| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Dept of Chest Diseases and Thoracic Oncology, Hôpital Nord, St. Etienne University Hospitals, Saint-Etienne, France, 2 Division of Respiratory Medicine, Klinikum der Universität München - Innenstadt, University of Munich, Munich, Germany, 3 The Yorkshire Laser Centre, Goole & District Hospital, Goole, UK.
CORRESPONDENCE: J-M. Vergnon, Dept of Chest Diseases and Thoracic Oncology, Hôpital Nord, St. Etienne University Hospitals, Saint-Etienne, France. Fax: 33 477828090. E-mail: vergnon{at}univ-st-etienne.fr
Keywords: Brachytherapy, bronchoscopy, cryotherapy, lung cancer, photodynamic therapy
Received: January 30, 2006
Accepted March 29, 2006
 |
ABSTRACT |
|---|
 TOP ABSTRACT CRYOTHERAPYBRACHYTHERAPYPHOTODYNAMIC THERAPYFinal conclusionACKNOWLEDGEMENTSREFERENCES |
|---|
These three methods were first proposed with palliative intent in inoperable patients with centrally located lung cancers. Now, the best indication is a curative intent in early stage lung cancers.
Of the three, cryotherapy is the cheapest method. It induces cell necrosis in a 3-mm radius around the probe, and is suitable for treatment of superficial tumours. However, clinical trials are limited. In contrast, many clinical studies have confirmed the efficacy of PDT in treatment of superficial lung cancers. Brachytherapy can cure more aggressive tumours with deeper invasion into the bronchial wall. Unfortunately, no comparative studies have been published. Each of these methods induces a delayed tumour necrosis, and thus neither is indicated in the treatment of obstructive tumours with acute dyspnoea. In many situations, these methods should be complementary, particularly cryotherapy and brachytherapy or PDT and brachytherapy.
The combination of these endoscopic methods with chemotherapy should be widely tested to promote the adjuvant role of the endoscopic methods in the treatment of lung cancers.
|
|
CRYOTHERAPY |
|---|
|
TOPABSTRACTCRYOTHERAPYBRACHYTHERAPYPHOTODYNAMIC THERAPYFinal conclusionACKNOWLEDGEMENTSREFERENCES |
|---|
Background
The analgesic and anti-inflammatory properties of cold have been known for centuries. Larrey used these properties in 1812 to achieve haemostatic and analgesic effects in surgical amputations during the Russian campaign. In 1851, Arnott 1 made reference to the role played by low temperatures in destroying tumours. In 1959, the first clinical application on brain tumours using closed-circuit probes was published 2. Later on, cryotherapy was widely used in the treatment of a variety of tumours. In 1968, Gage 3 reported the first endoscopic treatment on a bronchial tumour in the USA. Both articles 2, 3 received little attention, despite the fact that there were several publications from 1962 to 1983 4–8 dealing with the same subject. Laser therapy was preferred. Bronchial cryotherapy was renewed in France in 1986, following studies by Homasson 9. Since then, >1,500 patients have been treated in France and the UK 10–14. Based on this clinical experience, the techniques and limits of cryotherapy were defined on both bulky tumours and in early stage lesions. The combination of cryotherapy with irradiation or chemotherapy was then tested in humans and produced encouraging results 15, 16. Since 1996, interest in cryotherapy has grown in the USA with the introduction of flexible probes 17. Currently, the cytotoxic mechanisms of cryotherapy and the potential for synergistic action with chemotherapy are being investigated through in vivo studies 18.
Principles
Cryotherapy is a unique method of destruction based on the cytotoxic effects of cold on living tissue. The application of a low-temperature probe on a tissue first induces an immediate adherence between the probe and the tissue and then the appearance of intra- and extracellular ice crystals 19–23. These crystals damage intracellular organelles, especially mitochondria. The formation of pure extracellular ice crystals causes additional ion and water movements resulting in cellular dehydration. In order to obtain a maximum lethal effect, it is necessary to have large ice crystals, especially at the intra-cellular level. This effect is achieved by rapid cooling of the tissue followed by slow thawing 10. This principle is the opposite of cryopreservation. In tumour tissue, thawing occurs by vascularisation, where cold waves move radially around the point of application of the cryoprobe. At each point, cytodestruction varies according to the speed of freezing and thawing. Cytotoxicity diminishes with distance from the centre of application, as well as when near the permeable vessels 18, 19. This physical and cellular phenomenon is coupled with a vascular effect: an initial vasoconstriction occurs, which is followed by a vasodilatation. A complete vascular thrombosis appears 6–12 h later, thus completing the physical cytodestruction by induction of local infarction 19–23.
In the more peripheral area, the destruction is inhomogeneous, and the vessels that remain permeable protect some perivascular cells from destruction 21. It has been demonstrated that apoptosis is the main phenomenon in this zone 18.
The area of destruction through cryotherapy has a diameter of 
1 cm when a 3-mm diameter probe is used 9. When in lateral contact with a bronchial wall, cytotoxicity can be considered complete to a depth of 3 mm. Nonhaemorrhagic necrosis of the tissue occurs 8–15 days following the procedure. Collagen, cartilage or poorly vascularised tissues are very cryo-resistant 11.
