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Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Methodology, Drugs and Bidirectional Chemotherapy

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Abstract

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) combined have been recognized as standard of care for treatment of a subset of patients with peritoneal carcinomatosis (PC). The aim of CRS is to eliminate all macroscopic disease through a series of visceral resections followed by targeting any residual microscopic disease with intraperitoneal chemotherapy, exposing the peritoneal surfaces to a high concentration of chemotherapy with a lower systemic toxicity. Different regimes of intraperitoneal chemotherapy include HIPEC, early postoperative intraperitoneal chemotherapy (EPIC) and bidirectional chemotherapy. The efficacy and modality of treatment with intraperitoneal chemotherapy is dependent on multiple factors including the chosen cytotoxic agent and its pharmacokinetics and pharmacodynamics. There is no standardized methodology for intraperitoneal chemotherapy administration. This review will discuss the pharmacological principles of the various intraperitoneal chemotherapy techniques.
ORIGINAL ARTICLE
Hyperthermic Intraperitoneal Chemotherapy (HIPEC)
Methodology, Drugs and Bidirectional Chemotherapy
S. J. Valle
1
&N. A. Alzahrani
1,2
&W. Liauw
1,5
&P. H. Sugarbaker
3
&A. Bhatt
4
&
D. L. Morris
1
Received: 4 July 2015 /Accepted: 28 January 2016 /Published online: 5 February 2016
#Indian Association of Surgical Oncology 2016
Abstract Cytoreductive surgery (CRS) and hyperthermic in-
traperitoneal chemotherapy (HIPEC) combined have been
recognized as standard of care for treatment of a subset of
patients with peritoneal carcinomatosis (PC). The aim of
CRS is to eliminate all macroscopic disease through a series
of visceral resections followed by targeting any residual mi-
croscopic disease with intraperitoneal chemotherapy, expos-
ing the peritoneal surfaces to a high concentration of chemo-
therapy with a lower systemic toxicity. Different regimes of
intraperitoneal chemotherapy include HIPEC, early postoper-
ative intraperitoneal chemotherapy (EPIC) and bidirectional
chemotherapy. The efficacy and modality of treatment with
intraperitoneal chemotherapy is dependent on multiple factors
including the chosen cytotoxic agent and its pharmacokinetics
and pharmacodynamics. There is no standardized methodolo-
gy for intraperitoneal chemotherapy administration. This re-
view will discuss the pharmacological principles of the vari-
ous intraperitoneal chemotherapy techniques.
Keywords Hyperthermic intraperitoneal chemotherapy
(HIPEC) .Methodology .Peritoneal carcinomatosis (PC) .
Cytoreductive surgery (CRS) .Bidirectional chemotherapy
Introduction
The finding of a peritoneal malignancy raises major therapeu-
tic concerns and is associated with a poor prognosis. Systemic
chemotherapy regimens in the past functioned as a palliative
approach and palliative surgery was offered only with the aim
of reducing the symptoms. In the early 1990s, research began
into the development of a therapeutic approach for the treat-
ment of peritoneal surface malignancy. Since this time,
cytoreductive surgery (CRS) and intraperitoneal chemothera-
py (IPC) combined have been recognised as standard of care
for treatment of a subset of patients with peritoneal carcino-
matosis (PC) from pseudomyxoma peritonei, appendix ade-
nocarcinoma, colorectal cancer and mesothelioma and has
also showed promising results in selected patients with ovar-
ian and gastric cancer. Long-term survival has been achieved
in patients who have been treated with CRS followed by hy-
perthermic intraperitoneal chemotherapy (HIPEC). Elias et al.
[1] analysed the results of combined CRS and perioperative
chemotherapy in 1290 patients with a variety of peritoneal
malignancies reporting an overall 5-year survival of 37 %.
CRS/HIPEC is a complex therapeutic modality. The aim of
CRS is to eliminate all macroscopic disease through a seriesof
visceral resections and standardized peritonectomy proce-
dures [2] followed by targeting any residual microscopic dis-
ease with IPC, providing a high intraperitoneal concentration
and with a lower systemic toxicity. Perioperative IPC includes
HIPEC, which is delivered after the surgical procedure in the
operating room and/or early post-operative intraperitoneal
chemotherapy (EPIC), given via a port in the post-surgical
*S. J. Valle
sarah.valle@sesiahs.health.nsw.gov.au
*D. L. Morris
david.morris@unsw.edu.au
1
Department of Surgery, University of New South Wales & St George
Hospital, Kogarah, Australia
2
College of Medicine, Al-Iman Muhammad Ibn Saud Islamic
University, Riyadh, Saudi Arabia
3
Center for Gastrointestinal Malignancies, MedStar Washington
Hospital Center, Washington, DC, USA
4
Department of Surgical Oncology, Fortis Hospital, Bangalore, India
5
Cancer Care Centre, St George Hospital, Kogarah, Australia
Indian J Surg Oncol (June 2016) 7(2):152159
DOI 10.1007/s13193-016-0498-0
setting on days 1 to 5. More recently, bidirectional chemother-
apy combining synchronous intraoperative intraperitoneal
oxaliplatin and systemic chemotherapy with 5-fluorouracil
has been introduced, targeting both the peritoneal cavity and
subperitoneal blood vessels, and has shown long-term surviv-
al in patients with colorectal cancer and appendix adenocarci-
noma. Oncologists acknowledge that disease control may be
significantly improved when chemotherapy is administered
through the intraperitoneal route [3]. This is supported by ex-
tensive clinical and pharmacological research studies and un-
precedented therapeutic results have been reported [46]. The
efficacy and modality of treatment with IPC is dependent on
multiple factors including the chosen cytotoxic agent, pharma-
cokinetics and pharmacodynamics. Kusamura reported that
there are eight parameters which impact on pharmacokinetics
and the efficacy of HIPEC, which can be modified during
HIPEC. These are: the type of drugs, concentration of the drugs,
the combination of them, carrier solution, volume of the perfus-
ate, temperature, duration, and the technique of either open or
closed abdominal cavity [7].Thereisnostandardisedmethod
for the delivery of IPC, which varies according to the surgeon
and/or units preference. Most peritoneal surface malignancy
treatment centres use HIPEC exclusively, some use EPIC only,
and others use both sequentially. In this review, the methodol-
ogy, pharmacokinetics and pharmacodynamics of IPC, and the
benefits and risks associated with each technique are discussed.
