The IDH paradox: Meta-analysis of alkylating chemotherapy in IDH-wildtype and -mutant lower grade gliomas.

BACKGROUND: IDH-wildtype (-wt) status is a pre-requisite for the diagnosis of glioblastoma (GBM); however, IDH-wt gliomas with low grade or anaplastic morphology have historically been excluded from GBM trials and may represent a distinct prognostic entity. While alkylating agent chemotherapy improves overall survival (OS) and progression-free survival (PFS) for IDH-wt GBM and also IDH-mutant gliomas, irrespective of grade, the benefit for IDH-wt diffuse histologic lower grade gliomas is unclear. METHODS: We performed a meta-analysis of randomized clinical trials for World Health Organization (WHO) grade 2-3 gliomas (2009 to present) to determine the effect of alkylating chemotherapy on IDH-wt and -mutant gliomas using a random-effects model with inverse-variance pooling. RESULTS: We identified six trials with 1,204 patients (430 IDH-wt, 774 IDH-mutant) that evaluated alkylating chemoradiotherapy versus radiotherapy alone, allowing us to perform an analysis focused on the value of adding alkylating chemotherapy to radiotherapy. For patients with IDH-wt tumors, alkylating chemotherapy added to radiotherapy was associated with improved PFS (HR:0.77 [95%CI 0.62-0.97], P=.03) but not OS (HR:0.87 [95%CI 0.64-1.18], P=.17). For patients with IDH-mutant tumors, alkylating chemotherapy added to radiotherapy improved both OS (HR:0.52 [95%CI 0.42-0.64], P<.001) and PFS (HR=0.47 [95%CI 0.39-0.57], P<.001) compared to radiotherapy alone. The magnitude of benefit was similar for IDH-mutant gliomas with or without 1p19q-codeletion. CONCLUSIONS: Alkylating chemotherapy reduces mortality by 48% and progression by 53% for patients with IDH-mutant gliomas. Optimal management of IDH-wt diffuse histologic lower grade gliomas remains to be determined, as there is little evidence supporting an OS benefit from alkylating chemotherapy.

Systematic under-ascertainment of anaplastic large cell lymphoma cases in cancer registries: report from a comprehensive cancer center.

INTRODUCTION: Breast implant-associated anaplastic large cell lymphoma (ALCL) has been rapidly rising in the US and around the world, leading to a mandated "black-box" label on all silicone- and saline-filled implants by the Food and Drug Administration (FDA). Because regulatory decisions in the US and around the world have been influenced primarily by risk estimates derived from cancer registries, it is important to determine their validity in identifying cases of ALCL. METHOD: We reviewed all cases of ALCL submitted to the New York State Cancer Registry from a large comprehensive cancer center in New York City from 2007 to 2019. To determine the possibility of misdiagnosis or under-diagnosis of ALCL cases reported to cancer registries, we accessed the sensitivity and specificity of the ICD-O-3 codes 9714 (ALCL) and 9702 (Mature T-cell lymphoma, not otherwise specified [T-NOS]) to identify pathologically-proven ALCL. RESULTS: We reviewed 2286,164 pathology reports from 47,466 unique patients with primary cancers. Twenty-eight cases of histologically-proven ALCL were identified. The sensitivity and specificity of the ICD-O-3 code 9714 (ALCL) were 82% and 100%, respectively. The sensitivity of the combined codes 9714/9702 (ALCL/T-NOS) was 96% and the specificity was 44%. CONCLUSION: Previous epidemiological studies that influenced regulatory decisions by the FDA may have systematically underestimated the risk of ALCL by at least 20%. We encourage updated global risk estimates of breast ALCL using methods that ensure adequate case ascertainment.

Site-specific patterns of early-stage cancer diagnosis during the COVID-19 pandemic.

