Arch Gynecol Obstet DOI 10.1007/s00404-014-3252-2
Review
Intraperitoneal chemotherapy in advanced epithelial ovarian cancer: a survey Giuseppe Grosso · Diego Rossetti · Federico Coccolini · Giorgio Bogani · Luca Ansaloni · Luigi Frigerio
Received: 4 December 2013 / Accepted: 9 April 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Introduction Intraperitoneal chemotherapy preceded by cytoreductive surgery should be the standard of care in the treatment of advanced epithelial ovarian cancer. This combination has been extensively examined in both the clinical and preclinical settings with favourable oncologic outcomes. Unfortunately, despite the existence of these evidence-based data, this management strategy remains underutilised. Materials and methods We review and discuss the role of intraperitoneal chemotherapy with particular emphasis about the pharmacokinetics and pharmacodynamics aspects, the mode of administration, the reported side effects, the compliance of the patients and the clinical ongoing studies. Conclusions Further studies investigating the pharmacokinetics and pharmacodynamics aspect of IP route may help to reduce toxicity pending more effective treatments. Keywords Intraperitoneal chemotherapy · Advanced ovarian cancer · Cytoreductive surgery · HIPEC
G. Grosso · D. Rossetti (*) · L. Frigerio Department of Gynecology and Obstetrics, Papa Giovanni XXIII Hospital, Piazza OMS 1, Bergamo, Italy e-mail: [email protected] F. Coccolini · L. Ansaloni Department of Surgery, Papa Giovanni XXIII Hospital, Bergamo, Italy G. Bogani Department of Obstetrics and Gynecology, University of Insubria, Del Ponte Hospital, Varese, Italy
Introduction Epithelial ovarian cancer (EOC) constitutes the second most common gynaecological tumour in terms of frequency, but it represents the main cause of death [1]. Whilst patients with early-stage disease need to undergo an adequate surgical staging to make a prognosis and to be selected for adjuvant chemotherapy (AT) [2], in an advanced stage of the disease, primary cytoreductive surgery plays an important role [3]. The goal of such extensive surgery is to reduce the amount of tumour as much as possible in the abdominal cavity [4]. Thus, the main treatment for advanced disease is a combination of surgical removal of all resectable disease followed by intravenous (IV) chemotherapy, including a platinum compound with taxane [5]. Recent trials suggest that the patients in whom it has been possible to achieve an optimal cytoreductive surgery (CRS) could be suitable candidates for IV and intraperitoneal (IP) treatments [6–14]. The use of localised treatment, such as intraperitoneal chemotherapy, is absolutely intuitive and not new [15, 16]. First, in the 1950s, Weisberger injected nitrogen mustard directly into the peritoneal cavity to treat malignant ascites with the objective of killing cancer cells [16]. Unfortunately, there was no evidence that the procedure was effective, so it was abandoned. Other than one study conducted by Rutledge et al. [17] in 1966 in which a large volume of intraperitoneal fluid was used during a second-look laparotomy, this technique has been virtually ignored until 1978, when Dedrick et al. [18] published in “The Cancer Treatment Reports”, a pharmacokinetic rationale for IP chemotherapy in the treatment of epithelial ovarian cancer (EOC), based on the dose-intensification provided by the peritoneal plasma barrier. They assumed that the drug delivered directly into the peritoneal cavity moves slowly into the
13
systemic circulation, allowing doses 20 times higher that could be tolerated in the blood. Another theoretical advantage of IP chemotherapy is in the possibility that high local drug concentrations, overcoming the drug resistance of the cells, may penetrate directly into small tumour nodules, maximising the destruction of cancer cells and at the same time minimising the systemic toxic effect of the chemotherapeutic drugs [18]. In the same year, biomedical engineers, pharmacologist, and clinicians at NCI of Bethesda co-operated in the development of this concept, and using mathematical pharmacokinetic modelling and toxicological studies on rats, a phase I trial of IP methotrexate, administered in large volumes of dialysis fluid, was initiated. Results in three patients confirmed the practicability of this approach [19]. These key reports reawakened interest and this led to several phase I and II trials to study these concerns in the following 1980s [20–23].
