Guideline for radioimmunotherapy of rituximab relapsed or refractory CD20(+) follicular B-cell non-Hodgkin's lymphoma

This guideline is a prerequisite for the quality management in the treatment of non-Hodgkin-lymphomas using radioimmunotherapy. It is based on an interdisciplinary consensus and contains background information and definitions as well as specified indications and detailed contraindications of treatment. Essential topics are the requirements for institutions performing the therapy. For instance, presence of an expert for medical physics, intense cooperation with all colleagues committed to treatment of lymphomas, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how the treatment has to be carried out technically. Here, quality control and documentation of labelling are of greatest importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with those colleagues (haematology-oncology) who propose, in general, radioimmunotherapy under consideration of the development of the disease.     

Correlation of marrow dose estimates based on serial pretreatment radiopharmaceutical imaging and blood data with actual marrow toxicity in anti-CD20 yttrium-90 monoclonal antibody radioimmunotherapy of non-Hodgkin's B-cell lymphoma

The purpose of this study was to investigate whether marrow radiation absorbed dose estimates predict haematotoxicity following radioimmunotherapy with an yttrium-90 labelled anti-CD20 monoclonal antibody in non-Hodgkin's B-cell lymphoma (NHL). Radiopharmaceutical data from 12 NHL radioimmunotherapy patients were analysed retrospectively using three methods of marrow radiation absorbed dose estimation based on serial pretreatment indium-111 labelled anti-CD20 monoclonal antibody activity versus time data (0-144 h): (i) lumbar spine (LS) image counts; (ii) blood clearance (BL); and (iii) whole body (WB) activity. Linear regressions were performed between the methods, and between each method and the 0-6 month post-treatment platelet and white blood cell count nadir and absolute drop in count (ADC). For the range of yttrium-90 activities (740-1547 MBq), absorbed dose estimates (mean +/- sigma) were: LS, 142+/-50 cGy (range 62-233 cGy); BL, 89+/-21 cGy (range 63-140 cGy); and WB, 54+/-10 cGy (range 36-63 cGy). The LS and BL marrow estimates differed significantly (P <0.003), with a correlation coefficient r of 0.36 (P = NS), while WB correlated significantly with both LS (r = 0.50, P < 0.05) and BL (r = 0.58, P < 0.05). The range of r with platelet nadir and ADC was -0.20 < or = r < or = 0.01, except for WB with ADC (r = 0.38) (all P = NS). Values of r for white blood cell nadir were unexpectedly positive, being 0.13 for BL and 0.29 for LS (P = NS), and 0.60 for WB (P < 0.025). Values of r for white blood cell ADC were 0.36 for BL and -0.26 for LS (P = NS), and 0.50 for WB (P < 0.05). These results indicate that different commonly employed methods of estimating marrow radiation absorbed dose may yield significantly differing results, which may not correlate with actual radiation toxicity. Therefore, caution must be exercised in relying on these results to predict haematotoxicity.     

利妥昔单抗免疫化疗联合自体外周血干细胞移植治疗CD20+B细胞性非霍奇金淋巴瘤的临床研究

目的 分析和探讨利妥昔单抗联合自体外周血造血干细胞移植(APBSCT)序贯维持治疗对CD20+B细胞非霍奇金淋巴瘤(NHL)的疗效.方法 搜集2005年1月—2011年1月诊断为侵袭性和(或)难治复发性CD20+B细胞NHL并接受APBSCT治疗的60例患者的临床资料.分为2组:治疗组(n=25),APBSCT前应用利妥昔单抗3～4次,采集自体干细胞前1d加用利妥昔单抗治疗1次(375mg/m2)体内净化干细胞,移植后每3～6个月应用利妥昔单抗联合白细胞介素-2(100万U/次,缓慢静滴)维持治疗3～4次;对照组35例,除未用利妥昔单抗以外,其他处理与治疗组相同.结果 利妥昔单抗在移植前、干细胞采集前及移植后巩固治疗中均未发现明显不良反应.治疗组和对照组采集单个核细胞数分别为(8.2±2.9)×108/kg和(8.4±3.9)×108/kg(P=0.822),CD34+细胞数分别为(12.3±12.7)×106/kg和(13.2±13.9)×106/kg(P=0.799).治疗组均顺利完成造血重建,对照组3例造血重建失败.两组中性粒细胞恢复时间和血小板恢复时间差异无统计学意义.移植后所有病例均达完全缓解(CR),中位随访22(2 ～ 81)个月,治疗组2例复发,对照组6例复发.治疗组3年总体生存率有高于对照组的趋势(91.6％ vs 69.5％,P=0.060).结论 侵袭性和(或)难治复发性CD20+B细胞NHL患者APBSCT前后应用利妥昔单抗不影响造血干细胞的采集和造血重建,且有望提高治疗效果、改善总体生存.     

