Photodynamic therapy with new sublingual sensitiser Photosoft®E4 for cancer: a case series

Introduction

Cancer is the leading cause of death in the Western world, accounting for 13% of all deaths worldwide, and about three in ten deaths in Australia^1,2. It is estimated that 800,000 Australians (3.3% ) were living with cancer in 2007, and an additional 100,000–125,000 are expected to be diagnosed every year, contributing 19% of the total disease burden in 2012³.

An increasing number of patients seek complementary and unconventional cancer therapies. While in 1998 an average of 31.4% of patients in Western countries sought complementary and alternative medical (CAM) therapies⁴, three-quarters of the patients in a cancer centre in the United States used at least one CAM modality in 2005, and the majority of those (58%) were initiated after cancer diagnosis⁵.

The main CAM modalities sought in addition to conventional cancer therapies include special diets, dietary supplements and herbs, psychotherapy, movement therapy, mind-body therapies and spirituality based interventions^4–7. More recently, photodynamic therapy (PDT) has become an acceptable adjunct cancer therapy, providing some promising results. A systematic review of the effect of PDT - alone or in conjunction with conventional therapy - on patients with non-small cell lung carcinoma, showed a response rate of 30.8–84.8% on mainly inoperable disease, with a 5-year survival rate of 43.4–72%, a considerable improvement to the survival rate of 15–35% for inoperable and metastasised cancers using conventional treatment alone⁸. Other types of cancers treated with PDT such as head and neck cancer showed an 89% 5-year survival rate for superficial cancers, compared with 75% using conventional therapies alone^1,9,10.

PDT combines a photosensitiser and light to cause selective damage to the target tissue^10–13. Laser light of a specific wavelength of maximum absorbance matched to the photosensitiser is directly toxic to the cell and also interacts with local intracellular oxygen molecules to activate singlet oxygen, which in turn destroys the target tissue¹⁴. Cancer cells accumulate a higher concentration of the photosensitiser than surrounding healthy tissue, and therefore are a selective target for light treatment^10–13.

A range of photosensitisers are available for malignant tumours. Early drugs were based on haemato-porphyrin derivatives, while newer drugs based on porphyrin, chlorin or chlorophyll derivates have been developed to reduce the phototoxic effects of the early photosensitisers¹⁵. Pharmacokinetic in vitro studies on chlorophyll-based photosensitisers have demonstrated uptake in tumour cells with a range of clearance times¹⁶, and the safety of similar chlorophyll-based photosensitisers, such as Radachlorin® or Sonoflora/Sonnemed® has been demonstrated in animal studies and high tolerability has been observed in small human trials^17–19.

While most photosensitisers are administered intravenously, the new chlorophyll-based sensitiser Photosoft®E4 was developed to be taken sublingually²⁰. A similar chlorophyll-based and sublingually administered photosensitiser Sonoflora® was found to be safe and effective in the sonodynamic treatment (a combination of light and ultrasound) of breast cancer patients¹⁹.

As patients are increasingly seeking and accessing information on complementary treatment options for their cancer treatment, there is a need for the objective evaluation and dissemination of current clinical data on available therapies such as PDT, to help with decision making²¹.

Recently, a new generation photosensitiser has become available in Australia, Photosoft®E4. While there is extensive clinical experience with this sublingual photosensitiser in China where there have been several promising case study reports²², concerns have been expressed about the effectiveness of the modified technology by others^23,24.

For these reasons, there is a need to evaluate clinical experiences with PDT in other countries, including Australia. Here we report on the safety and tolerability of Photosoft®E4 and gauge the effect of the PDT treatment in a group of cancer patients not undergoing any concurrent therapies.

Methods

PDT treatment

The protocol was based on the protocol used at clinics in China at the time of the start of our trial²². The photosensitiser PhotoSoft®E4 (Chlorin-e6-Chlorophyllin-A-Zinc-complex, The Cho group, supplied by Sekhsaria Chemicals Lid, CTN 050/2012), was administered sublingually at a dose of 5mg/kg body weight.

A multi-frequency laser model PDT630II (The Cho group, Guilin Xingda Photoelectricity Medical Equipment Co Ltd, CTN 062/2012) emitting blue, red and infra-red laser light with peak wavelengths at 460 nm, 660 nm, and 870 nm with a total light-dose of 45 J/cm² and a fluence-rate of 25 mW/cm² was used to irradiate each tumour site for 30 min (Figure 1). After the external focused laser, all patients were treated in a whole-body LED-light-bed model NGPDT (The The Cho group, Guilin Xingda Photoelectricity Medical Equipment Co Ltd) emitting the same wavelengths as the external laser for 30 min to target any circulating tumour cells (Figure 2).

Figure 1. External focussed multi-frequency laser.

Figure 2. Full LED light bed.

