So by 2006 our standard of care has changed in regard to the two regimens that are acceptable. I personally think that there are two regimens that are reasonable. You could add a third. The two that most people would mention would be Taxol as a 24-hour infusion at a dose of 135 per meter square followed by cisplatin at 75 per meter square, as tested in GOG111. Or Taxol 175 per meter square over three hours followed by carboplatin, dosed to an AUC of 4-5 based on the best evidence that we have. Some would add also a third arm, a 24-hour infusion of Taxol at 135 per meter square followed by carboplatin dosed to an AUC of 4-5. Those would be reasonable approaches to the treatment of ovarian carcinoma at the present time, for advanced disease.

Now let’s look briefly at limited disease, stage I or stage II disease. The way we approach this disease really is to divide the patient population into two groups; a low risk group and a high risk group. These are the current GOG definitions of these two groups; patients at low risk are those who have all of the following features: grade I disease that is intracystic in nature. That is, it is contained within the substance of the ovary, there is no tumor on the surface of the ovary, so that one way you might picture it is that the tumor does not have access to the peritoneal cavity to seed. There is no evidence of disease outside of the ovary. In other words, this is not a stage II patient. Peritoneal cytology is negative and there is no ascites. If all of these features is present that patient will be at low risk for recurrence. Patients are at high risk for recurrence if any one of these features is present: grade II or grade III disease, extracystic disease – that is, disease on the surface of the ovary so it has access to the peritoneal cavity – disease outside the ovary, stage II disease, positive peritoneal cytology or ascites. If any one of those factors is present that patient will be at high risk for recurrence and their approximate relapse rate will be 40%. Quite high. For the low risk group the approximate relapse rate will be 10%.

Now how do we manage these? Well, the best evidence we have to date comes from an Italian trial run by the GCOG group where they looked at three groups of patients. One group they labeled low risk, and uses the exact definitions that I just gave you – that is grade I disease, intracystic, no ascites, no peritoneal cytology and no extra-ovarian disease. Group number two were deemed to be at what they called intermediate risk, and this increased risk was associated with either grade II or grade III disease. That was the only reason for putting these patients into a higher risk group. And in the third group, patients were at higher risk because of one of the other factors we talked about, either ascites, positive peritoneal cytology, extra-ovarian disease or disease on the surface of the ovary. In the first of these groups, those at low risk, they simply observed these patients. They had 92 patients on study, at a median follow-up of 45 months there have been five relapses. The five year disease-free survival is 90%, the five years overall survival is 92% and with continued follow-up there have been virtually no relapses beyond this point. So it would appear that with just simple observation you are going to have a cure rate of 90% or better. For that reason our standard of care in this group of patients is no further therapy.

What about carboplatin? There have been three trials internationally looking at carboplatin. A British study comparing AUC6 to AUC12. A Danish study comparing AUC4 to AUC8 and an Austrian study comparing cisplatin to a combination of cisplatin plus carboplatin. Again, no advantages to increasing the dose intensity of the platinum compound by escalation of carboplatin dose or by its addition to cisplatin. So it would appear, based on this, there is no reason to go above an AUC of 4 with carboplatin.

What about Taxol? Well Bristol-Meyers Squibb funded Johns Hopkins to do a metaanalysis of the first five phase II trials of Taxol in ovarian carcinoma. That was presented in 2006 at ASCO by Eric Lewinsky. What that showed was that there was an improved response rate with an increasing dose of Taxol up to a dose of 175 mg per meter square every three weeks. Beyond that there was actually a decrement in response for each additional 10 mg per meter square increase. We’ve had two randomized trials looking at this issue, one comparing Taxol 135 per meter square to Taxol 175 per meter square; 15% response rate with 135, 20% response rate with 175, not significantly different. Then another study comparing 175 to 250, a GOG trial, with response rate going from 27.5% at 175 to 36% at 250. No difference in progression-free survival and no difference in overall survival. If there is a dose-response relationship with Taxol, the slope of that curve is not steep at all but the slope of the toxicity curve is dramatic. So the best evidence we have today would appear to suggest that there is no reason to go beyond 175 mg per meter square of Taxol. So these would represent reasonable dose levels for these three drugs. You may want to ask, “Well, gee, why did you put 60-70 per meter square and why did you put AUC 4-5 when you’ve shown evidence for 60 and 4?” Well, it’s that little bit in me that got trained that said more is better. I just can’t let go of it. And neither can anybody else. So the data suggests that we certainly don’t need to go to higher levels than these because all we do with that is increase toxicity.