Whole-body CT for lymphoma staging: Feasibility of halving radiation dose and risk by iterative image reconstruction

Objectives

Patients with lymphoma are at higher-risk of secondary malignancies mainly due to effects of cancer therapy as well as frequent radiological surveillance. We thus aimed to investigate the objective and subjective image quality as well as radiation exposure and risk of full-dose standard (FDS), full-dose iterative (FDI), and half-dose iterative (HDI) image reconstruction in patients with lymphoma.

Material and methods

In 100 lymphoma patients, contrast-enhanced whole-body staging was performed on a dual-source CT. To acquire full-dose and half-dose CT data simultaneously, the total current-time product was equally distributed on both tubes operating at 120 kV. HDI reconstructions were calculated by using only data from one tube. Quantitative image quality was assessed by measuring image noise in different tissues of the neck, thorax, and abdomen. Overall diagnostic image quality was assessed using a 5-point Likert scale. Radiation doses and risks were estimated for a male and female reference person.

Results

For all anatomical regions apart from the lungs image noise was significantly lower and the overall subjective image quality significantly better when using FDI and HDI instead of FDS reconstruction (p < 0.05). For the half-dose protocol, the risk to develop a radiation-induced cancer was estimated to be less than 0.11/0.19% for an adult male/female.

Conclusions

Image quality of FDI and more importantly of HDI is superior to FDS reconstruction, thus enabling to halve radiation dose and risk to lymphoma patients.     

Radionuclides linked to a CD74 antibody as therapeutic agents for B-cell lymphoma: comparison of Auger electron emitters with beta-particle emitters.

We demonstrated previously that human B-cell lymphomas were effectively and specifically killed in vitro by an antibody to CD74 (LL1) linked to (111)In or other Auger electron emitters. This study was intended to more accurately compare the potency and specificity of 3Auger electron emitters, (111)In, 67Ga, and 125I, and to evaluate beta-particle emitters, 131I and 90Y. The unique property of LL1 is its high level of intracellular uptake. METHODS: Raji B-lymphoma cells were incubated with serial dilutions of the radiolabeled Abs for 2 d and then monitored for cell growth by 2 assays: a cell counting assay and a clonogenic assay. The uptake of radioactivity per cell was monitored at various time points, and the radiation dose was calculated using published S values for radioactivity located in the cytoplasm. Both specific and nonspecific toxicity were evaluated. RESULTS: The beta-particle emitters had considerably higher levels of nonspecific toxicity than the Auger electron emitters, but both 131I and 90Y, and particularly 131I, still had high levels of specificity. Both of these results were consistent with dosimetry calculations. Relative to the delivered disintegrations per cell, 131I and 67Ga were the most potent of the radionuclides tested, with 125I and (111)In being significantly weaker and 90Y being intermediate. The high potency of 67Ga, together with its low nonspecific toxicity, caused this radionuclide to have the highest specificity index. CONCLUSION: When delivered by Ab LL1, both Auger electron and beta-particle emitters can produce specific and effective toxicity. The choice of the optimal radionuclide for therapy may depend on the ease and efficiency of labeling, the specific activity obtained, the nature of the tumor being targeted, and other factors, but the high specificity indices of the Auger electron emitters may be an advantage.     

