Study Facility:
Pre-study Screening: Patients come to Ear, Nose, and Throat (ENT)/Oral and
Maxillofacial/Plastic and Reconstructive surgery outpatient facilities. Typically, an ENT
specialist handles early cases (biopsy proven malignancies), while ENT and plastic surgeons
jointly deal with advanced cases. Patients screening will take place in outpatient
departments. The investigator/s will interview each subject to develop a brief, relevant
medical history and determine that all selection criteria are met. The subject will receive
an explanation of the study objectives, possible risks and benefits of the study. After
history evaluation of the patients, Blood work will be done to check liver functions Test.
After the blood report and inclusion and exclusion criteria, the consultant will discuss and
educate the patients about photosensitization and Photodynamic Therapy (PDT). If patients are
willing to take part in the study, co-investigator will obtain a signed consent form. After
obtaining a signed consent form, the consultant will schedule an appointment for PDT therapy.
Procedure after enrollment: Investigators plan to enroll 30 patients with oral cancer in this
study. The study will take place at Jawaharlal Nehru Medical College (JNMC), Aligarh. This
timeline of procedures considers that many patients may need to travel from remote rural
areas with poor access to transportation, so it cannot be assumed that patients have
convenient access to return to the clinic for multiple repeated biopsies.
Aminolevulinic Acid (ALA) preparation and administration: The FDA-approved Aminolevulinic
Acid (ALA) from Dusa Pharmaceuticals, Inc., Wilmington, Massachusetts (MA) will be used in
powder form. Patients will initially receive a baseline ultrasound of the oral cavity prior
to ALA administration. In the case of potentially childbearing women, a serum pregnancy test
will be performed before ALA administration by SD (Standard Diagnostic Inc, India) Bioline
kit. One hour prior to ALA administration, analgesic (Aceclofenac 200mg, Intas
Pharmaceuticals, India), anti-inflammatory drug (HifenacSR 200mg; Intas Pharmaceuticals,
India) and antiemetic (Domperidone, Domperon, 10mg; Cadila Pharmaceuticals, Inc., India) will
be given to patients orally to avoid nausea and pain. ALA, totaling 60 mg/kg, will be
administered orally via three repeated doses of 20 mg/kg of ALA dissolved in either orange
juice or a soft drink, which lowers the potential of hydrogen (pH) of the solution, at 0, 1
and 2 hours.
Day One: Baseline imaging; Fluorescence measurement: PpIX (Protoporphyrin IX) fluorescence
will be recorded using 405nm excitation light delivered from an Light-Emitting Diode (LED)
source powered by a smartphone. This is a non-invasive system. The PpIX fluorescence will be
photographed using the camera embedded in the smartphone. The advantage of this step is that
in the long term it will obviate the need for biopsies to establish PpIX concentrations and
could allow for online dosimetry customized to individual patients. Three photographs will be
taken in each subject: first photograph will be taken prior to given ALA to the patients,
second photograph after 2-3 hours of ALA incubation, and third photograph will be taken
immediately after PDT treatment.
Imaging Procedure before treatment: After allowing 2-3 hours for PpIX conversion and
accumulation in the malignant tissue, a baseline image of the tumor will be obtained using
the smartphone PpIX imaging approach. In this clinical validation study, these PpIX
fluorescence images will be used to make treatment decisions beyond visual guidance for
applicator placement on the lesion.
PDT Procedure: Immediately after the brief imaging session (approximately 5 minutes), the PDT
treatment will proceed. Depending on the exact fractionation schedule determined, a total
fluence of 100Joule/cm2 at the lesion surface will be delivered with an area of applicators
or compressed applicator in for approximately 30-45 minutes. Placement will be such that the
full extent of the lesion falls within a 1mm margin of the applicator area. Every 10 minutes,
a 2-3 minute break is provided to the patient and the study personal will check for the
correct placement of the probe. The clinician will conduct applicator placement with the
assistance of a nurse as needed so that it fits tightly in contact with the active surface
facing the lesion. Care will be required when pressing an applicator tipped light delivery
system hard against tissue. If one press too hard and the tissue is rendered temporarily
hypoxic, there will be no PDT effect. During therapy patients will leave their mouth closed
around the optical fiber. Depending on the exact orientation of the lesion within the oral
cavity a mouth guard may be used to aid applicator positioning, or if this improves patient
comfort. Also, to aid in the stabilization of the fiber and improve patient comfort, an
ergonomic external positioning mount may be employed to help maintain the optical fiber in
position. Provided that care is taken that no incidental body movements during irradiation
lead to significant shifting of movement of the applicator, patients will be able to read a
magazine, watch television (TV) if available or other similar activities from a seated
position. Small lesions may receive a complete treatment in this time interval, while (as
noted above), larger lesions may require one or more additional applications. Patients will
receive analgesic Aceclofenac, HifinacSR (200 mg); Intas Pharmaceuticals, India to avoid
pain. Appropriate Laser safety glasses will also be provided to the patients during
irradiation.
Post-treatment imaging: At the conclusion of the PDT treatment, the light delivery fiber will
be removed and a follow-up smartphone fluorescence image will be obtained for later analysis
of PpIX photobleaching. Patients will receive guidance on the resumption of normal
activities. After the procedure, patient will be advised to avoid foods that are spicy, hot
or oily for at least 6 hours and advised to take analgesic as needed Aceclofenac, HifinacSR
(200 mg); Intas Pharmaceuticals, India. to avoid pain. Patients will also be advised to stop
smoking and chewing tobacco products.
