Impact of nodal regression on radiation dose for lymphoma patients after radioimmunotherapy.

Radioimmunotherapy for non-Hodgkin's lymphoma often results in surprisingly high response rates compared with those expected from estimated absorbed radiation doses. Several factors, including radiobiologic response, selective targeting, and heterogeneous absorbed radiation within the lymphoma, are likely to contribute to the lack of a dose-response relationship. This article investigates the impact of nodal regression on absorbed radiation dose and applies a correction factor to account for its effect. METHODS: The radioactivity in and regression of 37 superficial lymph nodes were measured in 7 non-Hodgkin's lymphoma patients treated with 775-3,450 MBq/m(2) of (131)I-Lym-1 monoclonal antibody. Nodal dimensions were measured with calipers and radioactivity was quantitated using gamma-camera imaging on multiple days after (131)I-Lym-1 injection. Both nodal regression and radioactivity were fit with monoexponential functions. Formulas were developed to account for simultaneous change in nodal mass and radioactivity. All lymph nodes with size and radioactivity measurements, and exponential-fit coefficients of determination of >0.8, were included in the analysis. RESULTS: A 3 orders-of-magnitude node-to-node variation in initial radiopharmaceutical concentration (MBq/g) was observed, with the highest concentrations in the smallest nodes. Reduction in radioactivity as a function of time (biologic half-life) varied by about a factor of 2. In contrast, the rate of nodal regression varied by orders of magnitude, from a 14-h half-time to no regression at all. Five nodes regressed with a half-time that was shorter than their observed effective radiopharmaceutical half-life. Accounting for the effect of nodal regression resulted in dose corrections ranging from 1 (no correction) to a factor of >10, with 70% of nodes requiring a correction factor of at least 20% and >50% of nodes requiring a correction factor of >2. Corrected for nodal regression, 46% of nodes analyzed had absorbed radiation doses of >10 Gy and 32% had doses of >20 Gy. CONCLUSION: These results highlight the importance of accounting for change in mass, particularly tumor regression, when assessing absorbed radiation dose for tissues whose mass changes during the time the radiation dose is being absorbed. The increase in calculated absorbed dose when this change is considered provides better insight into the high nodal response rates observed in non-Hodgkin's lymphoma patients.     

Weiss lecture. The dose-rate factor in radiation biology.

The dose-rate effect has been the topic of extensive radiobiological studies and has important implications in radiation therapy and in the field of radiation protection. Three examples will be discussed: two in radiation therapy and one in protection. First, continuous low dose-rate interstitial brachytherapy may be replaced by pulsed brachytherapy, using a single source moving through the catheters of the implant. This strategy, using a modern computer-controlled afterloading device, would allow better dose optimization and result in a considerable cost saving. Radiobiological data have proved useful in defining the pulse length and pulse frequency that is equivalent to continuous low dose-rate. Second, in the intracavitary treatment of carcinoma of the cervix, a few high dose-rate (HDR) fractions on an outpatients basis can replace the low dose-rate (LDR) treatment that requires the patient to be hospitalized for several days. Radiobiological data can be used to estimate the dose levels at HDR that are equivalent to conventional LDR protocols. Third, it is usually assumed in radiation protection that doses accumulated over a period of time at low dose-rate are less effective biologically than the same dose delivered in a single acute exposure. While this may be true for X- or gamma-rays, radiobiological data indicate that neutrons delivered at low dose or in a series of fractions spread out over a period of time may produce more oncogenic transformation than a single acute exposure. This has important implications in radiation protection.     

Basic review of radiation biology and terminology

OBJECTIVE: The purpose of this paper is to review basic radiation biology and associated terminology to impart a better understanding of the importance of basic concepts of ionizing radiation interactions with living tissue. As health care workers in a field that utilizes ionizing radiation, nuclear medicine technologists are concerned about the possible acute and chronic effects of occupational radiation exposure. Technologists should have a clear understanding of what they are exposed to and how their safety could be affected. Furthermore, technologists should be knowledgeable about radiation effects so that they can adequately assuage possible patient fears about undergoing a nuclear medicine procedure. After reading this article, the nuclear medicine technologist will be familiar with: (a) basic radiation biology concepts; (b) types of interactions of radiation with living tissue, and possible effects from that exposure; (c) theoretical dose-response curves and how they are used in radiation biology; (d) stochastic versus nonstochastic effects of radiation exposure, and what these terms mean in relation to both high- and low-dose radiation exposure; and (e) possible acute and chronic radiation exposure effects.     

