Dose-dependent differential effects of low and pulsed dose-rate brachytherapy in a radioresistant syngenic rat prostate tumour model

Purpose : To study the response of the Dunning prostate carcinoma (R3327-AT1 subline) to continuous low dose-rate (CLDR) and pulsed dose-rate (PDR) brachytherapy. Materials and methods : After subcutaneous tumour transplantation into the thigh of the Copenhagen rat, doses of 0, 20, 30, 40 and 50 Gy were applied to the tumour surface (tumour diameter 9 ±1mm). Eight animals were irradiated per dose group and exposure condition. Interstitial PDR (192 Ir source, 37 GBq) and CLDR (192 Ir seed, 150 MBq) brachytherapy were carried out with 0.75 Gy/pulse h -1 and a dose-rate of 0.75Gyh -1, respectively. Treatment response was assessed in terms of growth delay expressed as the time (T 5) required for each tumour to reach five times the initial tumour volume. Results : The median T 5 times for the CLDR groups (in the order: control, 20, 30, 40, 50 Gy) were 12 (12), 54.5 (21), 64.5 (31), 85.5 (51), and 65 (47.5) days. Values after PDR brachytherapy are given in parentheses and resulted in a significantly impaired tumour growth delay (log-rank test) in the 20Gy (p =0.006) and 30 Gy (p =0.036) groups. No significant difference was found in the 40-50 Gy dose range. Conclusions : In contrast to previous results and predictions of biological models we observed dose-dependent differential effects of PDR and CLDR brachytherapy with reduced efficacy of PDR in the lower dose range.     

Differential effects of CLDR and PDR brachytherapy on cell cycle progression in a syngeneic rat prostate tumour model

PURPOSE: The study consisted of two treatment arms comparing the effects of CLDR (continuous low dose rate) and PDR (pulsed dose rate) brachytherapy on cell cycle progression in a radioresistant rat prostate tumour model. MATERIALS AND METHODS: Interstitial PDR and CLDR brachytherapy (both 192-Ir, 0.75 Gy/h) were administered to Dunning prostate R3327-AT1 carcinomas transplanted subcutaneously into the thigh of Copenhagen rats. Increasing doses of up to 20 as well as up to 40 Gy were applied. Cell cycle distributions of the aneuploid tumour cell subpopulations were determined at 4 h (3 Gy), 24 h (18 Gy), 48 h (20 and 36 Gy), as well as during the subsequent redistribution period (20 and 40 Gy) at 72, 96, and 120 h. Tumours either implemented with an empty tubing system (n=5) or under undisturbed growth (n=5) served as controls. Three animals were irradiated per time point and exposure condition. At least two flow cytometrical analyses were carried out per animal. RESULTS: The aneuploid cells possessed a constant DNA-Index of 1.9+/-0.06. In contrast to sham-treated controls, the aneuploid cell fraction with G2/M DNA content was significantly increased (p<0.05) after initiation of both, CLDR and PDR brachytherapy. However, CLDR resulted in an earlier accumulation of tumour cells in G2/M (24 h: 28% CLDR vs. 19% PDR, p<0.05) with a concomitant reduction of cells in G1, whereas PDR yielded delayed, but then more pronounced cell cycle changes, particularly expressed during the redistribution period after both 20 and 40 Gy. CONCLUSION: CLDR and PDR brachytherapy showed differential effects on cell cycle progression. The induction of a significantly earlier but also less persistent G2/M cell cycle arrest after CLDR compared to PDR brachytherapy implies that a substantially higher fraction of tumour cells are irradiated in G2/M after CLDR.     

Differential effects of CLDR and PDR brachytherapy on cell cycle progression in a syngeneic rat prostate tumour model

Purpose: The study consisted of two treatment arms comparing the effects of CLDR (continuous low dose rate) and PDR (pulsed dose rate) brachytherapy on cell cycle progression in a radioresistant rat prostate tumour model.

