分次照射不同间隔时间对C57BL小鼠Lewis肺癌生长影响的研究

目的 通过对相同照射剂量、不同照射时间的放射对小鼠Lewis肺癌肿瘤生长延迟时间、小鼠生存时间的研究,探讨分次照射不同间隔时间对肿瘤的放射效应的影响.方法 将移植Lewis肺癌种鼠的肿瘤组织制备成1 × 107个/ml肿瘤细胞悬液,选掸48只8-10周雄性C57BL/6J小鼠右后肢外侧小腿腓肠肌处接种0.1 ml,建市移植瘤小鼠模型.肿瘤直径达0.8-1.0 cm时随机分成6个组:空白对照组、18 Gy单次照射组,9 Gy 2次每次间隔30 min组,2.57 Gy 7次每次间隔5 min组、9 Gy 2次每次间隔60 min组、2.57 Gy 7次每次问隔10 min组.隔日测量并记录肿瘤长短直径,观察肿瘤生长曲线、生长延缓时间及小鼠生存时间.结果 不同间隔时间各组生长延缓时间均<18 Gy单次照射组.照射总间隔时间30 min与60 min相比,小鼠肿瘤的生长变缓;而放射总间隔时间相同的各组,小鼠肿瘤生长延缓相似.与18 Gy单次照射组比较,放射总间隔时间延长缩短了小鼠生存时间;放射间隔时间30min和60min对小鼠肿瘤牛长影响相似.结论 小鼠Lewis肺癌模型中,相间照射剂量、放射总间隔时间延长降低了放射疗效,表现为缩短了小鼠肿瘤牛长延缓时间及总生存时间.对小鼠肿瘤生长影响程度与放射间隔时间的长短有关,间隔时间越长对小鼠肿瘤生长影响越大,但间隔30、60 min之间对小鼠生存时间影响差别不大.     

Investigating the temporal effects of respiratory-gated and intensity-modulated radiotherapy treatment delivery on in vitro survival: an experimental and theoretical study

PURPOSE: To experimentally and theoretically investigate the temporal effects of respiratory-gated and intensity-modulated radiotherapy (IMRT) treatment delivery on in vitro survival. METHODS AND MATERIALS: Experiments were designed to isolate the effects of periodic irradiation (gating), partial tumor irradiation (IMRT), and extended treatment time (gating and IMRT). V79 Chinese hamster lung fibroblast cells were irradiated to 2 Gy with four delivery methods and a clonogenic assay performed. Theoretical incomplete repair model calculations were performed using the incomplete repair model. RESULTS: Treatment times ranged from 1.67 min (conformal radiotherapy, CRT) to 15 min (gated IMRT). Survival fraction calculations ranged from 68.2% for CRT to 68.7% for gated IMRT. For the same treatment time (5 min), gated delivery alone and IMRT delivery alone both had a calculated survival fraction of 68.3%. The experimental values ranged from 65.7% +/- 1.0% to 67.3% +/- 1.3%, indicating no significant difference between the experimental observations and theoretical calculations. CONCLUSION: The theoretical results predicted that of the three temporal effects of radiation delivery caused by gating and IMRT, extended treatment time was the dominant effect. Care should be taken clinically to ensure that the use of gated IMRT does not significantly increase treatment times, by evaluating appropriate respiratory gating duty cycles and IMRT delivery complexity.     

Recovery from sublethal damage during intermittent exposures in cultured tumor cells: implications for dose modification in radiosurgery and IMRT

