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Eur J Surg Oncol. Author manuscript; available in PMC 2017 September 01. Published in final edited form as: Eur J Surg Oncol. 2016 September ; 42(9): 1378–1384. doi:10.1016/j.ejso.2016.02.249.
Prognostic factors after resection of colorectal liver metastases following preoperative second-line chemotherapy: Impact of RAS mutations G. Passota, Y.S. Chuna, S.E. Kopetzb, M.J. Overmanb, C. Conrada, T.A. Aloiaa, and J.-N. Vautheya,*
Author Manuscript
aDepartment
of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1484, Houston, TX, USA
bDepartment
of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1484, Houston, TX, USA
Abstract Background—After resection of colorectal liver metastases (CLM), RAS mutations are associated with modest survival benefit and second-line chemotherapy confers limited hope for cure. Objective—To evaluate the impact of RAS mutation after second-line chemotherapy for patients undergoing potentially curative liver resection for CLM.
Author Manuscript
Methods—Among 1357 patients operated for CLM between January 2005 and November 2014, patients with known RAS mutational status were identified. Outcomes after second-line chemotherapy were analyzed by RAS status.
Author Manuscript
Results—Among 635 patients undergoing resection of CLM, 46 received second-line chemotherapy before resection, including 14 patients (30%) with RAS mutations. Patients who received second-line chemotherapy had significantly larger and greater number of liver metastases and were more likely to undergo major hepatectomy. Median overall (OS) and recurrence free survival (RFS) were significantly worse among patients requiring second-line chemotherapy (OS: 44.4 vs. 61.1 months, p = 0.021; RFS: 7.3 vs. 12.0 months, p = 0.001). Among patients undergoing liver resection after second-line chemotherapy, RAS mutations were associated with worse median OS and RFS (OS: 35.2 vs. 60.7 months, p = 0.038; RFS: 3.6 vs. 8.3 months, p = 0.015). RAS mutation was the only independent factor associated with OS and RFS. All patients with RAS mutations recurred within 18 months. Among patients with RAS wild-type tumors, the receipt of second-line chemotherapy did not affect OS (p = 0.493). Conclusion—Among patients undergoing resection of CLM after second-line chemotherapy, RAS mutational status is an independent predictor of survival and outweighs other factors to select patients for liver resection. *
Corresponding author. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1484 Houston, TX 77030, USA. [email protected] (J.-N. Vauthey). Conflict of interest statement All of the authors indicate no conflict of interest.
Passot et al.
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Author Manuscript
Keywords RAS; Colorectal; Liver; Metastases; Chemotherapy
Introduction
Author Manuscript
For patients with stage IV colorectal cancer, the liver is the most common site of distant metastases.1 Advances in modern chemotherapy and targeted agents have significantly improved response and survival rates for patients with colorectal liver metastases (CLM).2–4 To date, surgical resection of CLM offers the only possibility for cure.5 Tumor progression during preoperative chemotherapy is associated with poor outcomes after resection of CLM.6 For patients who progress on first-line chemotherapy, a change to a second-line regimen is recommended. However, survival in patients undergoing liver resection after second-line chemotherapy is limited with a modest hope of cure.7 Rat sarcoma viral oncogene homolog (RAS) mutations, found in up to 35% of patients with resected CLM, have been reported as a major prognostic factor for patients undergoing resection of CLM, irrespective of chemotherapy regimen.8 The prognostic impact of RAS mutations in patients undergoing hepatectomy after second-line chemotherapy has not been previously reported. The purpose of this study was to determine the outcomes of patients with RAS mutations who received second-line preoperative chemotherapy before CLM resection.
