Increasing Radiation Effectivness

radiationI intend to have this post evolving over time as I have a large collection of research indicating various approaches to enhance the effectiveness of radiotherapy. Therefore, I am not going to debate on whether radiotherapy is good or bad. Instead, I will focus on how to make the best of it once we decided to use this anti-cancer tool. So here are some relevant aspects on this line:

Increasing the chance for a radiation induced abscopal effect: A neutrophil perspective

The so-called “abscopal effect” is the effect in which radiation therapy delivered to a primary site of cancer also results in shrinkage or elimination of cancer cells in other metastatic sites that were not exposed to radiation. This effect has been observed for decades in some lucky patients. However, this “abscopal effect” is not controllable and it happens randomly as it is not well understood by scientists. What is clear is that somehow, in some special conditions, killing cancer cells at a specific location in the body triggers a T cell-mediated anti-tumor immune response.

Interestingly, an article published in Science Daily on 21st September 2016, sumerizes a recent publsihed paper that brings more clarity extactly on this very interesting subject:  Neutrophils are key to harnessing anti-tumor immune response from radiation therapy, study finds

This recent study indicates that the reason for the radiation induced “abscopal effects” seems to be the following:  radiation destroys tumor-associated neutrophils (TANs), recruiting new neutrophils into the tumor; these new radiation-induced neutrophils (RT-Ns) attack the tumor cells by producing molecules that damage them, generating a downstream tumor-specific, T cell-mediated anti-tumor immune response.

Moreover, the researchers were able to enhance the tumor killing capacity of the RT-Ns by administering G-CSF (Granulocyte-colony stimulating factor), a naturally occurring protein (cytokine) in the body that stimulates bone marrow to produce more white blood cells including neutrophils. Note that G-CSF (commercially available) is routinely used to treat neutropenia. Granulocyte-colony stimulating factor is indicated for neutropenia caused by cancer chemotherapy, osteomyelodysplasia symptom-complex and aplastic anemia, congenital and idopathic neutropenia, etc, and also promoting increase of neutrophil count after bone marrow transplant. (Ref.)

Interestingly, G-CSF may be stimulated by corticosteroids (Ref.). Thus, glucocorticoids dose-dependently increase plasma levels of granulocyte colony stimulating factor (G-CSF) (Ref.). As a result, I assume that if G-CSF is not available, administrating corticosteroids before radiation may also help to increase neutrophils  in the blood. Having the radiation in the morning may also help as cortisol (a corticosteroid) is at the highest levels early in the morning with its peek at around 8-9 am (Ref.). Indeed, here is a study indicating the correlation between cortisol circadian variation and neutrophils variation (Ref.).

In conclusion, administration of G-CSF or corticosteroids prior to radiation may increase the chance for a whole body anti cancer response. Administrating radiation early in the morning may further help on the same line.

Increasing the chance for a radiation induced abscopal effect: A T-cell perspective

In order to induce an abscopal anti-tumor immune response following radiation, besides the role of neutrophiles discussed above, T cells’s capability to act against cancer cells is essential.

Recently, it has been shown that a patient with a cancer type known not to respond to T-cell “release” focused therapy based on ipilimumab (a human monoclonal anti-CTLA-4 antibody) experienced an immune response when ipilimumab was administrated just next day after radiation session. Here is the very nice case report: An Abscopal Response to Radiation and Ipilimumab in a Patient with Metastatic Non-Small Cell Lung Cancer http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930458/ As it can be seen from this report, the patient had a very nice and sharp results that led to the immune system cleaning up his entire body of metastasis.

What I can learn from this, is that administration of immunotheraphy just after radiation session (e.g. next day) will increase the chance for an abscopal effect. anti-CTLA-4 or anti-PDL1/PD1 immuno therapies can be used for this as they should be available to anyone (at list in Germany that is the case). Personally, I would consider lowering the typical dose of immuno therapies from 3mg/kg typically suggested to about 1mg/kg and administer both of them (e.g. ipilimumab and nivolumab) at the same time to eliminate more mechanisms that regulate the action of T-cells. (I would lower the doses of the two therapies to both reduce the toxicity and the cost, while it is known (from private clinics in Germany) that response to these therapies can also be obtained at lower doses, as low as 1mg/kg/month/patient.)

Note that, preclinical models support use of hypofractionated RT in daily doses of 6 to 8 Gy given 5 or 3 times, over a single high dose treatment of 20 Gy, in order to maximize likelihood of generating an effective anti-tumor immune response with anti-CTLA-4. Consistent with this finding, the most dramatic cases of abscopal effect reported with ipilimumab and RT have utilized RT doses and fractionation [26, 27, 29, 30] similar to the RT regimens effective in preclinical studies. However, abscopal effects were also reported in patients treated with a wider range of RT doses [26, 29, 31]. (Ref.)

