Perioperative Neurocognitive Function in Glioma Surgery.

PURPOSE OF REVIEW: This review provides a concise overview of the recent literature regarding preoperative and postoperative neurocognitive functioning (NCF) in patients with glioma. Brief discussion also covers contemporary intraoperative brain mapping work, with a focus on potential influence of mapping upon NCF outcomes following awake surgery. RECENT FINDINGS: Most patients with glioma exhibit preoperative NCF impairment, with severity varying by germ line and tumoral genetics, tumor grade, and lesion location, among other characteristics. Literature regarding postoperative NCF changes is mixed, though numerous studies indicate a majority of patients exhibit immediate and short-term worsening. This is often followed by recovery over several months; however, a substantial portion of patients harbor persisting declines. Decline appears related to surgically-induced structural and functional brain alterations, both local and distal to the tumor and resection cavity. Importantly, NCF decline may be mitigated to some extent by intraoperative brain mapping, including mapping of both language-mediated and nonverbal functions. Research regarding perioperative NCF in patients with glioma has flourished over recent years. While this has increased our understanding of contributors to NCF and risk of decline associated with surgical intervention, more work is needed to better preserve NCF throughout the disease course.

Intraoperative language mapping guided by real-time visualization of gamma band modulation electrocorticograms: Case report and proof of concept.

Background: Electrocorticography (ECoG) language mapping is often performed extraoperatively, frequently involves offline processing, and relationships with direct cortical stimulation (DCS) remain variable. We sought to determine the feasibility and preliminary utility of an intraoperative language mapping approach guided by real-time visualization of electrocorticograms. Methods: A patient with astrocytoma underwent awake craniotomy with intraoperative language mapping, utilizing a dual iPad stimulus presentation system coupled to a real-time neural signal processing platform capable of both ECoG recording and delivery of DCS. Gamma band modulations in response to 4 language tasks at each electrode were visualized in real-time. Next, DCS was conducted for each neighboring electrode pair during language tasks. Results: All language tasks resulted in strongest heat map activation at an electrode pair in the anterior to mid superior temporal gyrus. Consistent speech arrest during DCS was observed for Object and Action naming tasks at these same electrodes, indicating good correspondence with ECoG heat map recordings. This region corresponded well with posterior language representation via preoperative functional MRI. Conclusions: Intraoperative real-time visualization of language task-based ECoG gamma band modulation is feasible and may help identify targets for DCS. If validated, this may improve the efficiency and accuracy of intraoperative language mapping.

Decoding the clinical effects of low-grade glioma-induced cortical excitability.

OBJECTIVE: Patients with low-grade glioma (LGG) in eloquent regions often present with seizures, and findings on detailed neuropsychological testing are often abnormal. This study evaluated the association between cortical excitability, seizures, and cognitive function in patients with LGG. METHODS: LGG patients who underwent transcranial magnetic stimulation (TMS) from January 2021 to December 2022 were studied. Cortical excitability was measured using the resting motor thresholds (RMTs) of the upper and lower extremities. Early postoperative seizures served as the seizure endpoint. Neuropsychological assessment was completed prior to surgery contemporaneous with the TMS studies. RESULTS: A total of 31 patients were analyzed for seizure outcome. Median (interquartile range [IQR]) upper-extremity RMT was 39% (34%-46%) of maximum stimulator output, and the median (IQR) lower-extremity RMT was 69% (51%-79%). Lower-extremity RMT was higher in patients with early postoperative seizures, especially in those with motor region tumors (p = 0.02); however, RMT was not associated with seizures at presentation or long-term seizure control. A total of 26 patients completed neuropsychological assessment. There were significant negative correlations between upper-extremity RMT and psychomotor processing speed (Wechsler Adult Intelligence Scale-Fourth Edition [WAIS-IV] Processing Speed Index r = -0.42, p = 0.031; WAIS-IV Coding r = -0.41, p = 0.036; WAIS-IV Symbol Search r = -0.39, p = 0.048), executive function (Trail Making Test Part B r = -0.41, p = 0.036), and hand dexterity (Grooved Pegboard Test r = -0.50, p = 0.047). CONCLUSIONS: RMT was positively correlated with early postoperative seizure risk and negatively correlated with psychomotor processing speed, executive function, and hand dexterity. These findings support the theory of local and regional resting oscillatory network dysfunction from a glioma-brain network.

Treatment-Related Cognitive Impairment in Patients with Prostate Cancer: Patients' Real-World Insights for Optimizing Outcomes.

