Rhenium-188-Labeled DTPA: a new radiopharmaceutical for intravascular radiation therapy

Balloon angioplasty is a standard treatment for artherosclerotic coronary artery disease. However, its clinical value is reduced by a high restenosis rate. A new concept in preventing restenosis is the use of a liquid-filled balloon containing a beta-emitting radioisotope. In this study, we performed biodistribution studies of Re-188 perrhenate and Re-188 diethylenetriaminopentaacetate (DTPA) to assess the resulting organ dose values in the event of balloon rupture if these agents are used for the clinical inhibition of restenosis after percutaneous transluminal coronary angioplasty (PTCA). After injecting Re-188 preparations intravenously, rats were killed at 10 min, 30 min, 60 min, 2 h, and 6 h ( n =5 per group). Tissue concentrations were calculated and expressed as percent injected dose per gram or per milliliter (%ID/g or %ID/mL). In addition, urine excretion and thyroid gland uptake were evaluated in rats ( n=5 per group) with a gamma camera after administration of 37 MBq (1 mCi) of each agent. Our data showed that both agents were excreted primarily via urine. However, the excretion of Re-188 DTPA was much faster than that of Re-188 perrhenate via the urinary system. The biodistribution data revealed that radioactivity levels in the stomach and the thyroid gland were high in the perrhenate group but low in the Re-188 DTPA group. The concentration levels in other tissues including lung, liver, testis, muscle, and blood were low throughout this study for both agents. The thyroid radiation value in the Re-188 perrhenate group was 0.163 mGy/MBq, which was much higher than that of the Re-188 DTPA group (0.0167 mGy/MBq). The stomach radiation value was as high as 0.127 mGy/MBq for Re-188 perrhenate, compared with 0.013 mGy/MBq for Re-188 DTPA. In conclusion, in the event of balloon rupture, the release of Re-188 DTPA results in lower radiation doses than Re-188 perrhenate, especially to the thyroid gland and the stomach. Our data suggest that Re-188 DTPA is a useful radiopharmaceutical for endovascular irradiation.     

基于图谱库的自动轮廓勾画软件在宫颈癌自适应放疗中的应用

目的 评估基于图谱库的自动轮廓勾画软件(ABAS)在宫颈癌自适应放疗中的应用.方法 选取2014年1月至3月收治的21例已行第1程调强放疗的宫颈癌患者,将其已勾画器官的CT图像及第2程未勾画器官的定位CT图像传输至ABAS软件系统,以第1程图像为模板图像,第2程定位图像作为目标图像.在第2程定位图像上手工勾画出靶区和危及器官,将ABAS软件自动勾画图像和医师手工勾画的靶区、危及器官图像传输至飞利浦Pinnacle计划系统,对两组结果进行评估.比较相似性指数(DSC)和勾画体积.结果 ABAS自动勾画与医师手工勾画的DSC平均值均大于0.7,其中靶区的DSC最大为肿瘤临床靶区(CTV, 0.89±0.08),最低为肿瘤区(GTV, 0.72±0.16).对于危及器官,DSC最高的为右股骨头(0.88±0.05),最低为直肠(0.73±0.07).左右髂骨自动勾画体积较手工勾画小,且差异具有统计学意义(t=3.37、2.74, P<0.05),其他轮廓体积差异无统计学意义.结论 宫颈癌放疗过程中,基于图谱库的ABAS勾画软件,节省了临床器官勾画工作时间,加强自动勾画后的轮廓修改,并建立患者模板数据库,得到满意度更高的重合结果,也为开展自适应放疗提供了强有力的支持.     

The birth,decline, and contemporary re-emergence of endovascular brachytherapy for prevention of in-stent restenosis

Despite the advent of drug-eluting stents and dual antiplatelet therapy in the interventional management of cardiovascular disease, restenosis rates remain high with significant sequelae. Endovascular brachytherapy—popular in the 1990s and early 2000s—has recently resurfaced as a cost-effective treatment option. In this work, we outline the history of endovascular brachytherapy starting with its earliest promise in the 1990s. We discuss the development of drug-eluting stents and dual antiplatelet strategies and their impact on the perceived benefit of endovascular brachytherapy. For the contemporary era, we propose novel roles for endovascular brachytherapy in complex coronary artery disease and in high-risk patients managed with drug-eluting stents. We discuss the impetus for reducing the requirement and duration of dual antiplatelet therapy using endovascular brachytherapy. We also review innovative opportunities for endovascular brachytherapy after bare-metal stent placement in both coronary and noncoronary territories and offer economic arguments in favor of endovascular brachytherapy. Trials of endovascular brachytherapy in these regimes are merited.     

