Very Good Article: IP vs Dose Dense Chemo

http://tinyurl.com/4vxhmga
The author explains the commonality between both chemo regimes and why they may work equally well.

IP Chemo:
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.

Dose Dense:
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).

The Comparison:
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.

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Thank you very much rozetta for sharing this. My partner had three round of traditional paclitaxel and carbo prior to surgery, and six rounds of dose-dense after. She experienced both hematologic toxicity and neuropathy. But she said that the dose dense regimen was actually easier overall than the standard single dose every three weeks. Plus, she kept most of her hair whereas the standard chemo caused it all to drop. We're only a month out from finishing treatment... so no word on efficacy from us yet.

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Brian,
My oncologist told me that the reason he switched to dose dense treatment is that he had heard
an oncologist speak a few years ago and he said that he had patients who did not seem to respond
to traditional IV carbo/'taxol every three weeks who did really well when he switched to the dense dose
regime.

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Our oncologist told us that it seemed to be much better - that they were 60 months out of the study and hadn't reached the median survival point yet. We were scared of the effects, but Kathy made it through without too many problems. We had to pay out of pocket for neupogen though.

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Brian,

So sorry you had to pay for the injections out of pocket. I am wishing you and Kathy all the best!

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A good reasono for the success with dose-dense is that many chemotherapy drugs, in addition to killing tumor cells, also fight angiogenesis. However, the anti-angiogenic effects of dose-intense (high-dose) therapy may be masked and marginalized by the way it is usually administered.

The reason dose-intense chemotherapy was not stopping angiogenesis was that chemotherapy is usually given in big doses, with long breaks between drug administration that are necessary to allow the patient to recover from the harmful side effects of treatment.

The anti-angiogenic effect does not translate into a significant therapeutic benefit because the damage to the vasculature of the tumor can be largely repaird during the long rest and recovery periods between successive cycles of therapy.

During the breaks, the tumor's blood vessels could grow back. By giving chemotherapy more often, at lower doses, it might prevent the regrowth of blood vessels and kill the tumor or at least slow its growth. The more freaquent, regular, lower-dose therapy can have an impressive anti-angiogenic and anti-tumor effects.

The main targets of dose-intense chemotherapy are presumed to be proliferating tumor cells. The main targets of dose-dense (low-dose) chemotherapy are the endothelial cells of the growing vasculature of a tumor. In other words, chemotherapeutics can be used as anti-angiogenic agents.

When administering both anti-tumor and anti-angiogenesis drugs, the endothelial cells (involved in angiogenessis) are the first in the tumor to undergo cell death (apoptosis).

Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy, so if cancer cells become drug resistant, these medicines should still be able to shrink tumors by destroying their blood supply.

When administering both anti-tumor and anti-angiogenesis drugs, the endothelial cells (involved in angiogenesis) are the first in the tumor to undergo cell death (apoptosis).

Too much/too aggressive chemotherapy can shorten as much as it can prolong life.

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Greg, my oncologist did tell me that the dose dense chemo did have an anti-angiogenesis effect.
He was my second consult. I had planned on asking him about dose dense chemo, but he jumped
the gun on me. This was one of the reasons I went with him over the first oncologist. It felt like we
were on the same wavelength and I couldn't ignore that. I wouldn't have known about dose dense
chemo if you hadn't written about it in answer to one of my questions . . . so thanks!

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Iam proof positive that this regime of dose dense can work. I have been in constant chemo of some sort for a little over 2 years. started 10 months ago with dose dense taxol/ with bi-avastin. My ca markers are the LOWEST they have ever been in over three years. My blood counts are stable and I feel like I did before cancer. I have no visible cancer on the scan I recently had. Who knew that a small amount of chemo every week can work better (a least for me) than the higher dosage. I always believed that I have to be sick to be well in the scheme of chemotherpay. I just hope it continues to work so I can get a little stronger when I have to go on something else. Nikki

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I've been on dose-dense carboplatin/taxotere/Avastin since Oct.26. We were trying for 18 straight weeks, but I had to take the fourth week off due to a fever. I then had 12 straight weeks. LAst week my body just couldn't take any more, so I requested a week off and the doctor agreed. We didn't do the Bloodwork. This week the Bloodwork for my upcoming treatment showed the neutrophils are too low for Chemo. The onc team said they possibly were even lower last week and we'll next week if they are actually rising

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Rozetta--
Didn't you get through dose dense with no delays? were you very healthy from the outset? do anything special to keep your counts up?

It's too bad they have added Avastin to GOG 252. It would be great to see dose dense and IP comapred without it. If dose dense and IP both work as angiogenesis, then perhaps Avastin is not a complement at all.

