Abstract
Intraperitoneal chemotherapy is associated with a significant pharmacokinetic and pharmacodynamic benefit and can, alone or in combination with systemic chemotherapy (bidirectional chemotherapy), be used for treating primary and secondary peritoneal surface malignancies. Due to the peritoneal–plasma barrier, high intraperitoneal drug concentration can be achieved by intraperitoneal chemotherapy, whereas systemic concentration remains low. Bidirectional chemotherapy may provide in addition adequate drug concentrations from the side of the subperitoneal space to the peritoneal tumour nodules. Major pharmacological problems of intraperitoneal chemotherapy are limited tissue penetration and poor homogeneity of drug distribution to the entire seroperitoneal surface. Significant pharmacological determinants of intraperitoneal chemotherapy are choice of drug, drug dosage, solution volume, carrier solution, intra-abdominal pressure, temperature, duration, mode of administration, extent of peritonectomy and interindividual variability. Drugs most commonly applied for intraperitoneal chemotherapy include mitomycin C, cisplatin, carboplatin, oxaliplatin, irinotecan, 5-fluoruracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, premetrexed and melphalan. The drugs and their doses that are used vary widely among centres. While the adequate drug choice for intraperitoneal and bidirectional chemotherapy is essential, randomized clinical trials to determine the most optimal drug or drug combination are lacking, and only eight retrospective comparative clinical studies are available. Further clinical pharmacological studies are required to determine the most effective drug regimen for intraperitoneal and bidirectional chemotherapy in various indications. In the future, reliable drug sensitivity testing and genetic profiling of peritoneal metastases will be needed for enabling patient-specific therapy.
Introduction
Peritoneal metastases represent an advanced stage of abdominal tumours and have been generally associated with a dismal prognosis, while it often results in severe morbidity and mortality. Although progress has been made in establishing the diagnosis by modern imaging techniques, the treatment of peritoneal surface malignancy has remained a difficult issue. While surgery will most probably leave at least microscopic disease behind, resulting in progression or recurrence of peritoneal disease, peritoneal metastases are relatively resistant to systemic chemotherapy. Hence, surgery, systemic chemotherapy and their combination are in general ineffective, and patients will ultimately die of their peritoneal disease. An apparent dose–effect relation exists for most chemotherapeutic agents, but systemic toxicity limits the height of the dose that can be administered intravenously. Moreover, the so-called ‘peritoneal–plasma barrier’ reduces the penetration of the cytotoxic agents from plasma into the peritoneal tumour nodules and the ascites [1].
Although peritoneal metastases represent metastatic disease, their presence should be considered regional disease instead of systemic disease. Intra-abdominal malignancies with tumour deposits on peritoneal surfaces may remain confined to the peritoneal cavity for a prolonged period of time. Therefore, peritoneal metastases are not equivalent with distant metastases, providing a rationale for regional treatment such as intraperitoneal chemotherapy [1]. Since this treatment modality has been applied for the first time in 1955 by Weisberger [2], much progress has been made in the treatment of peritoneal surface malignancies with intraperitoneal chemotherapy.
Pharmacokinetic aspects of intraperitoneal chemotherapy
A large number of experimental and clinical studies on intraperitoneal chemotherapy have been published during the last decades [3, 4]. The major benefit of intraperitoneal chemotherapy is the regional dose intensity that is gained, which may surmount the problem of relative drug resistance. This will result in a higher efficacy of the chemotherapeutic drug in the case of the existence of a dose–effect relation [3].
When the drug is administered into the peritoneal cavity delivery, high intraperitoneal concentrations can be accomplished, whereas systemic drug concentrations remain low. The difference in concentrations in these compartments is mainly caused by the slow absorption of the drugs from the peritoneal cavity into the systemic blood circulation (peritoneal clearance). The so-called ‘peritoneal–plasma barrier’ is responsible for this pharmacokinetic advantage, causing a high ratio of cytotoxic drug concentration between peritoneal cavity and plasma [5, 6]. The ‘peritoneal–plasma barrier’ consists of peritoneal mesothelium, subserosal interstitium and capillary walls, with the latter component being probably the most important in impeding the transfer of large molecules through this barrier. Moreover, drug extraction by the liver after absorption from the peritoneal cavity and high renal drug clearance may reduce systemic drug exposure. The area under the concentration (AUC)–time curve gradient of the drugs from the peritoneal cavity to plasma expresses most adequately the pharmacological advantage of intraperitoneal administration of a certain drug. The intraperitoneal to plasma drug AUC ratio of drugs varies from a factor 10 to a factor 1,000, depending on their molecular weight and the hepatic and renal clearance [4]. An additional advantage of intraperitoneal chemotherapy is that cytotoxic drugs administered intraperitoneally may potentially treat hepatic micrometastases after their transport through the peritoneal surface and the portal vein to the liver [7]. Additionally, drug transport after absorption from the peritoneal cavity through lymphatics to the systemic circulation may treat concurrent metastases in the lymph nodes [8].
Pharmacodynamic aspects of intraperitoneal chemotherapy
Although the pharmacokinetic advantage is essential, pharmacodynamics is also of major importance. Whereas pharmacokinetics investigates what the body does to the chemotherapeutic agent, pharmacodynamics examines what such a drug does to the body. High intraperitoneal drug concentration and exposure constitute the two key aspects affecting the eradication of free intraperitoneal tumour cells. However, these favourable pharmacokinetic parameters may not correlate with the drug amount in peritoneal tumour nodules. It is more important to achieve also adequate tumour tissue penetration and concentration of the drug rather than high drug concentrations in the peritoneal fluid only [9].
