tended to be better in RAS WT.

Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage II colon cancer: the randomized phase III ACHIEVE-2 trial.

BACKGROUND: Oxaliplatin-based adjuvant chemotherapy may be associated with debilitating peripheral sensory neuropathy (PSN) in patients with high-risk stage II colon cancer. This open-label, multicenter, randomized phase III trial was conducted as a prospective pooled analysis to investigate the non-inferiority of 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy. PATIENTS AND METHODS: From 12 February 2014 to 31 January 2017, 525 Asian patients with high-risk stage II colon cancer were randomly assigned to 3- and 6-month treatment arms. The treatment consisted of either modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine combined with oxaliplatin (CAPOX). The primary end point was disease-free survival (DFS). The secondary end points were treatment compliance and safety. RESULTS: Of the 525 randomized patients, 11 were not treated. Among the 514 participating patients (255 in the 3-month arm; 259 in the 6-month arm), 432 (84%) received CAPOX, and 184 (36%) presented with T4 as a high-risk factor for recurrence. The 3-year DFS rate was 88.2% in the 3-month arm and 87.9% in the 6-month arm [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.67-1.87]. With CAPOX, the 3-year DFS rate was 88.2% in the 3-month arm and 88.4% in the 6-month arm (HR, 1.13; 95% CI, 0.65-1.96). The discontinuation rate in the 3- and 6-month arms was 10% and 31% for mFOLFOX6 (P = 0.0193), and 15% and 35% for CAPOX (P < 0.0001), respectively. The incidence of grade ≥2 PSN was significantly lower in the 3-month arm than in the 6-month arm (16% and 43%, respectively, P < 0.0001). CONCLUSIONS: Three months of combination therapy presented significantly less grade ≥2 PSN than the respective 6-month regimen. The shortened therapy duration did not affect the 3-year DFS rate, suggesting that a 3-month course of CAPOX can be an effective treatment option. CLINICAL TRIAL INFORMATION: UMIN Clinical Trials Registry, UMIN000013036 and Japan Registry of Clinical Trials, jRCTs031180128.

Large-scale prospective pharmacogenomics study of oxaliplatin-induced neuropathy in colon cancer patients enrolled in the JFMC41-1001-C2 (JOIN Trial).

BACKGROUND: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.

Triiodothyronine resuscitates the impaired liver function after Pringle's maneuver.

OBJECTIVE: To evaluate the changes in thyroid hormone levels and the effectiveness of exogenous triiodothyronine (T3) in shock caused by prolonged use of Pringle's maneuver (cross-clamping of hepatic triads). DESIGN: Pringle's maneuver was performed on dogs for 1 hour. In the T3 group (n = 7), 1 microgram/kg per hour of T3 was administered intravenously for 3 hours after declamping. In the control group (n = 7), the same volume of saline solution without T3 was administered. MAIN OUTCOME MEASURES: Serum T3, reverse T3, thyroxine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and the ketone body ratio (AKBR), which reflect the hepatic energy charge, were measured. Tissue blood flow, tissue blood velocity, and tissue blood mass of the liver were measured by means of a laser Doppler flowmeter. Oxygen saturation of the hemoglobin in the liver tissue was measured by tissue near-infrared spectroscopy. Dogs were observed until the seventh postoperative day. RESULTS: In the control group, the low T3 syndrome was observed. None of the dogs recovered from the shock and none survived for more than 24 hours. In the T3 group, all dogs recovered from the shock and survived. In the control group, hepatic tissue blood flow and oxygen saturation of hemoglobin in liver tissue were decreased, and the AKBR was deteriorated. In the T3 group, however, these parameters were markedly improved. CONCLUSION: It is suggested that T3 administration is beneficial in managing the critical resuscitation period of liver function after Pringle's maneuver is performed in dogs.

Living-related liver transplantation for biliary atresia.

