Clinical and Translational Oncology (2019) 21:46–54 https://doi.org/10.1007/s12094-018-02002-w CLINICAL GUIDES IN ONCOLOGY SEOM clinical guidelines for diagnosis and treatment of metastatic colorectal cancer (2018) M. A. Gómez‑España1 · J. Gallego2 · E. González‑Flores3 · J. Maurel4 · D. Páez5 · J. Sastre6 · J. Aparicio7 · M. Benavides8 · J. Feliu9 · R. Vera10 Received: 27 November 2018 / Accepted: 28 November 2018 / Published online: 18 December 2018 © The Author(s) 2018 Abstract Colorectal cancer (CRC) is the second cause of cancer death in Spain, the objective of this guide published by the Spanish Society of Medical Oncology is to develop a consensus for the diagnosis and management of metastatic disease. The optimal treatment strategy for patients with metastatic CRC should be discussed in a multidisciplinary expert team to select the most appropriate treatment, and integrate systemic treatment and other options such as surgery and ablative techniques depending on the characteristics of the tumour, the patient and the location of the disease and metastases. Keywords Colorectal cancer · Metastases · Surgery · Chemotherapy · Targeted agents · Ablative treatments · Frail patients Introduction nearly 50% of patients will eventually develop metastases, which explains the high mortality rates reported for CRC. In Spain, 41,441 new cases of CRC were estimated for In fact, this tumour accounts for 13.7% and 14.3% of all 2015, representing the second most common tumour type cancer deaths in men and women, respectively, in our coun- in both sexes. It was more frequent in men (24,764) than try. SEOM gathered ten CRC experts based on their major in women (16,677) [1]. Twenty to twenty-five per cent of scientific contributions in the field. The purpose of this patients have metastatic disease at initial diagnosis and paper was to define the current “state of the art” through 1 * M. A. Gómez‑España Servicio de Oncología Médica, H. Universitario Reina magespanya@hotmail.com Sofía, IMIBIC, CIBERONC, Av. Menéndez Pidal, s/n, 14004 Córdoba, Spain J. Gallego 2 j.gallegoplazas@gmail.com Servicio de Oncología Médica, Hospital General Universitario, Elche, Spain E. González‑Flores 3 encarnagonzalezflores@gmail.com Servicio de Oncología Médica, H. U. Virgen de las Nieves, Granada, Spain J. Maurel 4 JMAUREL@clinic.cat Servicio de Oncología Médica, Hospital Clinic, Barcelona, Spain D. Páez 5 dpaez@santpau.es Servicio de Oncología Médica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain J. Sastre 6 jsastrev@salud.madrid.org Servicio de Oncología Médica, Hospital Clínico San Carlos, IdISSC, CIBERONC, Madrid, Spain J. Aparicio 7 aparicio_josurt@gva.es Servicio de Oncología Médica, Hospital Universitari i Politècnic La Fe, Valencia, Spain M. Benavides 8 manuel.benavides.sspa@juntadeandalucia.es Servicio de Oncología Médica, H.U. Regional y Virgen de la Victoria, Málaga, Spain J. Feliu 9 jaimefeliu@hotmail.com Servicio de Oncología Médica, H. U. La Paz, UAM, CIBERONC, Madrid, Spain R. Vera 10 ruth.vera.garcia@navarra.es Servicio de Oncología Médica, Complejo Hospitalario de Navarra, IdiSNA, Pamplona, Spain 13 Vol:.(1234567890) Clinical and Translational Oncology (2019) 21:46–54 47 the use of evidence based medicine. The available medical Biomarkers literature was reviewed according to main topics of disease management, and classified by scientific levels of evidence In the mCRC setting, biomarkers may be classified as and grades of clinical recommendation (Table 1) [2]. The prognostic or predictive biomarkers. resulting text was reviewed, discussed, and approved by all Prognostic biomarkers: Classical clinical and biochemi- authors. cal parameters such as ECOG performance status, WBC count, alkaline phosphatase (AP), lactate dehydrogenase (LDH) and number of metastatic sites have been consid- Staging ered as the main prognostic factors for survival. Recently, a multivariate analysis carried out by the GERCOR group The extent of the disease must be carefully assessed, as well in patients receiving oxaliplatin or irinotecan first-line as tumour biology and patient-related factors before starting combinations has shown that ECOG, LDH and number of cancer-specific therapy. metastatic sites are the independent most important