Cognitive impairment (CI) is an issue that needs to be at the forefront of unmet healthcare needs in patients with prostate cancer (PCa) as it can negatively impact quality of life during long-term care. CI in patients with prostate cancer is thought to be influenced by treatment, androgen deprivation therapy (ADT), and novel androgen receptor (AR) pathway inhibitors in particular; however, current understanding is limited on how treatment affects cognition. Additionally, the experience of patients with CI who are receiving PCa treatment is not well understood or represented in clinical literature, which is a barrier to optimal patient outcomes in managing prostate cancer treatment-related cognitive impairment (PCa-TRCI). To help understand the patient journey and elucidate management gaps in PCa-TRCI, an international roundtable of healthcare provider and patient panelists was convened. The panelists focused on four key topic areas: (1) the patient experience when afflicted with, or at risk of, PCa-TRCI, (2) the physical, emotional, and social impact of CI on patients' quality of life (QoL), (3) the challenges that patients with PCa-TRCI face, and their impact on clinical decision-making, and (4) ways in which managing PCa-TRCI should evolve to improve patient outcomes. The purpose of the roundtable was to include patients in a direct discussion with healthcare providers (HCPs) regarding the patient journey and highlight real-world evidence of areas where patient outcomes could be improved in the absence of clinical evidence. The resulting discussion highlighted important healthcare gaps for patients with, and at risk of, PCa-TRCI and offered potential solutions as a roadmap to effective medicine.

Impact of Apolipoprotein E Genotype on Neurocognitive Function in Patients With Brain Metastases: An Analysis of NRG Oncology's RTOG 0614.

PURPOSE: Whole-brain radiation therapy (WBRT) is a common treatment for brain metastases and is frequently associated with decline in neurocognitive functioning (NCF). The e4 allele of the apolipoprotein E (APOE) gene is associated with increased risk of Alzheimer disease and NCF decline associated with a variety of neurologic diseases and insults. APOE carrier status has not been evaluated as a risk factor for onset time or extent of NCF impairment in patients with brain metastases treated with WBRT. METHODS AND MATERIALS: NRG/Radiation Therapy Oncology Group 0614 treated adult patients with brain metastases with 37.5 Gy of WBRT (+/- memantine), performed longitudinal NCF testing, and included an optional blood draw for APOE analysis. NCF test results were compared at baseline and over time with mixed-effects models. A cause-specific Cox model for time to NCF failure was performed to assess the effects of treatment arm and APOE carrier status. RESULTS: APOE results were available for 45% of patients (n = 227/508). NCF did not differ by APOE e4 carrier status at baseline. Mixed-effects modeling showed that APOE e4 carriers had worse memory after WBRT compared with APOE e4 noncarriers (Hopkins Verbal Learning Test-Revised total recall [least square mean difference, 0.63; P = .0074], delayed recognition [least square mean difference, 0.75; P = .023]). However, APOE e4 carrier status was not associated with time to NCF failure (hazard ratio, 0.86; 95% CI, 0.60-1.23; P = .40). Memantine delayed the time to NCF failure, regardless of carrier status (hazard ratio, 0.72; 95% CI, 0.52-1.01; P = .054). CONCLUSIONS: APOE e4 carriers with brain metastases exhibited greater decline in learning and memory, executive function, and the Clinical Trial Battery Composite score after treatment with WBRT (+/- memantine), without acceleration of onset of difference in time to NCF failure.

Phase I dose-escalation study of procaspase-activating compound-1 in combination with temozolomide in patients with recurrent high-grade astrocytomas.

Background: Procaspase-3 (PC-3) is overexpressed in various tumor types, including gliomas. Targeted PC-3 activation combined with chemotherapy is a novel strategy for treating patients with high-grade gliomas, with promising preclinical activity. This study aimed to define safety and tolerability of procaspase-activating compound-1 (PAC-1) in combination with temozolomide (TMZ) for patients with recurrent high-grade astrocytomas. Methods: A modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered at increasing dose levels (DL; DL1 = 375 mg) on days 1-21, in combination with TMZ 150 mg/m2/5 days, per 28-day cycle. Dose-limiting toxicity was assessed during the first 2 cycles. Neurocognitive function (NCF) testing was conducted throughout the study. Results: Eighteen patients were enrolled (13 GBM, IDH-wild type; 2 astrocytoma, IDH-mutant, grade 3; 3 astrocytoma, IDH-mutant, grade 4). Dose escalation was discontinued after DL3 (ie, PAC-1, 625 mg) due to lack of additional funding. Grade 3 toxicity was observed in 1 patient at DL1 (elevated liver transaminases) and 1 at DL 2 (headache). Two partial responses were observed at DL1 in patients with GBM, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated. Two patients had stable disease, and 11 experienced progression. NCF testing did not show a clear relationship between PAC-1 dose, treatment duration, and declines in NCF. Conclusions: Combination of PAC-1 and TMZ was well tolerated up to 625 mg orally daily and TMZ orally 150 mg/m2/5 days per 28-day cycle. The maximum tolerated dose was not reached. Further dose escalation of PAC-1 in combination with TMZ is advised before conducting a formal prospective efficacy study in this patient population.