PURPOSE: In stereotactic irradiation using a linear accelerator and intensity-modulated radiation therapy (IMRT), radiation is administered intermittently, and 30 min or longer is often required in one treatment session. The purpose of the present study was to determine how different the dose delivered with such intermissions is from that delivered continuously and to estimate dose-modifying factors. METHODS AND MATERIALS: Murine EMT6 and SCCVII cells in culture were used. First, two doses of 4 Gy were given with an interruption of 15 min to 6 h or 1-10 min, or without interruption. Next, five fractions of 1.6 Gy were given with interfraction intervals of 1 to 5 min each. Doses of 6.5-8 Gy were also given without interruption to estimate dose-modifying factors. Cell survival was determined by a colony assay. Furthermore, a total dose of 2 Gy was given in 5 or 10 even fractions at intervals of 1-5 min or 30 s-3 min each, respectively, and the results were compared with those obtained after 1.6-2 Gy delivered continuously by using a cytokinesis-block micronucleus assay. RESULTS: In the two-fraction experiments, a significant increase in cell survival resulting from recovery from sublethal damage (SLDR) was observed when the interruption time was 2 min or longer in EMT6 cells and 3 min or longer in SCCVII. With a 5-min interval, cell survival increased by 13% in EMT6 and by 18% in SCCVII. In the five-fraction experiments, SLDR was evident when the interfraction interval was 2 min or longer in both 8-Gy and 2-Gy dose experiments. In the 10-fraction experiment using a dose of 2 Gy, SLDR was evident when the interfraction interval was 1 min or longer. In the 5-fraction and 10-fraction experiments, the dose-modifying factors were between 1.08 and 1.16 when the total time for irradiation was between 20 and 30 min. CONCLUSIONS: The effects of stereotactic radiosurgery and IMRT that require considerably long beam interruption (e.g., 8 min or longer in total) may be less than those of the same dose administered continuously. In treatments that take 20 min or longer, dose modification appears necessary based on biologically estimated dose-modifying factors.     

Enhancement of fractionated-dose irradiation by retinoic acid plus interferon

Purpose: To evaluate the relative cytotoxicity of fractionated-dose radiation in the presence and absence of 13-cis-retinoic acid (RA) plus α-2a-interferon (IFN), as a function of overall treatment time.Methods and Materials: Studies were performed with the human squamous cell carcinoma line FaDu, in vitro. Attached exponential phase cells were treated with RA + IFN for 8–10 h and then exposed to single graded doses of radiation, or 1 to 6 doses of radiation at 2 Gy per dose, or to 5 doses of radiation at 2 Gy/dose with a time interval of 4–24 h between treatments. Following irradiation, the cells were incubated with drugs present throughout colony formation, and the fraction of survivors in the presence and absence of the combined drugs was calculated.Results: For single graded-dose irradiation, the surviving fraction ratio at 2 Gy in the absence vs. presence of drugs was 1.27 ± 0.19 in 3 repeat experiments. Following administration of 6 doses of radiation at 2 Gy/fraction with a 5-h time interval between treatments and, after correcting for cell proliferation between treatments, the surviving fractions differed by a factor of 3.25, again indicating an average difference in survival of 1.26 after each of the 6 2-Gy/fractions. Treatment with 5 2-Gy doses of irradiation with 24 vs. 4 h elapsing between doses, resulted in a 3-fold greater decrease in survival in the presence of drugs vs. no drug. The relatively greater cell kill due to 24 vs. 4 h between treatments was due to drug inhibition of cell proliferation between the more prolonged treatments.Conclusions: The results of this study indicate that retinoic acid plus interferon both sensitizes and inhibits cell proliferation during treatment. These results suggest that this combination of radiation and drugs, when used concurrently, may be effective for inhibiting tumor cell proliferation or accelerated repopulation during clinical fractionated radiotherapy.     

How valid is the assumption of equal effect per fraction?

