Radiation

Radiation to the brain is a daunting prospect to many, with good reason. There are many downsides to such a powerful cytotoxic therapy as radiation, yet it can undoubtedly shut down tumour growth for long periods of time in tumour types that are sensitive to it. This page will explore various means of further sensitizing tumours to radiation therapy, maximizing its therapeutic potential.

Human Evidence

Radiochemotherapy and valproic acid (Depakote)

Valproic acid and sodium valproate (trade name Depakote) is an anti-seizure medication currently under investigation as an anti-cancer agent. Valproic acid has long been used in glioma therapy to prevent seizures and retrospective analysis has detected a survival benefit in those patients taking valproic acid during standard of care radiochemotherapy [7]. One anti-cancer mechanism of action of this drug is the inhibition of histone deacetylase (HDAC). HDAC inhibition has been found to have radiosensitizing effects, and this has been demonstrated for valproic acid in laboratory studies [8].

The most impressive results with valproic acid comes from a phase 2 trial for which the data was first presented in abstract form at the annual SNO conference, held in Miami in November 2014. 37 glioblastoma patients were evaluated on this trial, with 97% having had surgical resection and 3% having biopsy only. Patients were started on 10-15 mg/kg valproic acid one week before the start of radiation and this was tapered up to 25 mg/kg/day (divided into two doses) by the start of chemoradiation. Valproic acid was taken daily until the end of chemoradiation. Median progression-free survival was a favorable 10.5 months and 2-year survival rate was a very favorable 56%. A majority of patients received Avastin therapy after disease progression. Given these positive results, valproic acid deserves to be given serious attention as an addition to standard of care radiochemotherapy.

Radiation and hyperbaric oxygen therapy

Hyperbaric oxygen therapy consists of breathing 100% oxygen in a chamber in which air pressure is increased to three times normal to allow the lungs to take in more oxygen.

In one non-randomized trial in Japan [3], 15 malignant glioma patients were treated with hyperbaric oxygen therapy immediately prior to radiation (within 15-30 minutes). Hyperbaric oxygen treatment consisted of “15 min of compression with air, 60 min of 100% oxygen inhalation using an oxygen mask at 2.5 atmospheres absolute and 10 min of decompression with oxygen inhalation.”

11 of 15 patients (73%) had tumour shrinkage with hyperbaric oxygen immediately prior to radiation sessions. The three complete responses and eight partial responses all occured in patients who had irradiation within 15 minutes after hyperbaric oxygen. The four non-responders (no tumour regression) were irradiated approximately 30 minutes after hyperbaric oxygen.

A phase 2 trial, also in Japan, tested hyperbaric oxygen therapy immediately prior to radiation in combination with PAV chemotherapy [4]. 31 glioblastoma and 10 grade III glioma patients were included in the study. “Hyperbaric oxygenation treatment was performed in a multiplace hyperbaric chamber according to the following schedule: approximately 18 min of compression with air, 30–60 min of 100% oxygen inhalation using an oxygen mask at 2.8 atmospheres absolute and approximately 18 min of decompression with oxygen inhalation.” Hyperbaric oxygen sessions were followed within 15 minutes by irradiation. Of the 30 patients with residual tumour following surgery, four patients (13%) had a complete response to the combined treatments, 13 patients (43%) had a partial response, 12 patients (40%) had disease stabilization, and only one patient had progressive disease through treatment.

Most significantly, median time to progression for the glioblastoma patients was 12.3 months from diagnosis, which is a favorable outcome compared to the most recent (2014) phase 3 trials with median time to progression in the neighborhood of 8 months from diagnosis.

Rodent evidence

Radiation, ketogenic diet, and intermittent fasting

The following paragraphs were taken from the Standard of Care page.

