J Gastrointest Canc DOI 10.1007/s12029-014-9594-y
ORIGINAL RESEARCH
Impact of Preoperative and Postoperative FOLFOX Chemotherapies in Patients with Resectable Colorectal Liver Metastasis Matthieu Faron & Mircea Chirica & Hadrien Tranchard & Pierre Balladur & Aimery de Gramont & Pauline Afchain & Thierry Andre & François Paye
# Springer Science+Business Media New York 2014
Abstract Purpose Whether the survival benefit of perioperative FOLFOX in patients with liver metastases of colorectal cancer (LMCRC) is provided by preoperative chemotherapy (CT), postoperative CT, or both remains unclear. This study aimed to evaluate, in patients with resectable LMCRC, the survival impact of preoperative and postoperative separately. Methods Between 2000 and 2010, the 179 patients (126 men, age 61±11 years) with initially resectable LMCRC, who underwent liver resection (LR) and were offered pre- and/or postoperative FOLFOX were included. Twenty-four (13 %) patients did not receive CT, 27(15 %) patients received only preoperative CT, 71 (40 %) patients received only postoperative CT, and 57 (32 %) patients received both pre- and postoperative CT. Results Operative morbidity and mortality rates were 19 and 0.6 %, respectively. At 1, 3, and 5 years, OS and DFS rates were 97, 66, 46 and 60, 32, and 24 %, respectively. Postoperative FOLFOX was an independent predictor of increased OS (HR=0.55 [95 % CI, 0.35–0.87] p=0.01) and DFS (HR=0.54 [0.36–0.82] p=0.0017), whereas the synchronous onset of the metastasis and the presence of radiographically occult liver metastases were independent predictors of poorer OS. Alternatively, preoperative FOLFOX had no
M. Faron : M. Chirica : H. Tranchard : P. Balladur : F. Paye (*) Department of Digestive Surgery, AP-HP Hôpital Saint Antoine, 184, rue du Faubourg Saint Antoine, Paris 75012, France e-mail: [email protected] P. Balladur : A. de Gramont : T. Andre : F. Paye University Pierre et Marie Curie UPMC Univ Paris 06, Paris, France A. de Gramont : P. Afchain : T. Andre Department of Oncology, AP-HP Hôpital Saint Antoine, Paris, France
significant influence on OS (HR=0.96 [0.57–1.60] p=0.83) or DFS (HR=1.05 [0.66–1.66] p=0.87). Conclusions The survival benefit of FOLFOX in patients with resectable LMCRC may be provided by postoperative rather than preoperative administration. Keywords Colorectal cancer . Liver metastasis . Chemotherapy
Introduction Liver resection is the mainstay of curative treatment for patients with liver metastasis of colorectal cancer (LMCRC) and provides 5-year survival rates ranging from 36 to 58 % [1]. Several new cytotoxic and targeted agents used in patients with unresectable metastatic colorectal cancer over the past two decades have resulted in improved survival and highresponse rates [2]. Relying on these promising results, various chemotherapy (CT) regimens have been offered to patients with resectable LMCRC in order to further improve outcomes [3–7]. However, the real benefits of CT used as either neoadjuvant or adjuvant treatment to liver resection remains a matter of debate in the literature [8–10]. The only available randomized controlled study including both preoperative and postoperative CT is the European Organization for Research and Treatment of Cancer (EORTC) 40983 phase III trial [7] in which perioperative FOLFOX was compared to surgery alone. This study included 364 patients and showed better progression-free survival in the FOLFOX group; the difference was even more significant when the analysis was restricted to patients who underwent curative resection. Despite lack of significant overall survival improvement in the perioperative FOLFOX arm, oxaliplatin-based perioperative CT has
J Gastrointest Canc
become the standard of treatment of resectable LMCRC in many centers across the world. Toughly, the EORTC trial [7] was not designed to evaluate the respective influence of preoperative and postoperative CT on patients’ outcome. It, thus, remains unclear whether the survival benefit in this study was related to the administration of preoperative CT, the administration of postoperative CT, or a synergic action of both of them. There is growing evidence supporting the survival advantage conferred by various adjuvant CT regimens after resection of LMCRC [3, 8, 11]. In contrast, most retrospective studies comparing the influence of preoperative and postoperative CT on patient outcome after liver resection (LR) of LMCRC failed to demonstrate a benefit of preoperative CT [8, 11] on survival. Along with the pioneering work of our group [2] since January 2000, patients with LMCRC evaluated for LR in our center were systematically considered for perioperative oxaliplatin-based CT. The aim of the present study was to evaluate the respective influence of preoperative and postoperative FOLFOX CT on long-term survival in patients with resectable LMCRC.