BACKGROUND AND PURPOSE: The validity of the assumption of equal biological effect with dose per fraction in fractionated radiotherapy has been examined for the acute skin reaction in a rat foot model using a variable number of 2-Gy daily fractions followed by graded top-up doses. MATERIAL AND METHODS: Mature female rats were used. Both hind feet of each rat were irradiated with a range of fractionated and top-up doses of 60Co gamma-rays. The dose-related incidence of moist desquamation was used as an end-point. Quantal data for the incidence of moist desquamation were analysed using probit analysis and ED50 (+/-SE) values were obtained. The results were also compared with predicted values obtained from the application LQ-model. RESULTS: After a single 2-Gy fraction followed by top-up doses 24 h later, the dose effect curve for the top-up doses used was shifted to lower doses as expected and the ED50 for moist desquamation of 19.78 +/- 0.13 Gy was 1.16 Gy less than the ED50 of 20.94 +/- 0.15 Gy for large single dose exposure alone. This implied that only approximately 58% of the initial 2-Gy fraction was effective, and the rest was repaired within a 24-h interval between the 2 Gy and top-up doses. However, after two or three 2-Gy daily fractions the dose effect curves for the subsequent top-up doses moved to the higher doses again and the ED50 for top-up dose increased to 20.33 +/- 0.21 and 20.75 +/- 0.11 Gy, respectively. A further increase in the number of 2-Gy daily fractions shifted the dose effect curves for the top-up doses to lower doses and ED50 values for the top-up doses decreased progressively. CONCLUSIONS: The findings were not in keeping with values predicted based on the assumption of equal effect per fraction and could not be explained by the use of a single alpha/beta ratio in the LQ-model.     

人肝癌细胞BEL-7402非常规照射模式生物效应探讨

目的 探讨不同照射模式对人肝癌细胞株BEL-7402生物效应变化影响及其与人肝细胞株QSG-7701放射敏感度差异。方法 6MV X线两种模式照射BEL-7402细胞(包括0、1、2、3、5、7、9、10Gy共8个吸收剂量点,剂量率3Gy/min)：(1)急速照射组,照射完成时间0~4min;(2)模拟三维适形照射组：照射完成时间：12~15min。成克隆分析法计算存活分数,多靶单击数学模型拟合曲线,求出SF2、D0、Dq等参数值;6MV X线单次5Gy照射体外培养的BEL-7402、QSG-7701 细胞, 采用MTT 比色法、流式细胞术测定细胞受照后不同时间存活率、凋亡率、细胞周期。结果 BEL-7402细胞模拟急速照射组和三维适形照射组D0、Dq、SF2值分别为1.78和1.69、1.45和1.54、0.625和0.654;QSG-7701 细胞照后24 h 凋亡率最高(18 %),而BEL-7402细胞照后12h凋亡率最高(32 %),存活率最低(65%),两株细胞照后12 h 凋亡率和存活率差异最大（P<0.01）。结论 三维适形照射模式下分次照射时间延长,生物效应下降;BEL-7402及QSG-7701两株细胞在照后存在放射敏感度差异。     

模拟IMRT模式的生物效应研究初探

目的模拟临床调强适形放疗的照射模式对人大肠癌细胞系HT-29进行生物效应变化的初步研究。方法采用指数生长期的HT-29细胞制成单细胞悬液,于接种后12h内进行不同模式和剂量的照射。分成3个照射组：（1）急速照射组（包括0、1、2、3、5、7、10Gy共7个剂量点）,剂量点的照射完成时间为0～5min,剂量率为6Gy／min;（2）IMRT照射模式组（包括15min完成照射组及30min完成照射组）,剂量率同上,每组所含照射剂量点同急速照射组,其中15min和30min照射组指各剂量点完成照射时间分别是15min和30min。采用成克隆分析法计算存活分数,运用多靶单击数学模型拟合曲线,求出Do、Dq等参数值。结果急速照射组、15min照射组和30min照射组的Dq值分别为1．54、1．74和1．72Gy;Do值分别为0．82、0．89和1．00Gy;SF2分别为0．448、0．548和0．558。结论IM-RT模式下随分次照射时间的延长,相对剂量率降低,从而导致生物效应下降。     

Is there a “mucosa-sparing” benefit of IMRT for head-and-neck cancer?