Nivolumab and ipilimumab with concurrent stereotactic radiosurgery for intracranial metastases from non-small cell lung cancer: analysis of the safety cohort for non-randomized, open-label, phase I/II trial.

BACKGROUND: Up to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without surgery. There are no prospective data on the safety of stereotactic radiosurgery (SRS) concurrent with immune checkpoint inhibitor therapy for BM. This is the safety cohort of the phase I/II investigator-initiated trial of SRS with nivolumab and ipilimumab for patients with BM from NSCLC. PATIENTS AND METHODS: This single-institution study included patients with NSCLC with active BM amenable to SRS. Brain SRS and systemic therapy with nivolumab and ipilimumab were delivered concurrently (within 7 days). The endpoints were safety and 4-month intracranial progression-free survival (PFS). RESULTS: Thirteen patients were enrolled in the safety cohort, 10 of whom were evaluable for dose-limiting toxicities (DLTs). Median follow-up was 23 months (range 9.7-24.3 months). The median interval between systemic therapy and radiation therapy was 3 days. Only one patient had a DLT; hence, predefined stopping criteria were not met. In addition to the patient with DLT, three patients had treatment-related grade ≥3 adverse events, including elevated liver function tests, fatigue, nausea, adrenal insufficiency, and myocarditis. One patient had a confirmed influenza infection 7 months after initiation of protocol treatment (outside the DLT assessment window), leading to pneumonia and subsequent death from hemophagocytic lymphohistiocytosis. The estimated 4-month intracranial PFS rate was 70.7%. CONCLUSION: Concurrent brain SRS with nivolumab/ipilimumab was safe for patients with active NSCLC BM. Preliminary analyses of treatment efficacy were encouraging for intracranial treatment response.

Sustained Preservation of Cognition and Prevention of Patient-Reported Symptoms With Hippocampal Avoidance During Whole-Brain Radiation Therapy for Brain Metastases: Final Results of NRG Oncology CC001.

PURPOSE: Initial report of NRG Oncology CC001, a phase 3 trial of whole-brain radiation therapy plus memantine (WBRT + memantine) with or without hippocampal avoidance (HA), demonstrated neuroprotective effects of HA with a median follow-up of fewer than 8 months. Herein, we report the final results with complete cognition, patient-reported outcomes, and longer-term follow-up exceeding 1 year. METHODS AND MATERIALS: Adult patients with brain metastases were randomized to HA-WBRT + memantine or WBRT + memantine. The primary endpoint was time to cognitive function failure, defined as decline using the reliable change index on the Hopkins Verbal Learning Test-Revised (HVLT-R), Controlled Oral Word Association, or the Trail Making Tests (TMT) A and B. Patient-reported symptom burden was assessed using the MD Anderson Symptom Inventory with Brain Tumor Module and EQ-5D-5L. RESULTS: Between July 2015 and March 2018, 518 patients were randomized. The median follow-up for living patients was 12.1 months. The addition of HA to WBRT + memantine prevented cognitive failure (adjusted hazard ratio, 0.74, P = .016) and was associated with less deterioration in TMT-B at 4 months (P = .012) and HVLT-R recognition at 4 (P = .055) and 6 months (P = .011). Longitudinal modeling of imputed data showed better preservation of all HVLT-R domains (P < .005). Patients who received HA-WBRT + Memantine reported less symptom burden at 6 (P < .001 using imputed data) and 12 months (P = .026 using complete-case data; P < .001 using imputed data), less symptom interference at 6 (P = .003 using complete-case data; P = .0016 using imputed data) and 12 months (P = .0027 using complete-case data; P = .0014 using imputed data), and fewer cognitive symptoms over time (P = .043 using imputed data). Treatment arms did not differ significantly in overall survival, intracranial progression-free survival, or toxicity. CONCLUSIONS: With median follow-up exceeding 1 year, HA during WBRT + memantine for brain metastases leads to sustained preservation of cognitive function and continued prevention of patient-reported neurologic symptoms, symptom interference, and cognitive symptoms with no difference in survival or toxicity.

