Archive for the Endometrial Cancer category.
What about chemotherapy? Well the principle drugs we’ve focused on are those that have clearly been shown to be active in concerted phase II trials. The anthracyclines, the taxines and the platinum compounds. Here are the actual numbers for those. Doxorubicin and epirubicin have both shown excellent activity; 27%, 26%. Both platinum compounds, cisplatin and carboplatin, have been shown to be active in about the same range. The response rate in the one trial reported to date with Taxol is actually an excellent 36%. That’s the highest response rate for any single agent in the disease process. The study that has sort of defined what is accepted as the standard of care to this point is a protocol of GOG 107 which randomized patients with advanced or recurrent disease to either Adriamycin alone or a combination of Adriamycin plus cisplatin. Patients were given the regimen every three weeks for a total of eight cycles of treatment. The study had 223 patients on it. The response rate to the combination was 45% compared to 27% with a single agent, highly statistically significant. The complete response rate to the combination was 22% compared to 8% with a single agent, again statistically significant. Median progression free survival with the combination was 6.2 months compared to 3.9 months with the single agent. That difference was also highly statistically significant. There was no difference in overall survival, as you can expect with any overall response rate that is less than 50% in patients with advanced disease. So in terms of response rate, complete response rate and progression free survival, the combination was better. We’ve concluded that the combination ought to be the treatment of choice at the current time.
What is being done in randomized trials in the U.S. – most studies are being done by the GOG – this study has been completed. We are waiting for the data to mature. It compared doxorubicin/cisplatin to a combination of doxorubicin plus Taxol. Then our follow-up study, based on a phase I study that was reported at ASCO in 2006 compares doxorubicin/cisplatin to the three drug combination of doxorubicin/cisplatin/Taxol. This regimen requires GCSF support but those doses are tolerable with GCSF support. And that phase I trial is in abstract form in the proceedings of ASCO 2006. For now, though, the standard of care would have to be considered to be doxorubicin/cisplatin. What we know about chemotherapy; there are five drugs that produce a greater than 20% response rate. Both platinum compounds, two anthracyclines – both doxorubicin and epirubicin – and Taxol. Based on randomized trials doxorubicin/cisplatin is superior to single agents. Doxorubicin/cisplatin is superior to progestins except in receptor positive grade I lesions. Now this is not based on a randomized trial but is based on comparing the data on doxorubicin/cisplatin from the chemotherapy study to data that the GOG has generated on progestins. It’s also important to point out that doxorubicin/cisplatin produces a significant number of complete responses, 22%. The complete responders do have very durable responses that can last a long time.
Endometrial Cancer
To suggest that one ought to give chemotherapy as the first line of systemic therapy is sort of heresy. Chemotherapy yields a superior response rate of 44% versus 21% overall, and superior progression free survival of 6 as compared to 4 months when you put up numbers for the overall population. But if you break the population down by grade, in grade III tumors chemotherapy is clearly superior, 44% response rate versus 12% response rate. In grade I tumors, chemotherapy gives results that are roughly equivalent to progestins, 45 versus 44% response rates and very similar survivals. And that’s despite the fact that the chemotherapy is being given after patients have received prior progestin therapy. The inclusion of Taxol as a front line agent promises improvement. We don’t know that definitively yet but we have reason to believe that that might be the case.
Our recommendations on chemotherapy; doxorubicin/cisplatin is the current treatment of choice. It should be first line systemic therapy for those with grade II or III, or receptor negative tumors. Chemotherapy after failure on hormonal therapy is appropriate and active. The numbers that I’ve shown you for the chemotherapy trials have all been from patients who have received prior progestational therapy. And salvage Taxol is active after doxorubicin/cisplatin according to GOG data.
The last part of the mythology is that the higher the dose of the progestins the better the response rate and duration. Now this myth came from some breast cancer studies that suggested that if you gave high dose progestins to breast cancer patients you get a higher response. One particular study that comes to mind was a Piedmont Oncology Association study that suggested that. So we tried to look at this in endometrial carcinoma. Two hundred milligrams a day of medroxyprogesterone acetate, which is really a standard oral dose of this, yielded an overall response rate of 26% complete plus partial response rate. Five times that dose, 1,000 mg per day, yielded a response rate of 17.9%, actually lower, with a statistically significantly shorter progression free survival and a much higher incidence of toxicity, such as fluid retention and thromboembolic phenomenon. So there is no evidence that you need to go to extremely high doses of this.