Animal studies have shown that dietary interventions may be one of the most effective ways to increase the therapeutic benefits of radiation and chemotherapy. In one of the most impressive animal studies I’ve seen [1], mice implanted with GL261 mouse glioma cells were treated with either a standard diet (control group), a ketogenic diet, a standard diet plus two 4 Gy fractions of radiation to the head, or a ketogenic diet plus two 4 Gy fractions of radiation. The ketogenic diet consisted of the KetoCal commercial formula, which is 72% fat, 15% protein and 3% carbohydrates (4:1 ratio of fats to protein plus carbohydrates). All mice were fed ad libitum (not calorically restricted).

While the ketogenic diet improved survival slightly versus the standard diet, the results in the group receiving both radiation therapy and a ketogenic diet are nothing short of spectacular. The mice receiving radiotherapy plus a standard diet were mostly (10/11) dead by day 70, with one surviving to day 150. Amazingly, 9 of 11 (82%) mice receiving a ketogenic diet plus two 4 Gy fractions of radiation to the head had a disappearance of their tumours by about day 60. At day 104 these 9 mice were switched back to a standard diet. At day 299 the mice were sacrificed for examination, still without tumor regrowth. The mice in this group had similar glucose levels and higher circulating ketone levels than mice in the standard diet group at day 13. The ketogenic diet plus radiation group also had a dip in weight at 3-6 days following treatment, but had regained this lost weight by day 15. The exact cause of this dramatic response to radiation therapy while on the ketogenic diet is a matter of speculation.

A separate study [2] used the GL26 mouse model to test “short-term starvation” (48 hour fasting) prior to exposure to radiation or prior to and after chemotherapy with temozolomide. These experiments showed increased survival in mice undergoing 48 hour fasts at the time of either irradiation or chemotherapy. In the radiation experiment, only 1/9 mice in the fasted group had died by day 31, while about 6/9 mice in the irradiated but not fasted group had died by that time. Unfortunately, data beyond this time point is not given, so we do not know if survival benefits were as dramatic as in the previous study.

These two experiments show that some sort of dietary intervention at the time of radiation and/or chemotherapy may provide great benefits. This could mean restricted diets such as the ketogenic diet, or short-term fasting, or even calorie-restriction mimetic drugs such as metformin. See the Diet page for a fuller description of these options.

Radiation and Iron supplementation

The following paragraphs were taken from the Diet page.

A study with glioma-bearing rats tells us that depending on context, dietary iron supplementation could either be harmful or beneficial to cancer patients [5]. Iron is a critical nutrient for cell proliferation and high-grade gliomas have elevated expression of transferrin receptors [6]. Transferrin is the main iron carrier protein. In the rat study [5], male Wistar rats were implanted into the hip with a chemically-induced rat glioma cell line (strain 35), and after formation of a tumor node, the rats were divided into several treatment groups. Control rats were given tap water containing 0.2-0.3 mg/L of iron ions (Fe2+). Another group of rats was given drinking water supplemented with 60-63 mg/L iron ions (Fe2+). In the iron-supplemented group, tumours grew faster than in the control group, and iron-supplemented rats had 34% shorter lifespans than the control group.

In marked contrast, when rats were given a single 15 Gy dose of radiation to the tumour area, rats supplemented with iron had a much better response to radiation and longer survival than rats treated with radiation but no iron supplementation. These irradiated, iron-supplemented rats lived twice as long as the untreated control rats. Glioma cells in the irradiated, iron-supplemented group died by a combination of apoptosis and ferroptosis, a form of iron-dependent cell death. Thus, iron appears as an effective radiosensitizer, but can actually stimulate tumour growth outside of the context of radiation.

Radiation and Cannabinoids (THC and CBD)

The following paragraph was taken from the Supplements page.

A group from the University of London in the UK published research in November 2014, in which low doses of pure THC and CBD were injected into mice intraperitoneally, with or without irradiation [9]. The GL261 cell line was used, which is a high-grade mouse glioma grafted into immunocompetent wild-type mice. Mice were divided into four groups: untreated control mice; mice receiving a single dose of 4 Gy irradiation to the head on day 9; mice receiving 2 mg/kg each of pure THC and pure CBD on days 9, 13, and 16; and mice receiving both irradiation and THC/CBD. All mice were sacrificed at day 21 and tumour volumes were compared across the groups. The GL261 xenograft tumours were apparently resistant to a single dose of irradiation, which made no difference to the average tumour volume at day 21. Cannabinoid treatment alone slowed, but did not stabilize, tumour growth in the mice. Dramatically, cannabinoids combined with irradiation almost completely halted tumour growth, amounting to a 90% growth inhibition.