Patients and Methods Study Population Between January 2000 and 31 December 2010, 347 patients underwent liver resection of LMCRC (Fig. 1). Patients with extrahepatic disease (n=60), patients planned for two-stage LR (n=40), patients who received other CT regimens (n=36), and patients who underwent LR after CT downstaging of initially unresectable disease (n=32) were excluded. Thus, 179 patients with initially resectable liver metastasis who had no CT or received FOLFOX CT either in the preoperative period, the postoperative period, or both were included in the study. Preoperative Workup Systematic preoperative assessment included thoracic and abdominal helicoidal-computed tomography and/or magnetic resonance imaging (MRI) and, since 2007, a 2-[18-F]-fluoro2-deoxyglucose-PET scan [12]. Measurement of serum marker levels (CEA and CA 19.9) were performed systematically, and patients underwent control colonoscopy if previous complete colonoscopy dated from more than 1 year. Liver metastases diagnosed up to 6 months after treatment of the primary tumor were considered as synchronous. All treatment decisions were taken during multidisciplinary meetings involving surgeons, oncologists, radiologists, and pathologists specialized in colorectal cancer and liver surgery.
Liver Resection LR was undertaken only if complete resection of all liver metastatic sites with a minimal safety liver resection margin of 2 mm was preoperatively anticipated. Portal vein embolization was performed when the predicted remnant liver volume was less than 30 % of the standard liver volume. Intraoperative ultrasound (IOUS) was systematically used to assess the extent of liver involvement and define the transection line. Liver resection was performed using the clamp crushing method. Intermittent clamping of the hepatic pedicle (Pringle’s maneuver) was used to limit blood loss whenever necessary. Intraoperative radiofrequency ablation (RFA) was used for the destruction of single small (2) metachronous LMCRC. The response to CT was monitored every 2 months by CT imaging using the RECIST [15] criteria. Tumor progression contraindicated surgery and prompted second line CT with further reevaluation. Adjuvant CT was considered in all patients. All patients received FOLFOX chemotherapy. Cycles were administered every 14 days; 6 cycles were scheduled in both the pre- and postoperative periods.
J Gastrointest Canc Fig. 1 Flow Chart CT: Chemotherapy Note that due to study design, no direct comparisons are made between pre- and postoperative chemotherapy
Underwent liver resection for colorectal liver metastases: 347
Excluded: 168 (48%)
•
Extra-hepatic disease : 60
•
Two stage liver resection : 40
•
CT other than FOLFOX : 36
•
Initially unresectable metastases : 32
Included in the study: 179 (52%)
No CT
Pre-operative CT only
24 (13%)
Pre-operative and postoperative CT
27 (15%)
Post-operative CT only 71 (40%)
57 (32%)
No Preoperative CT 95 (53%)
Pre-operative CT 84 (47%)
Pre-operative CT evaluation groups
Follow-up Follow-up was conducted on an outpatient basis every 3 months during the first 2 years following liver resection, every 6 months the following 3 years, and annually after the fifth year. At each visit, physical examination, serum marker levels, and contrast-enhanced thoraco-abdomino-pelvic CT scan were performed. Patients who experienced resectable recurrence confined to the liver and/or the lungs were offered surgical resection after systematic 2-[18-F]-fluoro-2deoxyglucose-PET scan. Patients with unresectable recurrence were treated with exclusive CT. Statistical Analyses Quantitative variables are presented as mean (±SD) or median (interquartile range, IQR) when normality could not be assumed and compared with the Student’s t test or Wilcoxon’s test as appropriate. Qualitative variables are presented as count (proportion). Marginal associations between variables
No postoperative CT 51 (28%)
Post-operative CT 128 (72%)
Post-operative CT evaluation groups
are tested with the chi-squared test or Fisher’s exact test as appropriate. Overall survival (OS) and disease-free survival (DFS) were calculated from the date of the liver surgery to the date of death or recurrence, respectively. Survival curves were calculated according to Kaplan-Meier and compared with the log-rank test. Univariate hazard ratios were calculated with a single variable Cox proportional hazard model. Covariates achieving significance (p
ORIGINAL RESEARCH
Impact of Preoperative and Postoperative FOLFOX Chemotherapies in Patients with Resectable Colorectal Liver Metastasis Matthieu Faron & Mircea Chirica & Hadrien Tranchard & Pierre Balladur & Aimery de Gramont & Pauline Afchain & Thierry Andre & François Paye
