Dosimetric benefits and preclinical performance of steerable needles in HDR prostate brachytherapy.

Prostate cancer patients with an enlarged prostate and/or excessive pubic arch interference (PAI) are generally considered non-eligible for high-dose-rate (HDR) brachytherapy (BT). Steerable needles have been developed to make these patients eligible again. This study aims to validate the dosimetric impact and performance of steerable needles within the conventional clinical setting. HDR BT treatment plans were generated, needle implantations were performed in a prostate phantom, with prostate volume > 55 cm3 and excessive PAI of 10 mm, and pre- and post-implant dosimetry were compared considering the dosimetric constraints: prostate V100 > 95 % (13.50 Gy), urethra D0.1cm3 < 115 % (15.53 Gy) and rectum D1cm3 < 75 % (10.13 Gy). The inclusion of steerable needles resulted in a notable enhancement of the dose distribution and prostate V100 compared to treatment plans exclusively employing rigid needles to address PAI. Furthermore, the steerable needle plan demonstrated better agreement between pre- and post-implant dosimetry (prostate V100: 96.24 % vs. 93.74 %) compared to the rigid needle plans (79.13 % vs. 72.86 % and 87.70 % vs. 81.76 %), with no major changes in the clinical workflow and no changes in the clinical set-up. The steerable needle approach allows for more flexibility in needle positioning, ensuring a highly conformal dose distribution, and hence, HDR BT is a feasible treatment option again for prostate cancer patients with an enlarged prostate and/or excessive PAI.

Determination of the accuracy of implant reconstruction and dose delivery in brachytherapy in The Netherlands and Belgium.

PURPOSE: To gain insight into the accuracy of brachytherapy treatments, the accuracy of implant reconstruction and dose delivery was investigated in 33 radiotherapy institutions in The Netherlands and Belgium. MATERIALS AND METHODS: The accuracy of the implant reconstruction method was determined using a cubic phantom containing 25 spheres at well-known positions. Reconstruction measurements were obtained on 41 brachytherapy localizers, 33 of which were simulators. The reconstructed distances between the spheres were compared with the true distances. The accuracy of the dose delivery was determined for high dose rate (HDR), pulsed dose rate (PDR) and low dose rate (LDR) afterloading systems using a polymethyl methacrylate cylindrical phantom containing a NE 2571 ionization chamber in its centre. The institutions were asked to deliver a prescribed dose at the centre of the phantom. The measured dose was compared with the prescribed dose. RESULTS: The average reconstruction accuracy was -0.07 mm (+/-0.4 mm, 1 SD) for 41 localizers. The average deviation of the measured dose from the prescribed dose was +0.9% (+/-1.3%, 1 SD) for 21 HDR afterloading systems, +1.0% (+/-2.3%, 1 SD) for 12 PDR afterloaders, and +1.8% (+/-2.5%, 1 SD) for 15 LDR afterloaders. CONCLUSIONS: This comparison showed a good accuracy of brachytherapy implant reconstruction and dose delivery in The Netherlands and Belgium.

Manual calculation of treatment time for high dose rate brachytherapy with a flexible intraoperative template (FIT).

A method is presented for estimating the total treatment time for a brachytherapy radiation fraction with a planar flexible intraoperative template (FIT), using an 192Ir high dose rate afterloading device. The FIT can be rectangular or irregularly shaped. The manual calculation serves as an independent check of the treatment time calculated by the treatment planning system for applications with varying sizes, shapes and dose prescription depths. The parameters required for the calculation are the number of active dwell positions, the catheter spacing and dwell position spacing, the source strength, the applied dose and the depth of dose prescription. For a fixed depth of dose prescription (1.25 cm) and fixed dwell position and catheter spacing (0.5 and 1 cm respectively) the manual calculation accurately predicts (usually within 2%) the total treatment time as calculated by the treatment planning system. For varying catheter and dwell position spacings and dose prescription depths the accuracy is still within 7%. An action threshold of 5% allows detection of errors made in the number of active dwell positions (+/-9), catheter spacing (+/-1 mm) and dose prescription depth (+/-1 mm). Errors in dwell position spacing (0.25 cm or more) could also be accurately detected.

