Phase I Trial of SPECT-Guided Liver-Directed Radiotherapy for Patients with Low Functional Liver Volume.

BACKGROUND: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection. METHODS: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose limiting toxicities (DLTs) were assessed 6-8 weeks and 6 months after completing radiotherapy. RESULTS: All twelve patients had colorectal liver metastases and received prior hepatotoxic chemotherapy. Eight patients underwent prior liver resection. Median computed tomography (CT) anatomical non-tumor liver volume was 1,584 cc (range 764-2,699 cc). Median SPECT functional liver volume was 1,117 cc (range 570-1,928cc). Median non-target CT and SPECT liver volumes below the volumetric dose constraint were 997 cc (range 544-1,576 cc) and 684 cc (range 429-1,244 cc), respectively. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. No DLTs were observed during follow-up. One-year in-field control was 57%. One-year overall survival was 73%. CONCLUSION: Liver-directed radiotherapy can be safely delivered to high doses when incorporating functional SPECT into the radiation treatment planning process which may enable sparing of lower volumes of liver than traditionally accepted in patients with preserved liver function. TRIAL REGISTRATION: NCT02626312.

Patient-Reported Sexual Function, Bladder Function and Quality of Life for Patients with Low Rectal Cancers with or without a Permanent Ostomy.

BACKGROUND: Despite the increasing utilization of sphincter and/or organ-preservation treatment strategies, many patients with low-lying rectal cancers require abdominoperineal resection (APR), leading to permanent ostomy. Here, we aimed to characterize overall, sexual-, and bladder-related patient-reported quality of life (QOL) for individuals with low rectal cancers. We additionally aimed to explore potential differences in patient-reported outcomes between patients with and without a permanent ostomy. METHODS: We distributed a comprehensive survey consisting of various patient-reported outcome measures, including the FACT-G7 survey, ICIQ MLUTS/FLUTS, IIEF-5/FSFI, and a specific questionnaire for ostomy patients. Descriptive statistics and univariate comparisons were used to compared demographics, treatments, and QOL scores between patients with and without a permanent ostomy. RESULTS: Of the 204 patients contacted, 124 (60.8%) returned completed surveys; 22 (18%) of these had a permanent ostomy at the time of survey completion. There were 25 patients with low rectal tumors (≤5 cm from the anal verge) who did not have an ostomy at the time of survey completion, of whom 13 (52%) were managed with a non-operative approach. FACTG7 scores were numerically lower (median 20.5 vs. 22, p = 0.12) for individuals with an ostomy. Sexual function measures IIEF and FSFI were also lower (worse) for individuals with ostomies, but the results were not significantly different. MLUTS and FLUTS scores were both higher in individuals with ostomies (median 11 vs. 5, p = 0.06 and median 17 vs. 5.5, p = 0.01, respectively), suggesting worse urinary function. Patient-reported ostomy-specific challenges included gastrointestinal concerns (e.g., gas, odor, diarrhea) that may affect social activities and personal relationships. CONCLUSIONS: Despite a limited sample size, this study provides patient-centered, patient-derived data regarding long-term QOL in validated measures following treatment of low rectal cancers. Ostomies may have multidimensional negative impacts on QOL, and these findings warrant continued investigation in a prospective setting. These results may be used to inform shared decision making for individuals with low rectal cancers in both the settings of organ preservation and permanent ostomy.

Microbiome Dynamics During Chemoradiation Therapy for Anal Cancer.