Potential 166Ho radiopharmaceuticals for endovascular radionuclide therapy. II. Preparation and evaluation of 166Ho-DTPA

166Ho, with its favourable radiation characteristics of t(1/2) 26.8 h and Ebeta 1.85 and 1.75 MeV, is proposed as a suitable choice for the endovascular radionuclide therapy (EVRT) technique of liquid filled, low pressure balloon angioplasty. 166Ho was produced by the (n,gamma) reaction on a natural Ho2O3 target. The specific activity obtained was approximately 100 mCi x mg(-1) when irradiated at a flux of 2 x 10(13) n x cm(-2) s(-1) for approximately 7 days, and the possible contaminant 166Ho(m) was not detected. 166Ho was easily complexed with diethylenetriaminepentaacetic acid (DTPA) at a ligand to metal molar ratio ([L]:[M]) of 1:1 at room temperature (22-23 degrees C) and a reaction time of a few minutes. The radiochemical purity was >99%, as determined by paper chromatography using a mixture of pyridine, ethanol and water (1:2:4) as solvent. The complex had good stability up to 72 h at 37 degrees C in a serum environment. In a study using Swiss mice > 85% of the injected dose was cleared into the urine within 30 min post-injection, with insignificant retention in any major tissues. The studies show that the 166Ho-DTPA complex could be an alternative to the more expensive and difficult to access 188Re based products for EVRT, and provide adequate uniform radiation dose for the arterial vessel wall under treatment.     

A detailed evaluation of TomoDirect 3DCRT planning for whole-breast radiation therapy

The goal of this work was to develop planning strategies for whole-breast radiotherapy (WBRT) using TomoDirect three-dimensional conformal radiation therapy (TD-3DCRT) and to compare TD-3DCRT with conventional 3DCRT and TD intensity-modulated radiation therapy (TD-IMRT) to evaluate differences in WBRT plan quality. Computed tomography (CT) images of 10 women were used to generate 150 WBRT plans, varying in target structures, field width (FW), pitch, and number of beams. Effects on target and external maximum doses (EMD), organ-at-risk (OAR) doses, and treatment time were assessed for each parameter to establish an optimal planning technique. Using this technique, TD-3DCRT plans were generated and compared with TD-IMRT and standard 3DCRT plans. FW 5.0 cm with pitch = 0.250 cm significantly decreased EMD without increasing lung V20 Gy. Increasing number of beams from 2 to 6 and using an additional breast planning structure decreased EMD though increased lung V20 Gy. Changes in pitch had minimal effect on plan metrics. TD-3DCRT plans were subsequently generated using FW 5.0 cm, pitch = 0.250 cm, and 2 beams, with additional beams or planning structures added to decrease EMD when necessary. TD-3DCRT and TD-IMRT significantly decreased target maximum dose compared to standard 3DCRT. FW 5.0 cm with 2 to 6 beams or novel planning structures or both allow for TD-3DCRT WBRT plans with excellent target coverage and OAR doses. TD-3DCRT plans are comparable to plans generated using TD-IMRT and provide an alternative to conventional 3DCRT for WBRT.     

Neurovascular lesions and endovascular therapy: the role of MR

Summary Magnetic resonance imaging (MRI) studies were performed on 27 patients with vascular lesions of the central nervous system before and after embolization with either IBCA, polyvinyl alcohol foam particles, Avitene (microfibrillar collagen) or balloons. Thirteen pial brain arteriovenous malformations (AVMs), 3 brain AV fistulas, 2 giant aneurysms, 5 dural AVMs, 1 vertebro-vertebral fistula and 3 meningiomas were studied. The pre-embolization MR demonstrated the nidus and venous drainage of all pial AVMs. MR failed to detect 3 out of 5 dural AVMs using only spin echo sequences. A draining vein alone was seen in the remaining two cases. MR was superior to CT in detecting contiguous parenchymal changes such as atrophy, reversible ischemia, and mass effect in the pre-embolization studies. Following embolization, MR demonstrated partial or complete obliteration of the vascular nidus in all 13 pial AVMs. The embolized area was seen as an area of increased signal consistent with thrombus where previously there had been signal void. Ischemic or edematous changes in the brain parenchyma following embolization were seen on MR more easily than on CT scans. MR was accurate in the assessment of aneurysm patency, degree of thrombosis and balloon position in both giant aneurysms, and AV fistulae. These MR findings had an impact on patient management. MR will be an increasingly useful tool in the diagnosis and management of a number of neurovascular diseases requiring endovascular intervention.     

