Perioperative Complications After Neoadjuvant Chemotherapy With and Without Bevacizumab for Colorectal Liver Metastases

Purpose

Bevacizumab has been shown to increase progression free and overall survival in patients with metastatic colorectal cancer. Neoadjuvant bevacizumab is commonly used in patients undergoing liver resection. Our purpose was to evaluate whether bevacizumab is associated with increased rate of perioperative complications in patients undergoing hepatic resection for colorectal liver metastases (CRLM).

Methods

Retrospective analysis of patients undergoing hepatic resection for CRLM who received chemotherapy and bevacizumab (group 1, n?=?134), or chemotherapy alone (group 2, n?=?57). We compared demographics, surgical characteristics, and perioperative course.

Results

Perioperative complications developed in 35 % of patients in group 1, and 47 % in group 2 (p?=?0.11). Of those complications, 15 (11.2 %) in group 1, and 5 (8.8 %) in group 2 were considered major (p?=?0.617). Four patients, all of whom received preoperative bevacizumab, developed enteric leaks following combined liver and bowel resection. The rate of anastomotic leak in group 1 was 10 %, compared with 0 in group 2, p?=?0.56.

Conclusion

Neoadjuvant chemotherapy along with bevacizumab was not associated with an increased risk of postoperative complications after hepatic resection. Possible association of increased morbidity with simultaneous bowel and liver resections following bevacizumab administration was found and we recommend avoiding such treatment combination.     

结直肠癌肝转移的术前化疗

结直肠癌是最常见的恶性肿瘤之一,结直肠癌的肝脏转移是造成结直肠癌患者死亡的最主要原因之一。超过50%的结直肠癌患者会发生肝脏转移,其治疗的疗效直接影响着结直肠癌患者的预后。对于结直肠癌肝转移的患者行最佳支持治疗,患者的中位生存时间大约为6个月;行甲酰四氢叶酸钙(CF)+5-FU化疗,患者的中位生存时间为8～12个月;应用奥沙利铂或伊立替康的联合化疗(FOLFOX或FOLFIRI),其中位生存时间可延长至20～24个月。     

Preoperative Chemotherapy for Colorectal Liver Metastases: Impact on Hepatic Histology and Postoperative Outcome

Some investigators have suggested that preoperative chemotherapy for hepatic colorectal metastases may cause hepatic injury and increase perioperative morbidity and mortality. The objective of the current study was to examine whether treatment with preoperative chemotherapy was associated with hepatic injury of the nontumorous liver and whether such injury, if present, was associated with increased morbidity or mortality after hepatic resection. Two-hundred and twelve eligible patients who underwent hepatic resection for colorectal liver metastases between January 1999 and December 2005 were identified. Data on demographics, clinicopathologic characteristics, and preoperative chemotherapy details were collected and analyzed. The majority of patients received preoperative chemotherapy (n = 153; 72.2%). Chemotherapy consisted of fluoropyrimidine-based regimens: 5-FU monotherapy, 31.6%; irinotecan, 25.9%; and oxaliplatin, 14.6%. Among those patients who received chemotherapy, the type of chemotherapy regimen predicted distinct patterns of liver injury. Oxaliplatin was associated with increased likelihood of grade 3 sinusoidal dilatation (p = 0.017). Steatosis >30% was associated with irinotecan (27.3%) compared with no chemotherapy, 5-FU monotherapy, and oxaliplatin (all p < 0.05). Irinotecan also was associated with steatohepatitis, as two of the three patients with steatohepatitis had received irinotecan preoperatively. Overall, the perioperative complication rate was similar between the no-chemotherapy group (30.5%) and the chemotherapy group (35.3%) (p = 0.79). Preoperative chemotherapy was also not associated with 60-day mortality. In patients with hepatic colorectal metastases, preoperative chemotherapy is associated with hepatic injury in about 20 to 30% of patients. Furthermore, the type of hepatic injury after preoperative chemotherapy was regimen-specific. Presented at the American Hepato-Pancreato-Biliary Association 2006 Annual Meeting, March 11, Miami, Florida.     