Characterization of recurrence patterns and outcomes of medulloblastoma in adults: The University of Texas MD Anderson Cancer Center experience.

Background: Medulloblastoma in adults is rare and treatment decisions are largely driven from pediatric literature. We sought to characterize recurrent medulloblastoma in adults. Methods: From a single-institution dataset of 200 adult patients diagnosed with medulloblastoma during 1978-2017, those with recurrence were analyzed for clinical features, treatment, and outcome. Results: Of the 200 patients, 82 (41%) with median age of 29 years (18-59) had recurrence after a median follow-up time of 8.4 years (95% CI = 7.1, 10.3). Of these, 30 (37%) were standard-risk, 31 (38%) were high-risk, and 21 (26%) had unknown-risk diseases at the time of initial diagnosis. Forty-eight (58%) presented with recurrence outside the posterior fossa, of whom 35 (43%) had distant recurrence only. Median Progression-free survival (PFS) and OS from initial surgery were 33.5 and 62.4 months, respectively. Neither PFS nor OS from initial diagnosis differed between the standard-risk and high-risk groups in those who experience recurrence (P = .505 and .463, respectively). Median OS from first recurrence was 20.3 months, also with no difference between the standard-risk and high-risk groups (P = .518). Recurrences were treated with combinations of re-resection (20 patients; 25%), systemic chemotherapy (61 patients; 76%), radiation (29 patients; 36%), stem cell transplant (6 patients; 8%), and intrathecal chemotherapy (4 patients; 5%). Patients who received radiation at recurrence had better OS (32.9 months) than those who did not (19.2 months) (P = .034). Conclusions: Recurrent medulloblastoma in adults has a poor prognosis irrespective of initial risk stratification. Recurrence commonly arises outside the posterior fossa years after initial diagnosis.

Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial.

BACKGROUND: Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody-drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs. METHODS: In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. RESULTS: There were 639 randomized patients (median age 60, range 22-84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82-1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70-1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56-0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61-0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3-4), causing 12% to discontinue. CONCLUSIONS: Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.

Functional impact of androgen-targeted therapy on patients with castration-resistant prostate cancer.

Context: Second-generation androgen receptor inhibitors (ARIs) extend metastasis-free survival, prolong overall survival, and delay symptoms when added to androgen deprivation therapy for the treatment of castration-sensitive or castration-resistant prostate cancer (CRPC). However, ARIs may adversely impact physical and cognitive function, thereby decreasing quality of life and prognosis. Objective: To evaluate the evidence regarding the potential effects of ARIs on physical and cognitive function and to contextualize how drug-related adverse effects may influence treatment decisions in CRPC. Evidence acquisition: We performed a literature search using MEDLINE from January 1998 to June 2020 using terms relating to prostate cancer, androgen deprivation, and physical and cognitive function. We selected 61 publications for analysis. Evidence synthesis: Treatment-induced deterioration in physical and cognitive function may impair the independence and well-being of patients with CRPC. Patient-reported outcomes from clinical trials of ARIs provide quantitative evidence of their impact on these domains, which appears to vary between ARIs, reflecting the different adverse event profiles of these agents. Thus, the risk of physical or cognitive dysfunction may be managed or mitigated by appropriate selection of treatment options. Studies in patients with CRPC have assessed the cognitive effects of ARIs with validated instruments, whereas quantitative analysis of the impact on physical function has been limited. Conclusion: Several validated instruments utilized for the assessment of physical and cognitive function in clinical studies have been adapted for clinical practice; however, consensus on the standardization of these assessments is required. Future clinical studies employing validated tools may generate data on the impact of ARIs and guide treatment decisions for patients with CRPC. Patient summary: We review the hormonal therapies used to treat men with prostate cancer and the effects they have on physical and cognitive function. We discuss how to measure these effects and how this may assist when choosing treatment.

Perioperative considerations in patients with chemotherapy-induced cognitive impairment: a narrative review.