The COVID-19 pandemic caused widespread disruptions in cancer care. We hypothesized that the greatest disruptions in diagnosis occurred in screen-detected cancers. We identified patients (≥18 years of age) with newly diagnosed cancer from 2019 to 2020 in the US National Cancer Database and calculated the change in proportion of early-stage to late-stage cancers using a weighted linear regression. Disruptions in early-stage diagnosis were greater than in late-stage diagnosis (17% vs 12.5%). Melanoma demonstrated the greatest relative decrease in early-stage vs late-stage diagnosis (22.9% vs 9.2%), whereas the decrease was similar for pancreatic cancer. Compared with breast cancer, cervical, melanoma, prostate, colorectal, and lung cancers showed the greatest disruptions in early-stage diagnosis. Uninsured patients experienced greater disruptions than privately insured patients. Disruptions in cancer diagnosis in 2020 had a larger impact on early-stage disease, particularly screen-detected cancers. Our study supports emerging evidence that primary care visits may play a critical role in early melanoma detection.

Updated Analysis of Comparative Toxicity of Proton and Photon Radiation for Prostate Cancer.

PURPOSE: Previous comparative effectiveness studies have not demonstrated a benefit of proton beam therapy (PBT) compared with intensity-modulated radiation therapy (IMRT) for prostate cancer. An updated comparison of GI and genitourinary (GU) toxicity is needed. METHODS: We investigated the SEER-Medicare linked database, identifying patients with localized prostate cancer diagnosed from 2010 to 2017. Procedure and diagnosis codes indicative of treatment-related toxicity were identified. As a sensitivity analysis, we also identified toxicity based only on procedure codes. Patients who underwent IMRT and PBT were matched 2:1 on the basis of clinical and sociodemographic characteristics. We then compared GI and GU toxicity at 6, 12, and 24 months after treatment. RESULTS: The final sample included 772 PBT patients matched to 1,544 IMRT patients. The frequency of GI toxicity for IMRT versus PBT was 3.5% versus 2.5% at 6 months (P = .18), 9.5% versus 10.2% at 12 months (P = .18), and 20.5% versus 23.4% at 24 months (P = .11). The frequency of only procedure codes indicative of GI toxicity for IMRT versus PBT was too low to be reported and not significantly different. The frequency of GU toxicity for IMRT versus PBT was 6.8% versus 5.7% (P = .30), 14.3% versus 12.2% (P = .13), and 28.2% versus 25.8% (P = .21) at 6, 12, and 24 months, respectively. When looking only at procedure codes, the frequency of GU toxicity for IMRT was 1.0% at 6 months, whereas it was too infrequent to report for PBT (P = .64). GU toxicity for IMRT versus PBT was 3.3% versus 2.1% (P = .10), and 8.7% versus 6.7% (P = .10) at 12 and 24 months, respectively. CONCLUSION: In this observational study, there were no statistically significant differences between PBT and IMRT in terms of GI or GU toxicity.

Practical Considerations for the Treatment of an Adrenal Metastasis With Stereotactic Body Radiation Therapy.

The purpose of this paper is to summarize 3 methods for treating adrenal metastases with stereotactic body radiation therapy. This article is not meant to provide consensus guidelines but rather to present 4 practical examples of treatment techniques using different treatment platforms from 3 institutions.

Practical Implications of the American Society for Radiation Oncology Radiation Oncology Case Rate Program Proposal for Radiation Oncologists.

The American Society for Radiation Oncology has proposed the Radiation Oncology Case Rate Program (ROCR) to advocate for fair reimbursement for radiation oncologists. ROCR would replace Medicare fee-for-service with a case rate payment for each of the 15 most common cancer types treated with external beam or stereotactic radiation therapy. This topic discussion attempts to provide a concise overview of the practical implications for radiation oncologists should the ROCR payment program be legislated by Congress and subsequently implemented by the Center for Medicare and Medicaid Services. This topic discussion covers the practical changes to billing and reimbursement, the Health Equity Achievement in Radiation Therapy payment, the Quality of Care requirement, and the available tool to calculate the effect of the ROCR based on an individual practice's case mix.

2023 Radiation oncology highlights.

Radiation oncology plays an important role in the local treatment of cancers. Understanding recent advances in the application of radiation therapy to solid tumors is important for all disciplines. The radiation oncology section editors for this journal have selected the following articles for their overall significance, relevance to surgical oncologists, and to illustrate important concepts within the practice of radiation oncology.

Prognosis and risk of suicide after cancer diagnosis.

