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, rusable 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 2 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 judgeg 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. Hintergrund: Das Konzept der von Brenner und Hall inaugurierten gepulsten Brachytherapie basiert auf einem unüblichen Fraktionierungsschema. Die Effektivität und die Folgen dieser neuen Bestrahlungsmethode wurden an Patienten mit disseminierten Hautmetastasen des Mammakarzinoms nachbeobachtet. Patienten und Methode: Es wurde eine flexible, wiederverwendbare Hautmoulage (Gewicht 110 g) für ein PDR-Afterloading-Gerät entwickelt. Die Bestrahlungsmoulage enthält 18 äquidistant (10 oder 12 mm) angeordnete Bestrahlungskatheter (2 mm Durchmesser), welche in ein Plastiknetz eingezogen sind. Die Vorrichtung liegt zwischen zwei Platten aus festem Schaumgummi von 5 mm Dicke als Distanzhalter zur Haut. Die Brachytherapiemoulage erlaubt eine maximale Feldgröße von 20 2 23,5 cm auf der Haut. Die PDR-Bestrahlungen werden mit einer nominal 37 GBq Ir-192-Quelle mit Pulsen von 1 Gy und einer Pulsperiode von 1,2 Stunden durchgeführt (durchschnittliche Dosisleistung: 0,8 Gy/Stunde). Die routinemäßige Anwendung der geometrischen Optimierung ermöglicht eine Homogenität der Hautoberflächendosis von - 10%. Die 80%-Isodose liegt 5 mm unter der Hautoberfläche. Von April 1994 bis Dezember 1997 wurden 52 Patientinnen mit Hautmetastasen an der Thoraxwand mit 54 Feldern und Referenzdosen zwischen 38 und 50 Gy (median 42 Gy) behandelt, wobei jeweils zwei PDR-Serien mit einem Pausenintervall von vier bis fünf Wochen appliziert wurden. Ergebnisse: Im Juni 1998 wurden 46 Patientinnen (48 Felder) ausgewertet. Die mediane Nachbeobachtungszeit betrug 16 Monate (7,1 bis 46,2 Monate). In 40 von 48 Feldern (83%) bzw. bei 41 von 46 Patienten (89%) wurde eine lokale Kontrolle erreicht. Feuchte Epitheliolysen traten bei 52% der Patientinnen auf. Späte Strahlenreaktionen wurden nach einer minimalen Nachbeobachtungszeit von sechs Monaten geprüft. 32 der Bestrahlungsfelder waren nach externer Strahlenbehandlung mit Dosen zwischen 40 und 60 Gy vorbelastet. Unabhängig von der Vorbelastung entwickelten alle Patientinnen Teleangiektasien innerhalb von zwei Jahren nach der PDR-Brachytherapie. Im vorbelasteten Kollektiv (n = 32) traten bei jeweils 12% der Patientinnen Hautkontrakturen und/oder kleinere Hautnekrosen auf. Im nicht vorbelasteten Kollektiv (n = 14) wurden keinerlei Kontrakturen oder Hautnekrosen beobachtet. Schlussfolgerungen: Die gepulste Brachytherapie ist eine zeitsparende und effektive Methode zur Behandlung von Hautmetastasen bei Narbenrezidiven des Mammakarzinoms. Die Hautreaktionen sind vergleichbar mit der Orthovoltbestrahlung. Eine PDR-Split-Course-Bestrahlung von zweimal 20 Gy wird auch von der vorbelasteten Haut ohne schwerwiegende Strahlenfolgen toleriert.     

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.     

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.     

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.     

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.     

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.     

