Pleura and Peritoneum

Background: The body surface area (BSA) is taken as a measure for the effective contact area for dosing in hyperthermic intraperitoneal chemotherapy (HIPEC). Currently, the pharmacokinetic effect of the reduced peritoneal surface area (PSA) after cytoreductive surgery (CRS) during HIPEC remains unclear. Here a proprietary software solution (PEritoneal SUrface CAlculator (PESUCA)) to quantify the resectedPSA inpatientswithperitoneal surfacemalignancies (PSM) undergoing CRS and HIPEC is presented. Methods: The PESUCA tool was programmed as a desktop and online software solution. The applicability was evaluated in 36 patients. The programming-algorithm is briefly summarized as follows: (1) calculation of BSA, (2) correlation to PSA, (3) calculation of the relative proportion of 40 different anatomical regions to total PSA before CRS, (4) instantaneous input of each resected proportion in the 40 anatomical regions during CRS, and (5) determination of the resected and remaining PSA after CRS. Results: The proof of concept revealed a mean PSA of all patients before CRS of 18,741 ± 321 cm compared to 13,611 ± 485 cm after CRS (p < 0.0001). Patients’ supramesocolic and inframesocolic visceral and parietal peritoneal area before and after CRS procedure were quantitatively determined. Conclusions: Here the first tool that enables detailed PSA quantification in patients with PSM undergoing CRS is presented. This makes the software a valuable contribution to ensue more accurate assessment and improved comparability of peritoneal disease extent. Furthermore, after external validation, PESUCA could be the basis for dose adjustment of intraperitoneal chemotherapy regimens based on the remaining PSA after CRS.


Introduction
During the last two decades, new treatment protocols that combine cytoreductive surgery (CRS) and perioperative hyperthermic intraperitoneal chemotherapy (HIPEC) for patients suffering from peritoneal surface malignancies (PSM) were developed. Heated chemotherapeutic drugs are used locally, thereby reducing systemic toxicity [1,2]. Since HIPEC procedures were first developed in the 1980s, multiple studies have been conducted resulting in widespread discussions about its real benefit and associated patients' risks. Recently, these discussions were readdressed by the Prodige 7 trial [3] and the Dutch ovarian cancer HIPEC study [4]. Despite promising results showing its efficacy in the treatment of abdominal and pelvic malignancy, there is no standardized protocol for the use of HIPEC. Eight parameters affecting HIPEC efficacy are described so far: choice of chemotherapeutic agent, carrier solution, dosing regimen, perfusate volume, temperature, procedure duration, delivery technique, and adequate patient selection [5,6]. An important controversial issue is the choice of chemotherapeutic dosing regimen. Within the context of HIPEC, a dose is the amount of a drug administered at one specific time whereas dosage means the amount and rate of administration (time frequency) of a certain substance. A drug concentration is the amount of a substance per defined space. Currently, two dosing regimens are applied. Most centers use body surface area (BSA) (mg/m 2 ) (in a similar fashion to systemic chemotherapy) to determine the dose of chemotherapy, but concentration-based protocols are also applied [7].
In BSA-based protocols, fixed doses (mg/m 2 ) are diluted in different volumes of the carrier solution leading to different drug concentrations. Varying volumes are caused by several factors (e. g. patient's body composition and HIPEC delivery techniques). In contrast, concentration-based protocols with BSA-based drug doses and BSA-based or absolute volumes of carrier solution result in fixed drug concentrations [7,8].
Regardless of the method used to calculate the dose (BSA-vs. concentration-based), the remaining PSA after CRS is not considered. The two-compartment Dedrick model of intraperitoneal chemotherapy is an application of Fick's law of diffusion. It describes the transfer of a drug from the peritoneal cavity to the body compartment (blood): rate of mass transfer = PA (C P -C B ), where PA is permeability area (PA = effective peritoneal contact area, A × permeability, P), C P is the concentration in the peritoneal cavity, and C B is the concentration in the blood [9]. The size of the effective contact area of the peritoneum and the drug concentration are the most important components in this formula. Thus, the remaining intraperitoneal chemotherapy concentration depends upon the PSA.
Until now, it has not been possible to quantify the resected and the remaining PSA in patients undergoing CRS. Here, the applicability of the PEritoneal SUrface CAlculator (PESUCA) tool to quantify the PSA in 36 patients with PSM before and after CRS is presented.
PESUCA equates BSA with PSA if no values are inserted in any of the 40 anatomical regions according to Albanese et al., who reported that the PSA can be estimated from BSA formulas [10]. Depending on the inserted values inputted into the 40 different anatomical regions, PESUCA calculates the PSA in cm 2 . This is obtained by subtracting the inserted numbers from the total PSA. PESUCA was programmed with the following formulas: BSA (m 2 ) = 0.20247 × height (m) 0.725 × weight (kg) 0.425 [11] 2. Conversion of (m 2 ) in (cm 2 ) BSA (m 2 ) x 10,000 = BSA (cm 2 ) 3. Correlation of BSA (cm 2 ) and PSA (cm 2 ) (according to [10])

Statistical analysis
Continuous variables were expressed as mean ± SD after checking normality of the differences with the Shapiro-Wilk test. Differences in PSA before and after CRS were analyzed by the unpaired t-test. All tests were two-sided and p values < 0.05 were considered statistically significant. All statistical analyses in this report were performed using STATA (StataCorp. 2015. StataStatistical Software: Release 14. College Station, TX, USA, Stata-Corp LP) and GraphPad Prism version 6.00 for Windows, GraphPad Software, La Jolla, California, USA, www.graphpad.com.

