3.1.3 Photodynamic Therapy
Tom G. Sutedja
G. Sutedja, MD PhD
Department of Pulmonary Medicine, Vrije Universiteit Medical Center, PO Box 7057, 1007 Amsterdam, The Netherlands CONTENTS
3.1.3.1 Clinical Background 199 3.1.3.2 Photodynamic Therapy 200 3.1.3.3 Alternatives to PDT 201 3.1.3.4 Summary 203
References
2033.1.3.1
Clinical Background
The cure rate among lung cancer patients has re- mained dismal at 513% due to the advanced disease stage at which the majority are diagnosed (Benfi eld 1991; Weir 2003). Cure will not be possible and the presence of either detected or unforeseen nodal or distant metastasis will ultimately cause morbidity and lead to cancer death. Advances of staging proce- dures, e.g. positron emission tomography (PET) scan have led to better pre-treatment assessment leading to a more tailored approach (van Tinteren et al.
2002). Because patients cohorts are more properly identifi ed regarding their disease status, improve- ments of outcome in the various early stage cohorts only refl ect stage migration, since the majority of patients still have advanced disease at presentation.
Advanced stage lung cancer poses a serious threat to quality of life, due both to local problems and dis- tant metastasis. Central airway obstruction may lead to imminent suffocation and requires immediate intervention (Bollinger 2002; Dumon et al. 1984;
Sutedja and Postmus 1994). Techniques that can achieve immediate results to restore airways passage are therefore appropriate. Obstruction may be caused by intraluminal tumor growth, extraluminal tumor compression or a combination of both. Coagulation to prevent bleeding followed by tumor debulking in combination with stent placement in the case of sig-
nifi cant (residual) airway compression are key issues for interventional pulmonologists. There is agree- ment among experts with regard to several aspects of interventional pulmonology for both palliation and treatment with curative intent for early stage lung cancer (Sutedja and Postmus 1994; Bolliger et al.
2002; Colt and Dumon 1995; Mathur et al. 2003;
Furuse et al. 1993; van Boxem et al. 1999; Mathur 2003). Treatment plans must be diligently consid- ered to offer the optimal therapy. Patients referred to interventional pulmonologists are at risk because end-stage recurrences have usually failed chemo-ra- diotherapy. In addition imminent and poor physical condition reduce ventilation capacity much further, while one still has to solve the problems of central airways’ obstruction (Dumon et al. 1984; Sutedja and Postmus 1994; Bolliger et al. 2002; Colt and Dumon 1995).
For operable patients, surgery and lymph node dissection are considered the standard approach.
However, the risk of developing subsequent primaries (fi eld cancerization) and the fact that many individu- als may have limited pulmonary capacity (e.g. COPD), justify considering less invasive and morbid inter- ventional strategies (Mathur et al. 2003; Furuse et al. 1993; van Boxem et al. 1998, 1999). Early detection may lead to a signifi cant stage shift by fi nding more subjects with N0 lung cancer (Petty 2000; Lam et al.
1993). The integration of early diagnosis with mini- mally invasive procedures to preserve quality of life with optimal cost effectiveness are keys for success (Hayata 1996; Kato 1999). Diligent work-up is nec- essary, as currently the exact pathological TN status can be frequently only be determined retrospectively (Nagamoto et al. 1989; Usuda et al. 1993; Sutedja 2001). However, new staging and imaging procedures hold great promise for accurate assessment prior to intervention (Sutedja et al. 1996, 2001; Miyazu et al. 2002; Herder et al. 2001). Based on previous sur- gical and pathological data (Nagamoto et al. 1989;
Usuda et al. 1993; Endo et al. 1998), certain patients
cohorts with favorable prognosis can be identifi ed,
in whom a less aggressive intervention is warranted.
Medically inoperable early stage lung cancers can be treated successfully with bronchoscopic therapy such as PDT (Hayata 1996; Sutedja et al. 1994; Vonk Noordegraaf et al. 2003), and non-lung cancer re- lated morbidities and death remain important factors to be taken into account (Marcus 2000). The choice for a tailored approach for each particular patient is a valid one (Furuse 1993; Kato 1985; 2003). The role and limitations of photodynamic therapy (PDT), also in comparison with alternative bronchoscopic tech- niques, will be discussed.
