'Liver-first' approach for metastatic colorectal cancer - Future Medicine

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’Liver-first’ approach for metastatic colorectal cancer Marcello Donati*,1,2, Gregor A Stavrou2, Axel Stang3, Francesco Basile1 & Karl J Oldhafer2

ABSTRACT The liver-first approach was proposed for the first time in 2006 to obtain resectability of stage IV colorectal cancer patients and complete the therapeutic plan. From then some groups have used this new revolutionary approach reporting promising results. Other alternative strategies have been proposed for metastatic patients. The authors reviewed the literature weighing the pros and cons of each strategy proposed to manage these advanced tumor stages. The therapeutic options are analyzed in the light of oncologic problems and evidence. Also problems, questions and perspectives are given. Even if the ‘liverfirst’ approach seems to be a promising strategy, the ideal diagnostic–therapeutic flowchart for metastatic colorectal cancer is still difficult to standardize. The great heterogeneity of this population of patients is one of the main problems. A ‘tailored approach’ philosophy is necessary to calibrate, in a multidisciplinary setting, a case-by-case choice of therapeutic options. The surgical management of colorectal liver metastasis is one of the most studied medical problems today taking into account that about 25% of patients affected by colorectal cancer present liver metastatic disease at the moment of diagnosis [1] . The increasing incidence of colorectal cancer in developed countries as well as the progressive enlargement of resectability criteria for colorectal liver metastasis (CRLM) over the last 20 years [2] , together with the successful downsizing rate of new chemotherapeutic regimens [3,4] , has led physicians to often refer patients suffering with advanced colorectal cancer with metastatic disease to surgeons. The advantages of resecting such a group of patients in terms of overall survival in a multidisciplinary decision-making setting is well known [5] . From the beginning of this century, using preoperative radiotherapy for rectal cancer in early stages (T1-T2) has become an accepted standard [6] , such as neoadjuvant radiochemotherapy for advanced rectal cancer (T3–T4) [7,8] . Unfortunately with the increase of worldwide experience with metastatic colorectal cancer surgical treatment has quickly shown that most patients (at least 70%) are not primarily resectable [9] at the moment of diagnosis and some of them became not resectable [10] during the multistep traditional approach focused first on treatment of the primary tumor and then on metastatic disease, or at least they do not receive adequate treatment. A new socalled liver-first approach (also reknown as ‘reverse strategy’) has been relatively recently proposed by Mentha et al. [10] to overcome the last disappointing and frustrating inconvenience of the traditional approach and to offer better long-term results in terms of overall survival in this unlucky cohort of

KEYWORDS

• colorectal liver metastasis • liver-first • metastatic cancer • multidisciplinary tumor board • neoadjuvant chemotherapy • rectal cancer

Department of Surgery & Medical-Surgical Specialties, General & Oncologic Surgery Unit, Vittorio-Emanuele University Hospital, University of Catania, 95122 Catania, Italy 2 Department of Surgery, Divison of General & Abdominal Surgery, Asklepios Hospital Barmbek, Semmelweis University, Asklepios Campus Hamburg, 20099 Hamburg, Germany 3 Department of Oncology, Asklepios Hospital Barmbek, Semmelweis University, Asklepios Campus Hamburg, 20099 Hamburg, Germany *Author for correspondence: Tel.: +39 347 446 4093; Work: +39 095 743 5117; Fax: +39 095 743 5117; [email protected] 1

10.2217/FON.14.316 © 2015 Future Medicine Ltd

Future Oncol. (2015) 11(8), 1233–1243

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Perspective Donati, Stavrou, Stang, Basile & Oldhafer patients [11] . In a PubMed search using the following terms: ‘liver-first approach’, ‘reverse strategy’ and ‘stage IV colorectal cancer treatment’ only six papers were found. The aim of this work is to analyze the theoretical basis and results of this new strategy in terms of advantages and disadvantages for advanced metastatic colorectal cancer comparing it with classic or alternative strategies, in the light of the available published data. Surgical strategies in colorectal cancer The traditional vision of colonic surgery for stage IV patients is to treat the primary tumor first and to add adjuvant chemotherapy to achieve resectability of liver metastasis or alternatively to downsize the tumor burden and reduce extension of liver resection. These goals are achieved differently in rectal surgery in which neoadjuvant radiochemotherapy has shown better results in terms of local recurrences and long-term survival [12] . Therefore, we can distinguish three main approaches in stage IV colorectal cancer surgery: ●● For colonic surgery, primary tumor-adjuvant chemotherapy-liver resection, simultaneous resection (colonic/liver), liver-first approach; ●● For rectal cancer, neoadjuvant radiochemo-

therapy – rectal resection – liver resection, neoadjuvant radiochemotherapy-simultaneous resection (liver–rectum), liver-first/neoadjuvant radiochemotherapy – rectal resection. These approaches can be summarized as follows: ●● Classic strategies; ●● Simultaneous approaches; ●● ’Liver-first’ approaches or ‘reverse strategy’.