clini- Table 2 shows suggested staging procedures. The recom- cal prognostic factors [4]. A prognostic model classify mended staging system is the 8th edition of the American patients in low risk (0 points, median OS 29.8 months), Join Committee on Cancer (AJCC) [3]. Table 1  Levels of evidence and grades of recommendation Levels of evidence I. Evidence from at least one large randomized, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomized trials without heterogeneity II. Small randomized trials or large randomized trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity III. Prospective cohort studies IV. Retrospective cohort studies or case–control studies V. Studies without control group, case reports, experts opinions Grades of recommendation a. Strong evidence for efficacy with a substantial clinical benefit, strongly recommended b. Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended c. Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs,), optional d. Moderate evidence against efficacy or for adverse outcome, generally not recommended e. Strong evidence against efficacy or for adverse outcome, never recommended Table 2  Suggested staging procedures Clinical examination Laboratory tests including liver and renal function tests and prognostic markers (white blood cell count, alkaline phosphatase, lactate dehydroge- nase (LDH), bilirubin, and albumin) Carcinoembryonic Antigen (CEA) Pathological review of a tumour biopsy (histological subtype, tumour grade, microsatellite status, and KRAS, NRAS and BRAF mutational status) Computed tomography (CT) scan of the chest, abdomen and pelvis. Magnetic resonance imaging (MRI) could be considered in cases of hepatic metastases and locally advanced rectal tumours Complete colonoscopy to locate the primary tumour, to obtain tissue for histological diagnosis, and to detect potential synchronous colorectal lesions. Virtual colonoscopy or barium enema could be useful in case of tumours that impede the progression of the endoscopic tube Other tests such as a bone scan or a brain CT scan should be performed only if clinically indicated Needle biopsy of a patient with known histologic diagnosis is only recommended when it may change the therapeutic strategy Additional examinations, as clinically needed, are recommended prior to major abdominal or thoracic surgery with potentially curative intent Abdominal MRI with intravenous contrast may be considered If liver-directed therapy or surgery is contemplated, and for patients with iodine allergy A fluorodeoxyglucose (FDG)-positron emission tomography (PET–CT) scan should be performed in the case of potentially surgically curable M1 disease 13 48 Clinical and Translational Oncology (2019) 21:46–54 intermediate risk (1–2 points, median OS 19.5 months) Resectable colorectal metastases and high-risk (3–4 points, median OS 13.9 months). In the last years, primary tumour sidedness has emerged Resectable colorectal liver metastases (RLM) are defined as an important prognostic factor in wild-type RAS as metastatic liver disease in that a R0 resection can be patients receiving chemotherapy plus targeted therapy performed, leaving at least a 20–25% of total liver volume [5]. A significant worse prognosis is associated with right- as future liver remanent [10]. sided tumours in terms of response rate, progression-free Preoperative factors found to be independent predic- survival and overall survival. tors of poor survival are a primary tumour at stage T4, Among the biological biomarkers for survival in ≥ 4 liver metastases, the largest liver metastasis ≥ 5 cm in patients with metastatic CRC, BRAF mutation V600E diameter, and a serum CEA level ≥ 5 ng/ml. According to is the strongest poor prognostic factor [6]. The negative these factors, resectable patients could be divided in high prognostic role of RAS mutations has consistently been risk patients (3 or more factors) and low risk patients (less observed regardless the treatment regimen and the addition of 3 factors) [11]. or not of bevacizumab [6]. The optimal sequencing of systemic therapy and resec- Finally, the role of the circulating tumour cell count > 3 tion in RLM remains unclear. Patients with resectable dis- in 7.5 ml of blood, by the CellSearch