Background
Cytoreductive Surgery and Hyperthermic Intraperitoneal
Chemotherapy
CRS is the complete surgical removal of all macroscopic peri-
toneal disease. CRS is composed of five visceral or parietal
peritonectomy procedures. The techniques of CRS have pre-
viously been described by Sugarbaker [8]. Clinical data
strongly support in univariate and multivariate analyses that
complete cytoreduction of nodules <2.5 mm is the single most
important prognostic factor. Systemic chemotherapy is mini-
mally effective even when combined with CRS [9]asperito-
neal metastases are largely resistant to low intraperitoneal con-
centrations and adequate concentrations cannot be achieved
safely using this method.
HIPEC is the most widely explored modality of treatment
post-CRS that has a consistent, clinically improved outcome. It
is a locoregional chemotherapy treatment, which is heated to
increase the penetration and cytotoxicity of the chemotherapy
on the tumour cells. HIPEC is most commonly delivered once
CRS has been completed and before any digestive reconstruc-
tion or diversion is made, to expose bowel resection lines to the
chemotherapy in an effort to minimize the chance of anasto-
motic recurrence. The rationale of HIPEC is to eliminate the
peritoneal surface of any residual microscopic disease.
Moderate hyperthermia above 41 °C has a direct anti-tumour
effect by augmenting the cytotoxicity of some chemotherapeu-
tic agents and increasing the penetration depth of the chemo-
therapy into tumour nodules. Constant hyperthermia is obtained
during HIPEC by providing a continuous circuit with a pump
and heat exchanger, and temperature monitoring. During the
procedure, temperature probes are placed at different sites of
the circuit and intraperitoneal cavity; the heat generator, inflow
and outflow drains, bladder, liver and mesentery [10].
For various reasons, CRS and HIPEC must be performed at
the same time. Surgery without HIPEC can lead to fibrin en-
trapment of microscopic intraabdominal residual disease caus-
ing the peritoneal malignancy to recur rapidly and even prog-
ress. If patients undergo HIPEC post surgical recovery, adhe-
sions create barriers with a non-uniform drug distribution that
may lead to treatment failure.
Hyperthermic Intraperitoneal Chemotherapy Drugs
Most centres have used mitomycin C as the HIPEC drug of
choice in patients with PC of colorectal and appendiceal ori-
gin, and in a subset of patients with mesothelioma. The most
widely applied doses range from 12.5 mg/m
2
to 35 mg/m
2
over 90 min [11]. The AUC ratio of mitomycin C is 23.5.
Van der Speeten et al. [12] found that after 90 min, 71 % of
the drug had left the peritoneal space, which indicates that
29 % was discarded with the removal of the peritoneal fluid.
Patients thatpresent with pseudomyxomaperitonei and a large
volume of mucinous ascites will have an expanded peritoneal
diffusion surface. A more rapid clearance of mitomycin C
from the peritoneal space and higher plasma AUC is expected,
with an increase in the incidence of bone marrow toxicity.
Oxaliplatin and irinotecan have more recently been explored
as HIPEC in PC from colorectal and appendix adenocarcino-
ma. Oxaliplatin is a third generation platinum complex with
AUC ratio between 16 and 25 [13]. As oxaliplatin can only be
administered in a 5 % dextrose solution, hyperglycaemia and
hyponatremia should be expected during the perfusion [14].
Irinotecan is a camptothecin analogue that interacts with topo-
isomerase I-DNA complex and prevents resealing of single
strand DNA breaks [11]. Pharmacokinetics suggest a benefi-
cial pharmacologic profile at 42.5 to 43 °C during 30 min of
HIPEC. The standard doses for oxaliplatin and irinotecan are
reportedtovarybetween360to460mg/m2and360to
400 mg/m2 respectively [15]. Cisplatin HIPEC has been used
in mesothelioma, ovarian and gastric cancer with an AUC
ration of 7.8 [16]. Cisplatin is a platinum salt, which has
shown improved survival when combined with CRS, however
is associated with increased toxicity and complications [17],
which has resulted in slow acceptance of this treatment mo-
dality within the scientific community. Cisplatin HIPEC is
associated with an increased incidence of nephrotoxicity,
Indian J Surg Oncol (June 2016) 7(2):152159 153
which is found in 515 % of patients [18]. Saline diuresis and
a urine output of greater than 1 mL/kg/hr are necessary to
reduce the risk of nephrotoxicity. Many questions remain un-
answered in the treatment of gastric and ovarian cancer, in-
cluding the timing of drug delivery, hyperthermia and the
optimal choice of chemotherapeutic agent. As a result, the
regimens of IPC administration vary amongst institutions for
both gastric and ovarian cancers.
