Clinical outcomes of three vs four fractions of MRI-guided brachytherapy in cervical cancer.

PURPOSE: MRI-guided brachytherapy (MRgBT) is essential in the management of locally advanced cervical cancer. This study compares disease and toxicity outcomes in cervical cancer patients treated with 24 Gy/3 fractions (Fr) versus the conventional 28 Gy/4 Fr. METHODS AND MATERIALS: This retrospective study included 241 consecutive patients with FIGO 2018 stage IB-IVA cervical cancer treated with definitive chemoradiation between April 2014 - March 2021. Disease-free survival (DFS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Cumulative incidence of local failure (LF), distant failure (DF) and G2+ gastrointestinal (GI), urinary (GU) and vaginal toxicity were estimated using the cumulative incidence function with death as a competing risk and compared using the Gray's test. RESULTS: Of the 241 patients, 42% received 24 Gy/3 Fr and 58% received 28 Gy/4 Fr. With a median follow up of 3.2 (range 0.2-9.2) years, there were 14 local, 41 regional nodal and 51 distant failures in 63 (26%) patients. No significant differences were found between the 24 Gy/3 Fr vs 28 Gy/4 Fr group in 3-year DFS (77% vs 68%, P = 0.21), 3-year cumulative incidence of LF (5% vs 7%, P = 0.57), DF (22% vs 25%, P = 0.86), G2+ GI toxicity (11% vs 20%, P = 0.13), or G2+ vaginal toxicity (14% vs 17%, P = 0.48), respectively. The 3-year cumulative G2+ urinary toxicity rate was lower in the 24 Gy/3 Fr group (9% vs 23%, P = 0.03). CONCLUSION: Cervical cancer patients treated with 24 Gy/3 Fr had similar DFS, LF, DF, GI and vaginal toxicity rates, and a trend towards lower G2+ urinary toxicity rate compared to those treated with 28 Gy/4 Fr. A less resource-intensive brachytherapy fractionation schedule of 24 Gy/3 Fr is a safe alternative to 28 Gy/4 Fr for definitive treatment of cervical cancer.

Comparing dosimetry of locally advanced cervical cancer patients treated with 3 versus 4 fractions of MRI-guided brachytherapy.

PURPOSE: To demonstrate the feasibility of treating cervical cancer patients with MRI-guided brachytherapy (MRgBT) using 24 Gy in 3 fractions (F) versus a standard, more resource-intensive regimen of 28 Gy in 4F, and its ability to meet EMBRACE II planning aims. METHODS AND MATERIALS: A retrospective review of 224 patients with FIGO Stage IB-IVA cervical cancer treated with 28 Gy/4F (n = 91) and 24 Gy/3F (n = 133) MRgBT between 2016-2021 was conducted. Multivariable linear regression models were fitted to compare dosimetric parameters between the two groups, adjusting for CTVHR and T stage. RESULTS: Most patients had squamous cell carcinoma, T2b disease, and were treated with intracavitary applicator plus interstitial needles (96%). The 28 Gy/4F group had higher CTVHR (median 28 vs. 26 cm3, p = 0.04), CTVIR D98% (mean 65.5 vs. 64.5 Gy, p = 0.03), rectum D2cm3 (mean 61.7 vs. 59.2 Gy, p = 0.04) and bladder D2cm3 (81.3 vs. 77.9 Gy, p = 0.03). There were no significant differences in the proportion of patients meeting the EMBRACE II OAR dose constraints and planning aims, except fewer patients treated with 28 Gy/4F met rectum D2cm3 < 65 Gy (73 vs. 85%, p = 0.027) and ICRU rectovaginal point < 65 Gy (65 vs. 84%, p = 0.005). CONCLUSIONS: Cervical cancer patients treated with 24 Gy/3F MRgBT had comparable target doses and lower OAR doses compared to those treated with 28 Gy/4F. A less-resource intense fractionation schedule of 24 Gy/3F is an alternative to 28 Gy/4F in cervix MRgBT.