INTRODUCTION: Suicide rates are elevated after cancer diagnosis. Existential distress caused by awareness of one's impending death is well-described in patients with cancer. The authors hypothesized that suicide risk is associated with cancer prognosis, and the impact of prognosis on suicide risk is greatest for populations with higher baseline suicide risk. METHODS: The authors identified patients (≥16 years old) with newly diagnosed cancers from 2000 to 2019 in the Surveillance, Epidemiology, and End Results database, representing 27% of US cancers. Multiple primary-standardized mortality ratios (SMR) were used to estimate the relative risk of suicide within 6 months of diagnosis compared to the general US population, adjusted for age, sex, race, and year of follow-up. Suicide rates by 20 most common cancer sites were compared with respective 2-year overall survival rates (i.e., prognosis) using a weighted linear regression model. RESULTS: Among 6,754,704 persons diagnosed with cancer, there were 1610 suicide deaths within 6 months of diagnosis, three times higher than the general population (SMR = 3.1; 95% confidence interval, 3.0-3.3). Suicide risk by cancer site was closely associated with overall prognosis (9.5%/percent survival deficit, R2  = 0.88, p < .0001). The association of prognosis with suicide risk became attenuated over time. For men, the risk of suicide increased by 2.8 suicide deaths per 100,000 person-years (p < .0001) versus 0.3 in women (p < .0001). The risk was also higher for persons ≥60 old and for the White (vs. Black) race. CONCLUSIONS: Poorer prognosis was closely associated with suicide risk early after cancer diagnosis and had a greater effect on populations with higher baseline risks of suicide. This model highlights the need for enhanced psychiatric surveillance and continued research in this patient population.

MGMT promoter methylation in 1p19q-intact gliomas.

OBJECTIVE: Standard-of-care for 1p19q-intact anaplastic gliomas is defined by the international randomized phase III CATNON trial, which found an overall survival (OS) benefit for adjuvant temozolomide (TMZ) when added to radiotherapy. Paradoxically, TMZ did not appear to benefit patients with IDH-wildtype gliomas, regardless of MGMT promoter status. The authors concluded that well-powered prospective study on the clinical efficacy of TMZ for patients with IDH-wildtype anaplastic gliomas (meeting criteria for glioblastoma) is warranted. Given that the prognostic and predictive role of MGMT status for grade 2-3 gliomas is unresolved, we determined the effect of MGMT status on OS in patients with 1p19q-intact gliomas in the National Cancer Database (NCDB). METHODS: We queried the NCDB from 2018 to 2019 for patients with diffuse (grade 2) and anaplastic (grade 3) IDH-wildtype or -mutant astrocytomas who received chemotherapy with follow-up through 2022. The Kaplan-Meier method and Cox proportional hazards regressions models were used to determine the association of MGMT with OS. RESULTS: We identified 1514 patients who were newly diagnosed with IDH-wildtype (n = 802, 33% methylated) or -mutant astrocytomas (n = 712, 48% methylated) and received chemotherapy during initial management. An unmethylated promoter was associated with poorer survival in patients with IDH-wildtype (3-year OS 34% [95%CI 29-39%] vs. 46% [95%CI 39-54%], p < .001, adjusted HR 1.53 [95%CI 1.24-1.89]) but not IDH-mutant astrocytomas (3-year OS 79% [95%CI 74-84%] vs. 80% [95%CI 75-86%], p =0 .81, HR 1.04 [95%CI 0.73-1.50]). CONCLUSIONS: This ancillary analysis supports conclusions from the CATNON trial for adjuvant TMZ as standard-of-care for anaplastic astrocytomas (IDH-mutant and 1p19q-intact), irrespective of MGMT status. Determining the optimal strategy for diffuse gliomas that are IDH-wildtype will be particularly important. MGMT promoter methylation should be considered as a stratification factor in future clinical trials for these patients.

Increasing Use of Shorter-Course Radiotherapy for Prostate Cancer.

