Stereotactic body radiation therapy for colorectal liver metastases.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is a treatment option for colorectal liver metastases. Local control, patient survival and toxicity were assessed in an experience of SBRT for colorectal liver metastases. METHODS: SBRT was delivered with curative intent to 20 consecutively treated patients with colorectal hepatic metastases who were candidates for neither resection nor radiofrequency ablation (RFA). The median number of metastases was 1 (range 1-3) and median size was 2.3 (range 0.7-6.2) cm. Toxicity was scored according to the Common Toxicity Criteria version 3.0. Local control rates were derived on tumour-based analysis. RESULTS: Median follow-up was 26 (range 6-57) months. Local failure was observed in nine of 31 lesions after a median interval of 22 (range 12-52) months. Actuarial 2-year local control and survival rates were 74 and 83 per cent respectively. Hepatic toxicity grade 2 or less was reported in 18 patients. Two patients had an episode of hepatic toxicity grade 3. CONCLUSION: SBRT is a treatment option for patients with colorectal liver metastases who are not candidates for resection or RFA.

Curative stereotactic robotic radiotherapy treatment for extracranial, extrapulmonary, extrahepatic, and extraspinal tumors: technique, early results, and toxicity.

We investigated the technique, early results and toxicity of curative stereotactic radiotherapy with the CyberKnife (Accuray Incorporated, Sunnyvale, California, USA) in 15 extracranial, extrapulmonary, extrahepatic, and extraspinal tumors. Fourteen tumors were located close to the bowel or esophagus. The PTV = GTV + 2-5 mm. The dose to the tumors varied from 10 fractions of 4 Gy up to 3 fractions of 20 Gy (median dose/fraction: 7 Gy; median number of fractions: 6), and depended on the proximity of the bowel. A small volume of the bowel was allowed to receive a dose of 6 Gy/fraction. The dose to the PTV was prescribed to the 75-85% isodose line. With a median follow up of 18 months, the 2-year local control and overall survival was 100%. Due to our flexible fractionation schedules, we were able to prescribe the dose to at least 90% of the PTV (median 95%) without increasing the dose to the bowel > 6 Gy/fraction. Five acute side effects were seen in four patients: two patients had transient grade 1 lymph edema in the leg, one patient complained of grade 1 pain in the abdomen and diarrhea, and one patient complained of grade 1 radiation dermatitis. Late toxicity such as grade 1 rectal bleeding, grade 1 diarrhea, grade 2 painful subcutaneous fibrosis, grade 2 pain in a surgical scar on the abdominal wall and an asymptomatic occlusion of the ureter was observed. Curative stereotactic radiotherapy treatment with the CyberKnife for extracranial, extrapulmonary, extrahepatic, and extraspinal, locally recurrent or solitary metastatic tumors is feasible and results in excellent local control and survival with low acute and late toxicity. A small volume of the bowel is able to tolerate a dose of 6 Gy per fraction for a maximum of 6 fractions.

In vivo fluence rate measurements during Foscan-mediated photodynamic therapy of persistent and recurrent nasopharyngeal carcinomas using a dedicated light applicator.

The objective of this study was to evaluate the performance of a dedicated light applicator for light delivery and fluence rate monitoring during Foscan-mediated photodynamic therapy of nasopharyngeal carcinoma in a clinical phase I/II study. We have developed a flexible silicone applicator that can be inserted through the mouth and fixed in the nasopharyngeal cavity. Three isotropic fibers, for measuring of the fluence (rate) during therapy, were located within the nasopharyngeal tumor target area and one was manually positioned to monitor structures at risk in the shielded area. A flexible black silicon patch tailored to the patient's anatomy is attached to the applicator to shield the soft palate and oral cavity from the 652-nm laser light. Fourteen patients were included in the study, resulting in 26 fluence rate measurements in the risk volume (two failures). We observed a systematic reduction in fluence rate during therapy in 20 out of 26 illuminations, which may be related to photodynamic therapy-induced increased blood content, decreased oxygenation, or reduced scattering. Our findings demonstrate that the applicator was easily inserted into the nasopharynx. The average light distribution in the target area was reasonably uniform over the length of the applicator, thus giving an acceptably homogeneous illumination throughout the cavity. Shielding of the risk area was adequate. Large interpatient variations in fluence rate stress the need for in vivo dosimetry. This enables corrections to be made for differences in optical properties and geometry resulting in comparable amounts of light available for Foscan absorption.

