British Journal of Radiology (2005) 78, 236-241
© 2005 British Institute of Radiology
doi: 10.1259/bjr/51982166
Daytime pulsed dose rate brachytherapy as a new treatment option for previously irradiated patients with recurrent oesophageal cancer
W Harms, MD
R Krempien, MD
C Grehn, MD
C Berns, Phys
F W Hensley, PhD
and
J Debus, MD, PhD
Department of Radiooncology, University of Heidelberg, INF 400, 69120 Heidelberg, Germany
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Abstract
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The aim of this study was to evaluate the feasibility, effects, and toxicity of pulsed dose rate (PDR) brachytherapy for re-irradiation of oesophageal carcinoma. A total of 16 patients (median age 67 years) with inoperable recurrences from oesophageal cancer after primary radio-(chemo)-therapy (median 50 Gy) were re-irradiated using PDR brachytherapy (192Ir, 37 GBq). Treatment was carried out on an outpatient basis applying a weekly 5 Gy daytime schedule (0.5 Gy pulse–1 h–1, total dose 15–20 Gy). The dose was prescribed 10 mm from the mid-dwell position and encompassed the clipped tumour extension with 2 cm margins. The use of clips for delineation of tumour extent and catheter movement during irradiations was evaluated. All 61 PDR treatments were applied safely. The median catheter movement was 5 mm, range 2–12 mm. After a median follow-up of 8 months, three patients had a complete and five a partial remission. Body weight increased in 5 of 16 (31%) and was stable in 4 of 16 (25%) patients, respectively. The median grade 2 (RTOG/EORTC) dysphagia-free survival was 17 months. Seven patients experienced grade 1, five grade 2, and one grade 3 late toxicity. Three patients with uncontrolled locoregional disease showed grade 4 complications (oesophago-tracheal fistulae (n=2), fatal arterial bleeding (n=1). Daytime PDR brachytherapy proved to be feasible and provided effective palliation. Toxicity remains a major problem. Thus, total dose should be restricted to <15 Gy in this palliative situation.
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Introduction
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Despite the introduction of effective multimodal treatment regimens for oesophageal cancer, locoregional tumour control remains a major problem [1, 2]. The incidence of local recurrence or persistence of cancer as the first site of failure was 45% in the RTOG 85-01 and 39% in the Intergroup 0122 study [3, 4]. The comparable local failure rate with surgery alone was 61% in the Intergroup 0113 study [5]. Additionally, autopsy studies have revealed persistent locoregional disease in more than 75% of patients and visceral metastases in approximately 50% of patients treated either with surgery or radiation [6].
In patients with locoregional recurrences after primary radio-(chemo)-therapy re-irradiation is used only with caution because of the increased probability of normal-tissue complications. In this situation the application of endoluminal brachytherapy may have advantages over external beam radiotherapy (EBRT) since high doses may be applied to the local disease while dose to the spinal cord, lungs and other organs at risk can be spared. In comparison with the commonly used HDR (high dose rate) technique, which represents the gold standard for endoluminal brachytherapy in oesophageal cancer, PDR (pulsed dose rate) brachytherapy with its protracted irradiation schedule offers a potentially wider therapeutic ratio and may therefore reduce toxicity in previously irradiated patients [7–10].
The aim of this study was to introduce daytime PDR brachytherapy in the management of previously irradiated recurrent oesophageal carcinoma and to evaluate its feasibility, effects, and toxicity. Secondly, the routine use of surgical clips for delineating the tumour extent was assessed. Thirdly, catheter movement in the proximal and distal direction during prolonged irradiations was monitored.
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Materials and methods
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Patients
From April 2001 to January 2003, a total of 16 patients (median age 67 years, range 52–79 years) with inoperable recurrences from oesophageal cancer were treated at the Department of Radiooncology of the University of Heidelberg, Germany. Seven patients had previously been treated by definitive external beam radiotherapy and nine by combined radiochemotherapy. The median applied dose was 50 Gy, range 46–60 Gy. Time to recurrence was 15 months, range 4–37 months). All recurrences were proven by histology (n=12 squamous cell carcinoma, n=4 adenocarcinoma). Four patients presented with isolated local recurrences and 12 of 16 with locoregional recurrences. Six of 16 patients had concurrent distant metastasis.
