Endobronchial brachytherapy

INTRODUCTION — Brachytherapy refers to the placement of a radioactive source within or in close proximity to a malignancy in order to provide high doses of radiation in close proximity to the tumor [1,2]. Endobronchial brachytherapy is largely a palliative therapy for the treatment of locally advanced non-small cell lung cancer (NSCLC) involving the airway. However, the need for this technique has declined largely due to the expansion of other effective and less costly bronchoscopic ablative techniques including neodymium-doped yttrium aluminium garnet (Nd:YAG) laser, argon plasma coagulation, electrocautery, and cryotherapy.

The use of endobronchial brachytherapy for the treatment of NSCLC will be reviewed here. Other interventional treatment modalities, such as airway stents, bronchoscopic laser resection, endobronchial electrocautery, cryotherapy, and argon plasma coagulation are discussed separately. (See "Airway stents" and "Bronchoscopic laser in the management of airway disease in adults" and "Endobronchial electrocautery" and "Bronchoscopic cryotechniques in adults" and "Bronchoscopic argon plasma coagulation in the management of airway disease in adults".)

TECHNIQUE — The major goal of endobronchial brachytherapy (EBBT) is a reduction in tumor size so that airway symptoms can be relieved. For patients suitable for EBBT (see 'Patient selection' below), a flexible bronchoscope is typically used to place a radioactive source (usually Iridium-192) within or in close proximity to the target endobronchial lesion (usually malignancy) [3-7]. Compared with external beam radiation therapy (EBRT), local radiation is provided to the lesion with the intent of sparing the tissues in the pathway of external beam.

Bronchoscopy — While in the past, rigid bronchoscopy was used [8], flexible bronchoscopy is the typical modality of choice for EBBT. Using a flexible bronchoscope, a polyethylene catheter with a radiopaque wire is passed transnasally (through a side port or alongside the bronchoscope) and placed in the desired position within the airway under direct visualization. The catheter position is verified fluoroscopically. The bronchoscope is removed and the catheter is secured to the nose of the patient. Additional reverification of the position with a plain chest radiograph can be performed, if necessary, before removing the "dummy seeds" and loading the catheter with a radioactive source (“afterloading”). Afterloading is usually performed with a remote afterloading device to minimize radiation exposure to providers, but can be performed manually if needed.

Occasionally the catheter containing the radioactive seed is not centered inside the airway and lies directly adjacent to the airway wall. In such cases, the bronchoscopist can use centering devices such as balloons, cages, or sheaths, to maintain the radioactive source within the center of the bronchial lumen and avoid dose inhomogeneity [7].

As for all endobronchial interventions, emergency airway equipment and a resuscitation cart are required for safety.

Radiation type — The dose rate of brachytherapy depends upon the energy and rate of decay of the radionuclide used, which, for endobronchial therapy is usually Iridium-192 [3-7].

●High dose rate (HDR) – HDR EBBT involves greater than 10 to 12 Gray (Gy)/hour, with the total dose ranging from 5 to 40 Gy, and the dose per session (fraction) varying from approximately 3 to 10 Gy.

HDR EBBT is usually delivered in a series of dose fractions in order to optimize its effectiveness and minimize side effects. A wide variety of treatment schedules have been utilized; generally patients are treated no more than every one to two weeks because of the discomfort and logistical difficulties associated with more frequent bronchoscopies (ie, the catheter needs to be placed for each fraction of treatment).

Computerized tomographic pre-planning usually determines the radiation dose administered. The American Brachytherapy Society now advocates using computed tomography (CT) planning with three-dimensional target definition for endobronchial brachytherapy rather than point definition in order to improve coverage and avoid underdosing [9]. The radiation isotope is moved in 5-mm increments ("dwell") positions along a pre-planned pathway for pre-specified dwell times in the catheter to optimize the dose. The process takes a few minutes. The catheter is then removed and the procedure repeated a few weeks later.

HDR EBBT is more commonly employed than low dose rate (LDR) EBBT because treatment times are shorter, allowing it to be an outpatient procedure. Shorter catheter indwelling times also decrease the likelihood of catheter displacement, increase procedure efficiency, and reduce treatment cost. In addition, heavily shielded treatment rooms and the use of afterloading techniques for HDR EBBT equipment (ie, inserting the radionuclide into the bronchoscopically-placed catheter by means of a remotely controlled device) have made this a simpler and safer therapy.