Left ventricle volume measurements in cardiac micro-CT: the impact of radiation dose and contrast agent.

Micro-CT-based cardiac function estimation in small animals requires measurement of left ventricle (LV) volume at multiple time points during the cardiac cycle. Measurement accuracy depends on the image resolution, its signal and noise properties, and the analysis procedure. This work compares the accuracy of the Otsu thresholding and a region sampled binary mixture approach, for live mouse LV volume measurement using 100 microm resolution datasets. We evaluate both analysis methods after varying the volume of injected contrast agent and the number of projections used for CT reconstruction with a goal of permitting reduced levels of both X-ray and contrast agent doses.     

Prognostic evaluation of PET/CT in residual post-chemotherapy masses in patients with diffuse large B-cell lymphoma and its impact on survival

Aim of the work

To evaluate the prognostic value and accuracy of PET/CT in DLBCL patients with post-treatment CT-residual masses with concern in overall (OAS) and progression-free survival (PFS).

Materials and methods

We retrospectively studied 62 patients with DLBCL who had CT documented residual masses (CRu) after completion of chemotherapy.

Results

Forty-four patients with negative PET scan were free of relapse while 4 out of 18 patients with positive scan showed CR, the other 14 patients had developed relapse. PET attained a sensitivity of 100%, a specificity of 91%, a NPV of 100% and a PPV of 77.8% and an accuracy of 93.5%. The median OAS time was 33.59 months in patients with negative scan and 19.00 months in patients with positive scan with highly significant correlation (P value 0.0001) and the median PFS time was 29.53 months in patients with negative scan versus only 4.00 months in patients with positive scan with highly significant correlation (P value 0.0000).

Conclusion

PET/CT plays helpful part in evaluation of therapy response in DLBCL patients with CT residual mass and post-chemotherapy PET could be used as an accurate and good predictor of OAS and PFS.     

Therapeutic potential of 90Y- and 131I-labeled anti-CD20 monoclonal antibody in treating non-Hodgkin's lymphoma with pulmonary involvement: a Monte Carlo-based dosimetric analysis.

Pulmonary involvement is common in patients with non-Hodgkin's lymphoma (NHL). (90)Y- and (131)I-anti-CD20 antibodies (ibritumomab tiuxetan and tositumomab, respectively) have been approved for the treatment of refractory low-grade follicular NHL. In this work, we used Monte Carlo-based dosimetry to compare the potential of (90)Y and (131)I, based purely on their emission properties, in targeted therapy for NHL lung metastases of various nodule sizes and tumor burdens. METHODS: Lung metastases were simulated as spheres, with radii ranging from 0.2 to 5.0 cm, which were randomly distributed in a voxelized adult male lung phantom. Total tumor burden was varied from 0.2 to 1,641 g. Tumor uptake and retention kinetics of the 2 radionuclides were assumed equivalent; a uniform distribution of activity within tumors was assumed. Absorbed dose to tumors and lung parenchyma per unit activity in lung tumors was calculated by a Monte Carlo-based system using the MCNP4B package. Therapeutic efficacy was defined as the ratio of mean absorbed dose in the tumor to that in normal lung. Dosimetric analysis was also performed for a lung-surface distribution of tumor nodules mimicking pleural metastatic disease. RESULTS: The therapeutic efficacy of both (90)Y and (131)I declined with increasing tumor burden. In treating tumors with radii less than 2.0 cm, (131)I targeting was more efficacious than (90)Y targeting. (90)Y yielded a broader distribution of tumor absorbed doses, with the minimum 54.1% lower than the average dose; for (131)I, the minimum absorbed dose was 33.3% lower than the average. The absorbed dose to normal lungs was reduced when the tumors were distributed on the lung surface. For surface tumors, the reductions in normal-lung absorbed dose were greater for (90)Y than for (131)I, but (131)I continued to provide a greater therapeutic ratio across different tumor burdens and sizes. CONCLUSION: Monte Carlo-based dosimetry was performed to compare the therapeutic potential of (90)Y and (131)I targeting of lung metastases in NHL patients. (131)I provided a therapeutic advantage over (90)Y, especially in tumors with radii less than 2.0 cm and at lower tumor burdens. For both (90)Y- and (131)I-labeled antibodies, treatment is more efficacious when applied to metastatic NHL cases with lower tumor burdens. (131)I has advantages over (90)Y in treating smaller lung metastases.     