A synthetic schema summarizing the combination of all therapeutic resources in a meaningful flowchart taking into account main selection criteria for the three strategies is given. Flowcharts differ for stage IV colonic and rectal cancers (see Figure 1 & 2) ’Liver-first’ The main problem for physicians dealing with advanced colorectal cancer patients is to give an accurate oncologic therapeutic plan to improve both survival and disease free survival, and remove as much of the tumor as possible from the patient, paying attention to quality of life.

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Reviewing the last 10 years of the literature on this subject, we found several attempts to overcome the many problems induced by improved chemotherapeutic regimens especially regarding CRLM; one of the most challenging attempts is the so-called ‘liver-first’ approach [10] . This surgical strategy was proposed for patients affected by CRLM at the moment of diagnosis of the primary tumor. Especially for rectal cancer, it was observed that a quota of patients during the classic therapeutic strategy (primary tumor resection–chemotherapy–liver resection) became not resectable for the liver because of tumor progression of liver metastatic disease not allowing the execution of the second step [10] . Of course the problem affects mainly rectal cancer because of the long time before primary tumor resection from the time of first diagnosis due to long neoadjuvant chemoradiotherapy to reduce local recurrences [13,14] . Therefore, the idea was applied to resect first the metastasis supported by efficacious neoadjuvant chemotherapy and local radiotherapy, especially for rectal cancer, to downstage the primary tumor and also avoid liver damage of neoadjuvant chemotherapy placing some patients into the not-resectable group due to the risk of postoperative liver failure and lack of liver regeneration after resection. However, the concept was also applied to manage stage IV colonic cancer [15] . First we shall define what ‘liver-first’ means, given that also the author proposing it treated all patients with a neoadjuvant chemotherapy initially [16,17] (really ‘chemo-first’ approach), and that delaying tumor treatment, even primary, is becoming a new shared trend in surgical oncology [18,19] . In other words, instead of the classical approach of the primary tumor resection → chemotherapy → liver metastasis resection, in the ‘reverse strategy’ (liver-first approach is a synonym), the surgeon first resects the liver metastasis and then the primary tumor. Alternatively, a modified classic approach with a longer delay between neoadjuvant chemoradiotherapy and surgery of the primary tumor was also adopted, in fact, longer delays (more than the traditional 6 weeks) of the interval between neoadiuvant chemoradiotherapy and surgery of the primary tumor [20,21] seem to also be a reasonable and effective approach even if it is still in its infancy. This should offer additional advantages for the liver-first strategy (neoadjuvant radiochemotherapy-liver resection-primary tumor resection). In fact, the ‘reverse strategy’

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’Liver-first’ approach for metastatic colorectal cancer

Perspective

Stage IV colon cancer Not or boderline resectable Minor resection

Major resection

Simultaneous resection

Neoadjuvant chemotherapy

Consider adjuvant chemotherapy

Restaging

Asymptomatic

Symptomatic

Ileo/ colostomy

Resectable


Restaging

Not resectable

Still resectable Consider liver-first or classic strategy†

Second-line chemotherapy

Restaging

L-/C-

L+/C-

L-/C+

L+/C+

Not resectable

Classical approach or consider simultaneous

Liver-first approach

Simultaneous or classic approach

Potential role of liver-first approach

Palliation





Figure 1. Overview flowchart of possible strategies for stage IV colon cancer. † Decision-making criteria: tumor load ratio L/C and metastasis position. +: Major tumor load; -: Minor tumor load; C: Colon L: Liver.

was developed to overcome the problem of traditional strategies in which some patients could not complete the therapeutic plan (liver resection). Therefore the main advantages of the socalled ‘reverse strategy’ is to gain resectability in those patients in which while waiting for liver resection due to chemo damage [22,23] to the liver parenchyma (high risk of liver failure) or tumor progression (Figures 1 & 2) become unresectable [24] . This is exactly the first aim of this apparently foolish procedure. The liver-first approach facilitates optimal treatment of the liver metastases and adequate neoadjuvant treatment for the primary tumor, particularly important for rectal


cancer, due to documented high incidence of local recurrence in patients not undergoing neoadjuvant radiochemotherapy [25] . Neoadjuvant radiochemotherapy has been proven to increase R0-resection and sphincter-saving surgery [26] . The use of powerful systemic chemotherapy as the initial step allows immediate treatment of the liver disease, which is mainly responsible for the patient’s death. The strategy is a two-stage procedure, with initial hepatic resection followed by colorectal surgery. Theoretical advantages of this strategy include immediately treating the most important prognostic site (the liver), avoiding chemotherapy

