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Prognostic Factors after R0 Resection of Colorectal Cancer Liver Metastases: A Systematic Review and Pooled-Analysis Fausto Petrelli1,*, Andrea Coinu1, Alberto Zaniboni2, Filippo Pietrantonio2 and Sandro Barni1 1 2
Oncology Department, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Treviglio (BG), Italy; Oncology Department, Fondazione Poliambulanza, Brescia, Italy Abstract: Background: Prognostic variables associated with outcome after curative (R0) resection of colorectal cancer (CRC) liver metastases are paramount in identifying high-risk patients after surgery. The aim of this study was to identify risk factors related to overall survival (OS) after R0 resection of CRC liver metastases. Methods: A literature search on prognostic factors after resection of liver metastases was performed. Studies were eligible if covariates associated with OS were reported in patients with R0 resected CRC liver metastases. Independent prognostic factors associated with OS were identified using multivariate analysis. Results: Twenty-four publications with a total of 4855 patients were eligible. In multivariate analyses, a disease-free interval < 12 months (hazard ratio [HR] 1.47, P = 0.0002), the size of the largest metastasis (HR 1.56, P < 0.0001), the total number of metastases (HR 1.73, P < 0.00001), a primary tumor with node-positive status (HR 1.56, P = 0.002), a rectal primary tumor (HR 1.48, P < 0.00001), a high carcinoembryonic antigen level (HR 1.49, P = 0.02), a high tumor grade (HR 2.42, P < 0.00001), and extrahepatic disease (HR 2.03, P < 0.00001) were associated with an increased risk of death after R0 resection of CRC liver metastases in at least 3 studies. Conclusion: We identified 9 clinicopathological prognostic factors that could help identify high-risk patients and guide further treatment and follow up decisions. In particular burden of liver and extrahepatic metastases and grade are those associated with a higher risk of death.
Keywords: Colorectal cancer, liver metastases, meta-analysis, prognostic factors, radical surgery. INTRODUCTION Colorectal cancer (CRC) with distant metastasis is largely incurable, and the purpose of treatment is to prolong life and improve symptoms. The use of targeted agents has recently extended the median overall survival (OS) of patients with stage IV CRC to more than 30 months [1, 2]. Most patients with stage IV or metastatic CRC present with distant metastasis confined to the liver (20% at initial presentation, and the majority after recurrence) [1, 3]. Chemotherapy is administered to such patients to enable radical microscopic resection (R0) of the liver metastases, with the ultimate aim of a definitive cure. Assessment of prognostic factors in patients undergoing R0 resection would help guide adjuvant treatment planning, follow up, and stratification of patients in future phase III clinical trials assessing the efficacy of new drugs and reassure patients about their prognosis. In the seminal study by Adam et al. on 1439 patients with CRC and liver metastases, the actual rate of liver metastasis resectability with or without neoadjuvant chemotherapy was *Address correspondence to this author at the Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy; Tel: +39 0363424420; E-mail:
[email protected] 1574-8871/15 $58.00+.00
approximately 33% and the 10-year OS rate was 23% [4]. Seven preoperative factors were independently associated with decreased OS: a rectal primary tumor, >3 metastases at the time of liver resection, preoperative carbohydrate antigen 19-9 level > 100 UI/L, preoperative tumor size > 10 cm, non-curative (R1/R2) hepatectomy, incomplete tumor necrosis, and a history of 2 hepatectomies. These patients underwent R1-R2 resection of their liver metastases. In a metaanalysis by Abbas et al. of 11 studies of patients with CRC and liver metastases [5], the 10-year survival rate was 1236%. Factors that had a favorable impact on survival were an R0 resection margin, a low carcinoembryonic antigen (CEA) level, a single metastatic deposit, and node-negative primary disease; the only factor precluding cure was a positive resection margin. In another similar meta-analysis of 60 studies [6], prognostic factors for poor OS were node-positive primary disease, a high CEA level, extrahepatic disease, a poor tumor grade, a positive margin, multiple liver metastases, and a tumor diameter of >3 cm. However, 67% of the patients in the Adam study underwent R1-R2 resection of liver disease, and in the Abbas meta-analysis, 4 of the 11 series reported a 15% rate of positive surgical margins. Whereas several studies have investigated prognostic factors in unselected patients with metastatic CRC (mainly no resection or R0/R+ resection), few studies have assessed the © 2015 Bentham Science Publishers
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accurate prediction of survival and focused on patients with R0 resected liver metastases [7-10]. The aims of this metaanalysis were to identify baseline patient- or tumor-related prognostic factors for patients with metastatic CRC and R0 resected liver metastases. METHODS Search Strategy and Study Identification An electronic search was performed to identify relevant publications using electronic databases (PubMed, EMBASE, Web of Science, SCOPUS, and the Cochrane Register of Controlled Trials), from inception to October 20, 2014. The search was restricted to human adults and studies published in English. The search terms used were (colorectal cancer or colorectal carcinoma) AND (surg OR resection) AND (liver OR hepatic) AND (metastases) AND (prognosis OR prognostic OR predict) AND (survival and multivariate) AND (radical OR curative OR margin OR R0). The references of published original and review studies were also searched to identify studies.