There is no standardised HIPEC dosimetry for the treat-
ment of patients with PC.
Early Postoperative Intraperitoneal Chemotherapy
Early postoperative intraperitoneal chemotherapy is delivered
via a catheter or subcutaneous port placed through the abdom-
inal wall upon completion of CRS in the area at greatest risk of
recurrence. An outflow drain is inserted. EPIC is given in
patients with pseudomyxoma peritonei and in some units, pa-
tients with colorectal cancer, and can be applied with or with-
out HIPEC. It is administered on postoperative days 1 to 5
prior to wound healing, but can be initiated immediately post-
operatively or delayed, due to surgical complication or patient
condition. EPIC does not involve hyperthermia. EPIC has the
advantage of administering multiple cycles of chemotherapy
over a 24-h period, with a 23-h dwell time. However, as the
chemotherapeutic agents persist in the peritoneal cavity, there
is a greater risk of systemic absorption and adverse effects
[19]. The peritoneal surface tissues are repeatedly exposed to
the cytotoxic drug, which increases the benefit of its cell
cycle-specific activity [11]. The most common drug used in
this technique is 5-fluorouracil (5FU), which has a high first-
pass effect after portal absorption [20].Jacquetetal.[20]re-
ported an AUC ratio of >400 when studying the pharmacoki-
netics of intraperitoneal 5FU. It is a small molecule that moves
rapidly out of the peritoneal fluid into the plasma. Regardless of
the rapid metabolism of the drug in the liver and at other sites in
the body compartment, a large AUC ratio of peritoneal fluid to
plasma was maintained. An increased risk of infection has been
reported in patients who have received EPIC [19]. In a large
multi-institutional retrospective study, EPIC was found to sig-
nificantly increase the rate of postoperative complications in
504 patients with colorectal PC treated with CRS/IPC [21].
Elias et al. compared two groups of patients with colorectal
carcinomatosis where one was treated with EPIC using 5FU
and mitomycin C and the other with HIPEC using oxaliplatin
43 °C. Morbidity, mortality, recurrence rate and overall survival
favoured the HIPEC group [19,22].
Bidirectional Chemotherapy
Many current centre protocols advocate bidirectional chemo-
therapy. It is a two compartmental approach to the treatment of
PC that requires a simultaneous intraoperative intravenous
plus intraperitoneal chemotherapy infusion to obtain a bidirec-
tional fluid gradient in peritoneal tumour cells [11]. Timing is
critical to the success of the chemotherapy in relation to the
surgical procedure. Elias first reported this therapy and sug-
gested perioperative intravenous 5FU and leucovorin in con-
junction with oxaliplatin based HIPEC for colorectal cancer
[23]. Earlier in-vivo and in-vitro studies suggested that these
two drugs induced a synergic effect [24,25]. The AUC ratio of
peritoneal fluid to plasma was found to be 2.3 [23].
VanderSpeeten[26] reported on the pharmacology of 5FU
400 mg/m
2
, as a bidirectional protocol, administered by a drip
intravenous infusion in 250 mL 5 % dextrose and water, over
7.5 min. Leucovorin 20 mg/m
2
was simultaneously adminis-
tered through a separate line. Combined doxorubicin 15 mg/
m
2
and mitomycin C 15 mg/m
2
HIPEC was also infused si-
multaneously in 1.5 L/m
2
of 1.5 % dextrose at 41.5 °C. 5FU
levels were obtained from blood and peritoneal fluid at 15 min
intervals for 90 min. It rapidly circulated within the plasma
through both the arterial and venous systems to equilibrate
within the body tissue, including the large peritoneal and
subperitoneal surfaces of both the abdomen and pelvis. The
large volume of peritoneal fluid became saturated by 5FU
within approximately 20 min. High levels of 5FU persist in
the peritoneal fluid as the drug leaves the peritoneal space by
back diffusion through the peritoneal and subperitoneal tis-
sues [11]. 5FU penetrated into the heated tumour nodules even
though it was administered as a normothermic intravenous
solution. Heat targeting is achieved by modulating the timing
of intravenous chemotherapy [27]. The amount of 5FU pres-
ent in the tumour nodule is governed by both pharmacokinetic
(dose, duration, route of administration, volume, carrier solu-
tion and pressure) and non-pharmacokinetic (tumour size,
density, vascularity, interstitial fluid pressure, binding) vari-
ables [26]. By acting synergistically, this study showed that
bidirectional chemotherapy is pharmacokinetically beneficial
and yields a high tumour drug concentration and that intrave-
nous drugs can be targeted to the peritoneal surface if admin-
istered simultaneously with a large volume of intraperitoneal
chemotherapy solution.
