Is it time to standardize patient factors for HPB surgery?

Diametric conclusions by individual studies asking the same clinical question abound in the surgical literature. Potential significant contributors include heterogeneity of patient factors and definitions between studies. Within the last decade under the auspices of the international study groups for pancreatic and liver surgery, concerted efforts have been made to improve and standardize successfully the definitions of post-operative complications associated with pancreatic and hepatic surgery.1,2 Yet, pre-operative patient variables have remained largely undefined. With the explosion in systematic reviews and meta-analyses, this weakness in the surgical literature has been identified as a meaningful conclusion has been hampered by the lack of standard definitions and ways of comparing patient groups across various studies. Although successfully validated pre-operative nomograms3 can predict post-operative mortality for an individual or group of patients, these are not specific for specific complications such as a post-operative pancreatic fistula (POPF) or post-operative liver failure (POLF). There would, however, now appear to be hope on the horizon as demonstrated in this issue of HPB.4–6 For pancreatic surgery, three objective methods of classifying the risk associated with the development of POPF have recently been proposed. First, a fistula risk score (FRS) published and validated by Callery et al.7 proposes assessment of a score of 10 based on four variables: three pre-operative (pancreatic gland texture, pathology, duct diameter) and one intra-operative (blood loss). The score categorises accurately patients into groups of low, intermediate or high risk of POPF. These categories correlated with subsequent severity of the POPF. Similarly Kirihara et al.8 combined known risk factors for POPF, anthropomorphic measurements and anatomical volumes calculated from pancreatic CT into a multivariate model to predict clinically relevant POPF.8 The most accurate model included only two variables: visceral adipose tissue (cm2) and skeletal muscle area (cm2) but enabled patients to be stratified by probability of developing POPF. The concordance index of 0.959 for the model was strikingly similar to that proposed by Callery et al.7 Perhaps what was more interesting was the usefulness and association with other variables of the predicted remnant pancreatic volume (cm3) which correlated strongly with pancreatic duct diameter and the presence of a soft gland. Could this represent a method that assesses objectively gland texture pre-operatively? Could this strengthen the FRS? Roberts et al.4 have proposed a slightly different approach based on a patient body mass index and pancreatic duct diameter. The authors demonstrated high inter-observer reproducibility of the scoring system. The advantage of the proposed score by Roberts et al.4 is that it uses the source variables as continuous data and provides expected values with confidence intervals. In addition the score can be calculated via a website provided by the authors. The authors acknowledge the reduced accuracy as compared with the two scoring systems previously mentioned.7,8 Yet further refinement may be possible using other surrogates of steatosis within the pancreas, adjusting for use of somatostatin analgoues or the effect of routine drainage. What would be potentially interesting is whether further crucial factors contributing to POPF could be identifed by applying the proposed scoring systems across each dataset.4,7,8 Kunstman et al.5 have attempted to validate the FRS score in a population of patients undergoing a pancreaticoduodenectomy at a centre where intraperitoneal drainage was rarely used. In a study of 265 patients of whom <3% underwent routine drainage, the FRS was shown to have a perfect negative predictive value for those with a low FRS but the positive predictive value for those with a high FRS was significantly lower than that observed by Callery et al.7 Thus the overall concordance index was only 0.763. 5 The authors hypothesize several reasons and identified that routine drainage may alter clinically relevant (CR) POPF rates and that the amount of blood loss did not appear to be an independent predictor of CR-POPF. The authors suggested that the mean FRS was significantly greater than that in the initial Callery et al.7 study. Another potential explanation also exists for the apparent discrepancy. The effect of somatostatin analogues on CR-POPF has not obviously been accounted for in the study by Kunstman et al.5 In this issue of HPB, McMillan et al.6 demonstrate why this may be a crucial issue. In a multicentre study of 1018 patients undergoing a pancreaticoduodenectomy, a retrospective analysis of the effect of somatostatin analogues on POPF was performed. The results are striking. The authors elegantly demonstrate that by combining an accurate pre-operative risk of POPF with the well-validated ISGPS definition CR-POPF (clinically relevant POPF), the true effect of somatostatin analogues can be seen.6 Surprisingly, those patients who received somatostatin analogues had significantly higher rates of CR-POPF than those that did not. Its supposed benefical effect was limited to a reduction in biochemical POPF. Although these detrimental effects held true across all FRS groups it was most pronounced in those deemed to be at high risk of CR-POPF. Although limitations including the retrospective nature of the study, lack of randomization and uneven distribution of the number of resections by the surgeon, the conclusions that somatostatin analogues are harmful and should not be used are hard to refute.6 For liver surgery, the major determinant of POLF is the size and quality of the function of the future liver remnant (FLR). Traditionally, the extent of resection is provided as a surrogate of future hepatic function but this does not have a direct inverse relationship with the FLR. In addition, the extent of resection or FLR does not take into account hepatic function. Assessments of pre-operative hepatic function have been limited to global pre-operative function rather than the post-operative regional function of the predicted remnant as in the indocyanine green (ICG) clearance test. Although the percentage of ICG retained at 15 min can be used to predict post-operative liver failure, it is affected by the presence of jaundice or alterations in hepatic blood flow such as intra-hepatic shunting or regional portal venous obstruction.9 Therefore ICG has not been of value in calculating regional FLR hepatic function unless the biliary drainage of an individual segment has been externalized. Hepatobiliary scintography (HBS) combined with single photon emission computed tomography (SPECT) may now present a realistic alternative.9 The two most suitable isotopes for assessing hepatic function available currently are 99mTc- galactosyl human serum albumin and 99mTc-mebrofenin.9 Combining the concept of FLR based on segmental CT volumetry with HBS allows anatomically correct regions of interest to be drawn and the subsequent uptake rate (surrogate of clearance rates) of the radiolabelled tracer to be calculated (%/min/m2) thus generating an estimate of the future functional liver remnant (FFLR). This calculated FFLR has been shown to reflect accurately the actual function of the post-operative remnant liver10,11 and therefore allow pre-operative stratification of patients by risk of POLF. The potential power of these simple predictive tools should not be underestimated. Contemporary series of patients undergoing a pancreaticoduodenectomy or hepatic resection can be readily compared to determine whether they are truly comparable. It may also allow risk modification in real time and allow selection of smaller groups of high-risk patients for randomized trials thereby reducing the sample size without comprising statistical accuracy. With time, it may also be possible to potentially validate the effect of a treatment from within a study by statistically comparing expected to observed primary endpoints. For important issues for which randomized trials are not feasible, another level of evidence may be added to a researcher’s armamentarium. In the future, these crucial pre-operative variables should become part of a minimum dataset required for papers submitted for review.