Abstract
Purpose: Hyperthermic intraperitoneal chemotherapy (HIPEC) involves the continuous heating and circulation of chemotherapy throughout the abdominal cavity in an attempt to enhance cytotoxicity. Despite the potential of this chemotherapy procedure, there are scant anatomical temperature distribution studies reporting on this therapeutic process. Patients and methods: We prospectively evaluated the temperature of select anatomical (e.g. upper abdominal, mid-abdominal and supra-pubic) sites in 11 advanced stage ovarian cancer patients who were treated with consolidation HIPEC carboplatin (AUC 10). The temperature of the aforementioned anatomical regions and the inflow/outflow tubing was measured at baseline and at 15-min intervals until the procedure’s completion. Results: The lowest observed mean composite temperature was 41.1 °C at the supra-pubic site whereas the highest temperature was 42.6 °C, in association with the inflow/outflow tubing. During the various time intervals we also ascertained that the lowest composite temperature was 40.9 °C at baseline (i.e. time 0), whereas the highest value (41.8 °C) occurred at multiple time periods (e.g. 15, 45 and 60 min). Conclusion: The HIPEC temperature variation amongst the various abdominal sites and time intervals was minimal. We also discerned that uniform temperature distribution throughout the abdominal cavity was facilitated when the abdomen was both maximally distended with fluid and a high flow rate was maintained.
Introduction
Hyperthermic intraperitoneal chemotherapy (HIPEC) is a relatively innovative method of chemotherapy administration wherein heated chemotherapy is perfused into the abdomen throughout surgery [Citation1]. During HIPEC treatment, the chemotherapy is continuously heated and circulated within the abdominal cavity, which significantly enhances the absorption and tissue penetration of the cytotoxic agent [Citation2,Citation3]. The therapy is reportedly beneficial in the management of numerous peritoneal surface malignancies [Citation2,Citation4,Citation5].
Studies have also indicated that HIPEC is suitable for advanced stage ovarian cancer, a malignancy that often coincides with extensive peritoneal infiltration [Citation6,Citation7]. Moreover, HIPEC as consolidation therapy confers favourable outcomes in ovarian cancer [Citation3,Citation8,Citation9], particularly in highly chemo-sensitive patients may theoretically derive considerable benefit from prolonged therapy [Citation2,Citation10].
One of the primary goals of HIPEC is to achieve a pharmacokinetic advantage, which encompasses maximising local, heated drug exposure to areas of tumour while attenuating systemic toxicity [Citation11–13]. However, inasmuch as temperature attainment and maintenance are essential to HIPEC efficacy, there are scant data evaluating these mechanisms during the procedure’s administration [Citation5,Citation14,Citation15]. The objective of this study was to assess the intra-abdominal temperature distribution during consolidation HIPEC with carboplatin at specific anatomical locations and defined time intervals.
Patients and methods
From January 2013 until May 2013, advanced stage ovarian cancer patients who underwent optimal (≤1 cm residual disease) cytoreductive surgery [Citation16] and completed six cycles of adjuvant paclitaxel (175 mg/m2) and carboplatin (AUC 6) chemotherapy from which they obtained a complete response [Citation17,Citation18] were eligible to receive consolidation HIPEC with carboplatin (AUC 10). Consolidation HIPEC was not administered until 3 weeks following the completion of a patient’s final primary chemotherapy cycle to facilitate sufficient blood count restoration.
Patient study inclusionary and exclusionary criteria
Patients who were initially treated with neoadjuvant therapy underwent suboptimal cytoreductive surgery or who did not achieve a complete response to their primary induction therapy were excluded from this study. All subjects were extensively counselled on the risks and benefits of HIPEC within the context of previously documented clinical trials. This prospective study received institutional review board approval and consent was obtained in all patient cases prior to study enrolment.
Data collection
The following information was collected for the completion of this study: patient demographics, surgical and pathologic characteristics, primary chemotherapy regimen, body mass index (BMI), volume and dose of consolidation HIPEC carboplatin, and temperature values in accordance with predetermined anatomical locations and time intervals.
