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Considerable buccal toxicity of radiotherapy and/or chemotherapy in
patients with cancer can cause patients to become discouraged and can
alter their quality of life. In addition, such toxicity often necessitates
alterations of treatment planning, with grave consequences in term of
tumor response and even survival (concept of dose-intensity). With 5-fluorouracil
and head and neck radiotherapy for example, acute mucosal toxic effect
is the main limiting factor for which no clinically appropriate prophylaxis
or efficacious antidote has been found to date. Management of oral mucositis
is currently primarily directed at palliation of the symptoms, and prevention
of infections.
Low level HeNe laser (LLL), or "soft-laser", has been reported effective
in reducing the severity of oral mucositis lesions in a non-randomized
trial, initiated in Nice (France) by Ciais et al. (1). The efficacy
of this method in the prevention of chemotherapy induced oral mucositis
has been subsequently confirmed in two prospective, double-blind randomized
trials, in patients undergoing bone marrow transplant (2 ; 3).
These initial findings and the high incidence of radiation-induced mucositis
prompted a randomized multicenter trial to evaluate LLL for the prevention
of acute radiation-induced oropharyngeal mucosal lesions. The trial
was open to patients with carcinoma of the oropharynx, hypopharynx and
oral cavity being treated by external radiotherapy, with a total dose
of 65 Gy at a rate of 1 fraction of 2 Gy/day, 5 days a week, from cobalt-60
or linear accelerator photons, without prior surgery or concomitant
chemotherapy.
Between September 1994 and March 1998, thirty patients entered this
double-blind randomized study conforming to the Huriet law. The goal
was to determine whether preventive HeNe laser beam applications could
reduce or prevent oropharyngeal mucositis caused by radiotherapy.
Patients characteristics :
There were 26 men and 4 women. Mean age was 60.4 years (range 36 - 78).
Oral examination and preventive dental management were performed prior
to radiotherapy. Daily oral hygiene (cleaning of the teeth and dental
prosthesis) during treatment was recommended. Patients were assigned
to either laser treatment (L+) or sham-treatment (L-) by computer blocked
randomization. The protocol called for the inclusion of 30 patients,
15 in each arm. No associated anti-inflammatory or other treatment was
authorized. Analgesics could be prescribed, but not during the 2 days
preceding each week evaluation.
Patients received HeNe laser applications daily for five consecutive
days (Monday to Friday) each week, during the seven weeks of radiotherapy.
The malignant tumor had to be located outside the areas selected for
randomized preventive LLL application. Laser was delivered to the tissues
by a straight optical fiber with a 1.2 mm spot size. The 9 treatment
areas included : posterior third of buccal mucosa, soft palate and anterior
tonsillar pillars. Laser illumination consisted of a continuous beam
(wavelength: 632.8 nm; power: 60 mW), calibrated at the end of the optical
fiber every day. The treatment time (t) for each application point was
given by the equation : t (sec) = energy (J/cm2) x surface (cm2)/ Power
(W).
The average energy density delivered to the treatment areas was 2 J/cm2,
and was applied on these nine points, equally distributed on the treated
surfaces, for 33 s per point (each specific LLL session lasted approximately
5 minutes). The 60 mW lasers were designed and produced by Fradama S.A.
(Geneva, Switzerland). All laser illuminations were performed by the
same individual in each center. This operator was the only person to
know whether or not the patient was sham-treated, and did not participate
in the evaluation and scoring mucositis. During the sessions, patients
wore wavelength-specific dark glasses and were instructed to keep their
eyes closed, to assure that they did not know whether they were sham-treated
or whether they received laser applications. The laser made the same
noises, and the probe was held in the mouth exactly the same way, when
treating control subjects and when treating laser patients. The whole
irradiation field, the oral cavity and the visible oropharynx were inspected
weekly during seven weeks by the same physician (head and neck surgeon,
or radiation oncologist), blinded to the result of randomization. The
evaluation of mucositis and pain was performed on the oropharyngeal
areas (9 points). Criteria for evaluation were the standard WHO scale
for mucositis in the oropharynx; and a segmented visual analogic scale
for pain (patient self evaluation).