Importance: Randomized clinical trials have demonstrated the noninferiority of shorter radiotherapy (RT) courses (termed hypofractionation) compared with longer RT courses in patients with localized prostate cancer. Although shorter courses are associated with cost-effectiveness, convenience, and expanded RT access, their adoption remains variable. Objective: To identify the current practice patterns of external beam RT for prostate cancer in the US. Design, Setting, and Participants: This cohort study obtained data from the National Cancer Database, which collects hospital registry data from more than 1500 accredited US facilities on approximately 72% of US patients with cancer. Patients were included in the sample if they had localized prostate adenocarcinoma that was diagnosed between 2004 and 2020 and underwent external beam RT with curative intent. Analyses were conducted between February and March 2023. Exposures: Radiotherapy schedules, which were categorized as ultrahypofractionation (≤7 fractions), moderate hypofractionation (20-30 fractions), and conventional fractionation (31-50 fractions). Main Outcomes and Measures: Longitudinal pattern in RT fractionation schedule was the primary outcome. Multivariable logistic regression was performed to evaluate the variables associated with shorter RT courses. Covariables included age, National Comprehensive Cancer Network risk group, rurality, race, facility location, facility type, median income, insurance type or status, and Charlson-Deyo Comorbidity Index. Results: A total of 313 062 patients with localized prostate cancer (mean [SD] age, 68.8 [7.7] years) were included in the analysis. There was a temporal pattern of decline in the proportion of patients who received conventional fractionation, from 76.0% in 2004 to 36.6% in 2020 (P for trend <.001). From 2004 to 2020, use of moderate hypofractionation increased from 22.0% to 45.0% (P for trend <.001), and use of ultrahypofractionation increased from 2.0% to 18.3% (P for trend <.001). By 2020, the most common RT schedule was ultrahypofractionation for patients in the low-risk group and moderate hypofractionation for patients in the intermediate-risk group. On multivariable analysis, treatment at a community cancer program (compared with academic or research program; odds ratio [OR], 0.54 [95% CI, 0.52-0.56]; P < .001), Medicaid insurance (compared with Medicare; OR, 1.49 [95% CI, 1.41-1.57]; P < .001), Black race (compared with White race; OR, 0.90 [95% CI, 0.87-0.92]; P < .001), and higher median income (compared with lower median income; OR, 1.28 [95% CI, 1.25-1.31]; P < .001) were associated with receipt of shorter courses of RT. Conclusions and Relevance: Results of this cohort study showed an increase in the use of shorter courses of RT for prostate cancer from 2004 to 2020; a number of social determinants of health appeared to be associated with reduced adoption of shorter treatment courses. Realignment of reimbursement models may be necessary to enable broader adoption of ultrahypofractionation to support technology acquisition costs.

MGMT promoter methylation in 1p19q-intact gliomas.

Objective: Standard-of-care for 1p19q-intact anaplastic gliomas is defined by the international randomized phase III CATNON trial, which found an overall survival (OS) benefit for adjuvant temozolomide (TMZ) when added to radiotherapy. Paradoxically, TMZ did not appear to benefit patients with IDH-wildtype gliomas, regardless of MGMT promoter status. The authors concluded that well-powered prospective study on the clinical efficacy of TMZ for patients with IDH-wildtype anaplastic gliomas (meeting criteria for glioblastoma) is warranted. Given that the prognostic and predictive role of MGMT status for grade 2-3 gliomas is unresolved, we determined the effect of MGMT status on OS in patients with 1p19q-intact gliomas in the National Cancer Database (NCDB). Methods: We queried the NCDB from 2018-2019 for patients with IDH-wildtype or -mutant astrocytomas who received chemotherapy with follow-up through 2022. The Kaplan-Meier method and Cox proportional hazards regressions models were used to determine the association of MGMT with OS. Results: We identified 1,514 patients who were newly diagnosed with IDH-wildtype (n = 802, 33% methylated) or - mutant astrocytomas (n = 712, 48% methylated) and received chemotherapy during initial management. An unmethylated promoter was associated with poorer survival in patients with IDH-wildtype (3-year OS 34% [95%CI 29-39%] vs. 46% [95%CI 39-54%], p < .001, adjusted HR 1.53 [95%CI 1.24-1.89]) but not IDH-mutant astrocytomas (3-year OS 79% [95%CI 74-84%] vs. 80% [95%CI 75-86%], p = .81, HR 1.04 [95%CI 0.73-1.50]). Conclusions: This ancillary analysis supports adjuvant TMZ as standard-of-care for anaplastic astrocytomas (IDH-mutant and 1p19q-intact), irrespective of MGMT status. Determining the optimal strategy for diffuse gliomas that are IDH-wildtype will be particularly important. MGMT promoter methylation should be considered as a stratification factor in future clinical trials for these patients.