PURPOSE: Patients with localized squamous cell carcinoma of the anus (SCCA) who experience treatment toxicity or recurrences have few therapeutic options. Investigation into the microbiome's influence on treatment toxicity and its potential use as a predictive biomarker could improve these patients' outcomes. Our study presents the first longitudinal characterization of the SCCA tumor microbiome and its associations with treatment-related toxicities. METHODS AND MATERIALS: This prospective cohort study included patients with nonmetastatic SCCA receiving standard-of-care chemoradiation therapy. Anorectal swabs of the tumor site were collected before, during, and after treatment. Patient-reported quality-of-life metrics were collected at similar time points. 16S rRNA gene sequencing was used to perform diversity and taxonomic characterization of the SCCA microbiome. Wilcoxon signed-rank tests were used to compare microbial diversity and abundance over time. Wilcoxon rank-sum tests were used to compare microbial profiles of high and low toxicity groups. RESULTS: Twenty-two patients with SCCA were included in this study with a median age of 58.5 years (range, 39-77 years), and 18 (82%) were women. Alpha diversity remained relatively stable throughout chemoradiation therapy except for decreases in the Observed Features (P = .03) index at week 5 relative to baseline. Tumor microbial compositions changed significantly by the end of treatment (P = .03). Differential enrichment of bacteria at specific time points occurred during treatment, including the enrichment of Clostridia at follow-up (vs week 5, q = 0.019) and Corynebacterium at week 5 (vs baseline, q = 0.015; vs follow-up, q = 0.022). Patients experiencing high toxicity at week 5 had higher relative counts of Clostridia, Actinobacteria, and Clostridiales at baseline (P = .03 for all). CONCLUSIONS: The tumor microbiome changes during and after chemoradiation therapy, and patient-reported toxicity levels are associated with patients' microbial profiles. Further studies into these microbial characterizations and toxicity associations will elucidate the tumor microbiome's role in predicting treatment-related outcomes for patients with SCCA.

Stereotactic Versus Conventional Radiation Therapy for Patients With Pancreatic Cancer in the Modern Era.

PURPOSE: Patients with pancreatic cancer often receive radiation therapy before undergoing surgical resection. We compared the clinical outcomes differences between stereotactic body radiation therapy (SBRT) and 3-dimensional (3D)/intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: We retrospectively collected data from the University of Texas MD Anderson Cancer Center. Patients with borderline resectable/potentially resectable or locally advanced pancreatic cancer receiving neoadjuvant SBRT (median, 36.0 Gy/5fx), 3D conformal radiation (median, 50.4 Gy/28 fx) or IMRT (median, 50.4 Gy/28 fx) were included. Overall survival (OS) and progression-free survival were analyzed using Cox regression. RESULTS: In total, 104 patients were included in our study. Fifty-seven patients (54.8%) were treated with SBRT, and 47 patients (45.2%) were treated with 3D/IMRT. Patients in the SBRT group were slightly older (median age: 70.3 vs 62.7 in the 3D/IMRT group). Both groups had similar proportions of patients with locally advanced pancreatic cancer (SBRT: 30, 52.6%; 3D/IMRT: 24, 51.1%). All patients were treated with chemotherapy. Patients in the SBRT group underwent more surgical resection compared with the 3D/IMRT group (38.6% vs 23.4%, respectively). At a median follow-up of 22 months, a total of 60 patients (57.7%) died: 25 (25/57, 43.9%) in the SBRT group, and 35 (35/47, 74.5%) in the 3D/IMRT group. Median OS was slightly higher in the SBRT group (29.6 months vs 24.1 months in the 3D/IMRT group). On multivariable Cox regression, the choice of radiation therapy technique was not associated with differences in OS (adjusted hazard ratios [aHR] = 0.5; 95% confidence interval [CI], 0.2%-1.3%, P = .18). Moreover, patients that underwent surgical resection had better OS (aHR = 0.3, 95% CI, 0.1%-0.8%, P = .01). Furthermore, progression-free survival was also similar between patients treated with SBRT and those treated with 3D/IMRT (aHR = 0.9, 95% CI, 0.5%-1.8%, P = .81). CONCLUSIONS: SBRT was associated with similar clinical outcomes compared with conventional radiation techniques, despite being delivered over a shorter period of time which would spare patients prolonged treatment burden. Future prospective data are still needed to better assess the role of SBRT in patients with pancreatic cancer.

Multi-institutional retrospective review of stereotactic radiosurgery for brain metastasis in patients with small cell lung cancer without prior brain-directed radiotherapy.