Fractionated high-dose-rate brachytherapy in primary carcinoma of the nasopharynx.

PURPOSE: A growing body of data suggests that local control in nasopharyngeal cancer (NPC) is related to the radiation dose administered. We conducted a single-institution study of high-dose radiotherapy (RT), which incorporated high-dose-rate (HDR) brachytherapy (BT). These results were analyzed together with data obtained from controls who did not receive BT. PATIENTS AND METHODS: The BT group comprised 42 consecutive patients of whom 29 patients were staged according to the tumor, node, metastasis system as T1 through 3, 13 patients were T4, and 34 patients were N+ disease. BT was administered on an outpatient basis by means of a specially designed flexible nasopharyngeal applicator, and the dose distributions were optimized. Treatment for T1 through 3 tumors comprised 60 Gy of external-beam radiotherapy (ERT) followed by six fractions of 3 Gy BT (two fractions per day). Patients with parapharyngeal tumor extension and/or T4 tumors received 70 Gy ERT and four fractions of 3 Gy BT. The no-BT group consisted of all patients treated from 1965 to 1991 (n = 109), of whom 82 patients had stages T1 through 3, 27 patients had T4, and 80 patients had N+ disease. Multivariate Cox proportional hazards analyses were performed by using the end points time to local failure (TTLF), time to distant failure (TTDF), disease-free survival (DFS), cause-specific survival (CSS), and the prognostic factors age, tumor stage, node stage, and grade. Because the overall treatment time varied substantially in the no-BT group, the dependence of local failure (LF) on the physical dose as well as the biologic effective dose (BED) corrected for the overall treatment time (OTT) (BEDcor10) was studied. RESULTS: The BT group had a superior 3-year local relapse-free rate (86% v 60%; univariate analysis, P = .004). Multivariate analysis showed hazards ratios for BT versus no-BT of 0.24 for TTLF (P = .003), 0.35 for TTDF (P = .038), 0.31 for DFS (P < .001), and 0.44 for CSS (P = .01). The best prognostic group consisted of patients with T1 through 3, N0 through 2b tumors treated with BT who attained a 5-year TTLF of 94% and CSS of 91%. In contrast, the worst prognostic group, i.e., 5-year TTLF of 47% and CSS of 24%, was composed of patients with T4 and/or N2c through 3 tumors who did not receive BT. CONCLUSION: High doses of radiation (73 to 95 Gy) can be administered to patients with NPC with minimal morbidity by means of optimized HDR-BT. The use of a BT boost proved to be of significant benefit, particularly in patients with T1 through 3, N0 through 2b disease. The steep dose-effect relationship seen for the physical dose and the BEDcor10 indicates that the results are dose related. The analysis has identified a poor prognostic group in whom treatment intensification with chemotherapy (CHT) is indicated.

Reconstruction accuracy of a dedicated localiser for filmless planning in intra-operative brachytherapy.