Methods Population and definitions
Author Manuscript
This study was approved by the Institutional Review Board (IRB) of The University of Texas MD Anderson Cancer Center (IRB protocol PA15-0113). A retrospective review of a prospectively maintained database was performed of 1357 patients undergoing resection for CLM between January 2005 and November 2014. The study population was narrowed to patients with known RAS mutational status. Liver resection was considered curative when a complete tumor resection was achieved. Patients who received prior liver-directed treatment at other institutions were excluded. The electronic medical record was queried for demographic data, clinicopathologic factors, RAS mutation status, preoperative treatment, and surgical procedure. Pathologic response to preoperative chemotherapy was graded as previously described.9 A positive resection margin was defined as tumor cells within 1 mm of the margin.10
Author Manuscript
RAS mutation profiling
RAS mutational status was determined from the primary tumor or liver metastases, as previously described.11 Briefly, polymerase chain reaction-based primer extension assay was performed to screen for mutations in KRAS codons 12 and 13 in all patients and for mutations in KRAS codons 61 and 146 and NRAS codons 12, 13, and 61 in the majority of patients since 2012. The lower limit of detection of this assay was approximately one mutant allele in the background of nine wild-type alleles. Single mutations in the various codons of KRAS and NRAS were analyzed together and reported as RAS mutations.
Eur J Surg Oncol. Author manuscript; available in PMC 2017 September 01.
Passot et al.
Page 3
Perioperative chemotherapy
Author Manuscript Author Manuscript
At The University of Texas MD Anderson Cancer Center, the institutional guidelines for patients with CLM included preoperative chemotherapy in almost all patients.12 Patients with resectable CLM who developed CLM within a year after the end of adjuvant chemotherapy for primary tumor could be an exception to this strategy. First-line chemotherapy was proposed according to patient oncological history and adapted to RAS status for combination of anti EGFR therapy.13 After 4 cycles, restaging was performed to evaluate radiological response according to response evaluation criteria in solid tumor (RECIST)14 and morphological response.15,16 Criteria for resectability of CLM has previously been defined.17 For patients with response to chemotherapy, extrahepatic metastases identified on preoperative imaging were not considered a contraindication to liver resection with curative intent.18 Second-line chemotherapy was considered for patients with disease progression or suboptimal response after first-line chemotherapy, or for patients with unacceptable toxicity with the first-line regimen. A suboptimal response was defined as an insufficient response to allow a complete and safe resection based on preoperative volumetric assessment.
Author Manuscript
As previously described, a second-line chemotherapy was defined as any change in the chemotherapy regimen before liver resection of CLM.7 Adjuvant chemotherapy for primary tumor was not considered as first-line chemotherapy except in patients with synchronous CLM (CLM detected at same time as the primary tumor) and patients who developed CLM during adjuvant chemotherapy for the primary tumor. Reasons for receiving second-line chemotherapy were classified: (1) progression during first-line chemotherapy, (2) advanced metastases with suboptimal response to the first-line chemotherapy regimen, or (3) intolerable toxicity of the first-line chemotherapy regimen. Maintenance chemotherapy was not considered as a new line of chemotherapy. Chemotherapy after liver resection was proposed to complete a total of 12 cycles, including preoperative and postoperative chemotherapy. Statistical analysis Quantitative and qualitative variables were expressed as median and range and frequency. Comparisons between groups were analyzed using chi-squared test for proportions, Mann– Whitney U test for median as appropriate.
Author Manuscript
Survival was calculated from the date of first liver surgery, and patients died within 90 days after liver resection from postoperative complication were excluded from the survival analysis. Overall (OS) and recurrence free survival (RFS) were calculated by using the Kaplan–Meier method and compared using the log-rank test. Variables with p value of less than 0.1 from univariate analysis were entered into cox regression survival analysis with backward conditional method. p < 0.05 was considered statistically significant. Statistical analysis was performed using SPSS version 22 (SPSS Inc., IBM, Chicago, IL).
Eur J Surg Oncol. Author manuscript; available in PMC 2017 September 01.
Passot et al.