Influence of Preoperative Chemotherapy on the Intraoperative and Postoperative Course of Liver Resection for Colorectal Cancer Metastases

Background  

Liver resection is a possibly curative treatment for colorectal cancer (CRC) liver metastases. Preoperative chemotherapy may make initially irresectable tumors resectable. The aim of this study was to compare perioperative course and short-term mortality after liver resection for CRC metastases between patients who were and were not treated with preoperative chemotherapy.     

Extended Preoperative Chemotherapy Does Not Improve Pathologic Response and Increases Postoperative Liver Insufficiency After Hepatic Resection for Colorectal Liver Metastases

Background

The optimal duration, safety, and benefit of preoperative chemotherapy in patients with colorectal liver metastases (CLM) are unclear. We evaluated the association between the duration of preoperative chemotherapy with 5-fluorouracil (5-FU), leucovorin, oxaliplatin (FOLFOX) ± bevacizumab, pathologic response, and hepatotoxicity after hepatic resection for CLM.

Methods

A total of 219 patients underwent hepatic resection following FOLFOX with or without bevacizumab and were divided into 2 groups according to the chemotherapy duration: 1–8 cycles (short duration [SD]; N = 157) and ≥9 cycles (long duration [LD]; N = 62). The frequency of complete or major pathologic response, sinusoidal injury, and major postoperative morbidity were compared.

Results

Treatment consisting of ≥9 cycles was not associated with an increase in complete or major pathologic response (SD vs. LD, 57% vs. 55%; P = .74). The incidence of sinusoidal injury was higher in the LD group (26% vs. 42%; P = .017). The incidence of liver insufficiency was higher in the LD group (4% vs. 11%; P = .035). Sinusoidal injury did not predict postoperative liver insufficiency; multivariate analysis revealed ≥9 cycles was the only independent predictor of postoperative liver insufficiency (P = .031; odds ratio = 3.90). Chemotherapy including bevacizumab was associated with a significantly higher frequency of complete or major response in both SD and LD groups.

Conclusions

Extended preoperative chemotherapy increases the risk of hepatotoxicity in CLM without improving the pathologic response. The type of chemotherapy (FOLFOX with bevacizumab) has more impact on pathologic response than the duration of chemotherapy.     

Liver Resection for Primarily Unresectable Colorectal Metastases Downsized by Chemotherapy

This study was performed prospectively to assess the effect of systemic chemotherapy (FOLFIRI protocol) in patients with initially unresectable colorectal liver metastases (CRLM) and, after performing liver resection in patients with downsized metastases, to compare the postoperative and long-term results with those of patients with primarily resectable CRLM. Records from a prospective database including all consecutive admissions for CRLM between June 2000 and June 2004 were reviewed. The analysis addressed all patients who underwent hepatectomy for primarily resectable CRLM (Group A), or underwent chemotherapy for primarily unresectable CRLM and among these, particularly the patients who were finally resected after downsizing of CRLM (Group B). There were 60 primarily resected patients (Group A). Forty-two other patients underwent chemotherapy; after an average of nine courses, 18 of them (42.8%) with significantly downsized lesions were explored and 15 (35.7%, Group B) were resected, whereas three had peritoneal metastases. Group B differed from Group A for a significantly higher rate of synchronous CRLM upon diagnosis of colorectal cancer, a larger size of CRLM upon evaluation in our center, and a lower rate of major hepatectomies (20.0% vs. 51.6 %) at surgery. No patient in Group B had positive margins of resection. Operative mortality was nil and morbidity was 20.0% in both groups. In Group B vs. Group A median survival after hepatectomy was 46 vs. 47 months (n.s), 3-year survival rate was 73% vs. 71% (n.s.), disease-free survival rate was 31% vs. 58% (p = 0.04) and, at a median follow-up of 34 months, tumor recurrence rate was 53.3% vs. 28.3% (n.s.). Four out of the eight Group B patients with recurrence underwent a re-resection, and were alive at 9 to 67 months after the first resection. These results show that in about one-third of the patients with primarily unresectable CRLM, downsizing of the lesions by chemotherapy (FOLFIRI protocol) permitted a subsequent curative resection. In these patients, operative risk and survival did not differ from the figures observed in primarily resectable patients and, in spite of a lower disease-free survival with more frequent recurrence, re-resection still represented a valid option to continue treatment. Presented at the 2005 Surgical Spring Week AHPBA Meeting (April 14–17, 2005, Fort Lauderdale, Florida).     