Three-dimensional intravascular ultrasound assessment of noninjured edges of beta-irradiated coronary segments.

BACKGROUND: The "edge effect," late lumen loss at the margins of the treated segment, has become an important issue in the field of coronary brachytherapy. The aim of the present study was to assess the edge effect in noninjured margins adjacent to the irradiated segments after catheter-based intracoronary beta-irradiation. METHODS AND RESULTS: Fifty-three vessels were assessed by means of 3-dimensional intravascular ultrasound after the procedure and at 6- to 8-month follow-up. Fourteen vessels (placebo group) did not receive radiation (sham source), whereas 39 vessels were irradiated. In the irradiated group, 48 edges (5 mm in length) were identified as noninjured, whereas 18 noninjured edges were selected in the placebo group. We compared the volumetric intravascular ultrasound measurements of the noninjured edges of the irradiated vessels with the fully irradiated nonstented segments (IRS, n=27) (26-mm segments received the prescribed 100% isodose) and the noninjured edges of the vessels of the placebo patients. The lumen decreased (6 mm(3)) in the noninjured edges of the irradiated vessels at follow-up (P:=0. 001). We observed a similar increase in plaque volume in all segments: noninjured edges of the irradiated group (19.6%), noninjured edges of the placebo group (21.5%), and IRS (21.0%). The total vessel volume increased in the IRS in the 3 groups. No edge segment was subject to repeat revascularization. CONCLUSIONS: The edge effect occurs in the noninjured margins of radiation source train in both irradiated and placebo patients. Thus, low-dose radiation may not play an important role in this phenomenon, whereas nonmeasurable device injury may be considered a plausible alternative explanation.

Positive geometric vascular remodeling is seen after catheter-based radiation followed by conventional stent implantation but not after radioactive stent implantation.

BACKGROUND: Recent reports demonstrate that intracoronary radiation affects not only neointimal formation but also vascular remodeling. Radioactive stents and catheter-based techniques deliver radiation in different ways, suggesting that different patterns of remodeling after each technique may be expected. METHODS AND RESULTS: We analyzed remodeling in 18 patients after conventional stent implantation, 16 patients after low-activity radioactive stent implantation, 16 patients after higher activity radioactive stent implantation, and, finally, 17 patients who underwent catheter-based radiation followed by conventional stent implantation. Intravascular ultrasound with 3D reconstruction was used after stent implantation and at the 6-month follow-up to assess remodeling within the stent margins and at its edges. Preprocedural characteristics were similar between groups. In-stent neointimal hyperplasia (NIH) was inhibited by high-activity radioactive stent implantation (NIH 9.0 mm(3)) and by catheter-based radiation followed by conventional stent implantation (NIH 6.9 mm(3)) compared with low-activity radioactive stent implantation (NIH 21.2 mm(3)) and conventional stent implantation (NIH 20.8 mm(3)) (P:=0.008). No difference in plaque or total vessel volume was seen behind the stent in the conventional, low-activity, or high-activity stent implantation groups. However, significant increases in plaque behind the stent (15%) and in total vessel volume (8%) were seen in the group that underwent catheter-based radiation followed by conventional stent implantation. All 4 groups demonstrated significant late lumen loss at the stent edges; however, edge restenosis was seen only in the group subjected to high-activity stent implantation and appeared to be due to an increase in plaque and, to a lesser degree, to negative remodeling. CONCLUSIONS: Distinct differences in the patterns of remodeling exist between conventional, radioactive, and catheter-based radiotherapy with stenting.

Geographic miss: a cause of treatment failure in radio-oncology applied to intracoronary radiation therapy.