Materials and methods: Interstitial PDR and CLDR brachytherapy (both 192-Ir, 0.75 Gy/h) were administered to Dunning prostate R3327-AT1 carcinomas transplanted subcutaneously into the thigh of Copenhagen rats. Increasing doses of up to 20 as well as up to 40 Gy were applied. Cell cycle distributions of the aneuploid tumour cell subpopulations were determined at 4 h (3 Gy), 24 h (18 Gy), 48 h (20 and 36 Gy), as well as during the subsequent redistribution period (20 and 40 Gy) at 72, 96, and 120 h. Tumours either implemented with an empty tubing system (n = 5) or under undisturbed growth (n = 5) served as controls. Three animals were irradiated per time point and exposure condition. At least two flow cytometrical analyses were carried out per animal.

Results: The aneuploid cells possessed a constant DNA-Index of 1.9 ± 0.06. In contrast to sham-treated controls, the aneuploid cell fraction with G2/M DNA content was significantly increased (p < 0.05) after initiation of both, CLDR and PDR brachytherapy. However, CLDR resulted in an earlier accumulation of tumour cells in G2/M (24 h: 28% CLDR vs. 19% PDR, p < 0.05) with a concomitant reduction of cells in G1, whereas PDR yielded delayed, but then more pronounced cell cycle changes, particularly expressed during the redistribution period after both 20 and 40 Gy.

Conclusion: CLDR and PDR brachytherapy showed differential effects on cell cycle progression. The induction of a significantly earlier but also less persistent G2/M cell cycle arrest after CLDR compared to PDR brachytherapy implies that a substantially higher fraction of tumour cells are irradiated in G2/M after CLDR.     

5-Year Results of Pulsed Dose Rate Brachytherapy Applied as a Boost after Breast-Conserving Therapy in Patients at High Risk for Local Recurrence from Breast Cancer

PURPOSE: The aim of this study was to evaluate effect, toxicity, and cosmesis of a prospectively applied pulsed dose rate (PDR) brachytherapy boost schedule in patients with stage I/II/IIIa invasive breast cancer. PATIENTS AND METHODS: A total of 113 patients were treated after breast-conserving surgery (BCS) and external beam radiotherapy (median 50 Gy, range 46-52). The boost dose was graded in accordance to the pathologic tumor characteristics: 20-25 Gy: incomplete resection (n = 34), vascular invasion (n = 27), close margin resection (n = 41); 15 Gy: T2G3 stage (n = 11). PDR brachytherapy (37 GBq, (192)Ir source) was carried out after geometric volume optimization with 1 Gy/pulse/h. The implantation and dose specification were performed similar to the rules of the Paris system. RESULTS: The overall local failure rate after a median follow-up of 61 months was 4.4% (5/113). The actuarial 5- and 8-year local recurrence-free survival rates were 95% and 93%, respectively. Cosmesis was rated by 90% of the patients as excellent or good. 14/113 patients experienced grade III (all caused by planar telangiectasia) and none of the patients grade IV late toxicity of the skin (RTOG/EORTC). A boost dose of 25 Gy resulted in a significantly higher rate of late toxicity (Fisher's exact test, p < 0.01). CONCLUSIONS: PDR brachytherapy is safe, effective, and provides good cosmesis. A CLDR breast boost can be replaced by PDR brachytherapy without significant loss of therapeutic ratio.     

Daytime pulsed dose rate brachytherapy as a new treatment option for previously irradiated patients with recurrent oesophageal cancer

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 ((192)Ir, 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.     

Retrospective dosimetric comparison of low-dose-rate and pulsed-dose-rate intracavitary brachytherapy using a tandem and mini-ovoids.

The purpose of this study was to compare the dose distribution of Iridium-192 ((192)Ir) pulsed-dose-rate (PDR) brachytherapy to that of Cesium-137 ((137)Cs) low-dose-rate (LDR) brachytherapy around mini-ovoids and an intrauterine tandem. Ten patient treatment plans were selected from our clinical database, all of which used mini-ovoids and an intrauterine tandem. A commercial treatment planning system using AAPM TG43 formalism was used to calculate the dose in water for both the (137)Cs and (192)Ir sources. For equivalent system loadings, we compared the dose distributions in relevant clinical planes, points A and B, and to the ICRU bladder and rectal reference points. The mean PDR doses to points A and B were 3% +/- 1% and 6% +/- 1% higher than the LDR doses, respectively. For the rectum point, the PDR dose was 4% +/- 3% lower than the LDR dose, mainly because of the (192)Ir PDR source anisotropy. For the bladder point, the PDR dose was 1% +/- 4% higher than the LDR dose. We conclude that the PDR and LDR dose distributions are equivalent for intracavitary brachytherapy with a tandem and mini-ovoids. These findings will aid in the transfer from the current practice of LDR intracavitary brachytherapy to PDR for the treatment of gynecologic cancers.     

