Characterizing disparities in receipt of palliative care for Asian Americans, Native Hawaiians, and Pacific Islanders with metastatic cancer in the United States.

PURPOSE: Palliative care plays essential roles in cancer care. However, differences in receipt among individuals identifying as Asian American, Native Hawaiian, and Other Pacific Islanders (AA&NHPI) with cancer are not well-characterized, especially when these diverse groups are disaggregated. We characterized disparities in receipt of palliative care among AA&NHPI patients with AJCC Stage IV prostate, breast, or lung cancer. METHODS: We performed multivariable logistic regressions were performed in this retrospective cohort analysis, using deidentified data from the National Cancer Database (NCDB) of patients diagnosed with AJCC analytic group stage IV breast, lung, or prostate cancer (2004-2018) who were White or of Asian Indian/Pakistani, Chinese, Filipino, Hawaiian, Hmong, Japanese, Kampuchean, Korean, Laotian, Other Pacific Islander, Thai, or Vietnamese descent. We conducted multivariable logistic regression analyses in a retrospective cohort study using deidentified data from the National Cancer Database (NCDB). The study included patients diagnosed with AJCC analytic group Stage IV breast, lung, or prostate cancer between 2004 and 2018, who were White or identified as Asian Indian/Pakistani, Chinese, Filipino, Hawaiian, Hmong, Japanese, Kampuchean, Korean, Laotian, Other Pacific Islander, Thai, or Vietnamese descent. Adjusted odds ratios and 95% confidence intervals of receiving palliative care were measured when comparing White vs. AA&NHPI patients as one cohort and White vs. disaggregated AA&NHPI patients, adjusting for clinical, socioeconomic, and demographic covariates. RESULTS: Among 775,289 individuals diagnosed with cancer (median age: 68 years), no significant differences in palliative care receipt were observed between White patients and aggregated AA&NHPI patients among patients with prostate, breast, or lung cancer. However, disaggregated analyses revealed reduced palliative care receipt for breast cancer patients of Asian Indian/Pakistani descent (AOR 0.75, 95% CI, 0.60-0.94, P = 0.011) and for lung cancer patients of Chinese, Vietnamese, Thai, and Asian Indian/Pakistani descent compared to White patients (Chinese AOR 0.88, [0.81-0.94], P = 0.001; Vietnamese AOR 0.89, [0.80 to 0.99], P = 0.032; Thai AOR 0.64, [0.44-0.92], P = 0.016; Asian Indian/Pakistani AOR 0.83, [0.74-0.93], P = 0.001). Palliative care was greater for patients of Japanese and Hawaiian descent with prostate cancer (Japanese AOR 1.92, [1.32-2.75], P = 0.001; Hawaiian AOR 2.09, [1.20-3.66], P = 0.009), breast cancer (Japanese AOR 1.72, [1.21-2.43], P = 0.001; Hawaiian AOR 1.70, [1.08-2.67], P = 0.021), and lung cancer (Japanese AOR 1.92, [1.70-2.17], P < 0.001; Hawaiian AOR 2.95, [2.5-3.5], P < 0.001), as well as patients of Other Pacific Islander descent with lung cancer (AOR 1.62, [1.34-1.96], P < 0.001). CONCLUSIONS AND RELEVANCE: Our findings demonstrate disparities in receipt of palliative care upon disaggregation of diverse AA&NHPI groups, the need for disaggregated research and targeted interventions that address the unique cultural, socioeconomic, and healthcare system barriers to palliative care receipt.

Beyond conventional bounds: Surpassing system limits for stereotactic ablative (SAbR) lung radiotherapy using CBCT-based adaptive planning system.

PURPOSE: Online adaptive radiotherapy relies on a high degree of automation to enable rapid planning procedures. The Varian Ethos intelligent optimization engine (IOE) was originally designed for conventional treatments so it is crucial to provide clear guidance for lung SAbR plans. This study investigates using the Ethos IOE together with adaptive-specific optimization tuning structures we designed and templated within Ethos to mitigate inter-planner variability in meeting RTOG metrics for both online-adaptive and offline SAbR plans. METHODS: We developed a planning strategy to automate the generation of tuning structures and optimization. This was validated by retrospective analysis of 35 lung SAbR cases (total 105 fractions) treated on Ethos. The effectiveness of our planning strategy was evaluated by comparing plan quality with-and-without auto-generated tuning structures. Internal target volume (ITV) contour was compared between that drawn from CT simulation and from cone-beam CT (CBCT) at time of treatment to verify CBCT image quality and treatment effectiveness. Planning strategy robustness for lung SAbR was quantified by frequency of plans meeting reference plan RTOG constraints. RESULTS: Our planning strategy creates a gradient within the ITV with maximum dose in the core and improves intermediate dose conformality on average by 2%. ITV size showed no significant difference between those contoured from CT simulation and first fraction, and also trended towards decreasing over course of treatment. Compared to non-adaptive plans, adaptive plans better meet reference plan goals (37% vs. 100% PTV coverage compliance, for scheduled and adapted plans) while improving plan quality (improved GI (gradient index) by 3.8%, CI (conformity index) by 1.7%). CONCLUSION: We developed a robust and readily shareable planning strategy for the treatment of adaptive lung SAbR on the Ethos system. We validated that automatic online plan re-optimization along with the formulated adaptive tuning structures can ensure consistent plan quality. With the proposed planning strategy, highly ablative treatments are feasible on Ethos.