HIPEC technique
Initially, it is essential that the anaesthesiologist supervises the patient’s fluid management, vigilantly regulating the balance of crystalloids and colloids to ensure appropriate central venous pressure and urine output [Citation19]. Also, thermoregulation was attained via Bair Hugger™ forced-air warming blankets (3 M, St Paul, MN), Universal ThermoWrap® cooling blankets (Mennen Medical, Feasterville-Trevose, PA) and placement of ice packs around the head and neck of the patient.
A pneumoperitoneum was produced via insertion of a Veress needle at Palmer’s point and visual inspection was performed with a 5-mm laparoscope; if indicated, an adhesiolysis was performed. A total of five small skin stab incisions were made (two in the mid-clavicular line immediately caudal to the lowest rib, two in the mid-clavicular line inferior to the umbilicus, and one in the midline, immediately superior to the pubis). A 4-cm peri-umbilical incision was made and thereafter, an Alexis Ring (Applied Medical, Rancho Santa Margarita, CA) was positioned; the ring was tagged with a suture prior to insertion to facilitate subsequent removal.
The two inflow and outflow tubes for the HIPEC ThermoChem HT-2000 device (ThermaSolutions, St Paul) were positioned intra-abdominally. One inflow tube was placed beneath each hemi-diaphragm and both outflow tubes were positioned in the pelvis. The inflow/outflow tubes were then married via Y-connectors to their respective inflow/outflow trunk tubing; they were then traversed via a Gelport cap (Applied Medical), a device which significantly facilitates endoscopic procedures [Citation20], to complete the HIPEC circuit.
Originally, the treatment temperature for the heater system was adjusted to 42.5 °C, which was attained and closely maintained to optimise treatment efficacy and patient safety. Heated normal saline was added to the HIPEC circuit wherein the fluid was circulated around a single-use heat exchange until the abdomen was tensely distended and a high flow rate (1600–1800 cm3/min) was sustained. When the inflow/outflow temperature was stabilised at approximately 42.5/41.0 °C (delta T = 1.5 °C), carboplatin (10 AUC in 350 cm3 normal saline) was added to the circuit [Citation21]; circulation was continued for 90 min. Manual agitation (i.e. shaking) of the abdomen was performed for the final 45 min of the procedure [Citation22].
Once the 90-min circulation period was completed, the carboplatin-containing fluid was abstracted and the abdominal cavity was flushed with normal saline; the inflow/outflow tubing, Alexis ring and GelPort were extracted. The small peri-umbilical incision was closed with a running no.1 loop PDS fascial suture and the skin was then stapled.
Temperature measurement
Oesophageal temperature probes (DeRoyal, Powell, TN) were removed from their protective plastic sheathing and affixed to the inflow/outflow tubing; they were also percutaneously placed into the abdominal cavity. Two of the probes were inserted into the upper abdomen (e.g. diaphragm); two additional probes were placed in the lower abdomen (e.g. paracolic gutter) and one final probe was positioned in the supra-pubic region (see ). Temperature measurements were recorded from the intra-abdominal leads and the inflow/outflow trunk tubing at 15-min intervals during the HIPEC procedure. At the conclusion, all probes were zeroed in a 42.0 °C normal saline bath.
Figure 1. The Alexis™ ring and the base of the GelPort within the context of the upper abdomen (1), temperature sensors (2), inflow tubing (3), left lower abdomen (4), outflow tubing (5), supra-pubic region (6) and right lower abdomen (7).
Statistical analysis
For each patient the mean values of each temperature measurement in accordance with the location and time interval were incorporated in the statistical analyses. All computations were conducted using MedCalc statistical software for biomedical research (version 9.5.1 for Windows). The initial and final data analyses were calculated via a descriptive statistical approach; additional evaluation comprised 95% confidence intervals (CI) and separate one-way analyses of variance (ANOVAs), chi-square test and the Pearson correlation coefficient.
Results
Eleven advanced stage ovarian cancer patients (mean age 63 years, SD = 6.05) underwent surgery and adjuvant chemotherapy, and thereafter received one cycle of consolidation HIPEC carboplatin via a closed technique. Please see for the patients’ demographic and pathological characteristics.
Table 1. Demographic and pathological characteristics of the ovarian cancer patients treated with consolidation heated intraperitoneal carboplatin chemotherapy (n = 11).
