Optimal approach to potentially resectable liver metastases from colorectal cancer

Colorectal cancer (CRC) represents the second most frequent cause of cancer-related death in Western countries [1]. In the last decade, improvements in the management of metastatic CRC (mCRC) have led to median survival times exceeding 20 months [2]. These important results have been made possible by three main factors:

• • The introduction of new cytotoxic agents, such as irinotecan (CPT-11) and oxaliplatin (LOHP) and their combination with the 50-year old cornerstone of mCRC treatment, 5-fluorouracil (5-FU) [3–7];

• • The availability of safe, active and effective biological agents directed against VEGF (bevacizumab) [8] and the EGF receptor (EGFR) (cetuximab and panitumumab) [9,10];

• • The wider resort to resection of metastases, which represents the only chance for long-term survival and even cure for mCRC patients [11].

The liver is the most common and often unique site of metastases from CRC, either at the time of diagnosis (15% of cases) or in the course of the disease (in another 50% of patients) [12]. Considering the natural history and the recent advances obtained in palliation of mCRC, a major effort of clinical oncologists is now the identification of the optimal medical treatment with the potential of inducing a significant tumor shrinkage in initially unresectable mCRC patients, thus offering them the possibility of a radical resection of metastases. In fact, the prognosis of patients turned resectable and radically resected after response to chemotherapy is similar to the prognosis of patients resected up-front [13].

A matter of selection: defining & identifying potentially resectable patients

Definition of resectability is still a major source of debate [14]. As long as new historical and perspective data become available, a paradigm revolution is taking place: the definition of resectability is now no longer based on the disease that must be removed (i.e., number and size of metastases, presence of extrahepatic disease, ability to achieve adequate surgical margins) but is focused on the extent of apparently healthy liver that will remain after metastasectomy. According to the OncoSurge criteria proposed by Poston et al., absolute contraindications to curative resection are the presence of unresectable extrahepatic disease, a massive liver involvement (defined as more than 70% or six segments of the liver or all three hepatic veins involved) and the presence of liver failure or other medical comorbidities that contraindicate major hepatectomy [15]. In our editorial, we address the problem represented by potentially resectable patients: these can be defined as those patients whose metastases are judged radically resectable only if a major downsizing and, in some cases, the complete disappearance of specific lesions is achieved with preoperative treatment [16]. In particular, a patient with liver metastases may be judged only potentially resectable because of the dimensions, number and/or unfavorable location of the lesions. Moreover, such a category also includes patients with concomitant but relatively limited extrahepatic spread, such as small unilateral lung metastases, ilar nodal disease and/or even circumscribed peritoneal seeding. In many cases, not all sites of initial disease can be secondary resected even if major shrinkage occurs, and this implies that such lesions should disappear on conventional imaging, underlying that an important objective of treatment is to obtain a true pathological complete response. Therefore, potentially resectable patients represent a great challenge for medical oncologists who should keep in mind that the prognosis of such subjects is strongly related to the possibility of a radical surgical resection, whose feasibility and results rely on the activity of the up-front medical treatment.

The judgement of potential resectability should be the verdict of a multidisciplinary jury made up of medical oncologists, radiologists and surgeons with expertise in hepatobiliary procedures. Initial imaging work-up of mCRC patients is classically based on computed tomography (CT). In recent years, some authors evaluated the gain in staging accuracy obtained with PET and MRI and their impact on surgery results. A comprehensive review of these issues is beyond the scope of this editorial, we focus our attention on the possible role of these imaging techniques in mCRC patients who are candidates for liver resection. Published reports underline two main qualities of PET scanning [17–20]: first, a good (despite being size related, with lower accuracy for lesions <1 cm) sensitivity in detecting extrahepatic disease (thus allowing the avoidance of unnecessary liver surgery in patients initially judged resectable at diagnosis or after neoadjuvant therapy on the basis of CT imaging); second, its usefulness in the identification of early response to treatment (which could then be stopped and modified in unresponsive patients). However, the role of PET remains controversial, considering wide variations in sensitivity among different studies and the possibility that this could also be lowered by chemotherapy: therefore, CT is so far irreplaceable both for response evaluation and for definition of resectability, and PET should accompany, but never substitute, CT. Data regarding MRI for the study of metastases are more recent but appear to compare well with CT [21]: MRI scanning of the abdomen could then be extremely useful for a better definition of the surgical strategy, offering additional information on liver anatomy and the presence of even small (<1 cm) metastases.

Intensifying chemotherapy: triplet combination to improve resectability

After an accurate basal evaluation, the key question remains unanswered: how can we move from potential to actual resectability? Published and personal experience suggest that both intensifying chemotherapy regimens and adding biologics to standard treatments result in increased activity and, consequently, radical resection rate. The proven favorable safety profile of biological agents in combination with cytotoxics enables the intensiveness of chemotherapy to be increased without adding overwhelming toxicity.