Preoperative Chemotherapy and the Outcome of Liver Resection for Colorectal Metastases

Background Neoadjuvant systemic chemotherapy is being increasingly used prior to liver resection for colorectal metastases. Oxaliplatin has been implicated in causing structural changes to the liver parenchyma, and such changes may increase the morbidity and mortality of surgery. Patients and Methods A retrospective study was undertaken of 101 consecutive patients who had undergone liver resection for colorectal metastases in two HPB centers. Preoperative demographic and premorbid data were gathered along with liver function tests and tumor markers. A subjective assessment of the surgical procedure was noted, and in-hospital morbidity and mortality were calculated. The effect of preoperative chemotherapy on short-term and long-term outcome was analyzed, and actuarial 1 and 3 year survival was determined. Results Patients who received neoadjuvant chemotherapy had a higher number of metastases (median 2, range 1–8 versus median 1, range 1–5; P = 0.019) and more had synchronous tumors (24 patients versus 8; P < 0.001). Overall morbidity was 37% and hospital mortality was 3.9%. Operative and in-hospital outcome was not influenced by chemotherapy. Long-term survival was worse in patients who had received preoperative chemotherapy (actuarial 3-year survival 62% versus 80%; P = 0.04). Conclusions This study shows no evidence that neoadjuvant chemotherapy, and in particular oxaliplatin, increases the risk associated with liver resection for colorectal metastases. Long-term outcome is reduced in patients receiving preoperative chemotherapy, although they have more advanced disease.     

The Role of Preoperative Chemotherapy in Patients with Resectable Colorectal Liver Metastases

Background  Liver metastases develop in 40–50% of patients with colorectal cancer and represent the major cause of death in this disease. Surgical resection remains the only treatment procedure that can ensure long-term survival and provide cure when liver metastases can be totally resected with clear margins, when the primary cancer is controlled, and when there is no nonresectable extrahepatic disease. Five-year survival rate after surgical resection of colorectal metastases varies from 25% to 55%, but cancer relapse is observed in most patients. Aim  To review the potential benefits and disadvantages of neoadjuvant chemotherapy administered before surgery to patients with initially resectable metastases. Results  European Organization for Research and Treatment of Cancer (EORTC) study 40983 has shown that neoadjuvant chemotherapy could reduce the risk of relapse by one-quarter, and allows to test the chemosensitivity of the cancer, to help to determine the appropriateness of further treatments, and to observe progressive disease, which contraindicates immediate surgery. Neoadjuvant chemotherapy can induce damage to the remnant liver. Oxaliplatin-based combination regimen is associated with increased risk of vascular lesions, whereas irinotecan-containing regimens have been associated with increased risks of steatosis and steatohepatitis. Analysis of EORTC study 40983 showed that administration of six cycles of neoadjuvant systemic chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was associated with moderate increase of the risk of reversible complications after surgery, but mortality rate was below 1% and not increased. If patients are not overtreated, chemotherapy before surgery is well tolerated. The integration of novel targeted agents in combination with cytotoxic drugs is a promising way to improve outcome in patients with advanced colorectal cancer. Preliminary trials have shown that targeted agents combined with cytotoxic regimens can increase tumor response rates. Another impact of preoperative chemotherapy is that metastases that respond to treatment may no longer be visible on computed tomography (CT) scan or at surgery. Patients should be carefully monitored and receive surgery before metastases disappear. Conclusion  Treatment of most patients with liver metastases—those with resectable metastases as well as those with initially unresectable metastases—should start with chemotherapy. If drugs are well chosen and the duration of treatment is monitored with care during multidisciplinary meetings, benefits largely outweigh potential disadvantages.     

