Risk of leptomeningeal carcinomatosis in patients with brain metastases treated with stereotactic radiosurgery.

There is limited available literature examining factors that predispose patients to the development of LMC after stereotactic radiosurgery (SRS) for brain metastases. We sought to evaluate risk factors that may predispose patients to LMC after SRS treatment in this case-control study of patients with brain metastases who underwent single-fraction SRS between 2011 and 2016. Demographic and clinical information were collected retrospectively for 19 LMC cases and 30 controls out of 413 screened patients with brain metastases. Risk factors of interest were evaluated by univariate and multivariate logistic regression analyses and overall survival rates were evaluated by Kaplan-Meier survival analysis. About 5% of patients with brain metastases treated with SRS developed LMC. Patients with LMC (median 154 days, 95% CI 33-203 days) demonstrated a poorer overall survival than matched controls (median 417 days, 95% CI 121-512 days, p = 0.002). The most common primary tumor histologies  that lead to the development of LMC were non-small cell lung cancer (36.8%), breast cancer (26.3%), and melanoma (21.1%). No association was found between the risk of LMC and the location of the brain lesion or total volume of brain metastases. Prior surgical resection of brain metastases before SRS was associated with a 6.5 times higher odds (95% CI 1.45-29.35, p = 0.01) of developing LMC post-radiosurgery compared to those with no prior resections of brain metastases. Additionally, adjuvant WBRT may help to reduce the risk of LMC and can be considered in decision-making for patients who have had brain metastasectomy.

Cellular Response to Exponentially Increasing and Decreasing Dose Rates: Implications for Treatment Planning in Targeted Radionuclide Therapy.

The treatment of cancer using targeted radionuclide therapy is of interest to nuclear medicine and radiation oncology because of its potential for killing tumor cells while minimizing dose-limiting toxicities to normal tissue. The ionizing radiations emitted by radiopharmaceuticals deliver radiation absorbed doses over protracted periods of time with continuously varying dose rates. As targeted radionuclide therapy becomes a more prominent part of cancer therapy, accurate models for estimating the biologically effective dose (BED) or equieffective dose (EQD2α/ß) will become essential for treatment planning. This study examines the radiobiological impact of the dose rate increase half-time during the uptake phase of the radiopharmaceutical. MDA-MB-231 human breast cancer cells and V79 Chinese hamster lung fibroblasts were irradiated chronically with 662 keV γ rays delivered with time-varying dose rates that are clinically relevant. The temporal dose-rate patterns were: 1. acute, 2. exponential decrease with a half-time of 64 h (Td = 64 h), 3. initial exponential increase to a maximum (half time Ti = 2, 8 or 24 h) followed by exponential decrease (Td = 64 h). Cell survival assays were conducted and surviving fractions were determined. There was a marked reduction in biological effect when Ti was increased. Cell survival data were tested against existing dose-response models to assess their capacity to predict response. Currently accepted models that are used in radiation oncology overestimated BED and EQD2α/ß at low-dose rates and underestimated them at high-dose rates. This appears to be caused by an adaptive response arising as a consequence of the initial low-dose-rate phase of exposure. An adaptive response function was derived that yields more accurate BED and EQD2α/ß values over the spectrum of dose rates and absorbed doses delivered. Our experimental data demonstrate a marked increase in cell survival when the dose-rate-increase half-time is increased, thereby suggesting an adaptive response arising as a consequence of this phase of exposure. We have modified conventional radiobiological models used in the clinic for brachytherapy and external beams of radiation to account for this phenomenon and facilitate their use for treatment planning in targeted radionuclide therapy.

Potential of 3D printing technologies for fabrication of electron bolus and proton compensators.

In electron and proton radiotherapy, applications of patient-specific electron bolus or proton compensators during radiation treatments are often necessary to accommodate patient body surface irregularities, tissue inhomogeneity, and variations in PTV depths to achieve desired dose distributions. Emerging 3D printing technologies provide alternative fabrication methods for these bolus and compensators. This study investigated the potential of utilizing 3D printing technologies for the fabrication of the electron bolus and proton compensators. Two printing technologies, fused deposition modeling (FDM) and selective laser sintering (SLS), and two printing materials, PLA and polyamide, were investigated. Samples were printed and characterized with CT scan and under electron and proton beams. In addition, a software package was developed to convert electron bolus and proton compensator designs to printable Standard Tessellation Language file format. A phantom scalp electron bolus was printed with FDM technology with PLA material. The HU of the printed electron bolus was 106.5 ± 15.2. A prostate patient proton compensator was printed with SLS technology and polyamide material with -70.1 ± 8.1 HU. The profiles of the electron bolus and proton compensator were compared with the original designs. The average over all the CT slices of the largest Euclidean distance between the design and the fabricated bolus on each CT slice was found to be 0.84 ± 0.45 mm and for the compensator to be 0.40 ± 0.42 mm. It is recommended that the properties of specific 3D printed objects are understood before being applied to radiotherapy treatments.

