(May have seen this posted earlier?): Ovarian Cancer—New Thinking on Old Regimens

lindaprocopio

Ovarian Cancer—New Thinking on Old Regimens
2011 Feb 23, Nelson Teng

Nelson Teng, MD, PhD, is Director of Gynecologic Oncology and Associate Professor of Obstetrics and Gynecology at Stanford University School of Medicine. Dr. Teng is also Program Director for the Stanford/UCSF Gynecologic Oncology Fellowship Program in Stanford, California.

The basis for using intraperitoneal chemotherapy comes from several randomized studies including the now old Gynecologic Oncology Group (GOG) study by Armstrong et al, published in the New England Journal of Medicine in 2006; however, there is a renewed interest in this topic, which has now become an important subject.

In spite of all of the advances that biologics and newer drugs, the so-called triplet combinations, have made beyond the old standard doublet of carboplatin and paclitaxel as first line therapy, for the most part, either the result is not entirely confirmatory with survival data yet or the drug has shown minimal effect in other solid tumors. Case in point is the findings from the ICON7 trial2 and OCEANS trial which are very encouraging, but we don’t have the final results. It is not clear whether any of the studies of these new regimens will have the same kind of impact on survival of those that I would consider the most important studies published in ovarian cancer in the past decade.

One of those studies is the one I mentioned, which looked at intraperitoneal therapy, and the other one was published by the Japanese Gynecologic Oncology Group (GOG), and looked at dose-dense (not dose intense, e.g. with marrow transplant or stem cell support) chemotherapy in advanced ovarian cancer. We can compare these two studies.

In the first study, which is well-known, intraperitoneal vs intravenous cisplatin and paclitaxel were compared. Intraperitoneal therapy showed a tremendously impressive extension of not only the progression-free interval, but also overall survival. The median progression-free survival was increased from 18.3 months to 23.8 months (P = .05) and the median survival difference was 49 months vs 65 months (P = .03), a difference of almost 14 months, which is a whopper in any kind of drug study.

Had this study been not on just a procedure, a technique of intraperitoneal devices, but on a drug of some kind, showing this degree of improvement in survival, it would have been an instantaneous hit and the drug probably would be used even without waiting for completion of an additional confirmatory study. There have been at least three randomized trials that have demonstrated superiority of intraperitoneal over intravenous delivery of platinum-based chemotherapy in patients with optimally debulked advanced ovarian cancer, but intraperitoneal therapy hasn’t really caught on.

There has always been a question in my mind as to why this should be the case. Then, about a year ago, the Japanese GOG reported results from what I consider to be a very well-designed phase III trial showing the benefit of dose-dense, once weekly paclitaxel. When compared with the patients assigned to the conventional regimen of paclitaxel and carboplatin, those on the dose-dense paclitaxel plus carboplatin regimen showed improvement of both the progression-free interval and overall survival. Progression-free survival was 28.0 months and 17.2 months, respectively (hazard ratio [HR] 0.71; 95% CI 0.58–0.88; P = 0.0015). The 3-year overall survival rate was 72.1% vs 65.1% (HR, 0.75; CI, 0.57–0.98; P = 0.03).

A very interesting correlation can be made concerning the possible mechanism of intraperitoneal therapy and also the weekly dosing investigated by the Japanese study. If we consider the reasons that intraperitoneal therapy works, it becomes obvious that it is not simply just the fact that the drug is delivered directly into the abdominal cavity, where most of the ovarian cancers reside. The major mechanism may, perhaps, be a depot, slow release effect by which the intraperitoneal drug, paclitaxel or cisplatin, actually circulates into the blood systemically over time. We know that paclitaxel, when given intraperitoneally, has a very, very long half-life, hence a “dose-dense” effect.