What about Taxol schedule? We really don’t have hard data on a lot of this yet but I think that what we do know about Taxol schedule is the longer the infusion the greater the myelosuppression. The shorter the infusion the greater the non-hematologic toxicity. In fact with the longer infusions you don’t see cumulative toxicity with Taxol but with the shorter infusions you do see cumulative non-hematologic toxicity. The optimal schedule is not known. Either a three or 24-hour infusion is preferred right now because we have a lot of data on those. As of yet we don’t have any conclusive proof that a weekly one hour schedule is acceptable, although I know that a lot of you probably use that. And as of yet we don’t have much in the way of data in a 96-hour infusion, which is actually being tested in a randomized phase III trial now. Because, at least in breast cancer, there are some reasons to believe that a more prolonged infusion might be better and the preclinical data supports that. But right now either the three or 24-hour infusion, either one, would be a reasonable approach to the use of Taxol in ovarian carcinoma.

Now after you have completed the exploratory laparotomy you can stage the patient in more detail. This is the more detailed FIGO staging system for stage III and stage IV disease. What we’ve added here is a subdivision of stage III disease according to volume of residual disease; IIIa, those with microscopic disease only outside the pelvis, IIIb, macroscopic disease outside the pelvis but no nodule bigger than 2 cm in diameter, IIIc, nodules bigger than 2 cm in diameter outside the pelvis, or involvement of the retroperitoneal or inguinal nodes. The staging system refers to disease as it appears when the belly is open before the surgeon operates. The way we actually look at this disease clinically is to divide these patients into two groups; those who finish surgery with small volume residual disease – no nodule bigger than 2 cm remaining – and those who finish surgery with bulkier disease. According to the SERE in the United States, roughly 40% of all advanced disease patients will have small volume residual disease, about 60% will have large volume residual disease. But if you look just at the patients included in GOG studies, roughly 70% of the patients in surgery with small volume residual disease, 30% with bulky disease. I think it indicates the difference in having a gynecologic oncologist perform the surgery.
As of 1990 the standard of care for patients with bulky disease was a maximum attempt at cyto-reduction followed by chemotherapy. The standards at that time were Cytoxan/cisplatin or Cytoxan/carboplatin. What we want to look at is what has been done in the last nine years, in particular the last one to two years. There have been three themes that have dominated clinical research during the last decade. The integration of Taxol in to front line therapy, the choice of a platinum compound and the optimum dose of schedule of the drugs that need to be used. With regard to the first of these, the introduction of Taxol into front line therapy; there have now been four major randomized trials completed and reported. The most recent in May of this year at ASCO. GOG protocol 111, EORTC NCIC OV10, GOG protocol 132 and ICON-3. We want to look very briefly at each of these four.

GOG protocol 111 was the first of the studies to be published. This was published in the January 4, 2006 issue of the New England Journal of Medicine. This study took patients with large volume advanced disease, randomized them to receive either Cytoxan/cisplatin or Taxol as a 24 hour infusion followed by cisplatin with each regimen being given every three weeks for a total of six cycles of therapy. If you read the publication you know that in regard to the five major parameters looked at, Taxol/cisplatin was statistically superior to Cytoxan/cisplatin. Overall response rates, 73% versus 60%. Clinical complete response rate, 51% versus 31%. Percentage of patients grossly disease free at second-look laparotomy, 40% versus 24%. Median progression-free survival, 18 versus 13 months. Median overall survival 38 months versus 24 months. We now have follow-up out to nine-plus years and those differences continue to be maintained.