Chemotherapy-Associated Liver Injury: Impact on Surgical Management of Colorectal Cancer Liver Metastases

Chemotherapy is integral to the management of patients with advanced colorectal cancer liver metastases. Due to their improved efficacy, modern regimens can sometimes convert unresectable disease to a resectable state. As chemotherapy is often administered prior to hepatic resection, adverse effects on the liver are increasingly being recognized. Investigators have identified a wide spectrum of effects on the underlying liver parenchyma, ranging from mild forms of steatosis to severe steatohepatitis and sinusoidal obstruction syndrome. As the histopathologic definitions of these changes evolve, studies have identified specific patterns of hepatic injury related to the various chemotherapeutic agents. The impact of these changes on perioperative outcome after partial hepatectomy remains controversial. Timing and duration of chemotherapy may play a key role and account for discrepancies in outcomes seen among studies. In this review, we provide an overview of the spectrum of chemotherapy-associated liver injury and discuss its relevance to perioperative management of patients undergoing hepatic resection of colorectal cancer liver metastases.     

Optimal Future Liver Remnant in Patients Treated with Extensive Preoperative Chemotherapy for Colorectal Liver Metastases

Background

Patients with colorectal liver metastases (CLM) are increasingly treated with preoperative chemotherapy. Chemotherapy associated liver injury is associated with postoperative hepatic insufficiency (PHI) and mortality. The adequate minimum future liver remnant (FLR) volume in patients treated with extensive chemotherapy remains unknown.

Methods

All patients with standardized FLR > 20 %, who underwent extended right hepatectomy for CLM from 1993-2011, were divided into three cohorts by chemotherapy duration: no chemotherapy (NC, n = 30), short duration (SD, ≤12 weeks, n = 78), long duration (LD, >12 weeks, n = 86). PHI and mortality were compared by using uni-/multivariate analyses. Optimal FLR for LD chemotherapy was determined using a minimum p-value approach.

Results

A total of 194 patients met inclusion criteria. LD chemotherapy was significantly associated with PHI (NC + SD 3.7 vs. LD 16.3%, p = 0.006). Ninety-day mortality rates were 0 % in NC, 1.3 % in SD, and 2.3% in LD patients, respectively (p = 0.95). In patients with FLR > 30 %, PHI occurred in only two patients (both LD, 2/20, 10 %), but all patients with FLR > 30 % survived. The best cutoff of FLR for preventing PHI after chemotherapy >12 weeks was estimated as >30 %. Both LD chemotherapy (odds ratio [OR] 5.4, p = 0.004) and FLR ≤ 30 % (OR 6.3, p = 0.019) were independent predictors of PHI.

Conclusions

Preoperative chemotherapy >12 weeks increases the risk of PHI after extended right hepatectomy. In patients treated with long-duration chemotherapy, FLR > 30 % reduces the rate of PHI and may provide enough functional reserve for clinical rescue if PHI develops.     

Chemotherapy-Associated Liver Injury in Patients with Colorectal Liver Metastases: A Systematic Review and Meta-analysis

Background

Chemotherapy-associated liver injury is a major cause for concern when treating patients with colorectal liver metastases. The aim of this review was to determine the pathological effect of specific chemotherapy regimens on the hepatic parenchyma as well as on surgical morbidity, mortality and overall survival.

Methods

A systematic review of the published literature and a meta-analysis were performed. For each of the variables under consideration, the effects of different chemotherapy regimens were determined by calculation of relative risks by a random-effects model.

Results

Hepatic parenchymal injury is regimen specific, with oxaliplatin-based regimens being associated with grade 2 or greater sinusoidal injury (number needed to harm 8; 95?% confidence interval [CI] 6.4?C13.6), whereas irinotecan-based regimens associated with steatohepatitis (number needed to harm 12; 95?% CI 7.8?C26). The use of bevacizumab alongside FOLFOX reduces the risk of grade 2 or greater sinusoidal injury (relative risk 0.34; 95?% CI 0.15?C0.75).

Conclusions

Chemotherapy before resection of colorectal liver metastases is associated with an increased risk of regimen-specific liver injury. This liver injury may have implications for the functional reserve of the liver for patients undergoing major hepatectomy for colorectal liver metastases.     

Disappearing Colorectal Liver Metastases after Chemotherapy: Should we be Concerned?