The dosing in the Armstrong study is actually similar to the dose-dense chemotherapy in the Japanese study that was given weekly. Armstrong and colleagues gave 80 mg of paclitaxel per week for 3 weeks. Carboplatin was given at the standard dose, AUC of 6. If we add up the three treatments of paclitaxel, the total dose was 240 mg, which is higher than what we typically use as a pulsed dose of 175 mg. So, by distributing the dose over time, we may have achieved a similar mechanistic effect to that of the intraperitoneal depot effect.
Of course, one of the issues here is that hematologic toxicity is frequently dose-limiting. Hematologic toxicity, particularly thrombocytopenia, is carboplatin-related. Somehow, with intraperitoneal delivery or dose-dense therapy, we can actually reduce the incidence of this toxicity.

Another issue is higher hematologic toxicity with intravenous chemotherapy than with intraperitoneal chemotherapy. The real question is whether we are able to use these two studies to advance the field by looking at a different regimen, as well as a more convenient way of administering therapy instead of intraperitoneally, by actually using intravenous therapy.

Currently, GOG is conducting a trial, GOG 252, in which they compare the different intraperitoneal dose-dense regimens and, then, just to do the fashionable thing, will add bevacizumab to all of the regimens, which will be followed by bevacizumab maintenance therapy. It does not directly compare intraperitoneal and intravenous delivery; nevertheless, we may get a useful result. In short, there is a significant contribution to be made by really looking at the therapy that we already have on hand. For example, in pediatric acute lymphoblastic leukemia, significant improvement in survival was achieved in the past several decades without the introduction of any new drugs.

There are several things to consider in these two studies. One common criticism of both studies is the high dropout rate. Of interest, both studies have very similar dropout rates. In fact, in the intraperitoneal study, only 42% of patients received all six cycles of chemotherapy and in the experimental arm of the Japanese study, 48% received all six cycles. However, if all the patients had completed the six-cycle treatment in either of these two studies, the result would have been even more dramatic. The high noncompletion rate was caused, mainly, by severe hematologic and neurologic toxicity, pain, and fatigue.

Another criticism is that the Japanese population might be different from others, so there may be ethnic or racial differences. For example, there is a difference in histologic distribution of tumors, with higher incidence of clear cell carcinoma in the Asian population; clear cell carcinoma carries a poorer prognosis. However, when the Japanese analyzed only the serous papillary tumors, they still observed an improvement in survival. In fact, in their study, using the dose-dense schedule did not show an obvious impact on outcomes in patients with clear cell carcinoma.

There are other differences in the inclusion criteria, such as the inclusion of stage II disease in the dose-dense trial, whereas, only stage III patients were studied in the intraperitoneal trial. There might also be variation in the surgical debulking techniques used. The GOG 252 trial probably will be one of the studies in which these questions can be answered.

There are other intriguing mechanisms involved. For example, paclitaxel, given at a low dose may have, in itself, an anti-angiogenesis effect, which may be synergistic with the chemotherapy regimen, especially when paclitaxel is given in a dose-dense manner. One wonders if this would explain why in the phase III GOG 218 trial, which looked at bevacizumab in women with advanced ovarian cancer, an improvement in progression-free survival was only observed in patients who received continued bevacizumab maintenance therapy. Women treated with carboplatin and paclitaxel, with or without bevacizumab, showed no difference in progression-free survival.4 The anti-angiogenesis effect may already be maximized by paclitaxel, such that the addition of bevacizumab to chemotherapy showed no significant improvement.

By better dosing, which could be a lower dose of both carboplatin and paclitaxel, the hematologic and other toxicities can be reduced. The kinetics may be more similar to that of the traditional low dose, continuous metronomic chemotherapy. Although the verdict is still out on whether these traditional therapies should be pushed aside in favor of biologics, consideration must be given to the side effects of the newer agents, especially longer term and also a serious issue relative to cost.

These two seemingly very different types of regimen may share a common mechanistic fundamental. The result of one study actually affirmed the other. There were two different methodologies, evaluated in very different patient populations, yet showing comparable superior survival curves. Further investigation of the old drugs with innovative dosing and scheduling, and also delivery, may be in order.

