Disparities in brachytherapy utilization in cervical cancer in the United States: A comprehensive literature review.

Brachytherapy (BT) is an integral component of treatment for patients with locally advanced cervical cancer, significantly improving local control and overall survival. There is an overall trend of decreased utilization of BT in United States (US) in the last few decades with around 50% of patients being treated without BT. The cause of decreased utilization is multifactorial including physician comfort, facility volume, low reimbursements rates and costs of starting and maintaining a brachytherapy program. This decrease coincides with an increase in the use of newer advanced techniques like intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) boost resulting in inferior oncological outcomes and increased toxicity. Moreover, racial and socioeconomic disparities in BT utilization have been widely reported in the US. Various factors including age, race, socio-economic status, location, facility type, facility volume and insurance status result in limited access to brachytherapy, which jeopardizes oncologic outcomes. This comprehensive review discusses the BT utilization in the US, examines the impact of race and socioeconomic factors on BT utilization, and highlights its impact on outcomes.

Patterns of postmastectomy radiation therapy in clinically node-positive breast cancerpatients with pathologically negative lymph nodes after neoadjuvant chemotherapy.

BACKGROUND: To analyze postmastectomy radiation therapy (PMRT) utilization and its association with overall survival (OS) in patients presenting with node-positive breast cancer who are pathologically node-negative (ypN0) after neoadjuvant chemotherapy (NAC). METHODS: Using the National Cancer Data Base (NCDB), we identified patients diagnosed between 2004 and 2013 with clinical T1-4 node-positive nonmetastatic breast cancer who received NAC and underwent mastectomy with pathologically negative lymph node sampling. Multivariable regression models identified factors associated with PMRT use. The Cox proportional hazards model was used to evaluate predictors of mortality. RESULTS: The study included 8766 clinically node-positive patients who met the study criteria. PMRT was delivered to 61.5% of patients. Overall PMRT utilization rate increased over the study period from 54.4% in 2004 to 65.2% in 2011. Predictors of PMRT use included larger tumor size, increasing clinical N stage, higher grade disease, receipt of hormone therapy, and a greater number of lymph nodes examined. The unadjusted 5-year OS was 84.1% in the PMRT group and 83.8% in the non-PMRT group (p = NS). PMRT was not significantly associated with survival on multivariable analysis (hazard ratio [HR] 0.87; 95% confidence interval [CI] 0.73-1.03). DISCUSSION: The delivery of PMRT has increased over time in women presenting with clinically node-positive breast cancer who convert to ypN0 after NAC. While we identified multiple independent socioeconomic and clinical predictors of both PMRT utilization and survival, PMRT itself was not significantly associated with survival.

Incidence of clinical lymphedema in breast cancer patients treated with adjuvant proton-based radiotherapy.

Background: The purpose of this study was to evaluate the incidence of clinical lymphedema following adjuvant proton-based radiotherapy (RT) in breast cancer (BC) patients. Materials and methods: We performed a retrospective review of our institutional database to identify BC patients treated with adjuvant proton-based RT. Patients receiving re-irradiation for a BC recurrence or those with a history of ipsilateral chest wall radiation were excluded. Clinical lymphedema was determined by documentation in the chart at baseline and during follow-up. Results: We identified 28 patients treated with adjuvant proton-based RT who met the study criteria. Median age at diagnosis was 45 (range, 24-75). Eleven patients (39%) underwent mastectomy, and fourteen (50%) underwent axillary lymph node dissection (ALND). Median number of LNs removed was 6 (range, 1-28). Nineteen patients (68%) received neoadjuvant chemotherapy. Median whole breast/chest wall dose delivered was 50 Gy (range, 44-54.0 Gy). Target volumes included the axillary and supraclavicular lymph nodes in all patients and internal mammary lymph nodes in 27 (96%) patients. Mean dose to the axilla was 49.7 Gy, and mean dose to 95% of the axillary volume (D95) was 46.3 Gy (94% of prescription dose). Mean dose to supraclavicular (SCV) volume was 47.7 Gy, and D95 was 44.1 Gy (91% of prescription dose). Grade 3 dermatitis occurred in 14% of patients. Five patients (18%) had clinical lymphedema, 4 from the ALND subset (n = 14). Conclusions: The incidence of clinical lymphedema after proton-based RT is comparable to rates reported with photon-based RT with comprehensive nodal coverage.

Performance assessment of two motion management systems for frameless stereotactic radiosurgery.

