Towards personalised treatment of patients with colorectal liver metastases Hof, Joost
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Hof, J. (2019). Towards personalised treatment of patients with colorectal liver metastases. Rijksuniversiteit Groningen.
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Introduction and outline of this thesis
Colorectal cancer
In Europe, colorectal carcinoma (CRC) is the cancer with the third highest incidence and the second highest mortality rate [1]. In the Netherlands, CRC incidence was about 90 per 100,000 individuals in 2016 and has been increasing over the last decades. However, incidence of CRC is not spread evenly across the global population. Males have a slightly higher incidence of CRC compared to females. There are also large geographic differences in the incidence of CRC. Developed regions like the Netherlands have a much higher incidence compared to developing regions, where the incidence can be as low as 5 per 100,000 [2,3]. Survival rates after CRC diagnosis have improved over the last decades, especially in rectal cancer, in which the 10-year survival improved from 27% between 1960-1970 to 56% between 2006-2010. Although survival rates are improving, over 5,000 patients per year still die of CRC in the Netherlands (the Netherlands Cancer Registry, www.
cijfersoverkanker.nl, accessed 28-05-2018).
Risk factors for the development of CRC can be divided into non-modifiable and modifiable (environmental) risk factors. A non-modifiable risk factor associated with CRC is advancing age with a peak incidence occurring between 60-79 years. Patients with a family history of CRC and/or a proven genetic predisposition for CRC, adenomatous polyps or inflammatory bowel disease are at increased risk for developing CRC. Hereditary diseases that increase CRC risk are familial adenomatous polyposis and Lynch syndrome [3–5]. Environmental risk factors include a high body mass index, low physical activity, low intake of fruits, low intake of vegetables, consumption of red meat and smoking [3–5]. Of note, a large meta-analysis showed that the consumption of alcohol did not increase the risk of developing CRC [5].
Although the basic outline of CRC carcinogenesis was postulated many years ago by Fearon and Vogelstein [6], the molecular basis of CRC pathogenesis is still not completely understood [7]. Previous studies have shown that the Wnt pathway is important in CRC carcinogenesis, with APC as the most frequently mutated gene. In addition, TP53 (cell cycle regulator), KRAS (EGFR signalling) and BRAF (MAPK pathway) are also identified as key driver genes that are frequently mutated and contribute to CRC development [8,9].
Colonic epithelial cells can progress into cancer by these and other (epi)genomic events, resulting in the classification of three different mechanisms of instability. Chromosomal instability (CIN) is the observation of many somatic copy number alterations and occurs in 70% of all CRC patients. Approximately 15% of all CRCs are microsatellite instable (MSI).
These tumour cells have a defect in their mismatch repair system, leading to genome- wide instability of the repetitive DNA sequences called microsatellites, which in turn may cause functional gene defects. CpG Island Methylator Phenotype (CIMP) is a type of
epigenomic instability and occurs in 10-20% of CRCs. CIMP CRCs have a high proportion of hypermethylated CpG loci, resulting in a reduced expression of certain (tumour suppressor) genes [8,10]. A tumour can also exhibit CIMP in addition to CIN or MSI [7,11]. Recently, Guinney et al. (2015) proposed new molecular subtypes of colorectal cancer based on gene expression. They defined four different subtypes, each associated with multiple tumoural characteristics and different survival outcome (figure 1) [12]. Their analysis of the largest CRC cohort to date, for which comprehensive molecular characteristics were available, might form the future framework for better understanding CRC carcinogenesis and for guiding of treatment decisions and prognostication.
Figure 1 Proposed consensus molecular subtypes (CMS) by Guinney et al. [12]
The four subtypes with their characteristics are shown. Thirteen percent of the studied tumours were unclassified because of heterogeneous patterns of CMS mixtures. CIMP = CpG island methylator phenotype, MSI = microsatellite instability, SCNA = somatic copy number alterations.
Colorectal liver metastases and its treatment
The main cause of CRC-related patient death is the dissemination of cancer cells throughout the body and the formation of metastases. The liver is the most common site of metastasis in primary tumours from both the colon and rectum, and about 50% of all CRC patients will ultimately develop liver metastases [13]. The second most common site of CRC metastasis is the lung, which is more prevalent in rectal cancer [14,15]. At time of diagnosis of the primary CRC, about 20% of patients already have detectable metastasis (stage IV disease) [14,15]. A curative treatment of colorectal liver metastases (CRLM) is
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not possible in 75-80% of patients because of widespread liver involvement, extra-hepatic disease or comorbidity [16]. The gold standard treatment for CRLM is surgical resection (partial hepatectomy). If the CRLM are initially judged unresectable on CT or MRI scans, systemic chemotherapy can be administered to convert the CRLM into resectable tumours.
