Association Between Time From Surgery to Radiation Therapy and Multimodality Treatment Outcomes in HPV+ Head and Neck Cancer: A Multi-Institutional Cohort Experience.

Purpose: Oropharyngeal squamous cell cancers (OPSCCs) are traditionally managed with surgery and, if indicated, adjuvant radiation therapy (RT) with or without chemotherapy. NCCN recommends keeping the time from surgery to the start of RT (TSRT) within 6 weeks to avoid possibly compromising patient outcomes. HPV+ OPSCCs behave more favorably than HPV- OPSCCs. We hypothesized that TSRT beyond 6 weeks may not portend poorer outcomes for the former. Methods: We identified nonmetastatic, high-risk HPV+ OPSCCs treated with multimodal therapy at 2 institutions. Prolonged TSRT was defined as >6 weeks and was evaluated for association with recurrence-free survival (RFS). Radiation treatment time (RTT; time from the first to the last day of RT), total treatment package time (TTPT; time from surgery to the end of adjuvant treatments), de-escalated RT (dose ≤56 Gy), concurrent chemotherapy, smoking history, and treatment institution were evaluated as possible confounders. Results: In total, 96 patients were included. The median follow-up time was 62 months (4-123 months); 69 patients underwent transoral robotic surgeries, and 27 received open surgeries. The median postoperative RT dose was 60 Gy (50-70.8 Gy). The median TSRT, RTT, and TTPT were 38 days (11-208), 43 days (26-56 days), and 81 days (40-255 days), respectively. Ten patients failed treatment at a median of 8 months (4-64 months). Two locoregional and 4 distant failures occurred in the group without prolonged TSRT, whereas 2 locoregional and 2 distant failures were recorded in the prolonged TSRT group. Prolonged TTPT, de-escalated RT, chemotherapy, smoking history, and treatment institution were not associated with treatment failure. RTT was dropped from our analyses as no events appeared in the prolonged RTT group, and no reliable hazard ratio could be computed. Conclusions: TSRT > 6 weeks was not significantly associated with inferior outcomes in the postoperative management of HPV+ OPSCCs. Longer TSRT may facilitate better recovery from surgical toxicity, as needed, without compromising oncologic outcomes. The TSRT goal for these cancers should be investigated in future studies.

Efficacy of scalp-sparing volumetric-modulated arc therapy approach in reducing scalp radiation dose for patients with glioblastoma: a cross-sectional study.

BACKGROUND: Radiation is integral to the treatment of glioblastoma (GBM). However, radiation-induced scalp toxicity can negatively impact patients' quality of life. Volumetric modulated arc therapy (VMAT) optimizes the dose to organs at risk (OARs). We hypothesize that a scalp-sparing VMAT (SSV) approach can significantly reduce undesirable doses to the scalp without compromising the target dose. METHODS: This is a retrospective cross-sectional study of GBM patients who originally received radiation with non-SSV. We contoured the scalp as a 5 mm rind-like structure beneath the skin above the level of the foramen magnum. We replanned our patients using SSV techniques. We compared dosimetric data for the scalp, planning target volume (PTV), and select critical normal structures between non-SSV and SSV plans. RESULTS: Nineteen patients with newly diagnosed GBMs were included in our study. All patients received 60 Gy in 30 fractions. 9 patients received it in a single course. The rest received 46 Gy in 23 fractions to an initial volume followed by 14 Gy in 7 fractions to a cone-down volume (split course). New VMAT plans were generated after adding the scalp as an OAR. The median scalp volume was 416 cm3 (363-468 cm3). The median reductions in scalp Dmin, Dmax, and Dmean were 43.5% (-100% to 0%), 2.8% (+13.4% to -24.9%), and 15.7% (+2.1% to -39.9%) respectively. Median reductions in scalp D20cc and D30 cc were 19.5% (-2.7% to -54.5%), and 19.0% (-5.3% to -39.5%) respectively. The median volumes of the scalp receiving 30 Gy, 40 Gy, and 50 Gy were reduced by 42.3% (-70.6% to -12.5%), 72% (-100% to -2.3%), and 92.4% (-100% to +5.4%) respectively. There were no significant differences in the doses delivered to the PTV, brainstem, optic nerves, and optic chiasm between SSV and non-SSV plans. CONCLUSIONS: SSV can significantly reduce scalp radiation dose without compromising target coverage or critical normal structure doses. This may translate into reduced acute and late radiation toxicity to the scalp. A prospective trial evaluating the clinical benefits of SSV is ongoing (NCT03251027).