BACKGROUND/PURPOSE: Frameless stereotactic radiosurgery (SRS) requires dedicated systems to monitor patient motion in order to avoid inaccurate radiation delivery due to involuntary shifts. The purpose of this study is to assess the accuracy and sensitivity of two distinct motion monitoring systems used for frameless SRS. METHODS: A surface image-guided system known as optical surface monitoring system (OSMS), and a fiducial marker-based system known as high definition motion management (HDMM) as part of the latest Gamma Knife Icon® were compared. A 3D printer-based cranial motion phantom was developed to evaluate the accuracy and sensitivity of these two systems in terms of: (1) the capability to recognize predefined shifts up to 3 cm, and (2) the capability to recognize predefined speeds up to 3 cm/s. The performance of OSMS, in terms of different reference surfaces, was also evaluated. RESULTS: Translational motion could be accurately detected by both systems, with an accuracy of 0.3 mm for displacement up to 1 cm, and 0.5 mm for larger displacements. The reference surface selection had an impact on OSMS performance, with flat surface resulting in less accuracy. HDMM was in general more sensitive when compared with OSMS in capturing the motion, due to its faster frame rate, but a delay in response was observed with faster speeds. Both systems were less sensitive in detection of superior-inferior motion when compared to lateral or vertical displacement directions. CONCLUSION: Translational motion can be accurately and sensitively detected by OSMS and HDMM real-time monitoring systems. However, performance variations were observed along different motion directions, as well as amongst the selection of reference images. Caution is needed when using real-time monitoring systems for frameless SRS treatment.

The clinical impact of removing rectal gas on high-dose-rate brachytherapy dose distributions for gynecologic cancers.

PURPOSE: To evaluate the impact of gas removal on bladder and rectal doses during intracavitary and interstitial high-dose-rate brachytherapy (HDRB) for gynecologic cancers. MATERIAL AND METHODS: Fifteen patients treated with definitive external beam radiation followed by HDRB for gynecologic cancers for a total of 21 fractions, presented with a significant amount of rectal gas at initial CT imaging (CTGAS ) after implantation. The gas was removed via rectal tubing followed by subsequent scan acquisition (CTCLINICAL ), which was used for planning and treatment delivery. To assess the effect of gas removal on dosimetry, both bladder and rectum volumes were recontoured on CTGAS . In order to evaluate the clinical impact on the total Equivalent-Dose-in-2Gy-fraction (EQD2 ), each fraction was also replanned to maintain clinically delivered target coverage (HRCTV D90). EQD2 D2cm3 for bladder and rectum were compared between plans. The Wilcoxon signed rank test was performed to evaluate statistically significant differences for all comparisons (P < 0.05). RESULTS: Mean rectum and bladder Dmax , D0.1cm3 , D1cm3 , D2cm3 , and D5cm3 were significantly different between CTGAS and CTCLINICAL . The mean percent increases on CTGAS for bladder were 12.3, 8.4, 9.9, 10.2, and 9.5% respectively and for rectum were 27.0, 19.6, 18.1, 18.5, and 19.4%, respectively. After replanning with CTGAS to maintain HRCTV D90 EQD2 , bladder and rectum EQD2 D2 cm3 resulted in significantly higher doses. The mean EQD2 D2 cm3 difference was 2.4 and 4.1 Gy for bladder and rectum, revealing a higher impact of gas removal on rectal DVH. CONCLUSION: Rectal gas removal resulted in statistically significant differences for both bladder and rectum. The resulting larger EQD2 D2 cm3 for bladder and rectum demonstrates that if patients were treated without removing gas, target coverage would need to be sacrificed to satisfy the rectum constraints and prevent toxicities. Therefore, this study demonstrates the importance of gas removal for gynecologic HDRB patients.

The combined use of 2D scout and 3D axial CT images to accurately determine the catheter tips for high-dose-rate brachytherapy plans.

PURPOSE: To develop a method combining CT scout images with axial images to improve the localization accuracy of catheter tips in high-dose-rate (HDR) brachytherapy treatments. MATERIALS AND METHODS: CT scout images were utilized along with conventionally reconstructed axial images to aid the localization of catheter tips used during HDR treatment planning. A method was developed to take advantage of the finer image resolution of the scout images to more precisely identify the tip coordinates. The accuracies of this method were compared with the conventional method based on the axial CT images alone, for various slice thicknesses, in a computed tomography dose index (CTDI) head phantom. A clinical case which involved multiple interstitial catheters was also selected for the evaluation of this method. Locations of the catheter tips were reconstructed with the conventional CT-based method and this newly developed method, respectively. Location coordinates obtained via both methods were quantitatively compared. RESULTS: Combination of the scout and axial CT images improved the accuracy of identification and reconstruction of catheter tips along the longitudinal direction (i.e., head-to-foot direction, more or less parallel to the catheter tracks), compared to relying on the axial CT images alone. The degree of improvement was dependent on CT slice thickness. For the clinical patient case, the coordinate differences of the reconstructed catheter tips were 2.6 mm ± 0.9 mm in the head-to-foot direction, 0.4 mm ± 0.2 mm in the left-to-right direction, and 0.6 mm ± 0.2 mm in the anterior-to-posterior direction, respectively. CONCLUSION: Combining CT scout and axial images demonstrates the ability to provide a more accurate identification and reconstruction of the interstitial catheter tips for HDR brachytherapy treatment, especially in the longitudinal direction. The method developed in this work has the potential to be implemented clinically together with automatic segmentation in modern brachytherapy treatment planning systems, in order to improve the reconstruction accuracy of HDR catheters.