急性下肢深静脉血栓形成腔内治疗的中远期疗效观察

目的：评估血管腔内治疗急性下肢深静脉血栓形成（DVT）的中远期疗效。 方法：选取2007年10月至2017年5月东莞市人民医院收治的180例下肢DVT患者,其中120例接受血管腔内治疗联合导管接触性溶栓治疗（介入组）;60例在足量抗凝治疗基础上,经患肢足背静脉局部溶栓（对照组）;所有患者出院后抗凝治疗2年;介入组26例患者停止抗凝后血栓复发,再次接受血管腔内治疗,其后终身抗凝治疗;比较两组的治疗效果、髂静脉通畅率及血栓后综合征（PTS）发生率。 结果：介入组的有效率明显优于对照组（100% vs. 86.7%）,差异有统计学意义（Z=113.679,P<0.05）;介入组治疗1、2、5、10年后,患侧髂静脉血管通畅率分别为89.2%、95%、84.6%、100%,远高于对照组的8.3%、5%、0%、0%;介入组PTS发生率（13.3%）明显低于单纯抗凝治疗组（46.7%）,差异有统计学意义。 结论：血管腔内治疗能有效提高DVT患者的治疗效果,降低PTS的发生率,血管腔内治疗急性DVT安全、有效。     

Risk analysis of electronic intraoperative radiation therapy for breast cancer

PurposeTo evaluate the process and improve safety of intraoperative radiation therapy (IORT) for early-stage breast cancers treated with electronic brachytherapy.Methods and MaterialsA multidisciplinary team conducted a failure mode and effects analysis (FMEA) for IORT breast cancer treatments by first developing a process map. This map was then used to identify failure modes for all steps in the treatment workflow. Risk priority numbers (RPNs) were assigned to each failure mode and were calculated as the product of the failure mode's probability of occurrence (O), severity (S), and lack of detectability (D). Corrective steps were implemented to address failure modes with the highest risk, and a revised process was generated.ResultsThe steps with the highest risk failure modes were related to source calibration, use of correct plan and dwell times, and the correct site and intent. The introduction of a physician calibration check and an extended time-out checklist reduced the risk of these failure modes. The highest risk steps in the Xoft breast IORT treatment process are associated with source calibration and manual entry of dwell positions for each balloon size and volume combination. High-risk failure modes that could be mitigated with improved hardware and software interlocks were identified.ConclusionHigh-risk failure modes are identified with FMEA and addressed with corrective steps. This application of FMEA can be used in principle for clinical processes throughout breast cancer care. This analysis demonstrates the importance of well-designed QC policies, procedures, and oversight in a Xoft electronic brachytherapy program for breast cancer IORT.     

Studying the biological feasibility of [99mTc(CO)3]-dextran-cysteine-cysteine-mannose as a potential molecular radiopharmaceutical for sentinel node detection

Objective

The aim of this work was to radiolabel and bioevaluate the technetium-99m labeled dextran dicysteine mannose (DCCM) [^99mTc(CO)₃]-DCCM for sentinel lymph node detection.

Methods

Dextran dicysteine mannose was radiolabeled using the carbonyl method. Various parameters were studied such as in vitro stability at room temperature up to 5 h, protein binding and partition coefficient. Bioevaluation was performed in a rabbit model by developing images under a gamma camera at various time intervals. Biodistribution was performed in Wistar rat models (n = 3) by dissection and measurement of percent injected dose in various body organs, at 60 and 180 min post-injection intervals. Biodistribution was performed in two different groups of animals: in the first group, the radiolabeled compound was injected at a concentration of 200 μg/ml, thus delivering 10 μg radiolabeled compound at the site of injection; in the second group, the radiolabeled compound was injected at a concentration of 50 μg/ml, delivering 2.5 μg radiolabeled compound at the site of injection.