Potentially resectable patients are those who may benefit most from a highly active regimen, which offers great tumor shrinkage at the price of acceptable toxicity. Doublet combinations with a fluoropyrimidine plus either CPT-11 or LOHP represent the most widely accepted standard chemotherapy regimens in mCRC patients due to their equivalent efficacy. When our goal is achieving resectability, doublets are probably not the best available treatment option. In choosing the most effective approach to these patients, we cannot rely only on resection rates: in fact, wide variations in such an end point among studies can be explained mainly by differences in the resectability criteria adopted and in the characteristics of the enrolled patients. In this setting, response rate (RR) appears to be a more objective parameter in comparing different regimens, and secondary surgical resection of metastases is directly related to treatment activity [22]. Different combinations of 5-FU and CPT-11 or LOHP achieved objective tumor regression in approximately 40–50% of patients. Colucci et al. compared leucovorin–5-FU–irinotecan (FOLFIRI) and LOHP–leucovorin–5-FU (FOLFOX4) reporting no differences in either RR (31 and 34%, respectively) nor secondary liver resection rates (5.1 and 4.4%, respectively) [23]. A Phase III study by the GERCOR group tested the available doublets administered in two different sequences, FOLFIRI followed by LOHP–5-FU–folinic acid (FOLFOX6) or the reverse sequence; the trial proved the equal efficacy of both strategies, which achieved similar survival times [24]. As regards activity, first-line RRs were comparable between the CPT-11- and the LOHP-containing arms (56 vs 54%, respectively), but, interestingly, first-line leucovorin–5-FU–LOHP (FOLFOX) resulted in a higher rate of secondary surgery (22 vs 9%; p = 0.02), with a trend toward increased R0 resections (13 vs 7%; p = 0.26). The results of the Phase III trial N9741 indicate higher RR for FOLFOX4 over irinotecan–bolus 5-FU–leucovorin (IFL) and irinotecan–LOHP (IROX) regimens (45, 31 and 35%, respectively) and, as observed in the aforementioned trial, the use of LOHP allowed a higher number of curative resections [25–26]: chemotherapy turned 24 (3.3%) patients resectable and 22 (92%) had received either FOLFOX4 or IROX (11 patients each).

On the basis of preclinical results demonstrating the synergic and additive interaction of the three cytotoxics and considering their different mechanisms of action and dose-limiting toxicities, a reasonable strategy to increase the activity of the first-line treatment is represented by the administration of a triplet combination [27]. The Gruppo Oncologico Nord Ovest (GONO) conducted a Phase III study comparing infusional 5-FU–leucovorin–CPT-11–LOHP (FOLFOXIRI) with FOLFIRI in order to test the efficacy of an up-front three-drugs strategy [28]. The triplet regimen was feasible, with manageable toxicities and significantly improved RR (66 vs 41%; p = 0.0002), progression-free survival (9.8 vs 6.9 months; p = 0.0006) and overall survival (OS: 22.6 vs 16.7 months; p = 0.032). Moreover, FOLFOXIRI reported a significantly higher rate of radical secondary resections of metastases in initially unresectable patients (15 vs 6%; p = 0.033) and, if patients with liver-only metastases are evaluated, the resection rates were 36 and 12%, respectively (p = 0.017).

These results are also supported by the Phase II experience of Ychou et al., who evaluated the rate of R0 resections achievable with a slightly different triplet combination 5-FU–leucovorin–irinotecan–LOHP (FOLFIRINOX) in a population of 34 potentially resectable patients. The triplet showed high activity (RR: 70.6%) with a favorable toxicity profile and enabled the resection of liver metastases in 28 patients (82.4%), nine (26.5%) of whom achieved R0 resection [29].

Considering the results reported with doublets, the GONO FOLFOXIRI regimen can be considered, in our opinion, a preferable chemotherapy option for potentially resectable patients from which we should move on toward more active combination regimens [30]. The major criticisms directed at the up-front three-drugs, exposure strategy mainly underline two key points: on the one hand, the possibility that not all secondary resected patients achieve long-term survival (owing to short disease-free survival and rapidly progressing disease following an apparently radical surgery) and, on the other hand, the possible increased surgical risk related to chemotherapy-induced liver injury.

