**3. Brachytherapy of esophageal cancer**

Little is known about the results of the nonsurgical treatment of patients with adenocarcinoma. Based on a retrospective analysis of the results of 276 patients treated with definitive chemoradiotherapy for esophageal adenocarcinoma at the university of texas MD Anderson cancer center [18]. After a median follow-up of 54.3 months, 33.3% of the patients never had a relapse. Local relapse was present in 51% of the patients, and distant dissemination was

There are not enough phase III results in relation to adjuvant chemoradiation. In a retrospective study by Bedard et al. [19], data of 38 patients who had undergone surgery for nodepositive esophageal cancer, had received postoperative adjuvant chemoradiation (concurrent or sequential radiation therapy plus cisplatin and 5-FU ± epirubicin) were compared with data of patients who had undergone surgery only. Both the local control and median survival proved to be better in patients receiving adjuvant treatment, and so did overall survival. In another retrospective analysis [20], benefits of adjuvant chemoradiation were evaluated in 304 patients who had undergone surgery for node-positive esophageal squamous cell cancer. Based on the data, both the 5-year overall survival and the disease control proved significantly better in patients who had also received chemotherapy in addition to radiotherapy. According to a prospective study [21] that evaluated chemoradiation vs. chemotherapy and included 45 patients, neither survival benefit nor improved locoregional control was shown in the chemoradiation treatment arm relative to chemotherapy alone (cisplatin + 5-FU over 5 weeks plus 50

Eight hundred and two patients with either SCC or adenocarcinoma were randomized in the MRC OEO2 study [22]. Patients received either two cycles of cisplatin + 5-FU preoperatively or underwent surgery primarily. The 5-year overall survival was 23 vs. 17% in favor of the neoadjuvant treatment regimen. In Sjoquist's meta-analysis, data of 1981 patients were assessed. Nine neoadjuvant chemotherapies were compared to surgery alone [12]. Chemotherapy reduced mortality in the entire patient population receiving neoadjuvant chemotherapy. It was significant in patients with adenocarcinoma. Based on these, neoadjuvant chemotherapy

It is unclear whether neoadjuvant chemotherapy can be an alternative to neoadjuvant chemoradiation therapy. Stahl et al. [23] enrolled 119 patients with adenocarcinoma involving the lower third portion of the esophagus or the gastroesophageal junction. In one of the arms, patients received 15 weeks of chemotherapy (cisplatin + leucovorin + continuous 5-FU) followed by surgery. In the other arm, 12 weeks of chemotherapy were followed by concurrent chemoradiation therapy (low-dose radiation therapy and concurrent cisplatin + etoposide) over 3 weeks, and surgery was then performed. The ratio of pCR was significantly higher in the arm that included chemoradiation therapy (2 vs. 15.6%). However, there were no significant differences in median survival and the 3-year overall survival between the two treatment arms. Burmeister et al. [24] received similar results when they evaluated 75 patients with adenocarcinoma. Regarding pCR and R1 resection, chemoradiotherapy was significantly more

Gy of irradiation over 5 weeks vs. cisplatin + 5-FU over 5 weeks).

beneficial, but there were no significant differences in median survival.

detected in 43.5% of the patients.

62 Esophageal Abnormalities

*2.1.1. Neoadjuvant chemotherapy*

seems to be superior to surgery alone.

The results in a large cohort of patients indicated that HDR brachytherapy alone was an effective method for the palliation of advanced esophageal cancer [25]. Similar long-term results were reported in favor of treatments involving concurrent chemoradiotherapy followed by HDR brachytherapy [26]. Although brachytherapy was found to be preferable, there are studies (such as Refs. [27, 28]) suggesting the stent placement may play an important role for the palliation of disease. In that case, the prognostic models were used as evidence-based tools in decision making. However, the health-related life quality was reported to be improved in patients treated with the HDR brachytherapy. Recent studies suggested the usage of Californium-252 neutron brachytherapy combined with EBRT for esophageal cancer. The treatment resulted in favorable local control and long-term survival rates with tolerable side effects [29]. Patient selection, timing of brachytherapy and dose specifications were well documented [30–32]. Clinicians continue to urge caution in using brachytherapy treatment techniques since severe toxicity can occur post treatment [15, 26, 30]. Therefore, the addition of brachytherapy, with consequently high surface doses, should be limited to wellselected patients [33].

