Patterns of recurrence after radiotherapy for high-risk neuroblastoma: Implications for radiation dose and field.

BACKGROUND: Prognosis for patients with high-risk neuroblastoma (HR-NBL) is guarded despite aggressive therapy, and few studies have characterized outcomes after radiotherapy in relation to radiation treatment fields. METHODS: Multi-institutional retrospective cohort of 293 patients with HR-NBL who received autologous stem cell transplant (ASCT) and EBRT between 1997-2021. LRR was defined as recurrence at the primary site or within one nodal echelon beyond disease present at diagnosis. Follow-up was defined from the end of EBRT. Event-free survival (EFS) and OS were analyzed by Kaplan-Meier method. Cumulative incidence of locoregional progression (CILP) was analyzed using competing risks of distant-only relapse and death with Gray's test. RESULTS: Median follow-up was 7.0 years (range: 0.01-22.4). Five-year CILP, EFS, and OS were 11.9 %, 65.2 %, and 77.5 %, respectively. Of the 31 patients with LRR and imaging review, 15 (48.4 %) had in-field recurrences (>12 Gy), 6 (19.4 %) had marginal failures (≤12 Gy), and 10 (32.3 %) had both in-field and marginal recurrences. No patients receiving total body irradiation (12 Gy) experienced marginal-only failures (p = 0.069). On multivariable analyses, MYCN amplification had higher risk of LRR (HR: 2.42, 95 % CI: 1.06-5.50, p = 0.035) and post-consolidation isotretinoin and anti-GD2 antibody therapy (HR: 0.42, 95 % CI: 0.19-0.94, p = 0.035) had lower risk of LRR. CONCLUSIONS: Despite EBRT, LRR remains a contributor to treatment failure in HR-NBL with approximately half of LRRs including a component of marginal failure. Future prospective studies are needed to explore whether radiation fields and doses should be defined based on molecular features such as MYCN amplification, and/or response to chemotherapy.

Daily Head and Neck Treatment Assessment for Optimal Proton Therapy Planning Robustness.

Robust optimization in proton therapy ensures adequate target coverage; however, validation of fractional plan quality and setup uncertainty in patients has not been performed. We aimed to assess plan robustness on delivered head and neck proton plans classified into two categories: (1) primary only (PO) and (2) primary and neck nodal (PNN) coverage. Registration at the machine was utilized for daily CBCT to generate a synthetic CT. The dose for the clinical target volume (CTV) and organs at risk (OAR) was compared to the expected robustness bands using 3.5% range uncertainty and 3 mm vs. 5 mm setup uncertainty. The fractional deviation was defined as D95% and V100% outside of uncertainty constraints. About 203 daily fractions from 6 patients were included for analysis. The percentage of fractions that exceeded robustness calculations was greater in 3 mm as compared to 5 mm setup uncertainty for both CTV and OAR volumes. PO plans had clinically insignificant average fractional deviation, less than 1%, in delivered D95% and V100%. In comparison, PNN plans had up to 2.2% average fractional deviation in delivered V100% using 3 mm robustness. Given the need to balance dose accuracy with OAR sparing, we recommend the utilization of 3 mm setup uncertainty as an acceptable simulation of the dose delivered.

Recognition and Management of the Long-term Effects of Cranial Radiation.

OPINION STATEMENT: Cranial radiation is ubiquitous in the treatment of primary malignant and benign brain tumors as well as brain metastases. Improvement in radiotherapy targeting and delivery has led to prolongation of survival outcomes. As long-term survivorship improves, we also focus on prevention of permanent side effects of radiation and mitigating the impact when they do occur. Such chronic treatment-related morbidity is a major concern with significant negative impact on patient's and caregiver's respective quality of life. The actual mechanisms responsible for radiation-induced brain injury remain incompletely understood. Multiple interventions have been introduced to potentially prevent, minimize, or reverse the cognitive deterioration. Hippocampal-sparing intensity modulated radiotherapy and memantine represent effective interventions to avoid damage to regions of adult neurogenesis. Radiation necrosis frequently develops in the high radiation dose region encompassing the tumor and surrounding normal tissue. The radiographic findings in addition to the clinical course of the patients' symptoms are taken into consideration to differentiate between tissue necrosis and tumor recurrence. Radiation-induced neuroendocrine dysfunction becomes more pronounced when the hypothalamo-pituitary (HP) axis is included in the radiation treatment field. Baseline and post-treatment evaluation of hormonal profile is warranted. Radiation-induced injury of the cataract and optic system can develop when these structures receive an amount of radiation that exceeds their tolerance. Special attention should always be paid to avoid irradiation of these sensitive structures, if possible, or minimize their dose to the lowest limit.