In 2006 at ASCO the results of the confirmatory trial was presented, this was OV10 a European/Canadian study. There are several differences in this study compared to the GOG study. Number one, patients with both large and small volume disease were included. Number two, the Taxol was given as a three hour infusion. Number three, up to nine cycles of treatment were allowed, and most patients did receive more than six. As an aside I should add that what the study also demonstrated was that you do not want to use three hour Taxol with cisplatin because there is an unacceptably high rate of significant neurotoxicity, either grade III or grade IV. That’s been demonstrated not only in this study but in two other trials that used three hour Taxol with cisplatin. What this study did was essentially reproduce the GOG study. In terms of overall response rate, Taxol/cisplatin was superior; 77% versus 66%. Clinical complete response rate, 50% versus 36%. Median progression-free survival, 16.6 versus 12 months, and median overall survival 35 versus 25 months.

Important prognostic factors in ovarian carcinoma include age, and one thing to note about age; unlike most other solid tumors, older patients with ovarian carcinoma develop more aggressive disease. The older the patient the more aggressive the tumor is likely to be. The younger the patient, the less aggressive the tumor is likely to be. The reference is a supplement to Cancer in 1992 which summarizes cooperative group data from all over the world. Stage is also an important prognostic factor and perhaps the most important prognostic factor. In fact, this will be the factor that we use to make treatment recommendations. Volume of residual disease in patients with stage III ovarian carcinoma is an important prognostic factor. In early stage disease histologic grade and, as we’ve already discussed, occasionally histologic type is an important prognostic factor. There are beginning to be some molecular biological factors identified as predictive of a poor outcome. Most important prognostic factor though is the FIGO stage, which is shown in abbreviated form here on this slide. Stage I disease is disease confined to the ovaries. This accounts for about 20% of ovarian carcinoma. Stage II disease is disease outside the ovaries but confined to the pelvis and accounts for about 5% of ovarian carcinoma. So roughly 1:4 patients will have what we would call limited or early stage disease. The most common stage at presentation is stage III disease which is spread by direct seeding throughout the peritoneal cavity, or involvement of the retroperitoneal or inguinal lymph nodes. Fifty-eight percent of all patients will have stage III disease at diagnosis. Then finally, stage IV disease which has spread to more distant sites accounts for about 17% of patients. Stage III and stage IV together account for what we call advanced ovarian carcinoma.

Now because this is an intraabdominal disease process in the vast majority of patients, as we’ve indicated, all but 17% of the patients will have disease confined to the peritoneal cavity at the time of diagnosis. Because of that, exploratory laparotomy is an extremely important step in the diagnostic evaluation of the patient and it is also the first step in treatment of the patient. Now I’m not a surgeon, I’m a medical oncologist so I’m not going to try to tell you how to operate on ovarian cancer patients, but everybody dealing with ovarian cancer has agreed on three basic principles for exploratory laparotomy. Number one; the incision should permit the exploration of the entire peritoneal surface. Number two; if there is no gross disease outside the pelvis, multiple biopsies should be taken. By the way, I should emphasize, this slide used to say “multiple blind biopsies”.