Patterns of failure in colorectal patients with liver metastases after yttrium-90 radioembolization.

OBJECTIVES: To assess patterns of failure and factors affecting recurrence patterns in colorectal cancer patients treated with Y-labeled resin microspheres for metastatic liver disease. METHODS: We retrospectively reviewed 30 colorectal patients treated with Yttrium-90 radioembolization and assessed follow-up computed tomography scans and positron emission tomography scans to determine disease outcomes. All patients were included in survival analysis. Twenty-six patients with hepatic metastases were assessed for patterns of failure after radioembolization treatment and grouped into 3 patterns: (1) hepatic; (2) extrahepatic; and (3) intrahepatic and extrahepatic. RESULTS: The median overall survival and progression-free survival for all colorectal patients treated with radioembolization was 9.4 and 3.2 months, respectively. Overall survival and progression-free survival were not significantly different between patterns of failure (P=0.43 and 0.26, respectively). Logistic regression analysis demonstrated a trend toward the predictive value of tumor volume in determining patterns of failure. Smaller tumor volumes had a higher predictive probability for extrahepatic failure than larger tumor volumes (P=0.057). Tumor volumes <300 mL were predictive for extrahepatic failure patterns compared with hepatic recurrence (P=0.046). CONCLUSIONS: Radioembolization with Y-labeled resin microspheres continues to be an effective salvage treatment for colorectal liver metastases. Analysis of patterns of radiologic failure demonstrated that patients treated by radioembolization develop a greater proportion of extrahepatic failure. Tumor volumes >300 mL were predictive for hepatic recurrence, suggesting that increased dosing or retreatment of these lesions may lead to improved hepatic control of disease and better patient outcomes.

Heterogeneity-corrected vs -uncorrected critical structure maximum point doses in breast balloon brachytherapy.

Recent studies have reported potentially clinically meaningful dose differences when heterogeneity correction is used in breast balloon brachytherapy. In this study, we report on the relationship between heterogeneity-corrected and -uncorrected doses for 2 commonly used plan evaluation metrics: maximum point dose to skin surface and maximum point dose to ribs. Maximum point doses to skin surface and ribs were calculated using TG-43 and Varian Acuros for 20 patients treated with breast balloon brachytherapy. The results were plotted against each other and fit with a zero-intercept line. Max skin dose (Acuros) = max skin dose (TG-43) * 0.930 (R(2) = 0.995). The average magnitude of difference from this relationship was 1.1% (max 2.8%). Max rib dose (Acuros) = max rib dose (TG-43) * 0.955 (R(2) = 0.9995). The average magnitude of difference from this relationship was 0.7% (max 1.6%). Heterogeneity-corrected maximum point doses to the skin surface and ribs were proportional to TG-43-calculated doses. The average deviation from proportionality was 1%. The proportional relationship suggests that a different metric other than maximum point dose may be needed to obtain a clinical advantage from heterogeneity correction. Alternatively, if maximum point dose continues to be used in recommended limits while incorporating heterogeneity correction, institutions without this capability may be able to accurately estimate these doses by use of a scaling factor.

Lumpectomy closure technique does not affect dosimetry in patients undergoing external-beam-based accelerated partial breast irradiation.

BACKGROUND: During the breast lumpectomy procedure, surgeons traditionally elect to use either a superficial or full-thickness closure when sealing the wound depending on surgeon preference as well as desired outcomes. The purpose of this study was to examine dosimetric endpoints in patients with superficial versus full-thickness closures with accelerated partial breast irradiation (APBI). METHODS: Patients who underwent breast conservation surgery followed by 3D conformal external-beam APBI were identified (n = 45) and were separated according to the type of cavity closure performed: superficial and full thickness. Data gathered from the retrospective review of patient charts was analyzed according to criteria in the NSABP B-39 protocol in order to quantify the amount of radiation delivered to organs at risk. The patient seroma cavity was further given a cavity visualization score to assess the impact of wound closure on treatment planning. RESULTS: There was no significant difference in the mean CVS score for the 2 groups. There were no statistical differences in all dosimetric endpoints compared for the 2 types of closure, and both groups met NSABP B-39 guidelines for the ipsilateral breast, heart, and ipsilateral lung dosimetry. CONCLUSIONS: We found no significant difference in dosimetric outcomes in either the superficial or deep closure treatment groups. Breast surgeons should not alter their preferred closure strategy in anticipation of 3D-CRT APBI.

