High Dose Rate Endobronchial Brachytherapy in Lung Cancer in Patients with Central Airway Obstruction

One of the major role of EBBT is palliation of symptoms caused by endobronchial cancer ingrowth. Boost EBBT to endobronchial gross tumors combined with external beam radiotherapy (EBRT) provides not only palliative but curative possibilities2. In small endobronchial tumors EBBT is used as definitive curative treatment3.EBBT is also used for non-oncologic pathologies4,5. The majority of non-small cell lung cancer (NSCLC)found at loco-regionally advanced stage and frequently associated with bronchial obstruction Various endoscopic techniques available today are including cryotherapy, stent, laser, photodynamic, and EBBT6,7. Among these EBBT in the only one that provides biologically tumoricidal effect keeping the normal tissue structure as is.


Introduction
The term brachytherapy derives from the Greek "brachys", which means "short" or "close".I t i s t h e b r a n c h o f r a d i o t h e r a p y i n w h i c h the radioactive source is located near the therapeutic target.The reported first use of endobronchial brachytherapy (EBBT) done by Yankauer in 1992 1 ,.He inserted Radon seeds directly into lung tumors though a rigid bronchoscope.

Patients, materials and methods
From March 2006 to November 2009, 27 patients were treated with 82 HDR-EBBT procedures as palliative treatment for advanced cancer.
The indication criteria for included: Being able to tolerate decubitus supine position that allows fiberrbronchoscopy examination(FBC), there were clear evidence of tumors with intraluminal component (with or without extrabronchial component), life expectancy of over 3 months, no immediately life-threatening airway obstruction , and healthy coagulating condition.All patients were clinically assessed and the symptoms were evaluated according to Speiser and Spratling 8 , recommended by American Brachytherapy Society (ABS), (table 1), prior to and one week after the end of the treatment.
Premedication including included sedatives, and local endobronchial anesthesia which were commonly used in usual FBC.
We used two equipment: a. Video bronchoscope Fujinon, model EB-270S working channel of 2.0 mm, flexible tube of 4.9 mm in diameter.b.Fibrobronchoscope Olympus, model BF-TE2 working channel of 2.8mm, flexible tube of 4.9 mm in diameter.
During FBC, the physician evaluated the percentage of luminal obstruction of the air way (table 2), repeating these evaluations after the following FBC.
At the first FBC, the extension of the lesion was measured: the anatomic potion of thee carina was used as reference point to measure lesion extension towards cranium or caudal.After confirmation of the precise target location that was recognized as clearly limited or demarcated, one or two endobronchial brachytherapy applicator catheters (Varian (metaltipped 4.7, FR-150 cm long (PTFE) R)) were installed ,, with a radiopaque terminal that keeps its position by means of nasal fixing.After insertion of the catheter, or in advance, we used of codeine for managing cough caused by the dwelling catheters in the airway.
The HDR-EBBT planning was simulated on computer associated tomography (CAT) images.using planning computer ( Brachyvision system , Varian Medical Systems), which was transferred to are mote high loading dose (iridium-192 source) brachytherapy equipment (VariSource iX, Varian Medical Systems).We prescribed 1 to 4 fractions of 7 to 7.5 Gy (range of total, 7 -30Gy )at 1 cm depth point from the endobronchial surfacecovering the macroscopic lesion with a safety margin of additional 1 cm (Figure 2).The fractional interval between brachytherapy session was 1 week.In patients with significant or complete bronchial obstruction, we applied electrofulguration before installing the catheter, or installed the catheter through the tumor stenosis/obstruction into the peripheral end.
Both the catheter installation procedure by BFC and HDR-EBBT were performed in an outpatient setting.Patients were followed up and evaluated for effect and complications at next week of the last brachytherapy session and at the second month. .

Results
Patient consisted of 15 men and 12 women and their age ranged 32-85 years old.The most frequent histologic cancer type was NSCLC, with the main subtype being squamous carcinoma (40%).7 patients (26%) were previously treated with palliative radiotherapy:(5 patients received 40 Gy in 20 fractions, one received 30 Gy in 10 fractions, one 20 Gy in 5 fractions and the other one 8 Gy in 1 fraction..At the time of EBBT no patients were receiving concomitant chemotherapy, while a few received chemotherapy previously for relapsed tumor.Table 3 summarizes the characteristics of the 27 patients who received HDR-EBBT.
Lesion location, extent and degree of airway obstruction are described in Table 3 and Figure 3.
With this treatment, a significant improvement was observed in every evaluated symptom (hemoptysis, cough, dyspnea and obstruction).Table 4 compares symptomatic scores before and 1 week after treatment.One patient did not complete treatment for personal reasons, and another one died secondary to a hemorragic complication from the contralateral bronchial tree.Thus 25 patients were evaluable for dyspnea, hemoptysis and cough.22 patients underwent bronchoscopic reevaluation for degree of obstruction after treatment: One patient with significant clinical improvement refused the reevaluation.The EBBT procedure was well tolerated, with no acute complications registered.Two months after treatment, two patients (7%) had significant hemoptysis and bronchoscopic examination revealed these bleeding were originated from different locations..One patient discontinued treatment because of personal choice.
The average treated volume (100% isodose) was 38.1 cm 3 (SD  15.4)(this shows the smallness of the irradiated tissue volume with this technique)

Discussion
The HDR-EBBT provides rapid and significant symptomatic improvement of related to main airway obstruction when the selection of patients is adequate.Our results are consistent with that reported previously (Table 5).These excellent results, with the progress in radioisotope security issue and the outpatient treatment possibility owing to recent decade's technological advances, have made EBBT one of the major applications of brachytherapy in several nations 16 .
Currently, EBBT is a part of the therapeutic arsenal in interventional bronchoscopy, being complementary to other techniques such as cryotherapy, laser, photodynamic, stents and argon plasma 17 .