Adapt-On-Demand: A Novel Strategy for Personalized Adaptive Radiation Therapy for Locally Advanced Lung Cancer.

PURPOSE: Real-time adaptation of thoracic radiation plans is compelling because offline adaptive experiences show that tumor volumes and lung anatomy can change during therapy. We present and analyze a novel adaptive-on-demand (AOD) workflow combining online adaptive radiation therapy (o-ART) on the ETHOS system with image guided radiation therapy delivery on a Halcyon unit for conventional fractionated radiation therapy of locally advanced lung cancer (LALC). METHODS AND MATERIALS: We analyzed 26 patients with LALC treated with the AOD workflow, adapting weekly. We timed segments of the workflow to evaluate efficiency in a real-world clinic. Target coverage and organ at risk (OAR) doses were compared between adaptive plans (ADP) and nonadaptive scheduled plans (SCH). Planning robustness was evaluated by the frequency of preplanning goals achieved in ADP plans, stratified by tumor volume change. RESULTS: The AOD workflow was achievable within 30 minutes for most radiation fractions. Over the course of therapy, we observed an average 26.6% ± 23.3% reduction in internal target volume (ITV). Despite these changes, with o-ART, ITV and planning target volume (PTV) coverage (V100%) was 99.2% and 93.9% for all members of the cohort, respectively. This represented a 2.9% and 6.8% improvement over nonadaptive plans (P < .05), respectively. For tumors that grew >10%, V100% was 93.1% for o-ART and 76.4% for nonadaptive plans, representing a median 17.2% improvement in the PTV coverage (P < .05). In these plans, critical OAR constraints were met 94.1% of the time, whereas in nonadaptive plans, this figure was 81.9%. This represented reductions of 1.32 Gy, 1.34 Gy, or 1.75 Gy in the heart, esophagus, and lung, respectively. The effect was larger when tumors had shrunk more than 10%. Regardless of tumor volume alterations, the PTV/ITV coverage was achieved for all adaptive plans. Exceptional cases, where dose constraints were not met, were due to large initial tumor volumes or tumor growth. CONCLUSIONS: The AOD workflow is efficient and robust in responding to anatomic changes in LALC patients, providing dosimetric advantages over standard therapy. Weekly adaptation was adequate to keep pace with changes. This approach is a feasible alternative to conventional offline replanning workflows for managing anatomy changes in LALC radiation therapy.

Cancer Cachexia in STK11/LKB1 -mutated NSCLC is Dependent on Tumor-secreted GDF15.

Cachexia is a wasting syndrome comprised of adipose, muscle, and weight loss observed in cancer patients. Tumor loss-of-function mutations in STK11/LKB1 , a regulator of the energy sensor AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are associated with cancer-related weight loss in NSCLC patients. Here we characterized the relevance of the NSCLC-associated cachexia factor growth differentiation factor 15 (GDF15) in several patient-derived and genetically engineered STK11/LKB1 -mutant NSCLC cachexia lines. Both tumor mRNA expression and serum concentrations of tumor-derived GDF15 were significantly elevated in multiple mice transplanted with patient-derived STK11/LKB1 -mutated NSCLC lines. GDF15 neutralizing antibody administered to mice transplanted with patient- or mouse-derived STK11/LKB1 -mutated NSCLC lines suppressed cachexia-associated adipose loss, muscle atrophy, and changes in body weight. The silencing of GDF15 in multiple human NSCLC lines was also sufficient to eliminate in vivo circulating GDF15 levels and abrogate cachexia induction, suggesting that tumor and not host tissues represent a key source of GDF15 production in these cancer models. Finally, reconstitution of wild-type STK11/LKB1 in a human STK11/LKB1 loss-of-function NSCLC line that normally induces cachexia in vivo correlated with the absence of tumor-secreted GDF15 and rescue from the cachexia phenotype. The current data provide evidence for tumor-secreted GDF15 as a conduit and a therapeutic target through which NSCLCs with STK11/LKB1 loss-of-function mutations promote cachexia-associated wasting.

American Radium Society Appropriate Use Criteria for Unresectable Locally Advanced Non-Small Cell Lung Cancer.

