NRG/RTOG 1122: A phase 2, double-blinded, placebo-controlled study of bevacizumab with and without trebananib in patients with recurrent glioblastoma or gliosarcoma.

BACKGROUND: Targeting vascular endothelial growth factor (VEGF) alone does not improve overall survival (OS) in recurrent glioblastoma (rGBM). The angiopoiein (Ang)-TIE2 system may play a role in tumor survival under VEGF inhibition. We conducted a phase 2, double-blinded, placebo-controlled trial of bevacizumab plus trebananib (a novel Fc fusion protein that sequesters Ang1/Ang2) over bevacizumab alone in rGBM. METHODS: Patients ≥18 years of age with a Karnofsky performance status ≥70 and GBM or variants in first or second relapse were randomized to bevacizumab 10 mg/kg every 2 weeks plus trebananib 15 mg/kg every week or bevacizumab plus placebo. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: After an initial 6-patient lead-in cohort confirmed the safety of combining bevacizumab and trebananib, 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). In the control arm, 6-month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4-14.2 months), median PFS was 4.8 months (95% CI, 3.8-7.1 months), and radiographic response (RR) was 5.9%. In the experimental arm, 6-month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8-10.1 months), median PFS was 4.2 months (95% CI, 3.7-5.6 months), and RR was 4.2%. The rate of severe toxicities was not significantly different between arms. CONCLUSION: The combination of bevacizumab and trebananib was well tolerated but did not significantly improve 6-month PFS rate, PFS, or OS for patients with rGBM over bevacizumab alone. The shorter PFS in the experimental arm with a hazard ratio of 1.51 (P = .04) suggests that the addition of trebananib to bevacizumab is detrimental.

Outcomes after stereotactic radiosurgery for CNS lymphoma.

BACKGROUND: The standard of care for CNS lymphoma typically includes high dose methotrexate followed by whole brain radiation therapy, but there is an increased risk of neurotoxicity with this regimen. In our institution, we offered stereotactic radiosurgery (SRS) for disease refractory to HD-MTX in a subset of patients. A search of the literature on this modality for CNS lymphoma was also conducted. METHODS: Medical records of six patients who received partial brain radiation therapy for persistent CNS lymphoma were reviewed. SRS was given via 1-3 fractions to doses of 21 or 24 Gy. PubMed, SCOPUS, and Cochrane Library databases were systematically searched for articles reporting on outcomes for CNS lymphoma treated with SRS. RESULTS: Six patients (eleven lesions) were treated with SRS for CNS lymphomas. Median follow up was 15.6 months (range 3.3-37.8). Median RT dose per lesion was 21 Gy and median time to progression was 12.7 months. Median overall survival was not reached. Four patients had distant intracranial failure with two developing local recurrence. The search strategy yielded 16 studies of which only one was prospective and included a control group. 183 out of 256 evaluated lesions (69%) responded completely to treatment and 13 of 204 patients (6%) recurred within the treatment area at last follow-up. Overall, the treatment was well tolerated. CONCLUSION: SRS may provide favorable local control in patients with refractory CNS lymphomas. A prospective trial is warranted to validate the efficacy of such an approach.

First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

Bevacizumab and re-irradiation for recurrent high grade gliomas: does sequence matter?