Results

Radiolabeling efficacy was 97.5 ± 1 % which remained quite stable till 5 h. Protein binding data show that 71.1 ± 5 % drug exhibited binding with blood proteins. Partition coefficient results show that our radiopharmaceutical is quite hydrophilic in nature. It can be inferred from the imaging data that sentinel node can be visualized within 30 min post-injection. Rat dissection data showed that when the radiolabeled compound was injected at a concentration of 50 μg/ml, at 60 min post-injection, ~2.85 % of activity was retained in the sentinel node with a significantly less accumulation, e.g., ~0.12 %, in the secondary node, which resulted in very high popliteal extraction (PE) value, e.g., ~98 %. At 180 min post-injection, 2.46 ± 0.29 % was found to be retained in the sentinel node and PE (99.64 ± 0.23 %), thus resulting in almost complete washout from the secondary node (0.05 ± 0.01 %).

Conclusion

The study demonstrates that radiolabeled DCCM might be a successful radiopharmaceutical for sentinel node detection.     

妇科恶性肿瘤的介入治疗规范化讨论

经导管动脉内介入化疗或化疗性栓塞术因其创伤小、局部疗效较好,近些,年更为临床所重视。介入治疗为姑息治疗手段之一,与放、化疗配合应用,亦可作为手术前辅助治疗手段,对于少数病种可作为根治性治疗手段。一、介入治疗适应证和禁忌证(一)适应证①宫颈癌;②子宫内膜癌;③卵巢癌;④恶性滋养细胞肿瘤;⑤外阴癌。(二)禁忌证①不适合血管造影者,如造影剂过敏,甲亢,妊娠期等;②合并盆腔和宫腔感染者;③合并骨髓再生障碍或脑、心、肝、肾功能障碍者;④难以超选择性插管者为化疗栓塞术的相对禁忌证。二、介入术前准备①对术前需常规检查下列项目:血…     

Preclinical studies of the Chinese Herbal Medicine formulation PHY906 (KD018) as a potential adjunct to radiation therapy

Abstract

Objective: Abdominal and pelvic radiotherapy is limited by the radiosensitivity of the small and large intestine. PHY906 (KD018), a state-of-the-art, well defined adaptation of a traditional Chinese medicine, decreased intestinal injury from chemotherapy in preclinical studies and is in clinical trials with chemotherapy. This project assessed whether PHY906 would also reduce intestinal injury from abdominal irradiation in mice.

Materials and methods: BALB/c mice received whole-abdomen irradiation (2 Gy/day) ± PHY906 by oral gavage twice daily for 4 days. Intestinal injury was assayed by physiological observations and histological studies. Effects of PHY906 on EMT6 mouse mammary tumors were assayed in tumor growth studies.

Results: PHY906 decreased toxicity from fractionated abdominal irradiation. Radiation alone produced marked blunting and loss of villi, crypt hyperplasia and irregular crypt morphology, which were reduced by PHY906. The radiation-induced reduction in viable crypt numbers was also mitigated by PHY906. PHY906 did not alter radiation-induced weight loss, but resulted in more rapid recovery. PHY906 did not alter tumor growth, local invasion or metastatic spread and did not protect tumors from growth delays produced by single-dose or fractionated irradiation.

Conclusion: In this mouse model, PHY906 (KD018) decreased the toxicity of abdominal irradiation without protecting tumors and thereby increased the therapeutic ratio.     

左肾静脉受压综合征的介入治疗(附6例报道)

目的探讨左肾静脉受压综合征的影像学特征及介入治疗的方法和价值。方法对我院收治的6例行介入治疗的左肾静脉受压综合征患者的临床资料进行分析总结,讨论其临床特点、影像学特征及介入治疗的价值。结果6例患者影像学检查均呈典型胡桃夹综合征表现,CT血管造影多平面重建(MPR)图测得肠系膜上动脉与腹主动脉夹角为20.6°±4.04°,DSA造影术中测得受压近远侧血压差为(6.4±0.4)cmH2O;支架置入术后1年未发生支架移位、脱落及再狭窄等并发症,患者自觉症状改善明显。结论支架置入术治疗左肾静脉受压综合征安全、微创、有效。     

