Browse Month: December 2008

The drugs that would be chosen as alternative therapy

Let’s look at the drugs that would be chosen as alternative therapy. First there are a group of four drugs that have been shown in published studies to be active in patients who are platinum resistant by the definitions I showed you; Navelbine, about an 18% response rate in platinum resistant patients, tamoxifen, 13%, ifosfamide, 12%, and 5FU leucovorin 17%. All of these responses are in the mid-teens but there is some activity. The better group of drugs though are those drugs that have been shown to be active in Taxol/platinum resistant patients, resistant to both of those agents. These include oral etoposide, which has the highest raw response rate in patients with Taxol/platinum resistant disease, 32% in a GOG trial. Eight responses among 25 patients. Topotecan has a 13% response rate in Taxol/platinum disease. Doxil a 19% response rate. If you went to ASCO you saw a study presented showing 23% that had 63 patients on it. The full data base has 110 patients in it. It was collected by a pharmaceutical company which is now Abbott, and the overall response rate was 19%. Gemcitabine 14% response rate in Taxol/platinum resistant patients. My own personal order of choice here is oral etoposide as the first salvage. If and when they relapse after that, Doxil and then topotecan in that order. Though both topotecan and Doxil have FDA approved indications in ovarian cancer, etoposide is in the compendium as a salvage drug but the problem with oral etoposide is you have to go through the durable medical equipment provider to be reimbursed. So it’s a little more complicated, though I have never viewed pills as durable medical equipment. So that’s the situation with regard to salvage therapy.

Right as the last thing I want to comment very briefly on dose-intensive approaches like intraperitoneal therapy and bone marrow transplant. What we are looking for is a second threshold on that dose-intensity curve. We’ve shown you evidence that the dose-intensive curves flattens after a threshold of roughly 60 per meter square for cisplatin, AUC5 for carbo and 175 per meter square for Taxol. With these dose-intensive approaches we are looking for a second threshold. Because of time I will go through these quickly. There have been two randomized trials looking at IP therapy as front line therapy. The first was published in December of 2006 in the New England Journal of Medicine. This is Southwestern College Group, GOG Intergroup study, randomizing patients to IV Cytoxan/IV cisplatin, versus IV Cytoxan/IP cisplatin. That article will tell you that this makes intraperitoneal therapy the treatment of choice for small volume residual disease. It does not.  The study was flawed. The accrual was extended to 650 total patients. The original goal of the study, a hazard ratio of 0.67 was never reached. There was a difference of 49 versus 41 months median survival favoring IP therapy, hazard ratio of 0.77. But the study really gave us a counter-intuitive result because the 0 to 0.5 cm subset, the subset we thought would benefit the most because it had the smallest volume of disease, actually didn’t benefit. Benefit was seen in the larger nodule group which doesn’t make any sense. So for that reason this study served to keep the issue alive.

The patients who have grade II or grade III disease

Now what about the patients who have grade II or grade III disease? These patients were randomized to either observation or cisplatin as a single agent. The disease-free survival at five years for the cisplatin group was 83%, for the observation group was 64%. That’s highly statistically significant. The overall survival at five years was 87% versus 81%. Better with cisplatin than with observation, but not statistically significant. Now some people accept disease free survival improvement as a reason for treating, others don’t. My own opinion is that these patients ought to be treated with some form of platinum based therapy because of the difference that we see in the disease-free survival. But there is still an ongoing debate about this group.

