Good morning, my name is Dr. Robert Edwards and I’m going to be discussing peritoneal therapy in the treatment of women with ovarian cancer. 

Ovarian cancer is the sixth most common gynecologic malignancy, the fourth most common cause of death for women overall in the United States.  It accounts for 4% of all cancers in women and it’s estimated to cause around 24,000 causes a year, and about 14,000 deaths a year.  Lifetime risk of developing ovarian cancer is 1 to 2%. 

As you can see, ovarian cancer starts in the ovary and surrounding adnexal tissue including the tube and surrounding ovarian peritoneum but it quickly disseminates in very patho-pneumonic metastatic pattern around the peritoneal cavity. The spread of disease tends to be an encasing spread and not an invasive spread, and therefore it makes it fairly amenable to local regional treatment.  It’s estimated that only overall about 40% of women receive the appropriate recommended staging procedures and treatment for their ovarian cancer. And most of those deficiencies are in the surgical staging of the disease, about 10% of women are correctly staged for stage 1 disease, and for stage 3 disease most of the inappropriateness of the treatment has to do more with inappropriate management, improper surgery or not implementing systemic chemotherapy in the correct timeframe after the surgery.

The disease spreads into the peritoneal cavity as we said in the majority of patients and we are able to induce regression for this cancer in 75 to 80% of women.  Unfortunately there is no measure after the primary chemotherapy that’s felt to improve the overall cure rate, and eventually most women with this disease, upwards of 70% will eventually recur of their cancer, and about 25% of women will eventually succumb to their cancer.

Gynecologic oncologists or specialists trained in both aspects of surgery, particularly aggressive cytoreduction as well as in chemotherapy approaches, and do a 3 year fellowship, sometimes a 4 year fellowship, they exclusively treat women with cancers of the female genital tract and it has been shown in high volume centers, particularly  high volume centers that have gynecologic oncologists as part of their group that the outcomes for women treated with ovarian cancer are over 50% improved.

Proven factors of determined outcome are correct surgical staging with an optimal surgical effort that usually means an aggressive surgery more than primary hysterectomy, chemotherapy with platinum based agents again administered in the correct fashion, within the correct schedule after surgery and monitoring progress with frequent evaluations while the patients are under both postoperative care and the initiation surgical therapy.  The combination of these factors is felt to be a – the cause for the increased outcomes seen with this disease as most of the overall measures that affect survival occur with the initial treatment evaluation of the patient.

First line treatment is standard to perform a maximal cytoreduction surgery.  These surgeries can be anywhere from 2 hours up to 7 or 8 hours in length. They usually involve removing the uterus tubes and ovaries often with removal of upper abdominal disease including reflection and stripping of the diaphragm, removal of the spleen on occasion, sometimes doing surgery in the lesser sac and resections of the small and large bowel, even the stomach. 

Hoskins reported in 1994 the results of a metaanalysis from GOG trials showing that for small volume disease left at the end of surgery patients did much better. This has been confirmed by a number of single institutional trials as well as the metaanalysis performed by Bristow and colleagues which was reported by Bristow and Chi in 2002.  Most thought leaders and centers that treat a great deal of ovarian cancer now implement aggressive surgical approaches as part of their armamentarium. 

The more effective the surgery, and the more complete the surgical resection the better patients do.  This usually requires on block resection of uterus, tubes and ovaries and sometimes the sigmoid colon.  A complete omentectomy, not just an omental biopsy, selective lymph adenectomy, and that is performed to remove enlarged lymph nodes, bowel resection is often required as well as the other procedures that we mentioned.

The theory of peritoneal therapy takes advantage of the same effects that you see with the aggressive surgery, that is infusing the cytotoxic chemotherapy directly into the abdominal cavity, by applying the chemotherapy directly into the abdominal cavity you are able to increase the relative concentration of drugs to tumor, reduce the relative concentration of drug in the systemic circulation and therefore have increase in tumor kill with each consecutive treatment.  Because the tumor spreads by an exfoliative we refer to it with patients as a snow globe phenomenon, the peritoneal infusions perfuse all the surfaces and you are able to get much better exposure, penetration and tumor regression with this approach.