In addition, other treatment options to convert unresectable CRLM into resectable CRLM are a two-stage hepatectomy, portal vein embolization and ablative therapies [17].
Thermal ablation is a minimally invasive procedure that uses thermal energy to eradicate the tumour, and it can be applied in the same procedure as the partial hepatectomy.
Prognostication Clinical models
Five-year survival rates after liver surgery range from 15%-60%, and this large range can only partly be explained by clinicopathological tumour characteristics [13,18]. Several prognostic scoring systems have been developed to predict patient survival and guide treatment decisions. Unfortunately, these clinical models still have a high variability and a review found no prognostic factor that was common in all models [19]. Nevertheless, the prognostic model that is most often used is the clinical risk score (CRS) described by Fong et al. (1999) [18]. Each of the five risk factors included in this model are associated with survival, with more risk factors present per patient resulting in progressively decreasing survival rates (table 1).
Table 1 Clinical risk score from Fong et al. [18]
Survival (%)
Score 1-year 2-year 3-year 4-year 5-year Median (months)
0 93 79 72 60 60 74
1 91 76 66 54 44 51
2 89 73 60 51 40 47
3 86 67 42 25 20 33
4 70 45 38 29 25 20
5 71 45 27 14 14 22
Each risk factor is one point: node-positive primary, disease-free interval <12 months, >1 tumour, size >5 cm, CEA >200 ng/ml.
Our own unpublished data from a cohort of 628 patients shows large confidence intervals (CI) in overall survival per CRS after intentionally curative surgical treatment (table 2).
Patients with a CRS of 2 have a 95% CI of two years, ranging from 52 to 76 months. Given
this wide range, it is to be hoped that prognostication might be improved by molecular markers that explain tumour-specific characteristics not reflected by clinical models.
Table 2 Overall survival per CRS of unpublished own data.
CRS Number of patients Median survival in months 95% CI
0 30 132 66 - 198
1 144 77 53 - 101
2 227 64 52 - 76
3 182 41 36 - 46
4 40 20 16 - 24
5 5 21 14 - 28
CRS = clinical risk score. CI =confidence interval
Molecular markers
Rapidly evolving technologies have led to the expectation that biological markers will be able to outperform the current clinical scoring systems and provide more effective personalised treatment.
In breast cancer, for example, tumoural mRNA expression signatures have proven to be a stepping stone in achieving personalised treatment and are therefore included in the national guidelines [20–22]. Three molecular markers are currently included in the guidelines of the management of CRC patients (updated in June 2014). RAS mutation status is determined to ensure the effectiveness of EGFR-directed therapy. MSI status can be tested if hereditary colorectal cancer is suspected. Serum carcinoembryonic antigen levels are measured to detect recurrences after surgery for CRLM [23]. Although not (yet) included in the guidelines, MSI status and BRAF V600E mutation status can be used to guide the administration of chemotherapy [24–27]. No prognostic molecular marker is included in the guidelines, but modern technologies hold great promise for yielding an accurate prognostic biomarker that can guide treatment and follow-up after surgery for CRLM.
Clinical management using thermal ablation
Currently, surgical resection or ablation is the only way to potentially cure CRLM. Recent advances in the treatment of CRLM have extended the possibilities for increasing curability, but disease will still recur in many patients undergoing a potentially curative resection [17]. One of these advances in the treatment of CRLM is thermal ablation, which destroys tumours by heat generated at the tip of an inserted needle. Thermal ablation can be used
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under guidance of computed tomography (CT) scans or ultrasound and is recommended if a partial hepatectomy is not possible. The most common indications for thermal ablation are bilobar liver metastases, recurrences after previous partial liver resection, patient comorbidity and an increased risk of insufficient liver remnant after extended liver surgery. In practice, CT-guided percutaneous thermal ablation is performed as a stand-alone procedure and ultrasound-guided thermal ablation is performed alone or in adjunct to a partial hepatectomy. Currently there are two commonly used variants of thermal ablation, one that uses the heat of generated radiofrequency waves (350- 500 kHz, radiofrequency ablation, RFA) and the other that uses electromagnetic waves (300 MHz-300 GHz, microwave ablation, MWA). RFA is the type of thermal ablation that was performed most often in previous studies, as MWA more recently emerged as an alternative ablation technique. In a recent review comparing thermal ablation and partial hepatectomy, thermal ablation was associated with an inferior patient survival and had a higher recurrence rate [28]. Of note, the effectivity of thermal ablation is heavily dependent on tumour size, since larger tumours are more difficult to cure [29].