Our unit follows the French bidirectional protocol in colo-
rectal and appendix cancers and it is widely used in both
French and German centres [23]. The innovation of a simulta-
neous treatment of CRS plus perioperative intraperitoneal che-
motherapy may be responsible for the current successes in
treating some PC patients, considering previous failures [11].
Intravenous ifosfamide has also been given for ovarian and
gastric cancers. It shows true heat synergy, with 5- to 10-times
the duration of tumour control with 41.5 °C heat compared to
normal temperatures [28]. Its anti-cancer effects only occur
after it is metabolised in the liver and red blood cells to form
4-hydroxyifosfamide [26]. It is an unstable metabolite and
only exists for few minutes within the plasma or red blood
cell but has demonstrated excellent results when combined
154 Indian J Surg Oncol (June 2016) 7(2):152159
with intraperitoneal cisplatin. It can be concluded that the
cytotoxic effects of normothermic ifosfamide are maximised
on heated peritoneal surfaces while the adverse effects of this
agent would not occur at other sites within the body [11].
Neoadjuvant Intraperitoneal and Systemic
Chemotherapy (NIPS)
NIPS is an intravenous and intraperitoneal chemotherapy reg-
imen given as an option for reducing the tumour load prior to
CRS and therefore may even facilitate definitive CRS [28].
Radiological and clinical responses with NIPS have been re-
ported by several groups [2830]. However, disadvantages
include non-uniform intraperitoneal drug distribution due to
adhesions and it is also associated with an increased morbidity
and mortality on further surgical intervention as extensive
fibrosis can also occur, which can interfere with surgical
judgement [31]. NIPS is a promising approach that may be
of benefit in the management of peritoneal metastases from
gastric cancer [28].
Pharmacokinetics
Drug diffusion into tissue depends on tissue structure and drug
properties [23]. The pharmacologic rationale behind IPC con-
sists of dose intensification determined by the peritoneal plas-
ma barrier. The peritoneum is a three dimensional organ cov-
ering the abdominopelvic organs and the abdominal wall. The
peritoneum consists of a monolayer of mesothelial cells sup-
ported by a basement membrane and five layers of connective
tissue, which together accounts for a total thickness of 90um.
The accepted function of the peritoneum is to reduce friction
between intraabdominal organs and the abdominal wall by
producing a solution of glycosaminoglycans and phospho-
lipids [11]. It is of major importance in the host defence
against intraabdominal infections. The plasma-peritoneal bar-
rier inhibits attainment of effective intraperitoneal concentra-
tions with systemic chemotherapy administration, however
HIPEC uses this barrier in favour of the ability to maintain
localised therapeutic drug concentration levels [32].
Dedrick studied the pharmacokinetics of IPC and found
that hydrophilic cytotoxic drugs can maintain a significant
concentration gradient along the peritoneal plasma barrier;
with high intraperitoneal concentrations when added in the
abdominal cavity in large volumes [33], however is limited
by the restrictive penetration depth in tumour tissue of approx-
imately 1-3 mm. He stated that the peritoneal clearance of the
drug is inversely proportional to the square root of its molec-
ular weight [34] and stated the peritoneal permeability to a
certain drug is lower than the same drugsplasmaclearance
[35]. The two compartments, peritoneum and blood, are sep-
arated by a semipermeable membrane that allows a high peri-
toneal drug concentration, optimising its effect on the
intraperitoneal target and at the same time limiting drug pas-
sage into the plasma stream, which causes treatment toxicity
[23]. Following intraperitoneal delivery of the cytotoxic drug,
high regional concentrations can be achieved even whilst
keeping systemic concentrations low. The concentration dif-
ferential is in part due to the slow movement of the drug from
the peritoneal cavity into the plasma [36]. The peritoneal plas-
ma barrier maintains continuous high concentration gradient
of chemotherapeutic drug between the peritoneal cavity and
the plasma compartment [32]. Extensive removal of the peri-
toneum during CRS does not seem to affect the pharmacoki-
netics of intraperitoneal chemotherapy [37] in the transport of
chemotherapeutic agents from the peritoneal cavity to the
plasma compartment. Additionally, the blood drainage of the
peritoneal surface is by the portal vein. This, in theory, pro-
vides a first-pass effect exposing hepatic micrometastases to
cytotoxic drugs, presenting additional means of therapy [38].
After intraperitoneal administration, dose intensification re-
sults in a higher concentration of chemotherapy in the perito-
neal cavity than in the plasma. After cytoreduction, this con-
centration difference increases the possibility of exposing re-
sidual tumour cells to high doses of chemotherapeutic agents
with reduced systemic concentrations and lower systemic tox-
icity. This advantage is expressed by the area under the curve
(AUC) ratios of intraperitoneal versus plasma exposure (Table
1). High intraperitoneal concentration does not automatically
confer greater efficacy and penetration of the drug [11].