There are disadvantages to peritoneal therapy, it requires a second catheter, portions of these therapies are always given systemically and portions are given peritoneally, they are divided in various regimens and approaches, that’s what you’ll see in a minute, but the local symptoms can vary widely depending on the experience of the center providing the peritoneal therapy. 

The concentration as we stated has a very high drug concentration legal regionally, reduced concentration in systemic circulation, this is somewhat a product of the particular chemotherapy being given, Cisplatinum and Carboplatin are relatively small molecules, they do diffuse across the peritoneal cavity rather quickly, you can get very significant systemic levels within 24 hours of the infusion.  Paclitaxel is a very large aliphatic molecule that’s for Taxol is attached to a Cremophor and therefore has a slow absorption, has minimal systemic levels and the half life of the Paclitaxel is over 24 hours in the peritoneal cavity.  You see various toxicities related to single fact, Cisplatinum based infusions are problematic for causing increased risk of nausea and that’s likely due to systemic concentration levels but also increased possibility of electrolyte disturbances and distal renal tubule damage.  Paclitaxel rarely causes systemic symptoms and is usually associated with a bit more of an inflammatory reaction with the peritoneal infusion.

There have been a number of drugs tested through the years with various mouse models in human cancer cell studies, that include Doxorubicin, Methotrexate, the various taxanes, the various antibiotic based approaches, and there’s a long-standing tradition of using either a platinum or a Paclitaxel or a taxane or an antibiotic based infusion in the peritoneal cavity studies that have been done to date.

Concerns with IP therapy over local toxicity of the antineoplastic agent, complexity of the treatment, poor distribution if there are significant adhesions, limited drug penetration with each perfusion are often used by critics to point out the, the deficiencies in peritoneal therapy.  As you will see the studies are the studies and there are three randomized trials which speak to the point that consecutive infusion, prolonged infusion, repetitive infusion seems to produce improved overall cancer outcomes.

As we study there have been three gynecological oncology group cooperative group trials, each has been positive, each has – and they have used various recipes of intraperitoneal therapy.  The consistent findings for all three trials was progression free survival was improved when therapy was given intraperitoneally as compared to intravenously, the overall survival was also improved, particularly in the last trial which was GOG 172 which we’ll discuss in more depth. 

I want to go through the trials because it’s important to understand the cooperative group system and the various cooperative group trials so you understand why there is still some level of confusion and controversy over the use of peritoneal therapy.  Gynecologic oncology phase III trials have been focused on optimally resected disease. This definition has changed between the first trial GOG 104 and the second trial, GOG 114 from 2 centimeters to 1 centimeter. So larger volume disease was treated in the first trial but in fact the survival advantage was even with larger volume disease was maintained in the initial GOG trial reported by Alberts in New England Journal in 2005.  I’m sorry, in 1995. 

This first GOG trial was shown the schematic, you can see the Cisplatinum dose was 100 mg/m² in the intraperitoneal arm, the intravenous arm also had the exact same dose of Cisplatinum, this trial was actually the purest trial of the 3 gynecologic oncology group trials evaluating the effect of peritoneal therapy.  That is because the drug doses of intraperitoneal treatment were the exact same when they were given intravenously or intraperitoneally.  It’s interesting in the study while nausea was significant in an identical proportion of patients completed the intraperitoneal arm as completed the intravenous arm.  In fact the intraperitoneal arm had less ototoxicity and perhaps had less neuropathy symptoms, there was no report about the renal effects in this trial but it was very clear that when the dosing is the same even with Cisplatinum when it was administered intraperitoneally the toxicity is actually less.  It is when you get increased dose intensity in the peritoneal cavity as compared to the intravenous infusion that you see the increased toxicities that we see in the subsequent trials.

For first line chemotherapy with Cisplatinum in the GOG, the first GOG trial I just outlined there were 654 eligible patients, the negative second look right was 47% with the IP arm, this is the surrogate for progression free survival, the overall survival was 8 months longer. The P value on that was 0.02, suggesting that was statistically significant. This study reported by Alberts in the New England Journal in 1996. 

There are many issues that are still unresolved with peritoneal therapy and they continue – including peritoneal therapy, there are many other issues with ovarian cancer, the reason peritoneal therapy is still so controversial among all the issues we are addressing is we’ve had three different cooperative group trials with three different schedules.  And as you are going to see, the subsequent trials used different approaches other than the question of intravenous versus intraperitoneal and that is what is causing the difficulty with interpretating these three trials in 2011.