Therapeutic potential of melatonin for breast cancer radiation therapy patients

Melatonin is an endogenous hormone primarily known for its action on the circadian rhythms. But pre-clinical studies are reporting both its radioprotective and radiosensitizing properties, possibly mediated through an interaction between melatonin and the regulation of estrogens. Melatonin pre-treatment prior to ionizing radiation was associated with a decrease in cell proliferation and an increase in p53 mRNA expression, leading to an increase in the radiosensitivity of breast cancer cells. At the same time, a decrease in radiation-induced side effects was described in breast cancer patients and in rodent models. This review examines the potential for melatonin to improve the therapeutic outcomes of breast radiation therapy, specifically estrogen receptor positive patients. Evidence suggests that melatonin may offer a novel, non-toxic and cheap adjuvant therapy to improve the existing treatment modalities. But further research is required in the clinical setting before a clear understanding of its therapeutic benefits is determined.     

External beam planning module of Eclipse for external beam radiation therapy

Eclipse is a 3-dimensional (3D) treatment planning system for radiation therapy offered by Varian Medical Systems, Inc. The system has the network connectivity for the electronic transfer of image datasets and digital data communication among different equipment. The scope of this project for this special issue of Medical Dosimetry on 3D treatment planning systems is the assessment of planning tools in the external beam planning module of Eclipse to generate optimized treatment plans for patients undergoing external beam radiation therapy. This treatment planning system is relatively mature to be able to generate (1) simple treatment plans, (2) conformal radiation therapy plans, (3) static intensity-modulated radiation therapy (IMRT) plans, (4) volumetric-modulated arc therapy (VMAT) plans, and (5) treatment plans for electron beam therapy. The treatment planning tools are relatively plentiful to assist in the radiation therapy treatment planning. Some new features have been incorporated in the latest version and are helpful for making high-quality treatment plans. However, the location of the tools is not intuitive, and hence, familiarity with the user interface is essential to the efficient use of the treatment planning system. In addition, there are a number of dose algorithms available for the computation of dose distributions. The understanding of each dose computation algorithm is essential for the optimal use of this treatment planning system.     

Clinical effects of transcatheter hepatic arterial embolization with holmium-166 poly(l-lactic acid) microspheres in healthy pigs

PURPOSE: The aim of this study is to evaluate the toxicity of holmium-166 poly(L: -lactic acid) microspheres administered into the hepatic artery in pigs. METHODS: Healthy pigs (20-30 kg) were injected into the hepatic artery with holmium-165-loaded microspheres ((165)HoMS; n = 5) or with holmium-166-loaded microspheres ((166)HoMS; n = 13). The microspheres' biodistribution was assessed by single-photon emission computed tomography and/or MRI. The animals were monitored clinically, biochemically, and ((166)HoMS group only) hematologically over a period of 1 month ((165)HoMS group) or over 1 or 2 months ((166)HoMS group). Finally, a pathological examination was undertaken. RESULTS: After microsphere administration, some animals exhibited a slightly diminished level of consciousness and a dip in appetite, both of which were transient. Four lethal adverse events occurred in the (166)HoMS group due either to incorrect administration or comorbidity: inadvertent delivery of microspheres into the gastric wall (n = 2), preexisting gastric ulceration (n = 1), and endocarditis (n = 1). AST levels were transitorily elevated post-(166)HoMS administration. In the other blood parameters, no abnormalities were observed. Nuclear scans were acquired from all animals from the (166)HoMS group, and MRI scans were performed if available. In pigs from the (166)HoMS group, atrophy of one or more liver lobes was frequently observed. The actual radioactivity distribution was assessed through ex vivo (166m)Ho measurements. CONCLUSION: It can be concluded that the toxicity profile of HoMS is low. In pigs, hepatic arterial embolization with (166)HoMS in amounts corresponding with liver-absorbed doses of over 100 Gy, if correctly administered, is not associated with clinically relevant side effects. This result offers a good perspective for upcoming patient trials.     

