General theory behind of the Metronomic Chemotherapy

[Fictional]

I thought I would open up a new topic under Metronomic Chemotherapy because this may be an option for many metastatic ASPS'ers. The principle behind metronomics is that less is more - that is giving less toxic levels of anti-cancer medications over a longer period of time is more effective than high toxic cycles with breaks in-between. Metronomic therapy may work especially well in vascular, metastatic, and relatively slow growing cancers, so ASPS is a reasonable candidate.

The dilemma for "otherwise-healthy" stage IV ASPS'ers is that although they would like to clear their disease, they don't want to take any therapy that could make them sicker. This seems to have happened among people who were members of th ASPS registry...that's why people who follow the board and know individuals' stories back several years tend to want to avoid intensive regimens. But as difficult as it was to look back and people who got worse with treatments, there are some patterns that emerge - I could see that often problems did not develop with the treatment cycle itself, but rather in the weeks following...looked like partial response at first (promising), then the disease can roaring back. Often the reason for this is that the vascular system and tumor is partially killed, but then there is an aggressive regrowth of vessels (and then tumor), resulting in worse disease than before. The same thing might happen for rapid regrowth after surgery. You can see this with other vascular solid tumors as well, as well as not-so-good responses to e.g. stem cell transplants.

But there is significant evidence that metronomic therapy may be less toxic and more effective in diseases such as ASPS. If you look the few stage IV (metastatic) cases that have been able to get free of disease, many of them had some sort of chemo regimen over a long period of time (e.g. 1-2 years). Also When I looked back at long survival ASPS'ers in the literature, i found many had oral low-dose (metronomic) medications like Cytoxan or etoposide in addition to successive thoracotomies to eventually get to NED or stable disease for 10+ years. And as far as cancers go, the dividing time for ASPS cancer cells is definitely slow. It makes sense that if you have something around longer - you're more likely to catch all the cells (especially if they can go "dormant" - alive, but not dividing) if you can take something longer at low dose, than high doses in short spurts in which treatment may be over after 3-4 months.

Here are a few links about the principles of metronomic therapy in general: http://www.virtualtrials.com/pdf/Metron ... herapy.pdf
http://pdf.medrang.co.kr/paper/pdf/Crt/Crt039-04-02.pdf If you look at responses in other vascular solid tumors, partial and complete responses and stable disease occuring in a strikingly high percentage of cases.

It is something one might want to be aware of too, because sometimes clinical trial agents aren't available or one only has the option between taking something at a maximally tolerated dose (not the metronomic principle)(phase I trial) or getting placebo in a phase III trial.

Meds used in metronomics are available to everyone and they have been studied for decades. Looking at the side effect profile can be a little frightening, but metronomic doses are often more than 100-fold lower with what some think is neglible toxicity. At least metastatic ASPS seems worse than metronomic side effects. Anyway, thought I would bring this up for some of you how might consider this. We are definitely considering this after our daughter's redo thoracotomy. Also the most recent ASPS case (abstract in the library, I can send the full article by email if anyone wants) of the 11 year old cleared (thoracotomy, then metronomic - weekly vinblastine + low dose cytoxan for one year) now at least 6+ years out - is another case supporting its likely benefit.

[Amanda]

Hello
Would you mind e mailing this to me and i will take it to the oncologysts that i will be seeing and also get there imput.
If i do need a treatment i would actualy like to try this. I wil post back what they tell me. I will be seeing them in about three weeks.
AmandaVWA@aol.com

Amanda

[Fictional]

There's a lot more info about metronomic therapy - in this book excerpt on Google books: http://books.google.com/books?id=bSHef8 ... #PPA259,M1

Chapter 16 (p 277) is on metronomic chemotherapy. Also interesting, there's a thought metronomic therapy may actually boost the immune system because it enriches the population of cytoxic T cells...there was a comment that metronomic chemo might especially be a good follow up therapy to those of you who have had a tumor vaccine...for just this reason.

[Olga]

I have found a review written by Dr.Kerbel in 2007 with the free full text

Five Years of Clinical Experience with Metronomic Chemotherapy: Achievements and Perspectives
http://content.karger.com/produktedb/pr ... 0000111479

and the the free full text of the result of the
Phase II clinical trial results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib in patients with advanced solid tumors with
http://clincancerres.aacrjournals.org/c ... 12/10/3092

it looks like this regimen is the most similar to the one that 'K' has started on so the toxicity profile can be looked at in this study.
I think that there is no Phase 3 for this combination as rofecoxib went off market later on?

[Arch]

Is this kind of systemic treatment plan better suited when the tumor load is minimal? Something like a maintenance regime to be started after surgery of all visible tumors, just to ensure nothing new shows up?