These data explain the essential characteristics of cryotherapy: a spherical pure cytotoxic action leading to late tissue necrosis and an important late haemostatic effect. The high cold resistance of the supporting bronchial structure explains the safety of this method. There is neither risk of bronchial perforation nor scarring with residual fibrous stenosis. The cold wave kills poorly vascularised cells and spares perivascular cells. Thus, the vascular density increases in the residual tumour. The current author also observed an enhancement of vascular endothelial growth factor expression in the residual tumour cells. These results support the principles of cryo-radiotherapy 16 and cryo-chemotherapy studies 15.
Materials and methods
Devices
Two types of probes are available: liquid nitrogen probes, which are very powerful but awkward to use, and nitrous oxide (N2O)-driven cryoprobes (figs 1
and 2). Cooling is due to the Joule–Thompson principle, cooling of a gas by sudden expansion from a high to a low pressure zone. Flexible cryoprobes of 2–3 mm in diameter are available and can be used through a flexible fibreoptic bronchoscope 18. Recently, reinforced cryoprobes were manufactured in order to extract pieces of tumour after the adherence phase 24. Personally, the present author prefers and recommends rigid cryoprobes used through a rigid bronchoscope. The rigid cryoprobe is more powerful than the flexible probe. A footpad or a trigger on the handle allows immediate and active thawing of the probe after cooling. This contrasts with flexible probes where thawing is passive. Thus, with flexible probes, each cycle of freezing and thawing lasts double the amount of time compared with a rigid probe cycle. The rigid probe used by the present author is 60 cm long and 3 mm in diameter. Only the 1-cm tip of the probe causes freezing of tissues; the remainder of the probe is insulated. The external temperature obtained at the tip of the probe is <-40°C and is obtained in 1–2 s 22, 23. The probe is connected to a cylinder of purified N2O at a pressure of 50 bar. The main equipment is supplied by ERBE (Tübingen, Germany), but other equipment is supplied by DATE (La Motte d’Aveillans, France) or Spembly Medical Ltd (Andover, UK).
|
|
20 s. When an impedance meter is used, the freezing phase is stopped once a plateau of impedance is obtained. After three cycles, the tip of the probe is moved to touch an adjacent part of the tumour. Although the obtained ice-ball is 10 mm in diameter, the adjacent impact of the probe must be 5 mm from the first impact to make the ice-ball overlap. It is important to cover the entire surface of the tumour (30 or more cycles are often necessary). In cases of early stage lung cancers, the limits of the lesion should be delineated by autofluorescence endoscopy. Without this technique, a margin of 5 mm around the visible limits of the tumour should be treated. In cases of tumour located on a carina, the two sides of the carina and the crest should be treated. At the end of the procedure, the tumour appears undamaged. Indeed, cryothrombosis is delayed for several hours. In the present author's opinion, it is dangerous to mechanically remove any part of the tumour at this stage. For this reason, cryotherapy is not recommended when patients present with an acute dyspnoea. Even in large tumour treatment, the duration of a cryotherapy session using rigid cryoprobe (with active "immediate" thawing) remains short, between 20 and 45 min. Between 8 and 10 days after cryotherapy, the necrotic sloughed tissue is eliminated by expectoration or removed by forceps during a follow-up fibreoptic bronchoscopy. Generally, when cryotherapy is used alone, a second session should be planned to eliminate the residual tumour.
Indications and complications of cryotherapy
Indications
The effects of cryotherapy are delayed. This technique, therefore, is not indicated to achieve immediate debulking of an obstructive tumour. In these cases, the tumour will first be cored out mechanically with the tip of the rigid bronchoscope after coagulation (if necessary) with laser beam or electrocautery. After this first step, and in the same session, cryotherapy can be applied on the remaining infiltrative part of the tumour (fig. 3).
|
and b), adenoid cystic carcinomas or granulomas. In the present author’s experience, 18 cases of endoluminal typical carcinoids have been treated and cured with the combination of laser-assisted mechanical resection followed by cryotherapy. The median follow-up was 30 months. In lung cancers, the effectiveness of cryotherapy reaches 75%, regardless of the cellular type or the endoluminal aspect 12, 14, 19, 23. Due to the deep (3 mm) and safe cytotoxic action against tumour cells in the bronchial wall, this method can be used to safely treat in situ or micro-invasive carcinomas (fig. 2
). The results of a multicentre French study of 35 cases has been reported 25; an 80% complete cure with a mean follow-up of 32 months was observed. The remarkable action of cryotherapy on tumour vascularisation also explains its effectiveness on haemoptysis. The control ranged 60–86% 12, 19, 23.
|
Collagen tissue, poorly cellular tumours and fibrous scars are not so cryosensitive, thus cryotherapy alone is not indicated in benign strictures of the trachea or bronchi caused by fibromas, lipomas or post-intubation stenosis. Cryotherapy is not indicated in external compression of the bronchial tree. Cryotherapy is, however, useful to remove many foreign bodies from the airways (fig. 5). Efficient cryo-adherence is observed with porous structures, such as pills, food, blood clots or peanuts. In contrast, cryo-adherence is less efficient with bones, metal or teeth.