PURPOSE: To investigate whether intensity-modulated radiation therapy (IMRT) allows more mucosal sparing than standard three-field technique (3FT) radiotherapy for early oropharyngeal cancer. METHODS AND MATERIALS: Whole-field IMRT plans were generated for 5 patients with early-stage oropharyngeal cancer according to Radiation Therapy Oncology Group 0022 (66 Gy/30 fractions/6 weeks) guidelines with and without a dose objective on the portion of mucosa not overlapping any PTV. 3FT plans were also generated for the same 5 patients with two fractionation schedules: conventional fractionation (CF) to 70 Gy/35 fractions/7 weeks and concomitant boost (CB) to 72 Gy/40 fractions/6 weeks. Cumulative dose volume histograms (DVHs) of the overall mucosal volume (as per in-house definition) from all trials were compared after transformation into the linear quadratic equivalent dose at 2 Gy per fraction with a time factor correction. RESULTS: Compared with IMRT without dose objective on the mucosa, a 30-Gy maximum dose objective on the mucosa allows approximately 20% and approximately 12% mean absolute reduction in the percentage of mucosa volume exposed to a dose equivalent to 30 Gy (p < 0.01) and 70 Gy (p < 0.01) at 2 Gy in 3 and 7 weeks, respectively, without detrimental effect on the coverage of other regions of interest. Without mucosal dose objective, IMRT is associated with a larger amount of mucosa exposed to clinically relevant doses compared with both concomitant boost and conventional fractionation; however, if a dose objective is placed, the reverse is true, with up to approximately 30% reduction in the volume of the mucosa in the high-dose region compared with both concomitant boost and conventional fractionation (p < 0.01). CONCLUSIONS: Intensity-modulated radiation therapy can be potentially provide more mucosal sparing than traditional approaches.     

Dosimetry and radiobiologic model comparison of IMRT and 3D conformal radiotherapy in treatment of carcinoma of the prostate

INTRODUCTION: Intensity-modulated radiotherapy (IMRT) has introduced novel dosimetry that often features increased dose heterogeneity to target and normal structures. This raises questions of the biologic effects of IMRT compared to conventional treatment. We compared dosimetry and radiobiologic model predictions of tumor control probability (TCP) and normal tissue complication probability (NTCP) for prostate cancer patients planned for IMRT as opposed to standardized three-dimensional conformal radiotherapy (3DCRT). METHODS AND MATERIALS: Segmented multileaf collimator IMRT treatment plans for 32 prostate cancer patients were compared to 3DCRT plans for the same patients. Twenty-two received local-field irradiation (LFI), and 10 received extended-field irradiation (EFI) that included pelvic lymph nodes. For LFI, IMRT was planned for delivery of 2 Gy minimum dose to the prostate (> or =99% volume coverage) for 35 fractions. The 3DCRT plans, characterized by more homogenous dose to the target, were designed according to a different protocol to deliver 2 Gy to the center of the prostate for 37 fractions. Mean total dose from 35 fractions of IMRT was equal to mean total dose from 37 fractions of 3DCRT. For EFI, both IMRT and 3DCRT were planned for 2 Gy per fraction to a total dose of 50 Gy to prostate and pelvic lymph nodes, followed by 2 Gy per fraction to 20 Gy to the prostate alone. Treatment dose for EFI-IMRT was defined as minimum dose to the target, whereas for EFI-3DCRT, it was defined as dose to the center of the prostate. TCP was calculated for the prostate in the linear-quadratic model for two choices of alpha/beta. NTCP was calculated with the Lyman model for organs at risk, using Kutcher-Burman dose-volume histogram reduction with Emami parameters. RESULTS AND CONCLUSIONS: Dose to the prostate, expressed as mean +/- standard deviation, was 74.7 +/- 1.1 Gy for IMRT vs. 74.6 +/- 0.3 Gy for 3D for the LFI plans, and 74.8 +/- 0.6 Gy for IMRT vs. 71.5 +/- 0.6 Gy for 3D for the EFI plans. For the studied protocols, TCP was greater for IMRT than for 3D across the full range of target sensitivity, for both localized- and extended-field irradiation. For LFI, this was due to the smaller number of fractions (35 vs. 37) used for IMRT, and for EFI, this was due to the greater mean dose for IMRT, compared to 3D. For all organs, mean NTCP tended to be lower for IMRT than for 3D, although NTCP values were very small for both 3D and IMRT. Differences were statistically significant for rectum (LFI and EFI), bladder (EFI), and bowel (EFI). For both LFI and EFI, the calculated NTCPs qualitatively agreed with early published clinical data comparing genitourinary and gastrointestinal complications of IMRT and 3D. Present calculations support the hypothesis that accurately delivered IMRT for prostate cancer can limit dose to normal tissue by reducing treatment margins relative to conventional 3D planning, to allow a reduction in complication rate spanning several sensitive structures while maintaining or increasing tumor control probability.     

