Research proposal / Opportunity
For Llew Keltner
Photodynamic therapy is an established treatment for early primary mucosal head and neck squamous cell cancer, with local control rates equivalent to the oncological and surgical mainstays(1). The use of Light-emmitting diode technology to activate photosensitive agents is also long-standing (2). Recent advances in drug and LED technology have widened the scope of PDT beyond oncology, and into the treatment of vascular disease, in particular, post angioplasty neointimal hyperplasia(3). These advances have reduced skin photosensitivity post-injection of photosensitising drug down to 48 hours. Also, LED arrays are now much more efficient, reulting in increasing light fluence and dramatically reduuced heat production, meaning that bulky and complicated cooling systems are no longer required, and the LED array can now be driven off battery power(4). This allows lightweight, portable cylindrical LED arrays not much bigger than a needle to be produced. Sudies looking at primary hepatocellular carcinoma, and metastatic disease, have shown that this system is easy to use and effective (5).
Ultrasound – guided interstitial photodynamic therapy (IPT) via insertion of LED arrays into malignant neck nodes >3 cm largest diameter will enable down-staging of the disease so that primary radiotherapy, rather than primary surgery will lead to complete tumour resolution.
Conservative or more commonly, radical neck dissection for neck cancer bigger than 3cm greatest diameter is usually required to adequately treat malignant neck nodes. Nodes less than 3cm greatest diameter can usually be adequately treated by external beam radiotherapy alone, thus avoiding the significant morbidity of neck dissection (6). Neo-adjunctive techniques, such as the administration of 3 cycles of chemotherapy prior to irradiation, have not significantly helped in this area (7). An easy to deliver, relatively safe and quick interstitial technique to significantly reduce the bulk of neck nodes prior to treatment is therefore desirable.
Using a rat liver model (which we are familiar with), look at the zone, and in particular, diameter, of necrosis seen in photosensitised animals, varying the following parameters:
Drug: LS11, mTHPC, mTHPBC
Light: 360 degree LED array peaking at the red spectrum drug absorption peak, varying exposure time from 1,2,4,16 hours
Fluence: Vary fluence parameters above and below the current range (to be advised)
Drug-light interval: vary from 1,4,12,24,48,72 hours
This will give optimal PDT parameters for interstitial treatment and suggest the best drug
1) A series of 10 patients with a single neck node > 3cm largest diameter, with the primary cancer being treatable by external beam radiotherapy alone, as agreed by the regional Multidisciplinary team meeting. Other neck nodes may be involved, but will be <3cm largest diameter. A pre-treatment MRI scan will measure the volume of the node to be treated. The patient is admitted to hospital the day after the MDT decision to enter into the study. The patient is photosenstisied with an intravenous bolus of LS11, to the required level. The patient is then sent to the ultrasound centre for implantation of a single 3cm length 360 degree LED array, as close to the central axis of the node as possible, as much in the centre of the node as possible. Once 4 hours have passed since sensitisation, the LED array is activated for 3 hours, and then removed. The patient is then sent home, with advice about avoiding bright light for 48 hours. After 48 hours the patient is admitted into the planning process for external beam radiotherapy, to start 4 weeks after the MDT meeting. MRI scanning to determine tumour response/volume change is performed 3 weeks after photodynamic therapy. Significantly downstaged tumours will be re-presented to the MDT 2) Future directions - CT guided implantation of LED arrays into larger oropharyngeal, hypopharyngeal and laryngeal neoplasms to downstage. 2 arm study using neo-adjunctive and concomitant IPT for malignant neck nodes >3cm diameter. Multiple LED array insertion and IPT for larger neoplasms, including anaplastic thyroid cancer, palliative care of massive loco-regional recurrence.
A reduction in the need for radical surgery is desirable, particularly in the head and neck area. Radical neck surgery is performed at least 100 times per year in our unit, which serves a population of around 1,000,000. If half of these cases could be treated using the proposed plan, then nationally this technique could be used 2,500 times per year in England and Wales (pop approx 50,000,000). Clearly this could be extrapolated out to Europe, North America etc.
Mike Dilkes – Lead Clinican Head and Neck Surgery, Head and Neck Surgeon
Amen Sibtain – Chairman Head and Neck tumour board, Clinical Oncologist
NorthEast Thames Head and Neck Cancer Group, St Bartholomews Hospital, London.
1) M. Dilkes, Bapat U. Foscan photodynamic therapy for early head and neck cancer. 2005 Otolaryngology – Head and Neck Surgery, Volume 131, Issue 2, Pages P74-P75
2) DeJode M.L., Dilkes M.G., New Led source for Photodynamic Therapy: Preclinical study. Proc. S.P.I.E. 2629:299-305.
3) Nick Yeo, Personal Communication
4) Lustig et al 2003, Cancer 98:1767-71
5) Winship et al 2005 J. Clin. Oncol. 2005 ASCO Annual Meeting Proceedings 23, Supplement, 3663
6) Friedman, Michael, Rationale for Elective Neck Dissection in 1990, Laryngoscope,January 1990; 100:54-59.
7) Brockstein B, Vokes E. Neoadjuvant chemotherapy for locoregionally advanced head and neck cancer. General Aspects. http://patients.uptodate.com/