Toolbox makeover?

[Rich66]

Toolbox makeover?

I’ve been wood-shedding a bit and I have some very uncredentialed thoughts about current approaches. Not that anyone’s asking

Giving large doses (maximum tolerated dose/MTD) of potent but toxic chemo seems to necessitate steroid pre-meds and opiate painkillers that undermine the chemo. Then there's the chemo break which allows the patient to recover..and the cancer to regroup/mutate towards resistance in between big doses. So..is more really better?
I am seeing more and more about the metronomic approach (lower, more frequent dosing) and it seems like it might be a way to use chemo more in harmony with the body and more detrimental to the cancer in the long run...especially if the rare immediate complete remission (NED) is not the goal, but overall survival is. This idea of continuity is familiar and intuitive to anyone who’s gone through weeks of radiation therapy or taken antibiotics. A good portion of metronomics use milder chemos that aren’t even on the radar these days (cytoxan) due to long term tolerability and oral/daily delivery as opposed to schedule limited IV. In the shorter term, and when faster control is needed, more potent chemos at lower doses may be able to benefit from the same approach with better early control. Afterwards, a gentler metronomic regimen could be used as maintenance.
Hormonal treatments are in daily oral form and may derive a lot of their benefit from a metronomic approach without breaks. Lapatinib may fit this category as well and may account for some of the arguably increased benefit over Herceptin. Capecitabine is daily oral but tends to be given at max tolerance with chemo breaks and resistance issues are typical. There is some indication that Capecitabine can deliver slow but impressive results at 1/3 the usual dose but without breaks. Inhibiting angiogensis or stopping blood vessel growth seems to be important to the approach and drugs like Avastin work that way and can add to the metronomic approach but there seems to be a some concern over how or whether to stop Avastin once begun. Makes me wonder if focusing on the delivery without Avastin type drugs might be better in the long run. It is intriguing that there is a new Avastin type drug in an daily oral form. An anti-angiogenic drug to be delivered in an antiangiogenic fashion.
In terms of the usual chemos (taxanes/anthracyclines), the typical path patients take is using one potent chemo or combination at max dose (with steroids, opiates and breaks) until resistance builds up then moving to the next, each course tending to be less effective. It isn’t uncommon to have problems staying on the schedule, due to low wbc/neutropenia. An indicator of how important the delivery approach might be is demonstrated by studies that show chemos that previously “failed” could be effective if re-introduced on a metronomic schedule. This begs an important question. Are patients permanently turning their back on “failed” chemos when simply adjusting the delivery might extract extended benefit? This may be especially important for patients nearing the end of options with bodies deemed unable to tolerate more of the standard delivery approach.
And there are also plenty of suggestion that chronotherapy i.e. time of day of delivery considerations can make a given agent far more effective and less toxic. Looking at sequence issues, there are indications that delivering calcitrol 24 hrs before and Zoledronic Acid 24 hrs after chemo can multiply the effects. Giving a short, high dose of Lapatinib seems to prime the tumor vasculature to better receive chemo. So sequence may have a role to play.
An "outside the box" look at existing drugs’ abilities can increase the tools available. Old dog Tamoxifen seems to have new non hormonal tricks like additive and synergistic effect on ER independent pathways and ability to cross the blood brain barrier. Traditionally non-cancer oriented drugs can be helpful, especially since data from patients taking them may be in the books already. Metformin’s regulation of glycolysis is a great example of reframing a negative. It has been contraindicated prior to PET scan since it interferes with cancer cells uptake of glucose, a primary source of energy. Not surprisingly, we are now hearing that that’s a good thing. Prozac’s shut down of pumps that push chemo out of resistant cells (even cancer stem cells) holds great promise since the best chemo in the world is useless if it doesn’t stick around to wear out its welcome. In the almost surreal vein, Noscapine, a cough medicine, seems to have anticancer properties by way of microtubule interference similar to, but possibly showing resistance reversing qualities to, Taxanes with basically zero toxicity and oral, metronomic fiendly delivery options.

Certainly these approaches have deep ramifications in terms of lowering costs and providing easier, less facility based access to those who can't acquire the latest, greatest..but expensive agents available.

Combining metronomic delivery, chronotherapy, sequence and increased awareness of existing tools might give far more benefit and less need for a break from toxicity..ultimately giving better control of cancer.

Rich66, OB (oncologic bloviator)

[chrisy]

Ha ha Rich! Bloviate on!

Without attempting to tackle the details (just a suggestion, "white space" is good), I agree that less can be more.

[suzan w]

What you say makes alot of sense. When I was doing chemo, the steroids (decadron) made me nutty/and feel like sh#%. The opiates made me feel horrid. And then there was the chemo!!!

[Laurel]

Interesting logic, but really very basic at its core. Find a synergy with our bodies and our immune systems, rather than a full bore assault every other week or so. Chemo is violent and arcane. It begs to be revisited with a new approach.