|
Therapeutic associations
Cryotherapy may be of benefit in patients requiring chemotherapy or irradiation therapy, but this hypothesis needs to be proven. Preliminary reports both in animals and humans have shown that pre-treatment with cryotherapy could enhance the concentration of the chemotherapy agent into the tumour 15, 26. The benefit of combining cryotherapy with chemotherapy to enhance the induction of cell death either by necrosis or by apoptosis has also been found in a mouse model 18 (fig. 6). With irradiation, a prospective pilot study has been conducted 16, suggesting that the cryotherapy irradiation combination induces a very effective endoluminal control of the tumour associated with an increased survival. This result was confirmed by another study conducted by Maiwand and Homasson 12. The same results were observed in mice (fig. 7). Unfortunately, these preliminary studies have not yet been followed by larger randomised prospective protocols.
|
|
|
BRACHYTHERAPY |
|---|
|
TOPABSTRACTCRYOTHERAPYBRACHYTHERAPYPHOTODYNAMIC THERAPYFinal conclusionACKNOWLEDGEMENTSREFERENCES |
|---|
Background
Amongst the currently available interventional bronchoscopic procedures, endobronchial brachytherapy is one of the oldest techniques. The first successful endobronchial implantation of radium capsules (using the ideas from gynaecological implants) was documented as early as 1922, and further reports also on interstitial therapy have followed 27, 28. In the 1960s, cobalt-60 seeds were most frequently used as the radiation source. Both radium and cobalt implants deliver the dose with a relatively low dose rate and therefore require a long treatment time, up to days, which is not suitable for application in the airways. Also, rigid bronchoscopy and general anaesthesia are necessary.
By using brachytherapy, it is possible to deliver a maximum dose to the tumour with a minimum dose to the surrounding normal tissue. However, one of the major drawbacks of this method was found to be the high level of radiation to which the medical personnel were exposed. Therefore, the development of the remote afterloading technique in 1964 was essential for the widespread application of brachytherapy 29. The introduction of the iridium-192 radioisotope with the possibility of delivery with a HDR, and the refinement of the afterloading apparatus by using automated, computer controlled steering devices, has led to significant progress 30. The small size of the iridium source with its high activity (10 Gy at the beginning of the treatment) and HDR allows its placement in a hollow guidance catheter, which can be easily placed endoluminally by a flexible bronchoscope. Nevertheless, it was not until the widespread use of the neodymium yttrium-aluminium-garnet (Nd-YAG) laser recanalisation of tumour stenoses that endoluminal brachytherapy was used more frequently for the palliative treatment of endobronchial and parabronchial tumours. Here, brachytherapy stabilises the recanalising effect of Nd-YAG laser therapy. It can be used, either alone or in combination with other methods, in a more curative setting, such as early stage endobronchial tumours.
Performed by an experienced endoscopist, HDR brachytherapy has the same acute side-effects as routine fibreoptic bronchoscopy and, therefore, can be easily applied in an outpatient setting. Irradiation lasts only a few minutes.
Principles
Brachytherapy is a form of radiation therapy, where the irradiation source with a high dose is either within or very close to the malignant tissue. The primary radiation produced is gamma rays. The physical characteristics of these radioactive isotopes are characterised by the inverse square law which means that the dose rate decreases as a function of the inverse square of the distance to the source centre. This makes it possible to achieve a high irradiation dose in the centre of the irradiation source with a fast decrease towards the periphery. A typical distribution of isodoses is shown in figure 8. Usually the effects of irradiation are not direct killing of the cells, but single chain breaks of the DNA resulting in apoptosis and a decrease in cell proliferation. Therefore, the visible effects of brachytherapy with iridium-192 HDR are delayed, with the maximum visible and histological changes taking place 3 weeks after application. These effects are clearly less pronounced in normal, nonmalignant tissue 31, 32.
|
). A vascular guide wire is helpful for placing the catheter and a tube, such as a shortened gastric tube, is helpful in avoiding direct contact with the normal tissue 33. Centring devices, such as balloons, cages or sheaths, can be employed to maintain the radioactive source within the centre of the bronchial lumen and avoid dose inhomogeneity 34. A HDR source with high activity of iridium-192 is usually used for endoluminal brachytherapy of thoracic malignancies. Remote brachytherapy is performed in a shielded room with permanent oxygen delivery to the patient, who is monitored from outside by continuous assessment of oxygen saturation, pulse rate or electrocardiogram and direct visual control via a video camera. After removal of the dummy seed, the applicator is connected to the iridium-192 remote afterloading unit containing the irradiation source. The radiation source (diameter of 1 mm) is advanced to the intended position under computer control and then drawn backwards at intervals of 5 mm. It remains in each position for the time needed to apply the computed dose. By varying the source position and dwelling time, individual computer-assisted dose distribution can be achieved (fig. 10). The treatment can be interrupted and restarted whenever necessary.
|
|
2–10 Gy·h-1 35. The International Commission of Radiation Units defines HDR as the application of >20 cGy·min-1 (1 rad = 1 cGy), which means a delivery of >12 Gy·h-1, with the dose per session (fraction) varying from 300–1,000 cGy (calculated at 10 mm from the source axis) 36.