BACKGROUND: A recognized limitation of endovascular beta-radiation therapy is the development of new stenosis at the edges of the irradiated area. The combination of injury and low-dose radiation may be the precursor of this phenomenon. We translated the radio-oncological concept of "geographic miss" to define cases in which the radiation source did not fully cover the injured area. The aims of the study were to determine the incidence and causes of geographic miss and evaluate the impact of this inadequate treatment on the outcome of patients treated with intracoronary beta-radiation. METHODS AND RESULTS: We analyzed 50 consecutive patients treated with beta-radiation after percutaneous coronary intervention. The prescribed dose ranged between 12 and 20 Gy at 2 mm from the source axis. By means of quantitative coronary angiography, the irradiated segment (IRS) and both edges were studied before and after intervention and at 6-month follow-up. Edges that were injured during the procedure constituted the geographic miss edges. Twenty-two edges were injured during the intervention, mainly because of procedural complications that extended the treatment beyond the margins of the IRS. Late loss was significantly higher in geographic miss edges than in IRSs and uninjured edges (0.84+/-0.6 versus 0.15+/-0.4 and 0.09+/-0.4 mm, respectively; P<0.0001). Similarly, restenosis rate was significantly higher in the injured edges (10% within IRS, 40.9% in geographic miss edges, and 1.9% in uninjured edges; P<0.001). CONCLUSIONS: These data support the hypothesis that the combination of injury and low-dose beta-radiation induces deleterious outcome.

Residual plaque burden, delivered dose, and tissue composition predict 6-month outcome after balloon angioplasty and beta-radiation therapy.

BACKGROUND: Inhomogeneity of dose distribution and anatomic aspects of the atherosclerotic plaque may influence the outcome of irradiated lesions after balloon angioplasty (BA). We evaluated the influence of delivered dose and morphological characteristics of coronary stenoses treated with beta-radiation after BA. METHODS AND RESULTS: Eighteen consecutive patients treated according to the Beta Energy Restenosis Trial 1.5 were included in the study. The site of angioplasty was irradiated with the use of a beta-emitting (90)Sr/(90)Y source. With the side branches used as anatomic landmarks, the irradiated area was identified and volumetric assessment was performed by 3D intracoronary ultrasound imaging after treatment and at 6 months. The type of tissue, the presence of dissection, and the vessel volumes were assessed every 2 mm within the irradiated area. The minimal dose absorbed by 90% of the adventitial volume (D(v90)Adv) was calculated in each 2-mm segment. Diffuse calcified subsegments and those containing side branches were excluded. Two hundred six coronary subsegments were studied. Of those, 55 were defined as soft, 129 as hard, and 22 as normal/intimal thickening. Plaque volume showed less increase in hard segments as compared with soft and normal/intimal thickening segments (P<0.0001). D(v90)Adv was associated with plaque volume at follow-up after a polynomial equation with linear and nonlinear components (r = 0.71; P = 0.0001). The multivariate regression analysis identified the independent predictors of the plaque volume at follow-up: plaque volume after treatment, D(v90)Adv, and type of plaque. CONCLUSIONS: Residual plaque burden, delivered dose, and tiss composition play a fundamental role in the volumetric outcome at 6-month follow-up after beta-radiation therapy and BA.

Geometric vascular remodeling after balloon angioplasty and beta-radiation therapy: A three-dimensional intravascular ultrasound study.

BACKGROUND: Endovascular radiation appears to inhibit intimal thickening after overstretching balloon injury in animal models. The effect of brachytherapy on vascular remodeling is unknown. The aim of the study was to determine the evolution of coronary vessel dimensions after intracoronary irradiation after successful balloon angioplasty in humans. METHODS AND RESULTS: Twenty-one consecutive patients treated with balloon angioplasty and beta-radiation according to the Beta Energy Restenosis Trial-1.5 were included in the study. Volumetric assessment of the irradiated segment and both edges was performed after brachytherapy and at 6-month follow-up. Intravascular ultrasound images were acquired by means of ECG-triggered pullback, and 3-D reconstruction was performed by automated edge detection, allowing the calculation of lumen, plaque, and external elastic membrane (EEM) volumes. In the irradiated segments, mean EEM and plaque volumes increased significantly (451+/-128 to 490.9+/-159 mm(3) and 201.2+/-59 to 241.7+/-74 mm(3); P=0.01 and P=0.001, respectively), whereas luminal volume remained unchanged (250.8+/-91 to 249.2+/-102 mm(3); P=NS). The edges demonstrated an increase in mean plaque volume (26.8+/-12 to 32. 6+/-10 mm(3), P=0.0001) and no net change in mean EEM volume (71. 4+/-24 to 70.9+/-24 mm(3), P=NS), resulting in a decrease in mean luminal volume (44.6+/-16 to 38.3+/-16 mm(3), P=0.01). CONCLUSIONS: A different pattern of remodeling is observed in coronary segments treated with beta-radiation after successful balloon angioplasty. In the irradiated segments, the adaptive increase of EEM volume appears to be the major contributor to the luminal volume at follow-up. Conversely, both edges showed an increase in plaque volume without a net change in EEM volume.

