Browse Day: November 20, 2007

Endometrial Cancer. Part 9

Again, there is about a 40% response rate, there is very few complete responses, and the overall responding time frame is about seven months, so all these patient’s begin to grow, even though they have had a complete response to Adriamycin and cisplatinum. Recently, Taxol has been looked at, Taxol has a 20% response rate, it is currently being looked at in a SWOG protocol where they are utilizing carboplatinum and Taxol, substituting carbo for the cisplatin because it’s easier tolerated, against Taxol, and this seems to be a promising chemotherapy option, simply because Adriamycin is not well tolerated in the elderly and it’s a very difficult regimen to get patient’s through. Part of the problem with the GOG study was you were taking your best medical candidates to put them on the Adriamycin, your more sicker patient candidate who had heart disease and hypertension couldn’t qualify to get onto the Adriamycin.

Lastly is hormonal therapy, approximately one-third of patient’s with advanced or recurrent endometrial cancer will respond to progesterones, well differentiated tumors tend to have better response rate than undifferentiated tumors. Unfortunately, the tumors that tend to metastasize or become recurrent are the undifferentiated tumors and they have less of a response to progesterone, but it is recommended for patient’s who are not chemotherapy candidates who have received chemotherapy and are no longer chemotherapy candidates, about a third of them will respond to progestins and that includes patient’s that do not have hormonal receptors and they really don’t understand that mechanism. And lastly, they are looking at combining tamoxifen with progesterone, the reason for tamoxifen although it’s in the back of our mind that it causes endometrial cancer, but what tamoxifen does in recurrent or advanced endometrial cancer is produce progesterone receptors and so it is felt that it aids in the use of using Megace or progesterone agents in getting a hormonal response. There are some trials out there now looking at tamoxifen combined with progesterone therapy. Because endometrial cancer usually presents as stage I disease, it’s a very favorable cancer, usually surgery combined with postoperative radiation if needed, gets very long term survival and very good quality survival, our survival rates can be as high as 90% and well differentiated tumors and still even in stage II tumors which are advanced tumors, we are still getting five year 50% survival. So overall, it is a favorable tumor we can work with. Unfortunately, if you get a tumor that’s well advanced or recurrent, it is a very difficult tumor to irradiate because it’s not chemo sensitive and only a third will respond to progesterone agents.

Endometrial Cancer. Part 8

For patient’s that have grade II to grade III, they need a total abdominal hysterectomy, they need pelvic and periaortic lymph node sampling and they need peritoneal washings, particularly if they are a grade II, sometimes they can be bounced to a grade III, if they are grade III, they should definitely get peritoneal pelvic lymph nodes simply because they are at the risk, that is anywhere from 20 to 60% of having positive nodes and this is going to help tailor your treatment, and if you are dealing with a patient who is elderly and may not tolerate radiation, this may be very critical information to help you manage this patient postoperatively.

For people who have advanced stage II endometrial cancer, which means there is involvement of the cervix, if the cervix is not grossly involved, meaning there is only endocervical involvement and you have picked this up on a fractional D&C, these patient’s can still undergo a total abdominal hysterectomy, bilateral salpingo-oophorectomy plus your pelvic and periaortic lymph node dissection, send it to pathology and decide if this patient needs postop treatment or not. Most likely she is going to need postoperative radiation therapy because she has at least endocervical involvement. Some GYN oncologists were proposed to a radical hysterectomy for endocervical involvement and therefore necessity for adjunctive radiation therapy. This can be tough in patient’s who have endometrial cancer because #1, these patient’s tend to be elderly and doing radical hysterectomies in the elderly, although it is a completely acceptable treatment for a stage II disease, you are going to leave them with bladder atony and difficulty with their bowels, so it’s a tough surgery to put these patient’s through, plus a lot of them are morbidly obese, and therefore not a surgical candidate to undergo a radical hysterectomy. If the cervix is grossly involved, meaning there is no way you can get out, it’s 4 or 5 cm, what we usually do is treat with external beam radiation followed by one inter cavitary implant followed by an extra fascial hysterectomy following the surgery, and then for huge, large unresectable tumors, anything goes, you use a combination of chemotherapy, plus radiation, plus some surgery to give the patient the optimal palliative result.
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For patient’s who have recurrent or advanced endometrial cancer, there is chemotherapy and progestins. The most active chemotherapeutic agent for endometrial cancer to date has been Adriamycin, it has been proposed to have a 35 to 40% response rate. Now response rate means that if you take patient’s who have a measurable lesion, and given them Adriamycin , it does not mean that 40% of them will have a complete response, that means there will be some shrinkage of tumor. The response rates for Adriamycin last anywhere from seven months. The most active regimen that has been deemed by the gynecologic oncology group looked at single agent Adriamycin versus Adriamycin plus cisplatinum and there was a slightly higher response rate with a combination of cisplatinum and Adriamycin, so that is felt to be the gold standard for endometrial cancer and all the other trials are looking at that.

