LITERATURE REVIEW OF PHOTODYNAMIC THERAPY FOR HEAD AND NECK CANCER
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3.1 Introduction... 72 3.2 Clinical tria ls... 72 3.2.1 Superficial disease... 74 3.2.2 Depth of PDT damage with Photofrin®... 75 3.2.3 Second generation photosensitisers... 75 3.2.4 Light dosimetry/delivery specific to the oral cavity... 78 3.2.5 Fluorescence detection... 78 3.2.6 PDT in the nasopharynx... 79 3.3 Preclinical studies ... 80 3.4 C o n c lu sio n ... 81
3.1 INTRODUCTION
Although the first report of a patient receiving photodynamic therapy was in 1966 it was not until the early 1970's that Dougherty and co-workers reported the results of PDT on an appreciably larger group of patients with a variety of diseases (Dougherty et al., 1978; Lipson et at., 1966). Soon after, photodynamic therapy caught the attention of the head and neck surgeons and one of the earliest reports of PDT use in head and neck cancer appeared in 1983 by Dahlman et al. Since then there has been abundant reports of PDT research literature in the head and neck. The predominant sites for clinical PDT has been for diseases affecting the skin, aerodigestive and the gastrointestinal tract. These sites are inherently accessible directly or with the use of various scopes. Despite the enormous amount of clinical research within the upper aerodigestive tract much is anecdotal and preclinical research is relatively sparse. A review of the clinical and preclinical literature will be presented in the following sections.
3.2 CLINICAL TRIALS
Dahlman et al reported the use of PDT in 37 patients, twenty of whom presented with "ENT squamous cell carcinomas" with a 65% favourable response (complete response or partial response). This study did not provide clear definition for the outcome of the disease, however later studies in this region followed similar criteria, where:
• Complete Response (CR): no evidence of disease clinically or pathologically • Partial Response (PR): reduction in size of the lesion by at least 50% • No/Non Response (NR): reduction by less than 50% of the maximal
diameter of the lesion
Even in this early study the problem encountered with inadequate light delivery during PDT was noted. Implantation of the optical fibre into the tumour mass was carried out in
two of the patients with bulky tumours, however despite this, no obvious success was observed. The following year (Wile et a l, 1984) reported a series of 39 patients with complete response observed in 25% and partial response seen in 37%, moreover the follow up period for this group was also of a similarly short period as Dahlman (4 weeks). Carruth and Mckenzie were the first to report PDT in a group of 10 patients with either cutaneous metastasis or superficial tumour in the UK. They observed complete response in two of the three patients with head and neck tumours (Carruth, 1985).
Schuller et al reported the results of PDT using haematoporphyrin derivative (HpD) in a group of 24 patients with recurrent or metastatic disease in the head and neck. This group also used interstitial techniques for the thicker tumours, whilst using surface irradiation for the superficial areas. In three patients, adjunctive mtraoperative PDT was used following resection of the tumour and negative frozen sections at the margins. Like many of the early reports, this was a feasibility study and disease progression was observed in 15 patients within 6 weeks (Schuller et a l, 1985). Complications were reported in 5
patients, the most serious being exsanguination of a patient 24 hours following PDT for a tumour involving the carotid artery.
The move away from the use of bare fibre as the light delivery source to microlens and diffuser tips (cylindrical or spherical) was seen in the study by Keller et al, where Photofrin® with 25-60 J/cm^ of light was used. Following the treatment of 11 head and neck tumour patients, it was concluded that diffuse superficial lesion responded well to PDT, whilst only limited palliation was observed in the advances cases (Keller et a l,
1985). The disappointing overall response seen with the advanced cancers were also observed by a number of other investigators, with the suggestion that in these patients the skin photosensitivity may in fact worsen the quality of life (Calzavara et al., 1989; Gluckman, 1991a). For this group of patients, improvements must be found in terms of a more powerful photosensitisers with improved depth of damage, or the use of a photosensitisers with much shorter cutaneous photosensitivity, so allowing repeated treatments without the morbidity of prolonged skin sensitivity. In summary, the
disappointing results of PDT with the advanced bulky tumours are generally believed to be the result of inadequate light delivery to the whole tumour which is another area that research needs to be targeted (Dahlman et a l, 1983).
3.2.1 Superficial Disease
More favourable findings in patients with early superficial and diffuse disease have been well documented (Gluckman, 1991a; Schweitzer, 1990). Gluckman treated 13 patients with early oral and oropharyngeal lesions, following HpD or DHE (dihaematoporphyrin ether/ester) sensitisation with activation using red light from an argon ion pumped dye or gold vapour laser with light doses of SO-lOOJ/cm^. He observed an initial 85% complete response with 4 recurrences within 1 year. However, in the 8 patients with condemned
mucosal disease (field change disease) complete response was seen in all except one patient with follow up between 6 -53 months (Gluckman, 1991a).