In this phase III study, no adverse effect was noted with the use of
a 60-mW HeNe laser, though it is important to emphasize the importance
of preventing retinal damage by the use of wavelength-specific goggles.
This is consistent with previous reports. Laser applications delayed
time of onset, attenuated the peak severity and shortened the duration
of oral mucositis. The difference between L+ and L- patients was statistically
significant from week 4 to week 7. With the total delivered dose of
65 Gy, conventionally fractionated, all L- patients developed mucositis
at week 2, with a peak at week 5 (13 with grade 3 mucositis, and 2 with
grade 2 mucositis). All L+ patients also had mucositis at week 2, with
a peak at week 5 (5 with grade 3 mucositis, 9 with grade 2, 1 with grade
1). During the 7 weeks of treatment, the mean grade of mucositis in
L+ patients was significantly lower (p=0.01) than the mean grade in
L- patients . Results on decrease in pain intensity were also quite
convincing. Laser applications reduced the incidence and duration of
morphine administration. Ability to swallow was also improved. These
results confirm previous data collected with this method, especially
for patients undergoing bone marrow transplant (BMT).
In a prospective study, Barasch et al. (2) used a 25- mW laser on one
side of the mouth only and reported a statistically significant reduction
in oral mucositis on that side, according to the scoring system they
used. In the Barasch study, each patient was his or her own control,
which could be of importance, since mucosal damage on the sham-treated
side could have benefited also from a distant systemic laser effect.
Cowen et al. (3), using a 60 mW HeNe laser, performed a double-blind
randomized phase III trial, in which laser was administered to the treatment
group during conditioning, prior to the day of transplant.
This study showed a 33% reduction of grades 3 and 4 mucositis in L+
patients. In this trial, mucositis was scored according to an oral examination
guide, with a 16 items scale, of which 4 were assessed by the patients
themselves. Daily mucositis index was significantly lower in L+ patients
(p < 0.05) from d+2 to d+7 after BMT. The duration of grade 3 stomatitis
was also reduced in L+ patients (p = 0.01). Oral pain was lower (p =
0.05), and L+ patients required less morphinomimetics (p = 0.05). Finally,
xerostomia and ability to swallow were improved among L+ patients (p
= 0.05, and p = 0.01, respectively). All these results were in keeping
with previous observations, suggesting the efficacy of the method (1,
4). Schubert et al. for example (4), identified a trend towards lower
oral mucositis scores, on all examination days, in an interim results
report of a phase I/II study, in which laser application was performed
prophylactically during conditioning before BMT.
In conclusion, low level HeNe laser (LLL) seems to be a safe and efficient
method for the prevention of radiation-induced stomatitis, as it has
been demonstrated for chemo-induced mucositis, with a tremendous potential
interest for combined modality treatment.
The concomitant use of chemo- and radiotherapy is becoming the new standard
of care in advanced head and neck cancer, with very encouraging results,
even in nonresectable cases. Since the main limiting factor of these
combined protocols is the acute mucositis, this complementary treatment
option with low level HeNe laser could be important in enhancing the
feasibility of such regimens, and especially in the conservation of
dose-intensity effect. At Nice, where the method is now used routinely
during head and neck radiation, we project a new study testing LLL in
patients being treated with concomitant chemo- and radiotherapy for
advanced head and neck cancer. Even more than the improvement of patient
comfort, the therapeutic index of combined specific treatment should
be increased by the use of LLL, besides standard supportive care, oral
care and enteral nutrition. During this study, other laser wavelengths
and powers could be tested, and compared to 60-mW HeNe laser.
References :
1. CIAIS G., NAMER M., SCHNEIDER M., DEMARD F., POURREAU-SCHNEIDER N.,
MARTIN P.M., SOUDRY M., FRANQUIN J.C., ZATTARA H. (1992). La laserthérapie
dans la prévention et le traitement des mucites liées à la chimiothérapieé
anticancéreuse. Bull. Cancer 79 : 183-191.