Three-dimensional dosimetric considerations from different point A definitions in cervical cancer low-dose-rate brachytherapy.

PURPOSE: To investigate the dosimetric difference due to the different point A definitions in cervical cancer low-dose-rate (LDR) intracavitary brachytherapy. MATERIAL AND METHODS: Twenty CT-based LDR brachytherapy plans of 11 cervical patients were retrospectively reviewed. Two plans with point As following the modified Manchester system which defines point A being 2 cm superior to the cervical os along the tandem and 2 cm lateral (Aos), and the American Brachytherapy Society (ABS) guideline definition in which the point A is 2 cm superior to the vaginal fornices instead of os (Aovoid) were generated. Using the same source strength, two plans prescribed the same dose to Aos and Aovoid. Dosimetric differences between plans including point A dose rate, treatment volume encompassed by the prescription isodose line (TV), and dose rate of 2 cc of the rectum and bladder to the prescription dose were measured. RESULTS: On average Aovoid was 8.9 mm superior to Aos along the tandem direction with a standard deviation of 5.4 mm. With the same source strength and arrangement, Aos dose rate was 19% higher than Aovoid dose rate. The average TV(Aovoid) was 118.0 cc, which was 30% more than the average TV(Aos) of 93.0 cc. D2cc/D(Aprescribe) increased from 51% to 60% for rectum, and increased from 89% and 106% for bladder, if the prescription point changed from Aos to Aovoid. CONCLUSIONS: Different point A definitions lead to significant dose differences. Careful consideration should be given when changing practice from one point A definition to another, to ensure dosimetric and clinical equivalency from the previous clinical experiences.

Changes in liver and spleen volumes and liver function after radioembolization with yttrium-90 resin microspheres.

PURPOSE: To evaluate injury to normal liver parenchyma following radioembolization with yttrium-90 ((90)Y) resin microspheres as reflected by liver and spleen volume and liver function, and to investigate the influence of chemotherapy on these changes. MATERIALS AND METHODS: A retrospective review of a prospectively acquired database of patients undergoing (90)Y radioembolization with resin microspheres over a 24-month period was performed to assess for changes in liver and spleen volume and liver function. Patients undergoing whole-liver or sequential bilobar treatment with at least 3 months of follow-up were included in the study. Chemotherapy records were reviewed, and the influence of agents with known hepatotoxicity on liver and spleen volume and alteration in liver function was assessed. RESULTS: Thirty-seven patients were included in the analysis. Significant decrease in liver volume (12.5%; P = .002) and increase in spleen volume (63%; P = .003) were observed, as were trends for increases in serum bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels and decreases in platelet and white blood cell counts. Chemotherapy with agents with known hepatotoxicity administered before and after radioembolization increased the extent of liver injury, but this did not reach statistical significance. CONCLUSIONS: The normal liver is not spared radiation effects from (90)Y radioembolization as demonstrated by serial changes in liver and spleen volumes, as well as liver function. However, these changes were of limited clinical significance in the patients studied.

A comparison of helical intensity-modulated radiotherapy, intensity-modulated radiotherapy, and 3D-conformal radiation therapy for pancreatic cancer.

We assessed dosimetric differences in pancreatic cancer radiotherapy via helical intensity-modulated radiotherapy (HIMRT), linac-based IMRT, and 3D-conformal radiation therapy (3D-CRT) with regard to successful plan acceptance and dose to critical organs. Dosimetric analysis was performed in 16 pancreatic cases that were planned to 54 Gy; both post-pancreaticoduodenectomy (n = 8) and unresected (n = 8) cases were compared. Without volume modification, plans met constraints 75% of the time with HIMRT and IMRT and 13% with 3D-CRT. There was no statistically significantly improvement with HIMRT over conventional IMRT in reducing liver V35, stomach V45, or bowel V45. HIMRT offers improved planning target volume (PTV) dose homogeneity compared with IMRT, averaging a lower maximum dose and higher volume receiving the prescription dose (D100). HIMRT showed an increased mean dose over IMRT to bowel and liver. Both HIMRT and IMRT offer a statistically significant improvement over 3D-CRT in lowering dose to liver, stomach, and bowel. The results were similar for both unresected and resected patients. In pancreatic cancer, HIMRT offers improved dose homogeneity over conventional IMRT and several significant benefits to 3D-CRT. Factors to consider before incorporating IMRT into pancreatic cancer therapy are respiratory motion, dose inhomogeneity, and mean dose.