References
1. Armstrong DK,, Bundy B, Wenzel L, et al. Intraperitoneal Cisplatin and Paclitaxel in Ovarian Cancer. N Engl J Med.2006;354:34-43.
2. ICON7. A phase III randomised Gynaecologic Cancer InterGroup trial of concurrent bevacizumab and chemotherapy followed by maintenance bevacizumab, versus chemotherapy alone in women with newly diagnosed epithelial ovarian (EOC), primary peritoneal (PPC) or fallopian tube cancer (FTC). Paper presented at: 35th European Society for Medical Oncology (ESMO) Congress; October 8-12, 2010; Milan, Italy. Perren T, UK, Presenter. Abstract LBA4.
3. Katsumata N , Yasuda M ,Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. The Lancet. October 2009 374(9698):1331-8.
4. Burger RA, Brady MF, Bookman MA, et al. Safety and subgroup efficacy analyses in GOG218, a phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC) or fallopian tube cancer (FTC): a Gynecologic Oncology Group study. Paper presented at: 35th European Society for Medical Oncology (ESMO) Congress; October 8-12, 2010; Milan, Italy. Proffered Paper 978.4.

LaundryQueen

metronomic chemo
I didn't know what "metronomic chemotherapy" is so I found the following info from the "NCI Bulletin" volume 3 number 26 on the web site dated June 27, 2006:

A New "Target" for Chemotherapy?

Although not typically considered a "targeted therapy" along the lines of drugs like trastuzumab (Herceptin) or gefitinib (Iressa), most chemotherapy does have a general target: rapidly dividing cells. This description applies well to cancer cells but, unfortunately, also describes some healthy cells, such as those in the bone marrow or gut, which also draw chemotherapy's wrath.

But chemotherapy drugs also have another target: endothelial cells that form the lining of newly formed blood vessels, such as those whose creation is orchestrated by tumors to fuel their growth. There is a considerable body of evidence that even very low, nontoxic doses of chemotherapy drugs, when delivered frequently for a prolonged period of time, can **** tumor blood vessel growth (or angiogenesis) by destroying endothelial cells.

Treatment approaches along these lines are now being tested in clinical trials, and they've been coined metronomic chemotherapy.

"The definition of metronomic chemotherapy varies, but generally it refers to repetitive, low doses of chemotherapy drugs designed to minimize toxicity and target the endothelium or tumor stroma as opposed to targeting the tumor," says Dr. Harold J. Burstein of the Dana-Farber Cancer Institute, who has led several early-stage trials of metronomic chemotherapy in women with breast cancer.

"It's definitely an interesting approach that opens up the possibility of using chemotherapy differently than we have traditionally considered," says Dr. Burstein.

The metronomic approach was initially proposed and tested in animal models by Dr. Timothy Browder in Dr. Judah Folkman's lab at Harvard Medical School. In the studies, standard maximum-tolerated dose (MTD) chemotherapy regimens caused cell death of endothelial cells in the blood vessels feeding to the tumor first, followed by tumor cells. But the long breaks needed between the MTD regimens allowed the damaged blood vessels, and thus the tumor, to recover.

But significantly lower doses given more frequently on a prolonged schedule proved to be far more effective, including complete tumor regressions, even in mice that were resistant to the same drug when used in a standard MTD regimen.

Since then, several research groups have confirmed these findings. And studies conducted in cell lines and animal models have also suggested that combining metronomic chemotherapy with targeted anti-angiogenesis agents is more effective than metronomic chemotherapy alone.

"I think the preclinical data together with the clinical trial results seen so far make a strong argument for testing metronomic chemotherapy more aggressively in larger trials, including trials where it's combined with different targeted agents," argues Dr. Robert Kerbel, of Sunnybrook Health Sciences Centre in Toronto, who has led many preclinical studies of metronomic chemotherapy.

A true metronomic regimen of frequent, low-dose chemotherapy over a longer period has yet to be tested in any phase III trials in the United States. A number of phase I and II trials have been conducted, however, yielding some provocative, if not altogether convincing, results.