D
ifferentdrugregimenshavebeenusedovertheyearsfor
HIPEC. The choice primarily depends on suitability for ad-
ministration with hyperthermia and its known activity against
the disease being treated. Multiple single drug and drug
Tab le 1 Molecular weight and AUC ratios of intraperitoneal to
systemic exposure of chemotherapeutic agents used to treat peritoneal
metastases [11]
Drug Molecular Weight AUC Ratio
5-Fluououracil 130.08 250
Carboplatin 371.25 10
Cisplatin 300.10 7.8
Docetaxel 861.90 552
Doxorubicin 579.99 230
Etoposide 588.58 65
Floxuridine 246.20 75
Gemcitabine 299.50 500
Irinotecan 677.19 N/A
Melphalan 305.20 93
Mitomycin C 334.30 23.5
Mitoxantrone 517.41 115255
Oxaliplatin 397.30 16
Paclitaxel 853.90 1000
Pemetrexed 597.49 40.8
Indian J Surg Oncol (June 2016) 7(2):152159 155
combinations are currently in use. The carrier solution also
plays an important role in the clearance of the drug from the
peritoneal cavity to plasma. The chemical aspect of the carrier
however is not the sole factor that impacts on pharmacokinet-
ics and penetration ability. Factors such as concentration and
volume should be taken into consideration [7].
The ideal carrier solution should provide enhanced expo-
sure of the peritoneal surface, prolonged high intraperitoneal
volume, slow clearance from the peritoneal cavity and ab-
sence of adverse effects to peritoneal membranes [11]. This
improves both the distribution of the drug and efficacy of the
treatment. The carrier solution of 1.5 % dextrose isotonic peri-
toneal dialysis solution is the most widely used, however
some groups use normal saline or 5 % dextrose in water
[34], dependent on the type of chemotherapy agent. Body
surface area is an accurate predictor of drug metabolism and
is useful to estimate systemic drug toxicity. The accuracy in-
creases if the volume of the chemotherapy solution is deter-
mined by the body surface area [11]. Most researchers calcu-
late both drug dose and carrier solution volume based on body
surface area (mg/m
2
). Common perfusate volumes are 1.5 L/
m
2
or 2 L/m
2
[39,40]. The total volume of intraperitoneal
chemotherapy can vary widely between individuals and gen-
der difference in peritoneal surface area can affect absorption
characteristics. Females have a 10 % larger peritoneal surface
in proportion to body size than males [11]. The entire surface
of the abdominopelvic cavity should be targeted; therefore
different HIPEC techniques result in a wide variety of perfus-
ate volumes. Regulation of both the drug dose and carrier
solution volume based on the patients body surface area and
HIPEC delivery technique (open or closed) is necessary [41].
The cytotoxic effect is also relative to the duration of
exposure. In most reported studies, intraperitoneal drug
half-life is 90 min or less. Gardner modelled the dose-
response curves and their dependency on exposure time,
and according to this model a plateau in tumour cell kill
will be reached, after which prolonged exposure time of-
fers no further cytotoxic advantage [11]. Intraperitoneal
treatment length should be dependent on systemic expo-
sure and bone marrow toxicity. There is clinical data dem-
onstrating safety with different schemes established on an
empirical basis which includes a temperature of 41 °C
during 90 min and 43 °C for 30 to 40 min [15].
Pharmacodynamics
The basis for the use of hyperthermia in the treatment of peri-
toneal malignancy is multifactorial. An abundance of evi-
dence exists to support that hyperthermia has a direct anti-
tumour effect by enhancing the cellular uptake of cytotoxic
drugs, increasing membrane permeability and membrane
transport [42]. Synergism between various cytotoxic drugs
and hyperthermia starts at a temperature of 39 °C, but is
stronger at higher temperatures and as reported on in-vivo
studies on culture cells at temperatures of 45 °C, limited by
clinical tolerance [7]. Therefore, it is accepted that the moder-
ate hyperthermia level of 41 to 43 °C is optimal and selective-
ly induces cytotoxicity of malignant cells due to impaired
DNA repair, protein denaturation, and inhibition of oxidative
metabolism in the microenvironment of malignant cells,
which leads to increased acidity, lysosomal activation, and
increased apoptotic cell death [11] and inhibition of
angiogenesis.
Applying hyperthermia augments the specificity of a
subset of chemotherapeutic agents. Hyperthermia may also
increase the penetration of the chemotherapeutic agent into
the tissue and tumour nodules. Jacquet reported that tissue
penetration of doxorubicin is enhanced when a chemother-
apy solution is administered intraperitoneally at 43 °C [4]
as well as temperature dependent increases in drug action
inhibition of repair mechanisms [34]. Piche et al. showed
that increasing the temperature of oxaliplatin HIPEC even
reduces systemic toxicity [43]. The only study addressing
thermo-tolerance was performed in an animal (murine)
model. It was concluded that 44 °C during 30 min was
the maximum well-tolerated temperature [7]. Based on
Eliasexperience, to obtain a minimum of 42 °C in the
out-drains, it is necessary to have between 44 and 45 °C
in the in-drains [39]. Uncontrolled hyperthermia can result
in acute and late systemic side effects. During HIPEC,
heat is applied locoregionally and the bodyscoretemper-
ature is controlled by an anaesthetics team by applying ice
packs in the neck and groin regions.
In locoregional therapy, the drug passes from the periphery
to reach the tumour centre and so a major influential factor is
the interstitium and interstitial fluid pressure. Interstitial pres-
sure in tumours is usually increased [23]. Leunig et al. report-
ed that heat induced a dose-dependent reduction in the inter-
stitial pressure, therefore increasing the ability of the drug to
penetrate into the tissues [44]. Animal models show an in-
creased accumulation and anti-tumour effect of intraperitoneal
cisplatin, oxaliplatin and doxorubicin when abdominal pres-
sure was increased. This is however limited by respiratory and
haemodynamic tolerance [45].