Attenuation-based kV pair selection in dual source dual energy computed tomography angiography of the chest: impact on radiation dose and image quality

Objectives

The purpose of this study was to evaluate the impact of attenuation-based kilovoltage (kV) pair selection in dual source dual energy (DSDE)-pulmonary embolism (PE) protocol examinations on radiation dose savings and image quality.

Methods

A prospective study was carried out on 118 patients with suspected PE. In patients in whom attenuation-based kV pair selection selected the 80/140Sn kV pair, the pre-scan 100/140Sn CTDIvol (computed tomography dose index volume) values were compared with the pre-scan 80/140Sn CTDIvol values. Subjective and objective image quality parameters were assessed.

Results

Attenuation-based kV pair selection switched to the 80/140Sn kV pair (“switched” cohort) in 63 out of 118 patients (53%). The mean 100/140Sn pre-scan CTDIvol was 8.8 mGy, while the mean 80/140Sn pre-scan CTDIvol was 7.5 mGy. The average estimated dose reduction for the “switched” cohort was 1.3 mGy (95% CI 1.2, 1.4; p?<?0.001), representing a 15% reduction in dose. After adjusting for patient weight, mean attenuation was significantly higher in the “switched” vs. “non-switched” cohorts in all five pulmonary arteries and in all lobes on iodine maps.

Conclusions

This study demonstrates that attenuation-based kV pair selection in DSDE examination is feasible and can offer radiation dose reduction without compromising image quality.

Key Points

? Attenuation-based kV pair selection in dual energy examination is feasible. ? It can offer radiation dose reduction to approximately 50% of patients. ? Approximate 15% reduction in radiation dose was achieved using this technique. ? The image quality is not compromised by use of attenuation-based kV pair selection.

     

Single-source dual-energy CT angiography with reduced iodine load in patients referred for aortoiliofemoral evaluation before transcatheter aortic valve implantation: impact on image quality and radiation dose

Objectives

To compare image quality and radiation dose of pre-transcatheter aortic valve implantation (TAVI) aortoiliofemoral CT angiography (AICTA) provided by standard vs. dual-energy mode with reduced iodine load protocols.

Methods

One hundred and sixty-one patients underwent a two-step CTA protocol before TAVI including cardiac CTA with injection of 65 mL of iodinated contrast agent (ICA), immediately followed by AICTA. From this second acquisition, the following three different patient groups were identified: Group 1: 52 patients with standard AICTA (60 mL ICA, 100 kVp, mA automodulation); Group 2: 48 patients with dual-energy AICTA with 50 % iodine load reduction (30 mL ICA, fast kVp switching, 600 mA); Group 3: 61 patients with an identical protocol to Group 2, but exposed to 375 mA. The qualitative/subjective image quality (13-point score) and quantitative/objective image quality (contrast attenuation and image noise) were evaluated. The radiation dose was recorded.

Results

There was no significant difference in non-diagnostic images between the three protocols. Contrast attenuation, signal-to-noise ratio and contrast-to-noise ratio were significantly higher, whereas noise was significantly lower in the standard protocol (all P?P?Conclusions Dual-energy AICTA before TAVI results in a reduction of iodine load while maintaining sufficient diagnostic information despite increased noise.

Key Points

? Dual-energy AICTA before TAVI results in a 50 % reduction of iodine load. ?The reduction of iodine load maintains sufficient image quality despite increased noise. ? Using 375 mA in dual-energy mode results in a reduction of radiation dose. ? A high tube current setting (600 mA) should be used in overweight patients.     