system, as prognostic ease may undergo resection first, followed by postopera- factor, has been demonstrated in many prospective clinical tive adjuvant chemotherapy. Alternatively, perioperative trials and meta-analysis, but only the FDA has approved (neoadjuvant plus postoperative) systemic therapy can be this technology for clinical practice [7]. used. Predictive biomarkers: at the moment, no useful predic- A 2012 meta-analysis identified 3 randomized clinical tive biomarkers have been identified for patients receiving trials comparing surgery alone to surgery plus systemic first-line oxaliplatin or irinotecan-based combinations or therapy. The analysis showed a benefit of chemotherapy antiangiogenic drugs. In contrast, activating RAS (KRAS/ in PFS (progression free survival) and DFS (disease free NRAS) mutations have been identified as biomarkers for survival) but not in OS (overall survival). Another meta- cancer cell resistance to monoclonal antibodies directed to analysis combined data on 1.896 patients and also found epidermal growth factor receptor (EGFR) [8]. As a result, that perioperative chemotherapy improved DFS but not the European Medicines Agency (EMA) has restricted OS. Additional recent meta-analyses have also failed to the use of these drugs to patients with RAS wild-type observe an OS benefit with adjuvant chemotherapy [12]. tumours. All the studies that have validated the role of In low risk patients, perioperative treatment may not be RAS mutations as negative predictive factor for anti-EGFR necessary. (I,C) In high risk patients, perioperative com- therapy were done with available archived paraffin tumour bination chemotherapy should be administered. (I,B) In samples and then, should be kept as the gold-standard in high-risk patients, those who had received neoadjuvant clinical practice as long as the performing lab complies chemotherapy had a better overall median survival (38.9 m with nationally and internationally qualified quality assur- vs. 28.4 m) than those had not received it, and 5 years OS ance programs. High sensitivity technologies to test RAS rate of 39% vs 33% (p = 0.028). In low risk patients, this mutations in ctDNA have observed a high concordance difference in median survival (60.0 m vs. 60.0 m) was not with the standard procedures and might be an alternative found according to whatever received preoperative chemo- when no tumour sample is available or for testing second- therapy. In the case of low risk patients, who have not ary resistance [9]. received perioperative chemotherapy, there is no strong Preliminary data suggest that high-microsatellite insta- evidence to support the use of adjuvant chemotherapy (II, bility (MSI-H) or mismatch repair deficient (dMMR) and C) whereas patients with unfavourable criteria may benefit HER-2 over-expression or amplification, might have a role from adjuvant treatment. as predictive factors for therapy with check-point inhibitor The preferred treatment in RLM should be FOLFOX (or antibodies and trastuzumab plus lapatinib, respectively, alternatively CAPOX) as reported for the EPOC trial [13] but at the moment only check-point inhibitors are approved (IV, B). EGFR-targeting monoclonal antibodies are not by the FDA, but not for the EMA as immunotherapy for recommended to be used in this setting, based on the data resistant MSI-H/dMMR colorectal cancer patients. from the New EPOC trial [14]. No data with bevacizumab Recommendations: In all patients with metastatic colo- are available for this specific patient group. rectal cancer, exon 2, 3 & 4 mutations in RAS and V600E Colorectal metastatic disease sometimes occurs BRAF mutation should be tested. Furthermore, mismatch in the lung. Complete resection based on the ana- repair deficiency (IHC or MSI-H) is recommended to find tomic location and extent of disease with mainte- patients potential candidates for immunotherapy rescue. nance of adequate function is required. Ablative 13 Clinical and Translational Oncology (2019) 21:46–54 49 techniques may be considered alone or in conjunction Recommendations: Fit patients with borderline resect- with resection for resectable disease. All original sites able metastases should receive intensive induction therapy of disease need to