Perfusion Techniques
There are various methods for intraperitoneal administration
of HIPEC. There is no standardised methodology or consen-
sus for a superior method as there are advantages and disad-
vantages to each.
In the closed abdomen technique, inflow and outflow
lines are placed through separate incisions and afterwards,
the abdominal wall is closed before the delivery of
HIPEC. There has been no increased risk of anastomotic
recurrence or gastrointestinal fistula reported by centres
156 Indian J Surg Oncol (June 2016) 7(2):152159
that perform the closure prior to HIPEC [46]. The major
advantage of the closed technique is the ability to rapidly
achieve and maintain hyperthermia, as there is minimal
heat loss from a closed abdomen. It has also been studied
that the closed technique increases intraperitoneal pressure,
which is reported to enhance the penetrative ability of the
chemotherapy. However, deficiencies have been noted in
the distribution of methylene blue dye with the closed
technique, which may cause a higher frequency of com-
plications and non-uniform treatment [19].
The non-uniform distribution of HIPEC in the closed tech-
nique prompted the development of the open method, which
allows for the manual distribution of heat and the cytotoxic
solution [8]. This method, or Coliseum technique, involves
the skin edges of the abdominal incision being suspended
from a Thompson or Bookwalter retractor by a running suture
to create an open space in the abdominal cavity. A plastic sheet
is incorporated into this suture with a small opening in the
centre to allow for the surgeons hand to access the abdomen
and pelvis for manipulation during chemotherapy, usually
with one inflow and two outflow catheters. Temperature
probes are placed near the inflow catheters. Smoke evacuators
are placed to guard against any potential cytotoxic aerosol
contamination. Yonemura et al. introduced a peritoneal ac-
cess deviceto achieve optimal peritoneal expansion.
According to this technique, larger volumes of perfusion fluid
can be added allowing the small bowel to float in the cavity
expander [47]. A major advantage of these open techniques is
the creation of controlled distribution of heat and the cytotoxic
drugs however, disadvantages are also heat loss and possible
drug leakage, increasing potential exposure to theatre staff
[48].
Halkia et al. found that there were no statistically signifi-
cant differences observed in abdominal temperature, core tem-
perature, central venous pressure, heart rate, systolic blood
pressure and urinary output along with morbidity and mortal-
ity by adopting either open or closed technique [49]. A com-
parative study conducted on an animal model identified that
good thermal homogeneity was reached with both techniques,
however better chemotherapeutic absorption and tissue uptake
were achieved with the open technique [50]. Elias et al. [10]
performed a prospective phase II trial investigating seven
techniques in 32 patients. They found that the closed tech-
nique restricted the volume of the perfusion, decreased spatial
diffusion of the chemotherapy, and resulted in lack of thermal
homogeneity. The peritoneal cavity expander allowed imme-
diate thermal homogeneity but this technique isolated the ab-
dominal wall from the chemotherapy. The coliseum method
was identified as the best technique in terms of thermal homo-
geneity and spatial diffusion. Excessive heating of normal
tissue that can exacerbate post-operative ileus and increase
the incidence of post-operative perforation or gastrointestinal
fistula formation may be avoided when using the open
technique [51]. Stuart et al. evaluated the safety of operating
theatre personnel during the open technique and reported that
all assessments were found to be in compliance with
established safety standards [52]. The consensus statement
issued by the Peritoneal Surface Oncology Group
International, after the meeting in Milan, 2006, reached the
conclusion that the best technique for HIPEC delivery is via
the open method [7].
Laparoscopic HIPEC has been successfully administered
in palliating patients with malignant ascites from peritoneal
metastases. It has shown to provide treatment benefits
greater than conventional methods including diuretics, re-
peated paracentesis and systemic chemotherapy with a
complete and definitive resolution of the ascites was ob-
served in up to 94 % of patients [53,54,55]. Some
centres have also performed curative intent laparoscopic
CRS/HIPEC in selected patients with limited PC.
Esquivel et al. concluded that the laparoscopic procedure
was feasible and safe in patients with an appendiceal ma-
lignancy, a low tumour volume and no small bowel in-
volvement [56]. A longer follow-up period would be ben-
eficial to evaluate its long-term efficacy. Laparoscopic
CRS/HIPEC is not yet accepted as a standard of care
method as this procedure reduces the ability of assessing
all abdominopelvic areas and any prior surgical procedure
creates difficulty with adhesions, therefore tumour implants
can be missed promoting early recurrence, however it has
shown promising results in the palliative treatment of ma-
lignant ascites.
There are a variety of hyperthermic perfusion pumps
available internationally and some units deliver HIPEC
via a modified cardiac bypass/perfusion machine and dis-
posable cardiac lines, which is operated by a cardiac per-
fusionist. Automated pumps, specifically designed for in-
traoperative chemotherapy, are now being used in many
centres. These are portable, temperature regulated perfu-
sion pumps that continually monitor the infusion process
and all control systems. There has been no review to date
on the comparison of each of the commercially available
perfusion machines.
Conclusion
CRS and IPC combined are recognised as standard of care
for treatment of a subset of patients with PC. There is no
standardised method for the choice of drug or the delivery
of IPC however a significant improvement in disease con-
trol is seen when chemotherapy is administered through
the intraperitoneal route following CRS. The pharmacoki-
netic and pharmacodynamic data provides a strong phar-
macologic rationale for using perioperative chemotherapy
to treat patients with peritoneal surface malignancy.