What about patients who have metastatic disease that has not been resected yet? Is there anyone who has tried a combination of metronomic chemo and a low dose anti angeogenic agent with any success? Has it resulted in any shrinkage or made an inoperable situation operable ?

[Fictional]

From what I have read, metronomic chemo seems to be more effective with the quantity of metastatic disease is low...but even then there are exceptions...I recall reading about one metronomic chemo study where the majority of metastatic patients were actively progressing, and still about 1/3 were able to get to stability.

With a high tumor burden, several options could be discussed with your oncologist...some do conventional chemo followed by metronomic chemo, another possible option is adding an antiangiogenesis agent onto to metronomic chemo. There have been a few studies with this with Avastin, and adding the Avastin seemed to increase the number getting to partial remission or stable disease. Probably Avastin was used first because it was one of the earlier agents. In the case of ASPS, Sutent might be a reasonable choice. I mention Sutent because it is commercially available and could be used off label without having to get into an investigational trial. We have also thought about adding Sutent on at some point...but might wait to see how metronomic only goes because of the Greek case report of the 11 year old who was able to get to NED after just cytoxan and weekly vinblastine. There is an increasing sense that maximal efficacy may need to involve combinations of the new selective agents, rather the one-at-a-time which is preferred when companies are first trying out a drug.

Also looking at the few long term survivors of ASPS I was struck by the common feature of virtually all seemed to be long duration chemo (can check my data on them under Published Cases at the bottom of the board forum). There are reports of good outcomes with thoracotomy only, but only 1 I know of who did not have any chemo. The best documented anecdotal cases of long survival (8+ years) had long duration and not short cycle chemo. One had high dose chemo for 2 1/2 years (very difficult to bear), but survived it and appears cancer-free.

One patient who shared her story I think was essentially discharged to hospice due to too many lung mets, but she entered the Vinblastine-Celebrex trial (they do a lot of metronomic chemo at Toronto)...stabilized growth. Stopped vinblastine after 8 months because of nerve pains, continued Celebrex out of 1 year. Still stable, but then did a few AIM cycles when she switched from peds doc to adult doc, then found most of lung nodules resolved. One met continued to grow - and that was removed by thoracotomy. When I asked Mom recalled the largest was about 4 cm. She is now 8 years out or so and with a stable CT off all meds.

[Olga]

Arch - I want to point out that we have no long survival stage 4 cases on the chemotherapy only with no surgery first or in between the cycles for the citoreduction of the tumor load, so the use of the chemotherapy only of any kind in a high tumor load setting - conventional MTD (maximum tolerated dose) or any clinical trial for metronomic chemotherapy - was not found to be beneficial. We had people here who tried different conventional regimens (MAID, AIM, GemTax) in a stage of the unresectable advanced disease and did not see a sign that it was beneficial for them, most probably otherwise, I attribute it to the increased vascularity of the tumor while on the MTD chemos and to the impairment of their immune system in addition to a suppressing effect o the immune system that bulky tumors produce.
We also have a very limited experience with the metronomic chemotherapy in ASPS, just the case when the patient had her lung mets resected and on the next postsurgical CT scan there was a recurrence with a dozen of the new tiny mets found. She was then enrolled into the pediatric clinical trial Vinblastine-Celebrex in Toronto but taken off trial after a year (??) due to the excessive toxicity (I do not know what the Vinblastine dose was). She was not discharged to a hospice though as she was doing good otherwise and most of our patients here are with the same situation with the multiple small lung mets are not in hospice at all, leaving the close to normal life, they just left Toronto to go back to the small town where they usually live, they were staying in Toronto for a duration of the clinical trial. Then at home her oncologist placed her back to a Celebrex and keept under the observation, there was a next thoracic surgery planned but canceled last minute by the surgeon who was unconvinced that there is a point to resect mets that are stable on a few consecutive scans as she believed they might be necrotic undissolved nodules. It looks like she was correct in her suspicion as most of these nodules did dissolve with a few remain to be seen and stable.
The rest of the cases we know are not exactly metronomic chemotherapy but rather the cases when the chemo was done with a long duration of it - we have very little information about the case when the girl was on a clinical trial for the Gemzar (gemcitabine) for 18 month 3 weeks on 1 week off. The schedule of the gemcitabine is closer to the metronomic chemo as it is given once every week for 3 weeks and then one week off - there are no long intervals between the doses. I am not sure what was her tumor load as we had very minimal correspondence with her mother, I only know that she had lung and liver mets and after 18 month of this trial the liver mets regressed and most of the lung mets did as well with a few remaining mets stable for awhile and resected after they started to grow minimally. We know that she was in a good condition a few years off treatment but we have no contacts now and do not know what is her current status.
There are also a few known documented cases when people were apparently cured (NED for 10-25 years off treatment) by the conventional chemotherapy plus aggressive surgery to resect their visible lung metastases with the smallest mets found to be completely necrotic and the bigger mets only partial necrotic by the pathology report. Metronomic chemotherapy has its great promises but there is no information if it might be effective as there are relatively few clinical trials done. I have read a few studies avail. in a full text and they do not mention the tumor load as a limiting factor, what they mention is the slow growing versus fast progressing disease, most of the patients who benefited were with the slow growing cancer types.