Iridium-192 is the most commonly used source. As the source is in position for a shorter time, there is less chance the catheter will be displaced. A shorter treatment time also improves patient tolerance and reduces treatment costs. In contrast to LDR, HDR brachytherapy is usually delivered in a series of dose fractions in order to optimise its effectiveness and minimise side-effects. A wide variety of treatment schedules have been utilised; generally patients are treated no more than every 1–2 weeks because of the discomfort and logistical difficulties associated with more frequent bronchoscopies. There is only one controlled, randomised study to evaluate the effect of dose rate, overall radiation dose, fractionation and localisation of the afterloading catheter to survival rate, local control and complications. In the study 37, two treatment regimens with a comparable total irradiation dose of 15 Gy (at 1 cm from the source axis), but different doses per fraction (four fractions of 3.8 Gy on a weekly basis versus two fractions of 7.2 Gy at a 3 week interval) were compared. There were no disadvantages for the shorter fractionation regimen, with a similar survival time (19 weeks) and local control time in both groups. The complication rate was also similar, with fatal haemorrhage occurring in 21% of all patients.
Methods
In general, endoluminal brachytherapy using flexible bronchoscopy and an HDR regimen can be performed on an outpatient basis, as it is no more strenuous for the patient than a diagnostic bronchoscopy. In the case of LDR brachytherapy, hospitalisation for several days is usually required.
Preparations for the procedure
Flexible bronchoscopy is performed to localise the tumour region for irradiation. The afterloading catheters have an external diameter of 2–3 mm. lf there is subtotal stenosis of the bronchi due to submucosal or exophytic tumour growth, it is sometimes necessary to perform balloon dilatation or use other recanalisation methods for better applicator placement. If there has been previous laser treatment, it is recommended to wait 
3 days before brachytherapy treatment can be initiated, although the debate about this issue is still ongoing 38, 39. Endoluminal irradiation should be delivered with a safety margin of 1 cm at both ends of the visible endobronchial tumour length. The active length refers to the distance between the first and last dwelling point of the iridium source in case of HDR brachytherapy. As the distal end of the tumour cannot always been seen by the bronchoscopist, the distal end-point of the irradiation length must often be estimated from previous chest radiographs or computed tomography scans and controlled during bronchoscopy by fluoroscopy.
Placement of the applicator
The irradiation length is marked by external tags controlled by fluoroscopy. A guide wire is placed through the working channel of the bronchoscope, which is then removed. Manipulation of the guide wire and then of the applicator through a partially obstructed lumen requires skill, particularly within the upper lobe bronchi. However, with this technique areas can be reached that cannot easily be reached by other recanalising methods. For a better fit of the afterloading probe, a shortened gastric tube with an external diameter of 5 mm is usually inserted over the guide wire by the Seldinger technique. The gastric tube should be placed inside the tumour bulk. The irradiation applicator is then placed into the tube and taped to the tip of the nose to prevent it from being dislocated. This should be carried out under visual fluoroscopic control.
After placement of the afterloading probe, a dummy seed is inserted, and a set of orthogonal chest radiographs is obtained to document the correct placement of the catheter within the tumour bulk and to determine the necessary irradiation length, as indicated by the external tags (fig. 9). The treatment dose is prescribed by the radiation oncologist, usually specified at a depth taken 1 cm from the middle of source axis 40. One of the technical challenges is the obvious difference in luminal diameters of different segments of the tracheobronchial tree. It is uncommon to adjust for these differences, but Saito et al. 41 attempted to answer this problem by setting distinct diameters at different segments of the tracheobronchial tree and adjusting the dose evaluation point to the lumen diameter at the lesion site.
After removal of the dummy seed, the applicator connected to the iridium irradiation source (diameter 1 mm) is advanced to the intended position under computer control, then drawn backwards at intervals of 5 mm. The source remains in each position for the time needed to apply the computed dose. By varying the source position and dwell time, an individual computer-assisted dose distribution can be generated (fig. 10).
Follow-up
The maximal effect of a brachytherapy session is seen after 3 weeks. Therefore, a follow-up bronchoscopy is usually performed 3–6 weeks after the end of the planned treatment series.
Indications and complications of brachytherapy
Indications
The effects of brachytherapy are delayed. First effects can be seen after 1 week, and the maximum effect is only achieved after 3 weeks. However, brachytherapy probably has a longer-lasting effect and has greater tissue penetration than other tumour lysis techniques. It also destroys tumour outside of the bronchial wall and behind cartilage. HDR brachytherapy has the advantage of delivering a high dose of radiation over a short period of time to the tumour area without significantly affecting the adjacent lung parenchyma.
This technique is not indicated to achieve immediate debulking of an obstructive tumour. Therefore, in central tumours with imminent tracheal or bronchial occlusion, methods which rapidly destroy the tumour or stenting have to be applied. Thereafter, brachytherapy can be performed to achieve a longer-lasting effect on the tumour both inside and also outside the bronchial wall. Contraindications to endobronchial brachytherapy include the presence or the imminent danger of fistulas between bronchi and other structures.
Palliative setting
In most cases, brachytherapy is applied in a palliative setting. This is the case in metastatic diseases of patients with poor performance status. HDR endobronchial brachytherapy is then considered a palliative technique for alleviating dyspnoea resulting from major airway obstruction by primary and secondary malignant tumours. It is also indicated to palliate symptoms, such as cough, haemoptysis and dyspnoea, in patients who have received their maximal dose of EBRT.
Curative indications
Brachytherapy can be applied after surgery if there are microscopically positive resection margins.