A major problem in intraperitoneal chemotherapy is the limited penetration of the therapeutic agent into the tumour deposits. While for many drugs it is difficult to accurately determine tumour tissue concentration and penetration depth after intraperitoneal administration, the penetration depth of some drugs is estimated to be 2–5 mm at maximum, although for other drugs it may be a few cellular layers only [10, 11, 12, 13, 14, 15, 16]. This underlines the need for optimal cytoreductive surgery to precede intraperitoneal chemotherapy. Drug penetration into solid tumours is a complex mass transport process that involves multiple parameters not only related to the used cytotoxic agent, but also to the tumour tissue properties and even the therapeutic setup [17]. Besides the drug characteristics and pharmacokinetic variables, their penetration depth is determined by factors such as tumour nodule size, cell density, extracellular matrix, vascularity, interstitial fluid pressure and binding [18, 19]. Various mathematical models have been proposed which can provide unique insights into the different transport barriers that occur during intraperitoneal chemotherapy [17, 19, 20, 21].
Not only penetration of the drug into the residual peritoneal tumour from the site of the peritoneal cavity is important, but as well from the site of the subperitoneal space. Enhanced drug accumulation in the subperitoneal peritoneal space and subsequently in the tumour can be achieved by simultaneous intraperitoneal administration of vasoconstrictors such as epinephrine, which will reduce drug loss through the peritoneal and tumoural vascular networks from the subperitoneal space to the systemic compartment [22, 23, 24], simultaneous administration of intravenous chemotherapy and absorption of the intraperitoneally delivered drug to the systemic compartment (Figure 1) [3, 18].
Simplified scheme of drug transport from the peritoneal cavity and from the capillaries into the peritoneal tumour tissue during bidirectional chemotherapy (concurrent intraperitoneal and intravenous chemotherapy).
Pharmacology of bidirectional intraoperative chemotherapy
Intravenous chemotherapy may be used simultaneously with intraoperative intraperitoneal chemotherapy to increase treatment efficacy in residual tumour deposits after cytoreductive surgery. In this bidirectional intraoperative chemotherapy, the intraperitoneally delivered drug penetrates the residual tumour nodules from the site of the peritoneal surface, while the intravenous chemotherapy provides drug supply by capillary blood flow into the tumour deposits (Figure 1) [3, 18]. Consistent with the rationale of simultaneous intraperitoneal and intravenous chemotherapy, significant absorption of the chemotherapeutic agent from the peritoneal cavity to the systemic circulation may be even beneficial when it results in adequate plasma concentrations without considerable systemic toxicity. Consequently, the pharmacokinetic profile of intraperitoneally delivered agents as expressed by high peritoneal fluid to plasma maximal concentration and AUC ratios may not represent the actual pharmacokinetic advantage of intraperitoneal chemotherapy [3].
Additionally, the synergistic effect of some intravenously administered drugs can increase the efficacy of intraperitoneal chemotherapy. For example, 5-fluoruracil and leucovorin are administered intravenously shortly before intraperitoneal chemotherapy with oxaliplatin in order to potentiate its activity [25]. Moreover, when intraperitoneal chemotherapy is performed under hyperthermic conditions, an intravenously delivered drug may profit from the local synergistic effect of hyperthermia. Many recent treatment protocols involve bidirectional intraoperative chemotherapy [25, 26, 27, 28, 29, 30, 32].
Variables in pharmacokinetics and pharmacodynamics
While there is scientific data to advocate the combination of cytoreductive surgery and perioperative intraperitoneal chemotherapy as treatment modality for peritoneal surface malignancies [33, 34, 35, 36, 37, 38, 39], the second component is still far from standardized. Significant variations in intraperitoneal chemotherapy remain and may influence the pharmacokinetics and pharmacodynamics of intraperitoneally delivered drugs, including their dose, the volume and the kind of carrier solution, the technique (open or closed abdomen), the intra-abdominal pressure and temperature, the duration of the intraperitoneal chemotherapy and the extent of (peritoneal) resections (Table 1) [3, 18, 40]. Further, there might be considerable interindividual differences. Major challenges remain for intraperitoneal chemotherapy to optimize the contact of the drug to the entire seroperitoneal surface and to increase the penetration depth of the intraperitoneally delivered drugs [21]. Ongoing innovations in delivery technique and drug formulations are of major interest [21] and subject of other manuscripts in this journal’s issue.
Pharmacokinetic and pharmacodynamic variables in intraperitoneal chemotherapy.
| Pharmacokinetic variables | Pharmacodynamic variables |
|---|---|
| Molecular weight of the drug | Tumour nodule size |
| Hepatic metabolism and renal clearance | Cell density |
| Drug dose | Extracellular matrix |
| Volume of the carrier solution | Vascularity |
| Kind of carrier solution | Interstitial fluid pressure |
| Open or closed abdominal lavage | Binding |
| Intra-abdominal pressure | Temperature |
| Duration of intraperitoneal chemotherapy | |
| Extent of peritonectomies |
Dosage
In perioperative intraperitoneal chemotherapy protocols, a large variety of doses have been used for each drug [3, 18, 40]. Most centres calculate the drug dosage according to the estimated body surface area (mg/m2). However, it has been demonstrated that the correlation between the actual peritoneal surface and the estimated body surface is flawed and gender dependent [41]. Body surface area can accurately predict drug metabolism and consequently systemic toxicity. Others administer the drug with a fixed concentration or dosage the drug in mg/kg, mg/m2/L or mg/kg/L. Additionally, some administer a drug like mitomycin C in three doses instead of one single dose in order to achieve a more constant drug concentration and a higher peritoneal fluid AUC [42]. The dose limit is mostly bone marrow depression. In a recent study, it appeared that intraperitoneal concentration of mitomycin C at 30 min predicts the risk of neutropenia [43].