Treatment policy
The staging procedure before the initiation of PDR brachytherapy included abdominal ultrasound, a chest CT, and oesophago-gastroscopy. The chest CT was extended to the upper abdomen to rule out lymph node and liver metastases. All patients were evaluated by an experienced surgeon and deemed inoperable due to the extent of the recurrence or presence of co-morbidities. The indication for re-irradiation was clinically significant dysphagia and a Karnofsky Index >60%. Only patients with good performance status were eligible since each weekly outpatient treatment lasted 10 h per 5 Gy fraction. Patients with lower clinical performance status, involvement of the tracheo-bronchial tree, or reduced life-expectancy were referred for palliative stent placement or chemotherapy. All patients were treated solely with endoluminal PDR brachytherapy. The standard treatment schedule consisted of four fractions of PDR brachytherapy 1 week apart with 5 Gy per fraction. Since reasonable clinical data on re-irradiation for oesophageal cancer is scarce and little is known about toxicity we used lower doses for smaller tumours. Thus, in three patients with small recurrences the total dose was limited to 15 Gy (Table 1
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Table 1. Treatment parameters and results. Brachytherapy (BT) treatment schedule and clinical outcome (CR complete remission, PR partial remission, SD stable disease, PD progressive disease) on last day of follow-up (FU). Body weight was monitored during follow-up and classified as gain + (>+2 kg), no change ± (±2 kg), and loss – (>–2 kg)
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Brachytherapy
In all patients an oesophageal endoscopy was performed before starting brachytherapy in order to mark the upper and lower extension of the visible tumour with surgical clips. This approach was chosen to delineate precisely the tumour extent at the time of brachytherapy. The intention was to keep the brachytherapy volumes as small as possible so as to reduce toxicity. A chest X-ray was performed immediately after clip placement to document the position of the radiopaque markers (Figure 1). For subsequent insertions bony landmarks defined after the first treatment were used for definition of the planning target volume.
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Figure 1. This image shows the oesophageal brachytherapy catheter containing a ribbon of dummy seeds. Two surgical clips (arrows) delineate the cranial and caudal extent of the oesophageal recurrence.
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The catheter was placed via the oral (catheter diameter >8 mm) or nasal route (diameter 
8 mm) by the radiation oncologist. The procedure was performed after simple local anaesthesia with xylocaine spray and mild sedation with 1–2 mg midazolam intravenously. A self-made catheter consisting of two single hollow tubes (outer tube: oesophageal tube, Rüsch GmbH, Kernen-Rommelshausen, Germany; inner tube: duodenal tube, B. Braun Melsungen AG, Melsungen, Germany), which were placed within each other, was used for endoluminal irradiation. This approach ensured the central positioning of the 6 Fr brachytherapy catheter (Nucletron, Veenendaal, The Netherlands) within the oesophageal applicator (Figure 2). The applicators had an outer diameter ranging from 6 mm to 10 mm. The final position of the catheter loaded with a ribbon of dummy seeds was controlled by fluoroscopy.
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Figure 2. Schematic drawing of the oesophageal applicator: a self-made catheter consisting of two single hollow tubes (outer tube: oesophageal tube, Rüsch GmbH, Kernen-Rommelshausen, Germany; inner tube: duodenal tube, B. Braun Melsungen AG, Melsungen, Germany), which were stuck into each other, was used for endoluminal irradiation. This approach ensured central positioning of the 6 Fr brachytherapy catheter (Nucletron, Veenendaal, The Netherlands) within the oesophageal applicator. The applicators had outer diameters ranging from 6 mm to 10 mm.
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A PDR afterloading machine (microSelectron; Nucletron, Veenendaal, The Netherlands) with a single stepping source (192Iridium, 37 GBq) was used for brachytherapy. Centre-to-centre separations of the dwell positions were 5 mm. A standard dose of 5 Gy was applied weekly with 0.5 Gy per pulse per hour. The brachytherapy dose was prescribed to 10 mm off axis at mid-dwell position without computerized optimization [9]. The active length encompassed the clipped tumour extension with a 2 cm proximal and distal margin. This schedule resulted in total treatment times of approximately 10 h and was administered on an outpatient basis. A single PDR pulse given every hour lasted only a couple of minutes. In between the hourly pulses the patients were disconnected from the afterloading device. All patients had intravenous access for hydration and needed continuous suction of saliva since, owing to the inserted catheter, swallowing was impossible. After initial sedation with midazolam no further sedation was required during treatment.
Evaluation of catheter movement
Since the PDR schedule resulted in prolonged irradiation times catheter movement was assessed during irradiations in all patients. For this purpose the location of the catheter was documented twice during pulsed brachytherapy by repeated simulations. The variation of catheter localization was expressed as movement of the mid-dwell position in cranial or caudal direction in millimetres when compared with the initial simulation film. The bony structures of the thoracic vertebrae served as a reference.