[Fictional]

Agree with your clarification Olga, it was not really hospice, but I remember mom saying the doctor sent them out with the advice "Count every day a blessing..."

An encouraging thing about this case for patients who are told they are inoperable is that by the time so many lung metastases appeared, this patient was inoperable...but then long courses of chemo later, many metastases resolved and she became operable, had the operation to remove a growing tumor, and now appears to have no active disease (watching some remaining spots, as I understand) now out 8 or so years.

It does seem as though if the disease can be beaten down into stability after a few years, the threat of overwhelming cancer is lessened.

Overwhelming cancer seemed to have occurred when the disease has not been controlled from the start, uncontrolled primary, when immunosuppression occurs, when rebounding from cytotoxic chemo, high accumulated tumor burden, and bad bone metastasis (any of you know any other negative factors?). I also personally remain a bit wary of cryoablation and RFA. They seem to usually do well for the tumor that is treated, but some people have experienced unusual sites of new metastases in the months following those treatment. Both cryoablation and RFA differ from surgical removal in that the tumor is left at its site rather than completely removed from the body.

[Arch]

Thanks Olga and 'F' for your replies.

From what I understand about ASPS, I know surgery is the best thing to do.
But like in my husband's case, his primary is resected, lung is the only place of active tumor now, conventional thoractomy is not possible, Dr.Rolle also thinks a complete resection of his lung mets will not be possible(allthough I am still waiting to see if he would atleast do a partial resection, just waiting for Dr.Rolle to get back from his vacation), I don't know of any other good option. If just a few of the lung mets grow, we could consider cryoablation or radiosurgery, but now we are in a different situation. All the lung mets look stable since the diagnosis which was less than 3 months ago and we have many very small mets, doctors have not even given a number to it.

Conventional chemo at MTD has its problems, so I was just wondering if a metronomic chemo + celebrex would make any sense here. After his primary resection, the pathologist did mention that she saw very little nucleoli mitosis in the tumor and so she thought that the tumor cells were very slow dividing. I don't know if the lung mets could behave differently.
Would really appreciate your views, if any, on this.

[Fictional]

Metronomic chemo is a reasonable option to discuss with your oncologist. You can email me if you wnat copies of papers that I have (e.g. like Greek study in ASPS) that could support it.

From the studies I've read, stability in metastatic cancer (if seen) appeared by about 12 weeks / 3 months. Other options might include Sutent or Cediranib if available, or a promising clinical trial agent if available. It is possible the VEGF blockers like Sutent or Cediranib may be more benficial for the larger tumors (>1.5 com)

So far (only 2nd week) our daughter is tolerating her regimen well. Little nausea (no vomiting) driving home after her vinblastine and tired that night, but also her dog (sleeps in her room) had woken her up night the night before. Went to bed a half hour early. She needs to plenty of water while she is on Cytoxan. The nurse practitioner we saw said that she does not think we should expect a drop in wbc counts on the doses of vinblastine / Cytoxan used.

[Olga]

I was reading this article
Systems biology: a therapeutic target for tumor therapy.
http://www.ncbi.nlm.nih.gov/pubmed/19308694 that is avail. with the free full text and they reviewed the results of the Metronomic Chemotherapy in different trials and they quote the result in sarcomas that is pretty good. I noticed that they added transcription modulators, pioglitazone +/- dexamethasone or IFN-alpha to their regimens. May be it helped them with the chemoresistance? In my reading I saw that metabolic syndrome during puberty and normal development with glucose abnormalities can be one of the factors leading to the kids/adolescents cancer so may be our kids had/have it and at the same time it makes their cancer chemoresistant, so the chemo does not work? Ivan is very fit and trim now but it has not always been that way and it is a very conscious effort on his part - to keep his weight low, as a child he was very active but a little overweight which is a nonsense in a kid that moves that much - or he had some degree of this metabolic syndrome? Of interest are some other facts that might have significance:
parathyroid hormone (PTH) is associated with insulin resistance
Sleep disorders are being increasingly associated with insulin resistance
preterm birth is associated with metabolic syndrome
impaired glucose uptake is related to FAS activation and tumorigenesis