Introduction: Patients with small cell lung cancer (SCLC) brain metastasis (BM) typically receive whole brain radiotherapy (WBRT) as data regarding upfront radiosurgery (SRS) in this setting are sparse. Methods: Patients receiving SRS for SCLC BM without prior brain radiation were identified at three U.S. institutions. Overall survival (OS), freedom from intracranial progression (FFIP), freedom from WBRT (FFWBRT), and freedom from neurologic death (FFND) were determined from time of SRS. Results: Thirty-three patients were included with a median of 2 BM (IQR 1-6). Median OS and FFIP were 6.7 and 5.8 months, respectively. Median FFIP for patients with ≤2 versus >2 BM was 7.1 versus 3.6 months, p=0.0303. Eight patients received salvage WBRT and the 6-month FFWBRT and FFND were 87.8%. and 90.1%, respectively. Conclusions: Most SCLC patients with BM who received upfront SRS avoided WBRT and neurologic death, suggesting that SRS may be an option in select patients.

Radiation Oncology Strategies to Flatten the Curve During the Coronavirus Disease 2019 (COVID-19) Pandemic: Experience From a Large Tertiary Cancer Center.

During the coronavirus disease 2019 pandemic, minimizing exposure risk for patients with cancer and health care personnel was of utmost importance. Here, we present steps taken to date to flatten the curve at the radiation oncology division of a tertiary cancer center with the goal of mitigating risk of exposure among patients and staff, and optimizing resource utilization. Response to the coronavirus disease 2019 pandemic in this large tertiary referral center included volume reduction, personal protective equipment recommendations, flexible clinic visit interaction types dictated by need and risk reduction, and numerous social distancing strategies. We hope these outlined considerations can assist the wider radiation oncology community as we collectively face this ongoing challenge.

Radiation for Glioblastoma in the Era of Coronavirus Disease 2019 (COVID-19): Patient Selection and Hypofractionation to Maximize Benefit and Minimize Risk.

We describe the institutional guidelines of a major tertiary cancer center with regard to using hypofractionated radiation regimens to treat glioblastoma as a measure to minimize exposure to coronavirus disease 2019 (COVID-19) while not sacrificing clinical outcomes. Our guidelines review level one evidence of various hypofractionated regimens, and recommend a multidisciplinary approach while balancing the risk of morbidity and mortality among individuals at high risk for severe illness from COVID-19 infection. We also briefly outline strategies our department is taking in mitigating risk among our cancer patients undergoing radiation.

Predictors of urinary toxicity with MRI-assisted radiosurgery for low-dose-rate prostate brachytherapy.

PURPOSE: MRI-assisted radiosurgery (MARS) is a modern technique for prostate brachytherapy that provides superior soft tissue contrast. The purpose of this analysis was to evaluate treatment planning factors associated with urinary toxicity, particularly damage to the membranous urethra (MUL) and external urethral sphincter (EUS), after MARS. MATERIAL AND METHODS: We retrospectively reviewed 227 patients treated with MARS. Comparisons were made between several factors including preimplantation length of the MUL and EUS dosimetric characteristics after implantation with longitudinal changes in American Urological Association (AUA) urinary symptom score. RESULTS: Rates of grade 3 urinary incontinence and obstructive urinary symptoms were 4% and 2%. A piecewise mixed univariate model revealed that MUL and V200, V150, V125, and D5 to the EUS were all associated with increased rates of urinary toxicity over time. On univariate logistic regression, MUL >14.2 mm (odds ratio [OR] 2.03 per cm3, 95% confidence interval [CI] 1.10-3.77, p = 0.025), V125 to the EUS (OR 3.21 cm3, 95% CI 1.18-8.71, p = 0.022), and use of the I-125 isotope (OR 3.45, 95% CI 1.55-7.70, p = 0.001) were associated with subacute urinary toxicity (i.e., that occurring at 4-8 months). Optimal dose-constraint limits to the EUS were determined to be V200 < 0.04 cm3 (p = 0.002), V150 < 0.12 cm3 (p = 0.041), V125 < 0.45 cm3 (p = 0.033), D30 < 160 Gy (p = 0.004), and D5 < 218 Gy (p = 0.016). CONCLUSIONS: MARS brachytherapy provides detailed anatomic information for treatment planning, implantation, and quality assurance. Overall rates of urinary toxicity are low; however, several dosimetric variables associated with the EUS were found to correlate with urinary toxicity.