be amenable to ablation or resection. with chemotherapy doublets and a biologic agent, or chemo- Most of the treatment recommendations discussed for met- therapy triplets with or without biologics (II, A). In RAS astatic colorectal liver disease also apply to the treatment WT tumours, anti-EGFRs may be more effective than beva- of colorectal pulmonary metastases. Combined pulmonary cizumab in terms of tumour shrinkage, especially for left- and hepatic resections of resectable metastatic disease sided primary tumours (II, B). Figure 1. have been performed in very highly selected cases. In patients with limited peritoneal carcinomatosis, com- plete cytoreductive surgery and HIPEC can be considered Unresectable disease. First‑line treatment in centres with experience. Recommendations: Resection is recommended for resect- For the purpose of this guideline, treatment with chemo- able liver metastases. Criteria of resectability and prognostic therapy for fit patients with unresectable mCRC at diagnosis factors are necessary for guiding the need to administer sys- or deemed not eligible for radical treatment in the evolution temic perioperative/adjuvant therapy. Surgery for resectable of the disease is considered. In this scenario, main treat- lung metastases may be considered. Complete cytoreductive ment endpoints include prolonging patient survival, reliev- surgery and HIPEC can be an option if limited peritoneal ing symptoms caused by the disease while improving and carcinomatosis is present. sustaining quality of life. Factors considered to influence on first-line treatment decision for unresectable mCRC, once established that all components included in the recommendation should have Potentially resectable metastatic disease formal approved indication by national and local regulatory agencies, are patient characteristics and wishes, as well as Patients with initially unresectable, organ-confined liver and/ characteristics of the disease. Unfit patients treatment will be or lung metastases should be considered candidates for sec- covered anywhere in this guideline, hence we will only con- ondary surgery. Conversion therapy offers the best means cern for patients without conditions which would made them of achieving the goal of resectability. Survival times for unable to fulfil inclusion criteria for clinical trials that scien- patients resected after chemotherapy are slightly shorter than tifically endorse treatment combinations for first-line treat- for those patients with upfront resectable disease, but far ment of mCRC. Patient personal wishes and circumstances better than when surgery is not possible at all. Response to should always be taken into account before establishing any systemic therapy is a strong prognostic indicator and corre- lates well con with resection rates [15]. With the increasing efficacy of current regimens, resectability has to be reevalu- Conversion therapy ated every 2 months (to attain the maximal tumour shrink- age) and surgery scheduled as soon as possible (to minimize Molecular profile chemotherapy-induced liver toxicities and perioperative morbidity). CT morphologic criteria are more predictive RAS mutant RAS wild type BRAF mutant of pathological tumour response than RECIST in patients treated with bevacizumab [16]. For fit patients, the most active induction regimens should Right* Side be administered upfront, generally chemotherapy doublets FOLFOXIRI XELOX or + combined with a biologic agent or chemotherapy triplets FOLFOX or Left Bevacizumab plus/minus a biologic. Combinations of either oxaliplatin or FOLFIRI or irinotecan with fluoropyrimidines are considered adequate FOLFOXIRI options with similar efficacy albeit different toxicity profiles. + FOLFOX or Bevacizumab FOLFIRI Patient’s molecular profile should be considered for adding (or FOLFOXIRI**) targeted therapies. Comparative trials and meta-analyses + suggest that anti-EGFR agents may be more effective in anti-EGFR terms of tumour shrinkage than bevacizumab for RAS WT patients [17], especially in left-sided primary tumours [18]. Fig. 1  Conversion therapy. * The benefit of adding anti-EGFRs in right-sided RAS wild type metastatic colorectal cancer is controver- Triplet combination of FOLFOXIRI with or without