5-Year Results of Pulsed Dose Rate Brachytherapy Applied as a Boost after Breast-Conserving Therapy in Patients at High Risk for Local Recurrence from Breast Cancer

Purpose: The aim of this study was to evaluate effect, toxicity, and cosmesis of a prospectively applied pulsed dose rate (PDR) brachytherapy boost schedule in patients with stage I/II/IIIa invasive breast cancer. Patients and Methods: A total of 113 patients were treated after breast-conserving surgery (BCS) and external beam radiotherapy (median 50 Gy, range 46-52). The boost dose was graded in accordance to the pathologic tumor characteristics: 20-25 Gy: incomplete resection (n = 34), vascular invasion (n = 27), close margin resection (n = 41); 15 Gy: T2G3 stage (n = 11). PDR brachytherapy (37 GBq, ¹⁹²Ir source) was carried out after geometric volume optimization with 1 Gy/pulse/h. The implantation and dose specification were performed similar to the rules of the Paris system. Results: The overall local failure rate after a median follow-up of 61 months was 4.4% (5/113). The actuarial 5- and 8-year local recurrence-free survival rates were 95% and 93%, respectively. Cosmesis was rated by 90% of the patients as excellent or good. 14/113 patients experienced grade III (all caused by planar telangiectasia) and none of the patients grade IV late toxicity of the skin (RTOG/EORTC). A boost dose of 25 Gy resulted in a significantly higher rate of late toxicity (Fisher's exact test, p < 0.01). Conclusions: PDR brachytherapy is safe, effective, and provides good cosmesis. A CLDR breast boost can be replaced by PDR brachytherapy without significant loss of therapeutic ratio. Ziel: Diese Studie diente der Evaluierung von Effektivität, Toxizität und kosmetischen Ergebnissen eines prospektiv applizierten PDR- (pulsed dose-rate-)Brachytherapieboostkonzeptes bei Patienten mit invasivem Mammakarzinom im Stadium I/II/IIIa. Patienten und Methoden: Insgesamt wurden 113 Patienten nach brusterhaltender Therapie (BET) und externer Bestrahlung (Median 50 Gy, Range 46-52) behandelt. Die Boostdosis wurde anhand histopathologischer Tumorcharakteristika graduiert (Tabelle 1): 20-25 Gy: inkomplette Resektion (n = 34), Lymphgefäß- oder Gefäßinvasion (n = 27), "close-margin"-Resektion (n = 41); 15 Gy: T2G3 Stadium (n = 11). Die gepulste Brachytherapie (37 GBq, ¹⁹²Ir-Quelle) wurde nach geometrischer Volumenoptimierung mit 1 Gy/Puls/h durchgeführt. Applikation und Dosisspezifikation erfolgten in Anlehnung an das Pariser System. Ergebnisse: Die Lokalrezidivrate betrug nach einer medianen Nachbeobachtungszeit von 61 Monaten 4,4% (5/113). Das aktuarische lokalrezidivfreie 5- und 8-Jahres-Überleben betrug 95% bzw. 93% (Abbildungen 1 und 2). 90% der Patienten beurteilten ihre kosmetischen Ergebnisse als gut oder exzellent (Tablle 3). Bedingt durch flächige Teleangiektasien im Boostareal entwickelten 14/113 Patienten eine Grad-III-Spättoxizität (0/113 Grad IV) der haut (RTOG/EORTC, Tabelle 2). Eine Boostdosis von 25 Gy resultierte in einer signifikant erhöhten Spättoxizitätsrate (Fishers Exakt-Test, p < 0,01, Abbildung 3). Schlussfolgerung: Die gepulste Brachytherapie ist sicher und effektiv. Die kosmetischen Ergebnisse sind gut. Der interstitielle CLDR-Mammaboost kann durch die PDR-Brachytherapie ohne signifikanten Verlust an therapeutischer Breite ersetzt werden.     

