3.2.5 Intraluminal Radiotherapy
Ron Stout, Paul Burt, and Philip Barber
R. Stout, MD; P. Burt, MD; P. Barber, MD
Department of Clinical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK CONTENTS
3.2.5.1 Introduction 269
3.2.5.2 The Technical Aspects and Practical
Application of Endobronchial Brachytherapy 270 3.2.5.3 The Effi cacy of Endobronchial Brachytherapy 270 3.2.5.4 The Side-Effects of Endobronchial
Brachytherapy 271
3.2.5.5 The Role of Endobronchial Brachytherapy 272 3.2.5.6 Conclusion 273
References 273
3.2.5.1 Introduction
Approximately 75% of patients with non-small cell lung cancer present with locally advanced or meta- static disease which renders them inoperable and virtually incurable. The aim of treatment is often palliative and radiotherapy can give considerable relief of troublesome symptoms, thereby improving the quality of remaining life. A number of patients present with thoracic symptoms which are predomi- nantly due to the endobronchial component of their disease such as cough, hemoptysis, breathlessness and those of obstructive pneumonitis. Endobronchial radiotherapy in such circumstances has its attrac- tions because any adverse effects on normal tissues are confi ned to those within the immediate vicin- ity of the bronchus. Endobronchial brachytherapy holds out the prospect of similar levels of palliation with less morbidity than external irradiation. If a more radical approach to treatment is considered appropriate, brachytherapy may then be combined with external beam radiotherapy to boost the dose to the primary tumour, since the trachea and the main airways are relatively resistant to radiation injury being composed largely of fully developed
cartilage, a post mitotic cellular system. For the same reason, brachytherapy may be given to patients who require further palliation having relapsed after pre- vious external beam irradiation which was given to tolerance for the lung parenchyma, oesophagus or spinal cord.
Endobronchial brachytherapy was used for the fi rst time more than 80 years ago (Yankauer 1922).
Radon seeds were implanted through a rigid bron-
choscope directly into a tumour in 1921. Iodine-
125 and gold-198 have also been used for perma-
nent interstitial transbronchial implantation. The
early techniques, which were diffi cult to perform
and very demanding of physicians’ time, never
gained widespread acceptance because of the ad-
ditional risks of severe haemorrhage and oedema
and the problems of poor source distribution and
source displacement. In due course, after-loading
techniques were developed to facilitate intralumi-
nal brachytherapy using caesium-137, cobalt-60 or
iridium-192. Although this led to the more frequent
use of this treatment, it was still of limited applica-
tion because of the large size and low activity of the
radioactive sources, prolonged treatment times be-
cause of the low dose-rate and the exposure of staff
to signifi cant radiation doses. In addition, both
permanent interstitial implantation and temporary
intraluminal brachytherapy required general an-
aesthesia for insertion of the sources or their carry-
ing applicators. Technological advances in the mid
1980s led to the development of a miniature, high
activity, iridium-192 source which could be used in
a remote after-loading system and this overcame
many of the problems previously associated with
endobronchial brachytherapy. The introduction
of high dose-rate intraluminal radiotherapy, now
an outpatient procedure using local anaesthesia
and fl exible bronchoscopy, offered a practical and
safe treatment alternative which was well tolerated
by patients. Several studies have since shown that
high dose-rate is just as effective and safe as low
dose-rate brachytherapy (Mehta et al. 1992; Lo et
al. 1995).
3.2.5.2
The Technical Aspects and
Practical Application of Endobronchial Brachytherapy
The miniature iridium source (typically 1.1 mm diameter and 3.5 mm long) can be accommodated in a closed-end 2 mm diameter catheter which can access upper lobe and segmental bronchi previously beyond the scope of brachytherapy using larger sources. The small source size also permits the use of multiple catheters to enlarge the treatment volume and encompass bulkier tumours involving more than one of the bronchi. Various attempts have been made to ensure that the treatment applicator lies centrally within the bronchial lumen, so as to obtain a better dose distribution and avoid localised areas of high dose on the normal mucosa (Huber et al. 1997; Marsiglia et al. 2000; Nomoto et al. 1997).
