Scandinavian Journal of Gastroenterology. 2014; 49: 1399–1408

REVIEW

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Determinants of recurrence after intended curative resection for colorectal cancer

MICHAEL WILHELMSEN1, THOMAS KRING1, LARS N. JORGENSEN2,7, MOGENS RØRBÆK MADSEN3, PER JESS4, ORHAN BULUT1, KNUD THYGESEN NIELSEN5, CLAUS LINDBJERG ANDERSEN6 & HANS JØRGEN NIELSEN1,7 1

Department of Surgical Gastroenterology 360, Hvidovre Hospital, Hvidovre, Denmark, 2Digestive Disease Center, Bispebjerg Hospital, Copenhagen, Denmark, 3Department of Surgery, Herning Hospital , Herning, Denmark, 4 Department of Surgery, Hillerød Hospital, Hillerød, Denmark, 5Department of Surgery, Randers Hospital, Randers, Denmark, 6Department of Molecular Biology (MOMA) Aarhus, Denmark, and 7Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

Abstract Despite intended curative resection, colorectal cancer will recur in ~45% of the patients. Results of meta-analyses conclude that frequent follow-up does not lead to early detection of recurrence, but improves overall survival. The present literature shows that several factors play important roles in development of recurrence. It is well established that emergency surgery is a major determinant of recurrence. Moreover, anastomotic leakages, postoperative bacterial infections, and blood transfusions increase the recurrence rates although the exact mechanisms still remain obscure. From pathology studies it has been shown that tumors behave differently depending on their location and recur more often when micrometastases are present in lymph nodes and around vessels and nerves. K-ras mutations, microsatellite instability, and mismatch repair genes have also been shown to be important in relation with recurrences, and tumors appear to have different mutations depending on their location. Patients with stage II or III disease are often treated with adjuvant chemotherapy despite the fact that the treatments are far from efficient among all patients, who are at risk of recurrence. Studies are now being presented identifying subgroups, in which the therapy is inefficient. Unfortunately, only few of these facts are implemented in the present follow-up programs. Therefore, further research is urgently needed to verify which of the well-known parameters as well as new parameters that must be added to the current follow-up programs to identify patients at risk of recurrence.

Key Words: colorectal cancer, disease-free survival, follow-up program, recurrence, surgery

Background Colorectal cancer (CRC) represents a major health problem with ~1.2 million new individuals diagnosed with the disease and about 610,000 deaths every year [1]. At the time of diagnosis, 80% of the patients may undergo intended curative resection, but it is well established that recurrence is frequently observed within the following few years [2–5]. Conservative estimates show that 5% of the patients with stage I disease will recur, whereas the rate for patients with

stage II disease is 10–20% and 30–45% for stage III disease [6–9]. With respect to obstructive and/or perforating tumors and subsequent emergency resections, the overall recurrence rates are significantly higher than after elective resections [9]. In addition to resection, intended curative treatment includes neoadjuvant chemoradiation and/or adjuvant chemotherapy to various patient categories to reduce the risk of recurrence and overall mortality [10]. Despite these efforts, recurrences are still a major challenge for the treatment of patients with CRC.

Correspondence: Michael Wilhelmsen, MD, Department of Surgical Gastroenterology 360, University of Copenhagen, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark. Tel: +45 38 62 24 36. Fax: +45 38623760. E-mail: [email protected]

(Received 4 December 2013; revised 10 May 2014; accepted 12 May 2014) ISSN 0036-5521 print/ISSN 1502-7708 online  2014 Informa Healthcare DOI: 10.3109/00365521.2014.926981