Brachytherapy can also be used as an endobronchial boost to EBRT 41–45. HDR brachytherapy has been primarily used for previously untreated patients in conjunction with EBRT, often to quickly relieve obstruction and to reduce the volume of irradiated normal lung tissue. Brachytherapy can help to reduce the permanent fibrosis of normal lung tissue due to large external irradiation fields, particularly when atelectasis due to obstruction of a main or lobar bronchus is obscuring the true tumour margins. It has been calculated that this procedure can reduce the irradiation of normal tissues by an average of 32% 46. Apart from treatment for local stenosis, brachytherapy has the potential to increase local control and survival time when used in combination with external irradiation. Although none of the studies published so far could demonstrate a clear advantage in terms of survival in nonselected patients treated with this combined modality, there are indications that at least local control is better in patients with additional endoluminal brachytherapy 47.
In very early superficial cancers, brachytherapy may be curative. Surgical resection is widely accepted as the treatment of choice in early stage nonsmall cell lung cancer (NSCLC). However, when occult carcinoma in situ or small invasive endobronchial lesions are discovered incidentally by bronchoscopy, mostly due to symptoms like cough or haemoptysis, HDR brachytherapy, either alone or as a boost to EBRT 41, offers a treatment option with good results, low morbidity, low cost and little inconvenience for the patient. Especially in carcinoma in situ or limited invasive tumours without nodal involvement, HDR brachytherapy could represent the definite treatment due to the deeper and unrestricted penetration. As with other treatment modalities, data published on intraluminal brachytherapy in early stage NSCLC are limited 41, 47–51.
Nonmalignant indications
HDR brachytherapy can also be used for nonmalignant tracheal and bronchial obstruction. Typical applications are the treatment of recurrent granulation tissue formation in and around a stent or of granulation tissue at the bronchial anastomosis after lung transplantation 52, 53.
Effectiveness
In palliative indications, overall improvement and disappearance of symptoms has been shown in 65–95% of all patients. Haemoptysis can be treated with a high rate of success; this is also true for the reopening of obstructed bronchi. Improvement of cough, shortness of breath and pain was observed to a lesser degree. Palliation can be maintained in a high proportion of patients 35, 39, 43, 45, 54, 55. This can also be verified by bronchoscopy (fig. 11a and b) or lung function testing 56–58. There are even hints for survival advantage in selected cases 42, 59.
|
Temporary pleuritic pain or even pneumothoraces have been described when the guide wire or the applicator were placed too vigorously. However, the present author has never observed such serious side-effects during >2,000 placements of afterloading probes.
As with EBRT 59, radiation bronchitis and stenosis may occur days or weeks after therapy and can manifest with cough or wheezing (fig. 12). Histological changes consist of mild mucosal inflammation to severe bronchial fibrosis. Risk factors include large cell carcinoma histology, use of brachytherapy for curative intent, prior laser resection and concurrent external beam radiation 35. Overall bronchial stenosis has been shown to occur in 10% of patients after HDR EBRT for lung cancer 60. Therapy of these post-radiation effects consists of conventional treatment, such as inhaled steroids and antibiotics, or, for stenosis, balloon dilatation, laser resection and stenting.
|
10% 56. For the interpretation of these figures, it should be kept in mind that most of the studies published are not randomised and are not even prospective. The studies use different selection criteria concerning pre-treatment, catheter placement, dosages, fractionation, localisation and histology. The occurrence of fatal haemoptysis is usually considered as a complication of treatment and not related to the disease itself. However, the data on the natural course of lung cancer is sparse and it is often difficult to differentiate between treatment complications and tumour progression. One can argue that the incidence of fatal haemoptysis is related, for example, to tumour invasion into pulmonary vessels or related to the administered irradiation dose and fractionation regimen or even to the longer survival of the patients who receive brachytherapy. Squamous histology and tumour localisation in the mainstem bronchi predispose to fatal haemorrhage 61, 62. This localisation represents a further negative selection towards more frequent haemorrhages. It is possible that the combination of external and endoluminal irradiation increases the frequency of haemorrhages. However, one randomised trial could not demonstrate a statistically significant difference in comparison to external radiotherapy alone 27. One of the relevant factors for haemoptysis is the localisation of the radiation, especially the direct contact between the endobronchial brachytherapy applicator and the tracheobronchial walls at the vicinity of the great vessels 63. Furthermore, an increase of the dose per fraction over 10 Gy at a distance of 10 mm from the source axis increases the risk of bleeding dramatically 64. In general, the incidence of fatal haemorrhage is high and all efforts to minimise potential side-effects of endobronchial brachytherapy should be strengthened. However, with usual dosages and fractionation, fatal haemorrhage seems to be correlated more with the natural course of a longer survival than with endoluminal brachytherapy itself.
Overall, endobronchial brachytherapy is easy to perform in an outpatient setting with little discomfort to the patient and can be considered a well-tolerated treatment option, especially in patients with reduced performance status.
Combination with other endobronchial methods and chemotherapy
Adding brachytherapy to Nd-YAG laser therapy improves the local control 65. Furthermore, the combination of laser therapy and brachytherapy in early lung cancer seems to offer a significant survival advantage over either therapy alone 66. This is also reported for the combination of HDR brachytherapy after 6 weeks with PDT 67. The combination with systemic chemotherapy is feasible and seems to provide radiosensitisation 68.