BACKGROUND AND PURPOSE: With the use of HDR and PDR afterloaders containing a single stepping source, brachytherapy dose distributions can be optimised by varying the source dwell time. With the goal of implementing 'conformal brachytherapy', i.e. ensuring that the dose distribution conforms as accurately as possible to the target volume, we evaluated a set-up which enabled on-line implant localisation and dose planning during implantation. MATERIALS AND METHODS: The set-up, designated as an integrated brachytherapy unit (IBU), consists of a shielded operating room equipped with an HDR afterloader and a dedicated brachytherapy localiser connected to a treatment planning computer. The localiser is isocentric and has an extra degree of freedom in comparison to conventional simulators (i.e. an L-arm in combination with a C-arm) and enables viewing of the implant from any direction. A reconstruction algorithm which takes into account both rotation axes, i.e. the L-arm and C-arm angle, was developed for the localiser. The reconstruction procedure was tested by using the IBU localiser to measure the reconstruction accuracy with a phantom (containing 25 markers at well defined positions) and using reconstruction from radiographs. These results were compared to simulations where the accuracy of reconstruction was determined as a function of the reconstruction angle and the accuracy of read-outs of the localiser settings. On-line localisation and dose planning during implantation is based on filmless planning, i.e. fluoroscopy images and the corresponding localiser settings are imported into the treatment planning computer during implantation. The accuracy of filmless planning was determined using fluoroscopy images in the same set-up as for the experiments with the radiographs. The effect of reconstruction inaccuracies on the total irradiation time and the dose in target or normal tissue points was elucidated for clinically relevant implant geometries. The treatment plans of two phantoms based on reconstruction from films as well as fluoroscopy images were compared with plans for implants defined by exact co-ordinates. RESULTS: The average reconstruction error due to the accuracy of the read-out of the localiser settings varied between -0.18 and 0.24 mm, with a standard deviation (arising from digitisation errors) ranging from 0.11 to 0.22 mm. Using filmless reconstruction and the 10 inch field of view of the image intensifier (without applying correction for the geometric distortions) the average reconstruction error ranged from 0.01 to 0.65 mm, and the standard deviation ranged from 0.40 to 0.73 mm. These errors arose as a consequence of the finite pixel size and geometric distortions. These limited errors did not influence the treatment time for clinical implant geometries and had only a minor effect (<1%) on the dose in markers during filmless planning. CONCLUSION: This IBU set-up, with a dedicated brachytherapy localiser, allows for a rapid and accurate filmless planning procedure based on implant localisation from fluoroscopy images.

Fractionated high-dose-rate and pulsed-dose-rate brachytherapy: first clinical experience in squamous cell carcinoma of the tonsillar fossa and soft palate.

PURPOSE: Fractionated high-dose-rate (fr.HDR) and pulsed-dose-rate (PDR) brachytherapy (BT) regimens, which simulate classical continuous low-dose-rate (LDR) interstitial radiation therapy (IRT) schedules, have been developed for clinical use. This article reports the initial results using these novel schedules in squamous cell carcinoma (SCC) of the tonsillar fossa (TF) and/or soft palate (SP). METHODS AND MATERIALS: Between 1990 and 1994, 38 patients with TF and SP tumors (5 T1, 22 T2, 10 T3, and 1 T4) were treated by fr.HDR or PDR brachytherapy, either alone or in combination with external irradiation (ERT). Half of the patients were treated with fr.HDR, which entailed twice-daily fractions of > or = 3 Gy. The other 19 patients were administered PDR, which consisted of pulses of < or = 2 Gy delivered 4-8 times/day. The median cumulative dose of IRT +/- ERT series was 66 Gy (range 55-73). The results in these patients treated by brachytherapy were compared to 72 patients with similar tumors treated in our institute with curative intent, using ERT alone. The median cumulative dose of ERT-only series was 70 Gy (range 40-77). RESULTS: Excellent locoregional control was achieved with the use of IRT +/- ERT, with only 13% (5 of 38) developing local failure, and salvage surgery being possible in three of the latter (60%). Neither BT scheme (fr.HDR vs. PDR) nor tumor site (TF vs. SP) significantly influenced local control rates. The type and severity of the side effects observed are comparable to those reported in the literature for LDR-IRT. These results contrast sharply with our ERT-only series, in which 39% of patients (28 of 72) developed local failure, with surgical salvage being possible only in three patients (11%). Taking the data set of 110 patients, in a univariate analysis IRT, T stage, N stage, overall treatment time (OTT), and BEDcor10 (biological effective dose with a correction for the OTT) were significant prognostic factors for local relapse-free survival (LRFS) and overall survival (OS) at 3 years. Using Cox proportional hazard analysis, only T stage and BEDcor10 remained significant for LRFS (p < 0.001 and 0.008, respectively), as well as for OS (p < 0.001 and 0.003, respectively). With regard to the current (IRT) and historical (ERT) series, for the LRFS at 3 years, dose-response relationships were established, significant, however, only for the BEDcor10 (p = 0.03). CONCLUSION: The 3-year LRFS of approximately 90% for TF and SP tumors reported here is comparable with the best results in the literature, particularly given the fact that 30% of the patients (11 of 38) presented with T3/4 tumors. When compared with our historical (ERT-only) controls, the patients treated with IRT had superior local control. A dose-response relationship was established for the BEDcor10.

