Giuseppe Zimmitti

RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases

Objective: To determine the impact of RAS mutation status on survival and patterns of recurrence in patients undergoing curative resection of colorectal liver metastases (CLM) after preoperative modern chemotherapy. Background: RAS mutation has been reported to be associated with aggressive tumor biology. However, the effect of RAS mutation on survival and patterns of recurrence after resection of CLM remains unclear. Methods: Somatic mutations were analyzed using mass spectroscopy in 193 patients who underwent single-regimen modern chemotherapy before resection of CLM. The relationship between RAS mutation status and survival outcomes was investigated. Results: Detected somatic mutations included RAS (KRAS/NRAS) in 34 (18%), PIK3CA in 13 (7%), and BRAF in 2 (1%) patients. At a median follow-up of 33 months, 3-year overall survival (OS) rates were 81% in patients with wild-type versus 52.2% in patients with mutant RAS (P = 0.002); 3-year recurrence-free survival (RFS) rates were 33.5% with wild-type versus 13.5% with mutant RAS (P = 0.001). Liver and lung recurrences were observed in 89 and 83 patients, respectively. Patients with RAS mutation had a lower 3-year lung RFS rate (34.6% vs 59.3%, P < 0.001) but not a lower 3-year liver RFS rate (43.8% vs 50.2%, P = 0.181). In multivariate analyses, RAS mutation predicted worse OS [hazard ratio (HR) = 2.3, P = 0.002), overall RFS (HR = 1.9, P = 0.005), and lung RFS (HR = 2.0, P = 0.01), but not liver RFS (P = 0.181). Conclusions: RAS mutation predicts early lung recurrence and worse survival after curative resection of CLM. This information may be used to individualize systemic and local tumor-directed therapies and follow-up strategies.

Kinetic Growth Rate after Portal Vein Embolization Predicts Posthepatectomy Outcomes: Toward Zero Liver-Related Mortality in Patients with Colorectal Liver Metastases and Small Future Liver Remnant

BACKGROUND Standardized future liver remnant (sFLR) volume and degree of hypertrophy after portal vein embolization (PVE) have been recognized as important predictors of surgical outcomes after major liver resection. However, the regeneration rate of the FLR after PVE varies among individuals and its clinical significance is unknown. STUDY DESIGN Kinetic growth rate (KGR) is defined as the degree of hypertrophy at initial volume assessment divided by number of weeks elapsed after PVE. In 107 consecutive patients who underwent liver resection for colorectal liver metastases with an sFLR volume >20%, the ability of the KGR to predict overall and liver-specific postoperative morbidity and mortality was compared with sFLR volume and degree of hypertrophy. RESULTS Using receiver operating characteristic analysis, the best cutoff values for sFLR volume, degree of hypertrophy, and KGR for predicting postoperative hepatic insufficiency were estimated as 29.6%, 7.5%, and 2.0% per week, respectively. Among these, KGR was the most accurate predictor (area under the curve 0.830 [95% CI, 0.736-0.923]; asymptotic significance, 0.002). A KGR of <2% per week vs ≥2% per week correlates with rates of hepatic insufficiency (21.6% vs 0%; p = 0.0001) and liver-related 90-day mortality (8.1% vs 0%; p = 0.04). The predictive value of KGR was not influenced by sFLR volume or the timing of initial volume assessment when evaluated within 8 weeks after PVE. CONCLUSIONS Kinetic growth rate is a better predictor of postoperative morbidity and mortality after liver resection for small FLR than conventional measured volume parameters (ie, sFLR volume and degree of hypertrophy).

Optimal Morphologic Response to Preoperative Chemotherapy: An Alternate Outcome End Point Before Resection of Hepatic Colorectal Metastases

PURPOSE The purposes of this study were to confirm the prognostic value of an optimal morphologic response to preoperative chemotherapy in patients undergoing chemotherapy with or without bevacizumab before resection of colorectal liver metastases (CLM) and to identify predictors of the optimal morphologic response. PATIENTS AND METHODS The study included 209 patients who underwent resection of CLM after preoperative chemotherapy with oxaliplatin- or irinotecan-based regimens with or without bevacizumab. Radiologic responses were classified as optimal or suboptimal according to the morphologic response criteria. Overall survival (OS) was determined, and prognostic factors associated with an optimal response were identified in multivariate analysis. RESULTS An optimal morphologic response was observed in 47% of patients treated with bevacizumab and 12% of patients treated without bevacizumab (P < .001). The 3- and 5-year OS rates were higher in the optimal response group (82% and 74%, respectively) compared with the suboptimal response group (60% and 45%, respectively; P < .001). On multivariate analysis, suboptimal morphologic response was an independent predictor of worse OS (hazard ratio, 2.09; P = .007). Receipt of bevacizumab (odds ratio, 6.71; P < .001) and largest metastasis before chemotherapy of ≤ 3 cm (odds ratio, 2.12; P = .025) were significantly associated with optimal morphologic response. The morphologic response showed no specific correlation with conventional size-based RECIST criteria, and it was superior to RECIST in predicting major pathologic response. CONCLUSION Independent of preoperative chemotherapy regimen, optimal morphologic response is sufficiently correlated with OS to be considered a surrogate therapeutic end point for patients with CLM.