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Perspective Donati, Stavrou, Stang, Basile & Oldhafer

Stage IV rectal cancer Resectable

Not or borderline resectable Symptomatic Colostomy

Not symptomatic

Major resection

Minor resection

Aggressive neoadjuvant chemotherapy



Restaging Resectable

Not resectable

Consider liver-first approach†

Second-line chemotherapy and restaging

L+/R-

L+/R+

Liver-first approach

Hybrid approach‡

Classical approach§

Neoadjuvant radiochemotherapy

Adjuvant radiochemotherapy


Primary tumor resection

L-/R+ Simultaneous resection

L-/R-

Not resectable


Palliation


Liver resection Consider adjuvant chemotherapy

Figure 2. Overview flowchart of possible strategies for stage IV rectal cancer. † Decision-making criteria: tumor load ratio L/R and metastasis position. ‡ Hybrid approach is defined as primary tum or resection and simultaneous first step of classical two stage or Associating Liver Partition and Portal vein Ligation for Staged hepatectomy. § Consider neoadjuvant radiochemotherapy. +: Major tumor load; -: Minor tumor load; L: Liver; R: Rectum.

delay due to primary tumor resection morbidity and regularly performing adequate radiotherapy after liver resection before rectal resection. Some published experiences about liver-first approach already exist (Table 1) . Of course treating the liver first will be an advantage because in cases of anastomotic leakage, or other local rectal complications, this will not delay the treatment of the liver site [31] . This situation does not seem to be so rare after extended postirradiation rectal surgery [32,33] . Another argument in favor of the reverse strategy, by applying chemotherapy first, is to select patients in whom curative treatment could still be attempted – independently of the number and size of liver lesions – and avoid the subsequent steps of aggressive treatment

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in poor responders [34] who would most likely benefit from palliative management only. If, in fact, following this concept, before the liver step, on patients who are poor responders or not responders, no resections are performed, nonuseful operations and complications will be avoided [24,35] ; even if this concept is denied by other authors [36,37] , who think that tumor progression after neoadjuvant chemotherapy does not preclude subsequent surgical attempt of resection. Of course bilateral liver metastases seems to be a limit for the simultaneous approach given that associating a major liver resection with a colorectal resection is linked to a higher mortbility and mortality rate [38] . On the other hand some authors, in order to overcome the referred problem of resection of


’Liver-first’ approach for metastatic colorectal cancer

Perspective

Table 1. Liver-first approach: published experiences. Study (year)

Cases (n)

Mean age (years)

Colon/ rectum

Mean metastases, n (range)

Patients concluding procedure, n (%)

Complications, Disease-free n (%) survival (months)

Overall Ref. survival (months)

Mentha (2006) Ayez (2013) De Jong (2011) Brouquet (2010) Kardassis (2014) Mayo et. al. (2014)

20 42 22 27 11 28

56 61 65 48 65.7 58

9/11 0/42 3/19 19/8 11/0 13/15

5 (2–21) 4 (1–12) 2 (1–7) 3 (7–30) 4 (NR)

16 (80) 31 (74) 18 (∼82) 27 (66) 4 (36.4) NR

NR 7 (16) 6 (27.3) 10 (37) 5 (45) 11 (39)

46 69 35.5 50 27.2 50.9

25 14 14.5 7.7 NR

[10] [27] [28] [29] [15] [30]

NR: Not reported.

bilateral metastatic liver disease alternatively to the liver-first approach, have proposed a hybrid concept as an evolution of two-stage hepatectomy [39] . Following this alternative surgical tactic during the first stage, surgeons focused their attention on one side of the liver, performing only minor hepatic resection at the time of colectomy, leaving the major one for a second stage [38] . Therefore, the reverse strategy should be compared with this alternative method proposed for patients in the same advanced tumor stage (stage IV of TNM) [40] . It has been stressed that this strategy could be applied as a good alternative to the ‘reverse strategy’ mainly for two reasons: because the risk of delaying chemotherapy is prevented by its upfront administration with the primary tumor in place and chemoradiotherapy is scheduled whenever indicated, and the liver-first approach requires two surgical procedures. It has been demonstrated that simultaneous rectal and hepatic resection is feasible at the end of neoadjuvant treatment in about 90% of cases with an excellent outcome [38,39] . An interesting trial comparing the three strategies, even if on a limited number of patients, was carried out and the results showed a substantial equivalence among the different strategies in terms of overall survival, also making ‘reverse strategy’ acceptable [29] . The advantages and disadvantages of the three strategies: classical approach, reverse strategy and simultaneous strategy are shown in Table 2. Notably, some positive experiences adopting the ‘reverse strategy’ have already been published (Table 1) even if they gained no worldwide consensus or diffusion. The reason could be the difficulty to propose these experimental strategies and psychologically manage such extremely advanced oncologic patients. It should be stressed that some reviews on this topic already exist but