Clinical Outcomes and Patterns of Failure in Esthesioneuroblatoma: A Single Institutional Experience.

Esthesioneuroblastoma (ENB) is a rare sinonasal malignancy that is typically managed with a combination of surgical resection, radiotherapy and chemotherapy. Data used to guide therapeutic decision making are scant and typically obtained from small retrospective series due to the relative infrequency of the diagnosis. Here, we report our own institutional experience in the management of patients with ENB to help compliment these prior single institutional reports. Records from patients receiving treatment for ENB at the University of Minnesota Medical Center were obtained from 1994 to 2019. A total of 17 patients were identified from our retrospective review. Kadish stage at initial presentation was A in 2 (12%), B in 5 (29%), C in 9 (53%) and D in 1 (6%). All patients underwent surgical resection. Adjuvant radiotherapy was utilized in 12 (71%) patients with concurrent chemotherapy administered in 3 (18%) patients. One patient received neoadjuvant chemoradiotherapy followed by surgical resection. Four patients developed recurrent disease with locoregional failure presenting as the most common site of initial relapse within our study population. Isolated local recurrence occurred in 2 patients, one patient developed combined local and regional failure, while another had combined regional and distant failure with osseous metastases. Recurrent disease was managed by either combined salvage surgery and radiotherapy (RT) or RT alone. Three of the 4 patients who developed recurrence eventually succumbed to their disease. Estimates for 5-year DFS and OS were 65% and 90%, respectively, for the entire cohort.

Phase II Trial of Ipilimumab with Stereotactic Radiation Therapy for Metastatic Disease: Outcomes, Toxicities, and Low-Dose Radiation-Related Abscopal Responses.

Ipilimumab is effective for patients with melanoma, but not for those with less immunogenic tumors. We report a phase II trial of ipilimumab with concurrent or sequential stereotactic ablative radiotherapy to metastatic lesions in the liver or lung (NCT02239900). Ipilimumab (every 3 weeks for 4 doses) was given with radiotherapy begun during the first dose (concurrent) or 1 week after the second dose (sequential) and delivered as 50 Gy in 4 fractions or 60 Gy in 10 fractions to metastatic liver or lung lesions. In total, 106 patients received ≥1 cycle of ipilimumab with radiation. Median follow-up was 10.5 months. Median progression-free survival time was 2.9 months (95% confidence interval, 2.45-3.40), and median overall survival time was not reached. Rates of clinical benefit of nonirradiated tumor volume were 26% overall, 28% for sequential versus 20% for concurrent therapy (P = 0.250), and 31% for lung versus 14% for liver metastases (P = 0.061). The sequential lung group had the highest rate of clinical benefit at 42%. There were no differences in treatment-related adverse events between groups. Exploratory analysis of nontargeted lesions revealed that lesions receiving low-dose radiation were more likely to respond than those that received no radiation (31% vs. 5%, P = 0.0091). This phase II trial of ipilimumab with stereotactic radiotherapy describes satisfactory outcomes and low toxicities, lending support to further investigation of combined-modality therapy for metastatic cancers.

Management of Unresectable T4b Esophageal Cancer: Practice Patterns and Outcomes From the National Cancer Data Base.