Endometrial Cancer. Part 7

In the recent years, we have classified endometrial cancers into low risk, intermediate risk and high risk and this is to help us decide how we are going to treat endometrial cancer. Low risk is considered a grade I lesion that’s confined to the endometrium that has no extra uterine spread, you can do your hysterectomy and you’re done. Intermediate risk, this is the risk where everybody argues about this woman, needs adjunctive therapy, does not need adjunctive therapy and high risk, everybody can pretty much figure out, grade III deeply invasive or other factors that have high stage disease. If you look at the GOG data, when they broke it down into low risk, intermediate risk and high risk, and this is all on pathological specimens. We see that the low risk group, there were no incidences of pelvic and periaortic lymph, no metastases, and this is a grade I lesion with only endometrial involvement. The intermediate risk, if you had one factor was extremely low, but also we had two factors, your incidence of lymph node metastases was extremely low, so it was less than 10%, though it did exist, and then your high risk group, you were up to 20 to 60%, depending on how many risk factors you had as far as lymph node metastases. I bring the positive peritoneal cytology on this slide, it is an independent prognostic factor, in patient’s who have positive peritoneal cytology will have an apparent stage I, so you surgically stage these patient’s, the tumor is confined to the uterine cavity, there is no lymph node involvement but they have about 10 to 15% will have positive peritoneal cytology. It is unclear how to treat these patient’s. Piver has placed these patient’s who have positive peritoneal cytology with no other risk of lymph node metastases on Megace and restaged them in a year, and of the patient’s who restaged in a year, 80% did not have any further positive peritoneal cytology or positive nodes, 20% still had persistent either cytology or spread of disease and they were placed on Megace for another year and about half of those patient’s when they were restaged the second year had no persistent positive peritoneal cytology or evidence of endometrial cancer. So therefore, based on the Piver study, it is felt that patient’s who have positive peritoneal cytology, whether or not they receive adjunctive radiation therapy or need radiation therapy based on their surgical specimen should undergo Megace progesterone hormonal therapy postoperatively, and this brings us to the treatment of endometrial cancer which I briefly want to get into. If you have a well differentiated endometrial cancer, the obvious solution if the patient is a surgical candidate is to undergo a complete hysterectomy, send the uterus to the pathologist to see if there is deep myometrial invasion and of course always obtain peritoneal washings cause again, 10 to 15% will have positive cytology.

As GYN oncologists we do not send the specimen to pathology, you are asking your pathologist to do an awful lot on a frozen section. Sometimes it’s difficult, sometimes they will upgrade your tumor on the final histology and sometimes they will have foci of deep myometrial invasion or middle third myometrial invasion which cannot be picked up on the gross frozen section, so it’s very difficult to get a frozen section that sometimes 50% of the time can be changed. So in patient’s who undergo hysterectomies for endometrial cancers, I tend to sample their nodes. If, however, the patient has a well differentiated cancer or atypical hyperplasia, and there is not a GYN oncologist or somebody who can sample the nodes, a complete hysterectomy and peritoneal washings, it’s completely appropriate. Further adjunctive therapy would be based on the final hysterectomy specimen and the staging would then go to the old clinical systems.

Endometrial Cancer. Part 6

These adenocarcinomas tend to me all lumped together, everything is graded on the adeno component, whether there is a benign squamous or a malignant squamous involved. Papillary serous adenocarcinoma is a variant and is not related to the garden variety adenocarcinoma, it’s not related to over estrogen production, and it can occur in skinny, young, thin patient’s, they have their first episode of postmenopausal bleeding, you open them up and they have a very typical spread pattern of ovarian cancer. It does not behave like the run of the mill adenocarcinoma, it has a much worse prognosis, fortunately, it is not as common as the run of the mill adenocarcinoma, and again, clear cell carcinoma is a variant of adenocarcinoma and again, carries a worse prognosis. If we look at the different cell types, this is the cell type of adenocarcinoma, the garden variety, it’s swollen glands back to back, papillary serous has a different type of pattern and has like a serous papillary growth pattern.

Survival based on your histiologic cell type, if you have one of the adenocarcinomas, your survival is very good, depending on the tumor differentiation, so if you have a well differentiated adenocarcinoma you are going to do very well, if you have a grade III adenocarcinoma you are going to do far better than if you have papillary serous or clear cell carcinoma. These are variants of endometrial cancer and really don’t follow the lymph node metastases and other problems that we see with advanced adenocarcinoma of the endometrium. They behave uniquely and they behave very similar to ovarian cancers. As I eluded to before, as the tumor loses differentiation, the survival rate directly goes down and there are several reasons for that. Here is a nice, well differentiated cancer, you can tell if you look at that, you would say it almost looks like normal endometrium, it’s a little crowded but it’s probably going to behave pretty much like a normal endometrium, it probably has estrogen and progesterone receptors and this is probably a cancer that you would ordinarily see in somebody who is morbidly obese, you’re uterine specimen is very small, has very superficial myometrial invasion., and this again is aggressive, ugly, it’s going to infiltrate, it’s going to have your uterus enlarge, it’s going to be infiltrating deeply into the myometrium and into the myometrium there are several lymphatics and once it’s in the lymphatics, it can spread to the pelvis, the periaorta and out toward the adnexa and into the peritoneal cavity.

So as the tumor loses differentiation, so does it gain access into the aortic lymph nodes, the higher the grade, the higher the incidence of lymph metastases and the reason for that is, if you have myometrial invasion, if it’s deep myometrial invasion that’s your highest risk for lymph node metastases because the lymphatics are in the myometrial wall, and if you have a tumor that’s deeply invasive into the myometrium, it’s going to gain access into your lymphatic system. If you have a tumor that is confined to the endometrium, your chance of having aortic and lymph node metastases is about zero, if you have deep myometrial invasion, this is going to be a tumor that most likely if you look hard enough and do a more thorough dissection, you are going to find metastases. The survival directly goes down with the amount of myometrial invasion.