Rich66
11-19-2009, 02:40 PM
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 (http://her2support.org/vbulletin/showthread.php?p=214419&highlight=brain#post214419). 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)
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 (http://her2support.org/vbulletin/showthread.php?p=214419&highlight=brain#post214419). 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)