Temperature analyses incorporating the patients’ composite intra-abdominal locations and inflow/outflow tubing values
The patients’ mean composite (i.e. incorporating all five time intervals) temperature for the right upper abdomen was 41.5 °C (SD = 0.36, 95% CI = 41.16–41.83). Similarly, the composite temperature for the left upper abdomen was 41.9 °C (SD = 0.33, 95% CI = 41.67–42.28). For the right and left mid-abdominal locations the composite temperatures were 41.2 °C (SD = 0.36, 95% CI = 40.86–41.54) and 41.2 °C (SD = 0.43, 95% CI = 40.81–41.62), respectively (see ). The composite midline supra-pubic temperature measurement was 41.1 °C (SD = 0.31, 95% CI = 40.76–41.34). Finally, the inflow and outflow tube mean composite temperatures were 42.6 °C (SD = 0.09, 95% CI = 42.55–42.73) and 41.8 °C (SD = 0.29, 95% CI = 41.58–42.11), correspondingly (see ). Following an evaluation employing the chi-square test, we did not ascertain any relationship between anatomical location and time on patient temperature achievement (χ2(6) = 0.263; p = 0.067). Additional data exhibiting the patients’ median values, identification of outliers and corresponding interquartile range are illustrated in .
Figure 2. The patients’ mean composite temperature (°C) throughout the upper-abdomen, mid-abdomen and midline supra-pubic regions.
Figure 3. The patients’ mean composite temperature (°C) for the inflow and outflow tubes.
Table 2. Temperature analyses incorporating the patients’ composite intra-abdominal locations and inflow/outflow tubing values.
Temperature analyses in accordance with each time interval
At baseline (i.e. time 0) the composite temperature, which incorporated all of the patients’ intra-abdominal locations in conjunction with the inflow and outflow tubes, was 40.9 °C (SD = 0.77, 95% CI = 40.26–41.69). At 15 min and 30 min the composite temperatures were 41.8 °C (SD = 0.57, 95% CI = 41.3–42.57) and 41.7 °C (SD = 0.51, 95% CI = 41.18–42.13), respectively. For the time intervals of 45 min and 60 min, the composite temperatures were 41.8 °C (SD = 0.53, 95% CI = 41.31–42.29) and 41.8 °C (SD = 0.51, 95% CI = 41.36–42.31), respectively. Finally, with regard to the time periods corresponding to 75 min and 90 min, the composite temperatures were 41.7 °C (SD = 0.54, 95% CI = 41.16–42.15) and 41.6 °C (SD = 0.54, 95% CI = 41.14–42.14), respectively. A Pearson product-moment correlation coefficient was computed to assess the relationship between both time and anatomical location on temperature; we did not discern a relationship between time and temperature attainment (r = 0.179, n = 49, p = 0.217, 95% CI = −0.11–0.44) or anatomical location and temperature achieved (r = 0.078, n = 49, p = 0.596, 95% CI = −0.21–0.35). Additional data exhibiting the patients’ median values, identification of outliers and corresponding interquartile range are illustrated in .
Table 3. Temperature analyses in accordance with anatomic location and time interval.
Infusate volume
The mean volume of fluid utilised in the HIPEC circuit was 5239 cm3 (SD = 839.22, 95% CI = 4674.84–5802.43). The flow rates (1600–1800 cm3/min) during the procedure were high. The subjects’ height (70.7 cm, SD = 13.3), weight (75.99 kg, SD = 17.86) and BMI (29.4 kg/m2, SD = 6.2) were examined in regard to the average volume of chemotherapy per patient; in contrast to volume/weight (70.7, SD = 13.3) and volume/BMI (182.62, SD = 37.1), volume/height (32.6, SD = 4.96) was associated with the lowest degree of variability.
Manual abdominal agitation
Manual agitation (i.e. shaking) of the abdomen was performed for the final 45 min of the procedure. There were no observed HIPEC temperature distribution differences between the initial 45 min (i.e. no shaking) of the procedure (mean temperature = 41.54 °C (SD = 0.3680)) and the subsequent (with shaking) 45 min (mean composite temperature = 41.48 °C (SD = 0.3522, F(1,28) = 0.186, p = 0.855).