Conclusion
Bronchoscopic brachytherapy in its HDR form is an easy-to-perform outpatient treatment for endoluminal and paraluminal tumours. It is effective in palliating symptoms such as dyspnoea, haemoptysis, intractable cough, atelectasis and post-obstructive pneumonia. Brachytherapy can be combined with all other modalities of tumour therapy, e.g. external beam radiation, Nd-YAG laser therapy, PDT or chemotherapy and may improve the degree and duration of palliation. Small tumours can be cured by brachytherapy. Unfortunately, as with other endobronchial treatment modalities, experience is limited and further randomised studies are needed. Brachytherapy is a permanent interdisciplinary challenge with the need of a close contact between radiation oncologists and chest physicians. Further investigations are necessary to determine optimal dose fractionation and the ideal adjunctive use of the technique.
|
PHOTODYNAMIC THERAPY |
|---|
|
TOPABSTRACTCRYOTHERAPYBRACHYTHERAPYPHOTODYNAMIC THERAPYFinal conclusionACKNOWLEDGEMENTSREFERENCES |
|---|
Parallel with the development of Finsen's phototherapy, other scientists were focusing their attention on the biological effects of light-activated chemical compounds (photochemotherapy) on living tissue. In this area, Raab 71 and von Tappeiner and co-workers 72–74 were examining the effect of chemical compounds on infusoria. They made a number of observations, of which two were seminal in the development of PDT. They noted that the chemical compound acridine could affect the biological behaviour of paramecia and that the organism was killed when the preparation was exposed to daylight. They also discovered that air (oxygen) was necessary for the death of paramecia in the acridine plus light setting. These authors referred to the phenomenon as "Photodynamisch Wirkung" (photodynamic reaction/effect). During the 1960s and 1970s, experimental and clinical PDT evolved from these and subsequent observations, with the first recorded case of clinical PDT reported by Lipson et al. 75 in 1966. The case was a large recurrent ulcerating breast tumour treated by injection of haematoporphyrin derivative (HPD) followed by exposure to a filtered xenon arc lamp.
In the 1970s, a number of investigators were working on the photodynamic effects of different chemicals and their corresponding activating light. HPD and light in the red spectrum appeared as the most suitable combination to yield photodynamic action in the animal model and clinical situation 76, 77. Dougherty et al. 78 showed that systemic administration of HPD followed by exposure to red light from a xenon arc lamp could eradicate transplanted murine mammary tumour without much change to normal tissue surrounding the tumour. This same group started clinical trials in 1976 at Roswell Park Memorial Institute (Buffalo, NY, USA), which showed the effectiveness of PDT in a variety of malignant growths 76, 78, 79.
Bronchoscopic PDT began in 1982 at Tokyo Medical University (Tokyo, Japan), when Hayata et al. 80 treated a patient who had an operable early lung cancer but refused surgical intervention. The treatment was carried out with complete eradication of the tumour. After nearly 4 yrs the patient died from noncancer-related causes 81.
At that time, many of the PDT clinical trials were focused on cutaneous and subcutaneous cancer. Nevertheless, by virtue of its high incidence, advanced stage of disease at presentation and highly unresectable rate, lung cancer became one of the first cancers to be targeted for PDT trials 82–85.
This brief history demonstrates how clinical PDT evolved through phototherapy and photochemotherapy (table 1).
|
It therefore appears that the mechanisms of photodynamic reaction are both direct, through disturbed cellular metabolism, and indirect, mediated by vascular and extracellular fluid, which constitutes the cell environment’s "milieu interior".
Method
Bronchoscopic PDT for lung cancer is carried out as a two-stage procedure, namely, photosensitisation and illumination.
Photosensitisation stage
This stage is achieved by an intravenous administration of a suitable photosensitiser (the drug) to the patient. The first photosensitiser used for bronchoscopic PDT was derived from the porphyrin family. HPD was used systemically by intravenous injection at variable dose rates (2–4 mg·kg-1 body weight) 85. After manipulation and purification, HPD was commercialised for clinical use under the labels Photofrin® (Axcan Pharma Inc., Houdan, France) and Photosan® (Seehof Laboratorium Forschungs- und Entwicklungsgesellschaft mbH, Wesselburenerkoog, Germany), to name but a few. Photofrin® (Porfimer Sodium) is licensed for use in advanced-stage lung cancer by the Food and Drug Administration and European Union Licensing Authorities. At the present time, Photofrin® is the most commonly used photosensitiser for bronchoscopic PDT and has a long-standing safety record 69, 85–87. The recommended dose of Photofrin® is 2 mg·kg-1 body weight. At this dose, the drug is safe, reliable and nontoxic. However, it is not highly selective and indiscriminate illumination could result in collateral damage to normal adjacent areas with oedema and inflammation of the bronchial walls.
Chlorin family
Porphyrin-based photosensitisers were the first-generation sensitisers used for bronchoscopic PDT. Many other sensitisers have since been prepared and tested in the laboratory setting; although most have not reached clinical trial, a few have. Amongst the latter is meta-tetra(hydroxyphenyl)chlorin (Foscan®; Scotia Pharmaceuticals, Stirling, UK), which is not commonly used for bronchoscopic PDT. One group has employed Foscan® in a series of patients with apparent success and no major drawbacks 88. However, detailed information on its use for bronchoscopic PDT has not been published.