A novel method of island blocking in whole abdominal radiotherapy using a modified electronic tissue compensation technique.

Traditionally, large fields requiring island blocking used external beam radiation therapy (EBRT) with Cerrobend blocks to limit dose to the critical structures. It is laborious to construct blocks and use them on a daily basis. We present a novel technique for island blocking using a modified electronic tissue compensation (MECOMP) technique. Five patients treated at our institution were selected for this study. The study compared two planning techniques: a novel MECOMP and a conventional EBRT technique. Conventional fields were defined using anterior-posterior and posterior-anterior (PA) fields. The kidneys were contoured and an aperture cut-out block was fitted to the OAR with a 1-cm margin (OAR(CTV)) and placed in the PA field. A dynamic multileaf collimation (DMLC) plan with ECOMP was developed using identical beam and blocking strategy; this tissue compensation-based fluence map was modified to deliver a "zero" dose to the CTV(OAR) from the PA field. There were no significant differences in the mean, maximum, and minimum doses to the right or left kidney between the two methods. The mean, maximum, and minimum doses to the peritoneal cavity were also not significantly different. The number of monitor units (MUs) required was increased using the MECOMP (273 vs. 1152, p < 0.01). The MECOMP is effectively able to deliver DMLC-based radiotherapy, even with island blocks present. This novel use of MECOMP for whole abdominal radiotherapy should substantially reduce the labor, daily treatment time, and treatment-related errors through the elimination of cerrobend blocks.

Optimization of couch translational corrections to compensate for rotational and deformable target deviations in image guided radiotherapy.

The utilization of image-guided radiotherapy (IGRT) technologies helps correct temporal and spatial deviations of the target volume relative to planned radiation beams. With the aid of these IGRT technologies, it becomes possible to better identify the target volume before and even during radiation treatment. However, since components of the detected deviations may be translational, rotational, and deformable, the question remains whether simple treatment-couch translational movement can be optimized to compensate for these complicated deviations. Deviation of the target volume and changes in patient body shape from that acquired for treatment planning may further add to the variations from planned dose distribution. In this study, an optimization strategy is developed to investigate these issues. The optimization process involved the use of the hill climbing algorithm, the detected target volume and patient body shape, and the dose distribution based on acquired images at treatment. During the process, the planned dose distribution was iteratively adjusted to reflect the changes of depth and distance as the translational treatment couch movement was being optimized. The optimal treatment couch movement was considered achieved when the highest fraction of the detected target volume was covered by prescription dose. This optimization strategy was evaluated on clinical prostate cancer cases. For each of the cases, cone beam computed tomography (CBCT) images were acquired right after fiducial marker-based kilovolt orthogonal imaging verification and setup adjustment. Based on the CBCT images, the clinical target volume at the treatment was delineated and the translational treatment-couch movements were optimized with the developed strategy. The resultant dose coverage was compared to that without the optimization. The results showed that with the present strategy, rotational and deformable target deviations can be further compensated with translational couch correction.

Improvement in dose homogeneity with electronic tissue compensation over IMRT and conventional RT in whole brain radiotherapy.