Volume
A larger volume of peritoneal fluid can enlarge the effective contact surface of chemotherapeutic drugs with the peritoneum, leading to increased absorption of the drugs from the peritoneal cavity and consequently lower peritoneal fluid and higher systemic drug concentrations [25, 44]. This may result in lower treatment efficacy and higher systemic toxicity. A predictable systemic toxicity and exposure of the peritoneal tumour to the chemotherapeutic drug may be most effectively achieved by a using body surface area-based drug dose and carrier solution volume [18].
Carrier solution
The selection of the carrier solution in which the chemotherapeutic agent is dissolved for intraperitoneal chemotherapy can play a significant role in the clearance of the agent from the peritoneal cavity to plasma. The proper selection of the carrier solution may improve the efficacy of the chemotherapeutic agent, increasing tissue penetration and enhancing exposure of peritoneal tumour and residual malignant cells to the chemotherapeutic agent. The ideal carrier solution should provide the following: (1) exposure of cancerous surfaces within the peritoneal cavity to high levels of cytotoxic agent for as long as possible, (2) prolonged high intraperitoneal volume, (3) slow clearance from the peritoneal cavity and (4) absence of adverse effects on peritoneal membranes even after prolonged exposure [45]. Isotonic salt solutions and high-molecular-weight peritoneal dialysis fluids are most frequently used for intraperitoneal chemotherapy. Low-molecular-weight solutions are absorbed from the peritoneal cavity much more rapidly than high-molecular-weight solutions and a reduced carrier solution volume impairs the exposure of the entire seroperitoneal surface to the chemotherapeutic agent. The role of the carrier solution is much more important for early postoperative intraperitoneal chemotherapy (EPIC) than for intraoperative intraperitoneal chemotherapy, because of its longer treatment duration. In this case, long-standing maintenance of a high carrier solution volume is required for adequate drug distribution during the entire session and consequently optimal effectiveness of the treatment [3].
The use of hypotonic solutions has resulted in higher drug accumulation in tumour cells and increased cytotoxicity in experimental studies [46, 47, 48]. In contrast to these findings, in a clinical study [49], absorption and intratumoural oxaliplatin were not notably higher for hypotonic than for isotonic solutions. Noteworthy, in the group of patients with a hypotonic carrier solution, unexplained abdominal bleeding and severe thrombocytopenia were frequently observed.
Mode of action: open vs. closed abdominal lavage
The two principal methods to deliver intraoperative intraperitoneal chemotherapy are the open abdomen and the closed abdomen technique [50]. In a pig model, the open technique had significantly increased absorption of oxaliplatin to the systemic compartment and enhanced penetration of oxaliplatin into abdominal tissues when compared to the closed abdomen method [51]. While the platinum concentrations in the peritoneal surfaces at the diaphragm were similar or higher with the closed abdomen technique, higher peritoneal drug concentrations were measured in the pelvis and paracolic gutters with the open abdomen technique.
Intra-abdominal pressure
In various animal models [52, 53, 54], a higher intra-abdominal pressure resulted in increased drug concentrations in peritoneum, tissues and tumour nodules, an increased penetration depth of the drug into the tumour nodules and decreased intraperitoneal versus systemic AUC ratio. In a pig model, laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC), associated with an increased intra-abdominal pressure, resulted in higher drug absorption from the abdominal cavity to the systemic compartment when compared with the open abdomen, coliseum technique [55]. The practical use of highly increased intra-abdominal pressure is restricted by its adverse effect on the respiratory and hemodynamic systems. However, moderately increased intra-abdominal pressure has been shown to be feasible in a clinical study using a closed abdomen technique [56]. Moreover, laparoscopic HIPEC has been safely performed with an intra-abdominal pressure of 12–15 mmHg [57, 58].
Hyperthermia
The selective cytotoxic effect of hyperthermia on cancer cells and its potential to increase the effectiveness of many cytotoxic drugs make it a beneficial adjunct to intraperitoneal chemotherapy in the treatment of peritoneal surface malignancies [3, 59]. This advantage of hyperthermia is used in intraoperative HIPEC. Already in ancient times, it has been appreciated that heat has a direct cytotoxic effect. The father of modern medicine, Hippocrates (470–377 BC), stated in his Aphorisms: “Where drugs do not cure, iron does; where iron does not cure, heat does; where real heat does not cure, cure is impossible.” Ample experimental and clinical evidence exists that indicates that cancer cells are selectively destroyed by heat at temperatures of 41–43 °C. However, upregulation of heat-shock proteins can induce thermal tolerance, restricting the value of a direct cytotoxic effect of heat [60]. Additionally, thermal enhancement of the efficacy of drugs may arise in a number of ways at the cellular level [61]. Moreover, experimental data indicate that hyperthermia may enhance the penetration depth of intraperitoneally delivered chemotherapeutic drugs into tissues and tumour nodules, without changing the pharmacokinetic profile. The thermal enhancement of the drugs’ activity and penetration depth is often already observed at temperatures above 39–40 °C [14, 54, 61, 62, 63]. Regardless of these theoretical advantages, to our knowledge, there is no high-level evidence (i. e. a comparative clinical study) that HIPEC is superior to normothermic intraperitoneal chemotherapy.