they are very generic and do not completely analyze the need for the strategy, the theoretical basis, the possible advantages and future developments and even more important they do not give selection criteria for patients to be submitted to a liver-first approach [41,42] . Evidence No really strong evidence is available about this revolutionary approach; this is mainly due to the presence of the very small number of reports and the availability only of retrospective studies even if patients were prospectively collected in a database; recently Verhoef’s group have demonstrated in a small group of patients some possible advantages of the liver-first approach for stage IV patients affected by rectal cancer. In their report [27] these authors completed both resection steps (liver-first and then rectal) in 74% of their patients, reporting a 67% 5-year survival (differences in strategy completion percentage among different reports were probably due to different selection criteria and to the large heterogeneity of CRLM patients). This observation, even if coming from a retrospective study, could be of value if confirmed by larger studies if we take into account that in a prospective randomized controlled trial in 2004 Sauer et al. [43] demonstrated that up to 50% of patients do not receive optimal treatment after rectal surgery because of postoperative complications. Notably in the recent report of Verhoef ’s group, 91% of patients who were not resectable owing to their liver situation did not undergo rectal resection with a great sparing of unnecessary operations [27] . Safety was adequately demonstrated by Mentha [10] , while feasibility in almost four out of fiveof patients was demonstrated by De Jong et al. [28] . However, taking all this together with the published data we can easily argue that the surgeon choosing a strategy for stage IV rectal cancer patients is pressed by the risk

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Perspective Donati, Stavrou, Stang, Basile & Oldhafer Table 2. Summary of advantages and disadvantages of all the three main strategies. Advantages

Disadvantages

Classic

To treat the first and most important site of further metastatization

Simultaneous

To treat at the same time the primary tumor site and the metastatic site with theoreticall R0 intent

Liver-first

Gain of resectability in those patients who are likely to become irresectable owing to their liver situation Achieve similar disease-free survival and overall survival compared with other strategies

Some patients become not resectable during multistep strategy Complications can further delay the treatment of metastasis Difficult to perform in extended metastatic disease Increase of morbidity and mortality due to concomitance of too big interventions No selection criteria for these strategies Less published evidence and long-terms results Very heterogeneous cohort of patients (difficulty to conduct analysis)

of irresectability of liver metastases if starting with primary resection, the risk of progression of the primary tumor with new metastases and the morbidity and mortality of eventual contemporary rectal resection with minor liver resection compared with a two-step strategy or Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS), or the low quality of life related to the needs of colostomy or ileostomy. The subtle balance of risks/benefits will be easier even for a multidisciplinary approach when more data are published allowing a better stratification of patient populations. Complications during reversed strategy completion are different in all the four main reports as well as in the two multi-institutional studies but all are in an acceptable range 16–45% for liver surgery and most of them were Dindo I–II (Table 1) . Considering that there is very little evidence available (only one report refers about 2-year survival after liver-first approach comparing it with the other two strategies) [27] , it is singular that NCCN has already inserted in its 20th Guidelines on Colorectal Cancer treatment this surgical option as a standard of care for these groups of patients. Very recently some authors have tried to re-elaborate the published data through a meta-analytic work comparing, classic, combined and liver-first strategies [44] through two different analytic methods (pairwise and network meta-analysis), even if they did not observe any statistical significant difference for 30-day hospital mortality and postoperative complications and 5-year overall survival (OS), this study has the limitation of analyzing only two of the four published single-center experiences on liver-first approach. The first published mono-institutional data on atleast 2-year oncologic results seem to be promising

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even if they concern only 31 patients (those who completed the strategy) [27] . Another meta-analytic work conducted by Andres et al. analyzing LiverMetSurvey [45] data demonstrated similar OS and disease-free survival (DFS) in the two groups with classic or reversed approach (48 vs 46% 5-year OS; p = 0.965, and 30 vs 26% DFS; p = 0.992, respectively). These results were confirmed not only by mono-institutional study [29] but also by Mayo et al. in a large multi-institutional study [46] collecting only 28 (28/675; 2.8%) patients for liver-first approach. To date even a recent published metanalysis has shown that ‘liver-first approach’ with upfront chemotherapy is safe and feasible in selected patients and showed the same results in terms of OS, DFS and recurrence rate as the other two strategies [30] . Despite all this, there is still a need for a well-designed trial comparing classic and reversed strategies [42] . Matters of debate One important matter of debate on reversed strategy is: which patients should be reasonable candidates for the liver-first approach? There are no shared criteria to date and as regards published experience each group has shown its own selection criteria even unrelated to Tumor Board opinions. If synchronous colorectal liver metastasis is logically considered the first criteria, Mentha et al. proposed age