Venous thromboembolism: additional diagnostic value and radiation dose of pelvic CT venography in patients with suspected pulmonary embolism

Purpose

To assess the additional diagnostic value of indirect CT venography (CTV) of the pelvis and upper thighs performed after pulmonary CT angiography (CTA) for the diagnosis of venous thromboembolism (VTE).

Materials and methods

In a retrospective analysis, the radiology information system entries between January 2003 and December 2007 were searched for patients who received pulmonary CTA and additional CTV of the pelvis and upper thighs. Of those patients, the radiology reports were reviewed for the diagnosis of pulmonary embolism (PE) and deep venous thrombosis (DVT) in the pelvic veins and veins of the upper thighs. In cases with an isolated pelvic thrombosis at CTV (i.e. which only had a thrombosis in the pelvic veins but not in the veins of the upper thigh) ultrasound reports were reviewed for the presence of DVT of the legs. The estimated radiation dose was calculated for pulmonary CTA and for CTV of the pelvis.

Results

In the defined period 3670 patients were referred to our institution for exclusion of PE. Of those, 642 patients (353 men, 289 women; mean age, 65 ± 15 years, age range 18–98 years) underwent combined pulmonary CTA and CTV. Among them, PE was found in 227 patients (35.4%). In patients without PE CTV was negative in all cases. In patients with PE, CTV demonstrated pelvic thrombosis in 24 patients (3.7%) and thrombosis of the upper thighs in 43 patients (6.6%). Of those patients 14 (2.1%) had DVT in the pelvis and upper thighs. In 10 patients (1.5%) CTV showed an isolated pelvic thrombosis. Of those patients ultrasound reports were available in 7 patients, which revealed DVT of the leg veins in 5 cases (1%). Thus, the estimated prevalence of isolated pelvic thrombosis detected only by pelvic CTV ranges between 1–5/642 patients (0.1–0.7%). Radiation dose ranges between 4.8 and 9.7 mSv for additional CTV of the pelvis.

Conclusion

CTV of the pelvis performed after pulmonary CTA is of neglectable additional diagnostic value for the detection of VTE, because the additional radiation dose is high and isolated pelvic DVT is very rare. Venous imaging of the legs (preferably by radiation-free ultrasound) is sufficient for the diagnosis of underlying DVT in patients with suspected PE.     

Sinogram affirmed iterative reconstruction in head CT: Improvement of objective and subjective image quality with concomitant radiation dose reduction

Purpose

Iterative reconstruction has recently been revisited as a promising concept for substantial CT dose reduction. The purpose of this study was to assess the potential benefit of sinogram affirmed iterative reconstruction (SAFIRE) in head CT by comparing objective and subjective image quality at reduced tube current with standard dose filtered back projection (FBP).

Materials and methods

Non-contrast reduced dose head CT (255 mA s, CTDI_vol 47.8 mGy) was performed in thirty consecutive patients and reconstructed with SAFIRE and FBP. Images were assessed in terms of quantitative and qualitative image quality and compared with FBP of standard dose acquisitions (320 mA s, CTDI_vol 59.7 mGy).

Results

In reduced dose CT examinations, use of SAFIRE versus FBP resulted in 47% increase in contrast-to-noise ratio (CNR) (2.49 vs. 1.69; p < 0.0001). While reduction of tube current was associated with 13% decrease in CNR, quantitative degradation of image quality at lower dose was more than compensated through SAFIRE (2.49 vs. 1.96; p = 0.0004). Objective measurements of image sharpness were comparable between FBP and SAFIRE reconstructions (575.9 ± 74.1 vs. 583.4 ± 74.7 change in HU/Pixel; p = 0.28). Compared to standard dose FBP, subjective grading of noise as well as overall image quality scores were significantly improved when SAFIRE was used in reduced dose exams (1.3 vs. 1.6, p = 0.006; 1.3 vs. 1.7, p = 0.026).

Conclusion

At 20% dose reduction, reconstruction of head CT by SAFIRE provides above standard objective and subjective image quality, suggesting potential for more vigorous dose savings in neuroradiology CT applications.     