Page 4
Author Manuscript
Results Population
Author Manuscript
Among 635 patients with known RAS status undergoing potentially curative liver resection, 589 (93%) and 46 (7%) received
Eur J Surg Oncol. Author manuscript; available in PMC 2017 September 01. Published in final edited form as: Eur J Surg Oncol. 2016 September ; 42(9): 1378–1384. doi:10.1016/j.ejso.2016.02.249.
Prognostic factors after resection of colorectal liver metastases following preoperative second-line chemotherapy: Impact of RAS mutations G. Passota, Y.S. Chuna, S.E. Kopetzb, M.J. Overmanb, C. Conrada, T.A. Aloiaa, and J.-N. Vautheya,*
Author Manuscript
aDepartment
of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1484, Houston, TX, USA
bDepartment
of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1484, Houston, TX, USA
Abstract Background—After resection of colorectal liver metastases (CLM), RAS mutations are associated with modest survival benefit and second-line chemotherapy confers limited hope for cure. Objective—To evaluate the impact of RAS mutation after second-line chemotherapy for patients undergoing potentially curative liver resection for CLM.
Author Manuscript
Methods—Among 1357 patients operated for CLM between January 2005 and November 2014, patients with known RAS mutational status were identified. Outcomes after second-line chemotherapy were analyzed by RAS status.
Author Manuscript
Results—Among 635 patients undergoing resection of CLM, 46 received second-line chemotherapy before resection, including 14 patients (30%) with RAS mutations. Patients who received second-line chemotherapy had significantly larger and greater number of liver metastases and were more likely to undergo major hepatectomy. Median overall (OS) and recurrence free survival (RFS) were significantly worse among patients requiring second-line chemotherapy (OS: 44.4 vs. 61.1 months, p = 0.021; RFS: 7.3 vs. 12.0 months, p = 0.001). Among patients undergoing liver resection after second-line chemotherapy, RAS mutations were associated with worse median OS and RFS (OS: 35.2 vs. 60.7 months, p = 0.038; RFS: 3.6 vs. 8.3 months, p = 0.015). RAS mutation was the only independent factor associated with OS and RFS. All patients with RAS mutations recurred within 18 months. Among patients with RAS wild-type tumors, the receipt of second-line chemotherapy did not affect OS (p = 0.493). Conclusion—Among patients undergoing resection of CLM after second-line chemotherapy, RAS mutational status is an independent predictor of survival and outweighs other factors to select patients for liver resection. *
Corresponding author. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1484 Houston, TX 77030, USA. [email protected] (J.-N. Vauthey). Conflict of interest statement All of the authors indicate no conflict of interest.
Passot et al.
Page 2
Author Manuscript
Keywords RAS; Colorectal; Liver; Metastases; Chemotherapy
Introduction
Author Manuscript
For patients with stage IV colorectal cancer, the liver is the most common site of distant metastases.1 Advances in modern chemotherapy and targeted agents have significantly improved response and survival rates for patients with colorectal liver metastases (CLM).2–4 To date, surgical resection of CLM offers the only possibility for cure.5 Tumor progression during preoperative chemotherapy is associated with poor outcomes after resection of CLM.6 For patients who progress on first-line chemotherapy, a change to a second-line regimen is recommended. However, survival in patients undergoing liver resection after second-line chemotherapy is limited with a modest hope of cure.7 Rat sarcoma viral oncogene homolog (RAS) mutations, found in up to 35% of patients with resected CLM, have been reported as a major prognostic factor for patients undergoing resection of CLM, irrespective of chemotherapy regimen.8 The prognostic impact of RAS mutations in patients undergoing hepatectomy after second-line chemotherapy has not been previously reported. The purpose of this study was to determine the outcomes of patients with RAS mutations who received second-line preoperative chemotherapy before CLM resection.