Patterns of post-mastectomy radiation therapy in clinically node positive breast cancer patients with pathologically negative lymph nodes after neoadjuvant chemotherapy.

BACKGROUND: To analyze postmastectomy radiation therapy (PMRT) utilization and its association with overall survival (OS) in patients presenting with node positive breast cancer who are pathologically node negative (ypN0) after neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Using the National Cancer Data Base (NCDB), we identified patients diagnosed between 2004 and 2013 with clinical T1-4 node-positive non-metastatic breast cancer who received NAC and underwent mastectomy with pathologically negative lymph node sampling. Multivariable regression models identified factors associated with PMRT use. The Cox proportional hazards model was used to evaluate predictors of mortality. RESULTS: The study included 8,766 clinically node-positive patients who met the study criteria. PMRT was delivered to 61.5% of patients. Overall PMRT utilization rate increased over the study period from 54.4% in 2004 to 65.2% in 2011. Predictors of PMRT use included larger tumor size, increasing clinical N stage, higher grade disease, receipt of hormone therapy, and greater number of lymph nodes examined. Unadjusted 5-year OS was 84.1% in the PMRT group and 83.8% in the non-PMRT group (p=NS). PMRT was not significantly associated with survival on multivariable analysis (hazard ratio [HR] 0.87; 95% confidence interval [CI] 0.73-1.03). CONCLUSION: The delivery of PMRT has increased over time in women presenting with clinically node positive breast cancer who convert to ypN0 after NAC. While we identified multiple independent socioeconomic and clinical predictors of both PMRT utilization and survival, PMRT itself was not significantly associated with survival.

Impact of computed tomography (CT) reconstruction kernels on radiotherapy dose calculation.

PURPOSE: To quantitatively evaluate the effect of computed tomography (CT) reconstruction kernels on various dose calculation algorithms with heterogeneity correction. METHODS: The gammex electron density (ED) Phantom was scanned with the Siemens PET/CT Biograph20 mCT and reconstructed with twelve different kernel options. Hounsfield unit (HU) vs electron density (ED) curves were generated to compare absolute differences. Scans were repeated under head and pelvis protocols and reconstructed per H40s (head) and B40s (pelvis) kernels. In addition, raw data from a full-body patient scan were also reconstructed using the four B kernels. Per reconstruction, photon (3D and VMAT), electron (18 and 20 MeV) and proton (single field) treatment plans were generated using Varian Eclipse dose calculation algorithms. Photon and electron plans were also simulated to pass through cortical bone vs liver plugs of the phantom for kernel comparison. Treatment field monitor units (MU) and isodose volumes were compared across all scenarios. RESULTS: The twelve kernels resulted in minor differences in HU, except at the extreme ends of the density curve with a maximum absolute difference of 55.2 HU. The head and pelvis scans of the phantom resulted in absolute HU differences of up to 49.1 HU for cortical bone and 45.1 HU for lung 300, which is a relative difference of 4.1% and 6.2%, respectively. MU comparisons across photon and proton calculation algorithms for the patient and phantom scans were within 1-2 MU, with a maximum difference of 5.4 MU found for the 20 MeV electron plan. The 20MeV electron plan also displayed maximum differences in isodose volumes of 20.4 cc for V90%. CONCLUSION: Clinically insignificant differences were found among the various kernel generated plans for photon and proton plans calculated on patient and phantom scan data. However, differences in isodose volumes found for higher energy electron plans amongst the kernels may have clinical implications for prescribing dose to an isodose level.

The Impact of Everolimus and Radiation Therapy on Pulmonary Fibrosis.

Background and objectives: Everolimus (EVE) is a mammalian target of the rapamycin (mTOR) inhibitor that is widely used in cancer patients. Pulmonary toxicity, usually manifesting as interstitial pneumonitis, is a serious adverse effect of this drug. Radiation therapy, which is often administered in conjunction with chemotherapy for synergistic effects, also causes pulmonary fibrosis. In view of pulmonary damage development in these two forms of cancer treatment, we have examined the effect of EVE administration individually, in combination with radiation given in varying sequences, and its relation to the extent of pulmonary damage. Materials and Methods: We performed an experimental study in albino rats, which were randomized into five groups: (1) control group, (2) EVE alone, (3) EVE 22 h after radiation, (4) EVE 2 h after irradiation, and (5) only radiation. Sixteen weeks after thoracic irradiation, rat lung tissue samples were examined under light microscopy, and the extent of pulmonary damage was estimated. After this, we calculated median fibrosis scores in each group. Results: The highest fibrosis score was noted in Group 4. Among the five groups, the control group had a significantly lower median fibrosis score compared to the others. When the median fibrosis score of the group that received concurrent EVE with radiation therapy (RT) (Group 4) was compared with that of the control group, the difference was statistically significant (p = 0.0022). However, no significant differences were achieved among the study groups that received EVE only or RT only, whether concurrently or sequentially (p > 0.05). Conclusion: EVE is an effective treatment option for the management of several malignancies and is often combined with other therapies, such as radiation, for a more efficient response. However, an increased risk of pulmonary fibrosis should also be anticipated when these two modalities are combined, as they both can cause pulmonary damage, especially when administered concurrently.