One of my surgical colleagues informed me that only interns do blind biopsies. Surgeons always see what they are biopsying so we took the word “blind” out in deference to the gynecologic oncologists. Finally, the surgeon should be prepared to undertake an aggressive attempt at surgical cyto-reduction. Now the basis for this last recommendation is mostly retrospective data in the literature suggesting that patients who start chemotherapy with small volume residual disease have better survival and better response to chemotherapy than patients with large volume residual disease. Until recently we had no proof from a randomized trial of this principle. However we do now. In 1995 the European Organization for Research in the Treatment of Cancer, EORTC, published the results of this study in which they took patients who had been initially operated on and deemed to be not bulk-reducible. They gave them three cycles of chemotherapy. At that time cisplatin and Cytoxan was the treatment of choice. They then randomized them to undergo interval surgical cyto-reduction or no interval surgical cyto-reduction, and then everybody got three additional cycles of chemotherapy. What that publication shows is that those patients assigned to interval debulking surgery – and all were included regardless of whether interval debulking surgery could be accomplished – of those patients assigned to interval debulking surgery there was a statistically significant improvement in progression free survival; 15 months versus 12.5 months, and an overall improvement in survival of 27 months versus 19 months.

The reason you see a discrepancy here between 408 and a total of 299 is that 109 patients had progressed before the end of three cycles of chemotherapy and were removed from study. Everybody who reached randomization point, those who got interval debulking surgery did better. We are in the process of confirming these data now in the United States with this study that will finish up in about a year, that uses Taxol and cisplatin as the treatment but otherwise follows the same design as the EORTC trial. That is, Taxol, cisplatin for three cycles then interval debulking surgery, then three more cycles of chemotherapy; versus simply six cycles of chemotherapy. As of right now, the weight of evidence would suggest that surgical cyto-reduction ought to be done – that’s the weight of both retrospective and prospective evidence – if you are going to do it, the rationale for doing this favors doing the debulking surgery up front rather than in the middle of chemotherapy or after chemotherapy has been completed.

The rationale is to remove resistant clones of cells and to remove large bulky tumor that is poorly vascularized. That is better done before you give your chemotherapy. So right now, the standard of care is up front surgical bulk reduction – and this last statement, as a medical oncologist, I can say this – surgery should be performed by a gynecologic oncologist because they are better at removing bulky tumor.

In terms of molecular biology, we don’t have a lot of hard information on ovarian carcinoma. Things that you probably ought to take note of are that any mutations of P53 seen in ovarian carcinomas are probably a late change and have nothing to do with etiology. Number two, ras mutations are associated with borderline tumors of the ovary, which we will comment on in just a few moments. And number three, the frequency with which HER2/neu is over expressed is probably considerably lower in ovarian carcinoma than is the case in breast cancer. The GOG currently is running a trial looking at Herceptin ovarian carcinoma. We’ve had to screen 550 patients just to find 25 who are either 2+ or 3+ or HER2 and therefore candidates for clinical trial. And out of those 25 there has been only one responder to Herceptin. So it would appear that HER2/neu is going to be much less of an important factor in ovarian carcinoma than appears to be the case in breast cancer. As yet we have no unifying model relative to molecular factors.

In terms of environmental factors; there are a number of proposed risk factors, none of which have been confirmed. High dietary intake of meat and animal fat has been associated. A high ratio of lactose consumption to red blood cell galactose 1-phosphate uridyltransferase has been postulated. Again not proven. Consumption of coffee, tobacco and alcohol have all been studied. There are some positive reports in the literature but there are a lot of others that deny an association. Then finally, there have been associations reported with industrial exposure, radiation and talcum powder used at surgery. Also mumps. But none of these are confirmed. There are no clear environmental factors that have been directly related to the disease process as yet.

In the area of prevention, there have been four methods proposed; use of oral contraceptives, the use of fenretinide, tubal ligation and prophylactic oophorectomy. And we’ll dispense with these middle two very quickly. There is an ongoing trial in Europe looking at fenretinide and there will soon be a randomized trial in the United States looking at this as a means of preventing ovarian carcinoma, but as yet we have no proof of efficacy. Tubal ligation is associated with a clear reduction in the risk of ovarian carcinoma, and this gets back to what we talked about earlier. That it is reducing the exposure of the peritoneal cavity to external agents. At least we think that’s the case. There is a clear reduction in risk with tubal ligation.