Feasibility and Early Results of Interstitial Intensity-Modulated HDR/PDR Brachytherapy (IMBT) with/without Complementary External-Beam Radiotherapy and Extended Surgery in Recurrent Pelvic Colorectal Cancer

BACKGROUND: A new multimodality treatment concept consisting of extended resection and postoperative fractionated intensity-modulated interstitial brachytherapy (IMBT) was introduced for pelvic recurrence of colorectal carcinoma. PATIENTS AND METHODS: 46 patients received extended resection and single plastic tubes were sutured directly onto the tumor bed. IMBT was started within 2 weeks postoperatively with a median dose of 24.5 Gy (5-35 Gy). Patients were treated either with high-dose-rate brachytherapy (HDR; n = 23) or with pulsed-dose-rate brachytherapy (PDR; n = 23). 25 patients received complementary 45-Gy external-beam irradiation (EBRT) to the pelvic region after explanting the plastic tubes. RESULTS: Median follow-up was 20.6 months (7-107 months) and mean patient survival 25.7 +/- 25.8 months (median 17, range 1-107 months). After 5 years overall survival, disease-free survival and local control rate were 23%, 20% and 33%, significantly influenced by the resectional state. There was a trend in favor of PDR compared to HDR, which reached statistical significance in patients who had not received additional EBRT. CONCLUSION: The combination of extended surgery and postoperative interstitial IMBT is feasible and offers effective interdisciplinary treatment of recurrent colorectal cancer. In this small and inhomogeneous cohort of patients PDR seems to be more effective than HDR, particularly when application of complementary EBRT is not possible. None of the patients who required resection of distant metastasis survived > 2 years in this study.     

The Role of Interstitial Brachytherapy in the Treatment of Vaginal and Vulvar Malignancies

BACKGROUND: Irradiation has established itself as a treatment for vulvar and vaginal malignancies. Due to the sensitive nature of the vulvar and vaginal tissues, interstitial brachytherapy (iBT) provides an effective, gentle and individualized therapy. PATIENTS AND METHODS: Patients with vulvar (nine of 22) and vaginal (13 of 22) malignancies were treated using interstitial pulsed-dose-rate brachytherapy (PDR-iBT). Twelve out of 22 patients were additionally treated using external-beam therapy to the pelvis and regional lymph nodes. The median total dose of PDR-iBT administered to patients with vulvar carcinoma was 55.0 Gy. The median total PDR dose administered to patients with vaginal malignancies amounted to 20.25 Gy. RESULTS: The median follow-up time for patients with vulvar cancer was 19 months and for patients with vaginal malignancies 27 months. Acute mucositis or skin reactions during iBT were observed in 15 of 22 patients. Two of 22 patients showed delayed side effects. After 6 months, 77.8% of the patients with vulvar cancer (seven out of nine) and 100% of the patients with vaginal malignancies (13 out of 13) achieved complete local remission. One patient out of nine with vulvar carcinoma developed local recurrence, four out of nine regional recurrence, and two out of nine developed regional recurrence and had local tumor following therapy. In patients with malignancies of the vagina, no cases of local recurrence were observed, but distant metastases were found in five out of 13 patients. At the time of analysis, eleven out of 22 patients with vulvar or vaginal carcinoma were still alive. CONCLUSION: IBT achieved good local control without serious delayed side effects in both localizations. However, survival is limited by regional or distant metastases.     

Re-irradiation with interstitial pulsed-dose-rate brachytherapy for unresectable recurrent head and neck carcinoma

PurposeTo assess the long-term results of protocol-based interstitial pulsed-dose-rate (PDR) brachytherapy combined with simultaneous chemotherapy in selected patients with recurrent head and neck tumors not amenable to salvage surgery.Methods and MaterialsA total of 51 patients with recurrent head and neck cancer were treated with interstitial PDR brachytherapy. Forty patients (78%) had salvage brachytherapy alone using a median total dose of 60 Gy. Salvage brachytherapy in combination with external beam therapy was performed in 11 patients (22%) using a median total dose of D_REF = 27 Gy. Simultaneously with the PDR brachytherapy, a concomitant chemotherapy was administered in 35/51 (69%) of patients. The analysis was performed after a median followup of 58 months.ResultsLocal control rates calculated according to Kaplan–Meier after 2 and 5 years were 71% and 57%, respectively. Comparing results of salvage PDR brachytherapy with or without simultaneous chemotherapy, the 5-year local recurrence-free survival rates were 78.9% vs. 38.5% (p = 0.01), respectively. No other patient or treatment-related parameters had a significant influence on treatment results. A total of 9/51 (17.7%) and 6/51 (11.8%) patients developed soft-tissue necrosis or bone necrosis, respectively, but only 2% of patients required surgical treatment.ConclusionsPDR interstitial brachytherapy with pulse doses between 0.4 and 0.7 Gy/h/24 h with simultaneous chemotherapy is an effective and safe option for curative therapy in selected patients with head and neck cancer in previously irradiated areas, which are not suitable for salvage surgery.     