Interstitial hyperthermia and interstitial radiotherapy of a rat rhabdomyosarcoma; effects of sequential treatment and consequences for clonogenic repopulation.

Animal tumour experiments have been performed to elucidate the interactions between interstitial hyperthermia (IHT) and interstitial radiotherapy (IRT), and to obtain information about the most effective sequence of these treatment modalities. Experimental tumours, transplanted in the flank of Wag/Rij rats, were treated with IHT for 0.5 h at 44 degrees C, and with IRT using low dose-rate (LDR) iridium-192 sources. Both tumour cure probability and the fraction of clonogenic cells in vitro after different IHT and IRT treatments in vivo, were used as endpoints. The sequence of a short (0.5 h) IHT treatment followed by an extended LDR-IRT treatment lasting up to 10 days appeared to be very effective, and resulted in a significant thermal enhancement ratio of 1.34 at the 50% tumour cure probability level. A not significantly increased thermal enhancement of 1.06 was found when the same IHT treatment followed IRT. The level of clonogenic cell survival after IHT alone is high (0.24 +/- 0.08) compared with that after an IRT dose of 20 Gy (0.017 +/- 0.004). Clonogenic cell repopulation started 2-4 days after the in vivo treatment irrespective of the type of treatment. The in vivo combination of IHT and LDR-IRT resulted in lower surviving fractions compared with IRT alone, regardless of the time interval between the end of treatment and in vitro clonogenic assay. IHT followed by LDR-IRT appeared to be the most effective treatment in terms of tumour cure. The in vivo/in vitro studies indicated that the effect of hyperthermia is mainly attributed to radiosensitization, possibly by partial inhibition of sublethal damage repair processes during the subsequent irradiation. The hyperthermia-induced cytotoxicity was of minor importance as estimated from the surviving clonogenic fraction.

Optimization of interstitial volume implants.

For interstitial applications of high dose rate (HDR) afterloading brachytherapy, generally a single stepping iridium-192 source is used, enabling optimization of the dose distribution by optimization of the relative time (dwell time) that the source remains at a certain position (dwell position). We analysed the effects of geometric optimization in a regular volume implant, with strictly parallel catheters, and in an irregular volume implant, such as an implant for tumours of the base of the tongue characterized by a non-parallel geometry and varying catheter separations. In both examples the reference dose is specified at 85% of the mean central dose (as is done in the Paris system for dose specification) in the non-optimized as well as the optimized plan. The irradiated volume, the dose uniformity, and the choice of the reference dose of optimized and non-optimized dose distributions were compared. This was done by isodose plots for representative planes, volume dose histograms (distributed, contiguous, and natural), and dose non-uniformity ratios (DNRs). For the regular implant, optimization results in a 28% increase in the treated volume with a similar increase in the overdosed volumes. In order to keep the treated volume comparable with the non-optimized dose distribution, 90-95% of the mean central dose should be chosen as a reference dose or the range of active dwell positions should be shortened in case of optimization. In the case of the irregular volume implant at the base of the tongue, the method for dose specification should be kept unchanged after geometric optimization as the volume enclosed by the reference isodose does not increase. It is clear from the volume-dose histograms that there is a reduction of the overdosed volume due to optimization. This is accompanied by an increase in the uniformity index and a decrease of the DNR. In conclusion, geometric optimization appears to be an effective tool to improve the dose distribution of interstitial volume implants. Contiguous and natural volume dose histograms appear, apart from planar dose plots, valuable methods for evaluating the dose distribution of an implant.