Thanks for the post, Rich! Really worried about those eggos!

[Rich66]

Suzan, beyond making you feel crappy or wired, the Decadron apparently undermines the chemo. There are other antinausea drugs that can be used without defeating the purpose of the treatment itself. I'm hoping the same is true for opiates. Who would knowingly take painkillers that undermine the treatment that gave you the pain to begin with?
An ER+ pateint could be drinking coffee, pre-meding with Decadron and easing the pain with Oxycodone while getting treatment diminished by all of the above.
Let's do it again next week...if your wbc holds up. If not, skip treatment to give the cancer time to regrow and mutate. Tell me I have this wrong..please.

Sorry about the bad formatting. It looked better somehow in Word. Just be glad it's not in my handwriting.


But Laurel's right. Bigger issues loom. If we have an Eggo shortage, there will be no point in going on.

[ElaineM]

That is why I took my chemo without premeds. If the doc was worried about side effects I told him to prescribe pills or suggest over the counter remedies I could have at home just in case I needed them.
I never needed them and ended up throwing alot of stuff in the trash when it expired.

[Rich66]

Ok..but did you actually know the premeds could hamper the chemo? This is really an informed consent/hippocratic oath issue. It's fairly new information and maybe not "peer reviewed" or tested by trial. Who's going to do that? Maybe it's not common knowledge amongst docs here. The studies I found were mostly European. In any case, if there is any doubt about the Decadron, skip them or use the non-steroidal alternatives to be on the safe side. The opiate pain med issue seems more recent. Still not sure if it's all opiates or just ones that operate like morphine. Maybe the surgical dose is much larger too. But again, if a more divided dose would negate some of the need for support meds and is actually more effective over the long haul...what is the point of the traditional approach?

[ElaineM]

No. I had never read any studies. I just happen to know all drugs can have side effects, including pre meds. I made a personal decision to take chemo straight up without them. I decided less my body had to deal with the better it would be ---------- and it was.

[Rich66]

Well..apparently it was better instinct than you could have imagined. I just wish it had been alarmist. Seems like we shouldn't have to go by gut instinct in this arena.

[hutchibk]

FYI, this is a fantastic discussion.

[Rich66]

Dearest Hutchi,
Been meaning to suggest you consider the Old Dog Tamoxifen as your ER/Her2 crosstalk rectifier. With brain met issues, might be just the ticket since Tam crosses BBB. Might even complement the Aromasin since Tam works at the receptor and Aromasin works at the source. Endocrine blockade with BBB attributes beyond hormonal. Woo hooo. (don't complain to me about the joint aches)

[whatz]

Alas the discussion came too late for me as I took all IV premeds and had my last chemo yesterday (whohoo). Only reduction I did was from two Tylenol to one since I know about that and felt qualified to make the decision. I am however still on Herceptin. Meds for that according to my onc will be the anti-histamine and Tylenol. So I'm assuming I'm OK on this since they're neither opiate nor steroid. Correct?

[Carolyns]

Hi Rich,

I think it is a good discussion. I wish I could continue getting Herceptin weekly rather than the 3 week dose with TDM1. It is not up to me and I am grateful to be in the study... just in a perfect world I would get it weekly.

I went with the less is more approach ever since I was found to have mets. The original cancer center I went to had suggested the double barrel method. It was a very tough decision for me because I didn't want to believe that I could not be "cured" again. I also thought that I was wouldn't being trying hard enough if I didn't do the roughest treatment. In the end, with much research and discussion with oncologist that are "breast cancer" only doctors, I found that less is more. 4 years, 12 lines of therapy later I am still working full time and raising my 11 year old son.... living a full life... waiting for the cure. It has seemed to be the right thing for me so far and I would like to continue down this path of less is more.

Thanks for your thoughts and observations.

Carolyn

[Hopeful]

Rich,

I came to a similar conclusion as you about metronomic chemo two years ago, for many of the same reasons. In addition to all of the points in your post, let's not also forget the inflammatory/fatty acid issues R.B. spent a long time trying to educate us about, which have been shown to be ameliorated by statins. Another drum that Alaska Angel bangs loud and hard (and accurately, I believe) about the risk of using steroid pre-meds is that the associated weight gain and loss of muscle mass, leading to difficulties keeping weight off post treatment, causes survivors to struggle with unwanted weight that has been shown to increase the risk of bc recurrence. Finally, maximum tolerated doses of highly toxic chemos often require supplementation with growth colony stimulating factors, which have been shown in some instances to enhance recurrence and in others to shorten life spans. There absolutely has to be a better way.