beva- sial. Data from meta-analysis suggest a beneficial effect on response cizumab may be considered in selected (RAS- or BRAF- rates but not on survival times. ** Combination of FOLFOXIRI plus mutant) patients at the expense of an increased toxicity [19]. panitumumab or cetuximab has not been extensively evaluated 13 50 Clinical and Translational Oncology (2019) 21:46–54 final treatment recommendation. On the other hand, regard- In case of RAS or BRAF mutated tumours, independently ing disease characteristics, tumour KRAS, NRAS and BRAF of primary tumour location, first-line treatment recommen- mutational status, as well as tumour sidedness are factors to dation is chemotherapy combinations associated with beva- be considered when selecting first-line treatment for mCRC. cizumab (I, A) (Fig. 2). First-line treatment relies on a chemotherapy combina- Regarding first-line treatment combinations including tion in association with a biologic agent, either bevacizumab bevacizumab, intensified chemotherapy with FOLFOXIRI or one of the two agents against the epidermal growth fac- provides greater benefit to patients with right-sided tumours, tor receptor (EGFR), panitumumab or cetuximab [20, 21]. and this regime has been also suggested as preferred option Chemotherapy combinations include doublets of fluoropy- for BRAF mutated tumours [22] (II, B) (Fig. 2). rimidine (5-fluorouracil or capecitabine) and oxaliplatin or Although molecular knowledge of mCRC has introduced irinotecan. Considering all possible treatment combinations, new molecular factors to be considered (microsatellite insta- association of capecitabine and irinotecan, as well as asso- bility, HER2 amplification or mutation, BRAF subgroups, ciation of anti-EGFR antibodies with capecitabine are not RET fusions, and ALK, ROS, NTR1K rearrangements, recommended. The use of triplet combinations of chemo- among others), whilst generating consensus molecular sub- therapy including 5-fluorouracil, oxaliplatin, and irinotecan groups of CRC (immune, canonical, metabolic and mes- (FOLFOXIRI) has demonstrated safety and efficacy in phase enchymal), none of these have been established in clinical III trials, alone or combined with bevacizumab [22] (I, A). practice for first-line treatment of mCRC thus far. Evidence of tumour RAS (KRAS, NRAS) mutation has The recommendation concerning duration of first-line demonstrated to be a negative predictive factor for treatment treatment in mCRC, historically considered to be until dis- with antibodies against EGFR, cetuximab and panitumumab ease progression, unacceptable toxicity, or patient desire, (I,A). The consideration of tumour BRAF mutation as a has been modified in recent years so that nowadays it negative predictive factor is still nowadays a controversial is subjected to patient personal circumstances, cumula- issue, although analysis done so far suggest lack of benefit tive treatment toxicity, and aggressiveness of the disease. of the treatment with panitumumab and cetuximab in these Hence different strategies have emerged, including stop- patients [23]. and-go and intermittent treatment, as well as maintenance For patients with RAS and BRAF wild type tumours, pri- treatment consisting of fluoropyrimidines with or without mary tumour location may influence in treatment selection. bevacizumab, for patients for whom disease control has Results from the joint analysis of trials of chemotherapy been achieved (I,A). The approach to include these treat- associated to anti-EGFR antibodies demonstrated greater ment options goes through essential individualization and benefit of first-line treatment with these combinations in left- discussion with the patient. sided tumours; while for right-sided tumours greater benefit Recommendations: first line treatment for fit patients with in terms of survival is suggested for chemotherapy combined unresectable metastatic colorectal cancer should be based with bevacizumab [5] (I, A) (Fig. 2). upon patient characteristics and wishes, tumour sidedness and RAS y BRAF status. Unresectable Second and successive treatment lines mCRC More than 50% receive second line and more 25% receive third line of treatment. Therapy after first progression will Right-sided Left-sided primary