For that reason, the clinical implementation and accuracy in dose delivery is crucial for favorable treatment outcomes. The radiation dose is delivered using esophageal transoral or transnasal applicators with an external diameter of 0.6–1 cm. Ideally, the single channel applicator needs to be placed centrally in the lumen of the esophagus; however, there exists a possibility that the applicator will be closer to one side of the lumen, delivering a larger dose to the epithelium, lamina propria and muscularis mucosa, resulting in local esophageal complications. In those cases, stricture formation, fistula and esophageal ulceration are the common late toxicities of HDR brachytherapy [34]. A possible difference in the delivered dose is caused by disagreements in the choice of the dose point (i.e. mucosal surface or certain distance from the central line of the applicator) in various institutions, as reported in Ref. [35]. For instance, it was reported in the long-term experience with esophageal brachytherapy treatment [36] that radiation was delivered at a level of 5 mm below the surface of the mucosa. However, no correlation was found between the post-treatment complications and the diameter of the brachytherapy applicator [37]. In most of the HDR brachytherapy treatments, 3D treatment plans were generated using computed tomography (CT) images; however, magnetic resonance imaging (MRI) can be used to assist the localization of the tumor and the applicator [38]. The treatment planning for the esophageal cancer patient is performed using the TG-43 formalism [39], since the dose calculation accuracy of the TPS was confirmed in a homogeneous medium [40].

Overall, this HDR treatment is demonstrated to be well-tolerated and effective for superficial primary and recurrent esophageal cancer in inoperable patients [41, 42]. The authors concluded that dose escalation with larger diameter applicators may allow for improved therapeutic coverage without exceeding the organs ate risk tolerances [43]. The latest research in the combined approach (EBRT and HDR) to palliation in esophageal cancer together with the review of the current techniques is reported in Refs. [44, 45].

#### **3.1. Clinical implementation**

To decrease the dose to the organs at risk in the upper gastrointestinal region a novel disposable brachytherapy transoral balloon centering esophageal applicator (BCEA) with five independently inflatable balloons was developed [44]. The complete treatment process for this applicator consisted of three principal steps: pre-treatment preparation, treatment planning and treatment delivery (**Figure 1**). This applicator allows for the central placement of the radioactive source during treatment. The BCEA allows for the treatments outside the balloon region with the constraint where the BCEA becomes similar to the standard esophageal applicator (EA).

**Figure 1.** The detailed process map of the treatment was developed for improved treatment plan generation and quality assurance of the process.

The experience in the treatment of esophageal cancer using a standard intraluminal esophageal applicator (EA) was summarized in Ref. [45]. Unlike with the transnasal insertion (EA) where the endoscope would be placed via the anesthetized nose past turbinates and nasopharynx behind the larynx and into the esophagus, the BCEA is placed transorally.

#### **3.2. Treatment planning and delivery**

that dose escalation with larger diameter applicators may allow for improved therapeutic coverage without exceeding the organs ate risk tolerances [43]. The latest research in the combined approach (EBRT and HDR) to palliation in esophageal cancer together with the review of the

To decrease the dose to the organs at risk in the upper gastrointestinal region a novel disposable brachytherapy transoral balloon centering esophageal applicator (BCEA) with five independently inflatable balloons was developed [44]. The complete treatment process for this applicator consisted of three principal steps: pre-treatment preparation, treatment planning and treatment delivery (**Figure 1**). This applicator allows for the central placement of the radioactive source during treatment. The BCEA allows for the treatments outside the balloon region with the constraint where the BCEA becomes similar to the standard esophageal applicator (EA).

**Figure 1.** The detailed process map of the treatment was developed for improved treatment plan generation and quality

current techniques is reported in Refs. [44, 45].

**3.1. Clinical implementation**

64 Esophageal Abnormalities

assurance of the process.

The BCEA positions the catheter centrally when the balloons are inflated. Due to that fact, the treatment plan can be additionally optimized (not the case for the standard EA) for improved dose distribution and conformality. The treatment length was defined as a pretreatment tumor length with 1–2 cm distal and proximal margin determined by pretreatment imaging and confirmed by the CT images.

The prescription dose is usually planned to be delivered to the diameter of 1 cm with respect to the central catheter with an additional optimization to avoid the critical anatomical structures such as the heart, lung, pharyngeal constrictor and spine. The dose calculation is performed using the TG-43 formalism that includes the anisotropy corrections. With the standard EA, the dose point is defined at the mucosal surface or a certain distance from the central line of the applicator with identical dwell times along the treatment length. This was mostly done to minimize the uncertainties in dose delivery related to the positioning of the EA inside the esophagus. In standard approach when EA is used the dose optimization outside the balloon region should be avoided due to the complicated position reproducibility. **Figure 2** shows the differences in the treatment plans between the EA and BCEA.

The centrally placed catheter inside the esophagus lumen resulted in enhanced dose distribution and reproducibility in multi fractional treatment (**Figure 2**). The position of the applicator and the balloon diameters can be verified before the treatments using the planning CT images and the CT images obtained prior to each fraction. Three methods can be used to verify the

**Figure 2.** Sagittal images show: (a) the non-optimized plan using the EA and (b) optimized dose distribution achieved with the BCEA.

proper positioning of the BCEA prior to each treatment: (a) using an external marker to verify the length of the catheter in the patient, (b) evaluation of the position of 12 radio-opaque markers on the exterior side of the catheter in the CT images, and (c) measurements of the diameters of the balloons on CT images after inflation to confirm that they were properly inflated.