To answer these questions, we recently conducted a retrospective pooled analysis of the 196 initially unresectable mCRC patients first-line treated with FOLFOXIRI in Phase I–III trials conducted by the GONO group [31]. Of the 196 patients studied, 37 (19%) could undergo a secondary R0 surgery on metastases (with a complete pathological response demonstrated in four patients) after a median of 5.5 months of triplet chemotherapy. Considering common prognostic criteria, our population does not appear particularly selected: a median age of 64 years, an initial deterioration of the performance status in 30% of the cases, a synchronous detection of metastases in 65% and the presence of multiple sites of disease in 22%, with metastases confined to the liver only in 68%, are all factors that strengthen the efficacy of FOLFOXIRI in this setting. The histopathologic analysis of liver injury induced by chemotherapy showed modest grade vascular toxicity and steatosis, with steatohepatitis in only 5% of patients. No intraoperative or postoperative mortality and a low rate of perioperative complications (27% of cases), all of which were transient and resolved completely without sequelae, were reported. After a median follow-up of 5 years, 16% of the resected patients are free of progression and in 36% of the others, a second surgical resection or radiofrequency ablation of the disease was performed after second-line chemotherapy.

Together, this evidence demonstrates that an up-front triplet, such as FOLFOXIRI, should be considered in suitable subjects as the preferred option to achieve the actual resectability of a potentially resectable disease. Tumor response should be re-evaluated at short intervals to reduce liver injury and avoid the complete disappearance of liver metastases on imaging, performing resection as soon as the surgeon judges it radically feasible. Clinical complete responses only rarely correspond to real pathological complete responses and may compromise the performance of a radical surgery. On the other hand, however, it has to be noted that complete responses appear to confer a survival advantage and are rarely obtained with second- or third-line treatment [32].

A more complex scenario: surgery in the era of biologics

The availability of effective biologic agents, such as bevacizumab, cetuximab or panitumumab, has widened the options for the treatment of mCRC patients, raising a large number of questions concerning the optimal regimen with which they should be integrated, their use after disease progression and their potential benefits and risks in patients considered for liver resection.

Hurwitz et al. first reported the efficacy of a biologic agent in mCRC: the addition of bevacizumab to a bolus 5-FU and CPT-11 combination significantly increased RR (44.8 vs 34.8%; p = 0.004), time to progression (10.6 vs 6.2 months; p < 0.001) and median OS (20.3 vs 15.6 months; p < 0.001) [8]. Since then, numerous studies have established the role of bevacizumab in combination with fluoropyrimidines and CPT-11 or LOHP for the treatment of mCRC.

Bevacizumab has a peculiar toxicity profile, mainly hypertension, proteinuria, bleeding and thrombosis. On the basis of these data and considering its mechanism of action, the safety of its use in a neoadjuvant strategy before liver resection has been a major source of concern. Different authors have definitively demonstrated that stopping bevacizumab approximately 5 weeks before resection does not increase intra- and perioperative bleeding and complications, or impair postoperative liver function and the regeneration process [33,34].

Further data regarding the impact of bevacizumab on resection rate of metastases come from the Bevacizumab Expanded Access Trial (BEAT) [35], a large observational study evaluating the safety of the biologic with various first-line chemotherapy regimens in over almost 2000 mCRC patients: 6.0% of the treated patients were radically resected, with a slight advantage for LOHP-containing combinations (8.0%) over CPT-11-based regimens (5.1%). Moreover, serious surgery-related complications (such as wound-healing impairment or major bleeding) were reported in a minority of cases (<1.5% of cases) and among R0-resected patients, a 2-year OS rate of 89% was observed.

Despite its proven efficacy and safety in mCRC, the role of bevacizumab in the setting of potentially resectable patients in combination with highly active chemotherapy regimens, such as triplets, is still under investigation. The GONO group has recently conducted a Phase II trial testing the association of the FOLFOXIRI regimen and bevacizumab [36]. The addition of the antibody did not increase the expected toxicities of chemotherapy and translated into a 100% disease control rate (responses plus stability of disease). No patients progressed during treatment and 75% of them achieved an objective response (12% complete responses). Preliminary results in terms of conversion to resectability are promising, with eight patients (16%) who have undergone secondary surgery on liver metastases (seven R0 resections have been performed). A very active regimen that obtains a high RR could be a suitable option for potentially resectable patients. A definitive answer on the role of a triplet plus bevacizumab will come from a Phase III trial by the GONO group comparing the addition of bevacizumab with a standard first-line treatment, such as FOLFIRI, or a more intensive regimen, such as FOLFOXIRI.