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If we sum up what we know about progestins in endometrial cancer, both parenteral and oral agents will yield response rates that range from 17-16%, relatively short durations of response, and an overall survival of less than a year. The results with progestins are better in grade I or receptor positive tumors where we get response rates of around 40%, progression free survival of roughly nine months, and overall survival of around 14 months. The results are very poor in higher grade or receptor negative tumors; response rate 12%, progression free survival 3 months, overall survival 10 months. Doses higher than 200 mg per day orally of medroxyprogesterone acetate, or its equivalent, is 160 mg per day, all for no advantage.
Now what about tamoxifen? These are the four series that have been reported in the literature. There were two smaller series that suggested significant activity. The GOG then tested tamoxifen first to a 25 patient study then in a larger 63 patient study, in patients who had had no prior hormonal therapy. And what we found was very little activity. Much lower than what we saw with progestins. The bottom line on tamoxifen is that the larger trials show little or no activity. Even in those with prior hormonal responses – we did a subset that had responded to progestins and then later relapsed – and we tried tamoxifen in that group as we do with breast cancer, with successive hormonal therapies, we found no activity. So tamoxifen appears to have a relatively little role in treating endometrial cancer, a bigger role in causing it.
We can summarize hormonal therapy; progestins are clearly active. I think if you want to put a handle on one response rate, 20% is a good number to quote. Response correlates with grade and receptor status and is high only in grade I tumors. The duration of response is brief as is survival, except in those patients with grade I or receptor positive tumors. And no other hormonal agent other than progestin has really demonstrated significant activity. The GOG has tested a whole series of other agents looking for other agents that have reasonable activity.
Our recommendation is; when you choose hormonal therapy for your endometrial cancer patient use progestin. It should be the first line of systemic therapy in patients with grade I or receptor positive tumors. It should not be your first line of treatment in grade II, III tumors or known receptor negative tumors. Salvage hormonal therapy after chemotherapy failure can be considered because it has relatively little cost and toxicity and occasionally might work.
Now for disseminated disease, we have the small percentage of patients who present with primary stage IVb disease, which is 3% of the total, that is disease outside the pelvis and we also have those who recur after initial treatment. The mainstay of management here has been systemic therapy, either hormonal therapy or chemotherapy – and we want to look at each of these areas since these tend to be more the province for medical oncologists. Hormonal therapy has been looked at for gestational agents, the most common agents used, the antiestrogens have also been studied. Now let’s look first at the progestational agents. Now if you read any of the older gynecologic texts what you will see in there is that patients with advanced endometrial cancer do extremely well on progestins and you ought to put them on progestins and just forget about it, because they are going to do great. There’s a lot of mythology associated with progestins so let’s look at the mythology. The first part of the mythology is that the frequency of response to progestins in very high. Here is what the older literature shows. Roughly a 33-34% response rate to several different progestational agents. That’s not what I would call extremely high. But it’s not bad either. Here’s what the more recent studies have shown; response rates that range from 16-21%. These are much better documented studies with much clearer definitions of what constitutes a response. These last two here were done with oral medroxyprogesterone acetate by the gynecologic oncology group. You can see there are a large number of patients involved here, 625 to be exact, with response rates that range from 17-21%. So those numbers are fairly firm.
The second part of the mythology is that the duration of response as well as survival on progestins is often very low. These people do extremely well for decades. Let’s look at what the fact is here, and we are going to take a little more detailed look at this patient population’s makeup. If you look at patients who develop recurrent disease and receive progestational agents as treatment, what we find is that about 1:5 will have grade I disease, 36% will have grade II disease and roughly 43% will have grade III disease. Note that the response to progestins correlates with grade. Grade I patients have a 39% response rate, grade II 25%, grade III 10%. There’s a reason for that. Grade also correlates with the presence of receptors as it does in breast cancer. Grade I patients have a frequency of estrogen and progesterone receptor positivity of 84%. Grade II, 50%. Grade III, 25%. That mirrors the response rate. The response rate is about half of those numbers for each of those grades. There is also a clear correlation between receptor status and response. This shows you a summation of the world’s literature to date, only 134 patients reported with receptors; 62% response rate in those patients who were positive for estrogen and progesterone receptors, and 8% response rate to progestational agents in those who were negative for both receptors. So an excellent correlation, but in the largest group of patients – this is the GOG study here – while there is still a correlation, the response rate to progestins in the receptor positive group is only 44%, which is significantly less than what we see in the rest of these with much smaller numbers; 12% in those who were receptor negative.