In-vitro-Untersuchungen zur PDR-Brachytherapie

Background

Calculations on the basis on the LQ-model have been focussed on the possible radiobiological equivalence between common continuous low dose rate irradiation (CLDR) and a superfractionated irradiation (PDR=pulsed dose rate) provided that the same total dose will be prescribed in the same overall time as with the low doserate. A clinically usable fractionation scheme for brachytherapy was recommended by Brenner and Hall and should replace the classical CLDR brachytherapy with line sources with an afterloading technique using a stepping source. The hypothesis that LDR equivalency can be achieved by superfractionation was tested by means of in vitro experiments on V79 cells in monolayer and spheroid cultures as well as on HeLa monolayers.

Materials and Methods

Simulating the clinical situation in PDR brachytherapy, fractionation experiments were carried out in the dose rate gradient of afterloading sources. Different dose levels were produced with the same number of fractions in the same overall incubation time. The fractionation schedules which were to be compared with a CLDR reference curve were: 40×0.47 Gy, 20×0.94 Gy, 10×1.88 Gy, 5×3.76 Gy, 2×9.4 Gy given in a period of 20 h and 1×18.8 Gy as a “single dose” exposition. As measured by flow cytometry, the influence of the dose rate in the pulse on cell survival and on cell cycle distribution under superfractionation was examined on V79 cells.

Results

V79 spheroids as a model for a slowly growing tumor, reacted according to the radiobiological calculations, as a CLDR equivalency was achieved with increasing fractionation. Rapidly growing V79 monolayer cells showed an inverse fractionation effect. A superfractionated irradiation with pulses of 0.94 Gy/h respectively 0.47 Gy/0.5 h was significantly more effective than the CLDR irradiation. This inverse fractionation effect in log-phase V79 cells could be attributed to the accumulation of cycling cells in the radiosensitive G2/M phase (G2 block) during protected exposure which was drastically more pronounced for the pulsed scheme. HeLa cells were rather insensitive to changes of fractionation. Superfractionation as well as hypofractionation yielded CLDR equivalent survival curves.

Conclusions

The fractionation scheme, derived from the PDR theory to achieve CLDR equivalent effects, is valid for many cell lines, however not for all. Proliferation and dose rate dependend cell cycle effects modify predictions derived from the sublethal damage recovery model and can influence acute irradiation effects significantly. Dose rate sensitivity and rapid proliferation favour cell cycle effects and substantiate, applied to the clinical situation, the possibility of a higher effectiveness of the pulsed irradiation on rapidly growing tumors.     

CT-Guided Interstitial Brachytherapy of Primary and Secondary Lung Malignancies

BACKGROUND AND PURPOSE: CT-guided interstitial brachytherapy of primary lung malignancies and pulmonary metastases represents a novel interventional technique, combining conventional high-dose-rate (HDR) iridium-192 ((192)Ir) brachytherapy with modern CT guidance for applicator positioning and computer-aided 3-D radiation treatment planning. The purpose of this study was to assess safety and efficacy of this technique. PATIENTS AND METHODS: 30 patients with 83 primary or secondary lung malignancies were recruited in a prospective nonrandomized trial (Table 1). After catheter positioning under CT fluoroscopy, a spiral CT was acquired for treatment planning (Figure 1). All but two patients received a defined single dose (coverage > 99%) of at least 20 Gy from a (192)Ir source in HDR technique. RESULTS: Adverse effects were nausea (n = 3, 6%), minor (n = 6, 12%) and one major pneumothorax (2%). Post intervention, no changes of vital capacity and forced expiratory volume could be detected. The median follow-up period was 9 months (1-21 months) with a local tumor control of 91% at 12 months (Figure 2). CONCLUSION: CT-guided interstitial brachytherapy proved to be safe and effective for the treatment of primary and secondary lung malignancies.     

