Chemo induced mucositis
Results of multicenter phase III studies
LaserWorld Guest Editorial, 1 1999.
By René-Jean Bensadoun, France
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:
[email protected]
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