Many different technical variations of the ALPPS approach have been proposed. Even though the original technique as described by Schnizbauer et al. [11] consisted in a right trisectionectomy for patients with a tumor-free left lateral segment, Gauzolino and colleagues [26] later presented different technical variations of the ALPPS approach, including the “left ALPPS,” the “right ALPPS,” and the so-called “rescue ALPPS” in patients with failed PVE/PVL. An additional alternative was introduced by de Santibañes et al. [27], who preserved only segments 1 and 4 as FLR after performing a left lateral sectionectomy for extensive disease (Fig. 15.7). However, concerning FLR variants in ALPPS, the most important breakthrough was accomplished after demonstrating that monosegment remnants can be safely left behind when applying the ALPPS approach (Fig. 15.8) [15, 28]. This constitutes an important paradigm change in liver surgery, given that resectability has been traditionally defined as the complete tumor removal preserving at least two contiguous Couinaud’s segments with intact vascular inflow, outflow, and biliary drainage.

Given that ALPPS has been associated in preliminary series with increased incidence of major complications and mortality [11, 24, 25], many different technical innovations and refinements have been introduced recently with the aim of improving both short- and long-term outcomes. With regards to liver partition modifications, Robles et al. [29] from Murcia, Spain, described the application of a tourniquet around a parenchymal groove of no more than 1 cm in the transection line, and labeled this modification “ALTPS” (associating liver tourniquet and portal ligation for staged hepatectomy). Despite the attractiveness of the tourniquet, the 64% morbidity and 9% mortality in their series of 22 patients does not reflect a real improvement in terms of patient safety compared with most ALPPS series. More recently, other authors have proposed to replace parenchymal transection by using radiofrequency or microwave ablation (RALPP, LAPS) to create a virtual liver partition through a “necrotic groove” between both hemi-livers [30]. These approaches provided a similar hypertrophic profile than the standard ALPPS approach but with only minor complications, no mortality, and a high feasibility of being performed by laparoscopy. On the other hand, the application of PVE instead of PVL as method of portal vein occlusion, also known as “hybrid ALPPS”, is undoubtedly one of the most promising innovations among the different ALPPS proposals. This was first described by Li et al. [31], who successfully performed a percutaneous PVE during the postoperative period in two patients with gallbladder carcinoma infiltrating the right portal vein. The fact of avoiding portal pedicle dissection during first stage is more in line with the “non-touch” oncological principle and facilitates second stage by generating fewer adhesions. Finally, based on the several proven benefits of laparoscopic over open surgery, different authors have demonstrated that pure laparoscopic ALPPS is feasible and safe, reaffirming that ALPPS candidates might also benefit from minimally invasive surgery [15, 32, 33]. Given the existence of many technical variants with different names, the founding members of the International ALPPS Registry have recently reported a “consensus” terminology in order to establish a common language to adequately compare and further develop different variants of the original ALPPS technique [34].

The most impressive characteristic of the ALPPS approach is a very rapid and large FLR hypertrophy. Data from the ALPPS Registry in 202 patients indicated a FLR hypertrophy of 80% (range: 49–116%) within a median time interval of 7 days (range: 6–13 days) between surgery and volumetric CT-scan [17]. In a recent single-center series, 80% of patients treated with ALPPS achieved a sufficient hypertrophy in <10 days [15]. The hypertrophy seen in ALPPS is clearly superior to traditional strategies, especially for patients with initially very small FLR. A recent comparative study by Croome et al. [35] demonstrated that ALPPS was significantly superior to PVE in terms of both the degree of hypertrophy (84.3% vs 36%; P < 0.001) and the kinetic growth rate (32.7 cm³/day vs 4.4 cm³/day; P < 0.001). These results are in line with those of Schadde et al. [36], who demonstrated that kinetic growth rate was 11 times higher in ALPPS compared with PVE/PVL (34.8 cm³/day vs 3 cm³/day; P = 0.001).

The degree of hypertrophy after ALPPS is not unprecedented,; a similar phenomenon has been previously described, but in a totally different scenario. Nadalin et al. [37] observed that healthy liver donors who underwent a resection of 60% of liver volume exhibited a mean remnant liver hypertrophy of 88% within 10 days after surgery. More recently, a comparative study found similar or even greater kinetic growth rate in healthy liver donors compared with ALPPS [35]. Despite these experiences describing remarkable liver regeneration after partial hepatectomy, the rapid and large FLR hypertrophy observed with ALPPS is still impressive given that it is achieved in very ill patients with primarily non-resectable disease subjected to extended liver resections in a small-for-size setting, and with a remnant parenchyma of poor quality or even cirrhotic [11, 15, 17]. Furthermore, most patients treated with ALPPS undergo prolonged preoperative chemotherapy [11, 15, 17], which has been associated with less regenerative capacity, even in patients treated with the ALPPS approach [38]. On the other hand, the ALPPS has demonstrated to be an effective step-up alternative as a salvage procedure to induce further hypertrophy and allow resection in patients with CLM who fail to achieve a sufficient FLR after PVE or PVL [15, 39, 40]. Nowadays, this scenario has become an unquestionable indication for ALPPS.