# Springer Science+Business Media New York 2014
Abstract Purpose Whether the survival benefit of perioperative FOLFOX in patients with liver metastases of colorectal cancer (LMCRC) is provided by preoperative chemotherapy (CT), postoperative CT, or both remains unclear. This study aimed to evaluate, in patients with resectable LMCRC, the survival impact of preoperative and postoperative separately. Methods Between 2000 and 2010, the 179 patients (126 men, age 61±11 years) with initially resectable LMCRC, who underwent liver resection (LR) and were offered pre- and/or postoperative FOLFOX were included. Twenty-four (13 %) patients did not receive CT, 27(15 %) patients received only preoperative CT, 71 (40 %) patients received only postoperative CT, and 57 (32 %) patients received both pre- and postoperative CT. Results Operative morbidity and mortality rates were 19 and 0.6 %, respectively. At 1, 3, and 5 years, OS and DFS rates were 97, 66, 46 and 60, 32, and 24 %, respectively. Postoperative FOLFOX was an independent predictor of increased OS (HR=0.55 [95 % CI, 0.35–0.87] p=0.01) and DFS (HR=0.54 [0.36–0.82] p=0.0017), whereas the synchronous onset of the metastasis and the presence of radiographically occult liver metastases were independent predictors of poorer OS. Alternatively, preoperative FOLFOX had no
M. Faron : M. Chirica : H. Tranchard : P. Balladur : F. Paye (*) Department of Digestive Surgery, AP-HP Hôpital Saint Antoine, 184, rue du Faubourg Saint Antoine, Paris 75012, France e-mail: [email protected] P. Balladur : A. de Gramont : T. Andre : F. Paye University Pierre et Marie Curie UPMC Univ Paris 06, Paris, France A. de Gramont : P. Afchain : T. Andre Department of Oncology, AP-HP Hôpital Saint Antoine, Paris, France
significant influence on OS (HR=0.96 [0.57–1.60] p=0.83) or DFS (HR=1.05 [0.66–1.66] p=0.87). Conclusions The survival benefit of FOLFOX in patients with resectable LMCRC may be provided by postoperative rather than preoperative administration. Keywords Colorectal cancer . Liver metastasis . Chemotherapy
Introduction Liver resection is the mainstay of curative treatment for patients with liver metastasis of colorectal cancer (LMCRC) and provides 5-year survival rates ranging from 36 to 58 % [1]. Several new cytotoxic and targeted agents used in patients with unresectable metastatic colorectal cancer over the past two decades have resulted in improved survival and highresponse rates [2]. Relying on these promising results, various chemotherapy (CT) regimens have been offered to patients with resectable LMCRC in order to further improve outcomes [3–7]. However, the real benefits of CT used as either neoadjuvant or adjuvant treatment to liver resection remains a matter of debate in the literature [8–10]. The only available randomized controlled study including both preoperative and postoperative CT is the European Organization for Research and Treatment of Cancer (EORTC) 40983 phase III trial [7] in which perioperative FOLFOX was compared to surgery alone. This study included 364 patients and showed better progression-free survival in the FOLFOX group; the difference was even more significant when the analysis was restricted to patients who underwent curative resection. Despite lack of significant overall survival improvement in the perioperative FOLFOX arm, oxaliplatin-based perioperative CT has
J Gastrointest Canc
become the standard of treatment of resectable LMCRC in many centers across the world. Toughly, the EORTC trial [7] was not designed to evaluate the respective influence of preoperative and postoperative CT on patients’ outcome. It, thus, remains unclear whether the survival benefit in this study was related to the administration of preoperative CT, the administration of postoperative CT, or a synergic action of both of them. There is growing evidence supporting the survival advantage conferred by various adjuvant CT regimens after resection of LMCRC [3, 8, 11]. In contrast, most retrospective studies comparing the influence of preoperative and postoperative CT on patient outcome after liver resection (LR) of LMCRC failed to demonstrate a benefit of preoperative CT [8, 11] on survival. Along with the pioneering work of our group [2] since January 2000, patients with LMCRC evaluated for LR in our center were systematically considered for perioperative oxaliplatin-based CT. The aim of the present study was to evaluate the respective influence of preoperative and postoperative FOLFOX CT on long-term survival in patients with resectable LMCRC.
