John C. Roeske

MIRD Pamphlet No. 22 (Abridged): Radiobiology and Dosimetry of α-Particle Emitters for Targeted Radionuclide Therapy

The potential of α-particle emitters to treat cancer has been recognized since the early 1900s. Advances in the targeted delivery of radionuclides and radionuclide conjugation chemistry, and the increased availability of α-emitters appropriate for clinical use, have recently led to patient trials of radiopharmaceuticals labeled with α-particle emitters. Although α-emitters have been studied for many decades, their current use in humans for targeted therapy is an important milestone. The objective of this work is to review those aspects of the field that are pertinent to targeted α-particle emitter therapy and to provide guidance and recommendations for human α-particle emitter dosimetry.

Dosimetric comparison of bone marrow-sparing intensity-modulated radiotherapy versus conventional techniques for treatment of cervical cancer.

PURPOSE To compare bone marrow-sparing intensity-modulated pelvic radiotherapy (BMS-IMRT) with conventional (four-field box and anteroposterior-posteroanterior [AP-PA]) techniques in the treatment of cervical cancer. METHODS AND MATERIALS The data from 7 cervical cancer patients treated with concurrent chemotherapy and IMRT without BMS were analyzed and compared with data using four-field box and AP-PA techniques. All plans were normalized to cover the planning target volume with the 99% isodose line. The clinical target volume consisted of the pelvic and presacral lymph nodes, uterus and cervix, upper vagina, and parametrial tissue. Normal tissues included bowel, bladder, and pelvic bone marrow (PBM), which comprised the lumbosacral spine and ilium and the ischium, pubis, and proximal femora (lower pelvis bone marrow). Dose-volume histograms for the planning target volume and normal tissues were compared for BMS-IMRT vs. four-field box and AP-PA plans. RESULTS BMS-IMRT was superior to the four-field box technique in reducing the dose to the PBM, small bowel, rectum, and bladder. Compared with AP-PA plans, BMS-IMRT reduced the PBM volume receiving a dose >16.4 Gy. BMS-IMRT reduced the volume of ilium, lower pelvis bone marrow, and bowel receiving a dose >27.7, >18.7, and >21.1 Gy, respectively, but increased dose below these thresholds compared with the AP-PA plans. BMS-IMRT reduced the volume of lumbosacral spine bone marrow, rectum, small bowel, and bladder at all dose levels in all 7 patients. CONCLUSION BMS-IMRT reduced irradiation of PBM compared with the four-field box technique. Compared with the AP-PA technique, BMS-IMRT reduced lumbosacral spine bone marrow irradiation and reduced the volume of PBM irradiated to high doses. Therefore BMS-IMRT might reduce acute hematologic toxicity compared with conventional techniques.

Clinical Outcomes of Intensity-Modulated Pelvic Radiation Therapy for Carcinoma of the Cervix

PURPOSE To evaluate disease outcomes and toxicity in cervical cancer patients treated with pelvic intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS We included all patients with Stage I-IVA cervical carcinoma treated with IMRT at three different institutions from 2000-2007. Patients treated with extended field or conventional techniques were excluded. Intensity-modulated radiation therapy plans were designed to deliver 45 Gy in 1.8-Gy daily fractions to the planning target volume while minimizing dose to the bowel, bladder, and rectum. Toxicity was graded according to the Radiation Therapy Oncology Group system. Overall survival and disease-free survival were estimated by use of the Kaplan-Meier method. Pelvic failure, distant failure, and late toxicity were estimated by use of cumulative incidence functions. RESULTS The study included 111 patients. Of these, 22 were treated with postoperative IMRT, 8 with IMRT followed by intracavitary brachytherapy and adjuvant hysterectomy, and 81 with IMRT followed by planned intracavitary brachytherapy. Of the patients, 63 had Stage I-IIA disease and 48 had Stage IIB-IVA disease. The median follow-up time was 27 months. The 3-year overall survival rate and the disease-free survival rate were 78% (95% confidence interval [CI], 68-88%) and 69% (95% CI, 59-81%), respectively. The 3-year pelvic failure rate and the distant failure rate were 14% (95% CI, 6-22%) and 17% (95% CI, 8-25%), respectively. Estimates of acute and late Grade 3 toxicity or higher were 2% (95% CI, 0-7%) and 7% (95% CI, 2-13%), respectively. CONCLUSIONS Intensity-modulated radiation therapy is associated with low toxicity and favorable outcomes, supporting its safety and efficacy for cervical cancer. Prospective clinical trials are needed to evaluate the comparative efficacy of IMRT vs. conventional techniques.