Compliance with ethical standards
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Results
Patients (n=36) included in the study were mostly affected by peritoneal metastasis of colorectal (n=14), ovarian (n=7), and gastric (n=5) origin. Mean age was 55 years with equal sex distribution. Patients showed a mean peritoneal cancer index (PCI) score of 12. Baseline characteristics are shown in (Table 2). Individual PSA before and after CRS was calculated by PESUCA. The resected PSA of each anatomical region in all patients is shown in Figure 1.
The mean PSA of all 36 patients was 18,741 ± 321 cm 2 before CRS. By entering the peritonectomy extent (%) of each anatomical region (Table 1), PESUCA determined the mean PSA after CRS as 13,611 ± 485 cm 2 (p < 0.0001) ( Figure 2). We next analyzed the peritonectomy extent in the four anatomical categories as described in Table 1. The calculated SMCVP area before CRS was 3,464 ± 60 cm 2 compared to 2,832 ± 92 cm 2 after CRS (p < 0.0001) ( Figure  3A). SMCPP area before and after the procedure was 2,485 ± 43 cm 2 and 1,578 ± 154 cm 2 , respectively (p < 0.0001) ( Figure 3B). IMCVP area before and after CRS was 11,282 ± 194 and 8,544 ± 336, respectively (p < 0.0001) ( Figure 3C). IMCPP area before CRS was 1,491 ± 26 cm 2 compared to 644 ± 87 cm 2 after CRS (p < 0.0001) ( Figure  3D). In total, widest peritonectomy extent was performed in the IMCVP area with a mean resected peritoneal surface area (PSA) of 2,738 cm 2 (Figure 4). The SMCVP area showed lowest peritonectomy extent with a mean resected PSA of 633 cm 2 (Figure 4). There was a large range of resected PSA, as calculated by PESUCA using the values inputted for 40 different anatomical regions. Therefore, an analysis of the patient with the lowest (1,903 cm 2 ) and largest (17,661 cm 2 ) resected PSA ( Figure 5) was performed.

Discussion
To the best of our knowledge, here we present the first software solution (PESUCA) to quantify the individual PSA before and after CRS in patients with PSM. CRS combined with HIPEC is a promising therapeutic option for patients with PSM. Its benefit is still controversial even if some encouraging results have been published [4,12,13]. The lack of HIPEC procedure standardization could explain contradictory study results [14]. One of the eight parameters influencing HIPEC efficacy is the exact dosing regimen of chemotherapeutic drugs [5,6]. Sugarbaker et al. [15] assumed that predictions regarding chemotherapy toxicity would be less precise if drug dose and carrier solution volume are not calculated by BSA. Similarly, the COBOX trial showed recently that toxicity and efficacy of concentration based HIPEC protocols in patients suffering from colorectal PSM was higher. It was stated that the concentration-based application is the most standardized way of chemotherapy delivering to the tumor tissue [16]. However, in both current dosing regimens, BSA is used as an estimate of PSA even if CRS has been performed before. The Dedrick formula emphasizes the importance of the effective contact area of the peritoneum and the drug concentration [9]. In patients undergoing CRS with multivisceral resections and peritonectomy procedures the permeability area (PA = effective peritoneal contact area, A × permeability, P) in the Dedrick formula leads to a lower mass transfer of intraperitoneal chemotherapy into the blood. In contrast, an increased peritoneal surface will result in higher blood levels.
It has been shown that the pharmacokinetics and clearance of intraperitoneal chemotherapy is not affected by the degree of parietal peritoneal resection performed [17], which may be attributed, at least in part, to the fact that the parietal peritoneum only accounts for 20% of the total PSA compared to the visceral peritoneum [10]. Thus, removal of parietal peritoneum has a less-pronounced impact on the permeability area described by the Dedrick formula, than removal of visceral peritoneum. Indeed, it has been described that patients with PSM undergoing large organ resection (resulting in a large reduction in visceral PSA) and HIPEC showed decreased clearance of intraperitoneal chemotherapy [18].
Here, we describe the first tool that provides the ability to quantify the imperfect correlation between actual PSA and calculated BSA in patients undergoing CRS. With our new software, we want to stimulate a discussion regarding the merits of dose adjustment of intraperitoneal chemotherapy during HIPEC based on actual PSA (as calculated using PESUCA during CRS) versus BSA in the context of local chemotherapeutic toxicity. PESUCA considers the decreased permeability area after CRS which influences the chemotherapeutic drug transfer into the blood, and therefore the rate at which the drug can be eliminated from the intraperitoneal cavity. This is not included in both current chemotherapeutic dosing regimens (BSA-and concentrationbased). Results calculated by our tool may differ among surgeons performing CRS through variable intraoperative estimations of peritonectomy extent. Further studies are necessary to rule out if a standardized application of PSA calculation by PESUCA in patients undergoing CRS is feasible. After exclusion of peritonectomy estimation bias, our tool should be further investigated to examine if dose adjustments result in less local toxicity by maintaining the same therapeutic effects and thus ensure more patient safety. In addition, PESUCA should be evaluated to determine whether it can function as a new intraoperative   classification system and prognostic tool in analogy to the commonly used PCI score. PESUCA is one valuable contribution towards uniform HIPEC standardization, which still presents a major challenge. By establishing more standardization, discrepancies of HIPEC study results could be brought to light and further multicenter randomized controlled trials to rule out real benefits of HIPEC application would be enabled.