Clinical Evaluation of Deep Learning and Atlas-Based Auto-Contouring of Bladder and Rectum for Prostate Radiation Therapy.

PURPOSE: Auto-contouring may reduce workload, interobserver variation, and time associated with manual contouring of organs at risk. Manual contouring remains the standard due in part to uncertainty around the time and workload savings after accounting for the review and editing of auto-contours. This preliminary study compares a standard manual contouring workflow with 2 auto-contouring workflows (atlas and deep learning) for contouring the bladder and rectum in patients with prostate cancer. METHODS AND MATERIALS: Three contouring workflows were defined based on the initial contour-generation method including manual (MAN), atlas-based auto-contour (ATLAS), and deep-learning auto-contour (DEEP). For each workflow, initial contour generation was retrospectively performed on 15 patients with prostate cancer. Then, radiation oncologists (ROs) edited each contour while blinded to the manner in which the initial contour was generated. Workflows were compared by time (both in initial contour generation and in RO editing), contour similarity, and dosimetric evaluation. RESULTS: Mean durations for initial contour generation were 10.9 min, 1.4 min, and 1.2 min for MAN, DEEP, and ATLAS, respectively. Initial DEEP contours were more geometrically similar to initial MAN contours. Mean durations of the RO editing steps for MAN, DEEP, and ATLAS contours were 4.1 min, 4.7 min, and 10.2 min, respectively. The geometric extent of RO edits was consistently larger for ATLAS contours compared with MAN and DEEP. No differences in clinically relevant dose-volume metrics were observed between workflows. CONCLUSION: Auto-contouring software affords time savings for initial contour generation; however, it is important to also quantify workload changes at the RO editing step. Using deep-learning auto-contouring for bladder and rectum contour generation reduced contouring time without negatively affecting RO editing times, contour geometry, or clinically relevant dose-volume metrics. This work contributes to growing evidence that deep-learning methods are a clinically viable solution for organ-at-risk contouring in radiation therapy.

A Cost-Utility Analysis of Magnetic Resonance (MR) Guided Brachytherapy Versus Two-Dimensional and Computed Tomography (CT) Guided Brachytherapy for Locally Advanced Cervical Cancer.

PURPOSE: The standard treatment for locally advanced cervical cancer is external beam radiation therapy and concurrent cisplatin followed by brachytherapy. Traditionally, 2-dimensional brachytherapy (2DBT) or computed tomography guided brachytherapy (CTgBT) has been used, but magnetic resonance guided brachytherapy (MRgBT) improves clinical outcomes and has become the new standard of care. This cost-utility analysis was undertaken to compare MRgBT to CTgBT and 2DBT. METHODS AND MATERIALS: A Markov model was constructed to evaluate the cost-utility from the perspective of the public health care payer in Ontario. Treatment effectiveness, expressed as quality-adjusted life years, and costs, expressed in 2016 Canadian dollars, were evaluated for MRgBT, CTgBT, and 2DBT. Results were reported as incremental cost-effectiveness ratios for all patients and separately for low and high-risk subgroups. Sensitivity analyses were performed to assess the impact of uncertainty in model parameters. RESULTS: MRgBT improved tumor control, reduced side effects, and was less costly compared with either CTgBT or 2DBT for all patients and in low- and high-risk prognostic subgroups separately. Sensitivity analysis supported the robustness of the findings and identified the cost of treating cancer recurrence to be the single most influential model parameter. CONCLUSIONS: MRgBT is more effective and less costly than CTgBT or 2DBT by avoiding downstream costs of treating cancer recurrence and managing side effects. These findings will assist health care providers and policymakers with future infrastructure and human resource planning to ensure optimal care of women with this disease.

Technique adaptation, strategic replanning, and team learning during implementation of MR-guided brachytherapy for cervical cancer.