Grant et al reported the results in a similar group of 11 patients and observed similar success at the six to eight week stage. Ten patients in this study had a complete response, whilst the remaining patient had areas of residual leukoplakia (Grant et al., 1993b). There is a need to establish longer follow ups on such patients, as such conditions are notoriously difficult to manage by conventional means.
The following tables (3.1 and 3.2) summarises the results in 12 studies reported before the start of the work for this thesis. Table 3.1 summarises the results for the head and neck and Table 3.2 illustrates the number of cases treated with oral disease. The latter reports the main area of interest for this work.
These tables illustrate the variation in drug dose, drug-light interval, light dose and light delivery systems. The aim is to establish specific treatment parameters for use with a particular photosensitiser, and one method to evaluate this would be to establish what effects are achieved when a group of patients with the same disease under go the same treatment. The ultimate aim in clinical PDT would be to establish a protocol whereby a
specific drug and light dose combination is used dependant on the depth of tissue necrosis required. The dream of matching the light/drug dose to tumour depth and possibly even the tumour type would eliminate many of the clinicians' uncertainties concerning PDT.
3.2.2 D epth of PDT dam age with P hotofrin®
There is surprisingly sparse literature on the comparison of the depth of histological damage relative to the treatment dose in patients. There have also been much speculation as to the selectivity of clinical PDT, yet little data is available on this subject. The pathological changes 24 hours following PDT using HpD was examined in 10 patients, however no correlation was made between the depth of necrosis achieved and the drug and light dose used (Zhao et a l, 1987). In a similar study, 11 patients received Photofrin® (2mg/kg) followed by irradiation at 48 hours using SOJ/cm^ light energy. However, in this study the treated tumour was often resected at a later time interval, within 7 days in most cases, therefore allowing adequate time for maximal tumour necrosis to occur. The authors observed the absolute depth of necrosis to range from 1.1- 4.1mm (mean 2.1+0.9 s.d.) and no selectivity in PDT damage was seen both clinically and histologically (Grant et a l, 1997). The variable depth of damage is of concern, but corresponds to full thickness mucosal necrosis. However, most worrying is the evidence of viable tumour seen in two patients below the depth of necrosis.
3.2.3 Second G en eratio n P h o to sen sitisers
The move towards clinical treatment with more recently developed drugs possessing improved properties commenced with 5-aminolaevulinic acid (ALA). The basic properties of this agent have already been discussed in Chapter 3. ALA is a pro-drug which is converted in the body to the photoactive substance protoporphyrin IX (PpIX). The biggest advantage of using ALA induced PpIX in PDT is the extremely short cutaneous photosensitivity, which typically last 24 hours. Grant et al were the first to report tumour necrosis following photodynamic therapy after an oral dose of ALA. As with most Phase I studies, this was a feasibility study and 4 patients were sensitised with either 30 or
T able 3.1: Summary of photodynamic therapy in the treatment of head and neck cancer (excluding cutaneous and lung lesions)
A u th o r P t N o. (*) PS dose (m g/kg) D -L in te rv a l (h ours) L ig h t D ose J/c m ^ R esponse (%) Length of follow up (Dahlman eta l, 1983) 12 HpD (2-5) 72-120 5-20 5CR (42) 7PR (58) 30 days (Wile et al., 1984) 21 - 17-91 - 6CR (29) 12PR (57) - (Camith, 1985) 3 HpD - - 2CR IPR - (Keller ef a/., 1985) 11 HpD (2-3) DHE (1.5-2) 48-72 25-60 4CR (36) 6PR (55) up to 17 months (Schuller et al., 1985) 24 HpD (3-5) 72 not specified NA NA (Gluckman & Weissler,
1986) 16 HpD(3) or DHE (2) - - 9CR (56) 4PR (25) 3-19 months (Zhao etal., 1987) 94 HpD (2.5-5) 48-72 200-1440 62CR (66) 25PR (27) 1-4 years (Calzavara er a/., 1989) 5 Hp(5) HpD (2.5) - 120-150 5NR advance - (Feyh et al., 1990) 8 HpD ? dose 48 100 7CR <14 months (Schweitzer, 1990) 12 Photofrin® (2) 48-72 50-150 5CR 6PR INR 1-48 months