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.     

Fractionated Intraluminal HDR 192Ir Brachytherapy as Palliative Treatment in Patients with Endobronchial Metastases from Non-Bronchogenic Primaries

AIM: To evaluate the efficacy of iridium-192 high-dose rate (HDR) endobronchial brachytherapy for the palliation of symptoms caused by endobronchial metastases of non-bronchogenic primaries. PATIENTS AND METHOD: Between 1991 and 1998, eleven patients (female n = 3, male n = 8; age: median 66 years, range 44-81 years) underwent intraluminal HDR brachytherapy for histologically confirmed endobronchial metastases from non-pulmonary primary tumors of various sites like urogenital tract (n = 5), gastrointestinal tract (n = 3), ear/nose/throat (n = 2) and breast (n = 1). The median time between diagnosis of the primary non-bronchogenic tumor and histopathological diagnosis of the endobronchial metastases was 39 months, range 1-99 months. A total dose of 15-20 Gy was delivered in three to four fractions of 5-6 Gy once a week. No palliative chemotherapy was added. RESULTS: Median follow-up after palliative brachytherapy was 15 months (range 1.4-59 months). Objectively, complete endoscopic response was observed in three (27%) patients, and in five (46%) others partial opening of the initially obstructed airway was achieved. Treatment was judged unsuccessful in three (27%) patients. No patient showed up with local progression. At date of analysis five patients were alive with documented residual tumor (80%) or complete response (20%). Relief of symptoms occurred in the vast majority of patients (n = 8, 73%). CONCLUSION: HDR intraluminal brachytherapy palliates symptoms in patients suffering from endobronchial metastases of non-pulmonary primary tumors. The applied treatment is a safe, effective and well tolerated palliative procedure leading to an improved patient quality of life.     

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.     

Preliminary Report of Pulsed Dose Rate Brachytherapy in Head-and-Neck Cancer

PURPOSE: To assess the feasibility and acute/delayed toxicity of pulsed-dose-rate brachytherapy (PDR BT) in head-and-neck tumors. PATIENTS AND METHODS: 45 head and neck cancer patients underwent interstitial or contact PDR BT at a dose of 10.2-70 Gy (median, 70 Gy) and 0.6 or 1.0 Gy/pulse/h. 42 patients were administered BT as part of their curative treatment; 32 of them had sole BT. Three reirradiated patients with recurrent tumor had palliative BT. RESULTS: PDR BT was well tolerated. Intense bleeding was the only complication associated with catheter removal from the tongue and bucca. 44 patients who completed BT experienced acute mucositis. Grade 3 toxicity of skin and oral mucosa occurred in three (6.8%) and six patients (13.6%), respectively. At a median follow-up of 22 months (range, 2-67 months), late serious toxicity (grade 4, for soft tissue and bone) was seen in seven patients (15.9%). Among the parameters analyzed, only dental care performed before BT had a significant impact on mucosal side effects. Acute severe mucositis was observed in 23% of patients without dental care compared to 0% of those with dental care (p=0.044). Late severe mucositis occurred in 17.7% and 26.9% of the respective patients (p=0.035), overall in 23%. The larger the volume encompassed by the reference isodose, the more late (p=0.004) mucosal reactions were observed. CONCLUSION: PDR BT continued over a few days is a feasible and safe approach in head-and-neck tumors; however, it is accompanied by some toxicity. Dental care should precede isotope application.     