PURPOSE: MR-guided brachytherapy (MRgBT) with interstitial needles is associated with improved outcomes in cervical cancer patients. However, there are implementation barriers, including magnetic resonance (MR) access, practitioner familiarity/comfort, and efficiency. This study explores a graded MRgBT implementation strategy that included the adaptive use of needles, strategic use of MR imaging/planning, and team learning. METHODS AND MATERIALS: Twenty patients with cervical cancer were treated with high-dose-rate MRgBT (28 Gy in four fractions, two insertions, daily MR imaging/planning). A tandem/ring applicator alone was used for the first insertion in most patients. Needles were added for the second insertion based on evaluation of the initial dosimetry. An interdisciplinary expert team reviewed and discussed the MR images and treatment plans. RESULTS: Dosimetry-trigger technique adaptation with the addition of needles for the second insertion improved target coverage in all patients with suboptimal dosimetry initially without compromising organ-at-risk (OAR) sparing. Target and OAR planning objectives were achieved in most patients. There were small or no systematic differences in tumor or OAR dosimetry between imaging/planning once per insertion vs. daily and only small random variations. Peer review and discussion of images, contours, and plans promoted learning and process development. CONCLUSIONS: Technique adaptation based on the initial dosimetry is an efficient approach to implementing MRgBT while gaining comfort with the use of needles. MR imaging and planning once per insertion is safe in most patients as long as applicator shifts, and large anatomical changes are excluded. Team learning is essential to building individual and programmatic competencies.

Intermediate dose-volume parameters and the development of late rectal toxicity after MRI-guided brachytherapy for locally advanced cervix cancer.

PURPOSE: The dose delivered to the most exposed 2 cm3 [Formula: see text] of the rectum and bladder is predictive of late rectal and bladder toxicity in cervix cancer patients. We investigated the predictive value of intermediate doses to the rectum and bladder for late rectal/bladder toxicity after MRI-guided brachytherapy for patients with locally advanced cervix cancer. METHODS AND MATERIALS: Toxicity was prospectively graded using Common Toxicity Criteria for Adverse Events v4.0 and retrospectively verified for women with Stage IB-IVA cervix cancer treated consecutively with MRI-guided brachytherapy between 2008 and 2013. The minimum equivalent dose in 2 Gy fractions delivered to 0.1, 1, 2, 5, and 10 cm3 of the rectum and bladder and the absolute volume of the rectum receiving 55, 60, 65, 70, and 75 Gy3 (V55-75) were collected. The association between dose-volume parameters and Grade 2+ rectal/bladder toxicity was examined using logistic regression. RESULTS: With a median followup of 44 months, cumulative incidences of Grade 2+ rectal and bladder toxicity among the 106 patients were 29% and 15% at 3 years, respectively. All the dose-volume parameters were significantly associated with late Grade 2+ rectal and bladder toxicity (p < 0.05), except for bladder [Formula: see text] . On multivariable logistic regression, both [Formula: see text]  > 70 Gy3 and V55 > 11 cm3 (p < 0.05) were predictive of late Grade 2+ rectal toxicity, with improved model fitting and higher area under the curve compared with the model with [Formula: see text]  > 70 Gy3 alone. CONCLUSIONS: In this study, V55 was predictive of late Grade 2+ rectal toxicity. Adding V55 to  [Formula: see text] improved prediction accuracy.

Prospective evaluation of acute toxicity and quality of life after IMRT and concurrent chemotherapy for anal canal and perianal cancer.