The thermal enhancement varies among chemotherapeutic agents in experimental studies. Some of the agents with the highest thermal enhancement are melphalan, ifosfamide, platinum compounds, mitomycin C and doxorubicin. During HIPEC, the heat of the carrier solution has a limited penetration depth into tissue, underscoring the need for optimal cytoreductive surgery [64]. Remarkable is the large decline of the temperature in the first millimetres of the abdominal wall. Responsible for the loss of heat and the slope in temperature is probably the flow of relatively cool blood in the richly vascularized peritoneum. This phenomenon is acknowledged as the “heat sink effect”. Because of the differences in thermal enhancement among drugs in in vivo studies, the drug of choice in hyperthermic conditions may differ from that at physiological temperatures [65]. Theoretically, drugs used during HIPEC should be stable at increased temperatures. Although not tested for all those drugs, it seems that most drugs are stable at temperatures up to 42–43 °C [66, 67]. Moreover, since pharmacokinetic studies demonstrated for all drugs that are used in HIPEC high drug intraperitoneal drug concentrations during the entire procedure, it is to be assumed that all these drugs are considerably stable in moderate hyperthermia.
Duration
It is obvious that duration of intraperitoneal chemotherapy influences pharmacokinetics. A longer duration may lead to a number of events such as absorption of an increased amount of drug to the systemic compartment, increased drug uptake into the tumour nodules, potential gradually increased degradation of the drug in the peritoneal fluid and further decrease of intraperitoneal drug concentrations. While the drug solution is usually left in the abdomen for approximately 24 h in pre- or postoperative instillation peritoneal chemotherapy, the time period of HIPEC has been quite arbitrary and differs from 30 to 120 min among centres. Preferably, the time of perioperative intraperitoneal chemotherapy regimens should be driven by pharmacology data and not just arbitrary [18]. No definite data exist to support a certain time period. Duration of 90–120 min might be optimal according to the results from experimental and pharmacokinetic studies [3]. While data suggest that HIPEC should be performed for at least 90 min to gain the benefit of the drug’s thermal enhancement, it seems implausible that treatment for longer than 90 or 120 min will result in significantly improved efficacy, since at this point of time the amount of drug that is still present in the peritoneal cavity is small [3]. On the other hand, according to the cell line model by Gardner [68], a plateau in the destruction of tumour cells will be attained at a certain time, after which longer exposure to the chemotherapeutic drug does not provide additional benefit.
Additionally, a higher dose for a shorter exposure time may result in the same cancer cell kill than a lower dose for a longer exposure time. Elias and co-workers advocated administering very high drug doses for a much shorter duration (30 min) of HIPEC in order to achieve a most favourable peritoneal fluid AUC [25]. The intentionally short treatment time does allow only half of the drug dose to be absorbed, avoiding significant systemic toxicity, makes the use of higher intra-abdominal temperatures better tolerated and decreases operation theatre time and costs.
Extent of peritonectomies
One may wonder whether the resection of involved peritoneum affects the characteristics of the so-called ‘peritoneal–plasma barrier’ and subsequently whether the extent of peritoneum resections may influence the absorption of drugs from the abdominal cavity to the systemic compartment. When extensive parts of the peritoneum have been removed during cytoreductive surgery, the peritoneal–plasma barrier may be less intact, resulting in increased absorption from the intraperitoneally delivered drugs. This may then lead to higher plasma concentrations and AUCs and consequently lower intraperitoneal to plasma AUC ratios. In some studies, drug absorption was increased [69, 70], while in other studies no significant differences could be detected [6, 71]. Even though the results are inconsistent, it is implausible that adjustment of drug dose is required after more extensive parietal peritonectomy procedures, since differences in the clearance of drugs, if they exist, will be presumably small.
Interindividual differences
Population pharmacokinetics have demonstrated, despite a common dose administered under standard conditions, considerable diversity in peritoneal and systemic drug concentrations during intraperitoneal chemotherapy among patients, which consequently may result in differences in treatment efficacy and haematological toxicity [72, 73, 74, 75].
Drug choice
The choice of the chemotherapeutic agent that is to be delivered intraperitoneally is of utmost importance, and specific characteristics have to be taken into account [3, 40]. The agent should lack severe local toxicity after intraperitoneal delivery. Obviously, the drug should have a well-recognized activity against the type of malignancy that is dealt with. Usually, results concerning drugs’ efficacy in systemic chemotherapy are considered. The need for systemic metabolization (usually in the liver) into an active form excludes a drug for intraperitoneal use. Support for concentration- or exposure-dependent cytotoxicity of the drug from experimental or clinical studies is required, because otherwise a simpler intravenous route may be similarly effective. Further, it is of utmost importance that the drug is slowly absorbed from the peritoneal cavity and displays rapid hepatic and/or renal clearance allowing for a pharmacokinetic advantage with high intraperitoneal drug exposure and low systemic toxicity. For HIPEC, a synergistic effect with heat is favoured and a direct cytotoxic agent is required. Anti-metabolites, such as 5-fluorouracil, are not considered suitable for this type of intraperitoneal chemotherapy as the duration of the treatment is too short to be effective. The response on previously (intravenously) administered drug regimens should be considered in the assessment of the sensitivity of the tumour that is to be expected for a certain drug. Although the higher local drug concentrations achieved by its intraperitoneal administration may overcome relative drug resistance, clinically observed resistance to an intravenously administered drug is usually a reason to choose for another drug in intraperitoneal chemotherapy.
