We know that postoperative adhesions limit the availability and distribution of intraperitoneal chemotherapeutic agents to all areas of peritoneal cavity. It has also been shown that fibrin traps tumor cells and these cells in return become protected from any form of chemotherapy. Still the data on early postoperative intraperitoneal chemotherapy shows improvement in outcomes, especially for ovarian cancer. What is the mechanism of effectiveness if we know the drug is not evenly distributed in the peritoneal cavity and is likely not reaching all tumor cells.
I assume you are referring to HIPEC heated intra peritoneal chemotherapy where the peritoneal cavity is perfused with a chemotherapeutic agent heated to about 42 C. A number of agents are used including Mitomycin C, Carboplatin or Oxaliplatin. This is done immediately following aggressive surgical cytoreduction of visible tumor. While there is controversy over the exact mechanism its thought that heating increases the rate and depth of absorption of the agent. Besides ovarian cancer as you mentioned it is used frequently for peritoneal mesothelioma and for Pseudomyxoma peritonei (PMP). In PMP there is a large production of mucinous ascites (MUC-2) tumor cells certainly get trapped in the mucin but most of this is removed during cytoreduction. This procedure increases overall survival substantially for both PMP and mesothelioma. Since the drugs are perfused in a fairly large volume (3L) most cells will be exposed though obviously some patients will recur at a later time.
Thank you Peter for your response.
Although my question was regarding early postoperative chemotherapy, it was with the context of HIPEC in mind since intraoperative chemotherapy allows a more thorough distribution of the cytotoxic drug in all regions of peritoneal cavity before adhesions are formed.
Early postoperative therapy does not usually involve hyperthermia, but it is given after at least a week of surgery. Adhesions should start forming which limit delivery of drugs to certain areas within the peritoneal cavity. However, oncological outcomes reported at least for ovarian cancer seem to favor EPIC. I was wondering what is the mechanism by which this intraperitoneal chemotherapy works.
Perhaps there is an aspect that we have yet to learn about behavior of intraperitoneal/cancers therapy.
Actually intraperitoneal chemotherapy Is well studied in both animal models and clinical setting. Normothermic intraperitoneal chemotherapy works because of the achieved intraperitoneal concentrations of the drugs. Look at the pharmacokinetics of the different cytotoxic agents – AUC for intraperitoneal application is between tens and hundreds times higher compared to i.v. administration. Of course every next IP application is expected to be less effective due to adhesion formation, but in clinical setting there is evidence from RCTs that even normothermic intraperitoneal chemotherapy adds a statistically significant survival advantage for ovarian cancer pts. EPIC is usually discussed as complementary to HIPEC and the attempts are to start it as early as possible before the adhesion formation – i.e. on POD2-3. However its beneficial effect is less proven and surely EPIC is not considered as effective treatment option as a sole procedure without CRS+HIPEC.
You are wellcome Raza. Just for example - see at the attached table the peritoneal/plasma concentrations (midle row) as well as peritoneal/plasma AUC (right row) of some chemotherapeutic drugs in normothermic IP application.