Dr. Burstein presented data last December from a phase II clinical trial comparing a common metronomic regimen - a daily low dose of oral cyclophosphamide and a low dose of methotrexate twice a week - with or without the targeted anti-angiogenesis drug bevacizumab. The combination approach was superior to metronomic chemotherapy alone in delaying disease progression, but was not necessarily an improvement upon the results typically seen in similar patient populations treated with a standard MTD regimen.

Concerns about the toxic effects of conventional cancer treatments on pediatric patients also has prompted pediatric oncology researchers to investigate metronomic-like approaches to treatment. Some promising early results have been reported.

Based on the available clinical evidence, says Dr. Burstein, it's unclear in what setting metronomic chemotherapy might prove most useful.

"Those who are enthusiastic about it think it can be used anywhere," he says. "I think it's most likely to be used to treat more indolent, less threatening tumors because it may not work fast enough for those…with more aggressive disease."

Researchers like Dr. Kerbel, meanwhile, are making some headway on better understanding the nuts and bolts of metronomic chemotherapy, such as how to determine the lowest dose that can provide a potent benefit - the so-called optimal biological dose - and identifying biological markers that demonstrate whether the approach is having an anti-angiogenic effect.

Then there's this question: Can chemotherapy be delivered more frequently, even daily, at significantly higher doses than those used in most metronomic regimens but less than in MTD regimens? The toxicity might be greater than a "traditional" metronomic regimen, but so might the effectiveness, including in comparison with standard MTD regimens.

That's exactly what was shown in a phase III clinical trial presented earlier this month at the ASCO annual meeting. In women with locally advanced or inflammatory breast cancer, a presurgical (or neoadjuvant), metronomic-like regimen - using higher doses of cyclophosphamide, given daily; doxorubicin; and growth factor support to ensure the continued production of white blood cells - was superior to a standard MTD regimen at eliminating evidence of invasive cancer at the time of surgery. This outcome, explains Dr. Robert Livingston, a co-investigator on the Southwest Oncology Group-led trial, generally has been found to predict superior long-term outcome in patients.

The idea, according to Dr. Livingston, is to try to expose tumor cells to minimum concentrations of chemotherapy drugs for as long as possible.

"I think it's fair to call the regimen we have developed a hybrid," he says. "It can destroy tumor cells and, at the same time, the continuous exposure, particularly to cyclophosphamide, is having an anti-angiogenic effect."

By Carmen Phillips

LaundryQueen

LaundryQueen said:

metronomic chemo
I didn't know what "metronomic chemotherapy" is so I found the following info from the "NCI Bulletin" volume 3 number 26 on the web site dated June 27, 2006:

A New "Target" for Chemotherapy?

Although not typically considered a "targeted therapy" along the lines of drugs like trastuzumab (Herceptin) or gefitinib (Iressa), most chemotherapy does have a general target: rapidly dividing cells. This description applies well to cancer cells but, unfortunately, also describes some healthy cells, such as those in the bone marrow or gut, which also draw chemotherapy's wrath.

But chemotherapy drugs also have another target: endothelial cells that form the lining of newly formed blood vessels, such as those whose creation is orchestrated by tumors to fuel their growth. There is a considerable body of evidence that even very low, nontoxic doses of chemotherapy drugs, when delivered frequently for a prolonged period of time, can **** tumor blood vessel growth (or angiogenesis) by destroying endothelial cells.

Treatment approaches along these lines are now being tested in clinical trials, and they've been coined metronomic chemotherapy.

"The definition of metronomic chemotherapy varies, but generally it refers to repetitive, low doses of chemotherapy drugs designed to minimize toxicity and target the endothelium or tumor stroma as opposed to targeting the tumor," says Dr. Harold J. Burstein of the Dana-Farber Cancer Institute, who has led several early-stage trials of metronomic chemotherapy in women with breast cancer.

"It's definitely an interesting approach that opens up the possibility of using chemotherapy differently than we have traditionally considered," says Dr. Burstein.