Radiation therapy for patients with locally advanced pancreatic cancer: Evolving techniques and treatment strategies.

Despite ongoing efforts, patients with locally advanced pancreatic cancer (LAPC) continue to have a dismal prognosis. Such tumors are unresectable, and optimal treatment with chemotherapy and/or radiation therapy is still not established. While chemotherapy is conventionally aimed at preventing metastatic spread of disease, radiation therapy acts locally, improving local control which can potentially improve overall survival and most importantly quality of life. Here, we aim to review the primary literature assessing the role of diverse radiation therapy strategies for patients with LAPC. Many radiation regimens can be considered, and no standard treatment has demonstrated a clear improvement in clinical outcomes. We advise that the modality of choice be dependent on the availability of equipment, the dose and fractionation of treatment, as well as the dose received by normal tissue. Moreover, a candid discussion with the patient concerning treatment goals is equally as essential. Three notable strategies for LAPC are intensity-modulated radiation therapy, volumetric modulated arc therapy, and proton. These radiation modalities tend to have improved dose distribution to the target volumes, while minimizing the radiation dose to surrounding normal tissues. Stereotactic body radiation therapy can also be considered in LAPC patients in cases where the tumor does not invade the duodenum or other neighboring structures. Because of the high doses delivered by stereotactic body radiation therapy, proper respiratory and tumor motion management should be implemented to reduce collateral radiation dosing. Despite improved clinical outcomes with modern radiation modalities, evolving techniques, and more accurate planning, future studies remain essential to elucidate the optimal role for radiation therapy among patients with LAPC.

Non-English language validation of patient-reported outcome measures in cancer clinical trials.

Patient-reported outcome measures (PROMs) are increasingly incorporated as endpoints in oncology clinical trials but are often only validated in English. ClinicalTrials.gov was queried for cancer-specific randomized control trials (RCTs) addressing a therapeutic intervention and enrolling primarily in the USA. Peer-reviewed validation of Spanish and Chinese versions of each PROM was assessed. Of 103 eligible trials, a PROM was used as a primary endpoint in 25 RCTs (24.3%) and as a secondary endpoint in 78 RCTs (75.7%). A total of 61 of the 103 eligible trials (59.2%) and 17 of the 25 trials with a PROM primary endpoint (68.0%) used a PROM with either no Spanish or Chinese validation. The absence of validated PROM translations may diminish the voices of non-English language speaking trial participants. With an increasingly diverse US population, validation of non-English PROM translations may decrease disparities in trial participation and improve generalizability of study results.

From cells to tissue: How cell scale heterogeneity impacts glioblastoma growth and treatment response.

Glioblastomas are aggressive primary brain tumors known for their inter- and intratumor heterogeneity. This disease is uniformly fatal, with intratumor heterogeneity the major reason for treatment failure and recurrence. Just like the nature vs nurture debate, heterogeneity can arise from intrinsic or environmental influences. Whilst it is impossible to clinically separate observed behavior of cells from their environmental context, using a mathematical framework combined with multiscale data gives us insight into the relative roles of variation from different sources. To better understand the implications of intratumor heterogeneity on therapeutic outcomes, we created a hybrid agent-based mathematical model that captures both the overall tumor kinetics and the individual cellular behavior. We track single cells as agents, cell density on a coarser scale, and growth factor diffusion and dynamics on a finer scale over time and space. Our model parameters were fit utilizing serial MRI imaging and cell tracking data from ex vivo tissue slices acquired from a growth-factor driven glioblastoma murine model. When fitting our model to serial imaging only, there was a spectrum of equally-good parameter fits corresponding to a wide range of phenotypic behaviors. When fitting our model using imaging and cell scale data, we determined that environmental heterogeneity alone is insufficient to match the single cell data, and intrinsic heterogeneity is required to fully capture the migration behavior. The wide spectrum of in silico tumors also had a wide variety of responses to an application of an anti-proliferative treatment. Recurrent tumors were generally less proliferative than pre-treatment tumors as measured via the model simulations and validated from human GBM patient histology. Further, we found that all tumors continued to grow with an anti-migratory treatment alone, but the anti-proliferative/anti-migratory combination generally showed improvement over an anti-proliferative treatment alone. Together our results emphasize the need to better understand the underlying phenotypes and tumor heterogeneity present in a tumor when designing therapeutic regimens.