Figure 4 Scott 2014

Radiation and Pterostilbene

The following paragraphs were taken from the Supplements page.

Pterostilbene is a naturally-occurring resveratrol analog, found especially in blueberries. It may be purchased commercially as a nutraceutical from various suppliers. It has far better oral bioavailability than resveratrol and has been detected in mouse and rat brains after oral administration.

In one study [10], mice were subcutaneously implanted with GBM8401 tumor spheres. The mice were then injected with either a small dose of pterostilbene 3 times weekly, or given a single dose of 10 Gy radiation, or both of these treatments combined. Pterostilbene (PT) or irradiation alone significantly slowed tumour growth, while the combined treatment gave the largest effects.

2015 Huynh Pterostilbene in vivo

Radiation and COX-2 inhibitors

A study [11] published in April 2015 by a group at University of Sherbrooke (Canada) shows that supplementation with meloxicam, a COX-2 inhibitor, can limit the invasive phenotype of gliomas in the post-radiation period. First, the rats were intraperitoneally injected with 3 different dose levels of meloxicam (0.1, 0.5 and 1 mg/kg rat body weight) and 48 hours later their brains were irradiated with 15 Gy. In the control animals, brain irradiation increased prostaglandin E2 (PGE2) levels in the brain 9.7 and 7.2-fold at 4 hours and 15 days, respectively. Pre-treatment with meloxicam reduced PGE2 levels by 2-4 fold compared to controls, though PGE2 levels were still higher than those in the brain of non-irradiated rats.

In the following experiment, Fischer rats underwent irradiation to the brain followed one day later by intracranial implantation of syngeneic F98 glioma cells. One group of rats was treated with 0.1 mg/kg meloxicam 48 hours prior to radiation. Rats undergoing brain irradiation followed by F98 glioma implantation had 28% reduced median survival compared with non-irradiated rats implanted with tumours. Meloxicam reversed the adverse effects of radiation, as rats pre-treated with meloxicam followed by brain irradiation and tumour implantation had similar survival compared with the non-irradiated tumour-bearing control rats.

The beneficial effect of meloxicam was then investigated. Tumour cell infiltration beyond the edge of the tumour was increased 2.7-fold when tumours were implanted into irradiated rat brains. This increased tumour cell infiltration in irradiated brain was partially reversed by meloxicam pre-treatment. In vitro, the addition of PGE2 increased the invasion of F98 cells by 1.5-fold. The activity of matrix metalloproteinase-2, a pro-invasive protease, was increased 2.5-fold at day 15 in irradiated brain versus non-irradiated. This stimulation of MMP-2 production was completely prevented by meloxicam pre-treatment.

Messenger RNA (mRNA) levels of pro-inflammatory cytokines were then measured in irradiated and non-irradiated brains. Four hours post-radiation, significantly increased levels of the cytokines IL-1β, IL-6, and TNF-α was observed. In vitro, the addition of interleukin-1β (IL-1β) increased the invasion of F98 rat glioma cells 5-fold in invasion chambers. This stimulation of invasion was completely reversed by adding meloxicam.

In summary, radiation to the brain caused increased production of pro-invasive molecules such as prostaglandin E2 (PGE2), matrix metalloproteinase-2 (MMP-2), and interlukin-1β, leading to increased infiltration of F98 rat glioma cells into the surrounding brain tissue. The increased infiltration of F98 glioma cells into rat brain was partially inhibited by treatment with meloxicam, a COX-2 inhibitor, and this led to increased survival times in the rats treated with meloxicam and radiation compared with rats only treated with radiation.