Background  

With increasing efficacy of preoperative chemotherapy for colorectal cancer, more patients will present with one or more disappearing liver metastases (DLM) on preoperative cross-sectional imaging.     

Radiofrequency Ablation to Improve Survival After Conversion Chemotherapy for Colorectal Liver Metastases

Introduction

Systemic chemotherapy is able to convert colorectal liver metastases (CRLM) that are initially unsuitable for local treatment into locally treatable disease. Surgical resection further improves survival in these patients. Our aim was to evaluate disease-free survival (DFS), overall survival, and morbidity for patients with CRLM treated with RFA following effective downstaging by chemotherapy, and to identify factors associated with recurrence and survival.

Materials and methods

Included patients had liver-dominant CRLM initially unsuitable for local treatment but eligible for RFA or RFA with resection after downstaging by systemic chemotherapy. Chemotherapeutic regimens consisted predominantly of CapOx, with or without bevacizumab. Follow-up was conducted with PET-CT or thoraco-pelvic CT.

Results

Fifty-one patients had a total of 325 CRLM (median = 7). Following chemotherapy, 183 lesions were still visible on CT (median = 3). Twenty-six patients were treated with RFA combined with resection. During surgery, 309 CRLM were retrieved on intraoperative ultrasound (median = 5). Median survival was 49 months and was associated with extrahepatic disease at time of presentation and recurrences after treatment. Estimated cumulative survival at 1, 3 and 4 years was 90, 63 and 45 %, respectively. Median DFS was 6 months. Twelve patients remained free of recurrence after a mean follow-up of 32.6 months.

Conclusion

RFA of CRLM after conversion chemotherapy provides potential local control and a good overall survival. To prevent undertreatment, the involvement of a multidisciplinary team in follow-up imaging and assessment of local treatment possibilities after palliative chemotherapy for liver-dominant CRLM should always be considered.

     

Multiagent Chemotherapy for Isolated Colorectal Liver Metastases: A Single-centered Retrospective Study

Background  Few studies identifying variables associated with prognosis after resection of colorectal liver metastases (CLM) account for treatment with multiagent chemotherapy (fluoropyrmidines with irinotecan, oxaliplatin, bevacizumab, and/or cetuximab). The objective of this retrospective study was to determine the effect of multiagent chemotherapy on long-term survival after resection of CLM. Methods  Demographics, clinicopathologic tumor characteristics, treatments, and long-term outcomes were reviewed. Results  From 1996 to 2006, 230 patients underwent resection of CLM. Treatment strategies before and after resection included fluoropyrimidine monotherapy (n = 34 and n = 39), multiagent chemotherapy (n = 81 and n = 73), and observation (n = 115 and n = 118). Prehepatectomy treatment strategy was not associated with overall survival. Actuarial 4-year survival was 63%, 39%, and 40% for patients treated with multiagent chemotherapy, fluoropyrimidine monotherapy, and observation after hepatectomy, p = 0.06. Posthepatectomy multiagent chemotherapy (p = 0.04, HR 0.52 [0.27–1.03]), duration of posthepatectomy chemotherapy treatment of 2 months or longer (p = 0.05, HR 0.49 [0.25–0.99]), carcino-embryonic antigen level >10 ng/mL (p = 0.03, HR 2.09, 95% CI [1.32–3.32]), and node positive primary tumor (p = 0.002, HR 1.79 [1.06–3.02]) were associated with overall survival in multivariate analysis. Conclusions  The association of posthepatectomy multiagent chemotherapy with overall survival in this retrospective study indicates the need for prospective randomized trials comparing multiagent chemotherapy and fluoropyrimidine monotherapy for CLM.     

Timing of Two-stage Liver Resection during Chemotherapy for Otherwise Unresectable Colorectal Metastases

Background

Tumor downsizing by effective chemotherapy while increasing remnant liver volume by two-stage hepatectomy can expand eligibility for resection of otherwise unresectable liver metastases. However, optimal timing of two-stage hepatectomy with respect to chemotherapy is undetermined.