(Wenig et al., 1990) 26 Photofrin® 24 125 (lens) 75J/cm- interstitial 20CR (77) 6-51 months (Grant etal., 1993b) 11 Photofrin® (2) 48 50-100 lOCR (91) 6-8 weeks Note: D-L -drug-light NA- not applicable
DHE- dihaematoporphyrin ether/ester
Pt No.-patient numbers
HpD- haematoporphyrin derivative Photofrin®-commercial form of DHE
Table 3,2: Summary of photodynamic therapy in the treatment of oral/oropharyngeal cancer A u th o r P atie n t n u m b er(* ) (Wile gfa/., 1984) 2 1 (Dahlman gr a/., 1983) 1 2 (Carruth, 1985) 3 (Keller gf a/., 1985) 3 (Schuller et a l, 1985) 7 Gluckman, 1986 1 0 Zhao etal., 1987) 6 6 (Calzavara et a i, 1989) 5 (Fcyh et al., 1990) 8 (Schweitzer, 1990) 2 (Wenig et al., 1990) 19 (Grant et al., 1993b) 1 1
60mg/kg ALA and multiple biopsies were taken to assess concentrations of PpIX by fluorescence microscopy study. The correlation between fluorescence and absolute PpIX levels, as determined by chemical extraction methods (HPLC) has already been discussed in Chapter 3. Three of these patients went on to receive a second dose of ALA with laser irradiation of the tumour between 4-6 hours post ALA administration, which corresponds to the peak PpIX fluorescence (and hence sensitiser concentration). All irradiated sites exhibited ulceration over 24 hours (Grant et a l, 1993a).
The search for a more powerful photosensitiser and the exciting clinical results following its use on patients with mesotheliomas, lead to the evaluation of meta tetrahydroxyphenyl chlorin (mTHPC) in the management of head and neck tumours (Ris et a l, 1991). Savary et al were the first to report the use of mTHPC-PDT on 13 patients with early SCC in the upper aerodigestive tract, oesophagus and tracheobronchial tree. This group suggested that 0.1 mg/kg mTHPC is not sufficient to induce necrosis with light doses up to 90J/cm^, whereas good results were observed with 0.15mg/kg (Savary et a l, 1993).
3.2.4 Light Dosimetry / delivery specific to the oral cavity
The literature illustrates the wide variation in light doses used for treatment of head and neck tumours with ranges from 17-1620J/cm^. The light dose chosen is often based on empirical data following the testing on normal tissue. There is also a wide variation in the power density used (12- SOOmW/cm^) (Zhao et a l, 1987)(Zhoa et al 1990)(Edge & Carruth, 1988), it has been suggested that power densities above 200mW/cm^ may result in thermal damage (Svaasand, 1985). Although thermal effects may enhance the PDT necrosis produced, undesirable features such as scarring may occur (Barr et a l, 1987a).
The geometry of the upper aerodigestive tract makes uniform light delivery particularly difficult. Even with the use of a conventional microlens it can be difficult to deliver light perpendicular to the lesion. Consequently, light delivery systems have been constructed at Lausanne where the cylindrical diffusers are positioned on a Savary-Gillard dilatation bougie, which can be inserted directly into tumours e.g. posterior tongue lesions (Monnier et a l, 1990). There is also interest in developing a light delivery device within a highly reflective cone which may be held over a particular lesion so that the whole of the lesion may be equally irradiated and loss of energy from reflection will be reduced significantly. Such light delivery systems are already available for cutaneous treatments (Diomed LED light source). The other aspects of light dosimetry and delivery have already been discussed in the last chapter.
3.2.5 Fluorescence detection
Photodetection of cancers by light induced fluorescence has been exploited since the very early studies and provides a convenient and non invasive method of analysing the tissue status (Policard, 1924). This relies on the detection of either autofluorescence, resulting from endogenous chromophores such as NADH, collagen, flavins, haem or tryptophan containing proteins and endogenous porphyrins or fluorescence following administration of exogenous substances e.g. Photofrin®. The use of exogenous agents depends on the preferential accumulation of the drug in tumour. These methods may enable detection of disease distant from clinically visible limits or aid the determination of tumour margins
and aid pharmacokinetic studies. There are two methods of utilising fluorescence detection in-vivo and ex-vivo, the latter method will be described in Chapter 6.