Accelerated Partial-Breast Irradiation with Interstitial Implants

PURPOSE: To describe relative skin dose estimations and their impact on cosmetic outcome in interstitial multicatheter accelerated partial-breast irradiation (APBI). PATIENTS AND METHODS: Between April 2001 and January 2005, 105 consecutive patients with early breast cancer were recruited in Erlangen, Germany, for this substudy of the German-Austrian APBI phase II trial. 51% (54/105) received pulsed-dose-rate (PDR), and 49% (51/105) high-dose-rate (HDR) brachytherapy. Prescribed reference dose for HDR brachytherapy was 32 Gy in eight fractions of 4 Gy, twice daily. Prescribed reference dose in PDR brachytherapy was 49.8 Gy in 83 consecutive fractions of 0.6 Gy every hour. Total treatment time was 3-4 days. With a wire cross on the skin surface during the brachytherapy-planning procedure the minimal, mean and maximal relative skin doses (SD(min%), SD(max%), SD(mean%)) were recorded. Endpoint of this evaluation was the cosmetic outcome in relation to the relative skin doses. RESULTS: Median follow-up time was 38 months (range, 19-65 months). Cosmetic results for all patients were excellent in 57% (60/105), good in 36% (38/105), and fair in 7% (7/105). The SD(min%) (27.0% vs. 31.7%; p = 0.032), SD(mean%) (34.2% vs. 38.1%; p = 0.008), and SD(max%) (38.2% vs. 46.4%; p = 0.003) were significantly lower for patients with excellent cosmetic outcome compared to patients with a suboptimal outcome. SD(mean%) (37.6% vs. 34.2%; p = 0.026) and SD(max%) (45.4% vs. 38.2%; p = 0.008) were significantly higher for patients with good cosmetic outcome compared with the patients with excellent results. CONCLUSION: The appraisal of skin doses has been shown to be relevant to the achievement of excellent cosmetic outcome. Further investigations are necessary, especially on the basis of CT-based brachytherapy planning, to further improve the treatment results of multicatheter APBI.     

Experimental studies on metastases from an irradiated tumor]

This study was carried out to determine the effect of irradiation of a tumor on the development of lung metastases. SANH, a spontaneous sarcoma, was isotransplanted in the right thighs of C3H mice which were either locally preirradiated (30 Gy: TBR) or non-irradiated. When the tumors had grown to 7 mm in diameter, they received 20-30 Gy of electron beams (RTx). The tumor-bearing legs were amputated at various tumor sizes, and the incidence of metastasis and number of lung nodules were compared in each treatment group. The incidences of metastases from 7 mm tumors in mice with regrowing tumors after RTx (30 Gy) and non-irradiated mice were 28% and 4%, respectively. When tumors grown in preirradiated legs were removed at 7 mm in diameter, the incidence of metastases (58%) was also enhanced by preirradiation of the tumor bed. Seven millimeter tumors that were growing in TBR legs and received RTx (20 Gy) developed a higher incidence (82%) and greater numbers of metastases than either the RTx or TBR groups. To determine the relationship between the interval of tumor bearing and development of metastases, tumors were removed at various intervals after tumor transplantation in 4 groups, namely, non-irradiated, TBR, RTx and TBR with 20 GyRTx. Lung metastases came later but increased steeply in mice given either TBR or RTx, compared with non-irradiated mice. Tumors growing in TBR and receiving RTx (20 Gy) developed many more metastases than any other group.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Pulsed-dose rate brachytherapy with concomitant chemotherapy and interstitial hyperthermia in patients with recurrent head-and-neck cancer

PURPOSE: We attempted in our clinic to evaluate the efficacy and feasibility of a simultaneous application of a cis-platinum-based chemotherapy and interstitial hyperthermia to interstitial pulsed-dose rate (PDR) brachytherapy in patients with recurrent head-and-neck cancer. METHODS AND MATERIALS: Between April 1999 and September 2001, 15 patients with recurrent head-and-neck cancer were treated with PDR brachytherapy, chemotherapy, and interstitial hyperthermia. All patients had received prior radiation therapy. A dose per pulse of 0.46 to 0.55 Gy was given up to a median total dose of 55 Gy. Simultaneously to the PDR brachytherapy, chemotherapy was given with cis-platinum 20 mg/m2 as a short i.v. infusion each day and 5-fluorouracil 800 mg/m2 by continuous infusion from Day 1 to Day 5. After the PDR brachytherapy was finished, all patients were treated with a single session of interstitial hyperthermia. RESULTS: All the patients could receive the whole treatment. After treatment, only mild oral mucositis occurred. One patient developed soft tissue ulceration. None of the patients developed osteoradionecrosis. After a median follow-up of 6 months, the local tumor control rate was 80% (12 of 15), and the 2-year overall survival was 67% (10 of 15). CONCLUSIONS: The intensification of the interstitial PDR brachytherapy with chemotherapy and hyperthermia is feasible and safe, and the preliminary results are encouraging.     