It has been hypothesized that edema, liver congestion, or inflammation might explain macroscopic FLR hypertrophy during ALPPS. However, there is already consistent evidence both in animals [41] and humans [11, 16, 42] indicating that there is true histological correlation through proliferative and architectural changes accompanying macroscopic hypertrophy during ALPPS. Despite the fact that the surgical interruption of bilateral cross-portal circulation appears to be the main catalyst of the enhanced liver hypertrophy observed in ALPPS, the exact regenerative kinetics behind the restoration of hepatovascular mass remains poorly understood, and is most likely multifactorial. This phenomenon could possibly be explained by the following mechanisms: (1) PVL creates a redistribution of portal blood flow and hepatotrophic factors to the FLR; (2) parenchymal partition impairs collateral circulation and causes a surgical trauma that might per se induce the systemic release of circulating proliferating factors that could be crucial for liver growth; (3) this new approach might also involve a preconditioning phenomenon for the FLR, where the diseased hemi-liver acts as a transitory auxiliary liver that assists the growing FLR in metabolic, synthetic, and detoxifying functions for the first and critical week after resection. Additionally, preliminary data indicates that portal flow modulation and portal pressure might also influence the hypertrophic phenomenon observed in ALPPS, where the arterialized auxiliary liver may play an alleviating hemodynamic role during the interval period that becomes less important once the FLR has recovered [15]. The restoration of the hepatovascular mass is a fascinating field in regenerative medicine. Certainly, the ALPPS is an innovative surgical model that will progressively give rise to more research and knowledge of the regulatory networks that control the regenerative mechanisms of the liver.

Patient management during the interval period between both surgical stages is key for the successful application of ALPPS. Morbidity and mortality during ALPPS have been associated in most series with inappropriate patient selection, unsuitable timing of the second stage, and errors in clinical judgment due to the lack of experience with the application of a new technique [11, 17, 24, 25]. The fact that mortality occurs more frequently after the second stage and PHLF remains an important cause of death [17, 43, 44], indicates that the criteria being used to judge FLR sufficiency before reoperation might not be adequate enough.

Given that remnant liver volume is a known predictor of PHLF [5, 6], most authors have defined FLR sufficiency during the interval period based in volume rather than function, simplifying postoperative functional assessment between the two stages to daily clinical evaluation and liver function blood tests. However, the results obtained from such functional evaluation could be misleading, as it provides total liver function assessment, which in this scenario includes that of the diseased hemi-liver that will be removed. Moreover, the fact that PHLF remains the most important cause of death in the ALPPS Registry indicates that the established volumetric criteria being used to judge FLR sufficiency before reoperation might not be sufficient, particularly when taking into account that these volume measurements are applied to a fast-growing parenchyma. Even though previous studies have observed proliferative and architectural changes at histological level accompanying macroscopic FLR hypertrophy in ALPPS, rapid volumetric increase may not be immediately corresponded by an equal increase in function, as recently suggested by histologic findings showing hepatocytes immaturity in nontumorous FLR parenchyma [45]. Even though there is agreement that the second stage should be postponed until a satisfactory function has been reached, the key question yet unanswered is how good the FLR function has to be in order to avoid PHLF. From the various more sophisticated liver functional studies available (HIDA test, galactose elimination capacity, the indocianine green test or the LiMAx test), hepatobiliary scintigraphy (HBS) is probably the most promising, given that it provides information on sectorial liver function [46]. This fact is particularly important in the case of ALPPS, where the decision to perform the second procedure must be done taking into account the regional FLR functionality. In a previous study, we found that none of the patients with a FLR representing at least 30% of total liver function by HBS (%FLR-C) before the second stage developed PHLF (Fig. 15.9) [15]. However, a major drawback of the %FLR-C is that it does not take into account if the overall liver function is indeed good or not, which could lead to misinterpretations and errors in clinical judgment. This fact, along with the impossibility of using the 2.69%/min/m² FLR-function (FLR-F) cutoff proposed by the AMC group in Amsterdam [46], since it was not established using modern HBS assessment (Gmean and SPECT analysis), lead us to develop a new formula to measure FLR sectorial function during ALPPS interval. The Hospital Italiano de Buenos Aires Index (HIBA-index) is a dynamic measure that represents the proportion of radionuclide accumulating in the FLR during the phase between 150 and 350 s post-injection and is calculated using the area under the time-activity curves (AUC) with the following formula expressed as %:

Between 2011 and 2016, 20 out of 39 patients (51%) underwent HBS before completion of ALPPS second stage at the Hospital Italiano de Buenos Aires. After comparing the individual performance of three interstage FLR functional parameters (%FLR-C, FLR-F, and HIBA-index), a HIBA-index with a cutoff value of 15% was found to be the most accurate parameter to predict clinically significant PHLF after the second stage [47]. The predicted risk of PHLF in patients with a HIBA-index lower than 15% was 80%, whereas no patient with a HIBA-index higher than 15% developed PHLF. This practical cutoff value may become of paramount importance to avoid futile indication of ALPPS second stage, as current standard volumetric criteria have so far proved insufficient to adequately guide the safe timing of ALPPS stage 2.

In general, common sense indicates that second stage should be undertaken only if the patient is in good condition and functional and volumetric studies have demonstrated FLR sufficiency. Even though the feasibility of ALPPS to remove tumor in a short period of time is very high, the 1-week interval dogma has been penalized in several series with high complication rates and mortality. It is therefore important to remark that while ALPPS is a indeed a two-stage procedure, the second stage should be delayed or even abandoned in case of compromised clinical status, active complications, or abnormal liver function tests in order to avoid mortality. In cases where the patient is in good condition but FLR sufficiency has not been achieved, the patient can be discharged home and readmitted for second stage once FLR sufficiency has been certified during periodic outpatient evaluation [15].

Even after more than 5 years from the inaugural publications of the ALPPS approach, the available evidence in the existing literature remains low and mostly represented by retrospective studies including a limited number of patients, making the interpretation of outcome data difficult [48].