PURPOSE/OBJECTIVES: We report the outcomes of the largest cohort to date of patients receiving both bevacizumab (BEV) and fractionated stereotactic radiotherapy (FSRT) for progressive or recurrent high grade glioma (HGG). Furthermore, the sequence of these two treatment regimens was analyzed to determine an optimal treatment paradigm for recurrent HGG. MATERIALS/METHODS: After Institutional Review Board approval, patients with pathologically confirmed WHO grade III anaplastic astrocytoma (AA) or IV glioblastoma multiforme (GBM) glioma who subsequently underwent re-irradiation at recurrence with FSRT were retrospectively reviewed. Patients from this group who had received BEV were also identified. Survival from initial diagnosis, as well as from recurrence and re-irradiation, were analyzed as study endpoints. Date of recurrence was defined as the date of radiographic evidence of progressive/recurrent disease. Kaplan-Meier curves were generated utilizing a log-rank test with a p-value ≤ 0.05 considered significant to compare treatment sequences in terms of survival outcomes. RESULTS: A total of 118 patients with recurrent/progressive HGG (GBM = 87, AA = 31) had received both BEV and FSRT. Patient characteristics were as follows: median KPS at recurrence was 80 (range 50-100); median age at recurrence was 57 years; median time to radiographic recurrence/progression was 10.8 months (mo) and 33.1% of patients had surgery for recurrence. The median time from the start of BEV to FSRT was 6.4 months and from FSRT to the start of BEV was 5.1 months. For the entire cohort, median overall survival (OS) was 26.7 months and median survival time (MST) from recurrence was 13.8 months (24.4 months and 11.9 months for GBM only). In patients that received BEV prior to FSRT (n = 50), median OS and MST from recurrence were 25.2 and 13.3 months respectively. In patients receiving FSRT first (n = 56), median OS and MST from recurrence were 28.8 months and 13.9 months, respectively. Sequencing of BEV and FSRT at recurrence was not significantly associated with OS (p = 0.08) or median survival from recurrence (p = 0.75). CONCLUSIONS: The combination of FSRT and BEV for recurrent/progressive HGG provides promising results in terms of overall survival and survival from recurrence. Combining these treatment modalities appears to improve upon the historic outcomes of either treatment alone. The outcomes data from this study support the ongoing RTOG trial exploring the combination of BEV and FSRT for recurrent HGG.

Correction to: Salvage fractionated stereotactic re-irradiation (FSRT) for patients with recurrent high grade gliomas progressed after bevacizumab treatment.

The fourth author's name was incorrect in the initial online publication. The original article has been corrected.

Salvage fractionated stereotactic re-irradiation (FSRT) for patients with recurrent high grade gliomas progressed after bevacizumab treatment.

Bevacizumab failure is a major clinical problem in the management of high grade gliomas (HGG), with a median overall survival (OS) of < 4 months. This study evaluated the feasibility and efficacy of fractionated stereotactic re-irradiation (FSRT) for patients progressed after Bevacizumab treatment. Retrospective review was conducted of 36 patients treated with FSRT after progression on bevacizumab. FSRT was most commonly delivered in 3.5 Gy fractions to a total dose of 35 Gy. Survival from initial diagnosis, as well as from recurrence and re-irradiation, were utilized as study endpoints. Univariate and multivariate analysis was performed. The median time from initial bevacizumab treatment to FSRT was 8.5 months. The median plan target volume for FSRT was 27.5 cc. The median OS from FSRT was 4.8 months. FSRT treatment was well tolerated with no grade 3 or higher toxicity. Favorable outcomes were observed in patients with recurrent HGG who received salvage FSRT after bevacizumab failure. The treatment was well tolerated. Prospective study is warranted to further evaluate the efficacy of salvage FSRT for selected patients with recurrent HGG amenable to FSRT, who had failed bevacizumab treatment.

Rethinking medulloblastoma from a targeted therapeutics perspective.

INTRODUCTION: Medulloblastoma is an aggressive but potentially curable central nervous system tumor that remains a treatment challenge. Analysis of therapeutic targets can provide opportunities for the selection of agents. METHODS: Using multiplatform analysis, 36 medulloblastomas were extensively profiled from 2009 to 2015. Immunohistochemistry, next generation sequencing, chromogenic in situ hybridization, and fluorescence in situ hybridization were used to identify overexpressed proteins, immune checkpoint expression, mutations, tumor mutational load, and gene amplifications. RESULTS: High expression of MRP1 (89%, 8/9 tumors), TUBB3 (86%, 18/21 tumors), PTEN (85%, 28/33 tumors), TOP2A (84%, 26/31 tumors), thymidylate synthase (TS; 80%, 24/30 tumors), RRM1 (71%, 15/21 tumors), and TOP1 (63%, 19/30 tumors) were found in medulloblastoma. TOP1 was found to be enriched in metastatic tumors (90%; 9/10) relative to posterior fossa cases (50%; 10/20) (p = 0.0485, Fisher exact test), and there was a positive correlation between TOP2A and TOP1 expression (p = 0.0472). PD-1 + T cell tumor infiltration was rare, PD-L1 tumor expression was uncommon, and TML was low, indicating that immune checkpoint inhibitors as a monotherapy should not necessarily be prioritized for therapeutic consideration based on biomarker expression. Gene amplifications such as those of Her2 or EGFR were not found. Several unique mutations were identified, but their rarity indicates large-scale screening efforts would be necessary to identify sufficient patients for clinical trial inclusion. CONCLUSIONS: Therapeutics are available for several of the frequently expressed targets, providing a justification for their consideration in the setting of medulloblastoma.