We reviewed our initial experience of 29 living-related liver transplantations (LRLT) for children with biliary atresia in terms of postoperative complications and management to analyze the factors that may influence the outcome. All patients underwent an initial portoenterostomy at 17-134 days of age. The age distribution at the time of LRLT ranged from 6 months to 12 years, following revised portoenterostomy 0 to 3 times, and with (n=5) or without enteric stoma (n=24). Living-related donors provided the partial liver grafts weighing 170 to 630 g according to recipient size. Twenty-six of the 29 recipients are alive and well with follow-up between 1 and 27 (mean=14) months. Three patients died of extrahepatic complications including aspiration asphyxia, Candida infection and lymphoproliferative disorder. Four of 5 children with enteric stoma had 9 incidences of postoperative complication, while only 4 incidences occurred in 4 out of 24 children without stoma (p=0.007). Children hospitalized at the time of transplantation seemed to have early postoperative complications more frequently than home-bound children (p=0.06). The present results indicated that LRLT could offer satisfactory outcome for children in whom repeated Kasai's operation could not attain adequate biliary diversion and for those who developed cirrhosis despite good initial bile drainage.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of triiodothyronine on canine hepatic ischemia caused by Pringle's maneuver.

BACKGROUND: A significant reduction in the serum concentration of triiodothyronine is frequently observed in surgical stress and may influence the severity and prognosis of the underlying disease. METHODS: Alterations of thyroid hormone levels and effects of triiodothyronine were evaluated in the shock state after Pringle's maneuver for 60 minutes in dogs. Triiodothyronine (1 micrograms/kg/hr) was infused intravenously for 3 hours after declamping in the triiodothyronine-treated group. The effect of triiodothyronine on hepatic mitochondrial function was investigated by measuring the arterial ketone body ratio (AKBR). RESULTS: In the control group (n = 6) the low triiodothyronine syndrome was observed and progressive deterioration of AKBR and standard liver functions represented by aspartate aminotransferase, glutamic-pyruvic transaminase, and lactic dehydrogenase were noted after declamping. All dogs went into shock and died within 24 hours. By contrast, in the triiodothyronine-treated group (n = 6), hemodynamics were stabilized and standard liver functions were maintained favorably (p < 0.01). AKBR was fully restored to the preischemic liver within 30 minutes after declamping, with a decrease in serum lactate levels (p < 0.05). All dogs survived at least 7 days after operation (p < 0.01). CONCLUSIONS: These results indicate that triiodothyronine has beneficial effects on cytoprotection, hemodynamics, and hepatic energy metabolism in the ischemic liver injury. Furthermore, it improves survival in the shock state after Pringle's maneuver.

Arterial ketone body ratio as a predictor of donor liver viability in human liver transplantation.

The viability of the donor liver was assessed with regard to early postoperative survival in human liver transplantations from 40 brain-dead donors at Hannover Medical College and 13 living donors at Kyoto University by measuring the arterial ketone body ratio (AKBR). Of 40 grafts harvested from brain-dead patients in Hannover, 35 survived the first week after operation, but 5 developed initial nonfunction of the transplanted graft within the first week. The mean AKBR values were 1.11 +/- 0.11 for grafts that survived and 0.44 +/- 0.10 for grafts that failed (P < 0.01). The AKBR values of the 5 initially nonfunctioning cases were all below 0.7. Of 13 grafts harvested from the living donors in Kyoto, all survived the first week. The AKBR values of the donors were all above 1.0, with a mean value of 1.87 +/- 0.23. Among all 53 cases, the survival rate of the grafts with AKBR above 0.7 was significantly higher than that of the grafts with AKBR below 0.7 (100% vs. 62%, P < 0.01). No other donor parameters, including age, dose of dopamine administered, and clinical laboratory findings, were significantly related to differences in graft survival rates. AKBR is a useful index for the evaluation of donor liver viability. Grafts used from donors with AKBR of less than 0.7 have a significantly increased risk of early nonfunction. Grafts from donors with AKBR of greater than 1.0 have, in our experience, always been viable after transplantation.

Beneficial effect of combined 3,5,3'-triiodothyronine and vasopressin administration of hepatic energy status and systemic hemodynamics after brain death.

