New Prevention and Treatment Options for Oral Mucositis

Infrared therapy is officially recommended for Oral Mucositis but CMS denies reimbursement.

This page will tell you something about a very nasty iatrogenic disease, a high-tech cure involving physics, and the ways that the governmental-corporate-medical industry is delaying access to the cure. Specifically, this page is a starting point for exploring the use of photobiomodulation to protect against and treat oral mucositis. Here you will find some basic explanation and pointers to more information.

Oral Mucositis (OM) is a dose-limiting side-effect of cancer treatment by radiation and chemotherapy. Dose-limiting means that people stop their therapies, preferring the disease to the treatment. Those who have personal experience with OM know how unpleasant the side-effect can be since it interferes with eating and drinking. One might better call it "Ouch Mouth" except that the phrase is much too mild to describe the condition.

Children are least able to cope with OM since they can't understand the idea of short-term pain for long-term gain. Also, they are more vulnerable to starvation and thirst. I am focusing on children here but the logic applies equally to adults. Unfortunately, the side effect occurs more much more often in children. An estimated 65 percent of pediatric cancer patients get oral mucositis; see pediatric risk (and some comments), compared to 30 to 40 percent among adults. As there are 16,000 new pediatric cancers found every year, there are about 10,000 American children suffering currently with oral mucositis (and about half a million adult cancer patients with OM).

I will not claim to be unbiased. I've read and studied the technical literature for a number of years, and it seems to be really very clearly established that laser medicine is extremely effective against oral mucositis and that more generally photonic methods will replace current pharmaceutical treatments for many wide-spread illnesses involving pain and sleeplessness. It is quite possible that the therapeutic effects of light-based technology will cure illnesses which are not curable today and even conceivable that laser treatments could produce longer and healthier lifespans. Preliminary evidence is very positive but a lot more needs to be done. What I particularly want to call attention to is the fact that so little effort is being made to explore the bonanza of modern day photonic successes in physics in its obvious applications to medicine. Oral Mucositis is just one among many conditions where photobiomodulation should be the approach of choice.

Studies involving the use of lasers and light-emitting diodes show nearly complete avoidance of oral mucositis when children are pre-treated. There are Randomized controlled trials (RCT) which support the advantages of photonic therapy compared to the alternatives. See for instance a recent summary (J Lasers Med Sci. 2014 Winter; 5(1): 1–7), which cites important articles such as Efficacy of low-level laser therapy (LLLT) in the management of neck pain: a systematic review and meta-analysis of randomised placebo or active-treatment controlled trials which appeared in the highly regarded medical journal, the Lancet, in 2010.

For a recent and extremely positive assessment of laser treatment of OM, see Low-power laser in the prevention of induced oral mucositis in bone marrow transplantation patients: a randomized trial. The abstract of the article concludes: "Our results indicate that the use of upfront LPLT in patients who have undergone HSCT is a powerful instrument in reducing the incidence of OM and is now standard in our center." A front-line view of the effectiveness of the photonic approach can be seen in the May 2015 article Laser Treatment Halts Oral Mucositis in Its Tracks which reports the very encouraging results from a pilot study at the University of Pittsburgh Cancer Institute. The Medscape article cited here is (sometimes) behind a pay-wall but searching directly for "medscape oral mucositis laser May 2015" should take you to it. An oncology nurse, Annette Quinn, describes nearly complete protection against OM by pre-treating patients photonically prior to chemotherapy. Also see a 2012 French study.

Two of the studies cited in the 2014 (J Lasers Med Sci) summary article did not support the conclusion that low-level laser therapy is effective against OM; for instance, a Brazilian article from 2007 did not find supporting evidence but the particular case they studied is now considered by MASCC/ISOO to be a recommended situation for photonic intervention.

Thus, a few negative negative test results don't mean LLLT is bogus. Absence of evidence is not evidence of absence. Each study makes assumptions about laser wavelength, intensity, and other treatment protocols. There is also an operator effect - positive or negative "bedside manner" - and the study group was small. Finally, the study only investigated cure, rather than prevention. The scientific evidence is now sufficiently supportive of the value of laser therapy that MASCC/ISOO (the official cancer support organizations) recommend photobiomodulation to prevent and treat oral mucositis.