In clinical practice, the drug choice is usually determined by local tradition and experience, empiricism, extrapolation from its efficacy in systemic chemotherapy, favourable pharmacokinetics and pharmacodynamics, results from experimental studies and outcome in comparative clinical studies.
To our knowledge, to date, there are no drugs specifically approved by the FDA, EMA or other federal agency for intraperitoneal chemotherapy, except cyclophosphamide, nitrogen mustard and catumaxomab. While cyclophosphamide and nitrogen mustard are not used regularly for such a treatment, catumaxomab is only used for palliative treatment of malignant ascites. The current practice is off-label use of drugs approved for intravenous administration.
Because of the discrepancies between the settings on the laboratory bench and the conditions in the human body, extrapolation of results from experimental studies to clinical practice should be done cautiously. In the clinical setting, conditions are much more complicated and the activity of drugs and their interaction with hyperthermia are influenced by numerous physiological factors, such as microcirculation, pH, hypoxia and tumour physiology. Moreover, the utilization of different cell lines and the application of diverse treatment protocols further complicate the interpretation of in vitro studies. However, the opportunity of creating standardized conditions in experimental studies may allow for proper evaluation of each individual treatment parameter, whereas it is practically impossible to do so in comparative clinical studies [3].
Drugs commonly administered in intraperitoneal chemotherapy
The drugs commonly used in intraperitoneal chemotherapy for various peritoneal surface malignancies (Table 2) are briefly discussed below. The characteristics that are most important for their application in intraperitoneal chemotherapy are summarized in Table 3 [4, 20, 66, 67].
Drugs commonly administered in intraperitoneal chemotherapy according to the main histological tumour types.
| Histological tumour type | Drug |
|---|---|
| Pseudomyxoma peritonei | Mitomycin C Oxaliplatin 5-Fluorouracil |
| Colorectal and appendiceal adenocarcinoma | Mitomycin C Oxaliplatin Irinotecan 5-Fluorouracil |
| Malignant peritoneal mesothelioma | Cisplatin Doxorubicin Paclitaxel |
| Gastric adenocarcinoma | Cisplatin Paclitaxel Docetaxel |
| Ovarian cancer | Cisplatin Carboplatin Doxorubicin Gemcitabine Paclitaxel Docetaxel |
Main characteristics of drugs commonly administered in intraperitoneal chemotherapy.
| Drug | Molecular weight | AUC ratio | Thermal enhancement | Penetration depth |
|---|---|---|---|---|
| Alkylating agents | ||||
| Mitomycin C | 334.3 | 13–80 | + | 2–5 mm |
| Melphalan | 305.2 | 17–63 | + | NA |
| Platinum compounds | ||||
| Cisplatin | 300.1 | 12–22 | + | 1–5 mm |
| Carboplatin | 371.3 | 15–20 | + | 0.5 mm |
| Oxaliplatin | 397.3 | 16 | + | 1–2 mm |
| Topoisomerase inhibitors | ||||
| Irinotecan | 677.2 | 15a | ± | NA |
| Doxorubicin | 580.0 | 162–230 | + | 4–6 cell layers |
| Antimicrotubule agents | ||||
| Paclitaxel | 853.9 | 550–2,300 | – or minimal | >80 cell layers |
| Docetaxel | 861.9 | 150–3,000 | – or minimal | 1.5 mm |
| Antimetabolites | ||||
| 5-fluorouracil | 130.1 | 117–1,400 | minimal | 0.5 mm |
| Gemcitabine | 299.6 | 791–847 | ± | NA |
AUC, area under concentration vs. time curve; AUC ratio, peritoneal fluid AUC /systemic AUC.
aAUC ratio of 4 for its active metabolite SN-38.
±, contradictory results in experimental studies; NA, no data available.
Mitomycin C
The alkylating antibiotic mitomycin C has been extensively applied in HIPEC protocols for peritoneal metastases deriving from colorectal or appendiceal tumours, as well as pseudomyxoma. Its effectiveness against many malignancies, its favourable pharmacokinetics (mean peritoneal to plasma AUC ratio: 13–80), its significant thermal enhancement and its acceptable toxicity make mitomycin C an attractive drug for HIPEC [4, 65]. It is of importance that cell necrosis occurs irrespective of the tumour cell’s proliferative capacity, underscoring the potency of mitomycin C against tumours characterized by a low mitotic rate, like pseudomyxoma peritonei [4]. Its penetration depth into tumour nodule has been estimated to be 2–5 mm [4, 42]. There is a remarkable difference in drug dosimetry among different centres, varying from 12.5–15 mg/m2 in one dose to 40 mg divided over two doses (30 mg at the start and an additional 10 mg after 60 min) and 35 mg/m2 divided over three doses (starting with 50 %, 30 min later 25 % and after 60 min 25 %) [18]. This specific administration protocol was developed in the Netherlands Cancer Institute to maintain a high concentration throughout the entire 90 min perfusion time [42].