Late coronary occlusion after intracoronary brachytherapy.

BACKGROUND: Intracoronary brachytherapy appears to be a promising technology to prevent restenosis. Presently, limited data are available regarding the late safety of this therapeutic modality. The aim of the study was to determine the incidence of late (>1 month) thrombosis after PTCA and radiotherapy. METHODS AND RESULTS: From April 1997 to March 1999, we successfully treated 108 patients with PTCA followed by intracoronary beta-radiation. Ninety-one patients have completed at least 2 months of clinical follow-up. Of these patients, 6.6% (6 patients) presented with sudden thrombotic events confirmed by angiography 2 to 15 months after intervention (2 balloon angioplasty and 4 stent). Some factors (overlapping stents, unhealed dissection) may have triggered the thrombosis process, but the timing of the event is extremely unusual. Therefore, the effect of radiation on delaying the healing process and maintaining a thrombogenic coronary surface is proposed as the most plausible mechanism to explain such late events. CONCLUSIONS: Late and sudden thrombosis after PTCA followed by intracoronary radiotherapy is a new phenomenon in interventional cardiology.

beta-Particle-emitting radioactive stent implantation. A safety and feasibility study.

BACKGROUND: This study represents the Heart Center Rotterdam's contribution to the Isostents for Restenosis Intervention Study, a nonrandomized multicenter trial evaluating the safety and feasibility of the radioactive Isostent in patients with single coronary artery disease. Restenosis after stent implantation is primarily caused by neointimal hyperplasia. In animal studies, beta-particle-emitting radioactive stents decrease neointimal hyperplasia by inhibiting smooth muscle cell proliferation. METHODS AND RESULTS: The radioisotope (32)P, a beta-particle emitter with a half-life of 14.3 days, was directly embedded into the Isostent. The calculated range of radioactivity was 0.75 to 1.5 microCi. Quantitative coronary angiography measurements were performed before and after the procedure and at 6-month follow-up. A total of 31 radioactive stents were used in 26 patients; 30 (97%) were successfully implanted, and 1 was embolized. Treated lesions were in the left anterior descending coronary artery (n=12), the right coronary artery (n=8), or the left circumflex coronary artery (n=6). Five patients received additional, nonradioactive stents. Treated lesion lengths were 13+/-4 mm, with a reference diameter of 2.93+/-0. 47 mm. Minimum lumen diameter increased from 0.87+/-0.28 mm preprocedure to 2.84+/-0.35 mm postprocedure. No in-hospital adverse cardiac events occurred. All patients received aspirin indefinitely and ticlopidine for 4 weeks. Twenty-three patients (88%) returned for 6-month angiographic follow-up; 17% of them had in-stent restenosis, and 13% had repeat revascularization. No restenosis was observed at the stent edges. Minimum lumen diameter at follow-up averaged 1.85+/-0.69 mm, which resulted in a late loss of 0.99+/-0. 59 mm and a late loss index of 0.53+/-0.35. No other major cardiac events occurred during the 6-month follow-up. CONCLUSIONS: The use of radioactive stents with an activity of 0.75 to 1.5 microCi is safe and feasible.

Radioactive stents delay but do not prevent in-stent neointimal hyperplasia.