The other two topics have been looked at a good bit more in the literature. First of all, oral contraceptives; it’s clear that a five-year, five consecutive years of use, of oral contraceptives will reduce the risk of nulliparous women to that of multiparous women who don’t use birth control pills. So the use of birth control pills for five or more consecutive years is associated with a risk reduction. The use of birth control pills for ten or more years by patients with a positive family history will reduce their risk to below that of patients who don’t use oral contraceptives and who have negative family histories. The hazard ratio for women with positive family histories who use birth control pills as compared to those who do not is 0.5. A 50% reduction at 10 years, in the risk of developing ovarian carcinoma. Now there are no hard and fast recommendations on whether or not to use oral contraceptives. More importantly, we do not have good studies on the effects of oral contraceptives in those patients who have hereditary syndromes. So we do not know what the impact will be in that specific subset. So any decision regarding the use of oral contraceptives would have to be made in consultation with the patient and would also have to take into account other risks, such as the 1.46 hazard ratio associated with breast carcinoma in the ten or more years consecutive use of oral contraceptives.

Now in terms of etiology, there are three groups of factors that need to be taken into consideration; reproductive factors, genetic factors and environmental factors. Now the reproductive factors are shown here. There are specific associations that tend to reduce the risk, or at least are associated with a reduced risk; multiple parity, a history of breast feeding and oral contraceptive use. On the other hand, ovulation inducing drugs increase the risk for ovarian carcinoma and these facts have led to a postulation that ovarian carcinoma is related to incessant ovulation. The more you ovulate the more likely you are to develop ovarian carcinoma. For that reason, many have speculated that the rupture and then the subsequent repair of the coelomic epithelial layer overlying the ovary accounts for the chance to mutate and develop into ovarian carcinoma. Now actually this theory has not been held to quite as tightly as it was ten years ago, because everything that will reduce ovulation also reduces the motility of the fallopian tube and reduces the likelihood that external agents can be conducted into the peritoneal cavity. There are also some other factors that reduce the likelihood of external agents being conducted into the peritoneal cavity, and it seems that the more likely explanation is that all of these factors reduce the likelihood of exposure of the ovary to external agents that might participate in the carcinogenic process.

Genetic factors are listed here. Most of these are associated with a positive family history. These are the risks that we see; general population is at a 1:60 risk for developing ovarian carcinoma. That’s 1.6%. If your patient has one family member who has had ovarian carcinoma, the approximate risk is 4-5% for developing ovarian carcinoma at some point during lifetime. If that one family member is a first order relative the risk is slightly higher than this. If the one family member is less than a first order relative, the risk is slightly lower. But any family history is associated with an elevated risk. If two or more family members have ovarian carcinoma, the risk approximates 7%. Now of all ovarian carcinomas 7% of those cases will be associated with a positive family history. And among those with a positive family history, between 1-5% will have some form of identifiable familial syndrome. Most of the familial syndromes are autosomal dominant in inheritance pattern, at least we think so. Therefore the predicted risk for the offspring of someone who carries an abnormal gene would be a 50% risk. The most common of these is the breast/ovarian cancer syndrome. The breast/ovarian cancer syndrome is associated with the BRCA1 gene located on chromosome 17, region Q21. Again, this is an autosomal inheritance pattern. The penetrance appears to be about 44% by age 70. We should emphasize, but I’m sure about everybody in this audience already knows, that there can be multiple mutations of BRCA1 gene, not all of which are associated with increased risk. So you really need a family member who has the gene and also has the disease to say that that particular mutation is associated with an increased risk.

Canadian health care – order viagra professional online with special discounts for our regular customers.

The other two types of hereditary syndromes that have been identified to date are the ovarian cancer syndrome, which is an autosomal dominant inheritance pattern. The exact gene is still in dispute. And the Lynch type II syndrome which also is autosomal dominant in inheritance pattern, and is associated with colorectal, endometrial and breast carcinomas in addition to ovarian carcinomas.