Indian J Surg Oncol (June 2016) 7(2):152159 157
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... The model was implemented as a 3D cavity shape resembling the axial, sagittal, and coronal planes of an adult abdomen. Because chemotherapeutics in HIPEC, such as cisplatin (28), are commonly diluted in a water-based solution such as 1.5% dextrose isotonic peritoneal dialysis solution or saline (29,30), water was chosen as the simulated fluid. Accordingly, the cavity was modeled as an enclosure filled with water (net fluid volume: 18.5 L) assumed to contain rigid, unmovable organs. ...
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... The goal of CRS is to remove all visible tumors within the abdominal cavity [194]. Subsequently, heated chemotherapy is administered through HIPEC directly into the affected region to eradicate any residual cancerous cells [195]. Combining surgical and chemical modalities invigorates the immune system and elicits synergism with ICIs, making it a highly effective treatment strategy. ...
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An immune checkpoint is a signaling pathway that regulates the recognition of antigens by T-cell receptors (TCRs) during an immune response. These checkpoints play a pivotal role in suppressing excessive immune responses and maintaining immune homeostasis against viral or microbial infections. There are several FDA-approved immune checkpoint inhibitors (ICIs), including ipilimumab, pembrolizumab, and avelumab. These ICIs target cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1). Furthermore, ongoing efforts are focused on developing new ICIs with emerging potential. In comparison to conventional treatments, ICIs offer the advantages of reduced side effects and durable responses. There is growing interest in the potential of combining different ICIs with chemotherapy, radiation therapy, or targeted therapies. This article comprehensively reviews the classification, mechanism of action, application, and combination strategies of ICIs in various cancers and discusses their current limitations. Our objective is to contribute to the future development of more effective anticancer drugs targeting immune checkpoints.
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Introduction: Malignant ascites (MA) is the abnormal accumulation of fluid in the peritoneal cavity of patients with intraperitoneal dissemination of their disease and is associated with a short life expectancy. The most common clinical feature is a progressive increase of abdominal distention resulting in pain, discomfort, anorexia and dyspnoea. Currently, no treatment is established standard of care due to limited efficacy or considerable toxicity. The objective was to examine the efficacy of laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) in the palliation of refractory MA in patients who were unsuitable for cytoreductive surgery. Methods: From May 2009 to June 2015, 12 patients with MA due to their peritoneal malignancy were treated with laparoscopic HIPEC. The time between operation and repeat paracentesis, in-hospital data, and the proportion of patients that did not require repeat paracentesis was analyzed. Results: One patient (8%) was admitted to ICU for 1 day. The mean operating time and hospital stay was 149.3 minutes (range 79-185) and 4.6 days (range 2-11) respectively. Neither high-grade morbidity nor mortality was observed. The median OS was 57 days. In our experience, a complete and definitive disappearance of MA was observed in 83% of patients. Two patients (17%) developed recurrent MA 124 days and 283 days post-HIPEC. Conclusion: Laparoscopic HIPEC is a beneficial treatment for the management and palliation of refractory MA and results in an excellent clinical and radiological resolution in patients with a complete resolution observed in selected patients.
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Background Treatment of carcinomatosis may involve the use of heated intraperitoneal chemotherapy; the cytotoxic solution is administered in the operating room with the abdomen open so that manual distribution results in uniform treatment. The potential risk of this procedure to the operating room personnel has not been previously investigated. Methods Mitomycin C was perfused through the peritoneal cavity, which was partially covered by a plastic sheet. Large volumes of air were suctioned from 5 and 35 cm above the abdominal skin edge. Urine from the surgeon and from the perfusionist were assayed. Sterile gloves worn in the operating room for manipulating the viscera during treatment were assayed for their permeability to mitomycin C. All samples were analyzed by high-performance liquid chromatography. ResultsAnalysis of samples of operating room air and urine from 10 procedures showed no detectable levels of mitomycin C. Six tests of three different types of gloves showed a 10-fold range of mitomycin C penetration. The least permeable gloves leaked a mean of 3.8 parts per million over 90 minutes. Conclusions No detectable safety hazard to the surgeon or other operating room personnel was demonstrated.
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Although, numerous clinical attempts have been made to disintegrate mucin secreted by pseudomyxoema peritonei (PMP), none are in clinically recommended. Through examination of the pharmacologic characteristics of two novel agent, we titrated an optimized combination of Bromelain and N-Acetyl Cysteine that demonstrates in-vitro and in-vivo efficacy in the dissolution of mucinous ascites from PMP. In the in-vitro experiments, one gram of mucin was incubated in varying concentration of bromelain (0 - 400 ug/ml) and NAC (0-5%) individually followed by a combination before arriving at a therapeutic combination dose of 300 ug/ml bromelain + 4% NAC. This established an effective dose of Bromelain 300 ug/ml + 4% NAC at pH 7.0. When tested in a rat model implanted with 3g of mucin intraperitoneally (ip). IP administration of the drug in a rat model of PMP was shown to result in mucin disintegration within 72 hours with no toxicity observed. SIGNIFICANCE - An effective pharmacologic combination of two novel agents - bromelain and n-acetyl cysteine has been shown to have mucolytic properties in the dissolution of mucinous ascites from pseudomyxoma peritonei. This finding may allow further therapeutic development of this combination agent to provide a medical based approach to managing this complex disease. © 2013 Wiley Periodicals, Inc.