Cisplatin
Cisplatin has been widely administered as a means of intraperitoneal chemotherapy during the last decades, mainly due to specific cytotoxicity against gastric carcinoma, ovarian carcinoma and mesothelioma, despite the fact that its pharmacokinetic profile is not as favourable as that of other chemotherapeutic agents. The mean peritoneal to plasma AUC ratio ranges from 12 to 22 in various clinical studies, while the drug’s maximal concentration as measured in intraperitoneal fluid has been shown to be 10–36 times higher than that of plasma [60]. Its substantially increased potency at higher drug concentrations and its penetration depth which is reported up to 3–5 mm makes it an attractive drug for intraperitoneal use [4, 12, 15]. Moreover, significant thermal enhancement of its activity has been shown apparently in multiple studies [4, 65]. The administered dose varies among protocols from 50 to 120 mg/m2.
Carboplatin
Another platinum compound, carboplatin, is highly effective against ovarian cancer in systemic chemotherapy. Due to its higher molecular weight than cisplatin, its pharmacokinetic profile may be slightly more favourable, although the peritoneal to plasma AUC ratio is still 15–20 in pharmacokinetic studies [4]. Its toxicity profile is better, mainly due to the absence of renal failure. In experimental studies, its thermal enhancement is observed at higher temperatures than for cisplatin, and the penetration depth of carboplatin is much less than that of cisplatin, limiting its clinical application [12, 75]. Reported doses vary from 300 to 1,000 mg/m2 or AUC of 6 to 10.
Oxaliplatin
The third-generation platinum compound oxaliplatin has, in contrast to cisplatin, a demonstrated activity in colorectal and appendiceal tumors. The low peritoneal AUC (peritoneal to plasma AUC ratio: 16) is counterbalanced by the rapid drug uptake by tumour cells until an estimated depth of 1–2 mm, while hyperthermia enhances the tissue concentration [4, 76, 77]. Moreover, its activity during HIPEC is enhanced by concurrent administration of the combination of 5-fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) intravenously [25]. This bidirectional intraoperative strategy has been innovated by the group of Elias [25, 32, 76]. Intraperitoneal chemotherapy with oxaliplatin is generally well tolerated, but the high dose of 460 mg/m2 for 30 min was related to a significant risk of postoperative haemorrhage [78]. Therefore, many centres have reduced the dose to 300–360 mg/m2.
Because oxaliplatin is unstable in solutions containing chloride, it has been diluted in a dextrose 5 % solution, which has given rise to serious electrolyte disturbances and hyperglycaemia during and after intraperitoneal chemotherapy, especially at higher temperatures [79, 80]. However, in a recent in vitro study, the usage of carrier solutions containing chloride for oxaliplatin did not significantly affect its concentrations (<10 % degradation after 30 min as well as <20 % degradation after 120 min at a temperature of 42 °C) [80]. Chloride probably promotes the formation of the active cytotoxic form of oxaliplatin and consequently could even enhance its cytotoxic effect. Using such a more physiological, chloride-containing carrier solution, only minor, clinically irrelevant electrolyte and glucose disorders were observed in a clinical study [26]. These data prove that intraperitoneal chemotherapy using oxaliplatin is safe and effective when the drug is added to a standard carrier solution shortly before intraperitoneal chemotherapy.
Irinotecan
<start>Its enhanced potency against gastrointestinal cancer, particularly when combined with 5-fluorouracil, coupled with the fact that dose intensification increases its efficacy, make the camptothecin derivate irinotecan a potentially useful agent to be tested for intraperitoneal chemotherapy [4, 81, 82]. Irinotecan is usually metabolized to its active form SN-38 by carboxylesterase in the liver. However, SN-38 has been demonstrated in the peritoneal fluid immediately after the initiation of the HIPEC procedure with irinotecan, proposing the existence of carboxylesterase in the peritoneal cavity of patients suffering from peritoneal metastases [83]. The mean peritoneal to plasma drug exposure ratio was 15 for irinotecan and 4 for its active form, SN-38 in a mouse model, respectively [84]. More importantly, the irinotecan concentration in the tumour region, bathed in the perfusate, was 16 to 23 times higher than that in non-bathed muscle tissue in a clinical study [83]. Controversy regarding the synergism between irinotecan and the application of heat exists in published experimental studies [4]. Usually a dose of 200–300 mg/m2, alone or in combination with oxaliplatin, has been used for HIPEC. Notably, the observed toxicity of HIPEC with irinotecan is high and consists mainly of haematological toxicity, lung complications and fistula [27, 85].
Doxorubicin
The anthracycline doxorubicin, an antitumour antibiotic and topoisomerase inhibitor, suggests an attractive agent for intraperitoneal use, due to its certain efficacy in ovarian, pancreas and gastric carcinoma, mesothelioma and sarcoma, its concentration-response relation and its highly favourable pharmacokinetics (peritoneal to plasma AUC ratio: 162–230) [4]. While in a mouse ovarian cancer model, the depth of doxorubicin penetration after intraperitoneal application has been assessed to be just 4–6 cell layers [10], doxorubicin concentration in tumour tissue was consistently found increased relative to the corresponding intraperitoneal drug’s concentration in a clinical study [86]. The mechanism of this sequestration phenomenon remains unknown. In most studies, doxorubicin exhibits thermal enhancement. With a dose of 15–35 mg/m2, a limited toxicity has been observed.