The influence of irradiation time per treatment session on acute and late skin reactions: a study on human skin

A comparison of the radiation effect of altering the treatment time per session in fractionated radiotherapy was performed on human skin with 12 MeV electrons. Four fractions of 7.2 Gy were given within 22 days, once a week. The dose per fraction was administered in 4 min and 32 min, respectively. The dose rate was about 2 Gy/min and the prolonged treatment time was achieved by dividing each dose fraction into three equal subfractions with intervals of 14-15 min. Prolongation of the treatment time resulted in a significant reduction of the skin erythema (p less than 0.001), pigmentation (p less than 0.05) and the degree of telangiectasia at 5 years (p less than 0.001). The relative biological effectiveness (RBE) for the prolonged (32 min), in relation to that of the short (4 min) treatment time, RBE4 min/32 min, was 1.09-1.10 for erythema and 1.07-1.12 for telangiectasia. These findings indicate that prolongation of the treatment time per session has to be adjusted for in clinical radiation oncology.     

Intravaginal high-dose-rate brachytherapy for stage I endometrial cancer: a randomized study of two dose-per-fraction levels

PURPOSE: To compare two different fractionation schedules for postoperative vaginal high-dose-rate (HDR) irradiation in endometrial carcinomas. METHODS AND MATERIALS: In a complete geographic series of 290 low-risk endometrial carcinomas, the efficacy and side effects of two different fractionation schedules for postoperative vaginal irradiation were evaluated. The patients were treated during the years 1989-2003. The tumors were in International Federation of Gynecology and Obstetrics Stages IA-IB and Grades 1-2. The HDR MicroSelectron afterloading equipment (iridium-192) was used. Perspex vaginal applicators with diameters of 20-30 mm were used, and the dose was specified at 5 mm from the surface of the applicator. Six fractions were given, and the overall treatment time was 8 days. The size of the dose per fraction was randomly set to 2.5 Gy (total dose of 15.0 Gy) or 5.0 Gy (total dose of 30.0 Gy). One hundred forty-four patients were treated with the 2.5-Gy fraction and 146 patients with the 5.0-Gy fraction. RESULTS: The overall locoregional recurrence rate of the complete series was 1.4% and the rate of vaginal recurrences 0.7%. There was no difference between the two randomized groups. The vaginal shortening measured by colpometry was not significant (p = 0.159) in the 2.5-Gy group (mean, 0.3 cm) but was highly significant (p < 0.000001) in the 5.0-Gy group (mean 2.1 cm) after 5 years. Mucosal atrophy and bleedings were significantly more frequent in the 5.0-Gy group. Symptoms noted in the 2.5-Gy group were not different from what could be expected in a normal group of postmenopausal women. CONCLUSION: The fractionation schedule recommended for postoperative vaginal irradiation in low-risk endometrial carcinoma is six fractions of 2.5 Gy when the HDR technique is used.     