EBBT Indications
There are several comprehensive publications that develop the indications and treatments techniques 6, 18.19 .
According to the recommendations of the ABS (American Brachytherapy Society) 18 and the ESTRO (European Society of Therapeutic Radiology and Oncology) 19 indications could be divided into: Palliative treatment, healing and non-oncologic pathology.

Palliative treatment
Patients with large endobronchial tumors which cause symptoms such as dyspnea due to obstruction, cough, bleeding, or post obstructive pneumonia, represent the most common EBBT indication.Contrary, those tumors that cause obstruction mainly due to extrinsic airway compression would not be candidates for this treatment.Patients with critical obstruction and airway compromise are not recommended for exclusive use of this technique, but it can be used after initial treatment with laser, cryotherapy, stents or electrocautery 20,21 with great results and ostensible improvement in quality of life.
According to Nag 18 , the EBBT might be more effective than a two or three weeks treatment with external beam radiotherapy (EBRT), indicated at first instance, in patients with life expectancy greater than three months that are not candidates for surgery or EBRT due to poor lung function after radiation therapy.Kelly et al, from MD Anderson, discussed their 10 years' experience with EBBT 11 .These authors treated a group of patients with the worst prognosis.Given that, two thirds had already received palliative EBRT.However, they got a 66% improvement of symptoms.Escobar-Sacristán et al, from the Military Hospital of Madrid, reported 85 patients with symptomatic advanced lung cancer who received 288 EBBT applications with 85% partial improvement in symptoms (cough, dyspnea, hemoptysis, and obstruction) and 60% complete responses using endoscopic EBBT 22 .
The treatment schedule, i.e., the dose and the number of applications vary in different sites and authors as shown in Table 5.When treatment is performed exclusively, most publications have suggested dose and fractionation schemes between 15 and 35 Gy in one to five applications, calculated within 1 cm from the source.However, more recent studies recommended not exceeding 30 Gy with EBBT 19 .The ABS recommends 3 fractions of 7.5 Gy, two of 10 Gy or four of 6 Gy.These fractions have the same radiobiological equivalent according to the linear quadratic model 23 , and the results are very similar ,7,13,24-26 .

Curative treatment
EBBT has been used in curative treatment of lung cancer, both in the exclusive treatment of early tumors with EBRT as overprint (boost or reirradiation) 2,3 .About the first indication, Marsiglia et al, reported a two year survival rate of 78% in 34 patients with small tumors without evidence of spread that were treated only with HDR-EBBT with a 30 Gy dose in 6 fractions 3 .Hennequin et al, in a series of 106 patients with localized tumors that were not candidates for surgery or EBRT, obtained a specific 3 and 5 years survival of 60% and 50% respectively 2 .The ABS recommended a healing (palliative) dose is 3 fractions of 5 to 7.5 Gy (total 15 -22.5Gy) when the patient already received 60 Gy pretreatment with EBRT, and 5 to 6 fractions of 5 to 7 Gy (total 25 -42 Gy) if this treatment is exclusively used 17 .

Non-oncologic pathology treatment
Several authors have published interesting experiences regarding the use of EBBT in nonmalignant pathology.This treatment modality has been used successfully in patients with granulomatous proliferation after metal stent placement because of non-malignant airway stenosis, or pulmonary transplant patients 4,5 .
In patients who have not received EBRT it is feasible to use the combination of EBBT and EBRT in order to improve results.In a randomized study, the combination of those treatments proved to be more effective than single-EBRT in symptomatic improvement 27 .Mantz and colleagues, obtained a significant increase in local control when using a EBBT www.intechopen.com High Dose Rate Endobronchial Brachytherapy in Lung Cancer in Patients with Central Airway Obstruction 87 boost or overlay to EBRT compared to exclusively use of EBRT (58 versus 32% at 5 years, respectively) 28 .
We understand that the EBRT is preferred as a palliative treatment when the airway compression is extrinsic, when EBBT is not indicated.In patients with tumors, with an intrinsic component in the airway lumen, Kelly and colleagues from MD Anderson, say that one of the advantages of HDR-EBBT would be the shorter treatment time 11 .

Conclusion
The HDR-EBBT is a useful technique in the symptomatic treatment of ambulatory patients with central airway obstruction.The procedure is well tolerated and effective with low complications rate.Main indications are patients with advanced lung cancer, where the objective is only palliative.It must also be considered in situations of incipient tumors for patients with contraindications for surgery or EBRT, boosted after a first treatment with EBRT or in benign disease with endobronchial or endotracheal scar proliferation.

Fig. 2 .
Fig. 2. Dose distribution of a treatment planning to main left bronchus lesion causing left superior lobar atelectasis.Thick green line: catheter in treatment position: Cayn clouered contur between red and yellow indicates 100% of the prescribed dose .

Table 2 .
Grade of obstruction

Table 3 .
This table summarizes the characteristics of the 27 patients who underwent endobronchial brachytherapy high doses (HDR-EBBT)

Table 4 .
Patient symptoms according to the Speiser-Spratling scale before and after HDR-EBBT

Table 5 .
Published results of HDR endobronchial brachytherapy as palliative treatment