Impact of the COVID-19 pandemic on brachytherapy and cancer patient outcomes: A systematic review.

PURPOSE/OBJECTIVE(S): To assess the impact of the COVID-19 pandemic on the use of brachytherapy in patients with gynecologic and prostate cancers including treatment delays, increased burden of mortality, and associated clinical outcomes. MATERIALS/METHODS: A comprehensive search of PubMed, Cochrane Library, CINAHL, Scopus, and Web of Science was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Databases were searched for studies published through September 2023 using MeSH terms and keywords related to "COVID and brachytherapy." Inclusion criteria included all studies reporting on the impact of COVID-19 on treatment delay, treatment omission, recurrence rates, and clinical outcomes in patients requiring brachytherapy for prostate or gynecologic cancers from December 2019 to September 2023. Data were extracted by two independent reviewers (LH, IV). RESULTS: Of the 292 screened records, 10 studies (9 retrospective, 1 prospective single-arm exploratory noninferiority) were included. Hypofractioned regimens were the preferred approach in radiation treatment (RT) centers, with 6 of 10 studies noting shift towards hypofractionation. For cervical cancer, intracavitary brachytherapy was limited to 3-4 fractions, reducing personnel and patient exposure. Treatment delays influenced by COVID-19 ranged between 19% and 53% and treatment omissions ranged between 2% and 28%. These disruptions arose from factors such as patient fear of contracting COVID-19, COVID-19 infection, barriers to accessing care, and operating room closures. Three studies reported on a single-application (SA) rather than a multiple application (MA) approach for cervical cancer. They reported excellent local control, shorter overall treatment time at the expense of higher grade ≥2 vaginal, genitourinary, and gastrointestinal events. For cervical cancer patients, overall treatment time (OTT) was significantly impacted by COVID-19 as reported by 2 studies from India. OTT > 60 days occurred in 40-53% of patients. CONCLUSION: This is the first systematic review to assess the impact of the COVID-19 pandemic on brachytherapy in patients with gynecologic and prostate cancers. Although many expert consensus recommendations have been published during the pandemic regarding radiation therapy, few studies evaluated its clinical impact on brachytherapy delivery and patient outcomes. The COVID-19 pandemic resulted in treatment delays, omissions in brachytherapy, and further adoption of hypofractionated regimens. Early results demonstrate that despite increased toxicities, local control rates with hypofractionated treatment are similar to standard fractionation. The impact of the pandemic on gynecologic and prostate cancers is yet to be determined as well as the long-term outcomes on patients treated during the lockdown period.

A novel technique for markerless, self-sorted 4D-CBCT: feasibility study.

PURPOSE: Four-dimensional CBCT (4D-CBCT) imaging in the treatment room can provide verification of moving targets, facilitating the potential for margin reduction and consequent dose escalation. Reconstruction of 4D-CBCT images requires correlation of respiratory phase with projection acquisition, which is often achieved with external surrogate measures of respiration. However, external measures may not be a direct representation of the motion of the internal anatomy and it is therefore the aim of this work to develop a novel technique for markerless, self-sorted 4D-CBCT reconstruction. METHODS: A novel 4D-CBCT reconstruction technique based on the principles of Fourier transform (FT) theory was investigated for markerless extraction of respiratory phase directly from projection data. In this FT technique, both phase information (FT-phase) and magnitude information (FT-magnitude) were separately implemented in order to discern projections corresponding to peak inspiration, which then facilitated the proceeding sort and bin processes involved in retrospective 4D image reconstruction. In order to quantitatively evaluate the accuracy of the Fourier methods, peak-inspiration projections identified each by FT-phase and FT-magnitude were compared to those manually identified by visual tracking of structures. The average phase difference as assigned by each method vs the manual technique was calculated per projection dataset. The percentage of projections that were assigned within 10% phase of each other was also computed. Both Fourier methods were tested on two phantom datasets, programmed to exhibit sinusoidal respiratory cycles of 2.0 cm in amplitude with respiratory cycle lengths of 3 and 6 s, respectively. Additionally, three sets of patient projections were studied. All of the data were previously acquired at slow-gantry speeds ranging between 0.6°/s and 0.7°/s over a 200° rotation. Ten phase bins with 10% phase windows were selected for 4D-CBCT reconstruction of one phantom and one patient case for visual and quantitative comparison. Line profiles were plotted for the 0% and 50% phase images as reconstructed by the manual technique and each of the Fourier methods. RESULTS: As compared with the manual technique, the FT-phase method resulted in average phase differences of 1.8% for the phantom with the 3 s respiratory cycle, 3.9% for the phantom with the 6 s respiratory cycle, 2.9% for patient 1, 5.0% for patient 2, and 3.8% for patient 3. For the FT-magnitude method, these numbers were 2.1%, 4.0%, 2.9%, 5.3%, and 3.5%, respectively. The percentage of projections that were assigned within 10% phase by the FT-phase method as compared to the manual technique for the five datasets were 100.0%, 100.0%, 97.6%, 93.4%, and 94.1%, respectively, whereas for the FT-magnitude method these percentages were 98.1%, 92.3%, 98.7%, 87.3%, and 95.7%. Reconstructed 4D phase images for both the phantom and patient case were visually and quantitatively equivalent between each of the Fourier methods vs the manual technique. CONCLUSIONS: A novel technique employing the basics of Fourier transform theory was investigated and demonstrated to be feasible in achieving markerless, self-sorted 4D-CBCT reconstruction.