Lack of therapeutic gain when low dose rate interstitial radiotherapy is combined with cisplatin in an animal tumour model.

The interaction of cisplatin with low dose rate interstitial radiotherapy was studied in an animal tumour model with a range of dose rats commonly used in clinical low dose rate brachytherapy. Small pieces of R1-rhabdomyosarcoma were implanted subcutaneously in the flanks of female Wag/Rij rats. When the tumour had grown to the desired treatment volume, four afterloading catheters were inserted in the tumour in a square geometry, and a fixed spacing was attained by means of a template. Subsequently, four 2 cm Ir192 wires were inserted. A range of tumour doses of 20-120 Gy at a mean dose rate of 48 cGy/h was applied; 15 mins before the implant an intraperitoneal bolus injection of 3 mg/kg cisplatin was given. For growth delay and cure rate, no modification of the effects of low dose rate brachytherapy by the addition of cisplatin was observed. The observed effects of the combination of cisplatin with low dose rate interstitial radiation in relation to the animal tumour are discussed.

Combined treatment with interstitial hyperthermia and interstitial radiotherapy in an animal tumor model.

An interstitial hyperthermia system operating at 27 MHz has been developed at the Dr. Daniel den Hoed Cancer Center. To test this system in combination with interstitial radiotherapy and to study the interactions of interstitial radiotherapy and interstitial hyperthermia, animal experiments were performed using rhabdomyosarcoma type R1 transplanted in the flanks of female Wag/Rij rats. Using the 27 MHz system, it appeared feasible to obtain hyperthermic temperatures. In this experiment a thermal dose of 44 degrees C for 30 minutes was delivered by controlling the temperature at the periphery of the tumor to 44 degrees C. The interstitial heating applicators were inserted in four standard afterloading catheters implanted with a fixed spacing of 7 mm; the same catheters were used for the radioactive sources for interstitial radiotherapy treatment following the interstitial hyperthermia sessions. Interstitial radiotherapy was given by means of four Ir192 wires with an average activity of 4.5.10(7) Bq/cm. Minimum tumor doses of 20 to 115 Gy with a mean dose rate of 47 cGy/hour were applied. Interstitial hyperthermia alone resulted in a growth delay (GD1) of 6 +/- 2 days without significant reduction of tumor volume. The 50% tumor cure dose after interstitial radiotherapy alone was 95 +/- 9 Gy. Combination of interstitial hyperthermia and interstitial radiotherapy resulted in reduction of the 50% tumor cure dose to 48 +/- 13 Gy. The dose-effect data for cure for these modalities are compared to existing data for external irradiation and external hyperthermia in the same tumor model. It was found that the addition of hyperthermia to different modes of irradiation, that is, either to single dose or protracted radiotherapy, results in a common level of radiosensitivity through impaired repair of sublethal damage. This study demonstrates the feasibility of the 27 MHz heating system in achieving hyperthermic temperatures; in the combined modality experiments a thermal enhancement factor of 2.0 +/- 0.3 (mean +/- standard deviation) was observed.

Application of a capacitive-coupling interstitial hyperthermia system at 27 MHz: study of different applicator configurations.