颈段食管癌固定野调强与旋转调强放疗计划比较研究

目的 通过比较颈段食管癌固定野调强放疗(IMRT)与旋转调强放疗(IMAT)计划,分析IMRT与IMAT在剂量学与实际应用方面特点和可行性.方法 选取10例在本院进行IMRT的颈段食管癌患者,针对相同CT图像与靶区制定单弧(IMAT1)、双弧(IMAT2)IMAT计划.使用Eclipse(R) ver 8.6计划系统,6 MV X线.模拟处方剂量为60 Gy分30次,计划要求97%计划靶体积(PTV)(V98)达98%处方剂量,超过110%处方剂量PTV(V110)<15%.脊髓最大剂量≤45 Gy.通过剂量体积直方图统计PTV相关剂量参数、适形指数(CI)、均匀指数(HI)、肺及心脏剂量体积参数,以及加速器总机器跳数、总治疗时间.用SPSS 13.0软件对3个组计划行单因素方差分析,LSD算法进行组内分析.结果 3个组PTV的D98、V98及CI,肺的V5、V10、V30、V40、V50及平均肺剂量差异均无统计学意义(P值均>0.05);PTV的D2、V110及HI,肺V20差异均有统计学意义(P值均<0.05).总机器跳数比较,IMRT组(1174.8 MU)比IMAT1(709.7 MU)、IMAT2(803.8 MU)组分别减少了39.6%、31.6%(F=39.25,P=0.000).总治疗时间比较,IMRT组(14.9 min)比IMAT1(1.9 min)、IMAT2(2.66 min)组分别减少了87.2%、82.1%(F=45.14,P=0.000).结论 IMAT可以达到与IMRT相似的剂量学要求,IMAT2计划优于IMAT1.IMAT具有较少总MU、总治疗时间优势,并减少了治疗中不确定性因素影响及患者不适感.     

Impact of intensity-modulated radiation therapy as a boost treatment on the lung-dose distributions for non-small-cell lung cancer

PURPOSE: To investigate the feasibility of intensity-modulated radiotherapy (IMRT) as a method of boost radiotherapy after the initial irradiation by the conventional anterior/posterior opposed beams for centrally located non-small-cell lung cancer through the evaluation of dose distributions according to the various boost methods. METHODS AND MATERIALS: Seven patients with T3 or T4 lung cancer and mediastinal node enlargement who previously received radiotherapy were studied. All patients underwent virtual simulation retrospectively with the previous treatment planning computed tomograms. Initial radiotherapy plans were designed to deliver 40 Gy to the primary tumor and involved nodal regions with the conventional anterior/posterior opposed beams. Two radiation dose levels, 24 and 30 Gy, were used for the boost radiotherapy plans, and four different boost methods (a three-dimensional conformal radiotherapy [3DCRT], five-, seven-, and nine-beam IMRT) were applied to each dose level. The goals of the boost plans were to deliver the prescribed radiation dose to 95% of the planning target volume (PTV) and minimize the volumes of the normal lungs and spinal cord irradiated above their tolerance doses. Dose distributions in the PTVs and lungs, according to the four types of boost plans, were compared in the boost and sum plans, respectively. RESULTS: The percentage of lung volumes irradiated >20 Gy (V20) was reduced significantly in the IMRT boost plans compared with the 3DCRT boost plans at the 24- and 30-Gy dose levels (p = 0.007 and 0.0315 respectively). Mean lung doses according to the boost methods were not different in the 24- and 30-Gy boost plans. The conformity indexes (CI) of the IMRT boost plans were lower than those of the 3DCRT plans in the 24- and 30-Gy plans (p = 0.001 in both). For the sum plans, there was no difference of the dose distributions in the PTVs and lungs according to the boost methods. CONCLUSIONS: In the boost plans the V20s and CIs were reduced significantly by the IMRT plans, but in the sum plans the effects of IMRT on the dose distributions in the tumor and lungs, like CI and V20, were offset. Therefore, to keep the beneficial effect of IMRT in radiotherapy for lung cancer, it would be better to use IMRT as a whole treatment plan rather than as a boost treatment.     

Estimation of radiobiologic parameters and equivalent radiation dose of cytotoxic chemotherapy in malignant glioma