The other group, those at high risk, because of other factors, were randomized to either intraperitoneal P32, which was a nice placebo, or cisplatin based therapy. Actually when this study was started this was considered the standard but we have reasonable evidence to suggest that it really has very little impact. At five years the patients who got cisplatin had an 81% disease-free survival compared to 66% with intraperitoneal P32 and there have been too few events in the overall survival at five years to permit any kind of reasonable analysis, but there is a small difference favoring the cisplatin based therapy. Again, the same reasoning applies here. Either you accept disease free survival improvement as a reason for treating or not. The consensus among the gynecological oncology community at least is shown on this side. That is, that everybody ought to have a hysterectomy, a bilateral salpingo-oophorectomy and a careful surgical exploration to document the exact stage of disease. Those deemed to be at low risk for recurrence, the low risk group, should receive no further therapy. And those deemed to be at high risk either because of grade or because of one of the other factors, should receive some form of platinum based therapy with expected improvement in disease free survival to 82% at five years as compared to 60% with not treatment. If I were picking the therapy I would use a combination of Taxol and platinum in this group but we have no studies as yet showing that that has any advantage over single agent cisplatin.

Now what do we do in the salvage setting? There’s actually on the ASCO site a summary of a lot of data on salvage therapy if you are interested. It’s in the section on the educational material from the 2006 meeting. But very briefly, what we are talking about here is a population of patients who either recur after or progress on front line therapy. And the general principle or approach to these patients is to look at what their response was to front line therapy and then base your decision on that. In that regard, what you do is try to divide the patients up into two groups. A group of patients that almost certainly are still sensitive to the drugs they received as a part of front line therapy, and a group of patients who almost certainly are going to be resistant to those drugs. Those who should be considered sensitive are those who responded to front line therapy and had a significant treatment-free interval before they required further treatment. Now the current definition the cooperative groups are using is six months. There is nothing magic about six months. What that real number should be, we don’t know for sure. It’s probably a continuum. Six months has been selected as the break-point by the cooperative groups. For chemo-resistant disease; this includes those patients who either progress while receiving front line therapy or whose best response to front line therapy was stable disease, or who had a short treatment-free interval before they recurred. That is, less than six months. In those who are chemo-sensitive, they ought to be retreated with a platinum-based regimen. And if you use Taxol/platinum front line, Taxol/platinum is what ought to be used second line. The best data we have suggests that the expected response rate here is between 50-60% and the median survival will approach two years. Those patients who were resistant to front line therapy should be treated with alternative drug therapy. Now the list of drugs actually includes a total of seven.

The two regimens that are acceptable

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

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.

Cisplatin or carboplatin

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. There was a Dutch trial that only had 182 patients on it, too few patients to allow any reasonable conclusions to be made. But there have been two subsequent studies, GOG protocol 158 and a German trial from the AGO group, both of which had almost 800 patients – 798 patients each. That’s enough patients to have equivalency conclusions to be drawn. Let’s look at those two. First the AGO study, presented at each of the last two ASCO’s. These studies randomized patients with IIb-IV disease – that is the both the large volume and small volume patients – to either Taxol over three hours plus cisplatin or Taxol over three hours plus carboplatin. And yes, they got a lot of neurotoxicity with three hour Taxol/cisplatin. They allowed up to six cycles of therapy. What they found was no difference. The trends all favored Taxol/cisplatin. The response rate 80% versus 70%. Clinical complete response rate 36% versus 30%, progression-free survival median 73 versus 69 weeks. Survival at one year 92% versus 91%. The trends here are very small, with cisplatin no significant difference.

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. Each regimen given every three weeks for six cycles. Here are the results. Pathologic complete response rate, 45% with Taxol/cisplatin, 52% with Taxol/carboplatin. Progression-free survival essentially identical between the two arms. If anything here, the trends favor Taxol/carboplatin. And what that speaks to is there is literally no difference between a combination of Taxol/carboplatin and a combination of Taxol/cisplatin. The disappointing thing is that there is also no difference in neurotoxicity between the two. In the GOG study the neurotoxicity in these two arms was exactly the same. In fact there was slightly more nausea and vomiting on the Taxol/cisplatin arm. There was more nephrotoxicity on the Taxol/cisplatin arm. There was more myelosuppression on the Taxol/carboplatin arm. So that while Taxol/carboplatin did have an advantage in terms of therapeutic index, it was not as great as we would have anticipated going into the 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. There have been two metaanalyses published on cisplatin; 2006 in the Journal of Clinical Oncology, 1993 in the Journal of the National Cancer Institute. What these two metaanalyses do, combined, is to establish a clear dose-response relationship up to a cisplatin dose of 60 mg per meter square but not beyond that. No advantage to increasing the cisplatin dose beyond 60 per meter square. There have been three randomized trials internationally now looking at the issue of 50 mg per meter square versus 100 mg per meter square of cisplatin. One GOG study and two Italian studies. No differences in response rate, no differences in survival by going up to the higher dose of cisplatin. So by the best evidence that we have to date there appears to be no advantage to going beyond a dose of cisplatin in the range of 50-60 mg per meter square every three weeks.