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Consequently, follow-up programs have been established to identify patients with recurrence at an early stage with the opportunity to perform a subsequent second resection with curative intent. At present, the most efficient follow-up program has not been determined, but the patients are offered surveillance according to various established national guidelines, which all include clinical examination, interval computed axial tomography, and/or magnetic resonance imaging scans, and colonoscopies [11–13]. In most programs, serum carcinoembryonic antigen analyses are also included as recommended by major organizations [14–16]. Meta-analyses, Cochrane reviews, and systematic reviews have concluded that an intensive regimen is both cost efficient [12] and improves overall survival [11–13], while early recurrences are not efficiently detected [11]. Various risk factors for recurrence have been identified, but most of these are still not registered as a part of the present follow-up programs. An overview of risk factors for recurrence is presented in Figure 1. It is assumed that implementation of such factors would improve identification of patients at risk of recurrence. Based on the improved biotechnology capabilities present, intensified research programs focus on further evaluation of specific biological markers in tissue and blood to improve early identification of patients at risk of recurrence. Overall, such markers include single proteins, proteomics, metabolomics, transcriptomics, genomics, and epigenomics. Results of such research approaches are awaited with interest.

Aim The aim of the present review is to focus on factors known to play significant roles in development of recurrence following intended curative treatment for sporadic CRC. Subsequently, a short discussion with suggestions for further improvements is included. Factors predictive of recurrent CRC Radiotherapy In rectal cancer, radiotherapy is often used to prevent local recurrences. It is presently only recommended to administer this therapy to patients with locally advanced rectal tumors preoperatively staged as T3 or T4 [17] as these have tendency to recur locally in 11–16 % of the cases if treated by total mesorectal excision (TME) surgery alone [18,19]. Radiotherapy induces cell death due to alterations of DNA, and it may downstage some tumors and prevent local recurrence [20]. The optimal duration of treatment is not yet clear, and that area presently undergoes intense investigation [21,22]. When offered in randomized controlled trials (RCTs), radiotherapy reduces local recurrence among these patients from 11–16% to around 5%, irrespective of the addition of chemotherapy [18,19]. There are several side effects to be considered. These include acute toxic effects and late radiation, i.e., damage to the bowel, rectal bleeding, and diarrhea [23,24].

Surgical strategy: -Emergency surgery -Stenting -Anastomosis Radiotherapy: -Locally advanced tumors

Biological variables: -Biological markers -Infections Recurrence

Surgical radicality -Assesment of specimens

Pathology: -Tumourstage -Location of tumor -Differentation Micrometastasis

Perioperative care: -Postoperative infections

Figure 1. A summary of factors known to be important for recurrence.

Cancer, recurrence, disease free survival, follow-up

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Surgery Apart from a definite role in curative treatment for CRC, surgery may also impact on subsequent development of recurrence under elective conditions [25–28], emergency procedures [2,9,29,30], and stenting [25,31] of obstructive tumors. Moreover, the surgeons skills may play a prominent role [30,32–36]. CRC may present as emergencies either due to obstruction or perforation of the large bowel, and around 10–15 % of CRC resections are performed in the emergency setting [3,9,30]. Such cases constitute a major clinical challenge [37]. Depending on the specific event, the operation is performed as an immediate procedure or delayed following endoscopic placement of a stent as a bridge between emergency care and subsequent elective resection. This principle reduces the incidence of well-known complications to major emergency operations [2,4,25,29,30]. Moreover, the stent procedure serves as a minimally invasive alternative to cecostomy, which can be performed in an emergency procedure [38]. However, stent treatment may cause oncologic unfavorable side effects such as increased local recurrence rates [39]. Currently, an RCT (CReST trial) is conducted to answer whether stenting or operation should be performed as first choice in this situation. The most unfavorable aspect of emergency surgery is the presentation of tumors at a more advanced stage with perforating lesions being particularly hostile [3,4]. If an emergency operation has to be performed, the surgeon should be specifically aware of the anastomosis, since this represents a potential source of surgical site infection. Moreover, anastomotic leakage (AL) increases overall morbidity, operative mortality, and recurrence [40,41]. A Hartmann procedure seems as a good choice both with regard to morbidity and overall survival [4]. Moreover, stomas following this procedure may be reverted, and it does not hinder the patient in receiving adjuvant chemotherapy [4]. In an effort to decrease the numbers of emergency operations, stenting procedures have been implemented to selected patients. A metal stent is, however, also associated with potential side effects, of which perforation occurs in around 4% of the cases and immediately results in an emergency operation [25,31]. In elective surgery the most optimal operative approach seems to be a laparoscopic-assisted procedure. Large RCTs have shown that laparoscopically assisted CRC resections are at least comparable to open surgery with regard to disease-free survival (DFS) [25– 28], which is defined as the time from primary treatment of a cancer without signs or symptoms of the disease [42]. In such procedures, conversion to open surgery