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This looks at survival figures according to receptor status. Patients who are receptor positive have a median progression free survival of 8.5 months and overall survival of 13.5 months. Those who are receptor negative, 2.5 months progression free survival, 9.5 months overall survival. But as far as the contention that these patients live for a long time and have durable responses, overall four month progression free survival, 10.5 month overall survival, progestins aren’t as good as they have been said to be in the older literature.
Now this is based on three-year follow-up. Surgical resection alone yields an 89% three year survival. Surgery followed by pelvic radiation in this group yields a 96% three-year survival. The basis for that is this study, GOG protocol 99. It did not include any of the IIIa patients but it did include all the patients with stage I disease who had myometrial invasion. Patients with stage II disease, that is cervix involvement, all of these patients – 390 of them – were subjected to a randomization after surgery to either no further therapy or pelvic radiation. This was reported at the site of the gynecologic oncology meeting about a year-and-a-half ago, 390 patients in the study. The progression-free survival at three years was 88% on the group that got surgery only, 96% on the group that got adjuvant radiation. The overall survival at three years, 89% versus 96% and those differences are statistically significant. There was also a significant reduction in the incidence of vaginal recurrence, from 17 recurrences down to 3 with pelvic radiation. So we recommend that the intermediate risk group receive pelvic radiation if their reason for being intermediate includes either cervix involvement or myometrial invasion.
Now for patients at high risk for recurrence, these include the patients who are stage III by virtue of the involvement of the vagina or the pelvic or periaortic lymph nodes. And also stage IVa patients. Those who are stage IV by virtue of involvement of the bladder or rectal mucosa. If you do surgery only on these patients, that is do a TAH – total abdominal hysterectomy – and bilateral salpingo-oophorectomy, a complete resection of gross disease, relapse rates exceed 50%. Now the truth is, nobody knows the definitive best treatment for this group. We don’t have any large prospective randomized trials, but currently what’s recommended is resection of all gross disease, radiation to areas that were involved with disease and then the issue of whether systemic therapy is indicated is currently under study. The gynecologic oncology group has done two phase II trials showing that there is some reason to believe that abdominal pelvic radiation is active in this setting, and also showing that there is reason to believe that a combination of doxorubicin and cisplatin is active. What’s currently being done within the GOG is a phase III trial comparing these two approaches. Patients on this study have either stage III or stage IVa disease, that is bladder or rectal mucosal involvement for stage IV. They are subjected to a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and tumor de-bulking so that nothing bigger than 2 cm remains. The tumor must be confined to the abdomen or pelvis and the patient must have had no prior therapy other than possibly progestins. They are randomized to receive either abdominal pelvic radiation or a combination of doxorubicin and cisplatin. That study is ongoing at the present time. But until that trial is completed, the standard of care is surgical resection of all gross disease if at all possible, followed by radiation to involved areas.
The way we classify the disease for the purpose of treatment approaches is shown on this slide. We divide the cases into those cases that are associated with local or regional involvement in the pelvic area or the abdominal cavity, and those who have disease that has disseminated to more distant sites. The local regional cases are subdivided into low risk, intermediate risk and high risk groups. Now the basis for this sort of subdivision of the patient population comes mainly from studies done by the gynecologic oncology group. One of these studies, GOG protocol 133, included 1,155 patients who were carefully surgically staged. There were another 222 on so-called GOG pilot 1, also all carefully staged endometrial carcinoma patients. The statisticians at GOG have subjected that database to detailed statistical analysis. The primary uterine risk factors associated with poor prognosis are higher grade, any degree of myometrial invasion – the deeper the greater the risk – and involvement of the cervix. Extrauterine factors that are considered risk factors are the involvement of the adnexae, spread to the peritoneal surface or involvement of the pelvic or periaortic lymph nodes. So those are the principal prognostic factors that are features of the tumor at the time of resection.