In-vivo fluorescence detection
Determination of tissue fluorescence depends on the excitation of the exogenous photosensitiser or endogenous chromophores in the tumour by the application of an appropriate wavelength. This is then followed by the detection of the fluorescence produced (emitted). When photosensitisers are used, it is necessary to deduct the fluorescence signal reading from that caused by the tissues own chromophores and thus it is possible to determine areas which exhibit higher signal. Theoretically this corresponds to the tumour as most sensitisers are preferentially taken up by neoplastic tissue as discussed in Chapter 2. In addition, with the changes in levels of photosensitisers, it would be possible to monitor its pharmacokinetic profile by repeated measurements of fluorescence with minimal inconvenience and discomfort to the patient. Numerous in- vivo fibre optic fluorescence detection systems have been developed that included endoscopes connected to devices such as charge coupled device cameras or photomultipliers and promising results have been observed clinically (Braichotte et al.,
1995a; Braichotte et a i, 1995b; Profio et al., 1983).
3.2.6 PDT in the nasopharynx
Much of the work so far has concentrated on the tumours within the oral or oropharyngeal regions. Accordingly, there is interest in the use of this modality in the treatment of nasopharyngeal carcinomas (NFC). A disease where the primary option is radiotherapy with it attending morbidities and cumulative toxicity. The surgical management of recurrent disease in this area is particularly difficult, therefore a modality such as PDT is extremely attractive. In an early study, two patients with NPC received either HpD or DHE followed by light activation with 200J/cm^. Complete responses were observed in both cases, however one patient died with liver metastasis, though still clear of local disease at 1 year, whilst the other developed recurrence at 14 months (Buchanan
(5mg/kg), Complete response rates of 44% (disappeared of disease for 1 month) were seen with identical numbers exhibiting "marked response" (over 50% reduction in tumour size) (Sun, 1990). A later report by the same author on 137 patients describes complete response in 55% of the patients. Both red (630nm) and green (488 and 514.5) activating light was used with better responses in the group irradiated with green light. These studies show encouraging results, however, PDT in this region is accompanied not only by light dosimetry difficulties but also the concern of possible damage to normal adjacent structures such as the brain, especially in cases with advance or recurrent disease. PDT is certainly an attractive option, but requires further evaluation prior to commencing a controlled clinical trial.
3.3 PRECLINICAL STUDIES
Surprisingly few studies had been carried out to assess the PDT effect on normal tissue in the vicinity of the treatment area, prior to a number of the early clinical trials. Meyer et al (1990), evaluated the PDT effect on normal tissue in a rabbit model following sensitisation with di-sulphonated aluminium phthalocyanine (AIS2PC). It was found that
bone was resistant to PDT damage, whilst muscle and salivary glands damage was related to the administered light dose. Mucosal and salivary gland damage regenerated following the PDT injury, but muscle healed with evidence of scarring (Meyer et al., 1991). However, phthalocyanines have have yet to be used clinically as photosensitising agents, so ideally the same study should be carried out on photosensitisers that are in clinical use.
The effect of PDT damage on the normal rabbit tongue following sensitisation with HpD (lOmg/kg) has been evaluated. Activation was carried with lOOJ/cm^ of light at 625nm, the authors observed mucosa and muscle damage up to 8mm deep with subsequent
healing by a mixture of regeneration and scarring (Jefferis et al., 1991). The PDT damage on skeletal muscle using 6 photosensitisers (HpD, Photofrin®, meta-, para-, and ortho
isomers of tetra (hydroxyphenyl)porphyrins (THPP) were evaluated in the hind leg of mice. Histological examination was carried out 48 hours following laser irradiation and
the most severe damage was seen with para-THPP. Similar long term results were seen by Jefferies (1991), showing muscle healing with regeneration and scarring, along with full return of muscle function (Chevretton et a l, 1992). The same group evaluated the cost-benefit of Photofrin®, the meso-tetra hydroxyphenyl porphyrins (mTHPP) and chlorins (mTHPC) in a mice model with implanted plasma cell tumour and concluded that mTHPC was the most selective for tumour compared with normal tissue whilst Photofrin® was the least, in addition to producing greater necrosis (Berenbaum et al.,
1993).
3.4 C O N C L U SIO N
Starting with the early reports, which should be considered feasibility studies, there has been a move to treating disease with a curative intent by selecting earlier and more superficial disease. However, there is the need to compare PDT with conventional therapy along with long term follow up and survival data. The majority of clinical studies carried out have used either haematoporphyrin derivative (HpD) or di-haematoporphyrin ether/ester (DHE/Photofrin®) but, as previously discussed (Chapter 2), these are not ideal photosensitisers and hence the move towards the newer agents with improved properties. The different effects observed with different photosensitisers suggest that there is a need to fully evaluate each sensitiser and not simply extrapolate the data already available with other sensitisers. Therefore each photosensitiser needs to be fully investigated in appropriate prechnical models prior to clinical evaluation.