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The currently accepted therapies for ovarian cancer have produced only limited numbers of extended complete remissions in advanced-stage disease. Studies of high-volume intraperitoneal chemotherapy have been initiated to define the toxicology, pharmacokinetics, and the therapeutic effectiveness of this treatment modality. This technique has been virtually ignored until recently, because little success has been achieved with it except in one study (Rutledge, 1966), in which large intraperitoneal fluid volumes were used. The general lack of success probably reflects inadequate attention to physiologic and pharmacologic principles of drug distribution and absorption in a space as large as the peritoneal cavity. Biomedical engineers, pharmacologists, and clinicians at the NCI have cooperated in the development of a rational chemotherapy for ovarian cancer. Following mathematical pharmacokinetic modeling and toxicologic studies in rat, a Phase I clinical trial of intraperitoneal methotrexate administered in large volumes of dialysis fluid was initiated. Results in three patients confirm the practicality of this approach, and further investigation is warranted.
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Extensive tumor implants secondary to sarcoma, sarcomatosis, or mesothelioma in children is rare. We conducted the first phase 1 trial of escalating doses of cisplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) in children with sarcomatosis. The most devastating complication of cisplatin therapy is nephrotoxicity. Here we present the anesthetic management and analysis of the impact of intraoperative fluid management on the incidence of renal failure. Of the 10 patients under 18 years of age who underwent HIPEC in the context of our phase 1 trial, six patients were under the age of 10 years. We reviewed the anesthetic management, intraoperative fluid and blood administration, and postoperative renal function in these patients. The average age and weight were 6 years and 20.9 kg, respectively. To avoid renal toxicity, urine output was maintained at an average of 3 ml/kg/h. Crystalloid and colloid were transfused at an average rate of 9 ml/kg/h. Percentage increase in creatinine postoperatively varied from 33 to 500 %. Volume of fluid administered did not correlate with percentage increase in creatinine. All patients had a temporary increase in their serum creatinine, but none required dialysis. Fluid administration at an average rate of 9 ml/kg/h was required to maintain satisfactory urine output. This rate of intraoperative fluid administration is similar to what is provided to adult HIPEC patients. There was no significant correlation in the volume or type of fluid delivered and the increase in serum creatinine. More studies are needed to determine optimal fluid management in children undergoing HIPEC with cisplatin.
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The purpose of this study was to report the pharmacokinetics of heated intraoperative intraperitoneal mitomycin C (MMC) and to analyze the impact of heat, extent of peritoneal resections, and effect of intraoperative hyperthermic chemotherapy on the pharmacological properties of the peritoneal plasma barrier. Sixty patients with peritoneal carcinomatosis were included in a phase I/II study combining cytoreductive surgery with 2 h of heated intraperitoneal mitomycin C in an intraoperative lavage technique and one cycle of early postoperative 5-fluorouracil (5-FU) given on postoperative days 1-5. Three pharmacokinetic analyses were performed: (1) pharmacokinetics of heated intraoperative intraperitoneal MMC was determined for 18 patients by sampling peritoneal fluid, plasma, and urine during the 2-h procedure; (2) impact of peritoneal resections on MMC pharmacokinetics was assessed by comparing a group of patients who underwent < or = 1 peritonectomy procedure (minimal surgery) to a group of patients who underwent > or = 2 peritonectomy procedures (extensive surgery), and (3) effects of heated intraoperative intraperitoneal chemotherapy on the pharmacokinetics of early postoperative intraperitoneal 5-FU by comparing a group of patients treated with heated intraoperative intraperitoneal MMC to a control group who did not receive heated intraoperative intraperitoneal chemotherapy. The mean dose of heated intraoperative intraperitoneal MMC per patient was 22.5+/-7.1 mg (12.9+/-3.8 mg/m2). Drug absorption from perfusate was 14.3+/-2.7 mg. The mean aeras under the curve (AUC) for perfusate and plasma were, respectively, 340+/-138 and 15+/-4 microg/ml x min. The mean AUC peritoneal fluid/plasma ratio was 23.5+/-5.8. Patients who underwent extensive peritoneal resections exhibited a significantly (p = 0.037; Wilcoxon rank test) increased peak plasma concentration of MMC, a significantly (p = 0.029) increased AUC of plasma concentrations and a significantly (p = 0.034) decreased peritoneal fluid/plasma AUC ratio. Pharmacokinetic studies of early postoperative intraperitoneal 5-FU showed no significant difference in plasma AUC, perfusate AUC and AUC ratio between patients who received and those who did not receive heated intraoperative intraperitoneal MMC. Heated intraoperative intraperitoneal chemotherapy achieves high peritoneal concentrations of MMC with limited systemic absorption. Systemic drug absorption during heated intraoperative intraperitoneal chemotherapy is increased when extensive peritoneal resections are performed, but such slight increases are unlikely to change the risk of systemic drug toxicities. Heated intraoperative intraperitoneal chemotherapy does not alter the pharmacokinetics of early postoperative intraperitoneal 5-FU.