None of these methods have gained widespread ac- ceptance.
The system is extremely fl exible. The single iridium source can be programmed to dwell in up to 48 dif- ferent positions within each catheter. If the distance between each position is 5 mm, then lengths of up to 24 cm of the bronchi may be treated anywhere within the last 28 cm of the closed-end catheter. The time that the source dwells in any one position can also be varied so that different isodose distributions can be obtained if so desired, e.g. cylindrical, dumb-bell or pear-shaped. The high activity of the source (nomi- nal activity 10 Ci or 370 GBq) enables treatment de- livery at high dose-rate resulting in short treatment times of approximately 15 min which signifi cantly improves patient compliance and acceptability.
Further details of the actual technique are described by Stout (1993).
In order to facilitate the comparison of results from different treatment regimes, it is generally accepted that the intraluminal dose should be specifi ed at a depth of 1 cm from the source axis. Typical prescrip- tions in previously untreated patients include: (a) radical intent: 64 Gy in 2 Gy fractions external plus 3 fractions of 5 Gy internal during weeks 1, 3 and 5; (b) palliative intent: 37.5 Gy in 2.5 Gy fractions external plus 3 fractions of 5 Gy internal; (c) palliative intent using brachytherapy alone: 3 fractions of 7.5 Gy at weekly intervals or a single fraction of 10–15 Gy. For recurrent tumours in patients who have previously received full dose radiotherapy, 5 Gy in 1–4 fractions of endobronchial brachytherapy is most commonly used.
3.2.5.3 The Effi cacy of Endobronchial Brachytherapy
The patients most likely to benefi t from endobron- chial brachytherapy are those with central tumours which are visible endoscopically in the trachea and main stem or lobar bronchi. The results of treatment with high dose-rate endobronchial brachytherapy in more than 4500 patients world-wide have been pub- lished since the mid 1980s. Numerous studies, mostly non-randomised but also supported by some phase 3 clinical trials, have documented good symptomatic, endoscopic, radiological and physiological responses for a range of doses given in one, or as many as six, weekly treatments per patient.
Response rates can vary considerably with patient selection, intention to treat (curative, palliative or re- lapse re-treatment) and the addition or otherwise of external beam radiotherapy. The assessment of pal- liation in lung cancer is further confounded by three other factors: (1) the imprecise nature of some of the symptom end points, e.g. it is easier to assign a symptom score for hemoptysis which is more likely to be accurate than it is for cough or breathlessness;
(2) some of the tumour related symptoms under con- sideration are also produced by pre-existing chronic obstructive pulmonary disease which may undergo acute exacerbations from time to time; and (3) the same symptoms may occur after treatment as a conse- quence of the early or late side-effects of brachyther- apy. These problems were highlighted and addressed by Stephens et al. (1999) in a publication from the Medical Research Council cancer trials offi ce. They proposed that the palliation of any symptom could be described using a four point scoring system and be expressed in terms of: (a) improvement (a reduction in moderate or severe symptoms to nil or mild), (b) control (no deterioration in mild symptoms) and (c) prevention (no deterioration in those with no symp- toms), see Table 3.2.5.1.
The accurate assessment of symptomatic response to a particular treatment may also require the use of patients’ self-ratings in a validated ‘quality of life’
analysis tool (Stephens et al. 1997). The disparities that can arise between clinician and patient assess- ments are illustrated in Table 3.2.5.2, taken from the fi rst UK trial of endobronchial brachytherapy (Stout et al. 2000).
In spite of these diffi culties of assessment, in- dividual symptom responses have been observed and reported in numerous publications with re- sponse rates consistently in the range of 50%–90%.
Hemoptysis, breathlessness and the symptoms of ob-
structive pneumonitis are generally better relieved than cough. Resolution of endobronchial tumour has been confi rmed endoscopically on many occa- sions with response rates (partial and complete) in the range of 55%–100%. Those reported by Spicer and Spratling (1993a) are typical. Complete resolu- tion is also supported by the reports of patients with small localised tumours who have survived long- term following brachytherapy as the sole treatment (Sutedja et al. 1994; Tredaniel et al. 1994; Gollins et al. 1996a; Perol et al. 1997; Marsiglia et al. 2000).