The duration of oral mucositis is 7 to 12 weeks, depending on the cancer treatment. It is interesting that no exact number is known for the total number or duration of OM; apparently, the new "big data" approach to coordinating medical information isn't able to track this.

If you or your child is scheduled for radiation and/or chemotherapy or has already undergone such a treatment, you should know that novel, non-pharmaceutical methods exist which may protect against occurence of Oral Mucositis and alleviate pain and discomfort if OM has already appeared. Indeed, there are at least three such methods now claimed to be effective at one or more of the goals of protection, healing, and soothing.

This page focuses on the technique now supported by randomized clinically controlled trials, Photobiomodulation (low-level light/laser therapy) which is recommended by MASCC/ISOO (see below for the citation).

Chief advantages of photobiomodulation are (potentially) very low cost, effective prevention of OM, good amelioration of pain when OM does occur, and an absence of side-effects. Since the technology of photonics is rapidly advancing, the same positive virtuous cycle that animated the computer revolution is available for laser medicine.

Other methods which may be worth investigating include:

Cryotherapy This heuristic aims to keep the oral cavity as cool as possible, and includes such high-tech interventions as ice cubes and popsicles. Cryotherapy should be cheap and without side-effects, and initial studies are promising.

and

Sucralfate medical device therapy. The device seems to be a "chelation methodology" that puts sucralfate molecules into a form which coats and protects mucosal linings and not just in the oral area. The author, R. W. McCullough, reports outstanding results and FDA approval for the device. This interesting "materials science" approach, however, remains investigational.

Recently, the FDA has approved Palifermin , a drug which stimulates the growth of epithelial cells, for treatment of OM. A small study in 2014 showed mild but statistically significant effects for children in the mid-range of severity of oral mucositis but not for the other two groups with milder and more severe cases. However, side-effects can result from this pharmaceutical treatment. Moreover, adding multiple drugs together can produce unanticipated results.

At ClinicalTrials.gov , one can search for "oral mucositis" AND x, where x = laser, Palifermin, cryogenic, or sucralfate to see a list of studies which involved those terms. There were 18 for x = laser, 22 for x = Palifermin, and only a few for cryogenic and sucralfate. In contrast, there were 300 hits for "oral mucositis" alone. This shows that, even now, a small fraction of the clinical trials studying OM involve photobiomodulation in spite of its very promising nature and substantial theoretical and practical advantages.

Photobiomodulation is a very modern, physics-based technology, using visible and infrared light to prevent OM and to decrease the pain if OM does occur. Laser healing of wounds has been investigated for 50 years since the work of Mester in Hungary, shortly after the first lasers were created. In the late 1990s, NASA developed a particular type of LED (Light-Emitting Diode) for space agriculture. The resulting diode technology was adapted and modified by a partnering small business to create a hand-held device - primarily for decreasing the pain of OM. See, e.g., the following:

NASA light-emitting diodes for the prevention of oral mucositis in pediatric bone marrow transplant patients, 2002 ,

2012 article: Amelioration of oral mucositis pain by NASA near-infrared light-emitting diodes in bone marrow transplant patients,

NASA press release, March 3, 2011

The effectiveness of photobiomodulation seems to primarily involve infrared radiation, which is simply light in the energy range below visible light and above radiant heat. Light rays are carried by particles called photons and we now know that infrared photons can interact with cellular and subcellular processes. The body is largely transparent to infrared and red light; a red laser pointer of 1 milliwatt (one thousandth of a watt) can be seen through your finger.

The fundamental idea of light as a healing energy is very old and is found in many religions. This may be one of the reasons that some scientists and doctors resist all evidence of the value of "photonic" devices.

Of course, ordinary light influences sleep-wake cycle and mood, while ultraviolet light (with higher-energy photons) is required for the production of vitamin D. But only relatively recently have we learned that infrared energy also interacts with cellular processes so biology can be modulated by photons. This interaction involves molecules related to the production of energy in the mitochondria inside the cell.