Follow-up program
All patients were followed up at 6 weekly intervals up to 3 months, and 3 monthly thereafter. At the time of presentation physical examination, barium swallow, and chest CT (including the upper abdomen) were performed. Routine endoscopy was performed 6 weeks after completing of brachytherapy. Thereafter, we performed endoscopy every 3 months. Acute and late effects on the oesophagus and the mucosa were assessed according to the RTOG/EORTC toxicity criteria [11]. Changes in body weight were observed during follow-up and classified as gain (>+2 kg), no change (±2 kg), and loss (<–2 kg). The median follow-up for all patients was 8 months (range 4–19 months).
Statistical evaluation
Overall survival time was defined as the time from the beginning of PDR brachytherapy to the death of the patient [12]. Partial remission (PR) was defined as a 
ge;50% reduction of tumour extent evaluated by endoscopy, barium oesophagography and CT during follow-up. Complete remission (CR) and progressive disease (PD) were respectively defined as: no evidence of local tumour; and further tumour growth of more than 25%. No change (NC) was defined either as a < 50% reduction of tumour extent or progression 25%.
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Results
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Clip placement, catheter movement
We observed no complications related to the placement of either the clips or the brachytherapy catheters. Marking the extent of the tumour with clips improved definition of the planning target volume. The clips are loosely adherent to the oesophageal mucosa. Therefore an X-ray should be taken immediately after endoscopy or at least before any oral intake to document the localization of the surgical clips. The median catheter movement in the proximal or distal direction, when compared with the initial simulation films was 5 mm and ranged from 2 mm to 12 mm.
Feasibility of PDR brachytherapy
All 61 PDR brachytherapy treatments were feasible. The treatment courses were applied safely and no complications occurred during protracted irradiations. The daytime PDR brachytherapy schedule was tolerated well by 12 of 16 patients, while the remaining 4 patients complained about the prolonged irradiation time.
Clinical outcome
The median overall survival was 8 months, range 4–19 months. At final analysis 10 of 16 patients were alive. One patient died 5 months after the initiation of brachytherapy from a cardiac arrest. The other five patients died from systemic progression (n=2) or locoregional progression with oesophago-tracheal fistulae (n=2). One patient suffered a fatal arterial bleed.
The response rate on the last day of follow-up was 50% (see Table 1
). Persisting local control with a follow up ranging from 12 months to 19 months was observed in three patients who presented with relatively small local recurrences. The median actuarial grade 2 dysphagia-free survival was 17 months (Figure 3). Body weight was improved in 5 of 16 (31%) and stable in 4 of 16 (25%) patients, respectively.
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Figure 3. Grade 2 (RTOG/EORTC) dysphagia-free survival after daytime pulsed dose rate (PDR) brachytherapy for re-irradiation of patients with recurrent oesophageal cancer. The endpoint of this analysis was the occurrence of grade 2 dysphagia (unable to take solid food normally, swallowing semi-solid food, dilatation may be indicated) during follow-up.
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Toxicity (RTOG/EORTC)
In terms of acute toxicity, the majority of patients (12 of 16) experienced mild dysphagia (grade 1) while 3 patients showed grade 2 (moderate dysphagia) and 1 grade 3 (severe dysphagia) dysphagia. We evaluated oesophageal late effects since 13 of 16 patients were followed ge;6 months. On the last day of follow-up seven patients had slight difficulties in swallowing solids (grade 1), five patients were unable to take solid food normally (grade 2), and one patient was able to swallow only liquids (grade 3). Three patients suffering from uncontrolled locoregional disease presented with grade 4 complications. One patient died due to a fatal arterial bleed 6 months after the initiation of brachytherapy while two patients presented with oesophago-tracheal fistulae 4 and 7 months after treatment, respectively. All patients suffering from grade 3/4 toxicity (EORTC/RTOG [11]) were treated with a total dose of 20 Gy (Table 1).
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Discussion
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Treatment of recurrent oesophageal cancer after primary radio-(chemo)-therapy is difficult and no general therapeutic rules are available. Possible treatment options include stent placement, feeding gastrostomy, photodynamic therapy, chemotherapy, radiotherapy and palliative resection [13–17]. Brachytherapy, in comparison with EBRT, offers rapid decrease in the extent of endoluminal tumour thus rapidly improving swallowing whilst delivering relatively low doses to the surrounding normal tissues, particularly spinal cord, lung and adjacent normal oesophageal mucosa [18]. Several studies have shown that HDR brachytherapy is effective in the curative or palliative treatment of oesophageal cancer [19].
