McGovern, Susan L.

Abstract Background To determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma (GBM). Methods Eligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs). Results A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02). Conclusions In this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.

Abstract Background We investigated differences in radiation-induced grade 3+ lymphopenia (G3+L), defined as an absolute lymphocyte count (ALC) nadir of <500 cells/µL, after proton therapy (PT) or X-ray (photon) therapy (XRT) for patients with glioblastoma (GBM). Methods Patients enrolled in a randomized phase II trial received PT (n = 28) or XRT (n = 56) concomitantly with temozolomide. ALC was measured before, weekly during, and within 1 month after radiotherapy. Whole-brain mean dose (WBMD) and brain dose-volume indices were extracted from planned dose distributions. Univariate and multivariate logistic regression analyses were used to identify independent predictive variables. The resulting model was evaluated using receiver operating characteristic (ROC) curve analysis. Results Rates of G3+L were lower in men (7/47 [15%]) versus women (19/37 [51%]) (P < 0.001), and for PT (4/28 [14%]) versus XRT (22/56 [39%]) (P = 0.024). G3+L was significantly associated with baseline ALC, WBMD, and brain volumes receiving 5‒40 Gy(relative biological effectiveness [RBE]) or higher (ie, V5 through V40). Stepwise multivariate logistic regression analysis identified being female (odds ratio [OR] 6.2, 95% confidence interval [CI]: 1.95‒22.4, P = 0.003), baseline ALC (OR 0.18, 95% CI: 0.05‒0.51, P = 0.003), and whole-brain V20 (OR 1.07, 95% CI: 1.03‒1.13, P = 0.002) as the strongest predictors. ROC analysis yielded an area under the curve of 0.86 (95% CI: 0.79–0.94) for the final G3+L prediction model. Conclusions Sex, baseline ALC, and whole-brain V20 were the strongest predictors of G3+L for patients with GBM treated with radiation and temozolomide. PT reduced brain volumes receiving low and intermediate doses and, consequently, reduced G3+L.

Abstract BACKGROUND While glioblastoma (GBM) is more prevalent in males, studies show that females with GBM tend to have longer overall survival (OS) than males. Pretreatment neutrophil to lymphocyte ratio (NLR) has also proven to be prognostic in GBM, with lower NLR having favorable outcomes. This secondary analysis of a prospective randomized trial of proton vs. photon intensity modulated radiotherapy aims to explore the interaction of gender and NLR on GBM outcomes. METHODS Analysis was performed on the full patient population. Kaplan-Meier methods estimated OS with censoring at last follow-up for those who were alive. Univariate (UVA) and multivariate (MVA)Cox proportional hazards models assessed predictors of OS. RESULTS Of 90 patients, 77 were included (43 males; 34 females) with median age of 52 years (range: 26–82 years). Median OS was longer for females than males (30.7 vs 18.2 months, p=0.004). On UVA, patients with NLR below median value (NLR= 3.1) tended to have longer OS than those above median, though not meeting statistical significance (23.1 vs. 17.9 months, p=0.051). Difference in OS was statistically significant in females (OS 36.4 months NLR >median vs. 16.7 months NLR< median, p=0.002), but not in males (OS 17.8 months NLR >median vs. 19.1 NLR< median, p=0.95). MVA analysis was consistent, with female gender predicting reduced hazard ratio (HR) (0.28, p=0.034) and females with below median NLR showing a reduced HR over those with above median (0.28, p=0.005). Again, males did not benefit (HR 0.90, p=0.77). CONCLUSION Consistent with prior publications, females and all patients with lower pre-treatment NLR with newly diagnosed GBM had longer OS. However, combining these two factors revealed that the benefits from lower pre-treatment NLR were conferred only in females with no impact on males. This different impact of NLR between genders may suggest innate immune differences in gender during response to malignancy.

Abstract PURPOSE/OBJECTIVE Dose constraints for re-irradiation of recurrent primary brain tumors are not well-established, especially for treatment volumes too large for stereotactic radiotherapy. This prospective trial was performed to test dose constraints for conventionally-fractionated re-irradiation of recurrent primary brain tumors MATERIALS/METHODS A single-institution, prospective trial of 21 adults with recurrent brain tumors was performed. Electronic dosimetry records from the first course of radiation (RT1) were obtained and deformed onto the simulation CT for the second course of radiation (RT2). Treatment plans for RT2 were developed that met protocol-assigned dose constraints for RT2 alone and the composite dose of RT1+RT2. Dose constraints were also based on histology and interval since RT1. The primary endpoint was the rate of symptomatic brain necrosis after RT2. RESULTS Twenty one adults enrolled from March 2017 to May 2018. Twelve had glioblastoma, four had oligodendroglioma, two had anaplastic astrocytoma, and one each had choroid plexus papilloma, hemangiopericytoma, and pleomorphic xanthroastrocytoma (PXA). Twenty patients were treated with VMAT and one was treated with proton CSI. Median RT1-RT2 interval was 45 months (range, 9–141 months). Median RT2 dose was 42.8 Gy (range, 17.5–60 Gy). Median PTV volume was 208 cc (range, 7–1537 cc). Median imaging followup was 9 months (range, 1–20 months). Two months after RT2, the patient with PXA developed a trapped temporal horn adjacent to the RT2 treatment volume; pathology from emergent resection revealed necrotic brain tissue. The patient recovered fully and lived another 18 months until dying of disease progression. No other patient developed symptomatic radionecrosis. Median overall survival from RT2 for all patients was 11 months (range, 3–20 months). CONCLUSION Re-irradiation can be performed with conventionally fractionated schemes. Given the low rate of symptomatic radionecrosis, the dose constraints described here are a starting point for future studies of conventionally fractionated re-irradiation.