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For patients who are deemed to have low risk disease, that is stage Ia – that is disease confined to the endometrium – grade I or grade II. Surgical resection alone has a five year survival that exceeds 90% and in some series goes as high as 98%. So the recommended treatment for these patients is total abdominal hysterectomy plus a careful surgical staging to insure that the disease process is truly stage Ia, that it is confined to the endometrium, grade I or grade II. These constitute the vast majority of patients who present with disease limited to the pelvis, which again accounts for the excellent overall survival rate of endometrial carcinoma. Patients are deemed at intermediate risk for recurrence when they have stage I, stage Ia, grade III. That is, stage I confined to the myometrium, grade III, or any degree of myometrium invasion which would make the patient either stage Ib, involvement of the inner half of the myometrium, or stage Ic, involvement of the outer half of the myometrium. It also includes patients who have cervix involvement, stage II, or who have stage IIIa disease. IIIa disease consists of patients who are stage III by virtue of the serosa of the uterus, the adnexae, or have positive peritoneal cytology. That constitutes the intermediate risk group that has a 15-20% chance of relapse with no further therapy.
From the standpoint of the molecular biology of the disease, frankly this disease is not well characterized. What is not on this slide here but you should remember is this is a hormonally influenced disease; estrogen and progesterone receptors are present in endometrial tissue and also in tissue associated with endometrial carcinoma. We’ll tell you a little more in a few minutes about the frequency of that and what impact that has on outcome with hormonal treatments. But remember that that is a part of the molecular biology of endometrial carcinoma. Endometrial carcinoma is also a part of the Lynch type II syndrome, as we pointed out in the talk on ovarian carcinoma. That syndrome has an increased frequency of breast, colorectal, endometrial and ovarian carcinomas. An over-expression of HER2/neu, we really don’t know what the facts are here. The frequency of HER2/neu over-expression ranges from 10% to 85%, depending upon what article in the literature you want to pull and look at. All of these are relatively small series so we don’t know the true frequencies yet. As is the case in both breast and ovarian carcinomas, HER2 over-expression is a poor prognostic factor. We have no idea as yet what role the monoclonal antibody might play in this disease or what over-expression of HER2/neu will tell us about the source of treatments we ought to be applying to these patients.
The disease presents in the peri and postmenopausal age groups, beginning at about age 40 and rising in incidence as you proceed into the postmenopausal years. As we’ve mentioned from the risk factor slide, associated factors are obesity, hypertension and diabetes. As a result of this, this has come to be known as a fragile patient population that does not tolerate aggressive treatment approaches well. Frankly, within the gynecologic oncology group we’ve not found that that’s the case. We started our trials of chemotherapy in these patients 25 years ago with very modest doses. The doses we use now are pretty much the doses we would use in breast cancer, ovarian cancer, and other diseases where those same drugs are appropriate. So despite the fact that this patient population does have comorbid conditions, the patients do appear to be able to tolerate reasonably aggressive approaches.
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The principal presenting manifestation of the disease is bleeding, and this accounts for why we are able to diagnose this disease process at an early stage in the vast majority of patients. If your patient presents with abnormal bleeding of any kind, particularly in the peri or postmenopausal years, that patient should be considered to have endometrial carcinoma until proven otherwise. That is an indication for sampling of the endometrium by your friendly gynecologist. The key prognostic factor for these patients is the extent of disease at the time of diagnosis or the stage. The staging system of endometrial carcinoma currently is a surgical/pathological staging system. This is an abbreviated version; stage I disease is disease confined to the corpus, stage II disease is disease that has extended to involve the cervix, stage III is regional spread to involve the adnexa, the serosa, positive peritoneal cytology, involvement of the vagina or the perimetrium. Stage IV disease is either bladder or rectal mucosal involvement, which is stage IVa, or spread outside the pelvis, which is stage IVb. Stages I, II and III are subdivided according to grade as well, so that the grade needs to be specified in order to get a good handle on what prognosis you might be dealing with. You’ll note that survival figures out here show that 90% of the patients who present with stage I disease will be cured, 60% with stage II, 40% for stage III and less than 10% for stage IV. The actual figures show that 75% of these patients are diagnosed as stage I, another 13% as stage II. So that’s 88% of all patients will have either stage I or stage II disease, which is amenable to surgical and radiotherapy approaches. Stage III disease accounts for 9% of all cases, and stage IV disease, 3% of all cases. So this is a disease process that’s diagnosed usually at an early stage of development because of the presenting manifestation of bleeding.