3.1.3.2
Photodynamic Therapy
The concept of phototherapy was rediscovered by Western civilization at the beginning of the twenti- eth century through the Dane Niels Finsen and the Germans Oscar Raab and Herman von Tappeiner (Daniell and Hill 1991). This concept has raised much interest regarding “selective” approach of tar- get tissues such as in malignancies. Dougherty et al. (1985) was the great initiator for research in pho- todynamic therapy (PDT) and Hayata et al. (1996) were the fi rst to apply PDT in the treatment of lung cancer, especially with regard to centrally located tumor.
After administration of photosensitizers and al- lowing the sensitizer molecules to accumulate in the target tissue, illumination with light of the ap- propriate wavelength induces a photochemical reac- tion (Sutedja and Postmus 1996). The formation of toxic radicals, e.g., singlet oxygens, leads to immedi- ate vascular thrombosis in the vascular bed, causing secondary hypoxia and tissue necrosis (Gomer et al.
1989; Nelson et al. 1988). The use of photosensitiz- ers in correspondence with light in the infrared re- gion for deeper penetration is desirable for treating bulky tumor mass (Braichotte et al. 1996). In con- trast, early cancer consists of several cell layers thick only, justifying the use of a different wavelength in the case of using Photofrin II® for achieving super- fi cial necrosis to prevent deep eschar formation, as clinical data failed to show that selective uptake of photosensitizers is clinically relevant (Kawaguchi et al. 1998; van Boxem et al. 2001; Grosjean et al.
1996; Wagnieres et al. 1998). Indeed, even with the use of new photosensitizer molecules, the issue of se- lective damage remains rather obscure. Local illumi- nation is therefore the most probable reason for “se- lective” local damage of the target tissue, even with
the use of new generation photosensitizers (Borle et al. 2003).
Many studies have used Photofrin II (di-hemato- porphyrin ether) for lung cancer treatment (Sutedja and Postmus 1996). Hematoporphyrin derivatives such as Photofrin II are mixtures of poorly defi ned active components with moderate phototoxicity (Gomer et al. 1989). Sensitizer molecules are re- tained in the skin causing all patients to be potentially skin photosensitive for several weeks (Dougherty 1990).
Although new sensitizers have been developed to increase effi cacy and reduce skin toxicity, there are still limitations for PDT in clinical practice. The two- step approach of injecting the sensitizers fi rst and performing light illumination afterwards, precludes intervention for emergency cases such as in patients threatened with imminent suffocation. Late necrosis after PDT requires an additional bronchoscopic pro- cedure for tissue debulking and prolonged skin toxic- ity limits patient mobility. PDT is therefore diffi cult to justify for treating end-stage cancers with limited life expectancy and is not the treatment method for im- minent suffocation (Bolliger et al. 2002). Currently, many bronchoscopic techniques are available which can achieve immediate benefi t. Therefore, the neces- sity for PDT should be carefully considered in each particular case.
Based on these factors, PDT can be compared with techniques such as cryotherapy and brachytherapy, in which the stepwise approach can be applied for non-emergency cases for treating symptomatic ob- struction. Several studies in which PDT is compared to or used as an adjunct, have shown prolonged re- sponses (Barber et al. 2002; Diaz-Jimenez et al.
1999). However, cost-effectiveness studies are lacking in which the skin-toxicity issue has been taken into account (Kato 1999). It is therefore understandable that immediate coagulation (Nd-YAG laser, electro- cautery, and argon plasma coagulation) combined with mechanical tumor debulking, are the most ap- plied techniques in many institutions. For treating extraluminal obstruction, stent placement is the only choice (Bolliger et al. 2002; Colt and Dumon 1995).