Patients with cancer may suffer from a decline in their cognitive function after various cancer therapies, including surgery, radiation, and chemotherapy, and in some cases, this decline in cognitive function persists even years after completion of treatment. Chemobrain or chemotherapy-induced cognitive impairment, a well-established clinical syndrome, has become an increasing concern as the number of successfully treated cancer patients has increased significantly. Chemotherapy-induced cognitive impairment can originate from direct neurotoxicity, neuroinflammation, and oxidative stress, resulting in alterations in grey matter volume, white matter integrity, and brain connectivity. Surgery has been associated with exacerbating the inflammatory response associated with chemotherapy and predisposes patients to develop postoperative cognitive dysfunction. As the proportion of patients living longer after these therapies increases, the magnitude of impact and growing concern of post-treatment cognitive dysfunction in these patients has also come to the fore. We review the clinical presentation, potential mechanisms, predisposing factors, diagnostic methods, neuropsychological testing, and imaging findings of chemotherapy-induced cognitive impairment and its intersection with postoperative cognitive dysfunction.

The Cognitive Effects of Radiotherapy for Brain Metastases.

Brain metastases are the most common intracranial neoplasm and are seen in upwards of 10-30% of patients with cancer. For decades, whole brain radiation therapy (WBRT) was the mainstay of treatment in these patients. While WBRT is associated with excellent rates of intracranial tumor control, studies have demonstrated a lack of survival benefit, and WBRT is associated with higher rates of cognitive deterioration and detrimental effects on quality of life. In recent years, strategies to mitigate this risk, such as the incorporation of memantine and hippocampal avoidance have been employed with improved results. Furthermore, stereotactic radiosurgery (SRS) has emerged as an appealing treatment option over the last decade in the management of brain metastases and is associated with superior cognitive preservation and quality of life when compared to WBRT. This review article evaluates the pathogenesis and impact of cranial irradiation on cognition in patients with brain metastases, as well as current and future risk mitigation techniques.

Assessment and Management of Cognitive Function in Patients with Prostate Cancer Treated with Second-Generation Androgen Receptor Pathway Inhibitors.

Preservation of cognitive function is an important outcome in oncology. Optimal patient management requires an understanding of cognitive effects of the disease and its treatment and an efficacious approach to assessment and management of cognitive dysfunction, including selection of treatments to minimize the risk of cognitive impairment. Awareness is increasing of the potentially detrimental effects of cancer-related cognitive dysfunction on functional independence and quality of life. Prostate cancer occurs most often in older men, who are more likely to develop cognitive dysfunction than younger individuals; this population may be particularly vulnerable to treatment-related cognitive disorders. Prompt identification of treatment-induced cognitive dysfunction is a crucial aspect of effective cancer management. We review the potential etiologies of cognitive decline in patients with prostate cancer, including the potential role of androgen receptor pathway inhibitors; commonly used tools for assessing cognitive function validated in metastatic castration-resistant prostate cancer and adopted in non-metastatic castration-resistant prostate cancer trials; and strategies for management of cognitive symptoms. Many methods are currently used to assess cognitive function. The prevalence and severity of cognitive dysfunction vary according to the instruments and criteria applied. Consensus on the definition of cognitive dysfunction and on the most appropriate approaches to quantify its extent and progression in patients treated for prostate cancer is lacking. Evidence-based guidance on the appropriate tools and time to assess cognitive function in patients with prostate cancer is required.

The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): an international, multicentre, randomised phase 3 trial.