放射性膀胱炎的治疗和预防

放射性膀胱炎是盆腔受照射后引起的一种并发症,主要临床表现为血尿。其有多种治疗方法,减少膀胱受照剂量是预防的主要措施。     

多层螺旋CT造影在主动脉病变腔内修复术后随访的价值

目的:探讨多层螺旋CT血管造影(multi-detector rowspiral computed tomography angiography,MDCTA)及后处理技术在主动脉覆膜支架腔内修复术(transluminal stent-graft placement,TSGP)术后随访的临床应用价值。方法:21例接受TSGP主动脉疾病患者,包括:Stanford B型夹层13例,真性动脉瘤3例,假性动脉瘤2例,弓降部穿透性溃疡1例,胸主动脉瘤合并局限性夹层1例,胸主动脉瘤合并Stanford B型夹层1例,术后采用MDCTA进行随访,平均随访13个月(1~24个月)。采用轴位图像与多种重建图像相结合来显示支架形态、术前术后主动脉管腔情况的变化和有无并发症。结果:13例主动脉夹层覆膜支架置入后:所有患者均真腔扩大,假腔减小或消失并伴血栓形成,支架未发现移位或断裂;共3例(14%)随访中发现内漏,1例Ⅱ型内漏,建议随访观察;1例术后8个月复查新发现支架近端Ⅰ型内漏,密切随访2个月后患者出现胸痛,复查CT内漏增多,转外科治疗。1例腹主动脉瘤术后1月复查发现Ⅲ型内漏。所有患者介入术后CT随访图像均满足临床诊断需要。结论:MDCTA对主动脉覆膜支架置入术后随访较其他检查手段具有多方面的优越性,能及时观察术后疗效、发现并发症,对主动脉疾病覆膜支架腔内修复术后随访具有重要价值。     

A catheter-based radiation detector for endovascular detection of atheromatous plaques

Purpose Although various radiopharmaceuticals have been developed for the detection of atheromas, external imaging techniques have limitations when it comes to the detection of small plaques. In this study, we developed a charged particle-sensitive detector for the endovascular detection of small plaques.Methods The device consists of a probe, an automatic pullback unit and a controller. The probe, which consists of a plastic scintillator and flexible optical fibres, is 1.0 mm in diameter. The probe was inserted into a catheter placed on ¹⁸F point sources, and then the radioactivity was measured as the probe was pulled out stepwise.Results The sensitivity for ¹⁸F was 9.3 cps/kBq, and there was a close linear correlation between the peak counts and source dose until at least 0.8 MBq. Furthermore, this device showed low background counts (<0.1 cps) and a low detection limit (0.21 kBq). To investigate the effect of background radioactivity on the measurement at the point sources, a ball phantom was prepared and five ¹⁸F point sources were set on the balls surface. Even though 298 MBq of ¹⁸F-fluorodeoxyglucose was injected into the ball, the point sources located every 10 mm on the balls surface were detectable separately.Conclusion The data gathered suggest that a catheter-based radiation detector in combination with charged particle-emitting radiopharmaceuticals is useful for the endovascular detection of small lesions such as coronary plaques.     

Dosimetric evaluation of multi-pattern spatially fractionated radiation therapy using a multi-leaf collimator and collapsed cone convolution superposition dose calculation algorithm

Purpose: In this paper, we present an alternative to the originally proposed technique for the delivery of spatially fractionated radiation therapy (GRID) using multi-leaf collimator (MLC) shaped fields. We employ the MLC to deliver various pattern GRID treatments to large solid tumors and dosimetrically characterize the GRID fields.Methods and materials: The GRID fields were created with different open to blocked area ratios and with variable separation between the openings using a MLC. GRID designs were introduced into the Pinnacle³ treatment planning system, and the dose was calculated in a water phantom. Ionization chamber and film measurements using both Kodak EDR2 and Gafchromic EBT film were performed in a SolidWater^® phantom to determine the relative output of each GRID design as well as its spatial dosimetric characteristics.Results: Agreement within 5.0% was observed between the Pinnacle³ predicted dose distributions and the measurements for the majority of experiments performed. A higher magnitude of discrepancy (15%) was observed using a high photon beam energy (18 MV) and small GRID opening. Skin dose at the GRID openings was higher than the corresponding open field by a factor as high as three for both photon energies and was found to be independent of the open-to-blocked area ratio.Conclusion: In summary, we reaffirm that the MLC can be used to deliver spatially fractionated GRID therapy and show that various GRID patterns may be generated. The Pinnacle³ TPS can accurately calculate the dose of the different GRID patterns in our study to within 5% for the majority of the cases based on film and ion chamber measurements. Disadvantages of MLC-based GRID therapy are longer treatment times and higher surface doses.