Improvements in chest X-ray appearances following brachytherapy are usually noted in 40%–90% of pa- tients depending upon the series. Signifi cant physi- ological as well as subjective, bronchoscopic and radiological benefi t has been well documented in a
small but carefully investigated group of patients by Goldman et al. (1993).
3.2.5.4
The Side-Eff ects of Endobronchial Brachytherapy
The commonest early side-effect which can be at- tributed to intraluminal radiotherapy is a transient exacerbation of cough which has usually settled within 2–3 weeks of treatment. When endobronchial brachytherapy is used as the sole treatment, there is usually no signifi cant radiation esophagitis. This results in less overall morbidity, an obvious gain in
Table 3.2.5.1. The defi nition of ‘positive’ and ‘negative’ endpoints for palliation Baseline
symptom
8-Week assessment Category Comment
None None Positive Prevention
None Mild, moderate, severe Negative
Mild None or mild Positive Control
Mild Moderate or severe Negative
Moderate or severe None or mild Positive Improvement Moderate or severe Moderate or severe Negative
Any Death Negative
Table 3.2.5.2. Palliation expressed as the percentage of positive symptom end- points (see Table 3.2.5.1) for each treatment as recorded by clinicians at 8 weeks to assess response and by patients at 8 weeks for comparison
Clinician Assessments Patient Assessments
8 Weeks 8 Weeks
EBT XRT EBT XRT
The number of completed assessments
46 46 40 43
Cough (%) 50 67 45 65
Hemoptysis 78 89 71 90
Breathlessness 59 78 38 49
Chest pain 61 80 43 77
Dysphagia 80 87 71 86
Anorexia 63 78 43 77
Tiredness 57 74 30 65
Nausea 83 87 58 81
Hoarseness 70 91 70 79
EBT, endobronchial brachytherapy; XRT, external beam radiotherapy.
favour of endobronchial brachytherapy when the aim of treatment is palliation. The later effects of radia- tion bronchitis and stenosis, elegantly described by Spicer and Spratling (1993b), and massive fatal hemoptysis, give rise to more concern.
The grading system for radiation bronchitis and stenosis as described by Spicer and Spratling is a use- ful tool to document what is seen at bronchoscopy at various time intervals following treatment. During the fi rst 3 months following treatment the reactions on the mucosa are predominantly infl ammatory.
A fi brotic reaction with associated stenosis is more prevalent beyond 6 months. The incidence of radia- tion bronchitis reported by them is highest in the patients receiving potentially curative radiotherapy using a combined approach of brachytherapy and external beam radiotherapy but the only signifi cant factor predicting for the severity of late response was length of follow-up. In our own series in Manchester, Gollins et al. (1996b) where the majority of patients were treated with a single exposure of brachytherapy as the sole treatment, a dose response relationship was identifi ed.
Massive hemoptysis is usually a fatal event which occurs in lung cancer whether or not ra- diotherapy has been given. Its exact incidence in untreated patients or in those who have received external beam radiotherapy and or chemotherapy is unknown but has been variously reported in the range of 5%–20%. Its occurrence following brachy- therapy with or without external beam radiother- apy has been documented in the range 0%–50%.
In the large retrospective series of 406 patients reported by Gollins et al. (1996b), massive fatal hemoptysis was 8% (32 patients). The review in- cluded 322 new cases of inoperable non-small cell lung cancer who were treated with a single fraction of high dose-rate brachytherapy to a total dose of 15–20 Gy. Massive hemoptysis leading to death usually occurred between 9 and 12 months after treatment whereas deaths from other causes oc- curred between 3 and 6 months. Associated treat- ment factors increasing the likelihood of massive fatal hemoptysis were a brachytherapy dose greater than 15 Gy, prior laser treatment, a second or third brachytherapy treatment at the same site and con- current external beam radiotherapy. However, in 25 of the 32 patients whose deaths were assessable, there was evidence of recurrent and or residual tu- mour in 20. The UK randomised trial reported by Stout et al. (2000) where brachytherapy (15 Gy) as a sole primary treatment was compared directly with a palliative course of fractionated external
radiotherapy (30 Gy in 8 fractions), the incidence of massive fatal hemoptysis was the same in both arms of the trial, occurring in only seven out of 99 patients overall.