Locally recurrent breast cancer: pulse dose rate brachytherapy for repeat irradiation following lumpectomy-- a second chance to preserve the breast

PURPOSE: To perform and assess the effectiveness of local excision of recurrent tumor followed by postoperative pulse dose rate (PDR) brachytherapy. MATERIALS AND METHODS: From 1994 to 2000, 17 patients who had small recurrent breast carcinomas after initially undergoing breast-conserving therapy (BCT), which included postoperative radiation therapy, were treated with local tumor excision and PDR brachytherapy. Recurrences occurred at a median time of 50 months (range, 11-208 months) after primary treatment. Eight patients underwent a combination of PDR brachytherapy (total dose range, 12.5-28.0 Gy) and external-beam radiation therapy (EBT) (total dose range, 12-30 Gy). Nine patients underwent radiation therapy with 40.2-50.0-Gy PDR brachytherapy only. The prescribed radiation dose was 0.5-1.0 Gy per pulse. Patients were examined for local tumor control and treatment-related side effects. RESULTS: Twelve of 17 patients had no local tumor at a median follow-up time of 59 months (range, 20-84 months); two of these patients showed signs of having distant disease. One patient died after a cerebral stroke without evidence of tumor. Four women treated with combined EBT and brachytherapy had secondary local tumor recurrences 4, 8, 8, and 11 months after therapy and had to undergo mastectomy. Despite having undergone radiation therapy previously, patients had side effects limited to moderate (grade 1-2) fibrosis. CONCLUSION: Local tumor excision combined with PDR brachytherapy for small local-regional tumor recurrences after primary BCT is feasible and well tolerated and might obviate mastectomy. Preliminary experiences are encouraging. Further studies are required for appropriate patient selection.     

Single dose irradiation response of pig skin: a comparison of brachytherapy using a single, high dose rate iridium-192 stepping source with 200 kV X-rays

An experimental brachytherapy model has been developed to study acute and late normal tissue reactions as a tool to examine the effects of clinically relevant multifractionation schedules. Pig skin was used as a model since its morphology, structure, cell kinetics and radiation-induced responses are similar to human skin. Brachytherapy was performed using a microSelectron high dose rate (HDR) afterloading machine with a single stepping source and a custom-made template. In this study the acute epidermal reactions of erythema and moist desquamation and the late dermal reactions of dusky mauve erythema and necrosis were evaluated after single doses of irradiation over a follow-up period of 16 weeks. The major aims of this work were: (a) to compare the effects of iridium-192 (192Ir) irradiation with effects after X-irradiation; (b) to compare the skin reactions in Yorkshire and Large White pigs; and (c) to standardize the methodology. For 192Ir irradiation with 100% isodose at the skin surface, the 95% isodose was estimated at the basal membrane, while the 80% isodose covered the dermal fat layers. After HDR 192Ir irradiation of Yorkshire pig skin the ED50 values (95% isodose) for moderate/severe erythema and moist desquamation were 24.8 Gy and 31.9 Gy, respectively. The associated mean latent period (+/- SD) was 39 +/- 7 days for both skin reactions. Late skin responses of dusky mauve erythema and dermal necrosis were characterized by ED50 values (80% isodose) of 16.3 Gy and 19.5 Gy, with latent periods of 58 +/- 7 days and 76 +/- 12 days, respectively. After X-irradiation, the incidence of the various skin reactions and their latent periods were similar. Acute and late reactions were well separated in time. The occurrence of skin reactions and the incidence of effects were comparable in Yorkshire and Large White pigs for both X-irradiation and HDR 192Ir brachytherapy. This pig skin model is feasible for future studies on clinically relevant multifractionation schedules in a brachytherapy setting.     