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variables were recorded, and results are given for prognostic factors found to be significantly associated with OS in multivariate analysis. Hazard ratios (HRs) for OS were used as the primary effect estimate in this meta-analysis. From the eligible studies, estimates of the pooled HR and its associated 95% confidence interval (CI) were calculated using Review Manager 5.3 (RevMan version 5.3; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) and NCSS 2007 software (version 07.1.21, NCSS, LLC. Kaysville, Utah, USA). Heterogeneity between the included studies was evaluated using the Q-measure for statistical significance and the I2 measure for the degree of heterogeneity, with P < 0.05 being statistically significant and I2 > 25% indicating significant heterogeneity. A random effects model based on the DerSimonian-Laird estimator was used in cases of significant heterogeneity, and a fixed-effect model based on the Mantel-Haenszel estimator was used otherwise [12]. The results of this systematic review are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [13]. RESULTS
Inclusion criteria were as follows: 1) a prospective/retrospective cohort design or clinical trial; 2) patients with CRC liver metastases who underwent R0 liver metastasis resection as curative treatment, regardless of (neo)adjuvant chemotherapy; 3) availability of OS data, and 4) multivariate analysis of variables associated with the final outcome (OS). Duplicate publications were excluded, and the report with the most relevant and comprehensive data was selected in cases of studies evaluating the same population. Studies were excluded if they reported treatment with radiofrequency ablation or other nonsurgical local treatment, or if they did not report margin status (unless radical or curative liver metastasis resection was reported in the method section). Studies with 2, DFI 5 cm, N° of M+ > 3, preoperative hypothension N°M+ >4, extrahepatic M+, adj
Figueras/2007
Retrosp.
501
64 vs 36
43 vs 57
87.4
55.6
20
6*
Small/2008
Retrosp.
54
85 vs 15
NA
100
100
NA
4*
CT response
Giuliante/2009
Retrosp.
251
68.9 vs 31.1
41.4 vs 58.6
93.6
35.1
37
8*
Intraoperative transfusion
Liu/2010
Retrosp.
50
66 vs 32
0 vs 100
92
100
35.5
5*
Adjuvant FOLFOX/FOLFIRI
Pilati/2012
Retrosp.
50
NA
0 vs 100
100
44
36
5*
CD133 gene level in blood
Ito/2013
Retrosp.
96
NA
NA
100
82
30
5*
Molecular risk score
Hsu/2013
Retrosp.
72
49 vs 51
100 vs 0
100
100
38.8
6*
Adjuvant FOLFIRI/IFL
Jiang/2013
Retrosp.
139
56 vs 44
42.4 vs 57.6
100#
48
25
6*
BMI, intraoperative blood loss
Ivanecz/2013
Retrosp.
98
49 vs 51
42 vs 58
100
41
103
7*
Tan/2013
Retrosp.
807
72 vs 28
NA
100
81% adj; 26%
87
9*
22% neoadj
HAI + adj Vauthey/2013
Retrosp.
193
79.8 vs 20.2
NA
90.1
100
33
8*
Nanji/2013
Retrosp.
320
53.8 vs 41.6
39.1 vs 60.9
98.5
45.2
40
8*
CT
Ki67 (positive); Clinical risk score (negative) DFI < 12 months; CEA > 200 ng/L RAS mutation, viable tumor cells > 50%, Synchronous M+, size M+ > 6 cm., pN+ primary tumor, adjuvant CT
67 vs 29.8;
43.6 vs 51.5; 4.9
2.3 Unkn.
Unkn.
199
71 vs 29
343
57 vs 43
Goos/2014
Retrosp.
507
Pang/2014
Retrosp.
Nagakawa/2014
Retrosp.
NA
29.6
NA
5*
PTGS2 and EGFR expression **
46 vs 54
81
NA
39
8*
Size M+ > 3.5 cm, n° of M+ >1
52 vs 48
100
83
54.4
7*
CEA > 30 ng/L; mGPS 0/1/2
# Radiofrequency or microwave ablation was used as a combination therapy in 15 patients to achieve R0 resection because of unfavorable tumor locations **In subgroup of patients who were not treated with systemic therapy (expression evaluated in 323 patients for EGFR and 351 patients for PTGS2; C : colon; R : rectum; Sinch : Sinchronous; Met : Metacronous; M : metastases; DFI : Disease free interval; Htert : human telomerase reverse transcriptase; Adj : adjuvant; Neoadj : neoadjuvant; TSP-1 : thrombospondin-1; BMI : body mass index; EGFR : epidermal growth factor receptor; PTGS2 : prostaglandin-endoperoxide synthase 2; mGPS : Modified Glascow prognostic score
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Fig. (1). Flow diagram of the study selection process.