Abstract PURPOSE To compare tumor progression based on clinical radiological assessment and on Response Assessment in Neuro-Oncology (RANO) criteria between GBM patients treated with proton radiotherapy (PT) vs. photon intensity modulated radiotherapy (IMRT). METHODS Eligible patients were enrolled on the described prospective phase II trial and had MR imaging at baseline and follow-up beyond 12 weeks from treatment completion. ‘Clinical’ progression was based on a radiology report of progression in combination with changes in treatment due to suspected disease progression. A single blinded observer applied RANO criteria to determine the RANO-based tumor progression. RESULTS Of 90 enrolled patients, 66 were evaluable, with median follow-up of 19.8 (Range: 3.2–65.1) months; median of 22.6 months for PT (n=25) vs. 18.9 months for IMRT (n=41). Median time to progression (TTP) was 7.9 months based on clinical progression criteria (8.1 months IMRT, 6.3 months PT) and 7.2 months (7.3 months IMRT, 5.7 months PT) by RANO criteria (p=ns for all). Median ‘clinical’ progression-free survival (PFS) was 8.7 (Range: 6.4–11.1) months; 8.9 months IMRT vs. 8.7 months PT (p=0.065). Median RANO PFS was 8.3 (range, 5.8–11.6) months: 8.3 months IMRT vs. 6.9 months PT (p=0.226). There were 14 discrepant cases: 3 had progression based on ‘clinical’ but not RANO criteria, and 11 had progression based on RANO but not ‘clinical’ criteria. CONCLUSION Based on this secondary analysis of a randomized trial of PT vs. IMRT for GBM, there was no difference in tumor progression relative to treatment technique used. There was no statistical difference in PFS noted between clinical and RANO-based assessments, but RANO criteria identified progression more often than clinical assessment, and TTP was shortened with the use of RANO criteria alone. Further development of tumor assessment tools that improve consistency and accuracy of determining tumor progression are needed to guide therapeutic trials in GBM.

AbstractPurpose/Objective(s)Bladder and prostate are unfavorable sites for rhabdomyosarcoma (B/P‐RMS), and represent a challenging location for radiotherapy.Materials/MethodsNineteen patients with B/P‐RMS were enrolled on a prospective registry protocol (2008‐2017) and treated with chemotherapy, proton beam therapy (PBT), and surgical resection (n = 8; 42%). Emphasis was given to treatment technique, disease‐related outcomes, and toxicity associated with PBT.ResultsThe majority of patients had bladder RMS (74%) of embryonal histology (95%), Group III (68%), and intermediate‐risk disease by Children's Oncology Group (COG) risk stratification (89%). Seven patients (37%) had primary tumors >5 cm in size. All patients were treated according to COG protocols. With a median follow‐up of 66.2 months, 5‐year overall survival (OS) and progression‐free survival (PFS) were 76%. Four patients (21%) experienced disease relapse, all presenting with local failure. The 5‐year local control (LC) rate was 76%. Tumor size predicted LC, with 5‐year LC for patients with >5 cm tumors being 43% versus 100% for those with ≤5 cm tumors (P = .006). Univariate analysis demonstrated an effect of tumor size on OS (tumor >5 cm, hazard ratio [HR] 17.7, P = .049) and PFS (HR 17.7, P = .049). Acute grade 2 toxicity was observed in two patients (11%, transient proctitis). Late grade 2+ toxicity was observed in three patients (16%; n = 1 grade 2 skeletal deformity; n = 3 transient grade 2 urinary incontinence; one patient experienced both).ConclusionsPBT for B/P‐RMS affords promising disease‐related outcomes with an acceptable toxicity profile. Higher local failure rates were observed for larger tumors, supporting dose‐escalation components of ongoing RMS clinical trials.

Abstract Purpose Proton therapy is currently used in the management of pediatric tumors to decrease late toxicities. However, one of the criticisms of proton therapy is the limited data regarding efficacy on disease control. The purpose of this study was to examine local and distant control rates after proton therapy for neuroblastoma. Methods and materials Eighteen patients with high‐risk ( n = 16) and locally recurrent neuroblastoma ( n = 2) were treated with curative intent and received proton therapy to the primary site and up to three post‐induction MIBG‐avid metastatic sites. Primary sites ( n = 18) were treated to 21–36 Gy (relative biological effectiveness [RBE]), and metastatic sites ( n = 16) were treated to 21–24 Gy (RBE). Local control and survival rates were calculated using the Kaplan–Meier method. Results With a median follow‐up of 60.2 months, two‐ and five‐year local control rates at the irradiated primary site were 94% and 87%, respectively. No failures at irradiated distant metastatic sites were observed. The five‐year progression‐free survival (PFS) was 64%, and the five‐year overall survival (OS) was 94%. The extent of surgical resection was not associated with local control, PFS, or OS. No radiation‐related nephropathy or hepatopathy was reported. Conclusions Excellent local control was achieved using proton therapy to the primary and post‐induction MIBG‐positive distant sites. The predominant site of failure is progression in post‐induction non‐MIBG‐avid distant sites. Although proton therapy provides high rates of local control with acceptable toxicity for neuroblastoma, further advances in systemic therapy are needed for the improved control of systemic disease.