BACKGROUND: Restenosis after conventional stenting is almost exclusively caused by neointimal hyperplasia. Beta-particle-emitting radioactive stents decrease in-stent neointimal hyperplasia at 6-month follow-up. The purpose of this study was to evaluate the 1-year outcome of (32)P radioactive stents with an initial activity of 6 to 12 microCi using serial quantitative coronary angiography and volumetric ECG-gated 3D intravascular ultrasound (IVUS). METHODS AND RESULTS: Of 40 patients undergoing initial stent implantation, 26 were event-free after the 6-month follow-up period and 22 underwent repeat catheterization and IVUS at 1 year; they comprised half of the study population. Significant luminal deterioration was observed within the stents between 6 months and 1 year, as evidenced by a decrease in the angiographic minimum lumen diameter (-0.43+/-0.56 mm; P:=0.028) and in the mean lumen diameter in the stent (-0.55+/-0. 63 mm; P:=0.001); a significant increase in in-stent neointimal hyperplasia by IVUS (18.16+/-12.59 mm(3) at 6 months to 27.75+/-11. 99 mm(3) at 1 year; P:=0.001) was also observed. Target vessel revascularization was performed in 5 patients (23%). No patient experienced late occlusion, myocardial infarction, or death. By 1 year, 21 of the initial 40 patients (65%) remained event-free. CONCLUSIONS: Neointimal proliferation is delayed rather than prevented by radioactive stent implantation. Clinical outcome 1 year after the implantation of stents with an initial activity of 6 to 12 microCi is not favorable when compared with conventional stenting.

Angiographical follow-up after radioactive "Cold Ends" stent implantation: a multicenter trial.

BACKGROUND: Radioactive stents with an activity of 0.75 to 12 microCi have shown >40% edge restenosis due to neointimal hyperplasia and negative remodeling. This trial evaluated whether radioactive Cold Ends stents might resolve edge restenosis by preventing remodeling at the injured extremities. METHODS AND RESULTS: The 25-mm long (15-mm radioactive center and 5-mm nonradioactive ends) Cold Ends stents had an activity of 3 to 12 microCi at implantation. Forty-three stents were implanted in 43 patients with de novo native coronary artery disease. Two procedural, 1 subacute, and 1 late stent thrombosis occurred. A restenosis rate of 22% was observed with a shift of the restenosis, usually occurring at the stent edges of radioactive stents, into the Cold Ends stents. The most severe restenosis occurred at the transition zone from radioactive to nonradioactive segments, a region located in dose fall-off. CONCLUSION: Cold Ends stents did not resolve edge restenosis.

Preserved endothelium-dependent vasodilation in coronary segments previously treated with balloon angioplasty and intracoronary irradiation.

BACKGROUND: Abnormal endothelium-dependent coronary vasomotion has been reported after balloon angioplasty (BA), as well as after intracoronary radiation. However, the long-term effect on coronary vasomotion is not known. The aim of this study was to evaluate the long-term vasomotion of coronary segments treated with BA and brachytherapy. METHODS AND RESULTS: Patients with single de novo lesions treated either with BA followed by intracoronary beta-irradiation (according to the Beta Energy Restenosis Trial-1.5) or with BA alone were eligible. Of these groups, those patients in stable condition who returned for 6-month angiographic follow-up formed the study population (n=19, irradiated group and n=11, control group). Endothelium-dependent coronary vasomotion was assessed by selective infusion of serial doses of acetylcholine (ACh) proximally to the treated area. Mean luminal diameter was calculated by quantitative coronary angiography both in the treated area and in distal segments. Endothelial dysfunction was defined as a vasoconstriction after the maximal dose of ACh (10(-6) mol/L). Seventeen irradiated segments (89.5%) demonstrated normal endothelial function. In contrast, 10 distal nonirradiated segments (53%) and 5 control segments (45%) demonstrated endothelium-dependent vasoconstriction (-19+/-17% and -9.0+/-5%, respectively). Mean percentage of change in mean luminal diameter after ACh was significantly higher in irradiated segments (P=0.01). CONCLUSIONS: Endothelium-dependent vasomotion of coronary segments treated with BA followed by beta-radiation is restored in the majority of stable patients at 6-month follow-up. This functional response appeared to be better than those documented both in the distal segments and in segments treated with BA alone.

"Edge Effect" of (32)p radioactive stents is caused by the combination of chronic stent injury and radioactive dose falloff.