●Low dose rate (LDR) – LDR EBBT delivers less than 2 Gy/hour and a total dose of 1500 to 5000 Gy, given over a few days (usually up to three days) [10,11]. LDR EBBT requires manual manipulation of the radionuclide, 30 to 70 hours of continuous treatment, cumbersome radiation protection measures, and the catheter has to be left in place for the few days of administration. It is usually an inpatient procedure frequently complicated by catheter displacement, and is more costly than HDR EBBT. Thus, it has largely fallen out of favor.

PATIENT SELECTION — Endobronchial brachytherapy (EBBT) is not a first line, curative, or sole therapy for lung cancer. It may be indicated for the palliative treatment of large obstructing central airway tumors (usually non-small cell lung cancer [NSCLC]) that are not amenable to surgical resection and/or external beam radiation.

EBBT has also been employed on rare occasions to treat recurrent airway NSCLC, metastatic airway tumors, early NSCLC that is limited to the airway, and non-malignant airway stenosis that has failed conventional therapy.

The need for this technique has declined due to the expansion of available ablative bronchoscopic therapies including laser, argon plasma coagulation, electrocautery, and cryotherapy.

Thus, patients with acute life-threatening symptoms of airway obstruction that need immediate relief can be treated with EBBT but only after other local ablative therapies or external beam radiation (EBRT) have been employed to shrink tumor size. (See "Bronchoscopic laser in the management of airway disease in adults" and "Bronchoscopic argon plasma coagulation in the management of airway disease in adults" and "Bronchoscopic cryotechniques in adults" and "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".)

It is noteworthy that the American Brachytherapy Society recommends postponing endobronchial brachytherapy for patients during the coronavirus disease 2019 (COVID-19) pandemic because of safety concerns for health care professionals [12].

Palliation of central obstructing airway tumors

Patient and tumor characteristics — High dose rate (HDR) EBBT can be used for the palliation of obstructive symptoms caused by large central airway tumors that are not amenable to surgical resection and/or external beam radiation [9,13-15]. It can also be used in this population when patients cannot tolerate or fail other local ablative therapies including neodymium-doped yttrium aluminium garnet (Nd:YAG) laser, argon laser, or cryotherapy. Importantly, the types of cancer that are responsive to EBBT include biopsy-proven NSCLC or an extrathoracic malignancy metastatic to lung. Patients with small cell carcinoma or carcinoid are not typically suitable but EBBT has been used anecdotally when these tumors are refractory to multiple therapies.

Although specific criteria that render a patient or tumor suitable for EBBT varies, the following is generally accepted among most experts:

●The tumor (or tumor effect) should be visible by bronchoscopy. Thus, tumors located in the trachea, main stem, or lower lobe bronchi (ie, accessible to placement of a brachytherapy catheter, usually down to the third order bronchus) are generally considered suitable for EBBT.

●The tumor can be either intrabronchial (intrinsic tumor of the airway) or extrabronchial (extrinsic compression of the airway) and may involve submucosal infiltration [16,17].

●The degree of obstruction by the tumor has to be of sufficient size such that the catheter for delivery of the radiation source can be passed distally.  

●The patient should have sufficient life expectancy (usually more than three months) to derive palliative benefit.

Importantly, patients with acute life-threatening symptoms of airway obstruction that need immediate relief can be treated with EBBT but only after other local ablative therapies or external beam radiation (EBRT) have been employed to shrink tumor size. This is because ablative therapies and EBRT are immediate in their effect. In contrast, the effect of EBBT is usually delayed by two to three weeks and the initial response may cause edema and inflammation which can temporarily worsen airway compromise. (See 'Contraindications' below.)  