Several studies have shown the effi cacy of PDT for treating early stage lung cancer (Edell 1992;
Furuse 1993; Sutedja et al. 1994; Hayata et al. 1996;
Sutedja and Postmus 2001; Grosjean et al. 1996;
Awadh et al. 1997; Kato 2003). Many patients were
treated because of medical inoperability (e.g., poor
lung function, cardiac status). Surgery requires rela-
tively wasteful removal of healthy lung parenchyma
because many centrally located cancers involve the bronchial spurs. The strategy in using PDT prior to surgical exploration, to enable less extensive re- section, is based on the same principle (Edell and Cortese 1992; Cortese et al. 1997; Kato et al. 1985).
Many data have shown the effi cacy of PDT for treat- ing early stage lung cancers, mainly in using hema- toporphyrin derivatives, e.g., Photofrin II, as sensi- tizers (Sutedja and Postmus 1996, 2001). Recently mono-L-aspartyl chlorine e6 or NPE6 by Kato and co-workers seemed to achieve similar effi cacy with less skin toxicity (Kato et al. 2003). Maier et al.
(2002) in comparing 5-ALA – 5-amine levulinic acid which is converted by the tumor tissue itself to ac- tive sensitizers of photo-porphyrin IX – for treating more advanced cancers in comparison to hemato- porphyrin derivatives, obtained less satisfactory results. In contrast, the results obtained by Awadh et al. (1997) in using 5-ALA in a limited number of early cancer patients seem quite promising. This underscores the basic principles of PDT and the exploitation of light-tissue physics to optimize ef- fi cacy (Braichotte et al. 1996). Clinical data using tetra(m-hydroxyphenyl)chlorine (m-THPC) and 5- ALA are scanty (Grosjean et al. 1996; Awadh et al.
1997; Kato et al. 2003; Maier et al 2002). Again the vascular effects of PDT may be the most important reason for achieving more profound tumor necrosis considering the use of systemic injection of photo- sensitizers in contrast to local application only. This may suggest the important aspect of angiogenesis in (pre-)neoplastic tissues regarding carcinogenesis (Keith et al. 2000).
Other bronchoscopic techniques have become in- creasingly popular with the recognition that accurate staging rather than technique per se is the most im- portant determinant for cure (van Boxem et al. 1999, 2001). Supported by surgical and pathological data- bases showing the correlation between smaller tu- mor size and higher response rates (Nagamoto et al.
1989; Usuda et al. 1993; Endo et al. 1998) – also with regard to PDT data (Hayata et al. 1996) – combined with better staging methods, e.g., autofl uorescence bronchoscopy, HRCT, endobronchial ultrasonogra- phy, and PET scan (Sutedja et al. 2001; Miyazu et al. 2002; Herder et al. 2001), the choice of a more tailored treatment without overkill will become the optimal strategy.
The curative potential of PDT for early stage can- cer has been tested in a prospective study to defi ne its role as an alternative for surgical resection (Edell and Cortese 1992; Cortese et al. 1997). PDT proved to be an effective modality, in which 43% of the patients
were spared surgery and considered cured. However, as mentioned previously, phase II data using alterna- tive bronchoscopic techniques seem equally promis- ing (Mathur et al. 2003; van Boxem et al. 1999).
3.1.3.3
Alternatives to PDT
Several alternatives for treating intraluminal tumor are currently available based on arguments discussed above for obtaining immediate palliation and for treatment with curative intent. Lasers (Nd-YAG la- ser, Argon, CO2), electrocautery, argon plasma coagu- lation, cryotherapy, and brachytherapy are feasible and details of these techniques have been extensively reviewed (Sutedja and Postmus 1994; Bolliger et al. 2002; Mathur et al. 2003; van Boxem et al.
1999; Ono 1995; Deygas 2001). Generally speaking – again from the clinical perspective of dealing with imminent suffocation – one can obtain immediate symptomatic relief by tumor coagulation followed by debulking quicker than applying techniques that obtain secondary or late effects (cryotherapy, PDT, and brachytherapy). All these techniques have been shown to be effective in achieving palliation, i.e., re- storing airway passage with symptomatic relief of dyspnea, hemoptysis, and obstructive pneumonia (Sutedja and Postmus 1994; Bolliger et al. 2002).