PURPOSE: Patients with unresectable cT4b esophageal cancer (EC) are rare and largely excluded from prospective trials. As a result, current treatment recommendations are based on limited evidence. This study sought to evaluate national practice patterns and outcomes for this population and evaluated 3 primary cohorts: patients receiving chemotherapy (CT) with or without subtherapeutic radiotherapy (RT), definitive chemoradiotherapy (CRT), or CT with or without RT followed by definitive surgery. MATERIALS AND METHODS: The National Cancer Data Base was queried for cT4b Nany M0 EC. Exclusion criteria were patients with unspecified staging, palliative treatment, improper, or no histologic confirmation, or lack of CT. Multivariable logistic regression determined factors predictive of receiving surgical therapy. Kaplan-Meier analysis evaluated overall survival (OS), and Cox proportional hazards modeling determined variables associated with OS. RESULTS: Altogether, 519 patients met inclusion criteria; 195 (38%) underwent CT, 291 (56%) underwent definitive CRT, and 33 (6%) underwent surgical-based therapy. Surgery was more likely performed in patients residing in rural areas, living farther from the treating facility, and N1 status (P<0.05 for all). Median OS in the respective cohorts were 6.0, 12.7, and 43.9 months (P<0.001). On multivariate Cox proportional hazards modeling, among others, nonsurgical treatment was associated with poorer OS (P<0.05 for both). CONCLUSIONS: In the largest study to date evaluating patterns of care for cT4b EC, as compared with CT alone, addition of definitive RT was associated with higher OS. Although causation is clearly not implied, well-selected responders to CT and/or RT may be able to undergo resection and numerically prolonged survival, but patient selection remains paramount.

Utilization of Intensity-Modulated Radiation Therapy for Malignant Pleural Mesothelioma in the United States.

BACKGROUND: Although postoperative radiotherapy (RT) for malignant pleural mesothelioma (MPM) has historically been delivered using 3-dimensional conformal RT (3DCRT) techniques, multiple reports show noteworthy safety and efficacy of the more advanced intensity-modulated RT (IMRT). To our knowledge, this is the only known study to evaluate national practice patterns of IMRT utilization for MPM. MATERIALS AND METHODS: The National Cancer Data Base was queried for newly-diagnosed MPM patients who underwent definitive surgery (extrapleural pneumonectomy [EPP] or extended pleurectomy/decortication [P/D]) followed by adjuvant RT. Patients with metastatic disease, non-EPP or P/D surgical techniques, and lack of RT receipt (or without specified RT technique) were excluded. Statistics included multivariable logistic regression, Kaplan-Meier overall survival (OS) analysis, and Cox proportional hazards modeling. RESULTS: Overall, 286 patients met criteria (181 [63%] IMRT and 105 [37%] 3DCRT). Temporal trends revealed that although 3DCRT was more common at initial time periods, IMRT utilization rose from 2004 to 2007 and stayed as a relatively constant majority thereafter. This was also present when substratifying the cohort according to EPP versus P/D approaches. IMRT was more often delivered at academic centers, along with institutions in the Southern United States, whereas 3DCRT was more frequently utilized in community facilities and in the Northeast (P ≤ .05 for all). RT technique did not affect OS (P > .05 for all comparisons). CONCLUSION: In the United States, IMRT is now the most commonly utilized adjuvant RT technique for MPM. Facility and regional differences might associate with IMRT delivery. The findings of this investigation have implications for insurance coverage, clinical referral patterns, and ongoing and future prospective trial design.

Reliable Radiation Technique to Minimize Ovarian Dose During Radiation Prophylaxis of Heterotopic Ossification.

BACKGROUND/AIM: Scattered radiation during radiotherapy (RT) directed at the hip joint poses concerns about ovarian function in patients of reproductive age. Here, we report the impact of using a split-beam technique (SBT) and different photon energies on the total ovary dose during radiation prophylaxis of heterotopic ossification (HO). PATIENTS AND METHODS: This was a single-institution, retrospective study of 32-patients with traumatic acetabular fractures (TAF). All underwent surgery followed by CT-based-RT within 72 h in a single fraction of 700 cGy. Ipsilateral (IL) and contralateral (CL) ovaries (OV) were contoured separately and dose volume histograms (DVH) generated. Additional planning trials were created for each patient by utilizing a SBT medially and by using different photon energies (6-18 MV) to investigate the difference in ovary dose among these maneuvers. RESULTS: The median Mean-dose delivered to ILOV was 59 cGy and the median Max-dose was 177 cGy. CLOV median Mean-dose was 6 cGy and median Max-dose was 10 cGy. SBT at the medial edge of the field led to a 27% and 22% dose reduction in the median Mean and Max. doses, respectively, to ILOV; 9% and 5% reduction was seen in the median Mean and Max. doses, respectively, to CLOV. Higher photon energies (10-18 MV) led to an additional 28% and 16 % reduction in median Mean and Max. doses, respectively, to ILOV when compared to those from 6 MV. The CLOV median Mean dose was reduced by 18% and the Max. dose was reduced by 12%. CONCLUSION: A biologically significant radiation dose is delivered to the ovaries during HO radiation prophylaxis at the hip joints. Ipsilateral ovarian dose could be reduced by half and contralateral by one-quarter by using CT-based treatment planning with a medial SBT and photon energies above 6 MV. We suggest using no more than 10 MV to minimize neutron contamination. Those techniques should be the standard of care as it provides a reliable method for minimizing the radiation dose to the ovaries, consequently, maximizing female fertility preservation during HO radiation prophylaxis. All female patients in childbearing age should be fully informed about ovarian radiation exposure and possible temporary alteration in ova production and morphology.