Multiplatform profiling of meningioma provides molecular insight and prioritization of drug targets for rational clinical trial design.

INTRODUCTION: Surgery and radiation therapy are the standard treatment options for meningiomas, but these treatments are not always feasible. Expression profiling was performed to determine the presence of therapeutic actionable biomarkers for prioritization and selection of agents. METHODS: Meningiomas (n = 115) were profiled using a variety of strategies including next-generation sequencing (592-gene panel: n = 14; 47-gene panel: n = 94), immunohistochemistry (n = 8-110), and fluorescent and chromogenic in situ hybridization (n = 5-70) to determine mutational and expression status. RESULTS: The median age of patients in the cohort was 60 years, with a range spanning 6-90 years; 52% were female. The most frequently expressed protein markers were EGFR (93%; n = 44), followed by PTEN (77%; n = 110), BCRP (75%; n = 8), MRP1 (65%, n = 23), PGP (62%; n = 84), and MGMT (55%; n = 97). The most frequent mutation among all meningioma grades occurred in the NF2 gene at 85% (11/13). Recurring mutations in SMO and AKT1 were also occasionally detected. PD-L1 was expressed in 25% of grade III cases (2/8) but not in grade I or II tumors. PD-1 + T cells were present in 46% (24/52) of meningiomas. TOP2A and thymidylate synthase expression increased with grade (I = 5%, II = 22%, III = 62% and I = 5%, II = 23%, III = 47%, respectively), whereas progesterone receptor expression decreased with grade (I = 79%, II = 41%, III = 29%). CONCLUSION: If predicated on tumor expression, our data suggest that therapeutics directed toward NF2 and TOP2A could be considered for most meningioma patients.

Phase I trial of panobinostat and fractionated stereotactic re-irradiation therapy for recurrent high grade gliomas.

Panobinostat is an oral HDAC inhibitor with radiosensitizing activity. We investigated the safety, tolerability and preliminary efficacy of panobinostat combined with fractionated stereotactic re-irradiation therapy (FSRT) for recurrent high grade gliomas. Patients with recurrent high grade gliomas were enrolled in a 3 + 3 dose escalation study to determine dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, tolerability, and preliminary efficacy. FSRT was prescribed to 30-35 Gy delivered in 10 fractions. Panobinostat was administrated concurrently with radiotherapy. Of 12 evaluable patients, 8 had recurrent GBM, and 4 had recurrent anaplastic astrocytoma. There were three grade 3 or higher toxicities in each the 10 and 30 mg cohorts. In the 30 mg cohort, there was one DLT; grade 4 neutropenia. One patient developed late grade 3 radionecrosis. The median follow up was 18.8 months. The PFS6 was 67, 33, and 83 % for 10, 20, and 30 mg cohorts, respectively. The median OS was 7.8, 6.1 and 16.1 months for the 10, 20 and 30 mg cohorts, respectively. Panobinostat administrated with FSRT is well tolerated at 30 mg. A phase II trial is warranted to assess the efficacy of panobinostat plus FSRT for recurrent glioma.

Re-resection for recurrent high-grade glioma in the setting of re-irradiation: more is not always better.