Toxicities and Locoregional Control After External Beam Chest Wall and/or Regional Lymph Node Re-irradiation for Recurrent Breast Cancer.

BACKGROUND/AIM: To evaluate toxicities and clinical outcomes in breast cancer (BC) patients who underwent external beam chest wall (CW) and/or regional lymph node (LN) re-irradiation (re-RT) for locoregional recurrence (LRR). PATIENTS AND METHODS: We performed a retrospective review of our institutional database to identify BC patients diagnosed with an isolated ipsilateral CW or nodal recurrence after prior whole breast/CW irradiation. RESULTS: Fifteen patients met the study criteria. Median time between completion of RT courses was 68.3 months (range=7.8-245.4 months). Median CW re-RT dose was 45 Gy (range=42.3-50.4 Gy). The majority of patients (80%) received proton beam re-RT. Grade 2-3 dermatitis occurred in 87% patients. Grade 2-3 pain was reported by 33% of patients. At a median follow-up of 14 months (range=1.0-90.5 months), the rate of isolated LRR was 13%. CONCLUSION: Re-RT of the CW and/or regional LNs is feasible with acceptable rates of toxicity and low rates of isolated LRR.

Adaptive Lumpectomy Boost Planning Can Reduce Normal Tissue Exposure in Patients Receiving Hypofractionated Whole Breast Irradiation.

BACKGROUND/AIM: To evaluate the change in lumpectomy cavity (LPC) volume during hypofractionated radiation (Hypo-RT) and assess the dosimetric benefits of adaptive boost planning on normal tissue exposure in breast cancer patients. PATIENTS AND METHODS: Two separate computed tomography (CT) simulation scans were obtained. The first (CT1) was used to plan whole breast irradiation, and the second (CT2) was used to plan LPC boost. LPC boost treatment planning was performed on both CT1 and CT2. RESULTS: Mean LPC volume was significantly smaller on CT2 compared to CT1. LPC boost plan comparison showed significant reductions from CT1 to CT2 in mean heart dose and mean lung dose. Mean volume of tissue receiving 95% of the prescribed boost dose (V95) was lower on CT2 (p=0.001), as was V80 (p<0.001) and V50 (p<0.001). CONCLUSION: LPC volume can change significantly during Hypo-RT. Adaptive LPC boost planning can be considered to reduce normal tissue exposure.

Risk Factors for the Development of Clinical and Subclinical Lymphedema Detected by Bioimpedance Spectroscopy.

BACKGROUND: Breast cancer-related lymphedema can significantly compromise quality of life. Bioimpedance spectroscopy (BIS) measures extracellular fluid in lymphedema. The purpose of this study was to determine the incidence of BIS-detected lymphedema using the L-Dex and identify risk factors associated with a positive score. MATERIALS AND METHODS: We performed a retrospective review of our institutional database to identify patients who underwent L-Dex U400 measurements. Patients with a score of > 10 L-Dex units or with an increase of > 10 units from baseline had a positive score. Clinical lymphedema was determined by documentation in the chart at the time of positive measurement. Otherwise, patients were considered to have subclinical lymphedema. RESULTS: Fifty-three patients met study criteria. Thirty patients (56.6%) underwent mastectomy, 22 (41.5%) axillary lymph node dissection (ALND), and 33 (62.3%) received radiation (RT). Twelve patients (22.6%) had a positive score. There were no differences in age, race, laterality, breast surgery, T stage, N stage, chemotherapy, or RT fields (none, breast only, breast with LNs) in patients with a positive score. ALND was more common (66.7% vs. 34.2%, P= .04). BMI > 30 approached significance (58.3% vs. 29.3%, P= .06). Seven patients had subclinical lymphedema. No differences were identified comparing patients with subclinical lymphedema to those with negative scores. All 5 patients with clinical lymphedema underwent ALND and received nodal RT. CONCLUSION: The combination of ALND and regional nodal RT is strongly associated with development of clinical lymphedema. It is difficult to identify patients at risk for subclinical BIS-detected lymphedema.