Comparison between radioimmunotherapy and external beam radiation therapy for patients with hepatocellular carcinoma

It has previously been observed in animal studies that, at equivalent doses, radioimmunotherapy (RIT) is 2.5 times more effective than multiple fractions of external beam radiation therapy (EBRT) in inhibiting tumour growth. In this study, we compared the use of RIT and EBRT in patients with hepatocellular carcinoma (HCC), treated during the past 10 years. Of 67 patients without extrahepatic involvement, 32 were treated with hepatic artery ligation combined with RIT (the RIT group) while 35 were treated with a combination of hepatic arterial chemo-embolisation and EBRT (the EBRT group). The patients in the RIT group received (131)I-Hepama-1 monoclonal antibody, which was infused through the hepatic artery catheter. The patients in the EBRT group received transcatheter arterial chemo-embolisation and limited-field EBRT using a linear accelerator. Parameters observed include tumour response, alpha-fetoprotein (AFP) level in serum, human anti-murine antibody (HAMA) assay, T lymphocyte subsets, survival rates, routine parameters, sequential resection rates and histopathological status of the resection specimens. The sequential resection rates were 53% (17/32) and 23% (8/35), and tumour response rates were 72% (23/32) and 86% (30/35) in the RIT and EBRT groups, respectively. The main side-effects in the RIT group were mild allergic reactions. The most common toxicity in the EBRT group was an increase in liver enzymes. The liver tissue in the target volume was injured by EBRT. The injured liver tissue revealed a low-attenuation area adjacent to the hepatic tumour within the target volume on follow-up computed tomography studies after EBRT. On pathological evaluation, the low-attenuation area revealed hyperaemia, distended hepatic sinusoids packed with erythrocytes and hepatic cell loss. The sequential resection specimens from both the RIT and the EBRT group showed residual cancer tissue located at the edge of the mass. The residual cancer cells presented as giant cells under microscopy. T lymphocyte subsets observed prior to treatment did not significantly change after RIT, but were significantly disturbed by EBRT. HAMA formation was the major reason for discontinuing RIT, the incidence being as high as 34% (11/32). Intrahepatic and pulmonary metastases occurred more frequently in the EBRT group (63%) than in the RIT group (22%). The 1-, 2-, 3- and 4-year survival rates were 50%, 41%, 34% and 31% in the RIT group, and 77%, 39%, 11% and 7% in the EBRT group, respectively. It is interesting that the serum AFP level showed a transient increase, the mechanism and importance of which are not known, but are discussed. Both RIT and EBRT are useful treatment modalities for unresectable HCC, serving to prolong survival. However, RIT is much less toxic than EBRT, the side-effects of which include radiation injury to the liver and disturbance of T lymphocyte subsets.     

Multicellular tumour spheroids in radiation biology.

PURPOSE: Multicellular tumour spheroids are being used with increasing frequency in various aspects of tumour biology, including studies dealing with radiation biology. This review attempts to outline recent studies using these three-dimensional systems in radiation biology with particular reference made to papers testing radiotherapeutic protocols with spheroids. DEFINITIONS: Multicellular tumour spheroids are three-dimensional structures composed of cancer cells. They are formed from monolayer tumour cells when these are grown by various in vitro methods (e.g. liquid-overlay, spinner flask and gyratory rotation systems). Because of the cellular organization in spheroids, they have been often shown to recreate in vivo tumours much more closely than two-dimensional in vitro models. CONCLUSIONS: Because of their particular architectural characteristics, multicellular spheroids are demonstrated to be extremely useful in testing radiotherapeutic protocols, including dose rate and fractionation, radioimmunotherapy and the effects of combined treatments (e.g. radiation and anti-neoplastic drugs). Further studies should seek not only to continue testing these protocols, but also to investigate the more fundamental questions of radiation-induced apoptotic cell death, cell-cycle events, cell-cell interactions and cell adhesion phenomena.     

Hepatocyte response to continuous low dose-rate radiation in radioimmunotherapy assessed by micronucleus assay.

The response of hepatocytes to low dose-rate irradiation was examined in mice following the injection of radiolabelled monoclonal antibody. Mice were injected intravenously with an 131I-labelled monoclonal antibody 196-14 which recognizes CA125 antigen, and the effect of continuous low dose-rate irradiation on hepatocytes was assessed using the micronucleus assay. The frequency of micronuclei increased in a dose-dependent fashion, but it was lower than the frequency induced by conventional external X-rays which was determined immediately after the irradiation. A linear quadratic model (micronucleus frequency = aD+bD2+c) showed that the value of b decreased with low dose-rate irradiation from the radiolabelled antibody. It is concluded that the micronucleus assay is useful for the evaluation of the response of hepatocytes to irradiation in radioimmunotherapy.     