Fig. (2). Carcinoembryonic antigen level.
(HR 1.49, 95% CI 1.05-2.11; P = 0.02). Because of the high level of heterogeneity (I2 = 76%), a random effects model was used. After exclusion of the study by Ohlsson29 that compared CEA levels >5 ng/ml vs. 3-5 cm vs. 3-5 cm) and OS. Fig. (4) shows the results of the pooled estimate for survival in relation to tumor size (HR 1.56, 95% CI 1.271.91; P < 0.0001). Histopathologic Grade (G) of the Tumor Three studies reported data on the effect of tumor grade on survival; the risk of death was higher in patients with G23 tumors versus well-differentiated lesions (HR 2.42, 95% CI 1.66-3.54; P < 0.00001). DISCUSSION The optimal post-operative treatment for patients who have undergone R0 resection of liver metastases is a matter of debate, and identifying high-risk patients who require further treatment remains challenging. Recently the importance of margin status was highlighted in a systematic review
where, 1 cm. of negative margin was found associated with a 20% less risk of death [38]. Therefore, in this meta-analysis, we attempted to identify the prognostic factors associated with poor survival after R0 treatment of liver disease, excluding other nonsurgical, locoregional ablation techniques. We identified mainly retrospective series that evaluated covariates associated with survival in multivariate analysis. These factors were, as expected, the tumor- and patient-related variables most frequently reported in the 24 included studies. The variables more frequently reported in these studies were the number and size of metastases (significantly associated in n=10 and n=8 studies respectively), CEA level (with n=7 studies reporting increased risk of death), the presence of primary rectal or pN+ primary tumors, and a DFI of 200 ng/ml. These 5 variables comprised a preoperative Fong score (0-5) that was highly predictive of outcome—no patient with a score of 5 was a long-term survivor. These same 5 covariates were more frequently reported as statistically significant in our meta-analysis of prognostic factors, thereby validating the Fong score in a larger number of CRC patients. There are several reasons to consider these results relevant to the aim of identifying high-risk patients at an earlier stage: first, adjuvant (postsurgical) chemotherapy could be delivered only in appropriately selected patients. Second, the recognition of high-risk factors could guide the intensity of surveillance for early recognition of any recurrence amenable to further surgery. A large review of more than 700 patients with intensive surveillance by CEA measurement and computed tomography (CT) found that further hepatectomies were in fact associated with prolonged survival. During follow-up, recurrence was found again in the liver in one-third of cases (444 recurrences were detected by CT). In total, recurrent disease was treated surgically in 124 patients. At every time point, patients treated by liver and/or lung resection had a significantly longer median OS than those who received palliative chemotherapy alone [39]. Third, these clinicopathological variables could be used to stratify patients in future randomized trials for the use of “adjuvant” chemotherapy after R0 surgery. Finally, patients with favorable prognostic factors can be reassured about their chance of cure and less intensive follow-up can be started, lessening distress and anxiety [40]. This meta-analysis has some clear limitations. First, it is a published literature meta-analysis. Second, many publications were excluded because data (survival curve or HRs) were not available in the full article, although their inclusion could have improved the power of analysis. Third, a few series with 10-20% of R1 surgeries were included. Finally, the included surgical series were performed since 1998, but the included subjects underwent resection up to around 30 years ago, when imaging was less accurate, treatment options were less effective, and tissue biomarkers did not have widespread acceptance. In fact, some more recent biomarkers were rarely considered in these earlier studies. However, the final analysis reported here includes about 5000 patients who underwent curative liver resection, and the prognostic factors were identified using multivariate analysis. Our metaanalysis has a relatively low heterogeneity, with the exception of 2 cases. Furthermore, this is to our knowledge, the first systematic evaluation of prognostic factors mainly in patients with R0 resected CRC liver metastases. Systemic and locoregional curative options (targeted agents, radioembolization, and stereotactic body radiation therapy to the
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liver) are increasingly used for CRC with liver metastases, and indications for surgery have been widened to include patients with more extensive hepatic disease and extrahepatic disease [41-44]. Therefore, the identification of patients with a higher risk of death after R0 resection of liver metastases is crucial. In conclusion, in the era of modern therapies, obtaining negative margins during liver resection of CRC metastases remains an important goal and determinant of survival and should be the primary aim of surgical therapy. We described at least 9 factors that worsen survival after R0 resection of CRC liver metastases. These include patient-related variables (CEA level and DFI) and adjuvant treatments, but mainly relate to tumor biology (size and number of lesions and primary tumor status). These results are informative for clinicians, who might be better equipped to make decisions regarding post-operative therapy and the intensity of followup, and for patients, who can be informed about their prognosis. Further prospective evaluation of biological variables (such as RAS mutations) and evaluation using individual patient data are needed. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS Declared none. REFERENCES [1] [2]
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Received: June 20, 2015
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Revised: October 02, 2015
Accepted: October 03, 2015