The influence of combined replenishment of L-3,5,3'-triiodothyronine (T3) and vasopressin (antidiuretic hormone [ADH]) on both hepatic metabolism and systemic hemodynamics was assessed in brain-dead dogs. Arterial ketone body ratio (AKBR) was measured as a parameter of hepatic metabolism, which reflects the redox state (free nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide) of liver mitochondria. Mean arterial blood pressure (MAP) was significantly decreased from 110.4 +/- 3.8 to 44.4 +/- 1.7 mmHg, at 1 hr after completion of brain death (P less than 0.01). In the control group AKBR was maintained thereafter at near control value of 1.0 with a significant decrease in serum lactate concentration in spite of marked hypotension. T3 infusion at a rate of 1 microgram/kg/hr elevated the AKBR but did not elevate MAP. Vasopressin infusion at a rate of 0.1 U/kg/hr sustained AKBR and elevated MAP significantly at 1 hr after administration but tended to decrease thereafter. Combined administration of T3 and ADH elevated the AKBR to about 2.0, and MAP was restored to near-normal level. Other parameters such as glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and lactic dehydrogenase, reflecting liver cell injury and serum creatinine, and blood urea nitrogen as renal function, were maintained within normal range. These results indicate that combined T3 and vasopressin administration has a beneficial synergistic effect on both hepatic energy metabolism and systemic hemodynamics without any detrimental influence to other conventional parameters. Therefore, it is suggested that this combined administration may contribute to the management of potential multiorgan donors.

Decrease in arterial ketone body ratio indicating graft dysfunction after liver transplantation.

In 3 cases of living related liver transplantation, arterial ketone body ratio (AKBR) showed secondary decrease in the early postoperative period, indicating the graft dysfunction more rapidly and sensitively than other liver function tests. Significance of AKBR for monitoring the graft function in postoperative management after liver transplantation is discussed.

Maintenance of liver graft viability in the state of brain death. Synergistic effects of vasopressin and epinephrine on hepatic energy metabolism in brain-dead dogs.

The influence of vasopressin and epinephrine on hepatic energy metabolism in the state of brain death was assessed by measuring arterial ketone body ratio (AKBR) and hepatic energy charge (EC) in brain-dead dogs. Mean arterial blood pressure (MABP) was significantly decreased from 125.5 +/- 5.5 to 53.4 +/- 1.7 mmHg after complete brain death (P less than 0.01). In the control group AKBR and EC were maintained at near the normal values thereafter, despite marked hypotension. Combined administration of vasopressin and epinephrine sustained AKBR normally and improved MABP above 90 mmHg (P less than 0.01). EC was also maintained within the normal range at 5 hr after initiation of administration of the drugs. By contrast, vasopressin or epinephrine alone maintained AKBR and EC at near the normal values, but improved MABP just slightly to around 60 mmHg (P less than 0.01). As for the volume control, the urinary output was significantly smaller in the vasopressin and epinephrine-treated group than in the control group (P less than 0.05). It is suggested that combined administration of vasopressin and epinephrine has a synergistic effect in improving the hemodynamics and maintenance of the energy status of the liver. This regimen is recommended as a good one for maintaining potential liver donors in the state of brain death.

Hepatic energy status in hypotension of different aetiologies in dogs.

1. The alterations in hepatic energy metabolism in hypotension induced by the administration of trimetaphan camsylate (Arfonad) were investigated in comparison with those produced by hypotension resulting from massive haemorrhage by measuring the arterial ketone body ratio, which reflects the hepatic mitochondrial redox state, and other indices of hepatic energy metabolism together with simultaneous measurement of hepatic blood flow in dogs. 2. Mean arterial blood pressure was decreased from 130 mmHg to 60 mmHg by the continuous intravenous infusion of trimetaphan camsylate or by the use of Wiggers' shock model. In hypotension induced by trimetaphan camsylate, the arterial ketone body ratio, ATP and total adenine nucleotide concentrations and energy charge were maintained at near-control values throughout the experimental period. By contrast, the arterial ketone body ratio decreased from 1.04 +/- 0.09 to 0.29 +/- 0.06 at 3 h after haemorrhage in Wiggers' shock model (P less than 0.01). The ATP and total adenine nucleotide concentrations and energy charge also decreased significantly in this model (P less than 0.05). The difference in hepatic energy status was also shown by data from 31P nuclear magnetic resonance spectroscopy. 3. During hypotension, portal venous and total hepatic blood flows diminished significantly compared with the control values in each group (P less than 0.01). Although there was no significant difference in total hepatic flow between the two groups, the portal venous blood flow in hypotension induced by trimetaphan camsylate was significantly higher than that in Wiggers' shock model (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)