The effectiveness of stenting also for end-stage ter- minal cancers has been shown (Bolliger et al. 2002;
Colt and Dumon 1995).
Arguments have been raised that the limited num- ber of patients with occult cancer treated in the vari- ous bronchoscopic studies does not justify the role of local bronchoscopic treatments for treatment with curative intent. However, less extensive surgical resection, e.g., segmentectomy and surgical bron- choplasty for patients considered high risk surgi- cal candidates is considered legitimate (Kato 1985;
Endo et al. 1998; Fujimura 2000). As early cancers in
the central airways are only several cell layers thick
(Auerbach 1961), the use of a fi beroptic broncho-
scope under local anesthesia is an attractive and cost
effective alternative to local intraluminal treatment
for superfi cial early stage lung cancer in comparison
to the more morbid surgical intervention (Pasic et
al. 2004). The potential of various bronchoscopic
techniques has been reviewed and guidelines have
been published (Mathur et al. 2003; van Boxem et
al. 1999). Early cancer is often diagnosed incidentally
and many are missed during routine bronchoscopy
(Sato et al. 1998). Even in cases with positive sputum cytology, the extreme burden of repeat bronchos- copies is necessary to localize the lesions, while the average delay of almost 2 years before proper treat- ment can be given is also counterproductive for stage shift efforts. However, new strategies such as sputum examinations, autofl uorescence bronchoscopy, high resolution CT scan, and endobronchial ultrasonog- raphy have increased the detection rate and accuracy in staging (Sutedja 2001, 2003; Miyazu 2002). New techniques also seem better in predicting the likeli- hood of malignant development than the conven- tional morphology classifi cations of pre-neoplastic lesions (Jeanmart et al. 2003; Pasic et al. 2003).
So far, inoperable patients with early stage cancer were the main candidates for bronchoscopic treat- ment. However, any bronchoscopic modality is po- tentially curative (Table 3.1.3.1), as long as “occult”
N0 cancers have been staged properly (van Boxem et al. 1999, 2001; Sutedja et al. 2001; Miyazu et al. 2002). This is quite obvious, as true occult can- cers are only several cell layers thick (3-mm range) (Auerbach 1961). Local treatment cannot achieve cure when regional lymph nodes already contain metastasis. Bronchoscopic treatment, be it PDT or other techniques, can only be successful for acces- sible cancer defi ned as 51-cm
2surface area, )3-mm thickness and with distinct borders (Nagamoto et
al. 1989; Usuda et al. 1993; Hayata et al. 1996; Edell and Cortese 1992; Corese et al. 1997; Fujimura et al. 2000). In retrospect, PDT data already indicated the limitations of bronchoscopic treatment as re- sponse rates were strongly correlated to tumor di- mension (Sutedja et al. 1994; Hayata et al. 1996).
Tumor growth in the deeper layers of the bronchial mucosa and nodal disease are limitations for any kind of local therapy. Therefore, there is no theoreti- cal argument why intraluminal bronchoscopic treat- ment is not justifi able in carefully selected cases.
The cutting edge of the scalpel will be combined with the cutting edge capacities of bronchoscopic treatment with clearly less morbidity and better outcome in terms of quality of life (Endo et al. 1998;
Nakamura et al. 2001). New imaging facilities be- yond the visible threshold of our eyes are currently being investigated in early clinical trials (Sutedja 2003). Recent studies using autofl uorescence bron- choscopy, high resolution CT scan, and endobron- chial ultrasound showed that bronchoscopic treat- ment with curative intent is a justifi able strategy in a carefully selected patient population (Sutedja et al.
1996, 2001; Miyazu et al. 2002; Herder et al. 2001).
Extension proximal to the maximally feasible resec- tion plane can be initially treated bronchoscopically to allow less extensive surgical removal (Kato et al.
1985).
Table 3.1.3.1. “Early stage” lung cancer in the central airways treated with curative intent using photodynamic therapy and other