Methods

We retrospectively analyzed the effect of timing of two-stage hepatectomy and chemotherapy using data from 95 patients whose colorectal liver metastases initially were considered unresectable.

Results

In 21 of 22 (95?%) patients whose first liver resection preceded chemotherapy (Hx-CTx group) and in 39 of 73 (53?%) patients whose chemotherapy preceded surgery (CTx-Hx group), macroscopic complete resection ultimately was achieved (P?P?P?=?0.12 and P?=?0.24, respectively), although poor response to chemotherapy was more frequent in the Hx-CTx group.

Conclusions

Optimal timing of hepatectomy and chemotherapy is difficult to specify, but performing the initial resection in a two-stage hepatectomy before chemotherapy may increase likelihood of macroscopic complete resection, even in patients with a poor response to chemotherapy or with limited courses of chemotherapy.     

结直肠癌切除同期射频消融联合化疗治疗肝转移

目的：探讨结直肠癌切除同期射频消融联合化疗治疗肝转移的临床疗效。方法：对39例病人先行原发肿瘤的切除，同期行射频消融联合化疗治疗肝转移，以螺旋CT增强扫描为主结合彩超综合评价治疗效果。结果：39例共82个肝转移病灶，完全坏死率85％。随访时间〉6个月者3l例，生存27例；随访时间〉12个月11例，生存8例。结论：结直肠癌切除同期射频消融联合化疗治疗肝转移的疗效较好，值得临床推广。     

Preoperative Imaging of Colorectal Liver Metastases After Neoadjuvant Chemotherapy: A Meta-Analysis

Background

Chemotherapy treatment induces parenchymal changes that potentially affect imaging of CRLM. The purpose of this meta-analysis was to provide values of diagnostic performance of magnetic resonance imaging (MRI), computed tomography (CT), fluorodeoxyglucose positron emission tomography (FDG-PET), and FDG-PET/CT for preoperative detection of colorectal liver metastases (CRLM) in patients treated with neoadjuvant chemotherapy.

Methods

A comprehensive search was performed for original articles published from inception to 2011 assessing diagnostic performance of MRI, CT, FDG-PET, or FDG-PET/CT for preoperative evaluation of CRLM following chemotherapy. Intraoperative findings and/or histology were used as reference standard. For each imaging modality we calculated pooled sensitivities for patients who received neoadjuvant chemotherapy as well as for chemonaive patients, defined as number of malignant lesions detected divided by number of malignant lesions as confirmed by the reference standard.

Results

A total of 11 papers, comprising 223 patients with 906 lesions, were included. Substantial variation in study design, patient characteristics, imaging features, and reference tests was observed. Pooled sensitivity estimates of MRI, CT, FDG-PET, and FDG-PET/CT were 85.7% (69.7?C94.0%), 69.9% (65.6?C73.9%), 54.5% (46.7?C62.1%), and 51.7% (37.8?C65.4%), respectively. In chemonaive patients, sensitivity rates were 80.5% (67.0?C89.4%) for CT, 81.3% (64.1?C91.4%) for FDG-PET, and 71.0% (64.3?C76.9%) for FDG-PET/CT. Specificity could not be calculated because of non-reporting of ??true negative lesions.??

Conclusion

In the neoadjuvant setting, MRI appears to be the most appropriate imaging modality for preoperative assessment of patients with CRLM. CT is the second-best diagnostic modality and should be used in the absence of MRI. Diagnostic accuracy of FDG-PET and PET-CT is strongly affected by chemotherapy.     

Resection of Colorectal Liver Metastases

Introduction  

The gold-standard treatment for colorectal liver metastases (CLM) is liver resection. Advances in staging, surgical technique, perioperative care and systemic chemotherapy have contributed to steady improvement in oncologic outcomes for patients following surgery in this subset of patients with stage IV colorectal cancer. The limits of resection continue to expand to include patients with more, larger and bilateral CLM, yet outcomes continue to improve with 5-year overall survival exceeding 50% following resection. Chemotherapy is an important element of treatment for patients with CLM, and chemotherapy can be combined safely with surgery to improve outcomes further.     

ALPPS for Colorectal Liver Metastases

Journal of Gastrointestinal Surgery -