BACKGROUND AND PURPOSE: To perform a dosimetric analysis of whole brain radiotherapy using electronic tissue compensation (ECOMP) with dynamic multileaf collimation (dMLC) and its comparisons with inverse-planned intensity modulated radiation therapy (IMRT) with optimization constraints and conventional whole brain radiotherapy (WBRT). MATERIALS AND METHODS: Ten patients (6 adult, 4 pediatric) who were treated at our institution were selected for this study. WBRT fields were defined using opposed lateral fields directed at the intracranial contents and MLC leaves were used to block the critical normal structures. A two-field inverse-planned IMRT plan was then developed using sliding window technique and two optimization constraints. Finally, a dMLC plan with electronic tissue compensation (ECOMP) was developed using identical beam and collimator angles and blocking strategy; the fluence map was generated based on tissue compensation and no additional constraints were given for optimization purposes. This tissue compensation based fluence map was applied to deliver a homogenous dose to the intracranial contents. Radiation dose was identically prescribed to the isocenter (30.0 Gy in 10 fractions) for all the cases. A dosimetric comparison was then performed for each method in our patient population. RESULTS: ECOMP significantly reduced the mean maximum dose (D(max)) to the intracranial contents as compared to both WBRT (103.9% vs. 112.4%, p<0.0001) and IMRT (106.1%, p=0.02). ECOMP also reduced the intracranial volume receiving greater than 103% of the prescribed dose (2.6% vs. 54.9%, p<0.0001) and the intracranial volume receiving greater than 105% of the prescribed dose (0% vs. 26%, p<0.0001) as compared to WBRT; there was no statistical difference in these two parameters between ECOMP and IMRT. The mean number of monitor units was increased, however, using both ECOMP and IMRT as compared to WBRT (870 and 860 vs. 318, p<0.0001). CONCLUSIONS: Dynamic multileaf collimation with electronic tissue compensation (ECOMP) leads to improved dose homogeneity with less 'hot spots' as compared to conventional and inverse-planned intensity modulated whole brain radiotherapy. At our institution, ECOMP is being used in all pediatric patients or select adult patients with a long life expectancy requiring cranial radiotherapy.

Intensity-modulated radiation therapy for orbital lymphoma.

PURPOSE: Orbital manifestations of non-Hodgkin's lymphoma (NHL) are rare and accounts for only 1% of all cases of NHL. There have been no reports of treating orbital lymphoma using intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Four patients were treated at our institution for orbital lymphoma using IMRT. Radiotherapy (RT) plans using wedged pair fields were developed for comparison. Clinical results using IMRT are presented and a dosimetric analysis between IMRT and RT was performed. RESULTS: All patients had a complete response based on their physical examinations and post-IMRT imaging. Symptoms that had been present at initial presentation resolved in all patients during the course of the treatment. All four patients experienced only grade 1 dry eye syndrome and keratitis. The average dose to the contralateral orbit, lacrimal gland, and lens were all significantly reduced (P < 0.01) in IMRT patients as compared to the RT patients. IMRT reduced the V5 and V10 for the contralateral lens, orbit, and lacrimal gland and the optic chiasm (P < 0.05). CONCLUSION: IMRT is feasible when treating orbital lymphoma and reduces dose to critical structures while providing excellent dose coverage of target volumes. IMRT offers patients with orbital lymphoma excellent clinical outcomes, similar to conventional RT, with no increased toxicity.

A strategy to objectively evaluate the necessity of correcting detected target deviations in image guided radiotherapy.

Image guided radiotherapy technologies are being increasingly utilized in the treatment of various cancers. These technologies have enhanced the ability to detect temporal and spatial deviations of the target volume relative to planned radiation beams. Correcting these detected deviations may, in principle, improve the accuracy of dose delivery to the target. However, in many situations, a clinical decision has to be made as to whether it is necessary to correct some of the deviations since the relevant dosimetric impact may or may not be significant, and the corresponding corrective action may be either impractical or time consuming. Ideally this decision should be based on objective and reproducible criteria rather than subjective judgment. In this study, a strategy is proposed for the objective evaluation of the necessity of deviation correction during the treatment verification process. At the treatment stage, without any alteration from the planned beams, the treatment beams should provide the desired dose coverage to the geometric volume identical to the planning target volume (PTV). Given this fact, the planned dose distribution and PTV geometry were used to compute the dose coverage and PTV enclosure of the clinical target volume (CTV) that was detected from imaging during the treatment setup verification. The spatial differences between the detected CTV and the planning CTV are essentially the target deviations. The extent of the PTV enclosure of the detected CTV as well as its dose coverage were used as criteria to evaluate the necessity of correcting any of the target deviations. This strategy, in principle, should be applicable to any type of target deviations, including both target deformable and positional changes and should be independent of how the deviations are detected. The proposed strategy was used on two clinical prostate cancer cases. In both cases, gold markers were implanted inside the prostate for the purpose of treatment setup verification and were used to determine potential target deviations. To derive the detected CTV geometry from the planning CTV based on the locations of the gold markers, the CTV was approximated with an elastic semirigid body model. The derived CTV geometry and shape were confirmed with CBCT imaging. The evaluation results and the related mathematical equations and computational algorithm are presented. It is concluded that the proposed strategy is potentially useful in establishing objective criteria for the necessity of correction of the target deviations.