BACKGROUND: Radioactive stents have been reported to reduce in-stent neointimal thickening. An unexpected increase in neointimal response was observed, however, at the stent-to-artery transitions, the so-called "edge effect." To investigate the factors involved in this edge effect, we studied stents with 1 radioactive half and 1 regular nonradioactive half, thereby creating a midstent radioactive dose-falloff zone next to a nonradioactive stent-artery transition at one side and a radioactive stent-artery transition at the other side. METHODS AND RESULTS: Half-radioactive stents (n=20) and nonradioactive control stents (n=10) were implanted in the coronary arteries of Yucatan micropigs. Animals received aspirin and clopidogrel as antithrombotics. After 4 weeks, a significant midstent stenosis was observed by angiography in the half-radioactive stents. Two animals died suddenly because of coronary occlusion at this mid zone at 8 and 10 weeks. At 12-week follow-up angiography, intravascular ultrasound and histomorphometry showed a significant neointimal thickening at the midstent dose-falloff zone of the half-radioactive stents, but not at the stent-to-artery transitions at both extremities. Such a midstent response (mean angiographic late loss 1.0 mm) was not observed in the nonradioactive stents (mean loss 0.4 to 0.6 mm; P< 0.01). CONCLUSIONS: The edge effect of high-dose radioactive stents in porcine coronary arteries is associated with the combination of stent injury and radioactive dose falloff.

Patient participation in clinical decision-making for treatment of T3 laryngeal cancer: a comparison of state and process utilities.

PURPOSE: To study the use of two different approaches, and feasibility of four commonly used utility assessment methods to assess preferences for treatment of T3-laryngeal cancer by surgery or radiation therapy (RT). METHODS: Utility assessment methods, namely, time trade-off (TTO), standard reference gamble (SRG), rating scale (RS), and direct comparison (DC), were used to assess utilities in two groups of former cancer patients (n = 10 for both), a group of clinicians (n = 9), and a group from the general population (n = 10). For the treatment modalities, ie, surgery and RT, two types of scenarios were developed and used: the state scenario, which describes a stable health state after treatment, and the process scenario, which describes a dynamic process. First, utilities were assessed based on state scenarios. Next, respondents were thoroughly informed and educated with respect to the relevant aspects of both treatment modalities. Subsequently, utilities were again assessed, but now based on the process scenarios. The outcome of each approach was calculated and expressed in a quality-adjusted life-expectancy (QALE) score for each treatment modality, and the treatment with the highest outcome was said to be the preferred treatment modality. RESULTS: In general, a higher QALE score for each treatment modality was found for clinicians and for the general population as compared with the former-cancer-patient groups. When the outcome of both approaches was compared on an individual level dependent on the utility assessment method, 32% to 43% of respondents showed an inconsistent treatment preference. CONCLUSION: The approach to assess utilities and the extent to which respondents are informed about treatment modalities have a major effect on individual treatment preferences.

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.

Endovascular brachytherapy for the prevention of restenosis after femoropopliteal angioplasty. Results of the VARA Trial.

AIM: Endovascular brachytherapy (EBT) has been proposed as a method to prevent restenosis. We performed a prospective randomised multicenter study to determine its efficacy for prophylaxis of restenosis after femoropopliteal percutaneous transluminal angioplasty (PTA). METHODS: Patients with symptomatic stenotic or totally occluding lesions in the femoropopliteal artery were randomised to be treated with PTA plus EBT or PTA alone. In case of EBT, 14 Gy was applied by an 192Ir source to the vessel wall. Clinical examination, ankle-brachial pressure index (ABPI) and duplex ultrasound were planned after 6 and 12 months. The primary endpoint was significant restenosis of the treated segment at duplex ultrasound after 12 months. RESULTS: Fifty-three of the 60 patients who eventually met the inclusion criteria could be studied. After 12 months, restenosis rates were 44% (12/27) in the PTA group versus 35% (8/23) in the PTA + EBT group (c2 test, P=0.51). There was no difference in mandatory reintervention between the 2 groups. Overall, EBT resulted in an absolute risk reduction of significant restenosis of 9%, yet in patients with totally occlusive disease this reduction was 32%. CONCLUSIONS: This study suggests an effect of EBT on the occurrence of restenosis only after PTA of occluded femoropopliteal lesions. Due to a too small number of patients analysed this difference is not statistically significant.

Radiation therapy of squamous cell carcinoma of the nasal vestibule.