The treatment comprised of three cycles, with each cycle consisting of 4–5 laser treatments on alternate days over the course of nine days, followed by a 4–5 week break. The photosensitiser was taken sublingually 18–26 hours prior to each laser treatment. In total, patients who completed the three treatment cycles received 12–15 light treatments (mean=14) over three months.

Results

Half of the patients (n=5) had breast cancer, three of which had declined surgery and were without metastases, and two had local reoccurrence and/or metastases after mastectomy (Table 1). Other types of cancer were basal salivary (n=1), neck (n=1), both of whom had no prior mainstream cancer treatment, and stage-IV cervical (n=2) and stage-IV pancreatic cancer (n=1) who had all undergone surgery and/or chemotherapy and radiotherapy previously (Table 1).

All breast cancer patients completed the full course of 3x4 treatments (n=5); other patients underwent 1–2 cycles of treatment before withdrawal due to disease progression (n=3) or uptake of other therapies (n=2).

Patients were treated with a 30 min external laser per tumour site plus 30 min exposure in the light bed, ranging from 1–2 hour-sessions for primary non-metastatic cancers (n=5), and 2–4 hour-sessions for patients with metastasis (n=5).

All patients tolerated the sublingual administration of the photosensitiser well and did not report any side effects other than unpleasant taste (n=10). Laser treatment caused localised sensations such as tingling in some patients (n=5). No phototoxic reactions were experienced. Some patients (n=3) reported localised tingling of variable intensity at the tumour site 1–2 weeks after treatment, lasting between 30 min to overnight.

One patient with a superficial breast tumour showed some localised reduction of tumour size (Table 1, ID4). Diagnostic imaging by CT, MRI or ultrasound scans showed evidence of disease progression in all patients after three months regardless of the type or stage of cancer (Table 1). However, one patient (ID1, breast cancer) who continued with PDT treatment reported clinically stable disease at six months after study completion (tumour-size 3.6 cm³).

Discussion

In our study, the photosensitiser PhotoSoft®E4 taken sublingually at a dose of 5 mg/kg up to 15 times over three months was tolerated well by all cancer patients and no phototoxic effects were observed. The high tolerability of the photosensitiser is in line with international reports from clinical centres using similar agents¹⁹. However, photodynamic therapy of the sublingually administered photosensitiser with external laser light did not improve the overall disease status in our group of patients.

To date, most photosensitisers are administered intravenously, and the pharmacokinetics of sublingually administered photosensitizing agents has not been studied extensively. However, one study found that biodistribution and pharmacokinetics of another photosensitiser 5-aminolaevulinic-acid (ALA) in the human gastrointestinal tract and urinary bladder was comparable if administered sublingually or intravenously²⁵. In addition, sublingual administration of Photosoft®E4 was shown to be taken up selectively by tumour cells in prostate cancer patients²⁶. However, more research is needed on the bio-distribution, uptake in different types of tumour tissue²⁷, and pharmacokinetics of the photosensitiser PhotoSoft®E4. Pharmacokinetic data would also ascertain the optimal time interval between drug intake and light administration²⁸. In our study, we used a 24-hour-interval, which is in line with intervals used in studies with early photosensitisers such as Photofrin®, as well as the chlorophyll-based photosensitiser Sonoflora®^19,29,30. Interestingly, a fractionated drug-dose (the administration of the photosensitiser at multiple time intervals before light activation) ranging between 15 minutes to four hours prior to light therapy has resulted in superior therapeutic effects for a variety of chlorophyll-based photosensitisers^11,29,31. Fractionated drug-dosing has been shown to target tumours by different mechanisms, involving either vascular damage with a short-interval laser treatment or direct tumour-cell apoptosis with a long-interval laser treatment²⁹. Furthermore, sonodynamic therapy has provided promising results with sublingually administered chlorophyll-based photosensitisers similar to PhotoSoft®E4¹⁹.

Our study had a few limitations, including the small number of patients, and the diverse range of cancer types and stages. However, patients were representative of the common clinical population seeking alternative options for their cancer treatment. In addition, the number of patients was sufficient to elucidate the potential effect of the treatment following the protocol as outlined.

A limitation of the protocol was that we used external laser equipment emitting wavelengths between 460–870 nm. Light penetration through skin or muscle increases with wavelength, and is estimated to reach with 37% density between 2.5 and 9 mm of tissue^32,33. Interstitial administration of laser light facilitates penetration and reach of deeper tumours³⁴, but may be too invasive for most patients.

Conclusions

This clinical study indicates the safety and high tolerability of the photosensitiser PhotoSoft®E4, if taken sublingually at a dosage of 5mg/kg up to 15 times within a three month period. However, the protocol for the photodynamic therapy used in this trial as well as in clinical settings by others previously provided no benefit to treatment-related outcomes. More research is required to determine the bioavailability and uptake in tumour tissue, pharmacokinetics and dosing regimen, as well as the best mode of light delivery for the activation of the in vivo sensitiser.