Illumination
Illumination consists of bronchoscopic exposure of the pre-sensitised tumour to a light of a specific matching wavelength. The overall effect is necrosis of the tumour. There are essentially two methods of illumination: interstitial and surface illumination. In the former, the light exposure is from within the tumour mass; in the latter, the exposure is over the surface of the tumour (fig. 13a and b).
|
Light delivery system
The light generated and emitted by a laser is delivered to the endobronchial tumour by optical fibres with either a cylindrical diffusing tip or a micro-lens. Cylindrical diffusers distribute light circumferentially and may be used for interstitial treatment when the diffuser is placed within the tumour mass. The micro-lens emits forward-firing light and is employed for surface application to treat superficial growth (fig. 14a and b). In either case, the delivery fibre is introduced via the biopsy channel of the fibreoptic bronchoscope, which provides access to the tumour (fig. 15). The light dose at its point of delivery is calculated to be 200 J·cm-1 of lesion or the equivalent length of the delivery device 89. This is usually made up of 400 mWx500 s (1 J = power (mW)xtime (s)).
|
|
).
Each method has advantages and disadvantages (table 2). The use of general anaesthetic necessitates the presence of an anaesthetist and more elaborate equipment, but provides a comfortable environment for the patient and facilitates the operative procedure. General anaesthesia and use of the rigid instrument allows the operator more time, better access to lesions and less risk of displacement of the delivery fibre in patients with bulky tumours and/or multiple lesions. However, a unifocal superficial lesion of limited extent can easily be treated using FFB under topical anaesthesia. In the present author’s experience, the use of the combined rigid and flexible instruments under general anaesthesia is best for patients with obstructive exophytic tumour of the major airway (trachea main stem bronchi), and should be recommended for such cases. For other cases the choice depends on the experience of the operator and patient choice.
|
Bronchoscopic PDT in practice
Patients selected for bronchoscopic PDT will have had standard lung cancer work up, including diagnostic bronchoscopy and confirmation by histo/cytology of the malignant tumour. Prior to photosensitisation, a further bronchoscopic examination is carried out using white light and fluorescence bronchoscopy (if available) in order to delineate the tumour and its extent (fig. 16a and b). It is important that the bronchial tree is examined in its entirety in order to map out synchronous lesions in adjacent or more distant sites from the main focus. After administration of the photosensitising drug, time is allowed for its absorption and its preferential retention in the tumour. The duration of this latent period depends, to a large extent, on the composition of the photosensitiser. For Photofrin®, this is 24–72 h. Following this period, bronchoscopic illumination is carried out. This consists of exposure of the pre-sensitised tumour (or all tumour sites) to laser light, as previously described.
|
) from the treated area and beyond with the use of biopsy forceps, followed by aspiration and lavage with normal saline solution. In patients with exophytic endoluminal obstructive tumours requiring interstitial treatment, it is necessary to carry out this procedure not only immediately after illumination, but also a few days later. At this time, some necrosis of the tumour occurs, as well as discharge of infected secretions collected beyond the bronchial obstruction. Clearance of the airways in patients with bulky obstructive tumours is most effectively carried out with the use of the rigid bronchoscope and its accessories.
|
Prevention of bronchopulmonary infection
This is particularly relevant to patients with significant lobar or segmental tumour obstruction. In such patients, post-PDT necrosis creates a good culture medium for organisms in the airway, notably beyond the obstructive lesion. Physiotherapy, breathing exercise and, at times, a course of antibiotics may be required.
Indications and patient selection for bronchoscopic PDT
It is generally agreed that surgical resection is the treatment of choice for lung cancer when the tumour is oncologically and technically resectable, and provided that the patient is fit for and consents to the operation. Considering this, it is also acknowledged that only a small proportion of patients, amounting to 
15–20% of the lung cancer population, could qualify for resectional surgery. It therefore follows that 80–85% of lung cancer patients are classified as inoperable, either by the nature of their advanced stage disease, because of poor general condition or from choice. This is a huge population, amounting to >25,000 individuals per annum in the UK alone. In 50–60% of this population, the tumour is central, projecting into the bronchial lumen, is visible bronchoscopically and is diagnosable by bronchial biopsy. For the purposes of interventional bronchoscopy (including bronchoscopic PDT), the present author classifies these tumours as type I lung cancer, as opposed to type II cancer, which are peripheral tumours not directly diagnosable bronchoscopically.
The prerequisite for bronchoscopic PDT is the presence of a malignant endobronchial lesion confirmed by cytohistology. By implication, only patients with central (type I) lung cancer will qualify for PDT. Theoretically PDT is indicated in every patient with type I lung cancer if their general condition allows bronchoscopic operation. In practice, at the present time, selection for bronchoscopic PDT is made from subjects unsuitable for surgery (inoperable/unresectable patients) according to the extent and stage of their disease. These inoperable patients are divided into two groups. 1) Those with advanced stage disease (stages III and IV) 90 at presentation (group/subtype A). These patients are inoperable because they are oncologically unresectable. 2) Those with early stage disease (group/subtype E) with oncologically and technically resectable cancer but who are, for a variety of reasons, unsuitable for surgical resection.
PDT is indicated in both groups but with different objectives. For group A patients, the aim is palliation of symptoms, whereas for group E patients, the aim is survival benefit and curative intent.