MGMT Promoter Methylation Predicts Overall Survival after Chemotherapy for 1p/19q-Codeleted Gliomas.

PURPOSE: While MGMT promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy and guides treatment decisions in glioblastoma, its role in grade 2 and 3 glioma remains unclear. Recent data suggest that mMGMT is prognostic of progression-free survival in 1p/19q-codeleted oligodendrogliomas, but an effect on overall survival (OS) has not been demonstrated. EXPERIMENTAL DESIGN: We identified patients with newly diagnosed 1p/19q-codeleted gliomas and known MGMT promoter status in the National Cancer Database from 2010 to 2019. Multivariable Cox proportional hazards regression modeling was used to assess the effect of mMGMT on OS after adjusting for age, sex, race, comorbidity, grade, extent of resection, chemotherapy, and radiotherapy. RESULTS: We identified 1,297 eligible patients, 938 (72.3%) of whom received chemotherapy in their initial course of treatment. The MGMT promoter was methylated in 1,009 (77.8%) patients. Unmethylated MGMT (uMGMT) was associated with worse survival compared with mMGMT [70% {95% confidence interval (CI), 64%-77%} vs. 81% (95% CI, 78%-85%); P < 0.001; adjusted HR (aHR), 2.35 (95% CI, 1.77-3.14)]. uMGMT was associated with worse survival in patients who received chemotherapy [63% (95% CI, 55-73%) vs. 80% (95% CI, 76%-84%); P < 0.001; aHR, 2.61 (95% CI, 1.89-3.60)] but not in patients who did not receive chemotherapy [P = 0.38; HR, 1.31 (95% CI, 0.71-2.42)]. Similar results were observed regardless of World Health Organization grade and after single- or multiagent chemotherapy. CONCLUSIONS: Our study demonstrates an association between mMGMT and OS in 1p/19q-codeleted gliomas. MGMT promoter status should be considered as a stratification factor in future clinical trials of 1p/19q-codeleted gliomas that use OS as an endpoint.

Nationwide changes in radiation oncology travel and location of care before and during the COVID-19 pandemic.

PURPOSE: Patients with cancer are particularly vulnerable to coronavirus disease (COVID). Transportation barriers made travel to obtain medical care more difficult during the pandemic. Whether these factors led to changes in the distance traveled for radiotherapy and the coordinated location of radiation treatment is unknown. MATERIALS AND METHODS: We analyzed patients across 60 cancer sites in the National Cancer Database from 2018 to 2020. Demographic and clinical variables were analyzed for changes in distance traveled for radiotherapy. We designated the facilities in the 99th percentile or above in terms of the proportion of patients who traveled more than 200 miles as "destination facilities." We defined "coordinated care" as undergoing radiotherapy at the same facility where the cancer was diagnosed. RESULTS: We evaluated 1,151,954 patients. There was a greater than 1% decrease in the proportion of patients treated in the Mid-Atlantic States. Mean distance traveled from place of residence to radiation treatment decreased from 28.6 to 25.9 miles, and the proportion traveling greater than 50 miles decreased from 7.7% to 7.1%. At "destination facilities," the proportion traveling more than 200 miles decreased from 29.3% in 2018 to 24% in 2020. In comparison, at the other hospitals, the proportion traveling more than 200 miles decreased from 1.07% to 0.97%. In 2020, residing in a rural area resulted in a lower odds of having coordinated care (multivariable odds ratio = 0.89; 95% confidence interval, 0.83-0.95). CONCLUSION: The first year of the COVID pandemic measurably impacted the location of U.S. radiation therapy treatment.

Prostate cancer in New York City: impact of neighborhood level social determinants of care.

Social determinants of health may impact prostate cancer presentation. Since neighborhoods may influence adjacent neighborhoods across often porous and arbitrary borders, we performed generalized spatial two stage least squares cross sections regression to assess direct and indirect (via adjacent neighborhoods) impact of neighborhood level independent variables. Using the New York State Public Access Cancer Epidemiology Data and the NYC Open neighborhood-level dataset, we discovered a direct association between Race and poverty with the likelihood of presenting with advanced prostate cancer. There were no indirect impacts of neighborhood variables, indicating the need to directly target neighborhoods to improve outcomes.