From 1978 until 1988, 63 consecutive patients with squamous cell carcinoma of the nasal vestibule were treated by radiation therapy. Mean follow-up time was 46 months. Thirty-five patients were classified as having T1N0 tumors, 24 as T2N0; four patients were staged as T1/2N+. Treatment of the primary consisted of external radiation (n = 17), interstitial radiation (n = 37), or external radiation combined with interstitial radiation (n = 9). With respect to the N0 patients, local relapse was found in 3% (1/35) of T1 tumors and in 21% (5/24) of T2 tumors. Three out of six failures were salvaged by surgery. Elective irradiation of both sides of the neck (40 Gy) was performed in 9 T1 and in 16 T2 patients. Two regional failures occurred in the electively irradiated necks, two in the non-irradiated necks. Regarding the T1/2N+ patients, three relapsed locally and/or regionally, and one remains NED. For all 63 patients, a 5-year corrected survival of 90%, a relapse-free survival of 80%, and an overall survival of 65% were observed. In summary, for optimal local control and cosmesis we feel that for T1,2 N0 tumor stages a dose of 60 Gy for T1 and 70 Gy for T2 tumors is adequate treatment. The primary tumor is irradiated preferentially in our view, by means of interstitial techniques; furthermore, our data do not support the use of elective neck RT. Although patients rarely present with lymph node metastasis (6%), the prognosis of T1,2 N+ patients remains grim and more aggressive (surgical) treatment might be needed for this category.

The history of radiotherapy in The Netherlands.

Soon after the discovery of x-rays by W. C. Roentgen in 1895, a publication on fluoroscopy and x-ray pictures/films appeared in the Dutch medical literature in February 1896. The present article reviews the subsequent developments in the field of therapeutic radiology in The Netherlands and, in particular, the evolution of radiation oncology as a distinct medical specialty.

Pulsed dose rate and fractionated high dose rate brachytherapy: choice of brachytherapy schedules to replace low dose rate treatments.

PURPOSE: Pulsed dose rate (PDR) brachytherapy is a new type of afterloading brachytherapy (BT) in which a continuous low dose rate (LDR) treatment is simulated by a series of "pulses," i.e., fractions of short duration (less than 0.5 h) with intervals between fractions of 1 to a few hours. At the Dr. Daniel den Hoed Cancer Center, the term "PDR brachytherapy" is used for treatment schedules with a large number of fractions (at least four per day), while the term "fractionated high dose rate (HDR) brachytherapy" is used for treatment schedules with just one or two brachytherapy fractions per day. Both treatments can be applied as alternatives for LDR BT. This article deals with the choice between PDR and fractionated HDR schedules and proposes possible fractionation schedules. METHODS AND MATERIALS: To calculate HDR and PDR fractionation schedules with the intention of being equivalent to LDR BT, the linear-quadratic (LQ) model has been used in an incomplete repair formulation as given by Brenner and Hall, and by Thames. In contrast to earlier applications of this model, both the total physical dose and the overall time were not kept identical for LDR and HDR/PDR schedules. A range of possible PDR treatment schedules is presented, both for booster applications (in combination with external radiotherapy (ERT) and for BT applications as a single treatment. Because the knowledge of both alpha/beta values and the half time for repair of sublethal damage (T 1/2), which are required for these calculations, is quite limited, calculations regarding the equivalence of LDR and PDR treatments have been performed for a wide range of values of alpha/beta and T 1/2. The results are presented graphically as PDR/LDR dose ratios and as ratios of the PDR/LDR tumor control probabilities. RESULTS: If the condition that total physical dose and overall time of a PDR treatment must be exactly identical to the values for the corresponding LDR treatment regimen is not applied, there appears to be less need for strong fractionation in PDR schedules. If the overall time is at least as long as that of the LDR schedule and if the total physical dose is (slightly) adapted, PDR schedules can be designed using longer pulse intervals of up to 3 h. Schedules with sufficiently long intervals have significant logistic advantages in terms of patient care and treatment tolerance. However, in general, PDR schedules that apply more fractionation have a lower risk of overdosing normal tissues in comparison to fractionated HDR schedules. Applying probable ranges for the values of alpha/beta and T 1/2, the model calculations indicate that the differences in effects between the proposed fractionated HDR and PDR schedules could be rather small. To detect the magnitude of these differences, (randomized) clinical studies with rather large patient groups might be needed. CONCLUSIONS: Pulsed dose rate treatment schedules with longer intervals of up to 3 h appear adequate to replace LDR treatment schedules. Whether PDR schedules can, indeed, replace LDR treatment schedules and whether they offer detectable advantages over schedules with less fractionation (fractionated HDR) should be tested in clinical studies.