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may be associated with reduced DFS due to either a complication during the operation or presence of advanced disease [28]. New emerging techniques are evolving and robotic-assisted surgery is presently being evaluated in RCTs such as the RolaRR trial (ClinicalTrials.gov Identifier: NCT01736072). Other new methods such as single incision laparoscopic surgery [43] and transanal microinvasive surgery [44] need evaluation in additional RCTs to be implemented into daily clinical practice. TME reduces local recurrence rates compared with conventional surgery [5,18,45–53]. Preoperative radiotherapy may reduce TME-associated low recurrence rates further, provided that patients have at least 2 mm circumferential resection margin (CRM) [54,55]. New results show that patients with a narrower CRM may benefit from selective radiotherapy [56]. In colonic resections, a similar approach known as the complete mesocolic excision (CME) has been advocated including extensive lymphadenectomy and central ligation of the vessels. Such excisions appear to reduce the incidence of recurrences, although the studies were exclusively performed in patients undergoing open colonic resections [57–59]. For CME these results still need to be reproduced and documented properly following laparoscopically assisted or open resections [60,61]. The least evaluated aspect of surgery is probably the surgeon’s skill. Theoretic knowledge is vital and the surgeon has to be aware of basic surgical principles such as en-bloc resection [62] and ‘no touch’ isolation techniques [63]. The impact of these theoretical aspects has been proven by Hermanek et al. with focus on rectal surgeons performing at least 15 resections per year and they found local recurrence rates of 4–55% [33]. Such differences among surgeons may reflect differences in both disease stages among the patients and the various operative procedures used at the resections. Comparison between departments has revealed that the incidence of recurrences varies from 10% to 37%, indicating room for improvement both at the surgeon and the department levels. A Norwegian study focused on surgeons in training and concluded that the radicality and recurrence rates were significantly improved, when a board-certified surgeon in CRC surgery was present at the table, although the specialist did not have to perform the operation [30]. A close communication and discussion between the surgeon and the pathologist on the characteristics of the resected specimen is an effective step toward improvement of surgical quality and radicality. Quirke and co-workers thus stated that assessment of rectal TME resections by trained pathologists improves the quality of surgery leading to lower recurrence rates [35,36].

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Pathology of resected specimen The importance of thorough examination of the resected specimen has been studied by several authors [5,35,36,45–48,50,64]. Large-size tumors are associated with advanced TNM stages and cancer-related death [65]. In addition, the location of the tumor and the number of lymph nodes within the resected specimen may play significant roles. With regard to the location of the tumor, the evidence is still debated. Some authors argue that the overall survival is similar [66], while others argue that right-sided tumors have a poorer prognosis than left-sided tumors. Recently, it has been shown that tumors located around the splenic flexure are most unfavorable although mechanisms are unclear [67]. The studies have various limitations as some do not take chemotherapy into account [68], others exclude patients who die within 30 days or do only include patients over 65 years of age [66]. The microscopic features of the lesions in relation to the location have been examined. It appears that mucinous histology and low degree of differentiation are more frequently observed in right-sided tumors than in left-sided tumors (Table I) [66], and that these features are associated with an increased risk of recurrence [69,70]. The number of harvested lymph nodes is of utmost importance in relation to the radicality of the resection. At present, it is a requirement for intended curative resections that at least 12 nodes are removed, although some argue that at least 20 lymph nodes should be removed for correct classification [6,71]. The risk of recurrence is reduced when the number of resected lymph nodes is increased [6]. Microscopic examinations of the lymph nodes are required to evaluate potential micrometastases, which play a definite role for the risk of developing recurrent disease [6,71–79]. A ratio between the number of lymph nodes with metastases and the total number of resected lymph nodes has also been proposed for risk assessment of both local and distant recurrence [74,80]. This ratio has proven valid after elective as well as emergency resections [80]. A more rational strategy could be sentinel node mapping [81], which is currently evaluated as a determinant for reduction of recurrence rates [78]. It is crucial that sentimental