Patients and Methods Study Population Between January 2000 and 31 December 2010, 347 patients underwent liver resection of LMCRC (Fig. 1). Patients with extrahepatic disease (n=60), patients planned for two-stage LR (n=40), patients who received other CT regimens (n=36), and patients who underwent LR after CT downstaging of initially unresectable disease (n=32) were excluded. Thus, 179 patients with initially resectable liver metastasis who had no CT or received FOLFOX CT either in the preoperative period, the postoperative period, or both were included in the study. Preoperative Workup Systematic preoperative assessment included thoracic and abdominal helicoidal-computed tomography and/or magnetic resonance imaging (MRI) and, since 2007, a 2-[18-F]-fluoro2-deoxyglucose-PET scan [12]. Measurement of serum marker levels (CEA and CA 19.9) were performed systematically, and patients underwent control colonoscopy if previous complete colonoscopy dated from more than 1 year. Liver metastases diagnosed up to 6 months after treatment of the primary tumor were considered as synchronous. All treatment decisions were taken during multidisciplinary meetings involving surgeons, oncologists, radiologists, and pathologists specialized in colorectal cancer and liver surgery.
Liver Resection LR was undertaken only if complete resection of all liver metastatic sites with a minimal safety liver resection margin of 2 mm was preoperatively anticipated. Portal vein embolization was performed when the predicted remnant liver volume was less than 30 % of the standard liver volume. Intraoperative ultrasound (IOUS) was systematically used to assess the extent of liver involvement and define the transection line. Liver resection was performed using the clamp crushing method. Intermittent clamping of the hepatic pedicle (Pringle’s maneuver) was used to limit blood loss whenever necessary. Intraoperative radiofrequency ablation (RFA) was used for the destruction of single small (2) metachronous LMCRC. The response to CT was monitored every 2 months by CT imaging using the RECIST [15] criteria. Tumor progression contraindicated surgery and prompted second line CT with further reevaluation. Adjuvant CT was considered in all patients. All patients received FOLFOX chemotherapy. Cycles were administered every 14 days; 6 cycles were scheduled in both the pre- and postoperative periods.
J Gastrointest Canc Fig. 1 Flow Chart CT: Chemotherapy Note that due to study design, no direct comparisons are made between pre- and postoperative chemotherapy
Underwent liver resection for colorectal liver metastases: 347
Excluded: 168 (48%)
•
Extra-hepatic disease : 60
•
Two stage liver resection : 40
•
CT other than FOLFOX : 36
•
Initially unresectable metastases : 32
Included in the study: 179 (52%)
No CT
Pre-operative CT only
24 (13%)
Pre-operative and postoperative CT
27 (15%)
Post-operative CT only 71 (40%)
57 (32%)
No Preoperative CT 95 (53%)
Pre-operative CT 84 (47%)
Pre-operative CT evaluation groups
Follow-up Follow-up was conducted on an outpatient basis every 3 months during the first 2 years following liver resection, every 6 months the following 3 years, and annually after the fifth year. At each visit, physical examination, serum marker levels, and contrast-enhanced thoraco-abdomino-pelvic CT scan were performed. Patients who experienced resectable recurrence confined to the liver and/or the lungs were offered surgical resection after systematic 2-[18-F]-fluoro-2deoxyglucose-PET scan. Patients with unresectable recurrence were treated with exclusive CT. Statistical Analyses Quantitative variables are presented as mean (±SD) or median (interquartile range, IQR) when normality could not be assumed and compared with the Student’s t test or Wilcoxon’s test as appropriate. Qualitative variables are presented as count (proportion). Marginal associations between variables
No postoperative CT 51 (28%)
Post-operative CT 128 (72%)
Post-operative CT evaluation groups
are tested with the chi-squared test or Fisher’s exact test as appropriate. Overall survival (OS) and disease-free survival (DFS) were calculated from the date of the liver surgery to the date of death or recurrence, respectively. Survival curves were calculated according to Kaplan-Meier and compared with the log-rank test. Univariate hazard ratios were calculated with a single variable Cox proportional hazard model. Covariates achieving significance (p