Methods Population and definitions
Author Manuscript
This study was approved by the Institutional Review Board (IRB) of The University of Texas MD Anderson Cancer Center (IRB protocol PA15-0113). A retrospective review of a prospectively maintained database was performed of 1357 patients undergoing resection for CLM between January 2005 and November 2014. The study population was narrowed to patients with known RAS mutational status. Liver resection was considered curative when a complete tumor resection was achieved. Patients who received prior liver-directed treatment at other institutions were excluded. The electronic medical record was queried for demographic data, clinicopathologic factors, RAS mutation status, preoperative treatment, and surgical procedure. Pathologic response to preoperative chemotherapy was graded as previously described.9 A positive resection margin was defined as tumor cells within 1 mm of the margin.10
Author Manuscript
RAS mutation profiling
RAS mutational status was determined from the primary tumor or liver metastases, as previously described.11 Briefly, polymerase chain reaction-based primer extension assay was performed to screen for mutations in KRAS codons 12 and 13 in all patients and for mutations in KRAS codons 61 and 146 and NRAS codons 12, 13, and 61 in the majority of patients since 2012. The lower limit of detection of this assay was approximately one mutant allele in the background of nine wild-type alleles. Single mutations in the various codons of KRAS and NRAS were analyzed together and reported as RAS mutations.
Eur J Surg Oncol. Author manuscript; available in PMC 2017 September 01.
Passot et al.
Page 3
Perioperative chemotherapy
Author Manuscript Author Manuscript
At The University of Texas MD Anderson Cancer Center, the institutional guidelines for patients with CLM included preoperative chemotherapy in almost all patients.12 Patients with resectable CLM who developed CLM within a year after the end of adjuvant chemotherapy for primary tumor could be an exception to this strategy. First-line chemotherapy was proposed according to patient oncological history and adapted to RAS status for combination of anti EGFR therapy.13 After 4 cycles, restaging was performed to evaluate radiological response according to response evaluation criteria in solid tumor (RECIST)14 and morphological response.15,16 Criteria for resectability of CLM has previously been defined.17 For patients with response to chemotherapy, extrahepatic metastases identified on preoperative imaging were not considered a contraindication to liver resection with curative intent.18 Second-line chemotherapy was considered for patients with disease progression or suboptimal response after first-line chemotherapy, or for patients with unacceptable toxicity with the first-line regimen. A suboptimal response was defined as an insufficient response to allow a complete and safe resection based on preoperative volumetric assessment.
Author Manuscript
As previously described, a second-line chemotherapy was defined as any change in the chemotherapy regimen before liver resection of CLM.7 Adjuvant chemotherapy for primary tumor was not considered as first-line chemotherapy except in patients with synchronous CLM (CLM detected at same time as the primary tumor) and patients who developed CLM during adjuvant chemotherapy for the primary tumor. Reasons for receiving second-line chemotherapy were classified: (1) progression during first-line chemotherapy, (2) advanced metastases with suboptimal response to the first-line chemotherapy regimen, or (3) intolerable toxicity of the first-line chemotherapy regimen. Maintenance chemotherapy was not considered as a new line of chemotherapy. Chemotherapy after liver resection was proposed to complete a total of 12 cycles, including preoperative and postoperative chemotherapy. Statistical analysis Quantitative and qualitative variables were expressed as median and range and frequency. Comparisons between groups were analyzed using chi-squared test for proportions, Mann– Whitney U test for median as appropriate.
Author Manuscript
Survival was calculated from the date of first liver surgery, and patients died within 90 days after liver resection from postoperative complication were excluded from the survival analysis. Overall (OS) and recurrence free survival (RFS) were calculated by using the Kaplan–Meier method and compared using the log-rank test. Variables with p value of less than 0.1 from univariate analysis were entered into cox regression survival analysis with backward conditional method. p < 0.05 was considered statistically significant. Statistical analysis was performed using SPSS version 22 (SPSS Inc., IBM, Chicago, IL).
Eur J Surg Oncol. Author manuscript; available in PMC 2017 September 01.
Passot et al.
Page 4
Author Manuscript
Results Population
Author Manuscript
Among 635 patients with known RAS status undergoing potentially curative liver resection, 589 (93%) and 46 (7%) received