For a summary of mechanisms of low-level light therapy, including some of the history, see M. R. Hamblin's preprint (Harvard Medical School and Wellman Center for Photomedicine, 8/14/2008) which appeared as an IEEE conference paper in 2009. According to Hamblin, less is more when it comes to laser-light therapy since some studies show that overly much energy diminshes the value of the therapy. But in the case of Oral Mucositis, the difficulty of reaching internal areas with suitable dosages is avoided; one can treat the oral cavity since light easily passes through the cheeks.

Amazingly, I have found only one site or organization dedicated to OM. The UK Oral Mucositis in Cancer Group (May 2015) provides Mouth care guidance and support in cancer and palliative care which has one mention of low-level laser therapy as a possible treatment for mild cases but has nothing on prevention of OM via infrared therapy. At the end of their 12-page report the authors state: "The expert group would like to acknoweldge EUSA Pharma for the unrestricted grant to enable the group to meet. EUSA Pharma had no input into the content of the guidance."

The Oral Cancer Foundation currently (December 2016) omits any mention of light-based therapy but an article from 1998 on their own website in the journal Best Practice (Volume 2, Issue 3) states that

"Low energy laser treatment may promote the proliferation of mucosal cells and wound healing, and has been tried as a treatment for chemo/ radiotherapy-induced mucositis. The limited evidence available supports its use in bone marrow transplant patients, but more research is required for non- transplant cancer patients."

Much work has been done in the intervening 20 years (though not as much as one might have expected) and the accumulated evidence is overwhelmingly favorable to LLLT for OM prevention and treatment - yet little or no action is occurring. For the Oral Cancer Foundation, however, the problem may be lack of knowledge, as their resources appear to be limited, rather than being backed by large pharmaceutical companies.

Another group SPOHNC.org (Support for People with Oral and Head and Neck Cancer) has only a single internal reference to laser - in connection with surgery - and nothing at all on LLLT/photobiomodulation or any other sort of light or infrared therapy. They specifically thank their corporate sponsors: AstraZeneca, EMD Serono, Lilly, Merz, and Merck.

Photobiomodulation produces various effects including pain-relief and healing of OM and healing of wounds, bed-sores, and diabetic ulcers. Further, PBM can protect against OM when it is used prior to the use of radiation or chemotherapy in treating cancer. According to Clinical Practice Guidelines for the Prevention and Treatment of Cancer Therapy–Induced Oral and Gastrointestinal Mucositis, E. B. Rubenstein et al., Cancer, Vol. 100, Issue S9, 1 May 2004, pp. 2026--2046; see p. 2035, "It appears that laser therapy produces no toxicity and is atraumatic to patients." In contrast, pharmaceutical and surgical approaches to which PBM is an alternative, have severe side-effects.

In the case of pain management, a key problem is drug abuse so the information on this page could be of value to groups concerned with preventing such problems. For example, the National Institute for Drug Abuse (NIDA) discussed research they had sponsored on a special type of photobiomodulation (called optogenetics) in order to eliminate drug cravings via targeted laser stimulation of modified cells in the brain’s prefrontal cortex. See Chen's 2013 paper in the journal Nature. But no other NIDA work involved with photobiomodulation seems to have been done.

NIDA and others have supported research in transcranial magnetic stimulation, TMS, which is an FDA-approved technique for treating depression by stimulating neurons in specific regions of the brain using magnetic fields. It appears that, unlike the light-based alternatives, use of powerful magnetic fields is approved for insurance reimbursement - see this cost-comparison site . In fact, PublicCitizen.org requested that CMS deny reimbursement for TMS. (They claim flaws in the studies and possible harm to patients.) I haven't been able to actually determine whether or not CMS allows reimbursement for TMS and this is a detour from our main focus on Oral Mucositis. However, the comparison of the two technologies is of some interest and in particular this page from the Federal Register , searched for "laser" or "transcranial" gives a good indication of the incredible bureaucracy involved here. Coupling this with the number of new and rapidly developing technologies involved, it becomes easier to understand the administrative paralysis.