Efficacy — Subjective and objective improvement following EBBT has been reported in 20 to 100 percent of patients [10,18-20]. The wide range likely reflects the variety of symptoms that existed prior to the procedure as well as the use of qualitative methods used during follow-up to assess response. Although most observational trials demonstrate improved symptoms, evidence is conflicting regarding true benefit when compared with other therapies. This was best demonstrated by a 2012 meta-analysis of 14 randomized trials involving 953 patients which reported that compared to external beam radiation (EBRT) and Nd:YAG laser therapy, there was no survival benefit associated with EBBT or EBBT in combination with chemotherapy [14]. Although some trials report that EBBT combined with EBRT may offer improved efficacy [21-28], the systematic review quoted above reported that the combination provided no greater symptom relief than EBRT alone [14]. Thus, while there are no high-quality studies directly comparing EBBT with EBRT, we agree with this analysis and suggest that for the majority of patients, EBBT should not be considered until patients have first undergone EBRT. (See "Management of stage I and stage II non-small cell lung cancer" and "Overview of the initial treatment of advanced non-small cell lung cancer".)

There is limited evidence suggesting that endobronchial brachytherapy plus endobronchial laser therapy may be superior to endobronchial laser therapy alone [5,29,30]. (See "Bronchoscopic laser in the management of airway disease in adults".)

Hemoptysis tends to improve most readily, with a greater than 90 percent response rate in many series [15,31-36]. Cough and dyspnea may improve less reliably, probably because they are frequently due to underlying conditions such as chronic obstructive pulmonary disease or radiation fibrosis. Additionally, EBBT may cause radiation bronchitis resulting in similar symptoms. As examples:

●In a prospective observational series of 98 patients with locally advanced inoperable lung cancer treated with HDR EBBT, hemoptysis-free survival was 232 days, cough-free survival 140 days, and dyspnea-free survival was 173 days [15].

●In another prospective study of 78 patients with malignant airway obstruction, 100 percent of patients with hemoptysis responded to HDR EBBT compared with 80 percent with post obstructive pneumonia, 57 percent with dyspnea, and 34 percent with cough [31].

●In a series of 50 patients treated with HDR EBBT, hemoptysis was relieved in 24 of 28 patients (86 percent), breathlessness in 21 of 33 (64 percent), and cough in 9 of 18 patients (50 percent) [32]. These responses were maintained for four months.

Responses in tumor size and the degree of airway obstruction are most commonly evaluated by chest radiography and bronchoscopy. Some investigators use an obstruction score, but this has not been widely utilized [29]. According to some series, approximately 70 percent of patients have greater than 50 percent improvement in patency that persists for at least six months [5,37]. Different series have enrolled patients with different characteristics, making the results difficult to generalize due to probable selection bias. In addition, a significant number of patients in some reports refused subsequent bronchoscopy, potentially resulting in an overestimation of effectiveness.

Other — Data to support HDR EBBT in other populations are limited. However, clinicians with expertise have used EBBT to successfully treat patients with recurrent NSCLC or metastatic tumors of the airway, early NSCLC that is localized to the airway, as well as patients with positive resection margins or a stump recurrence following surgery. A few case reports describe benefit in patients with nonmalignant airway stenosis that has failed conventional therapy.

Recurrent or metastatic airway tumors — Limited retrospective data report benefit from HDR EBBT in patients with local recurrence of NSCLC in an airway stump following surgery, as well as in patients with lung cancer that is metastatic to the airway [18,38]. EBBT has also been employed postoperatively in patients found to have tumor at resection margins in an attempt to improve cure rates, or in patients with early stage lung cancer who can only tolerate sublobar resections [38,39]. As examples:

●An observational study of 175 patients with lung cancer who received HDR brachytherapy for persistent or recurrent cancer of the airway (mostly NSCLC) demonstrated symptomatic improvement in 115 patients (66 percent) [18]. Repeat bronchoscopy found that 78 percent of patients responded to EBBT, when a response to therapy was defined as at least 50 percent reopening of the normal lumen. Treatment-related complications were detected in only 19 patients (11 percent). A small number of patients received Nd:YAG laser therapy prior to EBBT which may have resulted in an over estimation of the response.

●Preliminary results in 14 patients who underwent sublobar resections for stage 1 NSCLC (ie, peripheral nodules) reported that intraoperative brachytherapy implants (manually placed by the surgeon) reduced local recurrence rates at seven months [38]. The impact on survival and long term recurrence was not reported.