2. BARASCH A., PETERSON D., TANZER J.M., D'AMBROSIO J.A., NUKI K., SCHUBERT
M., FRANQUIN J.C., CLIVE J., TUTSCHKA P. (1995). Helium-Neon laser effects
on conditioning-induced oral mucositis in bone marrow transplantation
patients. Cancer 76 : 2550-2556.
3. COWEN D., TARDIEU C., SCHUBERT M., PETERSON D., RESBEUT M., FAUCHER
C., FRANQUIN J.C. (1997). Low energy helium-neon laser in the prevention
of oral mucositis in patients undergoing bone marrow transplant : results
of a double blind randomized trial.Int. J. Radiation Oncology Biol.
Phys. 38 (4) : 697-703.
4 . SCHUBERT M.M., FRANQUIN J.C., NICCOLI-FILHO F., MARCIAL F., LLOID
M., KELLY J. (1994). Effects of low-energy laser on oral mucositis :
a phase I/II pilot study. Cancer Researcher Weekly 7 : 14.
Dr René-Jean BENSADOUN,
Head of the External Radiotherapy Unit Centre
Antoine-Lacassagne 33 Av de Valombrose,
06189 Nice Cedex 2, France
Tel: 33 4 92 03 12 70 Fax: 33 4 92 03 15 70
E-mail: rene-jean.bensadoun@cal.nice.fnclcc.fr
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HOW TO FILL UP A GAP?
Low power laser therapy is used to stimulate tissue repair, in particular
to heal chronic skin wounds (which often were not healed by traditional
medical treatments) These reports have been criticized for lack of double
blind studies and placebo groups.
Indeed, double blind experimental data must be collected and the mechanisms
of underlying processes must be explained before further introduction
of "laser biostimulation" into clinical practice. Understanding of the
light effects on tissue repair mechanisms is developing [1] but the
question about appropriate modeling of chronic human wounds is still
not solved. What more, the question seems to be rather topical.
It is clear that one can not perform double blind studies with unique
and real human wounds (e. g. Buerger's disease, where the He-Ne laser
treatment is reported to be successful [2]). It is difficult to do this
also with trophic ulcers of various etiology (laser treatment is claimed
to be successful in these cases). Until yet the most common way to perform
statistically appropriate series of experiments has been the irradiation
of fresh experimental wounds of rodent skin. In most cases the conclusion
in this type of papers is that the irradiation neither increased the
wound closure, nor effected the healing by histological parameters.
What is not surprising [6,7] .
So, there is a large gap between often reported clinical cases of successful
use of low-power lasers and LED's in healing of human wounds on one
hand, and also rather often reported failure of well planned double-blind
experiments of stimulated healing of fresh rodent skin wounds, on the
other hand. It seems to be clear that using fresh rodent wounds for
modeling of human trophic ulcers is a dead end. A little bit more promising
seems to be using of diabetic rodents [3,4] or pig skin [5] but these
models are also far of being optimal. What then? I do not know. May
be it would be wise first to discuss this matter with participation
of wound repair specialists before continuing an endless game "laser
biostimulation is effective vs. it is not effective".
To finish this Editorial let me recall that one conclusion drawn out
both from in vitro cellular experiments as well as clinical "laser biostimulation"
literature is that the cells which are in conditions of low oxygen concentration,
acidic pH or lack of necessary nutrients are much more sensitive (and
susceptible) to irradiation than those in optimal or near optimal conditions
[6,7,8]. May be this knowledge can help to create an appropriate and
suitable animal model?
Tiina I.Karu
Laser Technology Res.
Center of Russian Acad. Sci.
142092 Troitsk, Moscow Region Russian Federation
Email:karu@isan.troitsk.ru
References
- Dyson M. The present state of laser therapy in tissue repair: recent
development and future directions. In: Proc. 2nd Congr. Word Assoc.