Clinical Evaluation of the Inverse Planning System Utilized in Gamma Knife Lightning.

Objectives: The purpose of this study is to independently compare the performance of the inverse planning algorithm utilized in Gamma Knife (GK) Lightning Treatment Planning System (TPS) to manual forward planning, between experienced and inexperienced users, for different types of targets. Materials and Methods: Forty patients treated with GK stereotactic radiosurgery (SRS) for pituitary adenoma (PA), vestibular schwannoma (VS), post-operative brain metastases (pBM), and intact brain metastases (iBM) were randomly selected, ten for each site. Three inversely optimized plans were generated for each case by two experienced planners (OptExp1 and OptExp2) and a novice planner (OptNov) using GK Lightning TPS. For each treatment site, the Gradient Index (GI), the Paddick Conformity Index (PCI), the prescription percentage, the scaled beam-on time (sBOT), the number of shots used, and dosimetric metrics to OARs were compared first between the inversely optimized plans and the manually generated clinical plans, and then among the inversely optimized plans. Statistical analyses were performed using the Student's t-test and the ANOVA followed by the post-hoc Tukey tests. Results: The GI for the inversely optimized plans significantly outperformed the clinical plans for all sites. PCIs were similar between the inversely optimized and clinical plans for PA and VS, but were significantly improved in the inversely optimized plans for iBM and pBM. There were no significant differences in the sBOT between the inversely optimized and clinical plans, except for the PA cases. No significant differences were observed in dosimetric metrics, except for lower brain V12Gy and PTV D98% in the inversely optimized plans for iBM. There were no noticeable differences in plan qualities among the inversely optimized plans created by the novice and experienced planners. Conclusion: Inverse planning in GK Lightning TPS produces GK SRS plans at least equivalent in plan quality and similar in sBOT compared to manual forward planning in this independent validation study. The automatic workflow of inversed planning ensures a consistent plan quality regardless of a planner's experience.

Does Prophylactic Paraortic Lymph Node Irradiation Improve Outcomes in Women With Stage IIIC1 Endometrial Carcinoma?

PURPOSE: To evaluate the impact of prophylactic paraortic lymph node (PALN) radiation therapy (RT) on clinical outcomes in patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 endometrial cancer (EC). METHODS AND MATERIALS: A multi-institutional retrospective study included patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 EC lymph node assessment, status postsurgical staging, followed by adjuvant chemotherapy and RT using various sequencing regimens. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. Univariable and multivariable analysis were performed by Cox proportional hazard models for RFS/OS. In addition, propensity score matching was used to estimate the effect of the radiation field extent on survival outcomes. RESULTS: A total of 378 patients were included, with a median follow-up of 45.8 months. Pelvic RT was delivered to 286 patients, and 92 patients received pelvic and PALN RT. The estimated OS and RFS rates at 5 years for the entire cohort were 80% and 69%, respectively. There was no difference in the 5-year OS (77% vs 87%, P = .47) and RFS rates (67% vs 70%, P = .78) between patients treated with pelvic RT and those treated with pelvic and prophylactic PALN RT, respectively. After propensity score matching, the estimated hazard ratios (HRs) of prophylactic PALN RT versus pelvic RT were 1.50 (95% confidence interval, 0.71-3.19; P = .28) for OS and 1.24 (95% confidence interval, 0.64-2.42; P = .51) for RFS, suggesting that prophylactic PALN RT does not improve survival outcomes. Distant recurrence was the most common site of first recurrence, and the extent of RT field was not associated with the site of first recurrence (P = .79). CONCLUSIONS: Prophylactic PALN RT was not significantly associated with improved survival outcomes in stage IIIC1 EC. Distant metastasis remains the most common site of failure despite routine use of systemic chemotherapy. New therapeutic approaches are necessary to optimize the outcomes for women with stage IIIC1 EC.

Potential underestimation of the internal target volume (ITV) from free-breathing CBCT.