Group A patients
The majority of patients in group A have an obstructive endobronchial lesion and are usually symptomatic with dyspnoea, cough and haemoptysis; the relief of obstruction will alleviate the symptoms (fig. 18). The initial trial of bronchoscopic PDT in the 1980s was directed towards symptomatic patients with endoluminal exophytic tumours causing major obstruction 83. In the light of subsequent and more recent experience, PDT indications in this group have become more stringent. The present selection criteria consist of the following: 1) patients with inoperable/unresectable tumour with existing or impending related symptoms; 2) patients with good performance status (Karnofsky performance status index >50% or World Health Organization (WHO) scale 3); and 3) patients without extrathoracic metastatic disease.
|
Group E patients
In the context of bronchoscopic PDT, the term early cancer is used to describe cases in which the tumour is limited in its extent to the bronchial tree and is confined in depth to the inner bronchial wall. It is important to emphasise that standard investigatory methods may not be capable of providing a precise diagnosis of early stage cancer according to the above definition. A carcinoma in situ involving superficial layers of bronchial epithelia can be radiologically occult and bronchoscopically invisible when examined using white light. It is also relevant to emphasise that a case with superficial synchronous (multifocal) endobronchial lesions should, for the purpose of bronchoscopic PDT, be considered as an early cancer even though, based on standard tumour node metastasis classification 90, it cannot be classed as stage I.
Two recently developed methods assist the bronchoscopic diagnosis of early cancer. Fluorescence bronchoscopy uses a blue light with greater discriminative power of differential fluorescence imaging than its white light counterpart. This more accurately displays mucosal abnormalities than white light bronchoscopy 91, 92 and is of use both for pre-PDT diagnosis of early endobronchial cancer and for monitoring response to treatment. The second development is endobronchial ultrasonography. This enables the imaging and estimation of the depth of bronchial wall involvement by the tumour 93–95.
At the time of writing, there is some consensus of opinion in respect of bronchoscopic PDT indications in early stage lung cancer. These are patients: 1) whose general condition puts them in such a high-risk category as to prohibit them being offered resectional surgery; 2) who have inadequate predicted post-operative (post-resection) pulmonary function (such patients may well recover from the operation but post-operatively they may become a respiratory cripple with unacceptably poor quality of life); 3) who have multifocal endobronchial early cancer whose surgical resection is either technically impossible or would entail too extensive a loss of pulmonary parenchyma; 4) who present with early stage metachronous cancer following previous extensive surgical resection; and 5) who decline surgical resection but consent to PDT.
Some patients with early lung cancer present with cough, blood-stained sputum and dyspnoea. The latter is not usually related to endobronchial tumours, but is associated with co-existing conditions such as chronic obstructive pulmonary disease.
Results/outcome
Bronchoscopic PDT results are evaluated using the following parameters: 1) mortality and morbidity; 2) local pathological response to treatment; and 3) patient satisfaction and clinical effect.
Mortality and morbidity
Over the years, experience has shown that bronchoscopic PDT is a safe treatment method. Technically the procedure can be mastered by the majority of bronchoscopists. There is no death associated with the procedure per se and the 30-day mortality rate (empirically set for surgical operations) is <1% (table 3). A recent review article 85 concerning 25 publications from the world literature and comprising 1,153 patients undergoing nearly 2,000 bronchoscopic PDT procedures for cancer confirms this.
|
. The morbidity of bronchoscopic PDT relates greatly to skin burn, i.e. photosensitive reaction of the skin exposed to sunlight. This was reported to be 20% for bronchoscopic PDT with Photofrin® in a multicentre trial. Skin burn can be an important drawback and a prohibitive factor for clinical PDT, particularly in those cancer patients with limited life expectancy. Nevertheless, it should be emphasised that this is an avoidable complication whose incidence can be reduced considerably by thorough counselling and regular reminders to the patient to avoid exposure to sunlight. At the Yorkshire Laser Centre (YLC; Goole, UK), with a total of nearly 500 PDTs using a systemically administered photosensitiser, the incidence of skin burn in different series has consistently been 3.5–5.3% of patients. Furthermore, in the last 50 patients, no cases of skin burn have been recorded.
Other complications of bronchoscopic PDT reported in the literature are listed in table 3.
Local pathological response to treatment
By convention, local response to treatment is described as complete response/remission (CR) when a treated area becomes macroscopically and microscopically (by cyto/histology) clear from tumour. Partial response/remission (PR) occurs when macroscopic extent of the tumour is reduced by 50% after treatment, but cyto/histology demonstrates presence of malignancy. No response occurs when there is little (<50%) or no change in the macroscopic extent of the tumour and the histology remains unaffected.
It is important to note that CR and PR are not precise measurements but are nevertheless a useful concept both in terms of monitoring of treatment and also in relation to decision-making for further management of the patient. It is also necessary to point out that response to treatment, be it CR or PR, becomes meaningful when it is further quantified by duration of response and related symptomatic relief.
Patient satisfaction
The level of patient satisfaction reflects the overall quality of care as well as subjective evaluation of the treatment; it is therefore important that these should be recorded.
Clinical effects and survival
Patients with advanced stage disease
In patients with advanced disease and significant endoluminal bronchial obstruction, PDT is capable of rel