Here is a clinical trial Phase 2 showing important abscopal effects in NSCLC patients including complete resolution after combining Radiotherapy with Ipilimumab: http://www.redjournal.org/article/S0360-3016(15)00890-1/fulltext The treatment approach included Ipilimumab (3mg/kg i.v.) within 24 hrs of starting RT (6 Gy x5 daily fractions) to one lesion. Ipi was repeated every 21 days x3.

Fractionation better than single-fraction treatment

The negative influence of hypoxic cells against local tumor control is apparently greater in hypofractionated SRT and the greatest in single-fraction treatment. During fractionation, however, surviving hypoxic tumor cells reoxygenate and become more sensitive to subsequent irradiation. (Ref.)

More content will be added asap on other approaches to increase radio therapy effectiveness.

References:

Current clinical trials testing the combination of immunotherapy with radiotherapy http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028964/

Increasing evidence demonstrates that radiation acts as an immune stimulus, recruiting immune mediators that enable anti-tumor responses within and outside the radiation field. There has been a rapid expansion in the number of clinical trials harnessing radiation to enhance antitumor immunity. If positive, results of these trials will lead to a paradigm shift in the use of radiotherapy. In this review, we discuss the rationale for trials combining radiation with various immunotherapies, provide an update of recent clinical trial results and highlight trials currently in progress. We also address issues pertaining to the optimal incorporation of immunotherapy with radiation, including sequencing of treatment, radiation dosing and evaluation of clinical trial endpoints.

Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. http://www.ncbi.nlm.nih.gov/pubmed/15701862/

The combination of local RT with CTLA-4 blockade is a promising new immunotherapeutic strategy against poorly immunogenic metastatic cancers.

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

Please read an extended version of the Disclaimer here: https://www.cancertreatmentsresearch.com/?page_id=1794

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57 Comments on "Increasing Radiation Effectivness"

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Meech
Member
I’ve been a bit busy lately but really wanted to key in on researching the abscopal effect. Dr. Williams tries to induce this effect (and based on certain things he showed me, has succeeded) by applying immunotherapy drugs intra-tumorally prior to inducing local tumour destruction through cryoablation. In a simplistic sense, all new immunotherapy drugs tend to try to induce the abscopal effect with some frequency. The problem is that they’re being applied systemically, and cause a huge deal of potentially fatal and dangerous side effects. I think immunotherapy might be one piece to the abscopal effect puzzle, but there… Read more »
Alex
Member

You know…… this rings right next to spontaneous remission.
If we would only know how to trigger it.

Thanks.
Alex

sirsna
Member

Hi, Daniel!

Thank You for Your posts! You do great job!!!!

I have secondary hormonal breast cancer in bones and currently on anastrazole, zoledronic acid and metformin, simvastatin, doxycycline (COC protocol).

As new bone spots appeared I will perform radiation therapy for few bone spots.
I read Your post and found very interesting idea about granulocyte colony-stimulating factor prior to radiotherapy.

http://www.pnas.org/content/113/40/11300.full

How do You think – should I stop to take metformin, doxycycline and statin during granulocyte colony-stimulating factor action and during radiotherapy? Could they work synergeticaly or they are antagonists?

Which granulocyte colony-stimulating factor do You sugest? Filgrastim could be ok?

Thank You!

sirsna
Member
Thank You, Daniel for answer ! I highly appreciate Your knowledge. After 2 week course of doxycycline 100mg/day I feel tired and my tongue is dark brown (I am surprised by this reaction because we used to take it for months as antimalaria`s drug 10 years ago without serious side effects). As I take COC medications on my own I do not have doctor to whom discuss about on or off doxycycline. According to doxycycline COC have mixed schedule – 1 month doxy, 1 month Mebendazole. I am in the middle of 1 month doxy. Naturally brewed sauerkraut is my… Read more »
sirsna
Member

Thank You, Daniel, for kind and informative answer!