●In an observational series of 34 patients with stage 1 NSCLC who had stump recurrence or positive margins following sublobar resection, HDR EBBT resulted in a disease free survival time of 17 months [39]. However, these rates may have been over estimated due to the inclusion of patients also treated with external beam radiation.  

Airway tumors without extrabronchial spread — Several observational studies report a beneficial response to HDR EBBT in patients with early NSCLC limited to the airway (eg, bronchial intraepithelial metaplasia, early endobronchial NSCLC without extrabronchial spread) who are not candidates for surgery or external beam radiation [37,40-46]. As examples:

●In a series of 226 patients with NSCLC (97 percent had squamous cell carcinoma) without extrabronchial spread who were not candidates for surgery or external beam radiation therapy, HDR EBBT was associated with a complete endoscopic response rate of 94 percent at three months [45]. The two- and five-year overall survival rates were 57 and 29 percent, respectively, while the two- and five-year cancer-specific survival rates were 81 and 56 percent, respectively.

●In a similar population of 106 patients, HDR EBBT was associated with an overall five-year survival of 24 percent and a cause-specific five-year survival of 49 percent [41]. The five-year survival rates reflect the high rate of deaths not related to lung cancer in this study.

●In another observational study of 34 patients with local endobronchial NSCLC, at two years HDR EBBT was associated with a local control rate of 85 percent and a survival rate of 78 percent [40].

Nonmalignant airway stenosis — Case reports suggest that in patients who have recurrent tracheal stenosis following repeated attempts at dilation and stenting, HDR EBBT (eg, a single 3 to 10-Gray [Gy] dose of Iridium-192) may be used to prevent the formation of granulation tissue and reduce the recurrence rate of restenosis [47-50]. In the largest series of 12 lung transplant patients, HDR EBBT (using a single dose application of 3 Gy of iridium-192) resulted in improved clinical status and lung function, and halved the rate of interventions needed for post-transplant tracheal stenosis [50]. (See "Noninfectious complications following lung transplantation", section on 'Anastomotic complications' and "Complications of the endotracheal tube following initial placement: Prevention and management in adult intensive care unit patients", section on 'Laryngotracheal stenosis'.)

CONTRAINDICATIONS — Contraindications to endobronchial brachytherapy (EBBT) include the following:

●The presence of fistulas between bronchi and other structures. EBBT in this setting increases the risk of viscus rupture and fatal hemorrhage. (See "Complications of the endotracheal tube following initial placement: Prevention and management in adult intensive care unit patients", section on 'Tracheoesophageal fistula' and "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula".)

●The presence of high-grade airway obstruction. Patients with significant airway compromise should be treated with bronchoscopic ablative techniques such as neodymium-doped yttrium aluminium garnet (Nd:YAG) laser, argon plasma coagulation, electrocautery, stent insertion, or external beam radiation before brachytherapy, because the use of brachytherapy will not immediately shrink tumor size (maximal effect is after three weeks) and, in fact, may result in postradiation tissue edema and complete airway obstruction. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".)

●Patients who are moribund or who have contraindications to bronchoscopy in general. (See "Flexible bronchoscopy in adults: Indications and contraindications", section on 'Contraindications'.)

Relative contraindications include the following [51-53]:

●Lesions in close proximity to large vessels (ie, at the anterior distal trachea, the orifice to the right upper lobe, the mid-distal left mainstem, or the carina between the left upper and lower lobes)

●Malignant involvement of the major arteries

●Significant destruction of the bronchial wall

●Mediastinal invasion

These factors increase the risk of fistula formation and fatal hemorrhage, which are serious, life-threatening complications of EBBT. Computed tomography (CT), magnetic resonance imaging, or digital subtraction angiography may be helpful in assessing these factors prior to the procedure. (See 'Complications' below and "Evaluation and management of life-threatening hemoptysis" and "Etiology of hemoptysis in adults" and "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula".)

Although small cell lung cancer or tumors other than non-small cell lung cancer (NSCLC) are not contraindications to EBBT per se, use of EBBT is anecdotal in patients with these tumors refractory to multiple therapies.