Photobiomodulation has four main drawbacks. (1) It works so well that it is rejected out-of-hand as "too good to be true." (2) It has gone by a variety of names including (at least) LLLT low level light therapy), LILT (low intensity laser therapy), LPLT (low power laser therapy), MIRE (monochromatic infrared energy), and now PBM. (3) Laser therapy uses a device, rather than a chemical, while physicians and their supporting infrastructure understand pills much better than physics. (4) PBM can be much less expensive than alternative therapies.

The last point seems illogical until you realize that, as a business, medicine aims to make money. The profit-margin for pills is much higher than for technology. Further, devices must be approved (in the US) by the FDA and this is a long and uncertain road.

Actual drawbacks of PBM are its novelty and dependence on physics (it is a new medical paradigm). Photonic devices, in quantity, can be quite inexpensive (e.g., in consumer applications like cell-phone displays). However, in limited production, these medical devices, requiring FDA approval, tend to be expensive and devices require suitable technical support, calibration, and maintenance. But let's do a little calculation. A device used 10 hours/day for 6 days a week and 50 weeks/year provides 3000 hours in a year. Typical laser treatments take about 10 minutes so allowing for set-up each device should be able to give at least 2 treatments per hour. Suppose the device costs $100,000 and further suppose that two technicians are required, each costing $200,000/year including overhead. That's a bit over $80 per treatment. Even if 15 treatments are required to prevent OM, the cost would be less than $1500 which is under 10 percent of the incremental cost for longer hospital stays when OM develops in patients.

Given the very favorable prospects for laser treatment and prevention of OM and the enormous financial costs and human suffering, it is hard to understand why so little has been done to expedite further use of PBM therapy.

In fact, more than a year after being recommended as therapy for OM by cancer-support organizations, all infrared therapy is still denied reimbursement by the Centers for Medicare & Medicaid Services.

Here are the details:

On May 15, 2014, the journal Cancer of the American Cancer Society, published an article by the Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) and in November 2014 the parent organizations released MASCC/ISOO Evidence-Based Clinical Practice Guidelines for Mucositis Secondary to Cancer Therapy which included the statement that there is strong evidence in favor of the use of low-level laser therapy and therefore recommends the use of PBM to prevent occurence of OM in bone marrow transplant patients (pediatric and adult), and suggests its use to alleviate pain in general.

Nevertheless, the Centers for Medicare & Medicaid Services (CMS.gov) continues to maintain their decision not to reimburse infrared therapy

Here is a summary of the CMS decision, CAG-00291N, with my emphasis.



Decision Memo for Infrared Therapy Devices

from cms.gov CAG-00291N 2006

CMS has determined that there is sufficient evidence to conclude that the use of infrared devices is not reasonable and necessary for treatment of Medicare beneficiaries for diabetic and non-diabetic peripheral sensory neuropathy, wounds and ulcers, and similar related conditions, including symptoms such as pain arising from these conditions. Therefore, we are issuing the following National Coverage Determination.

The use of infrared and/or near-infrared light and/or heat, including monochromatic infrared energy (MIRE), is not covered for the treatment, including symptoms such as pain arising from these conditions, of diabetic and/or non-diabetic peripheral sensory neuropathy, wounds and/or ulcers of skin and/or subcutaneous tissues in Medicare beneficiaries.



As a result of inertia, ignorance, and the (presumably unconscious) desire to preserve a comfortable and lucrative status quo by medical professionals, government bureaucrats, and pharmaceutical executives, many children are now suffering with pain that might have been prevented and could be mitigated.

Until CMS changes CAG-00291N and permits reimbursement for infrared therapy, photobiomodulation may be too expensive for many individuals. But laser therapy is available in many places including chiropractors, physical therapists, sports medicine, veterinarians, and dentists.

In addition, one can buy a hand-held, battery-operated LED device for about $800. Any adult should be able to use it to supply red and NIR (near infrared) light to various areas of the body and even to oral cavities since the cheeks are largely transparent to these wavelengths. The drawback is that the device requires recharging and a plethora of batteries. It worked out of the box but nearly immediately needed recharging. I did the full day-long recharge. Since then I have used it sparingly, a few times a week, for 9 months, and it has not yet needed a recharge. My use is for occasional stiff neck and for mild irritation of toes or fingers, as well as for oral health. Even the low-level energy produced by this device was reported as effective in treating the pain of Oral Mucositis according to the NASA studies. (By the way, I have no current or previous financial relationship with any photonic device manufacturers. In contrast, many of those involved in going slow with photobiomodulation have received long-term support from pharmaceutical companies.)