At that same meeting at ASCO

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. Again, each regimen was given every three weeks for a total of six cycles.

While we thought we knew what the results of this study would be before we started, and what we found out was that there is no significant different difference in overall survival. The Taxol single agent arm gave a lower response rate and a shorter progression-free survival, but overall survival was exactly the same. You might ask yourself, “Why did this study differ from OV10 and GOG111?” Well the circumstances were quite different. When GOG111 and OV10 were done Taxol was not available for salvage therapy in those countries. In the U.S. for 111 and in Canada and Europe for OV10. So patients who were assigned a Cytoxan/cisplatin did not get salvage Taxol. On the other hand, when this study was done, Taxol was commercially available and in fact what happened was that at the end of six cycles of therapy if patients had any residual disease left, they immediately got salvage therapy.

Patients assigned to the cisplatin arm got Taxol and patients assigned to the Taxol arm got cisplatin.

Patients assigned to the combination arm got a whole hodgepodge of different things, most of which probably did absolutely nothing or even harmed the patient.

So as a result, half the patients got some form of salvage therapy and we believe the crossover to the opposite drug accounts for the blunting of the survival differences that you see in the study. Also this was not merely salvage therapy. This was immediate use of the other drug without waiting for disease progression to take place. So in effect what we were really studying here was sequential cisplatin for six cycles followed by Taxol for 6-12 cycles or Taxol for six cycles followed by cisplatin for six cycles, or concurrent therapy. We proved something here that I think is going to turn out to be very useful for us. We’ve proved that you can give drugs concurrently or sequentially and achieve the same results. That sort of approach is going to be applied in trying to introduce additional active new agents to up front therapy, that is, sequential doublets will probably be used in that experimental approach.

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. One-third of the patients in the study on the control arm also received salvage Taxol. So there will be some blunting of any survival differences as you would expect, because of the salvage therapy. Seventy percent of the control patients received single agent carboplatin as a control, 30% received a three drug combination. Now I should tell you that there was an ICON study, ICON-2, that showed no difference between the three drug combination and carboplatin so it’s reasonable to lump the control arms. Now if you attended ASCO and attended the GYN session you know that the ICON investigators presented the following data; in terms of progression-free survival, no difference between the two arms.

In terms of overall survival, no difference between the two arms. What they did not present was presented by Dr. McGuire in his discussion and was obtained from one of the ICON collaborators and that is a more detailed breakdown of the data. And this is a very important subset analysis; 622 of the patients had stage I disease. Only 83 events had occurred in that subset. Too few events to allow any meaningful conclusions to be drawn. But 1,452 of the patients had either stage III or stage IV disease and among those 1,452 there had been 544 events, enough events to allow valid conclusions to be drawn. In this subset, which is the same subset studied in OV10 and a similar subset to GOG111, hazard ratio was 0.82 and that is statistically significant at a P value of 0.03. So in the same population of patients studies in OV10 and GOG111 you see the same result, a benefit from concurrent Taxol, platinum administration. If you put all four of these trials on the same slide you will note that three of the four, GOG111, OV10 and ICON-3, show a clear value for the Taxol/platinum combination. One, GOG132, shows no difference but is accounted for the immediate rather than the salvage use of the opposite drug. The weight of evidence in these four studies speaks to the standard of care as being a combination of Taxol and platinum. And if you are asked that on the Boards, that’s what your answer is.

FIGO staging system

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.

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