Feasibility of atlas-based active bone marrow sparing intensity modulated radiation therapy for cervical cancer.

BACKGROUND: To test the hypothesis that atlas-based active bone marrow (ABM)-sparing intensity modulated radiation therapy (IMRT) yields similar dosimetric results compared to custom ABM-sparing IMRT for cervical cancer patients. METHODS: We sampled 62 cervical cancer patients with pre-treatment FDG-PET/CT in training (n=32) or test (n=30) sets. ABM was defined as the subvolume of the pelvic bone marrow (PBM) with standardized uptake value (SUV) above the mean on the average FDG-PET image (ABMAtlas) vs. the individual's PET (ABMCustom). Both were deformed to the planning CT. Overlap between the two subvolumes was measured using the Dice coefficient. Three IMRT plans designed to spare PBM, ABMAtlas, or ABMCustom were compared for 30 test patients. Dosimetric parameters were used to evaluate plan quality. RESULTS: ABMAtlas and ABMCustom volumes were not significantly different (p=0.90), with a mean Dice coefficient of 0.75, indicating good agreement. Compared to IMRT plans designed to spare PBM and ABMCustom, ABMAtlas-sparing IMRT plans achieved excellent target coverage and normal tissue sparing, without reducing dose to ABMCustom (mean ABMCustom dose 29.4Gy vs. 27.1Gyvs. 26.9Gy, respectively; p=0.10); however, PTV coverage and bowel sparing were slightly reduced. CONCLUSIONS: Atlas-based ABM sparing IMRT is clinically feasible and may obviate the need for customized ABM-sparing as a strategy to reduce hematologic toxicity.

Longitudinal Changes in Active Bone Marrow for Cervical Cancer Patients Treated With Concurrent Chemoradiation Therapy.

PURPOSE: To quantify longitudinal changes in active bone marrow (ABM) distributions within unirradiated (extrapelvic) and irradiated (pelvic) bone marrow (BM) in cervical cancer patients treated with concurrent chemoradiation therapy (CRT). METHODS AND MATERIALS: We sampled 39 cervical cancer patients treated with CRT, of whom 25 were treated with concurrent cisplatin (40 mg/m2) and 14 were treated with cisplatin (40 mg/m2) plus gemcitabine (50-125 mg/m2) (C/G). Patients underwent 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and 1.5 to 6.0 months after treatment. ABM was defined as the subvolume of bone with standardized uptake value (SUV) above the mean SUV of the total bone. The primary aim was to measure the compensatory response, defined as the change in the log of the ratio of extrapelvic versus pelvic ABM percentage from baseline to after treatment. We also quantified the change in the proportion of ABM and mean SUV in pelvic and extrapelvic BM using a 2-sided paired t test. RESULTS: We observed a significant increase in the overall extrapelvic compensatory response after CRT (0.381; 95% confidence interval [CI]: 0.312, 0.449) and separately in patients treated with cisplatin (0.429; 95% CI: 0.340, 0.517) and C/G (0.294; 95% CI: 0.186, 0.402). We observed a trend toward higher compensatory response in patients treated with cisplatin compared with C/G (P=.057). Pelvic ABM percentage was reduced after CRT both in patients receiving cisplatin (P<.001) and in those receiving C/G (P<.001), whereas extrapelvic ABM percentage was increased in patients receiving cisplatin (P<.001) and C/G (P<.001). The mean SUV in pelvic structures was lower after CRT with both cisplatin (P<.001) and C/G (P<.001). The mean SUV appeared lower in extrapelvic structures after CRT in patients treated with C/G (P=.076) but not with cisplatin (P=.942). We also observed that older age and more intense chemotherapy regimens were correlated with a decreased compensatory response on multivariable analysis. In patients treated with C/G, mean pelvic bone marrow dose was found to be negatively correlated with the compensatory response. CONCLUSION: Patients have differing subacute compensatory responses after CRT, owing to variable recovery in unirradiated marrow. Intensive chemotherapy regimens appear to decrease the extrapelvic compensatory response, which may lead to increased hematologic toxicity.

