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PURPOSE Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [ P = .049] and 16.4% v 33.3% [ P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue ( P = .04), less difficulty with remembering things ( P = .01), and less difficulty with speaking ( P = .049) and using imputed data, less interference of neurologic symptoms in daily activities ( P = .008) and fewer cognitive symptoms ( P = .01). CONCLUSION HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

Purpose To evaluate the effect of rituximab in limited-stage diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter phase II trial combining rituximab with three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) followed by involved-field radiation therapy (IFRT). Patients and Methods Southwest Oncology Group (SWOG) study S0014 enrolled patients with newly diagnosed, aggressive, CD20-expressing non-Hodgkin's lymphoma (NHL). Patients had limited-stage disease and at least one adverse risk factor as defined by the stage-modified International Prognostic Index (nonbulky stage II disease, age > 60 years, WHO performance status of 2, or elevated serum lactate dehydrogenase). Four doses of rituximab were infused on days −7, 1, 22, and 43, and CHOP was administered on days 3, 24, and 45, followed 3 weeks later by 40 to 46 Gy of IFRT. Results Sixty patients with aggressive NHL were eligible. With the median follow-up of 5.3 years, treatment resulted in a progression-free survival (PFS) of 93% at 2 years and 88% at 4 years. Overall survival (OS) was 95% at 2 years and 92% at 4 years. These results were compared with those from a historic group of patients treated without rituximab on S8736, demonstrating PFS of 78% and OS of 88% at 4 years. Conclusion In limited-stage DLBCL, the addition of rituximab to three cycles of CHOP plus IFRT met prespecified study criteria of efficacy, with 2-year PFS of at least 84%, meriting further investigation. There is a pattern of continuing relapse with modest survival gains. We hypothesize that such a pattern may be the result of biologic differences between limited- and advanced-stage lymphoma.

Purpose Efaproxiral (RSR13) reduces hemoglobin oxygen–binding affinity, facilitates oxygen release, and increases tissue pO2. We conducted a phase II multicenter study that assessed the efficacy and safety of efaproxiral when administered with thoracic radiation therapy (TRT), following induction chemotherapy, for treatment of locally advanced non–small-cell lung cancer (NSCLC). Patients and Methods Fifty-one patients with locally advanced NSCLC were enrolled at 13 sites. Treatment comprised two cycles of paclitaxel (225 mg/m2) and carboplatin (area under the curve, 6), 3 weeks apart, followed by TRT (64 Gy/32 fractions) with concurrent efaproxiral (50 to 100 mg/kg). Survival results were compared with results of study Radiation Therapy Oncology Group (RTOG) 94-10. Results Overall response rate was 75% (37 of 49 patients). Complete and partial response rates were 6% (three of 49 patients) and 69% (34 of 49 patients), respectively. Median survival time (MST) was 20.6 months (95% CI, 14.0 to 24.2); overall survival rates at 1- and 2-years were 67% and 37%, respectively. Survival results were compared with the sequential (S-CRT) and concurrent (C-CRT) chemoradiotherapy arms of RTOG 94-10. MSTs for cases matched by stage, Karnofsky performance status, and age were: RT-010, 20.6 months; S-CRT, 15.1 months; and C-CRT, 17.9 months. Grade 3 to 4 toxicities related to efaproxiral that occurred in more than one patient included transient hypoxemia (19%), radiation pneumonitis (11%), and fatigue (4%). Conclusion Addition of efaproxiral to S-CRT represents a promising approach in NSCLC treatment, and a randomized study should be pursued. The low incidence of grade 3 to 4 toxicities suggests that the use of efaproxiral instead of a cytotoxic agent, as a radiation sensitizer, may be advantageous.

Purpose: This phase II, open-label, multicenter study assessed the efficacy and safety of the potential radiation enhancer RSR13 plus cranial radiation therapy (RT) in patients with brain metastases. The primary end point was patient survival in comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database (RTOG RPA BMD). Patients and Methods: Eligibility criteria were age ≥ 18 years, Karnofsky performance score ≥ 70, and brain metastases with solid tumor histology. Patients received cranial RT, 30 Gy in 10 fractions of 3 Gy each, preceded by RSR13, 50 to 100 mg/kg intravenously over 30 minutes. Univariate and multivariate comparisons of survival and cause of death were made between class II study patients and RTOG BMD patients. Results: Fifty-seven RPA class II patients were enrolled. With a minimum follow-up of 24 months, the median survival time and 1- and 2-year survival rates were 6.4 months, 23%, and 11% for the RSR13-treated patients compared with 4.1 months, 15%, and 3% for the RTOG BMD patients (P = .0174). In an exact-matched case analysis (n = 38), median survival time for RSR13 patients was 7.3 months versus 3.4 months for the RTOG BMD patients (P = .006). There was a 54% reduction in the risk of death for RSR13 patients (P = .0267). RSR13-related adverse events of greater than or equal to grade 3 toxicity that occurred in more than one patient included hypoxia, headache, anemia, fatigue, hypertension, and intracranial hypertension. Conclusion: RSR13 plus cranial RT resulted in a significant improvement in survival, as well as a reduction in death due to brain metastases, compared with class II patients in the RTOG BMD.