Laser Therapy (Sept. 2-5, 1998, Kansas City, USA), p. 9.
- Schindl L., Kainz A., Kern H. Effect of low level laser irradiation
on indolent ulcers caused by Buerger's disease; a preliminary report.
In: Ohshiro T., Calderhead R.G., eds. Progress in Laser Therapy. Chichester:
John Wiley and Sons, 1991:130-137.
- Yu W., Naim J.O., Lanzafame R.J. Effects of photostimulation on
wound healing in diabetic mice. Lasers Surg. Med. 1997; 20:56-63.
- Waynant R.W., Chenault V.M. The use of low level laser therapy
to accelerate wound healing in an animal model and preliminary/future
studies. In: Proc. 2nd Congr. Word Assoc. Laser Therapy (Sept. 2-5,
1998, Kansas City, USA), pp.112-113.
- Rezevani M., Nissan M., Hopewell J.W., van den Aardweg G.J.M.J.,
Robbins M.E.C., Whitehouse E.M. Prevention of x-ray-induced late dermal
necrosis in the pig by treatment with multi-wavelength light. Lasers
Surg. Med. 1992; 12:288-293.
- Karu T.I. Photobiological Fundamentals of low-power laser therapy.
IEEE J.Quantum Electronics, 1987; QE-23: 1703-1717.
- Karu T.I. Photobiology of Low-Power Laser Therapy. Chur, London:
Harwood Acad. Publ., 1989. 8. Karu T. The Science of Low Power Laser
Therapy. London: Gordon and Breach Sci. Publ., 1998.
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Treatment of Atopic Dermatitis by Low Power Laser
Takao Igarashi, MD, president of The Ikarashi Pediatrics Allergy Clinic.
The development of laser medicine is marvelous and widely used in
such ways as laser knifes, the laser coagulation in ophthalmology, the
blotch removal in dermatology, the PDT for the treatment of carcinoma
and the resolution of pain and inflamation.
Recently we found that the irradiation of very weak laser light, with
output between a few mW and several tens of mW to the affected part
of atopic dermatitis (AD), had the effect of suppressing itching sensation
and that the continuation of laser therapy could heal the AD itself.
As the effect of low power laser irradiation to suppress the itching
sensation continued for 3 to 5 days, parents were very satisfied, saying
that their children started to sleep well during nights and that they
could reduce the usage of the steroid paste.
Although it is almost 5 years since we started Low Power Laser Therapy
in our clinic, treating more than 200 patients, we have never experienced
any adverse effects and at present we continue to treat 20 to 30 patients
with LPL every day.
In this sense we can recommend this therapy to anybody who suffers from
AD. As the LPL instrument, we use FLAT-10 produced by Fuji Electric
(wavelength: 780nm, output:10mW). The irradiation starts from the most
itching part, selecting 4 points diagonally from the periphery of the
deseased part. The irradiation time is 10 seconds for each point and
40 seconds in total for each deseased part.
The total irradiation time for one patient is limited within 10 minutes
and the treatment is repeated 1 to 2 times a week. The result of our
study, selecting 14 patients of AD (middle and serious cases), between
1 and 18 years old, treated more than 20 times with LPL and continued
observation for 2 to 14 months, is summarized as below.
(1) The dermatitis was improved in 10 of the14 cases.(71%)
(2) The number of treatments until improvement of dermatitis was achieved
was 6 to 87 times. In 7 of the10 cases of which dermatitis was improved,
the number of treatments was 10 to 20 times.
(3) The number of days until improvement of dermatitis was achieved
was 14 to 210. 6 of the 10 cases in which dermatitis was improved were
improved within 3 months. Based upon the above results we concluded
that the LPL therapy was effective to AD and started to recommend it
to parents of patients. However, the Health Insurance is only applied
to the pain relief and the alleviation of inflammation and not to AD
in Japan. We hope that the application of the Health Insurance to AD
will be realized in the near future.
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