Normal Tissue Complication Probability Modeling of Acute Hematologic Toxicity in Cervical Cancer Patients Treated With Chemoradiotherapy

PURPOSE To test the hypothesis that increased pelvic bone marrow (BM) irradiation is associated with increased hematologic toxicity (HT) in cervical cancer patients undergoing chemoradiotherapy and to develop a normal tissue complication probability (NTCP) model for HT. METHODS AND MATERIALS We tested associations between hematologic nadirs during chemoradiotherapy and the volume of BM receiving≥10 and 20 Gy (V10 and V20) using a previously developed linear regression model. The validation cohort consisted of 44 cervical cancer patients treated with concurrent cisplatin and pelvic radiotherapy. Subsequently, these data were pooled with data from 37 identically treated patients from a previous study, forming a cohort of 81 patients for normal tissue complication probability analysis. Generalized linear modeling was used to test associations between hematologic nadirs and dosimetric parameters, adjusting for body mass index. Receiver operating characteristic curves were used to derive optimal dosimetric planning constraints. RESULTS In the validation cohort, significant negative correlations were observed between white blood cell count nadir and V10 (regression coefficient (β)=-0.060, p=0.009) and V20 (β=-0.044, p=0.010). In the combined cohort, the (adjusted) β estimates for log (white blood cell) vs. V10 and V20 were as follows: -0.022 (p=0.025) and -0.021 (p=0.002), respectively. Patients with V10≥95% were more likely to experience Grade≥3 leukopenia (68.8% vs. 24.6%, p<0.001) than were patients with V20>76% (57.7% vs. 21.8%, p=0.001). CONCLUSIONS These findings support the hypothesis that HT increases with increasing pelvic BM volume irradiated. Efforts to maintain V10<95% and V20<76% may reduce HT.

Radiation-Related Predictors of Hematologic Toxicity After Concurrent Chemoradiation for Cervical Cancer and Implications for Bone Marrow–Sparing Pelvic IMRT

PURPOSE To determine factors predictive for hematologic toxicity (HT) associated with concurrent chemoradiation for Stage II through IV cervical cancer. METHODS AND MATERIALS The medical records of 40 women receiving concurrent chemoradiation for cervical cancer were reviewed. Hematologic toxicity was defined by use of Common Terminology Criteria for Adverse Events (version 3.0). Variables predicting for HT including age, body mass index, transfusions, and bone marrow volumes irradiated were included in the data analysis. RESULTS Of the patients, 13 (32.5%) had Grade 0 or 1 HT and 27 (67.5%) had Grade 2 through 4 HT (HT2+). Multiple logistic regression analysis of potential predictors showed that only the volume of bone receiving 20 Gy (V20) for whole pelvic bone tended toward significance for predicting HT2+. A strong correlation was noted between HT2+ and V20 (r = 0.8, p < 0.0001). A partitioning analysis to predict HT2+ showed a cutoff value of 79.42% (approximately 80%) for V20 of whole pelvic bone. That is, if the V20 of the whole pelvis exceeds 80%, the risk of HT2+ developing increases by a factor (odds ratio) of 4.5 (95%, confidence interval, 1.08-18.69) (p < 0.05). CONCLUSIONS We have shown a correlation between bone marrow volume radiated and development of HT. This has implications for use of pelvic intensity-modulated radiation therapy, which can potentially decrease the volume of bone marrow radiated.

A multi-institutional acute gastrointestinal toxicity analysis of anal cancer patients treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy

Using previous dosimetric analysis methods, we identified the volume of bowel receiving 30 Gy (V(30)) correlated with acute gastrointestinal (GI) toxicity in anal cancer patients treated with intensity-modulated radiation therapy and concurrent chemotherapy. For V(30)>450 cc and < or =450 cc, acute GI toxicity was 33% and 8%, respectively (p=0.003).

Predictors of Tumor Control in Patients Treated With Linac-Based Stereotactic Radiosurgery for Metastatic Disease to the Brain

Objective:The objective of this study was to determine predictive factors for local control (LC) of brain metastases (BM) treated with Linac-based stereotactic radiosurgery (LB-SRS). Methods:Between January 1994 and July 2001, 80 patients (126 BM) underwent LB-SRS. All patients had follow-up imaging with computed tomography (40%) or magnetic resonance imaging (60%). Most patients had either lung (41%) or renal cell (20%) cancer. The median SRS prescription dose was 18 Gy (range, 10–21 Gy). Most patients (86%) also received whole-brain radiotherapy (WBRT). LC was defined as the absence of enlargement of the BM on follow-up scans. Actuarial LC analyses were performed by the method of Kaplan-Meier and compared with the log-rank test. Factors analyzed included histology, volume, prescription dose, maximum and minimum tumor dose, target volume ratio, number of arcs and isocenters, total degrees, and WBRT. Multivariate analysis was accomplished. Results:At a median follow up of 8.8 months, 11 BM failed (8.7%). The 1-and 2-year actuarial LC rates were 88.6% and 77.2%, respectively. The most significant factors correlated with LC were prescription (P = 0.0004) and minimum tumor (P = 0.002) doses, and tumor volume (P = 0.04). On multivariate analysis, the sole factor correlated with LC was minimum tumor dose (P = 0.03). Conclusion:Our results confirm that LB-SRS is associated with excellent LC rates in the majority of patients treated. However, particular attention should be given to minimum target dose to ensure optimal outcome.

