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New Treatments for Ovarian Cancer

Ovarian carcinoma is the second most common malignancy of the female genital tract, at least in the United States. It accounts for about 25,200 cases a year, currently. The important figure is here; 14,500 deaths. This represents 62% of all deaths due to cancers of the female genital tract.

Pathologically we are talking about several different neoplasms. Our focus is the coelomic epithelial carcinomas of the ovary, which is which is what everybody really means when they say ovarian cancer. These lesions arise from coelomic epithelium that invest the ovary during development, and also lines the entire peritoneal cavity.

Stromal tumors account for about 4% of all these tumors. These are granulosa thecal cell tumors primarily but include a variety of other tumors. We know relatively little about these tumors other than to take them out if you can and diagnose them early enough.

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.

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.

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.

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.

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 regard to prophylactic oophorectomy; there have been publications in the literature, most notably from Buffalo, suggesting that prophylactic oophorectomy in women with positive family histories was indicated. But if you look at their own data published in 1993 in Cancer, what you find is that after prophylactic oophorectomy - and they had a total of 324 women.

Screening for ovarian carcinoma; if you read luminary medical journals like Cosmopolitan and Redbook you will find that screening is something you really ought to be doing for your ovarian cancer patient. What those journals recommend is a combination of pelvic examination by the physician once a year, serial CA125’s annually, and annual transvaginal sonography. But the actual figures on the use of these show that, first of all, pelvic examination has no impact.

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

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.

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.

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.

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.

At that same meeting at ASCO the fly in the ointment was presented. That was GOG protocol 132. This study was done while we were waiting for the data on GOG 111 to mature. This randomized patients with large volume advanced disease to either cisplatin, Taxol or a combination of Taxol plus cisplatin, with the Taxol given as a 24 hour infusion.

Now the most recent study to be completed was ICON-3, the International Collaborators on Ovarian Neoplasms study number 3. This study was conducted in the United Kingdom and Italy. About 70% of the patients came from the United Kingdom, about 30% from Italy. Patients here were randomized to the experimental arm of Taxol/carboplatin, Taxol given as a three hour infusion followed by carboplatin. Or to one of two control arms. Each institution had to select which control arm the institution would use; either carboplatin alone or a three drug combination of Cytoxan, Adriamycin and cisplatin. All stages of the disease were allowed onto this study. So this study includes stage I, stage II, stage III and stage IV patients.

Now, what do you put? Cisplatin or carboplatin? I hope to goodness you are not going to be asked to distinguish between those two. But there have been three studies of this issue now, and we actually have an answer.

GOG158 was done in a patient population with small volume residual stage III disease. Again, the randomization here was the same but the Taxol/cisplatin regimen used 24 hour Taxol plus cisplatin, which gives much less neurotoxicity. The Taxol/carboplatin regimen used an AUC of 7.5 for the carboplatin because that was the MTD on the phase I study.

The weight of evidence suggests that three hour Taxol/carboplatin is a reasonable treatment for ovarian carcinoma. In fact I can tell you that it is used by over 80% of you in treating ovarian carcinoma, based on a survey that was done by Bristol-Meyers Squibb. Now how much of these drugs should we use? Cisplatin, carboplatin and Taxol which are the major three drugs in ovarian carcinoma. Let’s look at each of the three. First, cisplatin. T

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.