Benefits
Risks
Improved progression-free survival
Delayed surgery
Evaluation of chemoresponsiveness
More reversible surgical complications
Selection for surgery
Chemotherapy-associated liver injuries
Fewer “open and close”
Complete response making metastases difficult to find
Low operative mortality
Cost
To test the chemoresponsiveness of metastases while they are still measurable in the liver, which can help decide which treatment should be given after resection [4].
To eliminate micrometastatic disease and eradicate dormant cancer cells of liver metastasis.
To increase the complete resection rate and spare more non-tumorous liver parenchyma if tumor is shrinked during neoadjuvant chemotherapy [16].
To provide a useful tool to predict long-term survival. Indeed, several studies have demonstrated that response to neoadjuvant chemotherapy was a significant prognostic factor and could provide a better selection of candidates for surgical resection. Allen et al. [17] have compared the outcomes of patients referred for resection of synchronous colorectal liver metastases with previous neoadjuvant chemotherapy vs. without previous neoadjuvant chemotherapy. The 5-year survival was undifferentiated in two groups. Patients with stable disease or disease responding to chemotherapy had a better survival than patients who did not receive chemotherapy (85 % vs. 35 %, p = 0.03). In another study, tumor progression during neoadjuvant chemotherapy was also related to reduced 5-year survival rate when compared to patients with tumor response or stable disease (8 % vs. 37 % and 30 %, respectively, p < 0.001) [18]. In this study, tumor progression while on chemotherapy was an independent predictive factor associated with decreased survival and considered by the authors as a contraindication to liver resection. Recently, three studies have evaluated the impact of pathologic response to chemotherapy on outcome after resection [19–21]. Rubbia Brandt et al. have elaborated the tumor regression grading (TRG) system to evaluate tumor response to neoadjuvant chemotherapy. In this study, major histological tumor regression was associated with improved survival [19]. Two other studies have focused on the impact of complete pathologic response on long-term outcome [20, 21]. Results of these two studies are consistent: Complete pathologic response is associated with increased long-term survival rates and pathologic response to chemotherapy is an important prognostic factor.
12.3 Potential Risks of Preoperative Chemotherapy
Neoadjuvant chemotherapy has potential defects (Table 12.1).
Application of preoperative chemotherapy may induce pathologic application in the non-tumorous liver parenchyma [20–30]. There were reports that preoperative chemotherapy has two main types of chemotherapy-associated liver injuries: vascular changes including sinusoidal dilatation and nonalcoholic fatty liver disease related to chemotherapy including chemotherapy-associated steatosis and steatohepatitis (CASH). Application of 5-fluorouracil may increase the risk of steatosis [28]. Application of oxaliplatin-based combination regimens may be associated with an increased risk of vascular lesions in the liver [22, 25, 26, 30]. Irinotecan-containing regimens can increase the risks of steatosis and steatohepatitis [23, 25].
The critical question is whether chemotherapy-associated liver injuries have any clinical significance and in particular if they are associated with an increased risk of liver surgery for metastases. The relation between the type of lesions induced by chemotherapy and their potential clinical consequences has been reported. Kooby et al. showed that steatosis increase the risk of complications, in particular infectious complications, but had no effective impact on mortality [29]. Vauthey et al. showed that steatohepatitis was observed in 20 % of patients with irinotecan-based chemotherapy and may be associated with death due to postoperative liver failure in 7 % of patients with steatohepatitis [25]. Impact of vascular lesions on postoperative course after liver resection is controversial. Nakano et al. have reported that occurrence of sinusoidal injuries could increase the risk of major hepatectomy for colorectal liver metastases [30], whereas in the other report [25], vascular lesions were only associated with an increased risk of operative bleeding but not perioperative morbidity or mortality [25].
The European Organisation for Research and Treatment of Cancer (EORTC) Intergroup phase III study 40983 have compared the outcomes of perioperative chemotherapy with 5FU, leucovorin, and oxaliplatin (six cycles before surgery and six cycles after) to surgery alone in 364 patients [31]. The results of safety showed that in the two treatment arms, the mortality rate was both less than 1 % and was not statistically significant [31]. Morbidity rate was slightly higher in the chemotherapy arm than in the surgery-alone arm (25 % vs. 16 %; p = 0.04) (Table 12.2), but still in the range of other reports’ observation [5, 6, 32]. Intra-abdominal abscesses and transient biliary fistula were more frequent in the chemotherapy arm. Thus, preoperative administration of six cycles of FOLFOX (a kind of Chemotherapy regimen, including Oxaliplatin, Fluorouracil and Leucovorin ivgtt) is safe and feasible. Even though no report clearly demonstrated the correlation between increased morbidity rates and duration of neoadjuvant chemotherapy, there are several arguments to support the hypothesis of a cumulative toxicity of chemotherapy on non-tumorous liver parenchyma [24, 26, 30]. Preoperative chemotherapy is safe if it is properly chosen and monitored and if patients are not over chemotherapy-treated before surgery.