Study of the clinical thermoluminescent dosimeter in the direct measurement of radiation absorbed dose for radioimmunotherapy

One of the major obstacles facing radioimmunotherapy (RIT) is the lack of a device to measure directly tumor and normal tissue radiation absorbed dose. Calculations based on the clearance and imaging scans have several limitations; hence we design and fabricate a sheathed clinical thermoluminescent dosimeter (TLD) for the measurement of absorbed dose by implantation in humans. Preclinical studies are performed in nine normal rabbits. Complete blood count, body temperature monitoring, clinical observation and necropsy show no untoward effects from the TLD. Consistent bone marrow radiation doses are noted in the four rabbits receiving ¹³¹I-labeled monoclonal antibody A6H. By using up to 20 clinical TLDs in one sheath, it will be possible to determine macroscopic heterogeneities in organs undergoing RIT.     

188Re-C50对结肠癌细胞的凋亡诱导作用

目的　观察1 88Re 抗癌胚抗原 (CEA)单克隆抗体 (简称单抗 )C5 0放射免疫治疗 (RIT)对结肠癌细胞的凋亡诱导作用。方法　BALB c小鼠结肠癌模型分为治疗与对照组 ,每组 8只。治疗组每只瘤内注射 18 5MBq1 88Re C5 0 ,对照组每只瘤体内局部注射 0 16mgC5 0。 6h后取新鲜肿瘤组织制备肿瘤单细胞悬液 ,采用流式细胞仪 (FCM)行倍体与S期细胞比例检测 ;取肿瘤组织固定后行透射电镜观察与原位末端标记法 (TUNEL)检测。结果　RIT治疗后 6hC2 6结肠癌细胞在用碘化丙啶 (PI)染色的FCM直方图上出现典型凋亡峰 ,C2 6细胞凋亡百分比为 (16 6 4± 0 12 ) % ,对照组为 0 %。肿瘤S期细胞占 (10 4 1± 1 31) % ,对照组为 (33 14± 2 0 1) %。肿瘤G0 G1 期细胞占 (6 8 6 0± 4 82 ) % ,对照组为 (35 12± 2 6 3) % ,治疗后G1 期细胞呈明显阻滞现象。TUNEL检测肿瘤细胞出现凋亡改变 ,凋亡指数 (AI)为 (2 6 4± 0 97) % ,对照组无凋亡改变发生。电镜下癌细胞出现典型的凋亡细胞形态学改变。结论　诱导结肠癌细胞凋亡是1 88Re C5 0抗肿瘤效应的重要作用机理。     

Generator-produced yttrium-90 for radioimmunotherapy

Yttrium-90 is often considered to possess many favorable properties for radioimmunotherapy applications. Among these is its availability as a radionuclide generator product by decay of its parent, 90Sr. Nevertheless, most present and planned clinical trials with 90Y-labeled antibodies employ radioactivity obtained not from an in-house generator, but from commercial sources. To prepare for clinical trials at this institution with 90Y labeled to diethylenetriaminepentaacetic acid- (DTPA) coupled antibodies, we have adapted previously published procedures and have developed others to prepare antibodies labeled with generator produced 90Y for human use. Up to 25 mCi of 90Sr have been loaded without evidence of radiolytic degradation to the Dowex 50 cation exchange resin which serves as the solid support for the generator. Using 0.003M ethylenetriaminetetraacetic acid (EDTA) as eluant, elution efficiency averages 98% and 90Sr breakthrough averages 0.002%. The EDTA is destroyed remotely and the activity is dissolved in 0.5M acetate, pH 6. In this form, 90Y may be used to label DTPA-coupled proteins at specific activities of 1-3 mCi/mg (an order of magnitude improvement in specific activity results from the purification of 90Y by cation exchange prior to labeling). When properly labeled, size exclusion HPLC shows 90% or greater radiochemical purity and recovery without postlabeling purification. We conclude that these techniques provide a 90Y-labeled protein preparation which is safe for administration to patients.     

用于放免治疗的核素研究进展

放射免疫治疗肿瘤具有独特优势,许多新的核素被用于制备肿瘤放免治疗药物.高能α、β粒子及抗肿瘤导向载体的应用促进了放免治疗药物的发展.本文介绍了用于放射免疫治疗的核素最新研究进展,归纳了用于放射免治疗的常用放射性核素,并比较了各自的优缺点,指出了放射性核素用于放射免疫治疗过程中存在的问题、可能的解决方法及今后的发展趋势.