Vol. 103 No.

2 February 2007

COMMENTARY
Efficacy of oral lycopene in the management of oral submucous fibrosis
Oral submucous fibrosis (OSMF) is a condition that is
virtually unknown to health care providers in the West
because areca-nut use is rare. In Southeast Asia, including India where the authors of this study reside, arecanut use is widespread and the prevalence of OSMF in
users has been reported to be as high as 3.2%.1 Aside
from the significant reduction in oral function described
by Kumar et al. (presented in the previous article),
individuals with OSMF have a high risk for malignant
transformation.1 The relatively recent introduction of
gutkha (an areca-nut/tobacco mixture sold in a singleuse sachet, also referred to as pan masala), into the
Indian market is viewed as especially ominous because
of the youth appeal, the ease of procurement, low
expense, convenient packaging, and the lack of social
stigma. Gutkha users have higher rates of OSMF,2 and
this has given health authorities in India much reason
for concern about increased rates of oral cancer in a
younger population. Indeed, the majority of the subjects
in this study are gutkha users under the age of 30. Of
importance is the rise of OSMF in the West (including
the United States) owing to immigration of South
Asians who continue to consume the various areca-nut
products, including paan and gutkha.3,4
Historically, OSMF has been an enigmatic condition
both in terms of its poorly understood etiopathogenesis
and difficulty in management. Recently, however,
much progress has been made in our understanding of
its pathogenesis, offering insights into therapeutic strategies.5 Management strategies, as alluded to by Kumar
et al., are mostly based on uncontrolled trials or anecdotal reports, and in addition to habit cessation, these
strategies include conservative opening exercises, multivitamin therapy, intralesional injections with steroids
and other drugs, and a myriad of surgical interventions,
all of which have shown limited efficacy.
This prospective randomized and blinded, placebocontrolled study, despite some methodological limitations and a high drop-out rate, is the first to demonstrate
lycopenes efficacy in reducing both the signs and
214

symptoms of OSMF and as such it offers patients and

providers a noninvasive and safe alternative or adjunct
to conventional therapies. Of particular interest was the
authors finding that subjects with advanced OSMF
(20 mm of opening) were poor responders. The initial
inflammatory response in OSMF causes the burning
sensation and intolerance to spicy foods. Chronic inflammation subsequently leads to progressive fibrosis.
Steroids and other immunomodulatory drugs will effectively reduce inflammation, but will not reverse existing fibrosis and may explain why such therapies
show limited efficacy in patients who present too late
when fibrosis is severe. The results of this study suggest
that lycopene, similar to steroids, exerts an anti-inflammatory effect, rather than an antifibrotic effect. If this is
indeed the case, this therapy will have limited benefit if
not instituted early in the course of this disorder. It is
also important to point out that any treatment for OSMF
must include an intervention for the areca/tobacco dependence. Areca-nut products, particularly those mixed
with tobacco, are highly addictive, to the point that
patients with OSMF will, in many cases, continue the
habit despite the pain, loss of oral function, and the
knowledge that they are at risk of developing oral
cancer.
This study is also of interest because there is much
new information, both in the press and the medical
literature, about the benefits of fresh fruits and vegetables and nutritional supplements (such as lycopene) for
both prevention and treatment of diseases. As clinicians, we all too often prescribe medications with significant adverse effects, and certainly, if armed with
evidence to support using such nutrients as safer therapeutic alternatives, we would not hesitate to recommend them. Lycopene has also shown efficacy as a
chemopreventive agent for oral premalignant lesions,6
presumably because of its antioxidant activity. It would
thus be reasonable to hypothesize that lycopene could
exert a similar effect on malignant progression in
OSMF and more studies are needed. There are close to

OOOOE
Volume 103, Number 2

400 indexed articles listed in Medline with lycopene in

the title, and this naturally occurring nutrient (principally found in tomatoes, but also in red watermelon)
has been shown to confer multiple health benefits in
addition to its antioxidant activity, namely as an anticholesterol and anti-inflammatory agent.7
Some of the limitations of this study were described
by the authors; however, it is important to discuss these
limitations, not for the purpose of criticism, but for the
benefit of future studies. Having conducted clinical
research in India, I am aware of the challenges facing
investigators and applaud the authors for their efforts,
particularly in dealing with potential subjects who are
from, as the authors have written, a backward socioeconomic group. Such subjects are very poor, often
surviving day to day, and with little to no education,
which has implications not only from an informed
consent perspective, but also related to their inability to
return for follow-up visits that is reflected by the large
number of drop-outs in this study. Other limitations are
outlined as follows: (1) The selection and measurement
of the key objective end point (interincisal opening)
was acceptable; however, the selection and measurement of the other objective and subjective end points
were not optimal. Ariyawardana et al.8 describe different end points that may offer some advantages, in
particular the categorization of opening by stage (stage
I, 20 mm; stage II, 11-19 mm; stage III 11 mm),
which in this study could have been used as surrogates
for OSMF severity, enabling either an equal distribution of each stage during the randomization, or offering
a deeper interpretation of the results. The use of a visual
analogue scale (or other validated pain-rating scale) to
measure the oral burning is recommended at every
follow-up visit. Kumar et al. suggest that the stoicism
of this population abrogates the use of the visual analog
scale (VAS), and while it may be true that this cultural
difference could result in a lower baseline score, this
scale is very simple to incorporate into the design and
there is undoubtedly value in recording the changes at
different time points, even if only to find that the
hypothesis that the VAS is of no benefit is supported.
The only potential issue, which is acknowledged by the
authors, may be that subjects who cannot write may not
be able understand how to mark the scale. (2) This was
a randomized and double-blinded placebo-controlled
study, yet there are some issues related to the way in
which both the randomization, blinding, and indeed the
selection of groups were made. First, it is customary to
describe specifically how randomization occurs, and
this was not the case. Second, double-blinded insinu-

Kerr 215

ates that both the subject and all investigators had no

idea whether the capsules contained lycopene or placebo. In this study, although the investigator examining
the subjects was blinded, the other investigator seemed
aware of which capsules were dispensed. Third, in
future studies, authors might also consider adding an
additional control group for the steroid injection, and
possibly a no-treatment arm. (3) The monitoring of
habit abstinence by removing extrinsic staining and
monitoring for new stain was crude, albeit novel. Consideration of more objective measures of areca habit
abstinence, analogous to serum cotinine levels used to
gauge tobacco abstinence, is suggested particularly if
future studies were to contain a no-treatment arm. (4)
Finally, the safety of lycopene (and steroid injections)
was not reported in the methods as an end point of
interest in this study. Although lycopene is a nutritional
supplement with a low risk for adverse events, it is
customary and important to incorporate how adverse
event data are collected and reported. It is the hope that
the hard work by Kumar et al. will spawn future longitudinal prospective multicenter studies using validated objective and subjective measures to further explore the use of lycopene, or other novel therapies, for
the treatment of OSMF.
A. Ross Kerr, DDS, MSD
Department of Oral & Maxillofacial Pathology,
Radiology & Medicine
New York University College of Dentistry
New York, NY
doi:10.1016/j.tripleo.2006.11.012

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