PURPOSE: Localization prior to delivery of SBRT to free-breathing patients is performed by aligning the planning internal target volume (ITV) from 4DCT with an on-board free-breathing cone-beam CT (FB-CBCT) image. The FB-CBCT image is assumed to also generate an ITV that captures the full range of motion, due to the acquisition spanning multiple respiratory cycles. However, the ITV could potentially be underestimated when the ratio of time spent in inspiration versus time spent in expiration (I/E ratio) deviates from unity. Therefore, the aim of this study was to investigate the effect of variable I/E ratios on the FB ITV generated from a FB-CBCT scan. METHODS: This study employed both phantom and patient imaging data. For the phantom study, five periodic respiratory cycles were simulated with different I/E ratios. Six patient respiratory cycles with variable I/E ratios were also selected. All profiles were then programmed into a motion phantom for imaging and modified to exhibit three peak-to-peak motion amplitudes (0.5, 1.0, and 2.0 cm). Each profile was imaged using two spherical targets with 1.0 and 3.0 cm diameters. 2D projections were acquired with full gantry rotation of a kiloVoltage (kV) imager mounted onto the gantry of a modem linear accelerator. CBCT images were reconstructed from 2D projections using a standard filtered back-projection reconstruction algorithm. Quantitative analyses for the phantom study included computing the change in contrast along the direction of target motion as well as determining the area (which is proportional to the target volume) inside of the contour extracted using a Canny edge detector. For the patient study, projection data that were previously acquired under an investigational 4D CBCT slow-gantry imaging protocol were used to generate both FB-CBCT and 4D CBCT images. Volumes were then manually contoured from both datasets (using the same window and level) for quantitative comparison. RESULTS: The phantom study indicated a reduction in contrast at the inferior edge of the ITV (corresponding to inspiration) as the ratio decreased, for both simulated and patient respiratory cycles. For the simulated phantom respiratory cycles, the contrast reduction of the smallest I/E ratio was 27.6% for the largest target with the smallest amplitude and 89.7% for the smallest target with the largest amplitude. For patient respiratory cycles, these numbers were 22.3% and 94.0%, respectively. The extracted area from inside of the target contours showed a decreasing trend as the I/E ratio decreased. In the patient study, the FB-CBCT ITVs of both lung tumors studied were underestimated when compared with their corresponding 4D CBCT ITV. The underestimations found were 40.1% for the smaller tumor and 24.2% for the larger tumor. CONCLUSIONS: The ITV may be underestimated in a FB-CBCT image when a patient's respiratory pattern is characterized by a disparate length of time spent in inspiration versus expiration. Missing the full target motion information during on-board verification imaging may result in localization errors.

Optimization of treatment isocenter location in single-isocenter LINAC-based stereotactic radiosurgery for management of multiple brain metastases.

PURPOSE: Single-isocenter linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) has become a promising treatment technique for the management of multiple brain metastases. Because of the high prescription dose and steep dose gradient, SRS plans are sensitive to geometric errors, resulting in loss of target coverage and suboptimal local tumor control. Current planning techniques rely on adding a uniform and isotropic setup margin to all gross tumor volumes (GTVs) to account for rotational uncertainties. However, this setup margin may be insufficient, since the magnitude of rotational uncertainties varies and is dependent upon the distance between a GTV and the isocenter. In this study, we designed a framework to determine the optimal isocenter of a single-isocenter SRS plan for multiple brain metastases using stochastic optimization to mitigate potential errors resulting from rotational uncertainties. METHODS: Planning target volumes (PTVs), defined as GTVs plus a 1-mm margin following common SRS planning convention, were assumed to be originally treated with a prescription dose and therefore covered by the prescription isodose cloud. The dose distribution, including the prescription isodose, was considered invariant assuming small rotations throughout the study. A stochastic optimization scheme was developed to determine the location of the optimal isocenter, so that the prescription dose coverage of rotated GTVs, equivalent to the intersecting volumes between the rotated GTVs and original PTVs, was maximized for any random small rotations about the isocenter. To evaluate the coverage of GTVs, the expected V 100 % undergoing random rotations was approximated as the sample average V 100 % undergoing a predetermined number of rotations. The expected V 100 % of each individual GTV and total GTVs was then compared between the plans using the optimal isocenter and the center-of-mass (CoM), respectively. RESULTS: Twenty-two patients previously treated for multiple brain metastases in a single institute were included in this retrospective study. Each patient was initially treated for more than three brain metastases (mean: 7.6; range: 3-15) with the average GTV volume of 0.89 cc (range: 0.03-11.78 cc). The optimal isocenter found for each patient was significantly different from the CoM, with the average Euclidean distance between the optimal isocenter and the CoM being 4.36 ± 2.59 cm. The dose coverage to GTVs was also significantly improved (paired t-test; p < 0.001) when the optimal isocenter was used, with the average V 100 % of total GTVs increasing from 87.1% (standard deviation as std: 11.7%; range: 39.9-98.2%) to 94.2% (std: 5.4%; range: 77.7-99.4%). The volume of a GTV was positively correlated with the expected V 100 % regardless of the isocenter used (Spearman coefficient: ρ = 0.66 ; p < 0.001). The distance between a GTV and the isocenter was negatively correlated with the expected V 100 % when the CoM was used ( ρ = - 0.21 ; p = 0.004), however no significant correlation was found when the optimal isocenter was used ( ρ = - 0.11 ; p = 0.137). CONCLUSION: The proposed framework provides an effective approach to determine the optimal isocenter of single-isocenter LINAC-based SRS plans for multiple brain metastases. The implementation of the optimal isocenter results in SRS plans with consistently higher target coverage despite potential rotational uncertainties, and therefore significantly improves SRS plan robustness against random rotational uncertainties.