primary depend on prior treatments, ECOG and adequate organ func- tumour tumour tion, RAS/BRAF status and MSS. For patients who received oxaliplatin based therapy, FOL- FOLFOXIRI + bevacizumab RAS - BRAF FIRI, or irinotecan alone are the preferred options. When RAS MUT BRAF MUT or WT the previous treatment was an irinotecan-based combination, CT doublet + bevacizumab the recommended options are FOLFOX or XELOX. With CT doublet + respect to the use of targeted therapies, recommendations bevacizumab CT doublet + anti-EGFR CT doublet + bevacizumab or are as follows: FOLFOXIRI +/- bevacizumab Adding bevacizumab or aflibercept to chemotherapy is an option in second-line therapy (I,A) [24, 25]. For patients treated with first-line bevacizumab-containing Fig. 2  First-line treatment strategy for unresectable metastatic colo- rectal cancer (mCRC). WT Wild type; CT chemotherapy, EGFR epi- chemotherapy, the continuation of bevacizumab in con- dermal growth factor receptor, MUT mutated junction with a second-line chemotherapy improves 13 Clinical and Translational Oncology (2019) 21:46–54 51 Treatment of frail unresectable mCRC patients Thermalablation No consensus guidance exists regarding the definition of Non-surgical local therapies Radiofrequency ablation frailty in patients with cancer, otherwise this term almost Microwave ablation always associated with aging. Frailty is associated with Ethanol ablation Cryoablation dependence, comorbidity, polypharmacy, nutritional and functional status or geriatric syndromes. Treatment results may be biased because acting as a competing cause of Chemoembolisation Drug-eluting beads (DEBIRI) / TACE death and tolerability in this particularly vulnerable group of patients. ASCO recently published guidelines for geriatric oncol- ogy, recommends a geriatric assessment (GA) for the man- Local radiation therapies agement of vulnerabilities in older patients (> 65 years) Radioembolization: SIRT receiving chemotherapy. This GA should include at a High conformal hypofractionated irradiation: SBRT, HDR-brachytherapy minimum, the assessment of function, comorbidity, falls, depression, cognition, and nutrition to obtain estimates of chemotherapy toxicity risk and mortality [34]. However, GA is not a routine in daily practice, but may serve for future research including frail younger patients too. Evidence-based treatment decisions for unresectable Fig. 3  Ablative therapies. SIRT selective internal radiation therapy, mCRC in this population derives from trials in relatively SBRT stereotactic body radiation, DEBIRI drug-eluting beads loaded healthy elderly or different types of frail patients with very with irinotecan, TACE transarterial chemoembolization, SIRT selec- tive internal radiation therapy, HDR high-dose rate few ECOG-2 represented in the trials. To date, integration in a palliative care unit associated or not to specific systemic therapy, is the most important support in these patients. Both NCCN [35] and ESMO [36] or the adapted for OS as compared to just switching the chemotherapy sidedness ESMO-ASIA guidelines [37], recommend some regimen alone although the amount of benefit is infe- form of therapy in unresectable mCRC patients defined rior compared with bevacizumab-naïve patients [26]. as not appropriate for intensive therapy (NCCN) or unfit Aflibercept added to FOLFIRI in patients previously (but may be suitable) for ESMO. Fluoropyrimidine mono- progressing on a prior oxaliplatin containing regimen therapy is the most recommended in patients unable to is superior to FOLFIRI plus placebo in RR, PFS and tolerate aggressive treatment [I,B]. Bevacizumab has been OS [25]. largely study in randomized or not studies and may be Cetuximab and panitumumab appear to have efficacy added because was safe and increased PFS [38–40]. when used for salvage therapy in all RAS WT patients In wt-RAS and left-sided, anti-EGFR (2B NCCN) EGFR-naïve chemotherapy-refractory mCRC (II,A) [27, therapy can be recommended. A Spanish phase II study 28]. The reintroduction of EGFR inhibitors in subse- with first-line single-agent panitumumab in frail elderly quent treatment lines is not recommended for previously patients with wt-KRAS mCRC and poor prognostic factors exposed patients (I, C). showed activity and good tolerance and may be an option Regorafenib and TAS 102 give a modest benefit in for patients not candidates for chemotherapy [41]. third line therapy [29, 30] compared with best supportive If treatment is given, dose-attenuated chemotherapy is care, and therefore, its use should be restricted to selected always recommended and maintenance therapy or chemo- patients (I, B). therapy holidays may be appropriate. A randomized study Immunotherapy with pembrolizumab [31], of reduced chemotherapy in elderly and/or frail patients with nivolumab ± ipilimumab [32, 33] for MSI-H/dMMR mCRC (38% with both advanced age and frailty) suggested (4% of mCRC) could be an option for resistant colo- some benefit in PFS, significant increase in the ORR adding rectal cancer patients, but at the moment check- oxaliplatin to 5-FU and that the substitution of intravenous point inhibitors are approved by the FDA, but not FU with capecitabine had no effect on quality of life [42]. by EMA. Local ablation techniques are generally used for more Recommendations: the second-third line therapies will selected mCRC but may be considered in patients not ame- depend on the prior line, ECOG and organ functions. nable to surgery (IV, B). 13 52 Clinical and Translational Oncology (2019) 21:46–54 Early palliative care is recommended for patients with the objective responses in comparison with the FOLFOX/ metastatic colorectal cancer. bevacizumab arm (78% vs 54% at 2 months; p = 0.02) [45]. Recommendations: for vulnerable or frail patients with unresectable mCRC, best supportive care should made inte- Radioembolization gral part of their management. In unfit (but may be suit- able) patients, dose attenuated chemotherapy with or without Hepatic arterial radioembolization with yttrium-90 bound to monoclonal antibodies may be an option according to RAS/ resin microspheres plus fluorouracil (FU) was well tolerated BRAF and location. and significantly improved time to liver progression com- pared with FU alone in a small phase III trial in patients with refractory unresectable colorectal liver metastasis [46]. More recently, in a phase III trial (SIRFLOX study), Locoregional ablative treatments 530 chemotherapy-naïve patients with liver metastases were randomly assigned to receive either modified FOL- Non-surgical approaches for metastases confined to a single FOX ± bevacizumab or modified FOLFOX ± bevacizumab organ (most frequently the liver) may offer survival advan- plus selective internal radiation therapy using yttrium-90 tages beyond that of systemic therapy alone. If resection is resin microspheres (SIRT). Although the primary endpoint not feasible, image-guide ablation, embolization or stereo- was not met, SIRT delayed disease progression in the liver tactic body radiation therapy (SBRT) are reasonable options. (20.5 vs. 12.6 months in the chemotherapy only arm; HR, In patients with a limited number of lesions and involved 0.69; 95% CI 0.55−0.90; p = 0.002) [47]. sites, the selection of the best locoregional ablative therapy strategy should be discussed within a multidisciplinary team (Fig. 3). High conformal hypo fractionated irradiation Thermal ablation In several retrospective and prospective studies, SBRT and high dose rate brachytherapy have been reported to achieve Although there are many different thermal ablation tech- high local control rates. SBRT offers a safe alternative and niques (microwave ablation, ethanol ablation, cryoablation), non-invasive therapeutic option, for the treatment of selected the use of radiofrequency ablation (RFA) to treat cancer that patients not amenable to surgery with limited number of has spread to the liver is the best understood. In the phase liver or lung metastases. II CLOCC trial, 119 patients with non-resectable colorectal Recommendations: liver metastases were randomized to systemic treatment or systemic treatment plus RFA. The study met the primary end (1) Local ablative techniques such as thermal ablation or point on 30-month OS rate > 38%; however, this rate was high conformal radiation techniques (e.g., SBRT) can also achieved in the control arm. RFA plus systemic treat- be considered for colorectal liver and lung metastases ment improved PFS rate at 3 years