Scope of this thesis
Part I: Association of biomarkers in resected colorectal liver metastases with patient survival
The current clinicopathological prognostic models are not specific enough to be valuable for the individual patient, making personalised treatment very difficult. In this thesis, we aimed to identify prognostic markers in surgical tumour specimens that can improve prognostication after surgical resection. This is relevant because accurate prognostication can guide management for the individual patient, such as the administration of adjuvant chemotherapy after liver surgery and a patient-tailored follow-up (intensity, duration).
Paget’s ‘seed and soil’ theory describes how it is not only the tumour (seed = hematogenous dissemination of tumour cells from the primary CRC) but also the microenvironment in the hosting organ (soil = liver parenchyma) that is important for the development of metastases [30]. The biological behaviour of the tissue surrounding the tumour is crucial for successful outgrowth, e.g. in stromal interaction, immune response and angiogenesis [31]. Molecular characteristics of the liver parenchyma adjacent to the tumour might therefore be suitable for prognostication. We included samples of two groups of patients with extreme survival rates: poor survivors, who died of recurrent disease within 30 months after partial liver resection, and good survivors, who showed no evidence of
recurrent disease up to 60 months after liver resection. We aimed to discover molecular markers associated with our extreme survival groups, and subsequently, validate the discovered markers in larger cohorts.
Part II: The role of thermal ablation in the management of patients with colorectal liver metastases
In 75-80% of patients, an initial curative treatment of CRLM is not possible [16]. Moreover, more than 50% of patients who underwent curative liver surgery will develop recurrent disease [32,33]. The livers of these patients generally have a high tumour load, which might impede complete oncological treatment. Therefore, in many cases, a minimally invasive treatment could be of great value to increase curability and survival rates. Our aim in part two was to study the role of targeted treatment by RFA in patients with CRLM, focussing on patient survival.
Outline of this thesis
Part I: Association of biomarkers in resected colorectal liver metastases with patient survival
Chapter 2 is a systematic review of the literature on prognostic immunological and molecular markers studied in tumour tissue of resected CRLM. We first reviewed studies using tissue-based immunophenotypical protein markers. We then reviewed literature reporting tissue-based molecular markers by assessing tumour mRNA and microRNA expression. The review is restricted to molecules with a predominant role in the immune system.
In chapters 3, 4 and 5 we analysed the prognostic value of molecular markers after surgery of CRLM. All analyses were carried out on tissue obtained at surgical resection. The patient cohorts are at the extremes of outcome with respect to survival: poor survivors died of recurrent disease within 30 months after partial liver resection, while the good survivors showed no evidence of recurrent disease at least 60 months after liver resection.
Chapter 3 describes the search for new biomarkers using explorative mRNA sequencing to assess which genes are associated with poor or good survival after surgery. Both samples of tumour tissue and adjacent liver parenchyma were analysed. Subsequently, we performed immunohistochemistry to validate the mRNA sequencing results on protein level.
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Chapter 4 reports on the prognostic role of tumour microRNA expression after surgery for CRLM. MicroRNAs function in the post-transcriptional regulation of mRNA and are frequently dysregulated in cancer.
Chapter 5 describes the results on the relation between copy number variation in CRLM and patient survival. Copy number variation is a common feature in CRC and is established as an enabling characteristic for tumorigenesis [34].
Part II: The role of thermal ablation in the management of patients with colorectal liver metastases
Chapter 6 describes the clinical management of patients with CRLM with an emphasis on the treatment of recurrences. A repeat liver resection is feasible in selected patients with intrahepatic recurrences, but may not be possible due to anatomical or functional restraints. The aim of this study was to analyse patient survival following repeat interventions for recurrences, focussing on the role of RFA.
Chapter 7 addresses the application of thermal ablation in simultaneous treatment of synchronous liver metastases and primary CRC. About 20% of CRC patients have CRLM at the time of discovery of the primary CRC, and selected patients can be cured by simultaneous resection of both tumours in one surgical session. The aim of this chapter is to analyse short-term and long-term outcome of RFA in simultaneous treatment.
Part III: Overview and future
Chapter 8 summarizes and discusses the results of the studies we performed and presents ideas for future directions of research.
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