BACKGROUND: In men with a detectable prostate-specific antigen (PSA) level after prostatectomy for prostate cancer, salvage prostate bed radiotherapy (PBRT) results in about 70% of patients being free of progression at 5 years. A three-group randomised trial was designed to determine whether incremental gains in patient outcomes can be achieved by adding either 4-6 months of short-term androgen deprivation therapy (ADT) to PBRT, or both short-term ADT and pelvic lymph node radiotherapy (PLNRT) to PBRT. METHODS: The international, multicentre, randomised, controlled SPPORT trial was done at 283 radiation oncology cancer treatment centres in the USA, Canada, and Israel. Eligible patients (aged ≥18 years) were those who after prostatectomy for adenocarcinoma of the prostate had a persistently detectable or an initially undetectable and rising PSA of between 0·1 and 2·0 ng/mL. Patients with and without lymphadenectomy (N0/Nx) were eligible if there was no clinical or pathological evidence of lymph node involvement. Other eligibility criteria included pT2 or pT3 disease, prostatectomy Gleason score of 9 or less, and a Zubrod performance status of 0-1. Eligible patients were randomly assigned to receive PBRT alone at a dose of 64·8-70·2 Gy at 1·8 Gy per fraction daily (group 1), PBRT plus short-term ADT (group 2), or PLNRT (45 Gy at 1·8 Gy per fraction, and then a volume reduction made to the planning target volume for the remaining 19·8-25 ·2 Gy) plus PBRT plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A planned interim analysis of 1191 patents with minimum potential follow-up time of 5 years applied a Haybittle-Peto boundary of p<0·001 (one sided) for comparison of 5-year freedom from progression rates between the treatment groups. This trial is registered with ClinicalTrials.gov, NCT00567580. The primary objectives of the trial have been completed, although long-term follow-up is continuing. FINDINGS: Between March 31, 2008, and March 30, 2015, 1792 eligible patients were enrolled and randomly assigned to the three treatment groups (592 to group 1 [PBRT alone], 602 to group 2 [PBRT plus short-term ADT], and 598 to group 3 [PLNRT plus PBRT plus short-term ADT]). 76 patients subsequently found to be ineligible were excluded from the analyses; thus, the evaluable patient population comprised 1716 patients. At the interim analysis (n=1191 patients; data cutoff May 23, 2018), the Haybittle-Peto boundary for 5-year freedom from progression was exceeded when group 1 was compared with group 3 (difference 17·9%, SE 2·9%; p<0·0001). The difference between groups 2 and 3 did not exceed the boundary (p=0·0063). With additional follow-up beyond the interim analysis (the final planned analysis; data cutoff May 26, 2021), at a median follow-up among survivors of 8·2 years (IQR 6·6-9·4), the 5-year freedom from progression rates in all 1716 eligible patients were 70·9% (95% CI 67·0-74·9) in group 1, 81·3% (78·0-84·6) in group 2, and 87·4% (84·7-90·2) in group 3. Per protocol criteria, freedom from progression in group 3 was superior to groups 1 and 2. Acute (≤3 months after radiotherapy) grade 2 or worse adverse events were significantly more common in group 3 (246 [44%] of 563 patients) than in group 2 (201 [36%] of 563; p=0·0034), which, in turn, were more common than in group 1 (98 [18%] of 547; p<0·0001). Similar findings were observed for grade 3 or worse adverse events. However, late toxicity (>3 months after radiotherapy) did not differ significantly between the groups, apart from more late grade 2 or worse blood or bone marrow events in group 3 versus group 2 (one-sided p=0·0060) attributable to the addition of PLNRT in this group. INTERPRETATION: The results of this randomised trial establish the benefit of adding short-term ADT to PBRT to prevent progression in prostate cancer. To our knowledge, these are the first such findings to show that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term ADT results in meaningful reductions in progression after prostatectomy in patients with prostate cancer. FUNDING: National Cancer Institute.

Cognitive adverse effects of chemotherapy and immunotherapy: are interventions within reach?

One in three people will be diagnosed with cancer during their lifetime. The community of cancer patients is growing, and several common cancers are becoming increasingly chronic; thus, cancer survivorship is an important part of health care. A large body of research indicates that cancer and cancer therapies are associated with cognitive impairment. This research has mainly concentrated on chemotherapy-associated cognitive impairment but, with the arrival of immunotherapies, the focus is expected to widen and the number of studies investigating the potential cognitive effects of these new therapies is rising. Meanwhile, patients with cognitive impairment and their healthcare providers are eagerly awaiting effective approaches to intervene against the cognitive effects of cancer treatment. In this Review, we take stock of the progress that has been made and discuss the steps that need to be taken to accelerate research into the biology underlying cognitive decline following chemotherapy and immunotherapy and to develop restorative and preventive interventions. We also provide recommendations to clinicians on how to best help patients who are currently experiencing cognitive impairment.

Neurocognition and Health-Related Quality of Life Among Patients with Brain Tumors.

Patients with brain tumors experience great symptom burden across various domains of functioning, with associated decreases in health-related quality of life and general well-being. Impaired neurocognitive functioning is among the primary concerns of these patients. Unfortunately, most patients will experience such impairment at some point in the disease. However, impaired neurocognitive functioning, symptom burden, and well-being vary according numerous patient-, tumor-, and treatment-related factors. Recent work has furthered our understanding of these contributors to patient functioning and health-related quality of life and also points to various potential targets for prevention and intervention strategies, though more efficacious treatments remain needed.