2561 Background: Tumor hypoxia limits the response of glioblastoma multiforme (GBM) to radiotherapy (RT) and chemotherapy (temozolomide[TMZ]). Additionally, patient biomarkers are strong predictors of responsiveness to TMZ. The purpose of this study is to evaluate the use of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM and stratify the results based on predicted TMZ response. Methods: 11 adult GBM patients have been enrolled. Patients were administered DDFPe via IV infusion (2% w/vol at doses of 0.05, 0.1 or 0.17 mL/kg) an hour prior to each 2 Gy fraction of RT (30 fractions over 6-weeks) with supplemental oxygen. Patients also received standard concurrent and adjuvant TMZ. To confirm tumor re-oxygenation, patients underwent TOLD MRI before and after DDFPe administration. Archived tumor specimens were studied with GliomaSTRAT assay for methylated genes predictive of response. Patients were also studied with serial MRI scans per standard of care and followed for survival. Results: There were minimal acute adverse events related to DDFPe administration. One patient at each of dose levels 0.1 and 0.17 mL/kg developed symptomatic radiation necrosis, which was judged to be related to DDFPe. Enrollment has continued at the 0.1 mL/kg dose without additional significant DDFPe-related toxicity. TOLD MRI showed significant decrease in T1of tumor tissue consistent with tumor re-oxygenation (p=0.015) with no significant change in oxygenation of normal brain tissue. Historically, the average overall survival for GBM patients, for both TMZ responders and non-responders, is about 14.6 months. The progress chart for patient overall survival is listed below, 4 patients have died. All other patients are alive. Conclusions: DDFPe is a promising oxygen therapeutic for reversing tumor hypoxia. A Phase II study is being planned to assess its effectiveness. Clinical trial information: NCT02189109. [Table: see text]

TPS2107 Background: Tumor stem cells have been correlated with recurrence and clinical outcome in glioblastoma multiforme (GBM). ICT‑107 is an autologous vaccine consisting of the patient’s dendritic cells pulsed with 6 synthetic peptide CTL epitopes targeting the GBM tumor and tumor‑stem cell associated antigens MAGE‑1, HER‑2, AIM‑2, TRP‑2, gp100 and IL‑13Rα2. Phase I results showed a good safety profile and interesting clinical potential (ASCO, 2010, abs#2097 and ASCO, 2011, abs#2042) in 16 newly diagnosed GBM patients with a median progression-free survival (PFS) of 16.9 months (measured from surgery) and a median overall survival (OS) of 38.4 months. Methods: In this Phase II study eligible patients have newly diagnosed GBM and complete surgical resection or minimum residual tumor < 1 cm3, are HLA-A1 and/or HLA-A2 positive, older than 18, have Karnofsky Performance Score (KPS) of ≥ 70% and have adequate hematologic and chemistry parameters. Patients with a serious immune or autoimmune disorder or other systemic disease are excluded. Patients undergo apheresis to isolate peripheral blood mononuclear cells (PBMCs) to be used for preparation of study treatment (ICT‑107 and Control). Pre-study treatment consists of 6 weeks of concurrent temozolomide (TMZ) and radiation. After stratification by site and age, patients are randomized 2:1 to receive either ICT-107 or its matching control (autologous, unpulsed dendritic cells). Patients then receive induction ICT-107 or control once a week for four weeks. All patients subsequently receive maintenance TMZ for 5 days per month for 12 months. Booster vaccinations occur at Cycles 1, 3, 6 and 10, and every six months thereafter. The primary endpoint is OS and secondary endpoints include PFS, rates of OS and PFS at 6 months after surgery and every 3 months thereafter, safety and tolerability of ICT‑107, immune response to ICT-107 and predictors of response. 120 patients have been enrolled in this ongoing trial. It is expected that approximately 200 patients will be enrolled for screening with the intention to randomize at least 102 patients. The trial significance is alpha=0.025 one-sided.

590 Background: The multimodal approach of IBC resulted in improved survival but the IBC still remains the most aggressive form of breast cancer. The endpoints of the study were to a) evaluate the efficacy and safety of primary chemotherapy (EN), b) evaluate a better chemotherapy sequence (primary and adjuvant), and c) analyze the predictive value and changes of some biomarkers (ER, PR, Ki67 and HER2 status) in IBC. Methods: From 4/2002 to 10/2007, 56 patients with IBC entered the study. The molecular markers were obtained from tumor specimens before chemotherapy by biopsy and surgery after. After diagnosis the pts were randomized to the following sequence: EN (E 120 mg/m2 d 1 plus N 25 mg/m2 d 1 & 8) x 4 cycles -> surgery or radiotherapy -> adjuvant TXT (100 mg/m2) x 4 cycles (Group A) or EN x 4 cycles (Group B), all regimens q 3 wks. After adjuvant therapy all pts received RT and endocrine therapy in ER/PgR+ tumors. From 6/2006 the pts with HER2+ status also received trastuzumab adjuvant x 1 yr. The cha...

1561 Background: 538 patients with brain metastases from selected solid tumors were randomized in a study of standard WBRT (30 Gy in 10 fractions) and supplemental oxygen with or without the radiation sensitizer RSR13 (efaproxiral) (Control n=267, RSR13 n=271). A non-significant improvement in MST was seen in favor of the RSR13 arm when results were analyzed by undajusted log-rank. The study showed a survival advantage for RSR13-treated patients versus controls after adjusting for imbalances in prognostic factors (Cox multiple regression) with the patients with breast cancer deriving the largest benefit from RSR13. Since a clear PK/Pharmacodynamic (PK = RSR13 concentration in RBCs and Pharmacodynamic = p50 shift) correlation had been established for RSR13 in previous studies, PK analyses were incorporated in the design of the present study. Methods: Blood samples were drawn for RSR13 PK analyses on Day 1 of RSR13 and at least once during the second week of RSR13 therapy. 188 patients had at least 2 PK det...

1534 Background: Brain metastases represent a common cause of morbidity and mortality among cancer pts. The effectiveness of WBRT as primary therapy for brain metastases is limited by tissue hypoxi...