The optimal treatment for patients with recurrent high grade glioma (HGG) remains controversial. Available therapies include surgery, re-irradiation, alternating electric fields or systemic therapy. Here we investigate whether re-resection will improve survival in patients receiving repeat radiotherapy for tumor recurrence. 231 consecutive patients with recurrent HGG treated with re-irradiation between 1994 and 2012 were analyzed. 105 patients underwent re-resection. Re-irradiation was delivered using daily fractions of 3.5 Gy to a median total dose of 35 Gy. Survival was then analyzed comparing patients with and without re-resection. Overall survival (OS) and survival from the first recurrence are reported. Univariate and cox-proportional hazard modeling was performed in a step-wise multivariate analysis using known prognostic factors. The median follow-up time from initial diagnosis was 25.7 months. The median OS from initial diagnosis of the entire group was 22.5 months. There was no significant difference in median overall survival between patients who received re-resection versus no re-resection, 23 versus 21.9 months respectively (p = 0.6). Additionally, there was no difference in median survival from the time of first recurrence 10.5 months without re-resection versus 11.1 months with re-resection (p = 0.09). After adjusting for known prognostic variables, only age remained significant. Re-irradiation is an effective salvage therapy for patients with localized, progressive high grade glioma, achieving a median survival of 10-11 months from re-irradiation. Our data reveals no significant improvement in survival with the addition of re-resection to re-irradiated patients with HGG.

A phase 2 trial of verubulin for recurrent glioblastoma: a prospective study by the Brain Tumor Investigational Consortium (BTIC).

Treatment options are limited for recurrent glioblastoma (GBM). Verubulin is a microtubule destabilizer and vascular disrupting agent that achieve high brain concentration relative to plasma in animals. Adults with recurrent GBM who failed prior standard therapy were eligible. The primary endpoint was 1-month progression-free survival (PFS-1) for bevacizumab refractory (Group 2) and 6-month progression-free survival (PFS-6) for bevacizumab naïve patients (Group 1). Verubulin was administered at 3.3 mg/m(2) as a 2-h intravenous infusion once weekly for 3 consecutive weeks in a 4-week cycle. The planned sample size was 34 subjects per cohort. 56 patients (37 men, 19 women) were enrolled, 31 in Group 1 and 25 in Group 2. The PFS-6 for Group 1 was 14% and the PFS-1 for Group 2 was 20%. Median survival from onset of treatment was 9.5 months in Group 1 and 3.4 months in Group 2. Best overall response was partial response (n = 3; 10% in Group 1; n = 1; 4.2% in Group 2) and stable disease (n = 7; 23% in Group 1; n = 5; 21% in Group 2). In Group 1, 38.7% of patients experienced a serious adverse event; however only 3.2% were potentially attributable to study drug. In Group 2, 44% of patients experienced a serious adverse event although none were attributable to study drug. Accrual was terminated early for futility. Single agent verubulin, in this dose and schedule, is well tolerated, associated with moderate but tolerable toxicity but has limited activity in either bevacizumab naïve or refractory recurrent GBM.

Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme.

Retrospective data suggests that low serum glucose levels during the treatment of glioblastoma multiforme (GBM) may improve clinical outcomes. As such, many patients are implementing a ketogenic diet (KD) in order to decrease serum glucose flux while simultaneously elevating circulating ketones during radiation therapy and chemotherapy for the treatment of GBM. With IRB approval, a retrospective review of patients with high-grade glioma treated with concurrent chemoradiotherapy and adjuvant chemotherapy was carried out from August 2010 to April 2013. Serum glucose and ketone levels, dexamethasone dose, and toxicity of patients undergoing a KD during treatment were also assessed. Blood glucose levels were compared between patients on an unspecified/standard diet and a KD. Toxicity was assessed by Common Terminology Criteria for Adverse Events version 4. In total, 53 patients were analyzed. Six underwent a KD during treatment. The diet was well tolerated with no grade III toxicity and one episode of grade II fatigue. No episodes of symptomatic hypoglycemia were experienced. Four patients are alive at a median follow-up of 14 months. The mean blood glucose of patients on a standard diet was 122 versus 84 mg/dl for those on a KD. Based on this retrospective study, a KD appears safe and well tolerated during the standard treatment of GBM. Dietary restriction of carbohydrates through a KD reduces serum glucose levels significantly, even in conjunction with high dose steroids, which may affect the response to standard treatment and prognosis. Larger prospective trials to confirm this relationship are warranted.