node mapping is performed in a standardized way both with regard to research and in daily clinical practice [76]. Other ways of examining locally advanced disease is assessing whether vessels or nerves contain micro metastasis. The definition of local nerve invasion is tumor cells surrounding over 33% of the neural sheet [82]. If the neural sheet is invaded by tumor cells, the DFS drops significantly as demonstrated in both stage I, II and III CRC [83,84]. Perineural invasion is also important in identifying patients, who may benefit from chemotherapy [85]. It has also been demonstrated that tumor cell invasion in vessels is a predictor for distant metastasis and recurrence [86]; however, the degree of invasion in the vessels is dependent on the number of slides examined [87], and therefore, such information should be taken with caution. Postoperative bacterial infections and blood transfusions The highest incidence of postoperative bacterial infectious complications is observed among patients, who have undergone emergency surgery including laparotomies. Results from large series have shown bacterial infectious complication rates of around 11% without differences between right- and left-sided resections [66]. Apart from AL, significant complications include wound infections and pneumonia [40,41,88–90]. AL appears as the most significant adverse event with increased morbidity, risk of reoperations, length of hospital stay, and perioperative mortality [88–90]. At present, the exact mechanism is not clear, but it seems evident that bacterial infections following emergency surgery are associated with increased recurrence rates. The only infectious complication that is independently related to recurrence is AL [88] occurring in around 6% of the patients undergoing colonic or rectal resections [90]. AL is associated with male gender and the risk increases when the anastomosis is more distal with the highest rates after rectal resection [90]. The increased recurrence rates reported after AL may be associated with the fact that patients suffering from that complication receive less chemotherapy than patients without AL. Moreover, patients with AL may receive adjuvant treatment on a later stage due to reoperations and prolonged stay at the surgical ward [41].

Table I. Differences between right- and left-sided colorectal cancers. Parameter

Right sided

Left sided

Reference

Mucinous histology Differentiation degree Obstructive symptoms Kras mutation

Many Low Absent High

Few Higher Present Low

Halvorsen et al. [70] Halvorsen et al. [70] Cortet et al. [9] Bleeker et al. [102]

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Cancer, recurrence, disease free survival, follow-up The importance of perioperative blood transfusions and postoperative bacterial infectious complications has also been studied extensively [91]. Retrospective studies and a Cochrane analysis show that patients, who received perioperative blood transfusions, had significantly higher recurrence rates than the patients, who were not transfused [92,92–94]. The exact mechanism probably involves complex mechanisms suppressing the immune system [95,96], leaving patients more prone to infectious complications, which subsequently increases the risk of cancer recurrence [93,95]. Biological variability Several important aspects have to be considered in the context of biological variability, including location of the tumor, familial dispositions, genetic variations and mutations. A family history of CRC is scientifically defined as at least one first-degree relative with the disease [97,98]. In a study including only stage III patients stratified by positive or negative family history, the rates of mismatch repair genes (MMR) and microsatellite instability (MSI) were similar in the two groups. Patients with a positive family history had fewer recurrences and higher overall survival than those without relatives with CRC [97,98]. Such differences were even more obvious after inclusion of patients with higher numbers of relatives with CRC [98]. Two studies on patients with stage II or III colon cancer have focused on MMR deficiency and loss of heterozygosity at chromosomal location 18q (18qLOH). Compared with stage III, more stage II tumors were MMR-D and were intact (I) at 18q. Patients with MMR-D tumors exhibited higher 5-year DFS than those with MMR-I tumors. Finally, among patients with MMR-I tumors, the status of 18q did not influence the DFS rate at 5 years [99]. K-ras mutations are important for recurrence [100,101]. At present, seven subsets of the mutation have been identified to correlate with the risk of recurrence [100,101]. In this aspect, the location of the tumor seems important, as the frequency of K-ras mutations is higher in right-sided tumors suggesting an alteration of the sensitivity to chemotherapy [102], particularly EGFR inhibitor-directed treatment modalities and this may partly explain the higher risk of recurrence/distant metastases among patients with right-sided primary lesions. Chemotherapy Chemotherapy is recommended to selected stage II and most stage III CRC patients in order to prevent