Perioperative high-dose-rate brachytherapy (PHDRB) in previously irradiated head and neck cancer: Initial results of a Phase I/II reirradiation study

BACKGROUND: This study was undertaken to determine the feasibility of salvage surgery and perioperative high-dose-rate brachytherapy (PHDRB) at the dose/fractionation schedule proposed in patients with previously irradiated, recurrent head and neck cancer or second primary tumors arising in a previously irradiated field. METHODS AND MATERIALS: Twenty-five patients were treated with surgical resection and PHDRB. The PHDRB dose was 4 Gy b.i.d. x 8 (32 Gy) for R0 resections and 4 Gy b.i.d. x 10 (40 Gy) for R1 resections. Further external beam radiotherapy or chemotherapy was not given. RESULTS: Resections were categorized as R0 (negative margins of at least 10 mm) in 3 patients (12.0%) and R1 (negative margins of less than 10 mm or microscopically positive margins) in 22 (88.0%). Twelve patients with R1 resections had microscopically positive margins (48%), and 10 patients had close margins (40%), with a median of 2.0 mm. Ten patients (40.0%) developed Radiation Therapy Oncology Group Grade 3 or greater toxicity. Seven patients (28%) presented complications requiring a major surgical procedure. Four of these complications appeared in the immediate postoperative period and were surgical in nature (flap failure, n = 2; fistula, n = 2), and the other three were mainly related to the brachytherapy procedure (n = 2) or the radiation dose delivered (n = 1). One patient died on postoperative day 11 due to bleeding. After a median followup of 14 months, the 4-year local control rate and overall survival were 85.6% and 46.4%, respectively. CONCLUSIONS: Surgical salvage and PHDRB at the dose/fractionation proposed are feasible in this high-risk population. Toxicity is high, but not substantially different from other reirradiation series. Four-year local control results are encouraging taking into account that 22 of 25 patients (88%) had either close or microscopically positive margins.     

Percutaneous Computed Tomography–guided High-Dose-Rate Brachytherapy Ablation of Breast Cancer Liver Metastases: Initial Experience with 80 Lesions

PurposeTo analyze initial experience with computed tomography–guided high-dose-rate brachytherapy (CT-HDRBT) ablation of breast cancer liver metastases (BCLM).Materials and MethodsBetween January 2008 and December 2010, 37 consecutive women with 80 liver metastases were treated with CT-HDRBT in 56 sessions. Mean age was 58.6 years (range, 34–83 y). Treatment was performed by CT-guided applicator placement and high-dose-rate brachytherapy with an iridium-192 source. The mean radiation dose was 18.57 Gy (standard deviation 2.27). Tumor response was evaluated by gadoxetic acid–enhanced liver magnetic resonance (MR) imaging performed before treatment, 6 weeks after treatment, and every 3 months thereafter.ResultsTwo patients were lost to follow-up; the remaining 35 patients were available for MR imaging evaluation for a mean follow-up time of 11.6 months (range 3–32 mo). Mean tumor diameter was 25.5 mm (range 8–74 mm). Two (2.6%) local recurrences were observed after local tumor control for 10 months and 12 months. Both local progressions were successfully retreated. Distant tumor progression (new metastases or enlargement of nontreated metastases) occurred during the follow-up period in 11 (31.4%) patients. Seven (20%) patients died during the follow-up period. Overall survival ranged from 3–39 months (median 18 months).ConclusionsCT-HDRBT is a safe and effective ablative therapy, providing a high rate of local tumor control in patients with BCLM.     

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.