Immunotherapy and radiotherapy for older patients with locally advanced rectal cancer unfit for surgery or decline surgery: a practical proposal by the International Geriatric Radiotherapy Group.

The standard of care for locally advanced rectal cancer is total neoadjuvant therapy followed by surgical resection. Current evidence suggests that selected patients may be able to delay or avoid surgery without affecting survival rates if they achieve a complete clinical response (CCR). However, for older cancer patients who are too frail for surgery or decline the surgical procedure, local recurrence may lead to a deterioration of patient quality of life. Thus, for clinicians, a treatment algorithm which is well tolerated and may improve CCR in older and frail patients with rectal cancer may improve the potential for prolonged remission and potential cure. Recently, immunotherapy with check point inhibitors (CPI) is a promising treatment in selected patients with high expression of program death ligands receptor 1 (PD- L1). Radiotherapy may enhance PD-L1 expression in rectal cancer and may improve response rate to immunotherapy. We propose an algorithm combining immunotherapy and radiotherapy for older patients with locally advanced rectal cancer who are too frail for surgery or who decline surgery.

Immunotherapy and stereotactic body radiotherapy for older patients with non-metastatic renal cancer unfit for surgery or decline nephrectomy: practical proposal by the International Geriatric Radiotherapy Group.

The standard of care for non-metastatic renal cancer is surgical resection followed by adjuvant therapy for those at high risk for recurrences. However, for older patients, surgery may not be an option due to the high risk of complications which may result in death. In the past renal cancer was considered to be radio-resistant, and required a higher dose of radiation leading to excessive complications secondary to damage of the normal organs surrounding the cancer. Advances in radiotherapy technique such as stereotactic body radiotherapy (SBRT) has led to the delivery of a tumoricidal dose of radiation with minimal damage to the normal tissue. Excellent local control and survival have been reported for selective patients with small tumors following SBRT. However, for patients with poor prognostic factors such as large tumor size and aggressive histology, there was a higher rate of loco-regional recurrences and distant metastases. Those tumors frequently carry program death ligand 1 (PD-L1) which makes them an ideal target for immunotherapy with check point inhibitors (CPI). Given the synergy between radiotherapy and immunotherapy, we propose an algorithm combining CPI and SBRT for older patients with non-metastatic renal cancer who are not candidates for surgical resection or decline nephrectomy.

Immunotherapy and radiotherapy for older patients with invasive bladder cancer unfit for surgery or chemotherapy: practical proposal by the international geriatric radiotherapy group.

The standard of care for non-metastatic muscle invasive bladder cancer is either radical cystectomy or bladder preservation therapy, which consists of maximal transurethral bladder resection of the tumor followed by concurrent chemoradiation with a cisplatin-based regimen. However, for older cancer patients who are too frail for surgical resection or have decreased renal function, radiotherapy alone may offer palliation. Recently, immunotherapy with immune checkpoint inhibitors (ICI) has emerged as a promising treatment when combined with radiotherapy due to the synergy of those two modalities. Transitional carcinoma of the bladder is traditionally a model for immunotherapy with an excellent response to Bacille Calmette-Guerin (BCG) in early disease stages, and with avelumab and atezolizumab for metastatic disease. Thus, we propose an algorithm combining immunotherapy and radiotherapy for older patients with locally advanced muscle-invasive bladder cancer who are not candidates for cisplatin-based chemotherapy and surgery.

Immunotherapy and Hypofractionated Radiotherapy in Older Patients with Locally Advanced Cutaneous Squamous-Cell Carcinoma of the Head and Neck: A Proposed Paradigm by the International Geriatric Radiotherapy Group.

