James T. Allardice

Adjuvant intraoperative photodynamic therapy for colorectal carcinoma : a clinical study

The local recurrence rate of colorectal carcinoma after surgery is unacceptable in most series, and adjuvant therapies have made only a small impact on this. There is experimental evidence that adjuvant intraoperative photodynamic therapy (AIOPDT) may be effective. AIOPDT involves systematically photosensitizing the patient preoperatively with a drug (HpD) which relatively localizes to tumour and is activated using visible light. At operation the resected tumour bed is illuminated with a predetermined uniform light energy density to eradicate microscopic tumour deposits left at the lateral resection margin. We have previously investigated technical and biological factors leading to this clinical trial. Seventeen patients have received AIOPDT in a potentially effective dose, and safety and technical matters have been investigated. Cutaneous phototoxicity occurred in 3 patients. Three patients had anastomotic breakdown, none considered attributable to PDT. The intraoperative technique was a practical option. AIOPDT carried a low patient morbidity and should be investigated in prospective clinical trials to determine if local recurrence rates can be decreased.

Standardization of intralipid for light scattering in clinical photodynamic therapy

Intralipid is a light scattering medium used in photodynamic therapy (PDT) in both phantom studies and to obtain optimum light distributions from clinical light delivery systems. Light delivery to a target is one variable in PDT over which we have direct control, and should be as accurate as possible. Variations in the scattering ability of Intralipid from batch to batch will lead to an unpredictable light distribution and undesirable PDT effects. Furthermore, 10% and 20% stock solutions, when diluted to similar final concentrations, have different scattering abilities which will lead to inaccuracies in studies measuring scattering coefficients and imprecision in light distributions from light delivery systems. Batch to batch variations of similar stock solutions should lead to minimal differences in outputs from light delivery systems. A simple and quick assay system is described to define the concentration of Intralipid based on its light scattering ability, which enables testing of solutions prior to use. In the clinical setting where accurate light distribution is required, we suggest that only one stock solution (e.g. 20%) is used and that the final dilution scattering ability is checked using this assay system.

Multiple fibre interstitial photodynamic therapy of patients with colorectal liver metastases

Multiple fibre interstitial photodynamic therapy (IPDT) was performed in patients with colorectal hepatic metastases (CRHM) to determine treatment response and side-effects. Ten patients aged 48–75 years with 16 CRHM (seven solitary) were sensitized with (111 mg m−2) haematoporphyrin derivative intravenously. Forty-eight hours later a custom-designed light delivery system guided by ultrasound allowed 630 nm light from a copper vapour pumped-dye laser split into four 200 μm optical fibres to be geometrically positioned within the metastasis. This was performed percutaneously in four patients and at laparotomy in six. Metastases were imaged using computerized tomography and volumes measured by planimetry. Growth was expressed as a ratio relative to the initial volume (RVG). Following IPDT no complications occurred. Three metastases were not treated because of technical problems. No patient suffered skin photosensitivity reactions. Twelve weeks following IPDT, 12 metastases of less than 60 cc initial volume had a mean RVG of 0.99 (s.d. 0.27). One large solitary metastasis continued to grow after IPDT with a RVG of 1.9 after 12 weeks. Untreated hepatic metastases had a mean RVG of 2.13 after 12 weeks. These data suggest that IPDT can reduce the growth of small hepatic metastases and can be performed with low morbidity when applied at laparotomy and with minimally invasive techniques.

Photosensitized patients and operating lights

Photosensitized patients who receive intra-operative photodynamic therapy are subjected to the intense brightness of operating lights. In order to investigate the potential phototoxic effects of this therapy, light energy densities were measured in non-photosensitized patients undergoing major abdominal surgery. The results show energy densities of 0.14 to 12.51 J cm−2 of polychromatic light for different operative fields. By a consideration of photon absorption numbers, these levels have a photodynamic equivalent of 0.34 to 30.06 J cm−2 of 630 nm light at the surface of tissue. If surgeons are unaware of the possible phototoxic effects of operating lights, some tissues could receive an unacceptably high energy density of polychromatic light. However, operating lights should not give significant phototoxic effects if the surgeon is aware and takes simple precautions.

Safety studies for intraoperative photodynamic therapy

A new adjunctive therapy is needed for colorectal carcinoma surgery to decrease local recurrence rates. Photodynamic therapy (PDT) may be able to fulfil this role by activating the selective photosensitizer haematoporphyrin derivative (HPD) intraoperatively with laser light. This technique would necessitate the irradiation of normal tissues and therefore safety studies have been carried out in miniature pigs. Animals were photosensitized with HPD (5 mg kg−1), then 48 h later colonic anastomoses and ureters were irradiated with 50 J cm−2 of 510 nm-equivalent light. Anatomical, physiological and biochemical analyses were carried out, investigating both structure and function. Our results show that PDT applied in a potentially useful biological dose has no detrimental effect on the healing of anastomoses and ureteric structure and function. This work paves the way for intraoperative adjunctive PDT to be used effectively in man.

Cutaneous phototoxicity in photodynamic therapy: Clinical experience with and without histamine antagonists

We have investigated the incidence of cutaneous phototoxicity in 47 patients who received photodynamic therapy between April 1988 and March 1990. Of these, 15 patients received antihistamines as part of a pilot study to evluate their photoprotective role. Patients were followed-up for a minimum of 8 weeks. One out of the fifteen who received antihistamines and 15 out of the 32 patients who did not (p<0.005), developed cutaneous phototoxicity. On the basis of these results we have initiated a randomized double-blind trial to evaluate the role of antihistamines in haematoporphyrin derivative-induced cutaneous phototoxicity.

An interstitial light delivery system for photodynamic therapy within the liver

The design and application of an interstitial light delivery system suitable for photodynamic therapy of liver metastases is presented. The device incorporates an optical portion and a localization portion. Accurate geometric positioning of four 200 μm diameter optical fibres can be achieved and orientated within a metastasis after initial placement of a single fibre using real time ultrasound imaging. The device can either be applied using the percutaneous route or directly into the liver at laparotomy.