Pharmacokinetic principles of IP chemotherapy EOC is generally spread into the peritoneal cavity [24]. The ovary is a freestanding organ within the abdomen, allowing for sloughed EOC cells to disperse widely. Cancer cells seed peritoneal cavity by moving in the circulation of the peritoneal fluid, initially reaching the beginning of the more proximal surfaces, and progressively those more distant from their origin, but without going past the superficial layer of the peritoneal cavity. This type of metastatic spread, defined as a locally advanced spread, makes EOC more suitable for IP treatment. However, the destructive effect of the chemotherapeutic agents is partially erased by the fact that clusters of cancer cells, after having found a place, form nodules of various dimension (from
Review
Intraperitoneal chemotherapy in advanced epithelial ovarian cancer: a survey Giuseppe Grosso · Diego Rossetti · Federico Coccolini · Giorgio Bogani · Luca Ansaloni · Luigi Frigerio
Received: 4 December 2013 / Accepted: 9 April 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Introduction Intraperitoneal chemotherapy preceded by cytoreductive surgery should be the standard of care in the treatment of advanced epithelial ovarian cancer. This combination has been extensively examined in both the clinical and preclinical settings with favourable oncologic outcomes. Unfortunately, despite the existence of these evidence-based data, this management strategy remains underutilised. Materials and methods We review and discuss the role of intraperitoneal chemotherapy with particular emphasis about the pharmacokinetics and pharmacodynamics aspects, the mode of administration, the reported side effects, the compliance of the patients and the clinical ongoing studies. Conclusions Further studies investigating the pharmacokinetics and pharmacodynamics aspect of IP route may help to reduce toxicity pending more effective treatments. Keywords Intraperitoneal chemotherapy · Advanced ovarian cancer · Cytoreductive surgery · HIPEC
G. Grosso · D. Rossetti (*) · L. Frigerio Department of Gynecology and Obstetrics, Papa Giovanni XXIII Hospital, Piazza OMS 1, Bergamo, Italy e-mail: [email protected] F. Coccolini · L. Ansaloni Department of Surgery, Papa Giovanni XXIII Hospital, Bergamo, Italy G. Bogani Department of Obstetrics and Gynecology, University of Insubria, Del Ponte Hospital, Varese, Italy
Introduction Epithelial ovarian cancer (EOC) constitutes the second most common gynaecological tumour in terms of frequency, but it represents the main cause of death [1]. Whilst patients with early-stage disease need to undergo an adequate surgical staging to make a prognosis and to be selected for adjuvant chemotherapy (AT) [2], in an advanced stage of the disease, primary cytoreductive surgery plays an important role [3]. The goal of such extensive surgery is to reduce the amount of tumour as much as possible in the abdominal cavity [4]. Thus, the main treatment for advanced disease is a combination of surgical removal of all resectable disease followed by intravenous (IV) chemotherapy, including a platinum compound with taxane [5]. Recent trials suggest that the patients in whom it has been possible to achieve an optimal cytoreductive surgery (CRS) could be suitable candidates for IV and intraperitoneal (IP) treatments [6–14]. The use of localised treatment, such as intraperitoneal chemotherapy, is absolutely intuitive and not new [15, 16]. First, in the 1950s, Weisberger injected nitrogen mustard directly into the peritoneal cavity to treat malignant ascites with the objective of killing cancer cells [16]. Unfortunately, there was no evidence that the procedure was effective, so it was abandoned. Other than one study conducted by Rutledge et al. [17] in 1966 in which a large volume of intraperitoneal fluid was used during a second-look laparotomy, this technique has been virtually ignored until 1978, when Dedrick et al. [18] published in “The Cancer Treatment Reports”, a pharmacokinetic rationale for IP chemotherapy in the treatment of epithelial ovarian cancer (EOC), based on the dose-intensification provided by the peritoneal plasma barrier. They assumed that the drug delivered directly into the peritoneal cavity moves slowly into the
13
systemic circulation, allowing doses 20 times higher that could be tolerated in the blood. Another theoretical advantage of IP chemotherapy is in the possibility that high local drug concentrations, overcoming the drug resistance of the cells, may penetrate directly into small tumour nodules, maximising the destruction of cancer cells and at the same time minimising the systemic toxic effect of the chemotherapeutic drugs [18]. In the same year, biomedical engineers, pharmacologist, and clinicians at NCI of Bethesda co-operated in the development of this concept, and using mathematical pharmacokinetic modelling and toxicological studies on rats, a phase I trial of IP methotrexate, administered in large volumes of dialysis fluid, was initiated. Results in three patients confirmed the practicability of this approach [19]. These key reports reawakened interest and this led to several phase I and II trials to study these concerns in the following 1980s [20–23].
Pharmacokinetic principles of IP chemotherapy EOC is generally spread into the peritoneal cavity [24]. The ovary is a freestanding organ within the abdomen, allowing for sloughed EOC cells to disperse widely. Cancer cells seed peritoneal cavity by moving in the circulation of the peritoneal fluid, initially reaching the beginning of the more proximal surfaces, and progressively those more distant from their origin, but without going past the superficial layer of the peritoneal cavity. This type of metastatic spread, defined as a locally advanced spread, makes EOC more suitable for IP treatment. However, the destructive effect of the chemotherapeutic agents is partially erased by the fact that clusters of cancer cells, after having found a place, form nodules of various dimension (from