Cutaneous skin carcinoma is a disease of older patients. The prevalence of cutaneous squamous-cell carcinoma (cSCC) increases with age. The head and neck region is a frequent place of occurrence due to exposure to ultraviolet light. Surgical resection with adjuvant radiotherapy is frequently advocated for locally advanced disease to decrease the risk of loco-regional recurrence. However, older cancer patients may not be candidates for surgery due to frailty and/or increased risk of complications. Radiotherapy is usually advocated for unresectable patients. Compared to basal-cell carcinoma, locally advanced cSCC tends to recur locally and/or can metastasize, especially in patients with high-risk features such as poorly differentiated histology and perineural invasion. Thus, a new algorithm needs to be developed for older patients with locally advanced head and neck cutaneous squamous-cell carcinoma to improve their survival and conserve their quality of life. Recently, immunotherapy with checkpoint inhibitors (CPIs) has attracted much attention due to the high prevalence of program death ligand 1 (PD-L1) in cSCC. A high response rate was observed following CPI administration with acceptable toxicity. Those with residual disease may be treated with hypofractionated radiotherapy to minimize the risk of recurrence, as radiotherapy may enhance the effect of immunotherapy. We propose a protocol combining CPIs and hypofractionated radiotherapy for older patients with locally advanced cutaneous head and neck cancer who are not candidates for surgery. Prospective studies should be performed to verify this hypothesis.

Impact of COVID-19 pandemic on older cancer patients: Proposed solution by the International Geriatric Radiotherapy Group.

Older cancer patients are disproportionally affected by the Coronavirus 19 (COVID-19) pandemic. A higher rate of death among the elderly and the potential for long-term disability have led to fear of contracting the virus in these patients. This fear can, paradoxically, cause delay in diagnosis and treatment that may lead to a poor outcome that could have been prevented. Thus, physicians should devise a policy that both supports the needs of older patients during cancer treatment, and serves to help them overcome their fear so they seek out to cancer diagnosis and treatment early. A combination of telemedicine and a holistic approach, involving prayers for older cancer patients with a high level of spirituality, may improve vaccination rates as well as quality of life during treatment. Collaboration between health care workers, social workers, faith-based leaders, and cancer survivors may be crucial to achieve this goal. Social media may be an important component, providing a means of sending the positive message to older cancer patients that chronological age is not an impediment to treatment.

Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial.

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. Trial Registration: ClinicalTrials.gov Identifier: NCT00045968.

Immunotherapy and Modern Radiotherapy Technique for Older Patients with Locally Advanced Head and Neck Cancer: A Proposed Paradigm by the International Geriatric Radiotherapy Group.

The standard of care for locally advanced head and neck cancer is concurrent chemoradiation or postoperative irradiation with or without chemotherapy. Surgery may not be an option for older patients (70 years old or above) due to multiple co-morbidities and frailty. Additionally, the standard chemotherapy of cisplatin may not be ideal for those patients due to oto- and nephrotoxicity. Though carboplatin is a reasonable alternative for cisplatin in patients with a pre-existing hearing deficit or renal dysfunction, its efficacy may be inferior to cisplatin for head and neck cancer. In addition, concurrent chemoradiation is frequently associated with grade 3-4 mucositis and hematologic toxicity leading to poor tolerance among older cancer patients. Thus, a new algorithm needs to be developed to provide optimal local control while minimizing toxicity for this vulnerable group of patients. Recently, immunotherapy with check point inhibitors (CPI) has attracted much attention due to the high prevalence of program death-ligand 1 (PD-L1) in head and neck cancer. In patients with recurrent or metastatic head and neck cancer refractory to cisplatin-based chemotherapy, CPI has proven to be superior to conventional chemotherapy for salvage. Those with a high PD-L1 expression defined as 50% or above or a high tumor proportion score (TPS) may have an excellent response to CPI. This selected group of patients may be candidates for CPI combined with modern radiotherapy techniques, such as intensity-modulated image-guided radiotherapy (IM-IGRT), volumetric arc therapy (VMAT) or proton therapy if available, which allow for the sparing of critical structures, such as the salivary glands, oral cavity, cochlea, larynx and pharyngeal muscles, to improve the patients' quality of life. In addition, normal organs that are frequently sensitive to immunotherapy, such as the thyroid and lungs, are spared with modern radiotherapy techniques. In fit or carefully selected frail patients, a hypofractionated schedule may be considered to reduce the need for daily transportation. We propose a protocol combining CPI and modern radiotherapy techniques for older patients with locally advanced head and neck cancer who are not eligible for cisplatin-based chemotherapy and have a high TPS. Prospective studies should be performed to verify this hypothesis.