Feasibility study for linac‐based intensity modulated total marrow irradiation

Total body irradiation (TBI) is used as a preconditioning regimen prior to bone marrow transplant for treatment of hematologic malignancies. During TBI, large volumes of normal tissue are irradiated, and this can lead to toxicities, most significantly in the lungs. Intensity modulated total marrow irradiation (IMTMI) may be able to reduce these toxicities by directly targeting the bone marrow while minimizing the dose to critical structures. The goal of this study was to assess the feasibility of IMTMI by following the planning and delivery process for a Rando phantom. A three isocenter technique was used to provide a full body plan for treatment on a linear accelerator. Thermoluminescent detectors(TLDs) were placed at 22 positions throughout the phantom to compare the delivered doses to the planned doses. Individual intensity modulated radiation therapy verification plans were delivered to a solid water phantom for the three isocenters, and doses measured from an ion chamber and film were compared to the planned doses. The treatment plan indicated that target coverage was achieved with this IMTMI technique, and that the doses to critical structures were reduced by 29%–65% compared to conventional TBI. TLD readings demonstrated accurate dose delivery, with an average difference of 3.5% from the calculated dose. Ion chamber readings for the verification plans were all within 3% of the expected dose, and film measurements showed accurate dose distributions. Results from this study suggest that IMTMI using the three isocenter technique can be accurately delivered and may result in substantial dose reductions to critical structures.

Small-Scale Dosimetry: Challenges and Future Directions

The increased specificity of targeting agents has resulted in an interest in the use of radionuclides that emit particulate radiation: alpha particles, beta particles and Auger electrons. The potential advantage of these radionuclides is the ability to deliver therapeutic doses to individual tumor cells while minimizing the dose to the surrounding normal tissues. However, the dosimetry of these radionuclides is challenging because the dose must be characterized on a scale that is comparable to the range of these emissions, ie, millimeters for beta particles, micrometers for alpha particles, and nanometers for Auger electrons to. In this review, each class of particulate emitter is discussed along with the associated dosimetric techniques unique to calculating dose on these scales. The limitations of these approaches and the factors that hinder the clinical use of small-scale dosimetry are also discussed.

Markerless motion tracking of lung tumors using dual‐energy fluoroscopy

PURPOSE To evaluate the efficacy of dual-energy (DE) vs single-energy (SE) fluoroscopic imaging of lung tumors using a markerless template-based tracking algorithm. METHODS Ten representative patient breathing patterns were programmed into a Quasar™ motion phantom. The phantom was modified by affixing pork ribs to the surface, and a cedar insert with a small spherical volume was used to simulate lung and tumor, respectively. Sequential 60 kVp (6 mA) and 120 kVp (1.5 mA) fluoroscopic sequences were acquired. Frame-by-frame weighted logarithmic subtraction was performed resulting in a DE fluoroscopic sequence. A template-based algorithm was then used to track tumor motion throughout the DE and SE fluoroscopy sequences. Tracking coordinates were evaluated against ground-truth tumor locations. Fluoroscopic images were also acquired for two lung cancer patients, neither of which had implanted fiducials. RESULTS For phantom imaging, a total of 1925 frames were analyzed. The algorithm successfully tracked the target on 99.9% (1923/1925) of DE frames vs 90.7% (1745/1925) SE images (p < 0.01). The displacement between tracking coordinates and ground truth for the phantom was 1.4 mm ± 1.1 mm for DE vs 2.0 mm ± 1.3 mm for SE (p < 0.01). Images from two patients, one with a larger tumor and one with a smaller tumor, were also analyzed. For the patient with the larger tumor, the average displacement from physician defined ground truth was 1.2 mm ± 0.6 mm for DE vs 1.4 mm ± 0.7 mm for SE (p = 0.016). For the patient that presented with a smaller tumor, the average displacement from physician defined ground truth was 2.2 mm ± 1.0 mm for DE vs 3.2 mm ± 1.4 mm for SE (p < 0.01). Importantly, for this single patient with the smaller tumor, 15.6% of the SE frames had >5 mm displacements from the ground truth vs 0% for DE fluoroscopy. CONCLUSIONS This work indicates the potential for markerless tumor tracking utilizing DE fluoroscopy. With DE imaging, the algorithm showed improved detectability vs SE fluoroscopy and was able to accurately track the tumor in nearly all cases.