Margin Status Remains an Important Determinant of Survival after Surgical Resection of Colorectal Liver Metastases in the Era of Modern Chemotherapy

Objective:To determine the impact of surgical margin status on overall survival (OS) of patients undergoing hepatectomy for colorectal liver metastases after modern preoperative chemotherapy. Background:In the era of effective chemotherapy for colorectal liver metastases, the association between surgical margin status and survival has become controversial. Methods:Clinicopathologic data and outcomes for 378 patients treated with modern preoperative chemotherapy and hepatectomy were analyzed. The effect of positive margins on OS was analyzed in relation to pathologic and computed tomography–based morphologic response to chemotherapy. Results:Fifty-two of 378 resections (14%) were R1 resections (tumor-free margin <1 mm). The 5-year OS rates for patients with R0 resection (margin ≥1 mm) and R1 resection were 55% and 26%, respectively (P = 0.017). Multivariate analysis identified R1 resection (P = 0.03) and a minor pathologic response to chemotherapy (P = 0.002) as the 2 factors independently associated with worse survival. The survival benefit associated with negative margins (R0 vs R1 resection) was greater in patients with suboptimal morphologic response (5-year OS rate: 62% vs 11%; P = 0.007) than in patients with optimal response (3-year OS rate: 92% vs 88%; P = 0.917) and greater in patients with a minor pathologic response (5-year OS rate: 46% vs 0%; P = 0.002) than in patients with a major response (5-year OS rate: 63% vs 67%; P = 0.587). Conclusions:In the era of modern chemotherapy, negative margins remain an important determinant of survival and should be the primary goal of surgical therapy. The impact of positive margins is most pronounced in patients with suboptimal response to systemic therapy.

Portal vein embolization improves rate of resection of extensive colorectal liver metastases without worsening survival

Most patients requiring an extended right hepatectomy (ERH) have an inadequate standardized future liver remnant (sFLR) and need preoperative portal vein embolization (PVE). However, the clinical and oncological impact of PVE in such patients remains unclear.

Return to intended oncologic treatment (RIOT): A novel metric for evaluating the quality of oncosurgical therapy for malignancy

After cancer surgery, complications, and disability prevent some patients from receiving subsequent treatments. Given that an inability to complete all intended cancer therapies might negate the oncologic benefits of surgical therapy, strategies to improve return to intended oncologic treatment (RIOT), including minimally invasive surgery (MIS), are being investigated.

Ninety-Day Postoperative Mortality Is a Legitimate Measure of Hepatopancreatobiliary Surgical Quality

Objective: To investigate the legitimacy of 90-day mortality as a measure of hepatopancreatobiliary quality. Background: The 90-day mortality rate has been increasingly but not universally reported after hepatopancreatobiliary surgery. The legitimacy of this definition as a measure of surgical quality has not been evaluated. Methods: We retrospectively reviewed the causes of all deaths that occurred within 365 postoperative days in patients undergoing hepatectomy (n = 2811) and/or pancreatectomy (n = 1092) from January 1997 to December 2012. The rates of surgery-related, disease-related, and overall mortality within 30 days, within 30 days or during the index hospitalization, within 90 days, and within 180 days after surgery were calculated. Results: Seventy-nine (3%) surgery-related deaths and 92 (3%) disease-related deaths occurred within 365 days after hepatectomy. Twenty (2%) surgery-related deaths and 112 (10%) disease-related deaths occurred within 365 days after pancreatectomy. The overall mortality rates at 99 and 118 days optimally reflected surgery-related mortality after hepatobiliary and pancreatic operations, respectively. The 90-day overall mortality rate was a less sensitive but equivalently specific measure of surgery-related death. Conclusions and Relevance: The 99- and 118-day definitions of postoperative mortality optimally reflected surgery-related mortality after hepatobiliary and pancreatic operations, respectively. However, among commonly reported metrics, the 90-day overall mortality rate represents a legitimate measure of surgical quality.