Prospective Validation of a High Dimensional Shape Model for Organ Motion in Intact Cervical Cancer.

PURPOSE: Validated models are needed to justify strategies to define planning target volumes (PTVs) for intact cervical cancer used in clinical practice. Our objective was to independently validate a previously published shape model, using data collected prospectively from clinical trials. METHODS AND MATERIALS: We analyzed 42 patients with intact cervical cancer treated with daily fractionated pelvic intensity modulated radiation therapy and concurrent chemotherapy in one of 2 prospective clinical trials. We collected online cone beam computed tomography (CBCT) scans before each fraction. Clinical target volume (CTV) structures from the planning computed tomography scan were cast onto each CBCT scan after rigid registration and manually redrawn to account for organ motion and deformation. We applied the 95% isodose cloud from the planning computed tomography scan to each CBCT scan and computed any CTV outside the 95% isodose cloud. The primary aim was to determine the proportion of CTVs that were encompassed within the 95% isodose volume. A 1-sample t test was used to test the hypothesis that the probability of complete coverage was different from 95%. We used mixed-effects logistic regression to assess effects of time and patient variability. RESULTS: The 95% isodose line completely encompassed 92.3% of all CTVs (95% confidence interval, 88.3%-96.4%), not significantly different from the 95% probability anticipated a priori (P=.19). The overall proportion of missed CTVs was small: the grand mean of covered CTVs was 99.9%, and 95.2% of misses were located in the anterior body of the uterus. Time did not affect coverage probability (P=.71). CONCLUSIONS: With the clinical implementation of a previously proposed PTV definition strategy based on a shape model for intact cervical cancer, the probability of CTV coverage was high and the volume of CTV missed was low. This PTV expansion strategy is acceptable for clinical trials and practice; however, we recommend daily image guidance to avoid systematic large misses in select patients.

Survival in unresectable sinonasal undifferentiated carcinoma treated with concurrent intra-arterial cisplatin and radiation.

We report the successful use of RADPLAT to treat a patient with an unresectable T4N0 sinonasal undifferentiated carcinoma. This patient received 4 cycles of weekly intra-arterial cisplatin together with thiosulfate infusion with concurrent radiation therapy. Radiation therapy was given in 28 daily fractions to 54 Gy using intensity-modulated radiation therapy followed by a hypofractionated stereotactic boost of 3 fractions to 13 Gy to a total dose of 67 Gy in 31 fractions to the nasal sinus and bilateral neck. Intra-arterial cisplatin was administered using a bilateral approach due to the midline site of this tumor. Within days of the first intra-arterial cisplatin, there was an obvious decrease in tumor size. She has been followed with magnetic resonance imaging and positron emission tomography, and remains disease-free 47 mo post-treatment. Centers with expertise in intra-arterial chemotherapy could consider the RADPLAT approach for patients with unresectable sinonasal undifferentiated carcinoma.

De novo glioblastoma in the territory of a prior middle cerebral artery infarct.

We report a case of a patient who developed glioblastoma in the territory of a previous infarction. Two years after an ischemic stroke, the patient presented with a cystic, necrotic, and heterogeneously enhancing mass. Open biopsy and debulking of the mass with histological analysis revealed the mass to be glioblastoma. Though several cases of posttraumatic GBM have been reported, this is the first proposed case of GBM after an ischemic stroke. From this case, we suggest that the ischemic stroke, like other forms of cortical injury, may predispose to glioblastoma formation.