METRONOMIC ( low dose ) chemotherapy

[Maia]

I'll start to post in this thread articles and news about this subject.
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METRONOMIC ( low dose ) chemotherapy has the potential to be a resource / an alternative for those who are thinking about stopping treatment at all (when offered only MTD -maximum tolerated dose- chemotherapy- in a palliative setting); for those who want to hang in there until immunotherapy offers a long term, sure remission; for those looking for some maintenance regimen after NED.

Metronomic, low dose chemotherapy may *restore* sensitivity to already-used chemo agents; may put the immune system back in action, may keep the tumour burden low, even if not eliminating cancer completely, with good quality of life. Even if you have had some of the agents, don't think about the same side effects --it's about doses and schedule. Think of bleach --drinking bleach may be a bad idea, but if you put 2 drops of bleach per 1 liter of water, you have emergency purified water.
And don't think 'I already have failed (X), can't try again', because at a lower dose, the agent works via other mechanisms, so acquired resistance (or plain intolerance) may not be an issue.

There are many prestigious oncologists and researchers who work in this line, around the world. Of course, it's more investigated for pediatric populations, with the idea of finding gentler treatments.
In a way, Dr Lin's ADAPT therapy and Dr Marshall's approach with an alternative schedule of capecitabine (Xeloda) are in this line of thinking.

Definition:

Metronomic chemotherapy is the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration, at close regular intervals, with no prolonged drug-free breaks




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"Tumor angiogenesis offers a new target for anticancer therapy. In addition to the recently developed
molecularly targeted antiangiogenic agents and drugs, it was found that well-know and widely
applied chemotherapeutic agents, e.g. cyclophosphamide and etoposide, also show antiangiogenic
activity. Unfortunately, the antiangiogenic effect of conventional anticancer therapy based
on Maximum Tolerated Doses (MTD) is usually limited by the treatment protocol. The cells involved in
angiogenesis may regenerate during the three- to four-week interval between the doses which is
applied to avoid undesired toxic effects. Taking advantage of the fact that endothelial cells are
about 10–100 times more susceptible to chemotherapeutic agents than cancer cells, therapy based
on daily, oral, low-dose chemotherapeutic drugs was designed. This new approach, called
metronomic therapy, appears promising mainly due to the fact that its antiangiogenic and antitumorigenic
effects are accompanied by low toxicity. Limited side effects, oral dosing, and no
need for hospitalization makes this new therapeutic program not only more comfortable for the
treated patient, but also less expensive."

Bujak, Anna, Wojciech Kałas, and Uniwersytet Wrocławski. "Chemioterapia metronomiczna jako nowa strategia leczenia chorób nowotworowych /Metronomic chemotherapy: A new approach in cancer therapy." Journal cover 68 (2008).


"Metronomic treatments constitute an alternative strategy that is gaining
increasing interest in both adult and pediatric oncology. It represents
a promising therapeutic option particularly in patients with
high-risk refractory and/or relapsed cancer as well as in heavily pretreated
patient populations. Although complete responses remain
rare, these treatments often lead to long-term disease stabilization
and significant improvement of the quality of life of patients."

Pasquier, Eddy, et al. "Moving forward with metronomic chemotherapy: meeting report of the 2nd International Workshop on Metronomic and Anti-Angiogenic Chemotherapy in Paediatric Oncology." Translational oncology 4.4 (2011): 203-211.