PURPOSE: A prospective cohort study was conducted to evaluate toxicity, quality of life (QOL), and clinical outcomes in patients treated with intensity modulated radiation therapy (IMRT) and concurrent chemotherapy for anal and perianal cancer. METHODS AND MATERIALS: From June 2008 to November 2010, patients with anal or perianal cancer treated with IMRT were eligible. Radiation dose was 27 Gy in 15 fractions to 36 Gy in 20 fractions for elective targets and 45 Gy in 25 fractions to 63 Gy in 35 fractions for gross targets using standardized, institutional guidelines, with no planned treatment breaks. The chemotherapy regimen was 5-fluorouracil and mitomycin C. Toxicity was graded with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. QOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and CR29 questionnaires. Correlations between dosimetric parameters and both physician-graded toxicities and patient-reported outcomes were evaluated by polyserial correlation. RESULTS: Fifty-eight patients were enrolled. The median follow-up time was 34 months; the median age was 56 years; 52% of patients were female; and 19% were human immunodeficiency virus-positive. Stage I, II, III, and IV disease was found in 9%, 57%, 26%, and 9% of patients, respectively. Twenty-six patients (45%) required a treatment break because of acute toxicity, mainly dermatitis (23/26). Acute grade 3 + toxicities included skin 46%, hematologic 38%, gastrointestinal 9%, and genitourinary 0. The 2-year overall survival (OS), disease-free survival (DFS), colostomy-free survival (CFS), and cumulative locoregional failure (LRF) rates were 90%, 77%, 84%, and 16%, respectively. The global QOL/health status, skin, defecation, and pain scores were significantly worse at the end of treatment than at baseline, but they returned to baseline 3 months after treatment. Social functioning and appetite scores were significantly better at 12 months than at baseline. Multiple dose-volume parameters correlated moderately with diarrhea, skin, and hematologic toxicity scores. CONCLUSION: IMRT reduces acute grade 3 + hematologic and gastrointestinal toxicities compared with reports from non-IMRT series, without compromising locoregional control. The reported QOL scores most relevant to acute toxicities returned to baseline by 3 months after treatment.

Stage I seminoma: what should a practicing uro-oncologist do in 2009?

Testicular tumors are uncommon, but they continue to represent an important group of malignancies in young men. It is the most common solid malignancy in males between the ages of 20 and 35, and primary germ cell tumors are the most common histological type. In the United States in 2008, approximately 4800 cases of seminoma, approximately 4100 of which were stage I disease were projected after the completion of staging investigations. Remarkable progress has been made in the treatment of testicular seminoma over the past 25 years. Management options of stage I seminoma include radiotherapy, surveillance, or adjuvant chemotherapy. Standard management until recent years has been adjuvant retroperitoneal radiotherapy. Although providing excellent long term results, this approach has been associated with increased risk of gonadal toxicity, development of secondary malignancies and an increased risk of cardiovascular disease. The use of surveillance in management of patients with stage I seminoma is therefore becoming more frequent as it minimizes the burden of treatment and maintains the cure rate at virtually 100%. Adjuvant chemotherapy using Carboplatin has been investigated as an alternative management approach. However, the long term outcomes of patients managed with Carboplatin are not yet clear and this strategy should only be used in a study setting. It has been suggested that more patients with stage I seminoma will die of their treatment than of their cancer; therefore, the thrust of modern management should be to maintain 100% cure while minimizing the burden of treatment.

Interstitial permeability and elasticity in human cervix cancer.

Malignant tumors are characterized by abnormalities of the vasculature and interstitium, which may impede the distribution of drugs and imaging agents. Here we describe a method for estimating tumor interstitial permeability and elasticity based on fitting a spatio-temporal fluid dynamic model to the time course of interstitial pressure (IFP) measurements. The model assumes that sudden insertion of the IFP measurement needle transiently perturbs the steady-state fluid balance, which recovers over time as a function of the vascular and interstitial hydraulic conductivities (L(p)S and K), the interstitial bulk modulus (E) and the extracellular, extravascular volume fraction (phi). Initial simulations showed that the time course of IFP recordings was mainly determined by K and E/phi. Mean values of K and E/phi in 60 newly diagnosed cervix cancers were 1.5 x 10(-7) (SE 2.2 x 10(-8)) cm(2)/mm Hg s and 2230 (SE 212) mm Hg, respectively. For comparison, K and E/phi were also measured in orthotopic ME-180 human cervix cancer xenografts and KHT-C fibrosarcomas in mice. K was higher in both of these tumors (7.0 x 10(-7) and 9.3 x 10(-7)) than in cervix cancer, and E/phi was lower (497 and 433). To our knowledge, these are the first measurements of interstitial permeability and elasticity in individual human cancers. Serial evaluation of these parameters may provide a means of clinically monitoring response to treatments that specifically target the tumor microenvironment.