The metronomic approach was initially proposed and tested in animal models by Dr. Timothy Browder in Dr. Judah Folkman's lab at Harvard Medical School. In the studies, standard maximum-tolerated dose (MTD) chemotherapy regimens caused cell death of endothelial cells in the blood vessels feeding to the tumor first, followed by tumor cells. But the long breaks needed between the MTD regimens allowed the damaged blood vessels, and thus the tumor, to recover.

But significantly lower doses given more frequently on a prolonged schedule proved to be far more effective, including complete tumor regressions, even in mice that were resistant to the same drug when used in a standard MTD regimen.

Since then, several research groups have confirmed these findings. And studies conducted in cell lines and animal models have also suggested that combining metronomic chemotherapy with targeted anti-angiogenesis agents is more effective than metronomic chemotherapy alone.

"I think the preclinical data together with the clinical trial results seen so far make a strong argument for testing metronomic chemotherapy more aggressively in larger trials, including trials where it's combined with different targeted agents," argues Dr. Robert Kerbel, of Sunnybrook Health Sciences Centre in Toronto, who has led many preclinical studies of metronomic chemotherapy.

A true metronomic regimen of frequent, low-dose chemotherapy over a longer period has yet to be tested in any phase III trials in the United States. A number of phase I and II trials have been conducted, however, yielding some provocative, if not altogether convincing, results.

Dr. Burstein presented data last December from a phase II clinical trial comparing a common metronomic regimen - a daily low dose of oral cyclophosphamide and a low dose of methotrexate twice a week - with or without the targeted anti-angiogenesis drug bevacizumab. The combination approach was superior to metronomic chemotherapy alone in delaying disease progression, but was not necessarily an improvement upon the results typically seen in similar patient populations treated with a standard MTD regimen.

Concerns about the toxic effects of conventional cancer treatments on pediatric patients also has prompted pediatric oncology researchers to investigate metronomic-like approaches to treatment. Some promising early results have been reported.

Based on the available clinical evidence, says Dr. Burstein, it's unclear in what setting metronomic chemotherapy might prove most useful.

"Those who are enthusiastic about it think it can be used anywhere," he says. "I think it's most likely to be used to treat more indolent, less threatening tumors because it may not work fast enough for those…with more aggressive disease."

Researchers like Dr. Kerbel, meanwhile, are making some headway on better understanding the nuts and bolts of metronomic chemotherapy, such as how to determine the lowest dose that can provide a potent benefit - the so-called optimal biological dose - and identifying biological markers that demonstrate whether the approach is having an anti-angiogenic effect.

Then there's this question: Can chemotherapy be delivered more frequently, even daily, at significantly higher doses than those used in most metronomic regimens but less than in MTD regimens? The toxicity might be greater than a "traditional" metronomic regimen, but so might the effectiveness, including in comparison with standard MTD regimens.

That's exactly what was shown in a phase III clinical trial presented earlier this month at the ASCO annual meeting. In women with locally advanced or inflammatory breast cancer, a presurgical (or neoadjuvant), metronomic-like regimen - using higher doses of cyclophosphamide, given daily; doxorubicin; and growth factor support to ensure the continued production of white blood cells - was superior to a standard MTD regimen at eliminating evidence of invasive cancer at the time of surgery. This outcome, explains Dr. Robert Livingston, a co-investigator on the Southwest Oncology Group-led trial, generally has been found to predict superior long-term outcome in patients.

The idea, according to Dr. Livingston, is to try to expose tumor cells to minimum concentrations of chemotherapy drugs for as long as possible.

"I think it's fair to call the regimen we have developed a hybrid," he says. "It can destroy tumor cells and, at the same time, the continuous exposure, particularly to cyclophosphamide, is having an anti-angiogenic effect."

By Carmen Phillips

tumor regression despite drug resistance
This pearl is buried in the above article:

But significantly lower doses given more frequently on a prolonged schedule proved to be far more effective, including COMPLETE TUMOR REGRESSIONS, even in mice that were RESISTANT to the SAME DRUG when used in a standard MTD regimen!

It's been almost five years since that was published...sigh.