Testicular Dose During Prophylaxis of Heterotopic Ossification with Radiation Therapy.

AIM: A single-institution, retrospective study was performed to investigate potential techniques to minimize radiation exposure to the testicles during heterotopic ossification (HO) prophylaxis. We report the impact of split-beam technique (SBT) and different photon energies on the total dose of radiation received by the testicles during prophylaxis of HO. MATERIALS AND METHODS: Between 2008 and 2010, we identified 64 patients with traumatic acetabular fractures who underwent surgery followed by radiation therapy (RT) without testicular shielding. Postoperative RT was delivered within 72 h in a single fraction of 700 cGy using 6-18 MV photons, without testicular shielding due to patient refusal. All patients underwent 3-D RT planning in which the testicles were contoured as a region of interest and dose-volume histograms (DVH) were generated. Additional treatment planning trials were created for each patient by utilizing a SBT medially and by using different photon energies (6, 10 and 18 MV) to study the effects of these maneuvers on the delivered dose to the testicles. RESULTS: In reviewing the DVH, it was noted that the mean dose delivered to the testicles was 10 cGy (range=3-40). The maximum dose was 31 cGy (range=7-430). When SBT was utilized, a significant reduction in the mean (44%) and maximum (47%) doses delivered to the testicles was noted. Further reductions in the mean (26%) and maximum (14%) doses were achieved by using higher-energy (10-18 MV) beams. The radiation doses to the testicles from the CT simulation and the two portal images were estimated to be 4 and 1.5 cGy, respectively. CONCLUSION: Low-dose prophylactic RT to prevent HO around the hip causes a low, but likely biologically meaningful, radiation dose to be delivered to the testicles. This dose could be further reduced by using a medial SBT and photon energies above 6 MV. Testicular shielding should be offered to all male patients receiving such RT. In addition, all patients should be informed about the consequences of testicular radiation as part of their informed consent.

Can chemotherapy boost the survival benefit of adjuvant radiotherapy in early stage cervical cancer with intermediate risk factors? A population based study.

PURPOSE: The Gynecologic Oncology group (GOG) 0263 trial is currently exploring whether adding chemotherapy to adjuvant radiotherapy improves recurrence-free and/or overall survival in stage IB-IIA cervical cancer patients with pathologic intermediate-risk factors. Using the National Cancer Data Base, we evaluated the benefit of adjuvant chemoradiotherapy over adjuvant radiotherapy alone in the community practice setting. MATERIALS: The analysis included 869 stage IB-IIA cervical cancer patients who underwent radical hysterectomy retrieving intermediate-risk factors justifying adjuvant therapy. Adjuvant chemoradiotherapy and adjuvant radiotherapy were delivered in 440 and 429 patients, respectively. Chi-square test assessed the distribution of variables in each group and the overall survival was estimated using the Kaplan-Meier method. Proportional hazard models were performed to evaluate the impact of the different prognostic factors on survival and propensity score analysis adjusted variables imbalanced distribution. RESULTS: Adding chemotherapy to ART did not show a survival benefit at 48months median follow-up; the 5-year overall survival was 87% and 81% (p=0.6) in the adjuvant chemoradiotherapy and adjuvant radiotherapy groups, respectively. On univariate analysis, age older than 60, a higher comorbidity score, and stage IIA were significantly associated with worse survival, while none of the other covariates were significant prognosticator on multivariate analysis. The same findings held after propensity score analysis. CONCLUSION: Our analysis could not detect a significant survival benefit for adjuvant chemoradiotherapy over adjuvant radiotherapy in women with intermediate-risk factors. Until GOG 0263 results become available, the benefits of adjuvant chemoradiotherapy should be considered on an individual basis within a multidisciplinary approach.