In some centres, pegylated liposomal doxorubicin has been used for intraperitoneal administration because of its more favourable pharmacokinetics (peritoneal to plasma AUC ratio: ≥1,100) and higher uptake in tumour nodules [4, 87, 88]. In in vitro and in vivo studies on liposome-encapsulated doxorubicin, hyperthermia increased the drug’s release, rose tumour uptake of liposome-encapsulated adriamycin but not of free doxorubicin and improved its antitumour activity [4, 89]. The reported dose varies from 40 to 100 mg/m2. The observed toxicity is acceptable, with lower systemic adverse effects than standard doxorubicin, similar to what is observed in systemic chemotherapy.
5-Fluorouracil
One of the traditionally applied agents for intraperitoneal treatment of cancers of the gastrointestinal tract is 5-fluorouracil. Mostly because of its advantageous pharmacokinetic profile (peritoneal to plasma AUC ratio: 400), 5-fluorouracil is frequently utilized as a means of EPIC [4, 69]. In a rat model, its penetration depth has to be estimated to be approximately 0.5 mm [16]. Because it is an antimetabolite and requires prolonged exposure to the malignant cells, it is not suitable for intraperitoneal administration during HIPEC. However, due to its synergistic effect with oxaliplatin [25], 5-fluoruracil is often administered intravenously during HIPEC with oxaliplatin, as discussed above. The thermal enhancement of its efficacy is limited at the temperatures usually applied during HIPEC [65]. The common dose for EPIC is 650 mg/m2, while its toxicity is acceptable [69, 90].
Gemcitabine
Gemcitabine has proven efficacy against a broad spectrum of malignancies, especially pancreatic and ovarian cancer. In in vitro studies, increased drug exposure has been related to a higher degree of cytotoxicity [91]. The mean peritoneal versus plasma AUC ratio for the drug after intraperitoneal application was only 13–27 in a rat model [92], whereas in cancer patients, mean AUC ratios of 791 and 847, respectively, have been estimated [93, 94]. Higher concentrations have been achieved intra-abdominally under hyperthermic, rather than under normothermic conditions using a rat model [92]. Contradictory results considering the synergistic effect of gemcitabine and hyperthermia have been reported [4]. Being an antimetabolite, it can be less attractive for intraoperative than for postoperative intraperitoneal chemotherapy. Doses of 50–500 mg/m2 have been advocated for postoperative intraperitoneal chemotherapy and were associated with low toxicity [93, 94, 95]. Preliminary results demonstrated that HIPEC with 1,000 mg/m2 for 60 min as adjuvant treatment after curative excision of pancreatic carcinoma is well tolerated [96].
Paclitaxel
The taxanes paclitaxel and docetaxel are effective against ovarian cancer, gastric cancer and mesothelioma. Even in platinum-resistant ovarian cancer, both drugs appear to be active agents. Paclitaxel seems to be a fascinating drug for intraperitoneal chemotherapy because of its highly favourable pharmacokinetic profile (peritoneal to plasma AUC ratio: 550–2,300) due to its large molecular weight that delays absorption from the abdominal cavity [97, 98, 99]. As response to taxanes appears to be dose dependent for systemic chemotherapy, increased activity is to be expected during intraperitoneal chemotherapy [4]. Disadvantages are the limited, or even absent, thermal enhancement. Although in an in vitro model paclitaxel penetrated around 40 cell layers within 4 h and more than 80 cell layers within 24 h [100], in a clinical study the penetration depth was limited and estimated to be only 0.5 mm [101]. Intraperitoneal administration of paclitaxel has been applied intraoperatively and postoperatively. Doses from 60 to 175 mg/m2 have been reported, mostly with an acceptable toxicity profile [97, 98, 99, 102, 103].
Docetaxel
Docetaxel has been administered intraperitoneally for ovarian and gastric cancer. It has a similar favourable pharmacokinetic profile as paclitaxel, with its peritoneal to plasma AUC ratio being 150–3,000. Its thermal enhancement is limited, while the penetration depth is estimated to be 1.5 mm [97, 98, 104]. Using doses of 45–125 mg/m2, 40 mg as well as 60 mg/m2/L, the toxicity is acceptable in intraoperative and postoperative intraperitoneal chemotherapy. Yonemura [28, 105] has advocated a bidirectional neoadjuvant drug regimen for gastric cancer with peritoneal disease, including 20 mg/m2 docetaxel and 30 mg/m2 cisplatin intraperitoneally and 60 mg/m2 S-1 per os.
Premetrexed
Premetrexed is a novel promising drug for intraperitoneal chemotherapy in malignant peritoneal mesothelioma because of its high efficacy against mesothelioma in systemic treatment and its beneficial pharmacokinetics (peritoneal to plasma AUC ratio: 70) [29]. In animal model, hyperthermia increased the drug absorption by the tumour cells [106]. It has been used in postoperative bidirectional chemotherapy after cytoreductive surgery and HIPEC for malignant peritoneal mesothelioma [29]. The combination of intraperitoneal administration of 500 mg/m2 premetrexed with intravenous administration of 50 mg/m2 cisplatin was associated with low morbidity [29].
Melphalan
Melphalan, an alkylating agent, is an excellent salvage drug for HIPEC protocols due to its favourable pharmacokinetic profile (peritoneal to plasma AUC ratio: 17–63) and tissue distributions combined with its remarkable synergistic effect with heat and cytotoxicity against a wide range of malignancies, including colorectal and appendiceal malignancies [4, 18, 65, 107]. The usual dose is 60–70 mg/m2, which is well tolerable.