This is the follow-up survival on this trial as I previously stated.  This is the second trial GOG 114, now in this trial the approach was different because of the theoretical advantage of treating small volume disease as compared to large volume disease in this trial there was a kind of a neoadjuvant approach where infusion was initiated with Carboplatin at an AUC of 9 for two cycles and this was followed by the Cisplatinum regimen used in the first trial, 100 mg/m² in the Paclitaxel trial 135 mg intravenously. This is compared to the alternative arm which had no lead in treatment with high dose Carboplatin and had the both drugs given intravenously.  This was the standard of care at that time, with the arm on the above schedule.

There were multiple questions raised by the second trial, what was the role of the neoadjuvant therapy in producing the toxicity, which was significant. There was significant neutropenia but it wasn’t seen in the first trial GOG 104 and significant electrolyte disturbances.  In the third trial - but it also had increased survival advantages. 

In the third trial GOG 172 had a 17 month increase in overall medial survival, which is by far the best, highest value response seen in any GOG cooperative group trial. There was a 30% decreased risk of death, but there was very significant comparative toxicities compared with the first two trials, and this is likely due to the schedule and dose intensity of trial 3.  This is the schedule used in trial 3, you can see again the intravenous arm was Paclitaxel 135 mg/m² with Cisplatinum 75 mg/ m² which was considered the standard when the trial was designed in the mid-90s.  However in the experimental arm which was the peritoneal arm Paclitaxel was given 135 mg/ m² intravenously and then Cisplatinum was given at 100 mg/ m² and again this brings back the point that I had discussed earlier which is dose intensity associated with the intraperitoneal treatment, which likely led to some of the toxicity seen in the trial and again Paclitaxel is now administered for the first time intraperitoneally.  And that is given on day 8 in this regimen. So you have a patient coming in for one treatment each month in the intravenous arm but coming in for three consecutive treatments day 1, day 2 and day 8 in the experimental arm of the Armstrong GOG 172. 

However the progression free survival was increased in the IP arm, the overall survival was increased to 65.6 months, the risk of occurrence was decreased by almost 10%. Again this represents a landmark study for phase III cooperative group trials and there have been no trials to date that have matched this overall survival for optimally resected ovarian cancer.  So the 8% decrease in recurrence rate and that data has held up on long term analysis as well.  These are the survival curves, you note they do not come together in fact the overall survival curve appears to be separating and this is an interesting phenomenon as you look at this data.

The most notorious aspect of GOG 172, the Armstrong trial, reported in the New England Journal in 2006 as the lead article was the complication rate. Almost 32% of patients completed trial, a significant number of patients dropped out after only getting one or two courses of intraperitoneal therapy, so we wonder why the survival bands were so great when so few of the patients actually tolerated the treatment.  And that brings the question whether how much intraperitoneal therapy is necessary to produce a long term response. 

So there are many issues still to be defined for intraperitoneal therapy. There is a follow-up fourth peritoneal therapy trial, there was an NCI endorsement with a consensus statement released by the NCI in 2006 that followed the publication of GOG 172, the Armstrong study, in the New England Journal of Medicine.  And the current trial looks at the issue of reducing the dose intraperitoneally and then comparing that to equivalent doses in the intravenous infusion and then the presence or absence of Bevacizumab treatment which is the anti-angiogenesis, anti-VEGF target.  So there’s a lot of questions being asked in this subsequent trial but the dose reduction of intraperitoneal arm hopefully will produce similar outcomes with decreased toxicity and we’ll finally have a regimen that is employable for patients in the community setting.

The question comes to mind when you talk to a patient under peritoneal therapy what are our goals here?  We’ve already accepted the fact that aggressive cytoreductive surgery is important and necessary no matter what the mobility may be, if we can get the patient through this primary surgery and get them started on treatment they do better.  The morbidity seems to be acceptable in high volume centers and ovarian cancer does not appear to be pancreas cancer or colon cancer where aggressive cytoreduction may not have as high an impact.  So if we are going to pursue aggressive cytoreductive surgery we should also be at least considering in our younger patients offering them intraperitoneal treatment. And I believe that with dose modification these treatments can be given in the community setting and can have a major impact for women with ovarian cancer.