PURPOSE: To determine the radiobiologic parameters for high-grade gliomas. METHODS AND MATERIALS: The biologic effective dose concept is used to estimate the alpha/beta ratio and K (dose equivalent for tumor repopulation/d) for high-grade glioma patients treated in a randomized fractionation trial. The equivalent radiation dose of temozolomide (Temodar) chemotherapy was estimated from another randomized study. The method assumes that the radiotherapy biologic effective dose is proportional to the adjusted radiotherapy survival duration of high-grade glioma patients. RESULTS: The median tumor alpha/beta and K estimate is 9.32 Gy and 0.23 Gy/d, respectively. Using the published surviving fraction after 2-Gy exposure (SF2) data, and the above alpha/beta ratio, the estimated median alpha value was 0.077 Gy(-1), beta was 0.009 Gy(-2), and the cellular doubling time was 39.5 days. The median equivalent biologic effective dose of temozolomide was 11.03 Gy(9.3) (equivalent to a radiation dose of 9.1 Gy given in 2-Gy fractions). Random sampling trial simulations based on a cure threshold of 70 Gy in high-grade gliomas have shown the potential increase in tumor cure with dose escalation. Partial elimination of hypoxic cells (by chemical hypoxic cell sensitizers or carbon ion therapy) has suggested that considerable gains in tumor control, which are further supplemented by temozolomide, are achievable. CONCLUSION: The radiobiologic parameters for human high-grade gliomas can be estimated from clinical trials and could be used to inform future clinical trials, particularly combined modality treatments with newer forms of radiotherapy. Other incurable cancers should be studied using similar radiobiologic analysis.     

Radiotherapy for early glottic carcinoma (T1N0M0): results of prospective randomized study of radiation fraction size and overall treatment time

PURPOSE: To investigate in a prospective randomized study the effect of radiation fraction size and overall treatment time on the local control of early glottic carcinoma. METHODS AND MATERIALS: Between December 1993 and December 2001, 180 patients with early glottic carcinoma (T1N0M0) were treated at our department. The patients were randomly allocated to either treatment arm A (radiation fraction size 2 Gy, n = 89) or B (2.25 Gy, n = 91). The total radiation dose administered was 60 Gy in 30 fraction within 6 weeks for minimal tumors (two-thirds of the vocal cord or less) or 66 Gy in 33 fractions in 6.6 weeks for larger than minimal tumors (more than two-thirds of the vocal cord) in Arm A and 56.25 Gy in 25 fractions within 5 weeks for minimal tumor or 63 Gy in 28 fractions within 5.6 weeks for larger than minimal tumors in Arm B. RESULTS: The 5-year local control rate was 77% for Arm A and 92% for Arm B (p = 0.004). The corresponding 5-year cause-specific survival rates were 97% and 100% (no significant difference). No significant differences were found between these two arms in terms of rates of acute mucosal reaction, skin reactions, or chronic adverse reactions. CONCLUSION: Use of 2.25-Gy fractions with a shorter overall treatment time for Arm B showed superior local control compared with conventional use of 2-Gy fractions for Arm A without adverse reactions from the greater fraction.     

Selective radioprotection of hepatocytes by systemic and portal vein infusions of amifostine in a rat liver tumor model

PURPOSE: The tolerance of the liver to radiation is too low to permit an effective dose to be delivered to patients who have diffuse intrahepatic cancer. In this study we evaluated whether systemic or portal venous administration of the aminothiol compound, amifostine, could protect the normal liver from the effects of ionizing radiation without compromising tumor cell kill in a rat liver tumor model. METHODS AND MATERIALS: Rats implanted with liver tumors were infused with 200 mg/kg amifostine over 15 min via the femoral or portal vein. The livers were irradiated with a single 6-Gy fraction 15-20 min after the termination of amifostine infusion. Protection of the liver was assessed by an in vitro hepatocyte micronucleus assay and tumor protection by an in vivo-in vitro clonogenic survival assay. Tissue levels of the active metabolite, free WR-1065, were determined in the tumor and in the normal liver using a specific HPLC assay with electrochemical detection. RESULTS: After a 6-Gy fraction, the frequency of hepatocyte micronuclei after administration of saline, systemic amifostine, and portal venous amifostine was 18.7+/-1%, 6.8+/-1%, and 9.9+/-2%, respectively, corresponding to a radiation equivalent effect of 6 Gy +/- 0.5, 1.8 Gy +/- 0.3, and 2.5 Gy +/- 1.3, respectively. Both amifostine conditions showed considerably less radiation effect than saline-treated controls (p < 0.01); the two amifostine conditions did not differ (p = 0.3). The surviving fraction of tumor cells was not affected by amifostine treatment and was 0.03+/-0.02 and 0.05+/-0.03 for systemic and portal venous delivery and 0.06+/-0.02 for control animals (ANOVA analysis showed no significant difference of the means p = 0.34). Portal venous delivery produced significantly less WR-1065 in the tumor compared to systemic administration (54 microM +/- 36 vs. 343 microM +/- 88, respectively, p = 0.03). CONCLUSIONS: Both systemic and portal venous administration of amifostine effectively protect hepatocytes from ionizing radiation without compromising tumor cell kill in a clinically relevant animal model. These findings suggest that amifostine may be a selective normal tissue radioprotectant in liver cancer and that regional/portal infusions may be preferable to systemic dosing.     