Ifosfamide
Ifosfamide is effective against ovarian cancer, mesothelioma and sarcoma. Whereas ifosfamide is not suitable for intraperitoneal use due to the need for activation in the liver, it is a very attractive agent for intravenous administration during HIPEC because of the remarkable enhancement of its efficacy in hyperthermic conditions [4, 18, 65, 108]. It has been administered intravenously during HIPEC with cisplatin and doxorubicin for different peritoneal surface malignancies [108].
Comparative clinical studies
Direct comparison between intraperitoneal chemotherapy drug regimens is very sparse. In contradiction to in systemic chemotherapy, randomized clinical trials comparing different drug regimen for intraperitoneal chemotherapy are lacking. Moreover, the available comparative retrospective clinical studies are limited in number and contain usually a relatively small number of patients.
Oxaliplatin versus mitomycin C
In one study [109] that compared data from two centres, no apparent advantage in outcome for HIPEC using oxaliplatin or mitomycin C could be shown in patients with peritoneal metastases originating from colorectal malignancy. In a multicenter comparative study [110], data suggested that mitomycin C may potentially suggest a better agent for HIPEC compared with oxaliplatin in colorectal cancer patients with favourable histology and low disease burden. In patients with higher tumour burden before cytoreductive surgery, unfavourable histology and/or severe symptomatology, a non-significant better overall survival was found after HIPEC with oxaliplatin. A most recent single-centre retrospective study [111] demonstrated a significantly improved survival for patients suffering from colorectal or appendiceal peritoneal metastases treated with HIPEC using oxaliplatin when compared with those who underwent HIPEC with mitomycin C. Subgroup analysis demonstrated that this superior efficacy of oxaliplatin was observed only for patients not older than 65 years, female patients, well and moderate differentiated tumours, absence of signet ring cells and a moderate initial tumour burden (peritoneal cancer index 10–15). Therefore, prospective studies which stratify patients by age, gender, their initial tumour burden, histology and severity of symptoms and randomize them to HIPEC with mitomycin C versus oxaliplatin are warranted.
In a retrospective study on HIPEC for peritoneal metastases from colorectal or appendiceal origin, the haematological toxicity profile of oxaliplatin-based HIPEC was compared with that of mitomycin C-based HIPEC [112]. Oxaliplatin-based HIPEC was associated with higher platelet and neutrophil toxicity, while the white blood cell count was similar for both drugs.
Oxaliplatin versus irinotecan
In a retrospective analysis [27], bidirectional oxaliplatin-based and bidirectional irinotecan-based HIPEC had similar morbidity and toxicity rates in patients demonstrating peritoneal metastases from appendiceal and colorectal carcinomas, while oxaliplatin-based HIPEC was related to a small tendency towards improved survival. In a French study [113], the addition of irinotecan to oxaliplatin in HIPEC applied for the treatment of colorectal peritoneal metastases was related to higher morbidity and did not result in increased survival.
Paclitaxel versus carboplatin
In one non-randomized South Korean study on HIPEC during secondary surgery for ovarian cancer [102], no significant difference in outcome between the application of carboplatin or paclitaxel had been noted. Also in a second, Spanish, comparative study, no difference in the efficacy of these drugs could be demonstrated [103].
Patient-tailored drug choice
The above-mentioned pharmacokinetic and pharmacodynamic characteristics of the specific chemotherapeutic agent, as well as comparative clinical studies, do not constitute the sole determinant of the efficacy of intraperitoneal chemotherapy regimens. Ultimately, individual drug sensitivity of a tumour may be noteworthy to the same extent. Existing evidence supports a heterogeneous response of cytotoxic agents in peritoneal metastases samples in a variety of tumours [114]. Hence, drug choice depending on in vitro drug sensitivity testing may result in improved clinical outcome after HIPEC. Recently, low expression of Bloom syndrome protein in colorectal cancer cell lines was associated with high sensitivity to heated intraperitoneally administered mitomycin C and in peritoneal metastases of colorectal cancer patients with improved survival [115]. To date, however, there are no prospective studies demonstrating an improved clinical outcome from drug selection relying on in vitro drug sensitivity testing.
Conclusions
There is a definite rationale for perioperative intraperitoneal chemotherapy in patients with primary as well as secondary peritoneal malignancies. Intraperitoneally administered chemotherapy is related to a significant pharmacokinetic and pharmacodynamic advantage. Hyperthermia may enhance the efficacy of many chemotherapeutic drugs. The drugs and their doses that are used in perioperative intraperitoneal chemotherapy vary widely among centres. While many parameters of intraperitoneal chemotherapy treatment has not yet been standardized, adequate drug choice is essential. While the adequate drug choice for intraperitoneal and bidirectional chemotherapy is essential, randomized clinical trials to determine the most optimal drug or drug combination are lacking, and only eight retrospective comparative clinical studies are available. Hence, to date, the level of evidence of pharmacological studies on drug choice and doses in intraperitoneal chemotherapy is considerably low. Further clinical pharmacological studies are required to determine the most effective drug regimen for intraperitoneal and bidirectional chemotherapy in various indications. In the future, reliable drug sensitivity testing and genetic profiling of peritoneal metastases will be needed for enabling patient-specific therapy.
Author contributions: All the authors have accepted responsibility for the whole content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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