Systematic Use of an Intraoperative Air Leak Test at the Time of Major Liver Resection Reduces the Rate of Postoperative Biliary Complications

BACKGROUND After hepatectomy, bile leaks remain a major cause of morbidity, cost, and disability. This study was designed to determine if a novel intraoperative air leak test (ALT) would reduce the incidence of post-hepatectomy biliary complications. STUDY DESIGN Rates of postoperative biliary complications were compared among 103 patients who underwent ALT and 120 matched patients operated on before ALT was used. All study patients underwent major hepatectomy without bile duct resection at 3 high-volume hepatobiliary centers between 2008 and 2012. The ALT was performed by placement of a transcystic cholangiogram catheter to inject air into the biliary tree, the upper abdomen was filled with saline, and the distal common bile duct was manually occluded. Uncontrolled bile ducts were identified by localization of air bubbles at the transection surface and were directly repaired. RESULTS The 2 groups were similar in diagnosis, chemotherapy use, tumor number and size, resection extent, surgery duration, and blood loss (all, p > 0.05). Single or multiple uncontrolled bile ducts were intraoperatively detected and repaired in 62.1% of ALT vs 8.3% of non-ALT patients (p < 0.001). This resulted in a lower rate of postoperative bile leaks in ALT (1.9%) vs non-ALT patients (10.8%; p = 0.008). Independent risk factors for postoperative bile leaks included extended hepatectomy (p = 0.031), caudate resection (p = 0.02), and not performing ALT (p = 0.002) (odds ratio = 3.8; 95% CI, 1.3-11.8; odds ratio = 4.0; 95% CI, 1.1-14.3; and odds ratio = 11.8; 95% CI, 2.4-58.8, respectively). CONCLUSIONS The ALT is an easily reproducible test that is highly effective for intraoperative detection and repair of open bile ducts, reducing the rate of postoperative bile leaks.

Adjuvant Chemotherapy With FOLFOX for Primary Colorectal Cancer Is Associated With Increased Somatic Gene Mutations and Inferior Survival in Patients Undergoing Hepatectomy for Metachronous Liver Metastases

Objective:We hypothesized that metachronous colorectal liver metastases (CLM) have different biology after failure of oxaliplatin (FOLFOX) compared to 5-fluorouracil (5-FU) or no chemotherapy for adjuvant treatment of colorectal cancer (CRC). Background:It is unclear whether patients treated with liver resection for metachronous CLM after adjuvant FOLFOX for CRC have worse outcomes than those who received 5-FU or no chemotherapy. Methods:We identified 341 patients who underwent hepatectomy for metachronous CLM (disease-free interval ≥12 months, 1993–2010). Mass-spectroscopy genotyping for somatic gene mutations in CLM was performed in a subset of 129 patients. Results:Adjuvant treatment for primary CRC was FOLFOX in 77 patients, 5-FU in 169 patients, and no chemotherapy in 95 patients. Node-positive primary was comparable between FOLFOX and 5-FU but lower in the no-chemotherapy group (P < 0.0001). Median metastasis size was smaller in the FOLFOX group (2.5 cm) than in the 5-FU (3.0 cm) or no-chemotherapy (3.5 cm) groups, (P = 0.008) although prehepatectomy chemotherapy utilization, metastases number, and carcinoembryonic antigen levels were similar. Disease-free survival (DFS) and overall survival (OS) rates after hepatectomy were worse in patients treated with adjuvant FOLFOX [DFS at 3 years: 14% vs 38% (5-FU) vs 45% (no-chemo), OS at 3 years: 58% vs 70% (5-FU) vs 84% (no-chemo)]. On multivariate analysis, adjuvant FOLFOX was associated with worse DFS (P < 0.0001) and OS (P < 0.0001). Mutation analysis revealed ≥1 mutations in 57% of patients (27/47) after FOLFOX, 29% (12/41) after 5-FU, and 32% (13/41) after no chemotherapy (P = 0.011). Conclusions:Adjuvant FOLFOX for primary CRC is associated with a high rate of somatic mutations in liver metastases and inferior outcomes after hepatectomy for metachronous CLM.

Multicenter validation study of pathologic response and tumor thickness at the tumor-normal liver interface as independent predictors of disease-free survival after preoperative chemotherapy and surgery for colorectal liver metastases

To validate pathologic markers of response to preoperative chemotherapy as predictors of disease‐free survival (DFS) after resection of colorectal liver metastases (CLM).