It is likely that other COX-2 inhibitors, such as the more commonly used celecoxib (Celebrex) would have similar benefit in combination with brain radiation.

Radiation and Dichloroacetate (DCA)

An Australian group published a study [12] online in June 2015 showing that oral DCA combined with radiation to mouse brains (at a dose of 2 Gy every day for 10 days) improved mouse survival beyond that seen with either treatment alone. The first part of the study consisted of in vitro work showing that exposure of U87 glioblastoma cells to radiation increases glycolysis at 4 hours post-radiation, and that exposure of the cells to DCA synergized with irradiation by augmenting DNA double-strand breaks and impairing colony formation. One caveat is that a DCA concentration of 25-50 mM (millimolar) was used in these studies, which is far from achievable clinically (peak levels in plasma well under 1 mM are typically seen in clinical studies).

In further experiments, U87 glioblastoma cells were implanted into the brains of nude mice. The mice were then treated with either radiation, DCA, or both therapies combined. Untreated control mice survived for a median of 29 days. DCA prolonged survival very slightly (median 31 days). Irradiation was more effective than DCA (median survival 38 days). Most effective was the combination of DCA and radiation (median survival 43 days). The doses of radiation and DCA used in this study did not produce obvious toxicity in the mice.

Proton therapy

Proton therapy is an alternative to standard photon radiation therapy which can deliver the same radiation dose to the target area, while drastically reducing the exposure of healthy surrounding tissue.

Shih 2015 Proton radiation

Figure 1. Dosimetric plans of proton therapy versus photon therapy for a low-grade glioma of the left temporal lobe are shown. Equivalent tumor target dose coverage is achieved but markedly less radiation is delivered to nontarget tissues with proton therapy. From “Proton therapy for low-grade gliomas: Results from a prospective trial” Shih et al. 2015.

According to the National Association for Proton Therapy (USA), as of 2015 there are currently 14 proton centers in operation in the USA, with 11 more under construction. Currently operational proton centers that treat brain tumours are located at:

Stereotactic radiosurgery

Brain tumours less than 4 cm in diameter may be eligible for stereotactic radiosurgery using Gamma knife. Gamma knife is a procedure in which 201 sources of Cobalt-60, emitting gamma ray photons, allow for precision targeting of tumour tissue through the skull, without surgery. The treatment typically takes 10-60 minutes and is performed on an outpatient basis in a single sitting. Find Gamma Knife treatment centers at the elekta.com website.

References
  1. The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma. Abdelwahab et al. 2012.
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  2. Fasting Enhances the Response of Glioma to Chemo- and Radiotherapy. Safdie et al. 2012.
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  3. Effects of radiotherapy after hyperbaric oxygenation on malignant gliomas. Kohshi et al. 1999.
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  4. Phase II trial of radiotherapy after hyperbaric oxygenation with chemotherapy for high-grade gliomas. Ogawa et al. 2006.
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  5. Effects of Iron Ions and Iron Chelation on the Efficiency of Experimental Radiotherapy of Animals with Gliomas. Ivanov et al. 2015.
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  6. Transferrin receptors and glioblastoma multiforme: Current findings and potential for treatment. Voth et al. 2015.
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  7. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Weller et al. 2011.
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  8. In Vitro and In Vivo Radiosensitizing Effect of Valproic Acid on Fractionated Irradiation. Chie et al. 2014.
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  9. The Combination of Cannabidiol and Delta 9-Tetrahydrocannabinol Enhances the Anticancer Effects of Radiation in an Orthotopic Murine Glioma Model. Scott et al. 2014.
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  10. Pterostilbene suppressed irradiation-resistant glioma stem cells by modulating GRP78/miR-205 axis. Huynh et al. 2015.
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  11. Cyclooxygenase-2 inhibitor prevents radiation-enhanced infiltration of F98 glioma cells in brain of Fischer rat. Desmarais et al. 2015.
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  12. Sensitization of glioblastoma cells to irradiation by modulating the glucose metabolism. Shen et al. 2015.
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