Utilization of Hypofractionated Whole-Breast Radiotherapy With Concurrent Anti-Human Epidermal Growth Factor Receptor 2 (HER2) Therapy.

INTRODUCTION: Hypofractionated radiotherapy (Hypo-RT) is now considered the standard of care for the majority of patients receiving whole-breast irradiation (WBI). However, there are few data on the use of Hypo-RT in human epidermal growth factor receptor 2 (HER2)-positive patients receiving concurrent anti-HER2 therapy. In this study, we sought to examine patterns of WBI in HER2-positive patients. PATIENTS AND METHODS: Using the National Cancer Data Base, we identified women with nonmetastatic HER2-positive breast cancer diagnosed between 2010 and 2015 who received WBI. The Hypo-RT group was defined as those receiving 21 or fewer fractions. All other patients were in the conventional radiotherapy (RT) group. Multivariate logistic regression was used to identify predictors of Hypo-RT utilization. Five-year overall survival was estimated by the Kaplan-Meier method. RESULTS: The study included 15,776 patients, of whom 17.7% received Hypo-RT. The rate of Hypo-RT utilization increased from 7.4% in 2010 to 29.3% in 2015 (P = .004). Predictors of Hypo-RT use included older age (≥60 vs. < 60 years), higher median income quartile, further distance from the treatment facility (>50 vs. ≤50 miles), treatment at an academic facility, and later year of diagnosis. Unadjusted 5-year overall survival rates were similar among patients who received Hypo-RT and conventional RT (93.9% vs. 95.2%, P = .26). After adjusting for patient, facility, and tumor variables, Hypo-RT was not significantly associated with survival. CONCLUSION: Although Hypo-RT was not commonly delivered in patients with HER2-positive breast cancer, the utilization rate quadrupled over the study period. Multiple socioeconomic and clinical predictors of Hypo-RT receipt were identified. Adjuvant RT regimen was not significantly associated with overall survival.

Intrinsic radiomic expression patterns after 20 Gy demonstrate early metabolic response of oropharyngeal cancers.

PURPOSE: This study investigated the prognostic potential of intra-treatment PET radiomics data in patients undergoing definitive (chemo) radiation therapy for oropharyngeal cancer (OPC) on a prospective clinical trial. We hypothesized that the radiomic expression of OPC tumors after 20 Gy is associated with recurrence-free survival (RFS). MATERIALS AND METHODS: Sixty-four patients undergoing definitive (chemo)radiation for OPC were prospectively enrolled on an IRB-approved study. Investigational 18 F-FDG-PET/CT images were acquired prior to treatment and 2 weeks (20 Gy) into a seven-week course of therapy. Fifty-five quantitative radiomic features were extracted from the primary tumor as potential biomarkers of early metabolic response. An unsupervised data clustering algorithm was used to partition patients into clusters based only on their radiomic expression. Clustering results were naïvely compared to residual disease and/or subsequent recurrence and used to derive Kaplan-Meier estimators of RFS. To test whether radiomic expression provides prognostic value beyond conventional clinical features associated with head and neck cancer, multivariable Cox proportional hazards modeling was used to adjust radiomic clusters for T and N stage, HPV status, and change in tumor volume. RESULTS: While pre-treatment radiomics were not prognostic, intra-treatment radiomic expression was intrinsically associated with both residual/recurrent disease (P = 0.0256, χ 2 test) and RFS (HR = 7.53, 95% CI = 2.54-22.3; P = 0.0201). On univariate Cox analysis, radiomic cluster was associated with RFS (unadjusted HR = 2.70; 95% CI = 1.26-5.76; P = 0.0104) and maintained significance after adjustment for T, N staging, HPV status, and change in tumor volume after 20 Gy (adjusted HR = 2.69; 95% CI = 1.03-7.04; P = 0.0442). The particular radiomic characteristics associated with outcomes suggest that metabolic spatial heterogeneity after 20 Gy portends complete and durable therapeutic response. This finding is independent of baseline metabolic imaging characteristics and clinical features of head and neck cancer, thus providing prognostic advantages over existing approaches. CONCLUSIONS: Our data illustrate the prognostic value of intra-treatment metabolic image interrogation, which may potentially guide adaptive therapy strategies for OPC patients and serve as a blueprint for other disease sites. The quality of our study was strengthened by its prospective image acquisition protocol, homogenous patient cohort, relatively long patient follow-up times, and unsupervised clustering formalism that is less prone to hyper-parameter tuning and over-fitting compared to supervised learning.