Discussion
The persistent, heated dissemination of chemotherapy is an integral component of HIPEC [Citation6]. When considering carboplatin, heat exposure significantly augments the cytotoxicity of this chemotherapy agent [Citation23,Citation24]. Moreover, studies have reported that the level at which carboplatin pervades the cellular structure was higher following the heating process compared to treatment incorporating the simultaneous heating and administration of carboplatin [Citation25]. One could speculate that during hyperthermia the carboplatin-induced cytotoxicity results from an increased rate of DNA damage [Citation25,Citation26] although the data assessing the impact of temperature variation are limited [Citation5,Citation14].
We report on a group of advanced stage ovarian cancer patients who were treated with consolidation HIPEC carboplatin at specific abdominal sites and at predetermined time intervals; there was scant temperature variation (40.9–42.6 °C) amongst the various intra-abdominal sites and inflow/outflow tubing, irrespective of the time intervals. When considering the potential impact of hyperthermia, one would anticipate that thermal enhancement of carboplatin toxicity would correlate with cell death [Citation26], particularly if certain temperatures are achieved. We, however, did not encounter any significant temperature variability, particularly within the context of time and anatomical location. Furthermore, since this study did not include any survival data, any noteworthy temperature fluctuations that might affect clinical efficacy are indeterminate.
Van Ruth et al. [Citation5] assessed the heat penetration of HIPEC with mitomycin C in patients treated for pseudomyxoma peritonei and peritoneal carcinomatosis of colorectal origin. They indicated that the average initial temperature was 40.6 °C, which then decreased by 1.7 °C; the outflow temperature further declined by 1.5 °C. However, their temperature gradient was analysed at only two time points (at 10 and 80 min) and their probes were limited to largely peritoneal and surface muscle tissue. Hence, one could speculate that their reported variability could be attributed to evaluating the temperature at an insufficient number of time periods and not utilising intra-abdominal probes.
In another perfusion study, Celeen et al. [Citation14] assessed the temperature of hyperthermic intraperitoneal chemotherapy with oxaliplatin in a population of carcinomatosis patients. They documented that the intra-abdominal temperature fluctuated between 38.5–41.5 °C; although their measurements were assessed every 5 min during chemo-perfusion, only the temperature of three anatomical locations (the pelvis, right and lower abdomen) was evaluated.
We utilised high flow rates (1600–1800 cm3/min) and large volumes of both infusate (5239 cm3) and fluid (30–35 cm3/cm height). However, one consequence of employing a high flow rate while maintaining uniform intra-abdominal temperature distribution is the inherent risk for aspirating small or large intestine into the outflow tube; fortunately, we did not observe this complication.
After reviewing the volume of infusate per patient, we also discerned that height may be the most suitable measurement (i.e. associated with the least amount of variability) to consider in deriving the appropriate fluid amount. This may have noteworthy implications, especially since previous studies have indicated that fluid volume is calculated via body surface area or titration, both of which can engender significant variability [Citation12,Citation27].
Conclusion
The results from the current HIPEC study suggest that temperature variation amongst the various abdominal sites and time intervals was minimal. We further contend that uniform temperature distribution throughout the abdominal cavity was facilitated when the abdomen was both maximally distended with fluid and a high flow rate was maintained. Finally, studies have indicated that manually agitating the abdominal wall during perfusion promotes uniform heat distribution [Citation5,Citation22]. Nevertheless, we did not discern any significant intra-abdominal heat distribution differences with this technique, although our study design and method may not have sufficiently accounted for the effect.
There are several limitations that preclude us from deriving substantial conclusions regarding HIPEC intra-abdominal temperature distribution. In particular, our oesophageal temperature probe locations and time intervals were subjectively determined; also, since we did not suture the probes, the placement was not necessarily uniform, and precise measurement may have been confounded. Alternatively, one may consider utilising a probe within a Foley catheter to measure intracavitary temperatures [Citation28]. Additional study assessing intra-abdominal temperature distribution during consolidation HIPEC for the treatment of advanced stage ovarian cancer is warranted.
Declaration of interest
This study was supported by the Nancy Yeary Women’s Cancer Research Foundation, Newport Beach, CA. The authors alone are responsible for the content and writing of the paper.
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