Influence of cellular radiation sensitivity on local tumor control of human melanoma xenografts given fractionated radiation treatment

The radiocurability of human melanoma xenografts was studied by treating tumors with multiple fractions of 2.0 Gy and using local tumor control at 180 days as end point. Three melanoma lines (E. F., G. E., M. F.) that are only weakly immunogenic in athymic nude mice (BALB/c-nu/nu/BOM) were selected for the study. The tumor radiocurability was found to differ considerably among the lines; the radiation doses required to achieve local control of 50% of the tumors irradiated (TCD50s; mean +/- SE) were 85.0 +/- 4.7 Gy (E.F.), 60.3 +/- 5.4 Gy (G.E.), and 99.3 +/- 5.7 Gy (M. F.). The radiation sensitivity in vitro of cells isolated directly from tumors also differed significantly among the lines. The TCD50 showed positive correlations with the surviving fraction after 2.0 Gy in vitro, the surviving fraction after two doses of 2.0 Gy (4-h interval) in vitro, and the surviving fraction after 4.0 Gy at a low dose rate (1.25 cGy/min) in vitro. Thus, the differences in tumor radiocurability among the lines were mainly a consequence of cellular differences in the capacity to repair radiation damage. Comparisons of measured TCD50s with theoretical TCD50s, calculated from cell-surviving fractions measured in vitro after radiation treatment in vitro or in vivo, suggested that other tumor parameters, e.g., rate of population between radiation fractions, also had a significant impact on the TCD50. However, this study strongly supports the assumptions that the surviving fraction at 2.0 Gy in vitro is a useful parameter for prediction of clinical tumor radiocurability.     

Health-related quality of life in patients with locally advanced prostate cancer after 76 Gy intensity-modulated radiotherapy vs. 70 Gy conformal radiotherapy in a prospective and longitudinal study

PURPOSE: To compare quality of life (QoL) after 70 Gy conformal radiotherapy with QoL after 76 Gy intensity-modulated radiotherapy (IMRT) in patients with locally advanced prostate carcinoma. METHODS AND MATERIALS: Seventy-eight patients with locally advanced prostate cancer were treated with 70 Gy three-field conformal radiotherapy, and 92 patients received 76 Gy IMRT with fiducial markers for position verification. Quality of life was measured by RAND-36, the European Organization for Research and Treatment of Cancer core questionnaire (EORTC QLQ-C30(+3)), and the prostate-specific EORTC QLQ-PR25, before radiotherapy (baseline) and 1 month and 6 months after treatment. Quality of life changes in time (baseline vs. 1 month and baseline vs. 6 months) of > or =10 points were considered clinically relevant. RESULTS: Differences between the treatment groups for QoL changes over time occurred in several QoL domains. The 76-Gy group revealed no significant deterioration in QoL compared with the 70-Gy group. The IMRT 76-Gy group even demonstrated a significantly better change in QoL from baseline to 1 month in several domains. The conformal 70-Gy group revealed temporary deterioration in pain, role functioning, and urinary symptoms; for the IMRT 76-Gy group a better QoL in terms of change in health existed after 1 month, which persisted after 6 months. For both treatment groups temporary deterioration in physical role restriction occurred after 1 month, and an improvement in emotional role restriction occurred after 6 months. Sexual activity was reduced after treatment for both groups and remained decreased after 6 months. CONCLUSIONS: Intensity-modulated radiotherapy and accurate position verification seem to provide a possibility to increase the radiation dose for prostate cancer without deterioration in QoL.