Day Two to Three: Routine complete blood investigations including a liver function test (LFT)
will be performed at 1 to 2 days following ingestion of ALA. If abnormalities are noted,
follow-up blood work will be conducted that includes a renal function test (blood urea, serum
creatinine, uric acid) and blood electrolytes measurement.
Day Seven to Ten: At a follow-up examination, 7 days after treatment, an ultrasound of the
oral cavity will be conducted to assess treatment response by lesion area (cm2) and depth
(mm). As part of this study, ALA will also be re-administered (unless a particular patient
had an adverse reaction to ALA in the initial treatment) so that follow-up fluorescence
imaging can also be conducted. Again, at this stage, fluorescence imaging is included for
validation of the procedure itself, not to decide the next steps in treatment for this
patient cohort. However, the follow-up ultrasound will be a decision point to determine
whether a given patient needs to undergo surgical excision of residual tumor (possibly with
additional radio- and/or chemotherapy as determined by the clinician team), or if no residual
disease is present, a biopsy will be conducted at the original disease site for histological
confirmation of treatment response, and/or disease progression (development of invasive
disease). If the radiologist reports residual tumor after the ultrasound procedure, an ENT
surgeon will perform a biopsy and the tissue will be preserved in formalin and sent for
histopathology assessment. The depth of necrosis evaluated from the histopathology will serve
as endpoint for evaluating the technology. This histopathology data will also be used for
validation of imaging to establish fluorescence contrast agreement with histologically
confirmed malignant tissue.
Follow-up Model: Patients who have a good response to PDT will not need to undergo surgery,
which would compromise the excellent healing of the mucosa that has been reported with this
modality. At the same time, patients whose disease has partial or no response to PDT will
still receive the same standard of care (surgical excision, chemo/radiation) they would have
if they had not enrolled in the study. It is also possible that the PDT treatment, even if
the response was not complete, could reduce the scope of excision required in these subjects.
Therefore at the end of the study, we will have established the utility of this technology
without interrupting the flow of treatment/management of the patients whose disease has
partial or no response to PDT. Regardless of the flow of this study, additional follow-up on
all patients will be carried out at 1 month,3 months, 6 months, 9 months,12 months, and 2
years after treatment. All patient data obtained will be appropriately de-identified as per
local institutional guidelines before off-site analysis, which will continue throughout the
study.
The clinical validation study will also serve as an opportunity to gather patient data that
will be invaluable in two capacities 1) to obtain important information immediately relevant
to individual patient care and 2) with a mind toward sustainability, investigators will seek
to understand cultural barriers to acceptance or compliance with the proposed PDT treatment
that will be accounted for in outreach and training plans. The present validation study is
not powered to make a comparison between different interventions, but rather to provide a
validation that the safety and efficacy of the low-cost approach is equivalent to previous
reports of PDT treatment for oral cancer in traditional medical settings at JNMC.
Inclusion Criteria:
1. Age above 21 years, males or females
2. Subject has read and signed a written informed consent form
3. Subject is willing to have ALA administered and wait for 2-3 hours
4. Subject is willing to receive red light irradiation in the mouth via the fiber
probe/applicator and is willing to have the fiber probe/applicator in the mouth for a
maximum time of 1 hour
5. Subject is willing to allow investigators to take measurements using smart phone
imaging before, during and after light treatment
6. After the procedure, the subject is willing to avoid spicy, hot, or oily foods for at
least 6 hours
7. Subject willing to wear full sleeve shirt and full-length garments for couple of hours
Exclusion Criteria:
1. Pregnancy or nursing (ALA is a drug that belongs to FDA pregnancy category C).
2. History of photosensitivity diseases (e.g., lupus erythematosus, porphyrias).
3. Therapy with any photosensitizing medication, e.g., thiazides (for the treatment of
high blood pressure), fluoroquinolones, griseofulvin, or sulfonamides (for the
treatment of infections), sulfonylureas (for the treatment of diabetes),
phenothiazines (for the treatment of emotional problems), and other medications
reported to cause photosensitivity within the last 6 months.
4. Subject is unable or unwilling to comply with the study requirements.
5. Subject has any conditions or scars within the location of the test sites that may
interfere with the treatment or evaluation.
6. Allergy to porphyrins or ALA.
7. Subject has received laser treatment within 6 months in the area of the treatment.
8. Subject is participating in other potentially confounding research, e.g., currently
enrolled in a clinical study of any other unapproved investigational drug or device.
9. Any other condition or laboratory value that would, in the professional opinion of the
investigator, potentially affect response or participation in this clinical study.
10. Subject has inadequate organ function.
11. Subject has co-morbid systemic illnesses or severe concurrent disease.
12. Subject is being treated for vascular disease.
13. Subject is an employee of the participating sites directly supervised by the
investigator.
14. Subject with invasive deep carcinoma evaluated by biopsy.
15. Subject is currently being treated for other cancers with medical or radiation
therapy.
16. Subject has AIDS or other infectious diseases, including tuberculosis, hepatitis or
herpetic lesions (oral herpes).
17. Subject has oral submucous fibrosis (OSF) resulting in a patient inability to
comfortably hold the light applicator in mouth.
18. Subject has Human papillomavirus (HPV) positive tumor.
19. Subject has the tumor at Oropharynx area.
20. We will excludes the patients of the all other oral lesions at sites except: the
gingivobuccal sulcus, cheek, floor of the mouth and tongue.