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I have too many articles that I'd like to share, but let me start with the abstract from this recent Fourth Metronomic and Anti-angiogenic Therapy Meeting, 24–25 June 2014, Milan:

Abstract

The Fourth Metronomic and Anti-angiogenic Therapy Meeting was held in Milan 24–25 June 2014. The meeting was a true translational meeting where researchers and clinicians shared their results, experiences, and insights in order to continue gathering useful evidence on metronomic approaches. Several speakers emphasised that exact mechanisms of action, best timing, and optimal dosage are still not well understood and that the field would learn a lot from ancillary studies performed during the clinical trials of metronomic chemotherapies. From the pre-clinical side, new research findings indicate additional possible mechanisms of actions of metronomic schedule on the immune and blood vessel compartments of the tumour micro-environment. New clinical results of metronomic chemotherapy were presented in particular in paediatric cancers [especially neuroblastoma and central nervous system (CNS) tumours], in angiosarcoma (together with beta-blockers), in hepatocellular carcinoma, in prostate cancer, and in breast cancer. The use of repurposed drugs such as metformin, celecoxib, or valproic acid in the metronomic regimen was reported and highlighted the potential of other candidate drugs to be repurposed. The clinical experiences from low- and middle-income countries with affordable regimens gave very encouraging results which will allow more patients to be effectively treated in economies where new drugs are not accessible.
Looking at the impact of metronomic approaches that have been shown to be effective, it was admitted that those approaches were rarely used in clinical practice, in part because of the absence of commercial interest for companies. However, performing well-designed clinical trials of metronomic and repurposing approaches demonstrating substantial improvement, especially in populations with the greatest unmet needs, may be an easier solution than addressing the financial issue. Metronomics should always be seen as a chance to come up with new innovative affordable approaches and not as a cheap rescue strategy.

Bouche G, André N, Banavali S, et al. Lessons from the Fourth Metronomic and Anti-angiogenic Therapy Meeting, 24–25 June 2014, Milan. ecancermedicalscience 2014;8:463. doi:10.3332/ecancer.2014.463. Full article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162678/

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As they say there, metronomic chemotherapy (plus repurposed drugs, such metformin, celecoxib, cimetidine, etc.) is an approach specially worth-exploring in a low/ middle-income country as mine (Argentina), so we have down here a good team of people working on it. I'm copying below part of a good article that explains metronomic chemotherapy. If you have not time to read more, I recommend to read at least this one article, full -or make a copy for your onc:

Abstract

The introduction of the “maximum tolerated dose” in usual treatment protocols (and its concomitant overt toxicity) made necessary the imposition of rest periods between cycles of therapy—a practice that not only involves re-growth of tumour cells, but also growth of selected clones resistant to the therapy. To avoid the problems caused by traditional chemotherapeutic regimens, a new modality of drug administration called “metronomic chemotherapy” has been proposed. This name makes reference to the chronic, equally spaced administration of (generally) low doses of various chemotherapeutic drugs without extended rest periods. The novelty of this treatment modality lies not only in its antitumour efficacy with very low toxicity, but also in a cell target switch, now aiming at tumour endothelial cells. The knowledge acquired in the experimental field of metronomic chemotherapy, plus the increasing experience that is being obtained in the clinical setting, will help to lead a change in the design of therapeutic protocols against cancer.

1. INTRODUCTION

Chemotherapy regimens reflect a controversy that is by now historical: between efficacy in tumour killing and lack of toxicity, which way should the scale be tipped? On one side is the ability of chemotherapeutic drugs to disrupt the dna of tumour cells, rendering them unable to replicate and finally killing them, with a befitting corollary: “the higher the dose, the better.” On the other side is the toxicity expressed at several organ sites, which not only diminishes quality of life for the patient, but also conspires against a good resolution of the cancer treatment, adding more illness to the already existing one. The introduction of the maximum tolerated dose (mtd) in usual treatment protocols made necessary the imposition of rest periods between cycles of therapy—a practice that not only involves re-growth of tumour cells, but also growth of selected clones resistant to the therapy. Hence, the therapeutic success obtained during the first cycles of treatment reverts in the direction of growth of more malignant metastatic tumours with no therapeutic response.
(...)

3. CONCLUSIONS

The data so far obtained induced us and other authors to begin a changing of our way of thinking about cancer treatment. To date, the aim of chemotherapy has been to achieve complete tumour suppression, a goal reached only exceptionally. Tumour elimination has been elusive, and metastasis accounts for an important part of this failure. We now know that all tumour cells cannot be consistently eliminated by high dosing schemes. The repeated administration of MTD, which induces important remissions, is generally followed by recurrences with the development of tumours even more malignant.