Central nervous system anaplastic large cell lymphoma in an adult: successful treatment with a combination of radiation and chemotherapy

Anaplastic large cell lymphoma (ALCL) is 1 of 17 mature T cell neoplasms described by the World Health Organization. Primary central nervous system (PCNS) ALCL represents a distinct rare form of this family of non-Hodgkin lymphoma and discussions of prognosis and management are limited to case reports and case series. Therapies for this disease largely parallel that of other PCNS lymphomas. We report the case of a 38-year-old male soldier who presented with a parieto-occipital mass lesion and neurological sequelae without evidence of systemic disease. Pathologic evaluation of tissue from brain biopsy confirmed ALCL. We elected treatment with an intensive combination of systemic and intrathecal chemotherapy with radiotherapy. Our patient is in complete remission 15 months following therapy. Tailored therapies for PCNS ALCL are unavailable and this regimen may be an option for patients who can tolerate intensive treatments.     

Protection of testes during radiation treatment by irregular and focused fields of 25 MV X-rays: in vivo evaluation of the absorbed dose

During therapeutic irradiation of subdiaphragmatic nodal areas, the gonads are exposed to radiation from the primary beam and scatter. Since young patients have a high probability of cure, limiting exposure to the gonads should be pursued. Primary shielding may be supplemented by additional shields in order to reduce this exposure. Testes dose measurements were performed with thermoluminescent dosimetry (TLD) in 37 patients treated with 25 MV x-rays on subdiaphragmatic nodal areas. Each patient was measured 5 times while under treatment. In 27 cases, an additional shield was placed to protect the testes. For 9 cases, comparative measurements were performed on a phantom with and without additional shielding. The median dose received by gonads was respectively 3% with additional shielding (27 cases) and 5.8% without additional shielding (10 cases, p = 0.001 Mann Whitney test). In the 6 patients for whom the measurements were compared, the differences were also statistically significant (p = 0.028 paired Wilcoxon test). This study confirmed the benefit of additional gonadal shielding during subdiaphragmatic radiation treatment with 25 MV x-rays.     

CT coronary angiography in atrial fibrillation: a comparison of radiation dose and diagnostic confidence with retrospective gating vs prospective gating with systolic acquisition

Objective:

To compare unmodulated, retrospective electrocardiographic (ECG) gating to prospective ECG gating with systolic acquisition for CT coronary angiography (CTCA) in patients with atrial fibrillation (AF), considering the radiation dose and the diagnostic confidence achieved with each technique.

Methods:

A retrospective service evaluation was conducted before and after prospective gating with systolic acquisition replaced retrospectively gated imaging for patients with AF undergoing CTCA at our institution. 25 consecutive patients were examined in each group. The scan parameters and radiation dose information had been collected in a prospective fashion. The image sets were read by blinded, expert readers who rated their diagnostic confidence using a 5-point Likert scale.

Results:

The radiation dose received by patients was significantly greater in the retrospectively gated group than those being scanned using prospective gating (21 vs 5.9 mSv, p < 0.01). The prospective gating technique was also associated with greater diagnostic confidence (mean, per-patient score 3.09 vs 3.78, p = 0.02).

Conclusion:

Prospective gating with systolic acquisition appears to improve diagnostic confidence at a significantly reduced radiation dose compared with retrospective gating in patients with AF.

Advances in knowledge:

The use of prospective gating with systolic triggering significantly reduces the radiation exposure to patients in AF undergoing CTCA. The same protocol also appears to improve diagnostic confidence.     

The use of 80 kV versus 100 kV in pulmonary CT angiography: An evaluation of the impact on radiation dose and image quality on two CT scanners

Introduction

Use of CT in the investigation of pulmonary embolism in radiosensitive patients such as pregnant and young female patients entails the need for protocol optimization. The aim of this study was to analyze the dose reduction and image quality achieved by using 80 kV instead of 100 kV in CT pulmonary angiography protocols.