3.2.5.5
The Role of Endobronchial Brachytherapy
No evidence has yet been found from large retro- spective series or a limited number of prospective randomised trials, that the addition of endobron- chial brachytherapy to external beam radiotherapy (radical or palliative) has produced any signifi cant improvement in survival.
A trial by Huber et al. (1997) compared a planned dose of 60 Gy external radiotherapy with an ad- ditional boost of high dose-rate brachytherapy of 4.8 Gy immediately before and after external irra- diation. There was an improvement in local control in the combined arm and a trend towards improved survival which did not reach statistical signifi cance.
There was no signifi cant difference in the incidence of fatal hemoptysis between the two groups.
A similar trial by Langendijk et al. (2001) included patients who were being treated with palliative as well as radical intent. No survival benefi t was found in patients receiving external and internal treatment, although the trial was not designed to investigate survival. The addition of brachytherapy did provide higher rates of re-expansion of collapsed lung result- ing in a transient improvement in breathlessness. The benefi cial effect was only observed among patients with obstructing tumours in the main bronchus. The investigators concluded that the results did not sup- port the addition of endobronchial brachytherapy to external radiotherapy as a standard approach but combined treatment could be considered in patients with severe breathlessness due to an endobronchial tumour obstructing the main bronchus.
Two Manchester trials of palliative radiotherapy in 200 patients have compared a fractionated course of external radiotherapy, 30 Gy in 8 fractions, with the same treatment plus a boost of brachytherapy of 15 Gy in 1 session. A detailed analysis of palliation is being carried out in preparation for publication, but neither trial has demonstrated a survival gain in favour of the combined treatment.
In some patients it may be useful to re-expand a
collapsed lobe or lung before embarking on a course
of radical external beam radiotherapy. Re-expan-
sion of the collapsed lung may lead to a better defi -
nition of the gross tumour volume, a more accurate radiotherapy treatment plan and a reduced risk of a geographical miss. Theoretically, this could result in better local control and improved survival for more localised tumours.
Although endobronchial brachytherapy can pro- vide good symptom relief, if the aim of treatment is palliation, then external irradiation as the initial sole treatment would seem preferable to brachytherapy alone. That at least was the conclusion of the inves- tigators in the fi rst UK trial, Stout et al. (2000), who found that external radiotherapy gave better overall and more sustained palliation with fewer re-treat- ments, a modest gain in median survival of 287 ver- sus 250 days and a better 1-year survival of 38% ver- sus 22%. Brachytherapy alone clearly has a useful role where external irradiation is contra-indicated.
Endobronchial brachytherapy may also offer fur- ther palliation in patients who have symptomatic endobronchial relapse following previous external beam radiotherapy. In all, 60%–70% of these patients will obtain worthwhile symptom relief although the incidence of fatal hemoptysis and bronchial fi stulae may be high (Sutedja et al. 1992; Macha et al. 1995).
Care should be taken where external irradiation has been given to tolerance and where laser treatment has been used to clear the airway before brachytherapy.
Doses less than 10 Gy, e.g. 5 or 7.5 Gy, should be used and a single treatment is often suffi cient.
3.2.5.6 Conclusion
Endobronchial brachytherapy can undoubtedly provide good palliation of hemoptysis, breath- lessness, cough and obstructive pneumonitis when used alone or with external irradiation as described above. The optimal dose and number of fractions to provide the best symptom relief for the least morbidity still have to be defined. Individual practitioners will have their own preferences based on their experience and the evidence currently available in the literature. Where a more radical approach is required, it would seem that brachy- therapy can improve local control without making a significant impact on survival. As developments in chemo-radiotherapy lead to better tumour con- trol outside the airways, the role of brachytherapy as an intraluminal boost may become more impor- tant. Careful assessment in clinical trials will be required to document the potential benefits and
identify any excess morbidity when multi-modal- ity treatment is employed.
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