A second molecular pathway that can now be inhibited by biologics is that of EGFR: both cetuximab (a chimeric monoclonal antibody) [9] and panitumumab (a fully humanized monoclonal antibody) [10] have proved to be active and effective agents in EGFR-positive (at immunohistochemistry) mCRC patients. Cetuximab is the anti-EGFR drug for which we have more mature data, also in combination with chemotherapy from the first- to the third-line of treatment [9,37–39]. Comparing the results of different trials, we notice that, independent of the line of treatment and the regimen with which it is combined, cetuximab appears to provide an approximately 10–15% increase in RR. This gain in tumor shrinkage could translate into higher resection rates for patients with potentially resectable disease. Both in the Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial [37] and in the Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer (OPUS) study [39], the cetuximab plus chemotherapy arm (FOLFIRI and FOLFOX, respectively) reported an increased RR (46.9 vs 38.7 and 45.6 vs 35.7%, respectively). As a consequence, data regarding resection of metastases in the CRYSTAL trial indicate a more than double rate of radical surgery on hepatic lesions with the use of chemotherapy plus a biologic (9.8 vs 4.5%; p = 0.00265).

Recently, some experiences have been reported with the use of cetuximab plus a triplet chemotherapy regimen. Garufi et al. tested the combination of cetuximab plus chronomodulated CPT-11, LOHP and 5-FU in unresectable patients, reporting an impressive RR of 85% and achieving criteria for resectability in 75% of patients [40]. Preliminary results of a Phase II trial with the previously cited FOLFIRINOX regimen plus cetuximab indicate a promising activity of such a combination (two complete responses from 14 treated patients) [41]. These results need to be confirmed in larger populations and, with regard to feasibility, indicate that adding a biologic to intensive chemotherapy is possible with active patient management in order to avoid excessive toxicities.

To date, trials testing the combination of anti-VEGF and anti-EGFR agents have led to conflicting results. The great expectations following the publication of the BOND-2 study [42] have been dimmed by the report of other trials that pointed out great concerns regarding tolerability and efficacy [43]. Biologic agents have great potential in association with chemotherapy but these data remind us how far we still are from a complete knowledge concerning their optimal use.

Patient selection, again: biology for biologics

A major effort of biologists and medical oncologists is the identification of molecular predictive markers of efficacy of anticancer therapies in order to select patients for the treatment with the highest chances of success. In this process toward a truly personalized therapy, both chemotherapy and biologic agents have been investigated. Considering their mechanisms of action, toxicity profile, expense and the selective efficacy of cetuximab and panitumumab in only a subgroup of treated patients, monoclonal antibodies are the best candidates for the definition of a more selective approach.

Evidence exists that the efficacy of anti-EGFR agents is not limited to immunohistochemically EGFR-positive tumors [44]. This apparent paradox could be a consequence of both methodological problems and a more complex signaling pathway in which EGFR is only one of the main actors. Even though many potential predictive factors have been identified and studied [45], the mutational status of the K-RAS gene (tested either on the primary tumor or metastases) is the most validated marker of anti-EGFR agents efficacy. Many of trials agree on the lack of benefit from treatment for patients who are carriers of K-RAS mutations [46–50]: in the presence of a constitutively activated Ras protein, the inhibition of ligand–receptor binding by the antibody is completely futile. Therefore, considering an incidence of mutation of approximately 40%, a simple test could help clinicians to better select patients, thus avoiding unnecessary toxicities in almost a half of all mCRC patients.

With regard to bevacizumab, the identification of effective predictive markers is still far from its goal [51]. Interesting data are emerging that indicate that the benefit of this antiangiogenic agent is largely independent of K-RAS mutational status [52]. These results suggest that inhibition of VEGF-mediated angiogenesis has also established efficacy in patients for whom effective anti-EGFR agents are still unavailable and this could be a relevant finding in the setting of potentially resectable patients.

As toxicity limits the possibility of adding cyotoxics or biologics to current regimens, molecular factors are the main and most promising instrument to increase treatment activity in potentially resectable patients. Administering the right drugs to the right patients, we could maximize the benefit of the available agents and justify the risk of adverse effects, with the potential of achieving definitive cure for mCRC.

Conclusion

In the setting of mCRC, surgical resection of metastases is the best option to achieve long-term survival and represents the only chance for cure. Increasing the number of potentially resectable patients who can undergo radical metastasectomy is therefore a major goal of medical treatment. In these cases, the optimal approach relies on multidisciplinary management in which pathologists, radiologists, surgeons and medical oncologists are involved. A better initial work-up could identify and select patients for more intensive treatments: more accurate clinical selection (by using modern imaging techniques, such as PET and MRI) and definition of the molecular signature of single tumors (the identification of predictive markers for anticancer therapies) are unavoidable steps of this process. A triplet regimen with high activity, such as the GONO FOLFOXIRI, is of particular interest in potentially resectable patients. The addition of bevacizumab appears promising and needs further confirmation, while K-RAS wild-type patients could benefit from the addition of anti-EGFR monoclonal antibodies.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.