We can now focus on cancer therapy from a different angle. With low-dose chemotherapy, it may be possible to obtain a therapeutic effect in the clinical setting similar to that obtained experimentally. Should this hypothesis prove true, great progress will have made toward the solution of the cancer problem. On the other hand, present knowledge of tumour biology creates the recognition that tumour presence is not incompatible with patient survival. Therefore, it might not be necessary to aim for complete tumour eradication. A change from the apparently remote therapeutic objective of killing all tumour cells to the more pragmatic objective of diminishing tumour burden as much as possible and maintaining that diminishment over time can now be considered. This goal might be achieved by administering drugs in a low-dose metronomic schedule over time.

It is foreseeable that the knowledge acquired in the experimental field of mct, plus the increasing experience that is being obtained in the clinical setting, will spark a change in the way in which basic and clinical researchers design their therapeutic protocols against cancer.

Scharovsky, O. Graciela, Leandro E. Mainetti, and Viviana R. Rozados. "Metronomic chemotherapy: changing the paradigm that more is better." Current Oncology 16.2 (2009): 7. Full article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669231/


(As a kind of disclaimer, on a personal note... you may think, because of my posts, that my favouring of immunotherapy implies an opposition to chemotherapy itself. It's not the case. In fact, I think this approach, which uses chemo agents, is one of the better tools we have to 'hang in' there until immunotherapy is standard of care. It has the advantage that the agents (cytotoxic drugs, maybe some anti-angiogenic ones) are available. I do have, however, many preventions about the way chemotherapy is used at MTD, in the present guidelines. I'm sorry that I have not been posting about this metronomic approach before.
I'm posting this to honour Marc (lohidoc), who came to acknowledge the potential of this approach and was combining some metronomic regimen (in his case, capecitabine and celecoxib) with the immunotherapy he was taking (Coley's Fluid). Sadly, other personal circumstances prevented him from further exploring this path. For those who knew him and respected his science talents, know that this made sense to him, in this last period, despite his prevention against (maximum tolerated dose) chemotherapy. : ) )

[singingholly]

Thank you so much, as usual. And thanks to Marc too.
Olivia

[lauragb]

This is great info. Thanks for always being on the case.

Laura

[chrissyrice]

Thank you for this thread.... Also sounds hopeful for many types of cancer.

A gentler kinder type of chemo that can give QOL and remission rather than curative.

Chrissy

[DK37]

Definitely something to ask your doctor about if you have trouble tolerating chemo at MTD and/or have progressed and have started to run out of options. I think some real merit is possible.
Thanks for posting Maia-
-DK

[NWgirl]

This is food for thought. Thank you Maia.

[rp1954]

This is a way forward now without excessive human cost. It allows you to integrate multiple existing molecular and immune therapies using present day knowledge and technologies. It's actually been overdue for 10-20 yrs for the first two lines of treatment. A good way to reduce treatment toxicity, introduce new molecular entities, reduce recurrences, improve resectability and improve 10 yr OS. Xeloda is probably not the optimal oral chemo for a first line backbone for low stage chemo with small circulating cell clusters.

[Voxx66]

Thanks for posting. I'll ask my doctor about this though I expect he will advise me to see how well I tolerate Folfiri before experimenting.

[Maia]

Definitely something to ask your doctor about if you have trouble tolerating chemo at MTD and/or have progressed and have started to run out of options.

Yes, definitely, but no, too. Those are not the only two scenarios when one should ask the doctor about his, IMHO. This is other approach, no just a matter of chemo at lowered doses, or something to do because one cannot 'hit hard' 'the beast'. It's not a 'better than nothing'. It's other strategy, other targets. As they said in the conclusions in one of the articles cited above, "Metronomics should always be seen as a chance to come up with new innovative affordable approaches and not as a cheap rescue strategy."