for combined treatment in patients not suitable to surgery. (IV, B). (27.6% vs. 10.6% for systemic treatment alone; HR, 0.63; (2) Chemoembolization and radioembolization are options 95% CI 0.42–0.95; p = 0.025) [43]. For lung metastases from in highly selected patients with predominant hepatic CRC most evidence supports surgery as the most effective metastases (IV, B and II, B respectively). treatment option. Compliance with ethical standards Chemoembolization Conflict of interest MAGE reports financial support from Angem, Kyowakirin, Merck, Roche and Servier, outside the submitted work. Hepatic transarterial chemoembolization (TACE) therapy JG reports advisory board from Amgen, Bayer, Ipsen, Lilly, Merck, with drug-eluting beads loaded with irinotecan (DEBIRI) Roche and Sanofi. Speaker honoraria from Amgen, Ipsen and Lilly has been used in several prospective studies demonstrating and Subsidies from Amgen and Novartis, outside the submitted work. an acceptable toxicity profile. In a randomized phase II trial, EGF reports Advisory board from Roche, Amgen, Merck, Bayer, Ser- vier and Sanofi, outside the submitted work. JM reports Grants non- median OS was significantly longer for patients treated with remunerated (clinical trial principal investigator) from Merck and Am- DEBIRI than for those treated with FOLFIRI (22 moths vs. gen, and grants non-remunerated (Project lead principal investigator) 15 months p = 0.031) [44]. A recent trial showed that the from Nanostring and Biocartis. Also reports personal fees from Sirtex, simultaneous administration of modified FOLFOX (with or Pierre-Fabre, Shire, Astrazeneca, Bayer, Servier, Sanofi and Roche, outside the submitted work. DP reports personal fees and non-financial without bevacizumab) and DEBIRI significantly increased support from Amgen, personal fees from Sanofi, personal fees and non 13 Clinical and Translational Oncology (2019) 21:46–54 53 financial support from Merck Serono, personal fees and non-financial a meta-analysis of randomized, controlled trials. Ann Oncol. support from Servier, personal fees and non-financial support from 2015;26:13–21. F. Hoffmann-La Roche Ltd, outside the submitted work. JS reports 9. Graselli J, Elez E, Caratù G, Matito J, Santos C, Macarulla T, et al. personal fees from Merck, Ipsen, Roche, Lilly, Shire, Sanofi, Servier, Concordance of blood-and-tumor-based detection of RAS muta- Amgen, Bayer, Celgene, Bristol-Myers Squibb and Pfizer and non- tions to guide anti-EGFR therapy in metastatic colorectal cancer. financial support from Merck and Ipsen, outside the submitted work. Ann Oncol. 2017;28:1294–301. JA reports consultant or advisory role from Bayer, Servier, Merck, Sa- 10. Pawlik TM, Choti MA. Surgical therapy for colorectal metastases nofi, Amgen, Sirtex, Roche and Celgene, outside the submitted work. to the liver. J Gastrointest Surg. 2007;11:1057–77. MB reports personal fees and non-financial support from Roche, Am- 11. Zhu D, Zhong Y, Wei Y, Ye L, Lin Q, Ren L, et al. Effect of neo- gen, Sanofi, Merck, Abbvie, Sysmex, outside the submitted work. JF adjuvant chemotherapy in patients with resectable colorectal liver reports grants from Merck and advisory board from Amgen, Ipsen, metastases. PLoS ONE. 2014;9(1):e86543. Eisai, Celgene, Novartris, outside the submitted work. RV reports per- 12. Araujo RLC, Gönen M, Herman P. Chemotherapy for patients sonal fees from Sanofi, Roche, Msd, Merck, Amgen and Bristol-Myers with colorectal liver metastases who underwent curative resec- Squibb, outside the submitted work. tion improves long-term outcomes: systematic review and meta- analysis. Ann Surg Oncol. 2015;22:3070–8. Ethical approval The current study has been performed in accordance 13. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schalag with the ethical standards laid down in the 1964 Declaration of Hel- PM, Rougier P, et al. Perioperative FOLFOX4 chemotherapy sinki and its later amendments. and surgery versus surgery alone for resectable liver metasta- ses from colorectal cancer (EORTC 40983): long-term results Informed consent For this type of study formal consent is not required. of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14:1208–15. 14. 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