For now, there is no way to make a coherent voice calling for the immediate exploration of ``Laser Medicine,'' especially the use of photobiomodulation in healing and prevention of disease, including oral mucositis and other iatrogenic maladies. I hope, however, that soon a community will coalesce around the notion that the federal government and large medical businesses and organizations should be required to develop a rational strategy to rapidly and thoroughly explore all aspects of Laser Medicine.

Photobiomodulation has immediate applicability to protect, soothe, and heal, but we should also not be ignoring the photonic revolution in biomedical research which already provides myriad new windows into the body and modalities for interaction and control (e.g., optogenetics). These capabilities for diagnosis and therapy should be deployed in clinical medicine; the resulting economy of scale would make them much less expensive with easy-to-use interfaces.

As of this writing, Dec. 17, 2016, CAG-0291N, cited in the Wikipedia page on LLLT, has not been altered. But inertia in the CMS is not the only obstacle to deployment of photobiomodulation and Laser Medicine for pain relief and other purposes. The total amount of research funding to investigate and improve the effectiveness of light-based therapy is absolutely miniscule as a fraction of the total medical research budget. I hope that, as people become aware of what their government has done and is still doing, there will be increasing public pressure to change policies.

It is especially surprising to me that this clear embodiment of what the Institute of Medicine predicted has not been recognized by NIH and FDA leadership. The IOM (now NAM), formed in 1970, invented the notion of ``translational medicine'' and warned that the concentration of older scientists as lab heads, combined with the inflexibility of large bureaucracies, would tend to concentrate efforts in a few dominant specialties. Today it is clear that these dominant specialties are genetics and pharmaceuticals.

Laser medicine gets less than 6 percent of the research support given to genetics and pharmaceuticals by a rough estimate. I conclude this as follows: At ClinicalTrials.gov (a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world and provided by NIH) on December 17, 2016, I searched for "infrared" and got 888 hits, "LED" with 1,619, "laser" 2,674, "light" 3,735, "genetic" 13,044, and "pharmaceutical" 137,695. This is about 9,000 (assuming no repetition) trials involving light-based technology vs. 150,000 for trials involving either pharmaceutical or genetic approaches, which is 6 percent.

Jan. 13, 2017: A friend just sent me two URLs. The first mentions the recent addition of PBM to standard OM protocol in Brazil and other positive results concerning PBM in treating oral mucositis. The second points to a new study, carried out by a team from Trieste, Italy, which shows that laser therapy inhibits tumor growth in animal experiments. A few studies had shown the possibility that high-power lasers might promote tumor growth ex vivo (that is, outside the body) but the Italian study "Laser Therapy Inhibits Tumor Growth in Mice by Promoting Immune Surveillance and Vessel Normalization," EBioMedicine 11 (2016) 165–172, G. Ottaviani et al., shows that in the body, laser irradiation inhibited tumor growth. They conclude that PBM is safe to use for therapy (such as for oral mucositis) when the tumor may be exposed to the laser (or infrared) light and further "open(s) the way to its innovative use for cancer therapy." That is, PBM might not only prevent OM but could become a cure for the cancer itself. Obviously, a lot more study needs to be done but, as of now, such research does not seem to be a priority in the United States.

The 21st Century Cures Act was signed into law on December 13, 2016. Among interesting aspects of this legislation are Subtitle L--Priority Review for Breakthrough Devices and Subtitle M--Medical Device Regulatory Process Improvements. Combined with a new federal administration, I believe this is the right time for significant change in the prevention and treatment of Oral Mucositis and the intelligent utilization of physics-based medicine to improve medical care and public health.

Last but perhaps not least, Oral Mucositis costs the U.S. over $10 Billion/year; for the 500,000 cases each year, there is a direct expense of additional hospitalization of about $20,000. This does not include the cost of drugs to fight the pain nor does it include the lost productivity for patients and their families.

Paul C. Kainen, Department of Mathematics and Statistics, Georgetown University, January 7, 2017