COMPLICATIONS — Most studies report that the complication rate of endobronchial brachytherapy (EBBT) is at least 5 percent but it can be as high as 40 percent [31,33,51-54]. Complications of EBBT can occur early (hours to days) or late (days to weeks).

A commercially available catheter is designed to facilitate centralization of the radioactive source within the endobronchial lumen during radiation delivery and may limit damage due to eccentric positioning of the dose-delivering catheter [55].

Early — Early complications are infrequent and usually due to bronchoscopy or catheter insertion. Hemoptysis and catheter displacement are the most worrisome early complications. Other common early complications of bronchoscopy (eg, hypotension, bacteremia) are listed in the table (table 1). (See "Flexible bronchoscopy in adults: Indications and contraindications".)

Risk factors for early complications associated with EBBT have been reported and include hypertension, cardiac arrhythmias, and chronic obstructive pulmonary disease, as well as the presence of multiple risk factors and older age [54].

Late — Late complications are common and frequently include radiation bronchitis and airway stenosis. They can manifest with a cough or wheezing. Risk factors for these complications include large cell carcinoma, use of brachytherapy for curative intent, prior laser resection, and concurrent external beam radiation [33]. (See "Radiation-induced lung injury" and "Complications of the endotracheal tube following initial placement: Prevention and management in adult intensive care unit patients", section on 'Laryngotracheal stenosis'.)

Massive hemoptysis and fistula formation (eg, tracheoesophageal or tracheal-aortic fistula) are particularly serious late complications of endobronchial brachytherapy. Tracheobronchial ulceration often precedes massive hemoptysis. Case series indicate that such adverse outcomes occur in up to 42 percent of patients [5,6,16,18,51,52,56-62]. Potential risk factors for these complications include use of EBBT to treat malignant involvement of the major arteries, lesions with significant destruction of the bronchial wall or with mediastinal invasion [51-53]. (See "Evaluation and management of life-threatening hemoptysis" and "Etiology of hemoptysis in adults" and "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula".)

SUMMARY AND RECOMMENDATIONS

●Definition – Endobronchial brachytherapy (EBBT) refers to the placement of a radioactive source within or in close proximity to a malignancy in order to provide high doses of radiation close to the tumor. The need of this technique has declined largely due to the expansion of other effective and less costly bronchoscopic ablative techniques including neodymium-doped yttrium aluminium garnet (Nd:YAG) laser, argon plasma coagulation, and cryotherapy. (See 'Introduction' above.)

●Technique – EBBT is largely a palliative therapy for the treatment of locally advanced non-small cell lung cancer (NSCLC) involving the airway. Thus, the major goal of EBBT is a reduction in tumor size so that airway symptoms can be relieved. A flexible bronchoscope is typically used to place a radioactive source (usually Iridium-192) within or in close proximity to the target endobronchial lesion (usually malignancy). High dose rate (HDR) EBBT can be performed as an outpatient procedure and is more commonly used than low dose rate EBBT due to shorter treatment times and reduced cost. (See 'Technique' above.)

●Patient selection – HDR EBBT is not a first-line or curative therapy for lung cancer.

•HDR EBBT is usually indicated for the palliative treatment of large obstructing central airway tumors (usually NSCLC) that are amenable to resection and/or external beam radiation. EBBT is typically not a sole therapy in this population and is often combined with bronchoscopic ablative therapies. (See 'Patient selection' above and 'Palliation of central obstructing airway tumors' above.)

•HDR EBBT has also been employed on rare occasions to treat recurrent airway NSCLC, metastatic airway tumors, early NSCLC that is limited to the airway, and nonmalignant tracheal stenosis that has failed conventional therapy. (See 'Patient selection' above and 'Other' above.)

●Contraindications – Contraindications to EBBT include the presence of fistulas between bronchi and other structures and high-grade airway obstruction. In addition, EBBT should not be performed in patients who are moribund or in whom there are contraindications to bronchoscopy in general. (See 'Contraindications' above.)

●Complications – Complications of EBBT are common (up to 40 percent), and typically occur days to weeks after the procedure. They include radiation bronchitis and airway stenosis as well as more worrisome complications including tracheal ulceration, fatal hemoptysis, and fistulous formation with surrounding structures. (See 'Complications' above.)