Differences in clinical outcomes based on molecular markers in glioblastoma patients treated with concurrent tumor-treating fields and chemoradiation: exploratory analysis of the SPARE trial.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite enormous research efforts, GBM remains a deadly disease. The standard-of-care treatment for patients with newly diagnosed with GBM as per the National Cancer Comprehensive Cancer Network (NCCN) is maximal safe surgical resection followed by concurrent chemoradiation and maintenance temozolomide (TMZ) with adjuvant tumor treating fields (TTF). TTF is a non-pharmacological intervention that delivers low-intensity, intermediate frequency alternating electric fields that arrests cell proliferation by disrupting the mitotic spindle. TTF have been shown in a large clinical trial to improve patient outcomes when added to radiation and chemotherapy. The SPARE trail (Scalp-sparing radiation with concurrent temozolomide and tumor treating fields) evaluated adding TTF concomitantly to radiation and chemotherapy. METHODS: This study is an exploratory analysis of the SPARE trial looking at the prognostic significance of common GBM molecular alterations, namely MGMT, EGFR, TP53, PTEN and telomerase reverse transcriptase (TERT), in this cohort of patients treated with concomitant TTF with radiation and chemotherapy. RESULTS: As expected, MGMT promoter methylation was associated with improved overall survival (OS) and progression-free survival (PFS) in this cohort. In addition, TERT promoter mutation was associated with improved OS and PFS in this cohort as well. CONCLUSIONS: Leveraging the molecular characterization of GBM alongside advancing treatments such as chemoradiation with TTF presents a new opportunity to improve precision oncology and outcomes for GBM patients.

Case report: durable response of gliomatosis cerebri with concurrent tumor-treating fields (TTFields) and chemoradiotherapy treatment.

BACKGROUND: Gliomatosis cerebri (GC) is a rare and aggressive form of widely disseminated glioma infiltrating at least 3 lobes of the brain. It is a diffuse pattern of growth seen in glioma rather than a distinct pathological diagnosis based on new Word Health Organization (WHO) classification. Despite this, it is associated with worse prognosis than equally graded gliomas. Tumor treating fields (TTFields) treatment is a more recent advancement in glioma treatment delivered through low energy, intermediate frequency (200 kHz) electromagnetic fields, with multi-modal mechanisms of action. It is Food and Drug Administration (FDA) approved for newly diagnosed and recurrent glioblastoma (GBM). The aim of this case report is to present a durable response of GBM associated GC to concurrent TTFields with chemoradiation. CASE DESCRIPTION: We report a 64-year-old male with left parietal GBM, IDH wild type, WHO grade 4 with extensive GC change. After resection of the enhancing lesion, the patient received concurrent tumor-treating fields (TTFields) with radiation and temozolomide, enrolled in SPARE trial (NCT03477110). The patient had a rapid response in the areas of gliomatosis change demonstrated on the magnetic resonance imaging 1 month post-radiation treatment. The response of GC was durable. His glioma recurred 11 months after surgery with new enhancing lesions, treated with radiosurgery. He had further extensive progression of enhancing lesions 13 months after surgery, and received bevacizumab treatment. The patient ultimately passed away 17 months after surgery. Despite progression of enhancing lesions, the GC changes remained controlled. He also had favorable progression-free survival of 11 months and overall survival of 17 months. CONCLUSIONS: This case serves as an example of how combination TTFields with chemoradiation may elicit a durable response of GC in patients with GBM.

Concurrent chemoradiation and Tumor Treating Fields (TTFields, 200 kHz) for patients with newly diagnosed glioblastoma: patterns of progression in a single institution pilot study.

Current standard of care for glioblastoma (GBM) includes concurrent chemoradiation and maintenance temozolomide (TMZ) with Tumor Treating Fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We conducted a pilot clinical trial of concurrent chemoradiation with TTFields and report pattern of progression. MATERIALS AND METHODS: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed GBM were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent TMZ and TTFields. Maintenance therapy included standard TMZ and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. Incidence and location of progression was documented. Distant recurrence was defined as recurrence more than 2 cm from the primary enhancing lesion. RESULTS: Thirty patients were enrolled on the trial. Twenty were male with median age 58 years (19-77 years). Median KPS was 90 (70-100). Median follow-up was 15.2 months (1.7-23.6 months). Ten (33.3%) patients had a methylated promoter status. Twenty-seven patients (90%) had progression, with median PFS of 9.3 months (range 8.5 to 11.6 months). Six patients presented with distant recurrence, with median distance from primary lesion of 5.05 cm (2.26-6.95 cm). One infratentorial progression was noted. CONCLUSIONS: We observed improved local control using concurrent chemoradiation with TTFields for patients with newly diagnosed when compared to historical controls. Further data are needed to validate this finding. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03477110.

Tumor treating fields with radiation for glioblastoma: a narrative review.