CT-Guided Interstitial HDR Brachytherapy for Recurrent Glioblastoma Multiforme

BACKGROUND AND PURPOSE: Recurrences of glioblastoma multiforme (GBM) within previously irradiated volumes pose a serious therapeutic challenge. This retrospective study evaluates the long-term tumor control of recurrent GBM treated with interstitial high-dose-rate brachytherapy (HDR-BRT). PATIENTS AND METHODS: Between 1995 and 2003, 84 patients were treated for recurrent cerebral GBM located within previously irradiated volumes. All patients had received adjuvant external radiotherapy following primary surgery, with a focal dose up to 60 Gy. The median recurrent tumor volume was 51 cm(3) (3-207 cm(3)), and the HDR-BRT consisted of an afterloading (192)Ir implant which delivered a median dose of 40 Gy (30-50 Gy). Catheter implantation was implemented using interactive computed tomography (CT) guidance under local anesthesia and sedoanalgesia. RESULTS: After a median follow-up of 61 months, 5/84 patients (6%) were alive. The median post-BRT survival was 37 weeks, and the median overall survival 78 weeks. Moderate to severe complications occurred in 5/84 cases (6%). CONCLUSION: For patients with recurrences of GBM within previously irradiated volumes, CT-guided interstitial HDR-BRT is a feasible treatment option that can play an important role in providing palliation.     

Long-term results of pulsed irradiation of skin metastases from breast cancer. Effectiveness and sequelae.

PURPOSE: The concept of pulsed brachytherapy suggested by Brenner and Hall requires an unusual fractionation scheme. Effectiveness and sequelae of this new irradiation method were observed in patients with disseminated cutaneous metastases of breast cancer. PATIENTS AND METHODS: A flexible, reusable skin mold (weight 110 g) was developed for use with a pulsed dose rate (PDR) afterloader. An array of 18 parallel catheters (2 mm diameter) at equal distances of 10 or 12 mm was constructed by fixation of the catheters in a plastic wire mesh. The array is sewn between 2 foam rubber slabs of 5 mm thickness to provide a defined constant distance to the skin. Irradiations are possible up to a maximum field size of 20 x 23.5 cm using a nominal 37 GBq Ir-192 source. Pulses of 1 Gy reference dose at the skin surface are applied at a rate of 1 pulse every 1.2 hours (0.8 Gy per hour). The dose distribution is geometrically optimized to provide a homogeneous skin dose (100% +/- 10%). The 80% dose level lies at 5 mm below the skin surface. Between April 1994 and December 1997, 52 patients suffering from cutaneous metastases at the thoracic wall were treated with 54 fields and total doses of 38 to 50 Gy (median 42 Gy) applying 2 PDR courses with a pause of 4 to 5 weeks. RESULTS: Forty-six patients (48 fields) were eligible for evaluation in June 1998. The median follow-up was 16 months (range 7.1 to 46.2 months). Local control was achieved in 40 out of 48 fields (83%) or 41 of 46 patients (89%), respectively. Moist desquamation occurred in 52% of the patients. Late reactions were judged after a minimum follow-up of 6 months. Thirty-two fields had been previously irradiated with external beam therapy to doses of 40 to 60 Gy. Regardless of whether the skin was preirradiated or not all patients surviving long enough developed telangiectasia within 2 years after PDR irradiation. In preirradiated patients (n = 32) skin contractures and/or skin necrosis occurred in 12% each. In newly irradiated patients (n = 14) no contractures or skin necrosis were observed. CONCLUSIONS: Pulsed brachytherapy is an effective and time-sparing method for the treatment of cutaneous metastases from breast cancer. Skin reactions are comparable to the sequelae of orthovoltage therapy. Two sessions of approximately 20 Gy PDR were tolerated on preirradiated skin without severe sequelae.     

High dose rate (192)Ir afterloading brachytherapy for cancer of the vagina

We report results of brachytherapy for carcinoma of the vagina, utilizing a Nucletron high dose rate system for Delclos Vaginal Applicators (cylinder) and Syed Template Applicators (interstitial). The linear quadratic (LQ) model was used to determine the optimum time-dose-fractionation schedules. Interstitial doses were determined at the isodose line that included gross tumour. Cylinder doses were determined either at the vaginal surface (5 cases), at 0.5 cm depth (5 cases), or at 1.0 cm depth (1 case). For the first treatment (n=19), interstitial templates were utilized in 8 patients and vaginal cylinders in 11. 11 patients received second treatments: 6 templates and 5 cylinders. The median dose of external beam radiation (n=15) was 40.0 Gy followed, after a median 23 day interval, by high dose rate brachytherapy (HDRB) of 4 fractions in 30-42 h; then a median interval gap of 25 days, followed by repeat HDRB. The median total fractionated HDRB dose per patient was 23.0 Gy (range: 6.9 Gy to 40.4 Gy; calculated low dose rate equivalent of 29.8 Gy). Tumour histologies included 14 squamous cell carcinomas, 2 adenocarcinomas, 2 melanomas, and 1 small cell tumour. Three patients experienced early brachytherapy-related complications (diarrhoea, dysuria and labial dermatitis). Three patients (15.8%) developed serious/late complications including ureteral stenosis, painful vaginal necrosis and small bowel obstruction. The first of these patients received 2 templates, the second a cylinder followed by a template and a cylinder, and the third a single cylinder. The 2 year progression-free survival was 39.3% (median 15.7 months), while the 2 year overall survival was 66.1% (median 29.9 months). (192)Ir afterloading HDRB is a feasible approach to women with vaginal cancer with acceptable toxicity and tumour response. Potential advantages include patient preference, outpatient cost-effectiveness in the case of cylinder technique, and no radiation exposure to hospital personnel. Long-term follow-up is needed to further assess late complications, and larger studies are needed to confirm our results.     