It's chemo, at lower doses, on other schedule, in combination with other no cytotoxic agents.

This is in press:

Kareva, I., Waxman, D. J., & Klement, G. L. (2014). Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance. Cancer Letters.


Highlights

•Metronomic chemotherapy involves administering lower doses of chemotherapeutic drugs at more frequent intervals.
•Lower dosage allows targeting supporting tumor stroma without selecting for resistant cells, unlike in case of antibiotic resistance.
•Lower dosage and more frequent administration allow preservation and maintenance of anti-tumor immunity.
•Metronomic chemotherapy yields long-term improved clinical outcome despite slower initial decreases in tumor size.
•Cancer is a disease of both tumor cells and their microenvironment.

Abstract
The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed ‘metronomic’ chemotherapy, presents an alternative to standard maximal tolerated dose (MTD) chemotherapy. The primary target of metronomic chemotherapy was originally identified as endothelial cells supporting the tumor vasculature, and not the tumor cells themselves, consistent with the emerging concept of cancer as a systemic disease involving both tumor cells and their microenvironment. While anti-angiogenesis is an important mechanism of action of metronomic chemotherapy, other mechanisms, including activation of anti-tumor immunity and a decrease in acquired therapeutic resistance, have also been identified. Here we present evidence supporting a mechanistic explanation for the improved activity of cancer chemotherapy when administered on a metronomic, rather than an MTD schedule and discuss the implications of these findings for further translation into the clinic.

"Less is better", "Low and slow, you go further".

[kmv]

Maia, thank you for this. Very helpful and important information.

[midlifemom]

Maia, thanks for sharing. You always amaze me.
While I am certainly far from understanding much of these scientific articles, I like the thought (if understanding correctly) that this metrogenic approach looks at cancer as a long term chronic condition rather than acute care. Hope this makes sense.

[rp1954]

One of the upshots of low dose chemo is the need to try not to discontinue chemo in the face of a rising CEA/CA19-9 and/or growing mets on scans.

Rather the aim point is to prevent metastases from spreading by maximum treatment time coverage (least/no time gap) at surgery to curatively remove as many or, the worst, sites as possible. Just because some tumor mets are going haywire growing doesn't mean decent chemo (e.g. with cimetidine/celecoxib) isn't doing anything metastasis wise or inhibiting growth of other mets. This means that, in principle, the one or two site limitation of resectability is really more psychological and skill level in nature, short of encompassing drug resistance. Rather, multisite problems may be multistep or multimodal (and metronomic) in nature.

This low dose chemo to/through surgery will be contentious because US trained surgeons shudder at the thought of operating within weeks near chemo, rather than hours. Certainly the surgical site will make a difference what is possible exactly when and how. Real oncological surgeons will study up on pharmacokinetics, force better chemo treatment-drug choices prior to surgery (e.g. one that dissipates or turns off wound or bleeding tendencies just hours before surgery), better patient conditioning, better wound healing techniques, and then get 'er done. There is critical technology not being used.

[DK37]

Good points Maia - thanks for the new publication too-
-DK

[lpas]

Really, really interesting. Thanks so much for posting, Maia.

[Maia]

I like the thought (if understanding correctly) that this metrogenic approach looks at cancer as a long term chronic condition rather than acute care. Hope this makes sense.

Yes, what you say it's similar to what says in one of those articles:

"tumour presence is not incompatible with patient survival. Therefore, it might not be necessary to aim for complete tumour eradication. A change from the apparently remote therapeutic objective of killing all tumour cells to the more pragmatic objective of diminishing tumour burden as much as possible and maintaining that diminishment over time can now be considered".

There are certain cancers that are quite 'aggressive' (examples: small cell lung cancer, melanoma) so a metronomic approach may be difficult to implement but, in the case of an often relatively 'slow-growing' cancer as CRC, this certainly deserves more attention.

I'm glad some find this info helpful. : )