Table 12.2
Postoperative complications in EORTC intergroup trial 40983
Period CT group | Surgery group | |
|---|---|---|
Reversible postoperative complicationsa | 40 (25 %) | 27 (16 %) |
Cardiopulmonary failure | 3 (2 %) | 2 (1 %) |
Bleeding | 3 (2 %) | 3 (2 %) |
Biliary fistula | 13 (8 %) | 7 (4 %) |
Hepatic failure | 11 (7 %) | 8 (5 %) |
Wound infection | 5 (3 %) | 4 (2 %) |
Intra-abdominal infection | 11 (7 %) | 4 (2 %) |
Need for reoperation | 5 (3 %) | 3 (2 %) |
Urinary infection | 4 (3 %) | |
Pleural effusion | 2 (1 %) | 1 (1 %) |
Pulmonary embolism/deep venous | 2 (1 %) | 1 (1 %) |
Pneumopathy | 2 (1 %) | |
Neutropenia | 1 (1 %) | |
Ascites | 2 (1 %) | 1 (1 %) |
Ileus | 1 (1 %) | |
Cardiac arrhythmia | 1 (1 %) | |
Renal failure | 4 (3 %) | 1 (1 %) |
Other | 4 (2 %) |
The potential risks of liver surgery after administration of combinations of cytotoxic drugs and targeted agents are poorly understood. Anti-EGF agents, particularly cetuximab, which could interfere with surgery have little known side effect. In some researches, it is demonstrated that bevacizumab, an anti-VEGF, can be supervised securely before liver resection of colorectal liver metastases and that bevacizumab’s administration is discontinued 6–8 weeks before surgery. The feasibility and benefits of liver surgery after administration of novel, systemic targeted agents will be further elaborated in ongoing prospective clinical studies (EORTC study 40091 (BOS2 (Efficacy of FOLFOX Alone, FOLFOX Plus Bevacizumab and FOLFOX Plus Panitumumab in Patients With Resectable Liver Metastases) study)):
When there is a response to chemotherapy, certain liver metastases may be no longer visible on imaging and be considered as complete responses. It is significant to wonder whether these metastases are thoroughly eliminated or they are not visible on imaging but still exist. In order to deal with these puzzlers, 66 liver metastases that disappeared on CT scan were reviewed [35]. As a result, in more than 80% of the cases, at the initial site of liver metastases where still existed viable cancer cells, which were disappeared on imaging. It does not mean that complete radiologic responses stand for the cure of the disease [35]. So, to the patients with resectable liver metastases, they should not stop referral to surgeons until their liver metastases have completely disappeared. It is necessary to resect the initial site if the liver metastases were gone, and the surgeon is required to identify this site in the liver, a comparatively difficult and impossible task.
There will be another theoretical risk if the metastases progressed so seriously that it would become unresectable during preoperative chemotherapy. In the EORTC Intergroup phase III study 40983, in 12 of 182 (7 %) patients who accepted systemic chemotherapy, progressive diseases were observed [31]. In about 12 of these patients, four could even have resection of metastases. For the rest, half of the patients cannot have the resection due to the appearance of new extrahepatic lesions which can reappear in any site after immediate surgery. In only one third of cases, the cause of unresectability was the progression of known liver metastases. According to the research on chemotherapy, progression of liver metastases is a factor of poor prognosis after hepatic resection. Most of these patients develop early cancer recurrence. Thus, some authors consider that tumor progression while on chemotherapy is a contraindication for surgery [18].Related posts:
The Differential Diagnosis of Hepatic Metastasis by CT and MRI
Present Situation and Prospect of Diagnosis and Treatment of Colorectal Cancer
Targeted Therapy of Colorectal Cancer Liver Metastasis
Surgical Techniques for Metastatic Hepatic Carcinoma
Establishment of Postoperative Follow-Up and Database of Colorectal Cancer
Diagnostic Value of Ultrasound in Metastatic Liver Cancer
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