Imaging and modulating antisense microdistribution in solid human xenograft tumor models.

PURPOSE: The tumor microenvironment is complex and heterogeneous, populated by tortuous irregular vasculature, hypoxic cells, and necrotic regions. These factors can all contribute to the biodistribution difficulties encountered by most cancer therapeutic agents. Antisense oligodeoxynucleotides (ASO) are a class of therapeutics where limited information is available about their distribution within a solid tumor environment. EXPERIMENTAL DESIGN: To assess ASO distribution, a fluorescein-labeled phosphorothionated ASO based on the G3139 mismatch control was injected systemically (i.v.) into tumor-bearing severe combined immunodeficient mice. Hoechst 33342 was injected i.v. to visualize active vasculature. Unstained sections were imaged through tiled fluorescence stereomicroscopy and then quantitated using novel algorithms. Tumor sections from four human tumor models were examined (CaSki, DU-145, C666-1, and C15) for hypoxia, apoptosis/necrosis, and morphology. RESULTS: For all four tumors, ASO accumulated within regions of hypoxia, necrosis, and apoptosis. Scatter plots of ASO versus active vasculature generated for each individual tumor revealed a consistent pattern of distribution of the ASO within each model. In C666-1 xenografts, the slopes of these scatter plots were significantly reduced from 0.41 to 0.16 when pretreated with the antivascular agent ZD6126 48 h before ASO injection. This was accompanied by the formation of large disseminated necrotic regions in the tumor, along with a 13.1 mmHg reduction in interstitial fluid pressure. CONCLUSIONS: These data suggest the possibility that these algorithms might offer a generalizable and objective methodology to describe the distribution of molecular therapeutic agents within a tumor microenvironment and to quantitatively assess distribution changes in response to combination therapies.

Effects of the vascular disrupting agent ZD6126 on interstitial fluid pressure and cell survival in tumors.

Interstitial fluid pressure (IFP) is elevated in tumors due to abnormal vasculature, lack of lymphatic drainage, and alterations in the tumor interstitium. ZD6126 is a tubulin-binding agent that selectively disrupts tumor vasculature resulting in tumor necrosis. This study examined the effect of ZD6126 on tumor IFP and the response of tumors with different IFP levels to ZD6126. Pretreatment IFP was measured using the wick-in-needle method in tumors (murine KHT-C and human CaSki) growing i.m. in the hind legs of mice. Mice were treated i.p. with a single dose of ZD6126 (100 or 200 mg/kg) and posttreatment IFP measurements were made. Blood flow imaging was conducted using Doppler optical coherence tomography, whereas oxygen partial pressure was measured using a fiber optic probe. Clonogenic assays were done to determine tumor cell survival. In KHT-C tumors, IFP dropped significantly at 1 hour posttreatment, returned to pretreatment values at 3 hours, and then declined to approximately 25% of the pretreatment values by 72 hours. In CaSki tumors, the IFP decreased progressively, beginning at 1 hour, to approximately 30% of pretreatment values by 72 hours. Clonogenic cell survival data indicated that ZD6126 was less effective in tumors with high IFP values (>25 mm Hg). Vascular disrupting agents, such as ZD6126, can affect IFP levels and initial IFP levels may predict tumor response to these agents. The higher cell survival in high IFP tumors may reflect greater microregional blood flow limitations in these tumors and reduced access of the drug to the target endothelial cells.