My personal belief is that greater toxicity does not confer greater benefit, just greater side effects and permanent damage to the body. We focus too strongly on the "shock and awe" mentality of blasting every last cancer cell to smithereens (as if we knew that to be actually possible), rather than focus on fine tuning whatever is out of balance in the body, to reduce carcinogenicity. It is my belief that the changes which cause or stimulate cancer are largely epigenetic, and could be corrected through a better appreciation of the endocrine system, and all of the related signalling pathways between the various hormonal systems in the body, not just sex hormones, as all of the hormones seem capable of utilizing all of the available hormonal pathways in the body, if push comes to shove.

As to whether anyone is asking for your thoughts, assume we are, and please put them out there as they come to you.

Hopeful

[Ellie F]

Hi Folks
My new onc wanted to try metronomic xeloda to try to maintain my NED status. I was for this approach having had a detailed discussion with a fellow bc survivor in the clinic who had been given 6 months to live and was still at clinic 2 years later. She confided that she had not taken the prescribed dose but a small amount each day and was doing very well!!
My onc was deterred from going ahead with this approach by his colleagues who do not agree less can be more.
Ellie

[Rich66]

Ahdubose,
I haven't heard of any problems with painkillers other than opiate based as Lani posted. It may just be morphine at high doses in surgical setting. But it might make sense to minimize/avoid opiates until this settles out. The pre-med issue seems easier since one could just get the non-steroidal flavor.

Carolyn, Herceptin at 3 weeks may be just fine since it is such a different animal than other "chemos". But when I think of antibiotics, more frequent seems to be better. I was just floating the hypothetical..just me yapping.

I have to mention 3 of the forum's liver mets success stories that I'm aware of got to NED and stayed there by way of MTD. Steph (Taxol), Andrea (Taxotere) and MamaCZ (Navelbine). So it's pretty hard to get dogmatic about any of this. It seems all 3 were pretty sturdy going in so they might have been good candidates for that approach. It would be good to know if they made it through without unscheduled breaks or growth factors. The continuity part seems to be the key to metronomic therapy. I am currently confused on the growth factor issue, having seen it portrayed as everything from detrimental to a therapy option in its own right. Not sure if it has to do with the difference between G-CSF and GM-CSF. Becky researched this heavily for her adjuvant therapy and went with GM-CSF. If you have info at hand, serve it up.

Ellie brings up an interesting (to understate it) concept: Oncs being peer pressured into treatment decisions. Oncs don't work in isolation and may feel like they have to go by the book even when their judgement says otherwise. There are probably liability concerns lurking in their decisions as well. Do what 9 out of 10 oncs would do and avoid controversy. From the perspective of career protection (hard to think of things this way), it wouldn't surprise me. I think an onc has to be pretty secure in their career to follow their own judgement to that degree.

Ellie, did the patient who did secret metronomic Xeloda do continuous days or the 1 wk on/1 wk off schedule? Did she take around 500mg? I would love to know more about her specifics. It seems similar to one of the case studies in the metronomic thread.

I think the most intriguing aspect of the metronomic approach is the idea it might give new life to previously "failed" treatments in patients who are really beat down and thinking they are out of options. Maybe a couple are reading this right now. There are also numerous drug approaches to reverse resistance..seems we never hear of anyone using either one of these approaches to replenish the toolbox. It's just..had that, got use out of it..step through the list and don't look back. And when a treatment is revisited, it seems to be done in the MTD setting. How many folks could be bettered if they used schedule and/or drug approaches to regain sensitivity with manageable toxity? There seems to be the idea out there that in metastatic setting, sequence or combination of drugs don't change survival, only toxicity. Have they employed all the tools in the best way when they arrive at that assertion?

[Ellie F]

Rich
She took 500mg for 14 days then had 7 days off.The time interval was what had been prescribed by her onc but he wanted her to take 1000mg initially building up to 1500mg.
She was also on oral morphine but had halved this dose once on this regime and believed that she would be able to stop it altogether soon as she felt so much better!
I think your comments about onc peer pressure probably hold true especially as a lot of cases are 'team' reviewed so any out of the norm prescribing would be subject to much scrutiny.
Ellie

[ElaineM]

This is a very interesting discussion. Metronomic chemo with cox 2 inhibitors/antianigogenisis therapies is something we can ask our docs about.
I took Herceptin every week instead of every 3 weeks. I read a smaller dose every week is easier on the heart. The doc asked me if I want Herceptin every three weeks several times and I said, "No. I prefer weekly."

[schoolteacher]

I have really enjoyed this discussion. This is really something to think about.

Amelia

[Hopeful]

I am currently confused on the growth factor issue, having seen it portrayed as everything from detrimental to a therapy option in its own right. Not sure if it has to do with the difference between G-CSF and GM-CSF. Becky researched this heavily for her adjuvant therapy and went with GM-CSF. If you have info at hand, serve it up.

Here are a few threads from this board with links to various articles and discussions:

http://her2support.org/vbulletin/sho...eferrerid=1173

http://her2support.org/vbulletin/sho...eferrerid=1173

http://her2support.org/vbulletin/sho...eferrerid=1173

Hopeful