Much appreciated,
ieva

Frank Liu
Guest

Radiotherapy: Changing the Game in Immunotherapy.
http://www.cell.com/trends/cancer/fulltext/S2405-8033(16)30036-X

Prospects for combining targeted and conventional cancer therapy with immunotherapy.
(The treatment of tumours with, for example, anthracycline-based chemotherapy can elicit an adaptive stress response that is accompanied by immune-stimulating pathways)
http://www.nature.com/nrc/journal/vaop/ncurrent/fig_tab/nrc.2017.17_F4.html

sirsna
Member
Hi, everyone ! I decided to post some updates according my radiotherapy. 2 weeks (11.04.2017.) prior radiotherapy my blood test showed: WBC leukocyte count, [email protected]/L 6.8 Neutrophil count, [email protected]/L 5.0 Lymphocyte count, [email protected]/L 1.3 In the time of this blood test I took folowing medications: Metformin, simvastatin, doxycycline, omeprazole, aspirin, probiotics, anastrazole, vit D, K2, omega 3, melatonin On 13.04.2017. started to take dipyridamole, slowly raising the dose from 25mg till 200mg/day. On 19.04.2017. stopped doxycycline, started antihistamine Loratadine. On 21.04.2017. started subcutaneous g-csf stimulant Tevagrastim 30IU – I had 1 dose 3 following days (21.-23). On 25.04.2017. first injection… Read more »
sirsna
Guest
Hi! A Little update from me Today I started my next radiation session. This time to femur where both lytic and blastic lesions appeared. Today before scans my blood count was : Leukocytes 12.6 (ten days ago 3.6) neutrophils 9.5 (ten days ago 1.2) Lymphocytes 1.98 (ten days ago 1.1) I used all the same medications plus two g-csf 30 iu (week ago and 5 days ago) zoledronic acid (bisphosphonates i/v) 2 days ago light immune stimulant Maitake (just it was at home already) I did not start “Immunomax” because when i got it I did not have enough time… Read more »
sirsna
Member

Also I do intermittent fasting, baicalein, continue PPI, H1&H2 blocators, probiotics & sauercraut juice, increased Dipyridamole, try to take Nitroglycerin (but I have low blood pressure), I drink Ho-Fi (sodium chlorophyllin solution in water) which shoud enchance oxigen in blood
https://en.wikipedia.org/wiki/Chlorophyllin
http://www.oceola.lv/eng/hofi.shtml.
I tried to hit all 3 points you mentioned 🙂

best,
i.

Wondering
Guest

hey sirsna,
what a fighter you are. keep up.
W

sirsna
Member

Hi W,
thanks 🙂 !

we all are fighters, as we are here !

i.

Helga
Member

Hi Ieva,

I found an article about Diclofenac and cancer. It also has some data about combining it with radiation, which resulted in an enhanced effect: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720497/ Maybe you could try it topically on your leg before radiation treatment. I wish you success!

Best,
Helga

sirsna
Member

Hi, Helga !

Thanks for post. Do You think Diclofenac topically could reach bone? hmm… Maybe I must try indeed.

Thank You,
ieva

Helga
Member

Hi Ieva,

I think it might reach bone topically more easily than orally although I am not sure. I guess, it is concentration-dependent. Also, DMSO is used as a carrier for a lot of treatments in cancer. It could work in your case as well, although it should be researched a bit.

Best wishes,
Helga

Helga
Member

Just as I suspected, topical Diclofenac is as effective as oral one for the treatment of knee osteoarthritis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141840/ And they do combine it with DMSO! If it works for knee, it should work for your femur as well, I guess.

sirsna
Member

In local pharmacies I can get topical Diclofenac 23.2mg/g. This must be very week, isn`t it?
what is DMSO? How to get it?

i.

Helga
Member

Hi Ieva,

23.2mg/g is not so bad. I just checked my Voltaren, seems even lower. I am not sure how to get DMSO but it seems quite a miraculous molecule: http://www.naturalnews.com/037485_DMSO_inflammation_muscle_pain.html

For sure, they use it in mol biol labs in research. You can probably order it on the internet, too.

Cheers,
Helga

sirsna
Member

Hi all!
I try to post maybe 10x :), but my post did not appeared.

i.

sirsna
Member
Hi, Helga! Thank You for ideas! I am not sure about iodine, how it will affect my thyroid as there is many knots inside. From thyroid blood sample perspective my thyroid works normally, I think so. Endocrinologist suggests to take out thyroid as the biggest knot is ~3cm, but guidelines is to cut out if knot is 2 cm. I should be fat if thyroid does not work enough, but I am not. As my cancer responds to hormones I would better try T4 depletion strategy from another Daniels post. That is one one of next plans for me in… Read more »
Helga
Member
Hi Ieva, I think T4 depletion strategy is a great approach as it is so easy to implement and seems so effective plus no side effects, I think. It seems to me that Ergin implemented it and the treatments for his mom seem to be working. One more reason for you to keep your thyroid! I read somewhere, maybe linked to Daniel’s article about this topic that T4 and the change in its level (decrease) may be behind most “spontaneous cure/remission” cases in cancer. Amazing that doctors don’t use it but the current doctor, dr Hercberg seems to achieve great… Read more »
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