Palliative Interstitial HDR Brachytherapy for Recurrent Rectal Cancer

PURPOSE: To report the methods and clinical results of CT-based interstitial high-dose-rate (HDR) brachytherapy procedures for the palliative treatment of recurrent rectal cancer. PATIENTS AND METHODS: A total of 44 brachytherapy implants were performed in 38 patients. CT-guided catheter implants were performed in 34 patients under local anesthesia and sedation, and four patients were implanted intraoperatively. Of 40 CT-guided implants, 20 were done using metallic needles introduced via the sacrum and 20 were transperineal implants of plastic tubes in the presacral region. Postimplant CT scans were used for three-dimensional (3-D) conformal brachytherapy planning. Patients implanted with metallic needles were given a single fraction of 10-15 Gy using HDR (192)Ir, and those who received transperineal implants of plastic catheters were given fractionated brachytherapy, 5 Gy twice daily to a total dose of 30-40 Gy. The median tumor volume was 225 cm(3) with a range of 41-2,103 cm(3). RESULTS: After a median follow-up of 23.4 months, a total of 13/38 patients were alive. The median postbrachytherapy survival was 15 months with 18 of the 25 deaths due to distant metastases. Tumor response was as follows: 6/38 partial remission, 28/38 stable disease, and 4/38 local progression. A planning target volume (PTV) coverage > 85% was achieved in 42/44 implants. The treatment was well tolerated, and no acute complications were observed. One patient developed a fistula after 8 months. Pain relief was recorded in 34 patients (89.5%), and the median duration of this palliative effect was 5 months with a range of 1-13 months. CONCLUSIONS: Interstitial HDR brachytherapy is a valuable tool for the delivery of high doses and achieves effective palliation in recurrent rectal carcinoma.     

Fricke gel-layer dosimetry in high dose-rate brachytherapy

The aim of this study was to evaluate the reliability of Fricke gel-layer dosimeters for the measurement of in-phantom dose distributions produced by a ¹⁹²Ir brachytherapy source. The doses obtained were compared to measurements performed with thermoluminescent dosimeters and treatment planning calculations. Fricke gel-layer dosimeters have proven to be a promising tool to measure three-dimensional dose distributions in high dose-rate brachytherapy.     

Role of Interstitial PDR Brachytherapy in the Treatment of Oral and Oropharyngeal Cancer

PURPOSE: To evaluate the role of pulsed-dose-rate interstitial brachytherapy (PDR IBT) in patients with head-and-neck malignancies. PATIENTS AND METHODS: From October 1997 to December 2003, 236 patients underwent PDR IBT for head-and-neck cancer at the authors' department. 192 patients received brachytherapy as part of their curative treatment regimen after minimal non-mutilating surgery, 44 patients were treated with irradiation alone. 144 patients had sole IBT (median D(REF) = 56 Gy), in 92 patients IBT procedures (median D(REF) = 24 Gy) were performed in combination with external irradiation. The pulses (0.4-0.7 Gy/h) were delivered 24 h a day with a time interval of 1 h between two pulses. The analysis of tumor control, survival and treatment-related toxicity was performed after a median follow-up of 26 months (6-75 months). RESULTS: At the time of analysis permanent local tumor control was registered in 208 of 236 patients (88%). At 5 years overall survival and local recurrence-free survival of the entire group were 82-73% and 93-83% for T1/2, and 56% and 83% for T3/4, respectively. Soft-tissue necrosis was seen in 23/236 patients (9.7%) and bone necrosis in 17/236 patients (7.2%). No other serious side effects were observed. CONCLUSION: PDR IBT with 0.4-0.7 Gy/h and 1 h between pulses is safe and effective. These results confirm that PDR IBT of head-and-neck cancer is comparable with low-dose-rate (LDR) brachytherapy - equally effective and less toxic.     