Linda

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Really good discussion. I didn't technically have dose dense treatment, but it was somewhat similar. I had my Gemzar/Carbo/Avastin every two weeks, with a reduced dose of Gemzar. My blood work was always good enough to receive next treatment. Have now been on the Avastin maintenance for a year (every two weeks) and we are decreasing it. Have gone from 10mg to 8 and now to 6 (per kilo of body weight). After three infusions, we are going to 4mg for three weeks and then stop altogether (unless my CA125 starts to rise). If I have to go back on in the future, I will ask to try both a lower dose of Gemzar and Carbo on a weekly basis (without the Avastin)...at least for the first half of the treatment.
"feellikeaguineapig"

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This is a really good discussion. Variations of minds. Good points Linda about seeing dose dense and IP compared without Avastin. If dose dense works as angiogenesis with either technique (IV or IP), then perhpas Avastin is not a complement at all. Also, if dose dense angiogenesis effects can attack all the pro-angiogenic factors: VEGF, FGF, PDGF, ephrin A1, angioprotein 1, IL-8, etc., then maybe they don't need the other drugs, which really don't get into the tumor so well. Angiogenic attack provides true selective toxicity, something which is sorely lacking with all of the other treatments.

Perhaps Verlinda could have gone beyond the 18 straight weeks without Avastin and still have the anti-angiogenesis effects without it? Or, even like Mimi, ratchet back on the anti-VEGF drug. Cancer patients may be taking doses of treatments that are possibly well in excess of what they need. Writing in the Journal of Clinical Oncology, Dr. Ian Haines cites Avastin, the dose being used is 15 milligrams per kilogram of body weight, despite other research showing it may work with 3 milligrams per kilogram of body weight.

Rozetta. Looks like you may have an oncologist that does the "thinking outside the box" with rational approaches to cancer treatment. Although vascular targeting with Avastin is a useful adjunct to therapy, the mechanism of action may more reflect the Vascular Permeability Factor effects and less to do with the anti-angiogenesis effects. You have to watch "how" and "when" Avastin is used.

Greg

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I just talked to my local ONCO's office about clinical trials in general. they participated in the earlier GOG trial with Avastin and told me every woman who had been on it has had to be re-treated. In other words, had a recurrence.

In contrast she cited several women, even one at stage IV, who has not yet had a recurrence on front Line IP chemo alone. (they did not do dose dense).

I have high hopes that if I have a recurrence I can have dose dense.

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Linda, I hope we don't need it but that's in the back of my mind too.

My moms recurrence was treated like dose dense though they didn't call it that. Low Taxol doses every week for 3 weeks then a week off. She did change to Taxotere (sp?) maybe 2/3 way through because of neuropathy issues. So far so good. Hoping she gets a long remission this time, first one was 15 months,

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Hi Heather-- did your mom have IP like you did the first time?

Linda

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No, she was sub optimally debulked, her Gyno onc left a 10cm tumor wrapped around her colon for starters. She ended up having a second surgery 5 weeks later and that gyno onc got everything out. It's quite a story. Gee, patient comes to you and basically hasn't been able to go to the bathroom for years so let's just leave that tumor in there! What an ass (pardon my language).

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Seadream,

I had one injection of neulasta at the end of the third month. Then during the fifth month I had two
treatments that were reduced dose. I really think I was in remission by then. During the sixth month
my last dose was just taxol, since my WB counts were low. I really didn't do anything holistically to
keep the WB counts up. Low WB counts is so common with chemo and can certainly be managed.

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Heather-- He does sound like an ass... I do remember you had on another post the suboptimal debulking. I am glad to hear she is doing well.

I just talked to the office that did my surgery and told a woman who has worked with my surgeon for 20 years that he scared me to death in the hospital with the prognosis. She said he is tough, but if she needed surgery he would be the one she picked. I of course said no argument there and I am grateful. Very grateful.

Linda

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Hi Rozetta- but not bad for dose dense and you stuck with it. It has a high drop out rate but it seems like some women like it better?

Linda

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Greg,

Yes, I do think my oncologist thinks outside the box. He, also, initiated having the ascites
drained from my abdomen, so it could be sent to Rational Therapeutics. I think one of the
reasons he had it done was to see if I was platinum sensitive. He was very pleased with the
results.

Although I had optimum debulking, he didn't consider me to be a good candidate for IP chemo
because he said my disease was too large - probably because I had PPC. His opinion is that IP
works the best with women who have had solid tumors and are optimally debulked.

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Seadream,

I have to say that the chemo was easy. I had hair loss and numbness in my toes that I'm hoping
will eventually go away. I never felt sick, had mouth sores, or aching, etc. After the second month
the tiredness went away. I do think that I have some issues with my gastrointestinal track that started
the fifth month, that is probably due to the Taxol, but nothing bad.

I think IP chemo is a lot harder and you made it through that. You're awesome!

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