Importance: The treatment of locally advanced non-small cell lung cancer (LA-NSCLC) has been informed by more than 5 decades of clinical trials and other relevant literature. However, controversies remain regarding the application of various radiation and systemic therapies in commonly encountered clinical scenarios. Objective: To develop case-referenced consensus and evidence-based guidelines to inform clinical practice in unresectable LA-NSCLC. Evidence Review: The American Radium Society (ARS) Appropriate Use Criteria (AUC) Thoracic Committee guideline is an evidence-based consensus document assessing various clinical scenarios associated with LA-NSCLC. A systematic review of the literature with evidence ratings was conducted to inform the appropriateness of treatment recommendations by the ARS AUC Thoracic Committee for the management of unresectable LA-NSCLC. Findings: Treatment appropriateness of a variety of LA-NSCLC scenarios was assessed by a consensus-based modified Delphi approach using a range of 3 points to 9 points to denote consensus agreement. Committee recommendations were vetted by the ARS AUC Executive Committee and a 2-week public comment period before official approval and adoption. Standard of care management of good prognosis LA-NSCLC consists of combined concurrent radical (60-70 Gy) platinum-based chemoradiation followed by consolidation durvalumab immunotherapy (for patients without progression). Planning and delivery of locally advanced lung cancer radiotherapy usually should be performed using intensity-modulated radiotherapy techniques. A variety of palliative and radical fractionation schedules are available to treat patients with poor performance and/or pulmonary status. The salvage therapy for a local recurrence after successful primary management is complex and likely requires both multidisciplinary input and shared decision-making with the patient. Conclusions and Relevance: Evidence-based guidance on the management of various unresectable LA-NSCLC scenarios is provided by the ARS AUC to optimize multidisciplinary patient care for this challenging patient population.

Disparities in Stage at Presentation Among Hispanic and Latinx Patients With Non-Small-Cell Lung Cancer in the United States.

PURPOSE: Hispanic and Latinx people in the United States are the fastest-growing ethnic group. However, previous studies in non-small-cell lung cancer (NSCLC) often analyze these diverse communities in aggregate. We aimed to identify differences in NSCLC stage at diagnosis in the US population, focusing on disaggregated Hispanic/Latinx individuals. METHODS: Data from the National Cancer Database from 2004 to 2018 identified patients with primary NSCLC. Individuals were disaggregated by racial and ethnic subgroup and Hispanic country of origin. Ordinal logistic regression adjusting for age, facility type, income, educational attainment, comorbidity index, insurance, and year of diagnosis was used to create adjusted odds ratios (aORs), with higher odds representing diagnosis at later-stage NSCLC. RESULTS: Of 1,565,159 patients with NSCLC, 46,616 were Hispanic/Latinx (3.0%). When analyzed in the setting of race and ethnicity, Hispanic patients were more likely to be diagnosed with metastatic disease compared with non-Hispanic White (NHW) patients: 47.0% for Hispanic Black, 46.0% Hispanic White, and 44.3% of Hispanic other patients versus 39.1% of non-Hispanic White patients (P < .001 for all). By country of origin, 51.4% of Mexican, 41.7% of Puerto Rican, 44.6% of Cuban, 50.8% of South or Central American, 48.4% of Dominican, and 45.6% of other Hispanic patients were diagnosed with metastatic disease, compared with 39.1% of NHWs. Conversely, 20.2% of Mexican, 26.9% of Puerto Rican, 24.2% of Cuban, 22.5% of South or Central American, 23.7% of Dominican, and 24.5% of other Hispanic patients were diagnosed with stage I disease, compared with 30.0% of NHWs. All Hispanic groups were more likely to present with later-stage NSCLC than NHW patients (greatest odds for Mexican patients, aOR, 1.44; P < .001). CONCLUSION: Hispanic/Latinx patients with non-small-cell lung cancer were more likely to be diagnosed with advanced disease compared with NHWs. Disparities persisted upon disaggregation by both race and country of origin, with over half of Mexican patients with metastatic disease at diagnosis. Disparities among Hispanic/Latinx groups by race and by country of origin highlight the shortcomings of treating these groups as a monolith and underscore the need for disaggregated research and targeted interventions.

Concerning safety and efficacy of concurrent and consolidative durvalumab with thoracic radiotherapy in PDL1-unselected stage III non-small cell lung cancer: brief report.