High-Dose-Rate Brachytherapy for Small-Sized Peripherally Located Lung Cancer

BACKGROUND: The demand for minimally invasive therapies is increasing in the treatment of small peripheral non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Twelve patients with T1-2 N0 M0 peripheral NSCLC were treated by high-dose-rate brachytherapy with (192)Ir radioactive source. RESULTS: A (192)Ir source was introduced into the tumors percutaneously in five patients (percutaneous brachytherapy) or transbronchially in seven patients (transbronchial brachytherapy). Whereas irradiation was performed with a single fraction of 20 Gy in percutaneous brachytherapy, it was hypofractionated from 5 x 5 Gy to 2 x 12.5 Gy in transbronchial brachytherapy. Complications were generally mild in all patients, although focal radiation pneumonitis was observed in most patients. Primary recurrence occurred in three patients, including one with a T2 tumor and one treated by brachytherapy as a salvage treatment for recurrence after conformal radiotherapy. When brachytherapy is evaluated as a primary treatment for T1 N0 M0 NSCLC, local control rate is 88.9% and estimated 5-year survival rate is between 60% and 70%. CONCLUSION: Brachytherapy has a potential to be a method to treat peripheral T1 N0 M0 NSCLC.     

Pulsed brachytherapy: a modelled consideration of repair parameter uncertainties and their influence on treatment duration extension and daytime-only "block-schemes"

OBJECTIVES: The radiobiological modelling of all types of protracted brachytherapy is susceptible to uncertainties in the values of tissue repair parameters. Although this effect has been explored for many aspects of pulsed brachytherapy (PB), it is usually considered within the constraint of a fixed brachytherapy treatment time. Here the impact of repair parameter uncertainty is assessed for PB treatments of variable duration. The potential use of "block-schemes" (blocks of PB pulses separated by night-time gaps) is also investigated. METHODS: PB schedule constraints are based on the cervical cancer protocols of the Royal Marsden Hospital (RMH), but the methodology is applicable to any combination of starting schedule and treatment constraint. Calculations are performed using the biologically effective dose (BED) as a tissue-specific comparison metric. The ratio of normal tissue BED to tumour BED is considered for PB regimens with varying total pulse numbers and/or "block-schemes". Results: For matched brachytherapy duration, PB has a good "window of opportunity" relative to the existing RMH continuous low dose rate (CLDR) practice for all modelled repair half-times. The most clear-cut route to radiobiological optimisation of PB is via modest temporal extension of the PB regimen relative to the CLDR reference. This option may be practicable for those centres with scope to extend their relatively short CLDR treatment durations. Conclusion: Although daytime-only "block-scheme" PB for cervical cancer has not yet been employed clinically, the possibilities appear to be theoretically promising, providing the overall (external beam plus brachytherapy) treatment duration is not extended relative to current practice, such that additional tumour repopulation becomes a concern.     

A review of the clinical experience in pulsed dose rate brachytherapy

Pulsed dose rate (PDR) brachytherapy is a treatment modality that combines physical advantages of high dose rate (HDR) brachytherapy with the radiobiological advantages of low dose rate brachytherapy. The aim of this review was to describe the effective clinical use of PDR brachytherapy worldwide in different tumour locations. We found 66 articles reporting on clinical PDR brachytherapy including the treatment procedure and outcome. Moreover, PDR brachytherapy has been applied in almost all tumour sites for which brachytherapy is indicated and with good local control and low toxicity. The main advantage of PDR is, because of the small pulse sizes used, the ability to spare normal tissue. In certain cases, HDR resembles PDR brachytherapy by the use of multifractionated low-fraction dose.