For the following reasons, we introduced a daytime PDR brachytherapy treatment schedule for endoluminal re-irradiation of recurrent oesophageal cancer. PDR brachytherapy combines the technical advantages of HDR (single stepping source, dose optimization) with the radiobiological advantages of continuous low dose rate (CLDR) brachytherapy. Thus, PDR offers, owing to its protracted irradiation schedule, a potentially wider therapeutic ratio than HDR and this may reduce toxicity [7, 8]. This applies especially to patients presenting with recurrences after full courses of previous radio-(chemo)-therapy. In comparison with CLDR brachytherapy, PDR offers flexible fractionation, and a more straightforward technical approach: a single stepping source replaces multiple line sources and advanced treatment planning (optimization, 3D treatment planning) is possible [20]. The 10 h daytime treatment schedule we used was feasible and acceptable to most of our patients. We are aware that the prolonged treatment time is a major disadvantage of the proposed method, but protracted irradiation was the only way to improve the therapeutic index of re-irradiation.
If we are using a prolonged treatment time and tailoring the treated length exactly to the endoscopical findings we need to know the extent of catheter movement during the treatment course. The comparison of repeated simulations revealed a relatively small median catheter movement of 5 mm (range 2–12 mm) during irradiations. Thus, applying 2 cm margins in each direction seems to be a reasonable compromise between the intended small treatment volumes and catheter movement. Since it is necessary to pass a scope through the tumour this technique is restricted to patients presenting with recurrences that do not completely obstruct the oesophageal lumen. In our experience this is true for most patients presenting with oesophageal recurrences after primary radiochemotherapy. In this study we encountered no problems in placing clips on the endoscopically visible tumour.
Since a theoretical basis for estimating equivalence of CLDR to PDR brachytherapy [7, 8] was not described until 1991, relevant clinical data on PDR brachytherapy is scarce. So far no studies have been published applying PDR brachytherapy in patients with recurrent oesophageal cancer. In the current study the median overall survival was 8 months. Treatment response was 50% and body weight was improved in 31% and stable in 25% of the patients, respectively. The median actuarial grade 2 (RTOG/EORTC) dysphagia-free survival was 17 months. These data are comparable with the published series applying HDR brachytherapy for palliation [14, 18, 19]. Small recurrences treated with a total dose of 15 Gy had reasonable survival rates indicating that this dosage may be a good compromise between treatment response and toxicity.
Sharma et al [18] retreated 15 patients with recurrent oesophageal cancer after a previous course of radiotherapy with two 6 Gy fractions of HDR brachytherapy. The authors observed strictures in 4 of 15 patients and ulcerations in 3 of 15 patients and concluded that toxicity remains a major concern in previously irradiated patients. Yu et al [14] published the largest re-irradiation series in the literature and reported on 81 patients with recurrent oesophageal carcinoma after primary radiotherapy. 21 patients failed to complete re-irradiation due to deterioration in general health (n=9) or major complications (oesophageal perforation n=8, fatal haemorrhage n=4). These findings are supported by our data. Three patients (19%) presented with grade 4 complications (oesophago-tracheal fistulae (n=2) or fatal arterial bleed (n=1). All these patients suffered from uncontrolled locoregional disease. Thus, it remains unclear whether grade 4 toxicity is truly treatment-related or due to progressive disease. We are aware that with the limited follow-up the true late toxicity rate may not be completely assessed. Conversely, the median overall survival of our patients is consistent with that reported in the literature: 6–8 months [14, 19]. Our data, with a median follow-up of 8 months, may give a reasonable estimate of the potential late effects of oesophageal re-irradiation using PDR brachytherapy in this particular selected group. Nevertheless, toxicity remains a major problem in previously irradiated patients and reduction of toxicity needs to be addressed in further studies. All patients who experienced grade III/IV toxicity had been treated with a total dose of 20 Gy. Thus, total dose should be restricted to 15 Gy in this palliative situation. Although we have reported on only small patient numbers this is supported by the fact that in the 15 Gy group no major toxicity occurred and reasonable survival times have been achieved.
In conclusion, daytime PDR brachytherapy proved feasible and provided effective palliation in previously irradiated patients with recurrent oesophageal cancer. Since toxicity remains a major problem the applied dose should be restricted to 15 Gy in this context. Taking into account the heterogeneity in this patient population it is important to offer each patient individualized treatment options.
Received for publication April 1, 2004.
Revision received September 6, 2004.
Accepted for publication November 15, 2004.
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Abstract
Introduction