A 27 MHz capacitive-coupling interstitial hyperthermia system has been developed. It uses thin flexible applicators which can easily be inserted in standard brachytherapy catheters. The system can be operated in two different configurations. In the external ground return configuration tissue is heated by currents passing from the catheters to external ground returns; in the balanced configuration, by currents passing between applicators with a phase difference of 180 degrees. The purpose of this study was to find out which configuration is preferable, in terms of temperature homogeneity and clinical usefulness. Model calculations show that, due to the high impedance associated with capacitive coupling, the applicators can be represented as current sources, in contrast to local current field electrodes which are voltage sources. SAR measurements in muscle-equivalent phantoms illustrate that homogeneous heating patterns along the catheters can be expected in both configurations in regular as well as in irregular implants. Using the external ground return configuration the power of each applicator can be controlled individually. Calculations and measurements show that cross-talk cannot be avoided completely in this configuration, but that it can be minimized by using applicators operating in phase.

Dose-effect relation of interstitial low-dose-rate radiation (Ir192) in an animal tumor model.

One way to deliver high doses of radiation to deep seated tumors without damaging the surrounding tissue is by interstitial techniques. This is commonly applied clinically; however, biological data of tumor response to interstitial low-dose-rate gamma irradiation are scarce. Therefore, we have studied the response of rhabdomyosarcoma R1 tumors implanted in the flanks of female Wag/Rij rats using an interstitial Ir192 afterloading system. A template was developed by which four catheters can be implanted in a square geometry with a fixed spacing. Subsequently four Ir192 wires of 2 cm length each are inserted. For dose prescription the highest isodose enveloping the tumor volume was chosen. Interstitial irradiation was performed using tumor volumes of 1500-2000 mm3. A range of minimum tumor doses of 20 up to 115 Gy were given at a mean dose-rate of 48 cGy/hr. Dose-effect relations were obtained from tumor growth curves and tumor cure data, and compared to data from external irradiation. The dose required for 50% cures with interstitial irradiation (TCD50) appears to be 95 +/- 9 Gy. The TCD50 for low-dose-rate interstitial gamma irradiation is 1.5 times the TCD50 for single dose external X ray irradiation at high dose rates, but is comparable to the TCD50 found after fractionated X ray irradiation at high dose rate. Sham treatment of the tumors had no effect on the time needed to reach twice the treatment volume. The growth rate of tumors regrowing after interstitial radiotherapy is not markedly different from the growth rate of untreated (control) tumors (volume doubting time 5.6 +/- 1 day), in contrast to the decreased growth rate after external X ray irradiation. It is argued that the absence of a clear tumor bed effect may be explained by some sparing of the stroma by the low-dose-rate of the interstitial irradiation per se as well as by the physical dose distribution of the interstitial Ir192 sources, giving a relative low dose of radiation to the surrounding normal tissues.

An interstitial hyperthermia system at 27 MHz.

An interstitial hyperthermia system using thin, flexible wires operating at a frequency of 27 MHz has been evaluated for possible use in combination with (iridium) brachytherapy applications employing flexible nylon afterloading catheters. This method of interstitial heating is argued to be a variation of local-current-field heating, however with the direct galvanic contact between electrode and tissue replaced by a capacitive coupling between wire and tissue. Through a special design of the wire the length of the heated area along the catheter can be chosen freely. Standard non-prepared implantation catheters can be used, so that no change from the established implantation techniques is required. Possible advantages of these 27 MHz wires over coaxial dipole antennas at higher frequencies are simplicity and low cost of the heating system, free choice of effective heating length for each wire and uniformity of heating along this effective heating length up to the tip of the wire. Flexibility of the wires is maintained, enabling application in curved (even U-shaped) catheters, e.g. for head and neck implantations. Impedance matching of the wires to the generator, necessary for an optimal transfer of power, appears possible by means of a variable air coil. Care should be taken to avoid stray capacitances of the connecting cables with respect to ground or among the different cables used. Measurements in muscle-equivalent split phantoms with infrared thermography have been performed with both single and multiple wires. The resulting SAR distributions confirm the working principle of these low-frequency wires (resistive heating) and illustrate the difference with radiative antennas at higher frequencies. The system is being applied both in experimental animal studies and in a clinical pilot study.