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recurrences in these patients, although this effect is doubtful in meta-analyses, mostly because information on recurrence is difficult to extract from the clinical trials [10,103]. In stage II colonic tumors, the efficacy of chemotherapy on the prevention of recurrence is far from shown in detail. Major RCTs and pooled analyses including stage II patients have not clearly documented differences in DFS, concluding that chemotherapy leads to an absolute 3.6% risk reduction of recurrence indicating just a slight positive effect among such patients [104]. As stated previously, stage II patients with MSS tumors have shorter DFS than patients with MSI tumors. This might be a part of the key in selecting stage II patients, who may benefit from chemotherapy [99]. Another important aspect of stage II disease is mucinous histology as this feature is an independent negative prognostic factor associated with shorter DFS and poorer responses to chemotherapy than non-mucinous histology [105]. Beneficial effects on recurrence and DFS among stage III colonic cancer patients have been reported by several RCTs [106–108]. Importantly, recent results indicate that tumor location may play a significant role for the sensitivity of chemotherapy in this group of patients [109]. In addition, age and comorbidity should be considered carefully before prescribing chemotherapeutic agents [110,111]. The antitumor treatment modality regimens are different between patients with rectal and colonic cancer. It is recommended to offer neoadjuvant radiation therapy to selected patients only with rectal cancer. Additionally, chemotherapy has been combined with radiotherapy, although there are geographical differences with regard to such offerings [103]. A recent meta-analysis [103] found only five studies where the disease stage was separately stated – two on stage II [104,112] and three on stage III rectal tumors [112–114] – which may complicate interpretation of the results. Currently, less evidence from studies of rectal cancers is available compared with colonic cancer. In stage II rectal cancer, a beneficial effect on DFS was encountered with a hazard ratio (HR) of 0.69. Unfortunately, this was only possible to interpret directly from one study [103,104]. In stage III rectal cancer, prolongation of DFS was also obtained with chemotherapy reaching HRs between 0.44 and 0.72 [104,113]. Discussion Several risk factors for recurrence of CRC have been documented (Figure 1). If these risk factors were implemented in the current follow-up programs, the number of unnecessary scans and examinations

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might be reduced. Subsequently, a more detailed approach to patients with high risk for recurrence would be possible across disease stages. It appears necessary to review the postoperative period carefully with regard to risk factors including infectious bacterial complications, perioperative blood transfusions, and whether or not emergency surgery was performed [9,41,94]. Systematic evaluation of the resected specimen is necessary to determine the correct tumor stage to properly select patients for administration of chemotherapy [36,80]. More data on the effect from chemotherapy are needed as the present evidence is difficult to interpret due to heterogeneity of the available studies [103]. In addition, focus should be addressed toward identifying patients, who would benefit from chemotherapy in terms of a reduced rate of recurrences. Whereas the place for chemotherapy to patients with stage II disease is uncertain, adjuvant chemotherapy is offered to almost all patients with stage III disease, despite the fact that not all patients may benefit from the treatment. Therefore, research is urgently needed to improve stage-independent selection criteria for chemotherapy and predict the benefit of certain treatment modalities. One such research area might be evaluation, validation, and final inclusion of biomarkers for prognosis, prediction, selection, and monitoring of disease. Such biomarkers may be identified in tumor tissue, but due to the lack of easy accessibility, tissue-based biomarkers do not represent the ideal medium. Currently, major research protocols and present results consider biomarkers in blood samples, which are easily accessible. Blood-based biomarkers may therefore be the ideal solution for all aspects of CRC prognosis, prediction, selection, and monitoring. The accelerated development of new and reliable methods in protein chemistry and molecular biology leads to a variety of compelling research and analysis platforms. Present research focuses on single proteins [115,116], proteomics [117,118], single genes [119,120], genomics [121], epigenomics [122], metabolomics [123], and translatomics [121,124]. Although specific or complex analyses are under development, such approaches must be evaluated and subsequently validated in accordance with the REMARK guidelines [125,126]. Future results from basic, translational, and clinical research are awaited with utmost interest. Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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