BACKGROUND AND OBJECTIVE: With a phase 3 clinical trial (EF-32, ClinicalTrials.gov: NCT04471844) currently underway examining the potential benefit of concurrent chemoradiation and tumor treating fields (TTFields) for patients with glioblastoma (GBM), we present the following narrative review to highlight the current evidence that supports this approach. The current management paradigm for GBM includes maximal safe surgical resection followed by concurrent chemoradiation with further temozolomide (TMZ) and TTFields used as maintenance therapy. Despite several treatment advances over the past few decades, the overall prognosis remains poor and new strategies are currently under investigation, including the use of chemoradiation concurrently with TTFields. METHODS: In this review, we will discuss the preclinical and clinical work that has been performed combining both TTFields with radiation. We performed a narrative review of peer-reviewed articles related to the management of glioblastoma with regard to concurrent chemoradiation and TTFields and synthesized the data in the context of our clinical experience and practice. PubMed, Medline, Embase, Cochrane Library, and various center-specific guidelines were searched for literature regarding concurrent chemoradiation with TTFields for patients with GBM. KEY CONTENT AND FINDINGS: Driven by preclinical studies demonstrating the synergy between TTFields and radiation, more recent clinical work has been performed and has shown that combining treatment is both feasible and tolerable. CONCLUSIONS: In this review, we will discuss the mechanism of action which TTFields and radiation share, as well as discuss the toxicities of combining therapy in patients with GBM. Based on institutional experiences, we will highlight treatment techniques, including scalp sparing methodology and modified computed tomography (CT) simulation workflow, when concurrent TTFields and radiation are given. Lastly, we will provide discuss management considerations, specifically scalp prophylactic interventions and treatments, when using concurrent TTFields with chemoradiation.

Overcoming the cardiac toxicities of cancer therapy immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have led recent advances in the field of cancer immunotherapy improving overall survival in multiple malignancies with abysmal prognoses prior to their introduction. The remarkable efficacy of ICIs is however limited by their potential for systemic and organ specific immune-related adverse events (irAEs), most of which present with mild to moderate symptoms that can resolve spontaneously, with discontinuation of therapy or glucocorticoid therapy. Cardiac irAEs however are potentially fatal. The understanding of autoimmune cardiotoxicity remains limited due to its rareness. In this paper, we provide an updated review of the literature on the pathologic mechanisms, diagnosis, and management of autoimmune cardiotoxicity resulting from ICIs and their combinations and provide perspective on potential strategies and ongoing research developments to prevent and mitigate their occurrence.

Scalp-Sparing Radiation With Concurrent Temozolomide and Tumor Treating Fields (SPARE) for Patients With Newly Diagnosed Glioblastoma.

Introduction: Standard-of-care treatment for patients with newly diagnosed glioblastoma (GBM) after surgery or biopsy includes concurrent chemoradiation followed by maintenance temozolomide (TMZ) with tumor treating fields (TTFields). Preclinical studies suggest TTFields and radiotherapy work synergistically. We report the results of our trial evaluating the safety of TTFields used concurrently with chemoradiation. Methods: This is a single-arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma and a Karnofsky performance score (KPS) of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with TMZ (75 mg/m2 daily) and TTFields (200 kHz). Maintenance therapy included TMZ and continuation of TTFields. Scalp-sparing radiation treatment was used to reduce radiation dermatitis. Radiation treatment was delivered through the TTFields arrays. The primary endpoint was safety and toxicity of tri-modality treatment within 30 days of completion of chemoradiation treatment. Results: There were 30 patients enrolled, including 20 (66.7%) men and 10 (33.3%) women, with a median age of 58 years (range 19 to 77 years). Median KPS was 90 (range 70 to 100). A total of 12 (40%) patients received a gross total resection and 18 (60%) patients had a subtotal resection. A total of 12 (40%) patients had multifocal disease at presentation. There were 20 (66.7%) patients who had unmethylated O(6)-methylguanine-DNA-methyltransferase (MGMT) promotor status and 10 (33.3%) patients who had methylated MGMT promoter status. Median follow-up was 15.2 months (range 1.7 to 23.6 months). Skin adverse events were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. The primary end point was met; no TTFields discontinuation occurred during the evaluation period due to high grade scalp toxicity. A total of 27 (90%) patients had progression, with a median progression-free survival (PFS) of 9.3 months (95% confidence interval (CI): 8.5-11.6 months). The 1-year progression-free survival was 23% (95% CI: 12%-45%). The median overall survival (OS) was 15.8 months (95% CI: 12.5 months-infinity). The 1-year overall survival was 66% (95% CI: 51%-86%). Conclusions: Concurrent TTFields with scalp-sparing chemoradiation is a feasible and well-tolerated treatment option with limited toxicity. A phase 3, randomized clinical trial (EF-32, clinicaltrials.gov Identifier: NCT04471844) investigating the clinical benefit of concurrent TTFields with chemoradiation treatment is currently enrolling. Clinical Trial Registration: Clinicaltrials.gov, identifier NCT03477110.