INTRODUCTION: Consolidative durvalumab, an anti-programmed death ligand 1 (PDL1) immune checkpoint inhibitor, administered after concurrent chemoradiation improves outcomes of patients with locally advanced non-small cell lung cancer (NSCLC) without substantially increasing toxicities. We studied a chemotherapy-free regimen of thoracic radiotherapy (RT) with concurrent and consolidative durvalumab. METHODS: This single-arm phase II trial enrolled patients with stage III NSCLC (regardless of tumor PDL1 expression), performance status ECOG 0-1, adequate pulmonary function, and RT fields meeting standard organ constraints. Participants received two cycles of durvalumab (1500 mg every 4 weeks) concurrently with thoracic RT (60 Gy in 30 fractions), followed by up to 13 cycles of consolidative durvalumab. RESULTS: After 10 patients were enrolled, the trial was closed due to poor clinical outcomes. With a median follow-up of 12 months, five patients had disease progression and eight patients died. Six patients experienced 15 treatment-related, grade ≥3 events, including one grade 4 acute kidney injury during consolidation and two fatal pulmonary events. One fatal pulmonary event occurred during the concurrent phase in an active smoker; the other occurred after the first cycle of consolidative durvalumab. The primary endpoint of progression-free survival (PFS) at 12 months was 20% (50% for PDL1≥1% versus 0% for PDL1 unavailable or <1%). Median overall survival (OS) was not reached, 10.5 months, and 7 months, for PDL1 ≥1%, <1%, and unavailable, respectively. CONCLUSIONS: In PDL1 unselected stage III NSCLC, thoracic RT plus concurrent and consolidative durvalumab is associated with high-grade toxicity and early disease progression.

A molecular pathway for cancer cachexia-induced muscle atrophy revealed at single-nucleus resolution.

Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single-nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-dependent gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. Short hairpin RNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of muscle atrophy associated with cancer cachexia and highlight potential therapeutic targets for this disorder.

BIOGUIDE-X: A First-in-Human Study of the Performance of Positron Emission Tomography-Guided Radiation Therapy.

PURPOSE: Positron emission tomography (PET)-guided radiation therapy is a novel tracked dose delivery modality that uses real-time PET to guide radiation therapy beamlets. The BIOGUIDE-X study was performed with sequential cohorts of participants to (1) identify the fluorodeoxyglucose (FDG) dose for PET-guided therapy and (2) confirm that the emulated dose distribution was consistent with a physician-approved radiation therapy plan. METHODS AND MATERIALS: This prospective study included participants with at least 1 FDG-avid targetable primary or metastatic tumor (2-5 cm) in the lung or bone. For cohort I, a modified 3 + 3 design was used to determine the FDG dose that would result in adequate signal for PET-guided therapy. For cohort II, PET imaging data were collected on the X1 system before the first and last fractions among patients undergoing conventional stereotactic body radiation therapy. PET-guided therapy dose distributions were modeled on the patient's computed tomography anatomy using the collected PET data at each fraction as input to an "emulated delivery" and compared with the physician-approved plan. RESULTS: Cohort I demonstrated adequate FDG activity in 6 of 6 evaluable participants (100.0%) with the first injected dose level of 15 mCi FDG. In cohort II, 4 patients with lung tumors and 5 with bone tumors were enrolled, and evaluable emulated delivery data points were collected for 17 treatment fractions. Sixteen of the 17 emulated deliveries resulted in dose distributions that were accurate with respect to the approved PET-guided therapy plan. The 17th data point was just below the 95% threshold for accuracy (dose-volume histogram score = 94.6%). All emulated fluences were physically deliverable. No toxicities were attributed to multiple FDG administrations. CONCLUSIONS: PET-guided therapy is a novel radiation therapy modality in which a radiolabeled tumor can act as its own fiducial for radiation therapy targeting. Emulated therapy dose distributions calculated from continuously acquired real-time PET data were accurate and machine-deliverable in tumors that were 2 to 5 cm in size with adequate FDG signal characteristics.

Long-Term Prospective Outcomes of Intensity Modulated Radiotherapy for Locally Advanced Lung Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The optimal radiotherapy technique for unresectable locally advanced non-small cell lung cancer (NSCLC) is controversial, so evaluating long-term prospective outcomes of intensity-modulated radiotherapy (IMRT) is important. Objective: To compare long-term prospective outcomes of patients receiving IMRT and 3-dimensional conformal radiotherapy (3D-CRT) with concurrent carboplatin/paclitaxel for locally advanced NSCLC. Design, Setting, and Participants: A secondary analysis of a prospective phase 3 randomized clinical trial NRG Oncology-RTOG 0617 assessed 483 patients receiving chemoradiotherapy (3D-CRT vs IMRT) for locally advanced NSCLC based on stratification. Main Outcomes and Measures: Long-term outcomes were analyzed, including overall survival (OS), progression-free survival (PFS), time to local failure, development of second cancers, and severe grade 3 or higher adverse events (AEs) per Common Terminology Criteria for Adverse Events, version 3. The percentage of an organ volume (V) receiving a specified amount of radiation in units of Gy is reported as V(radiation dose). Results: Of 483 patients (median [IQR] age, 64 [57-70] years; 194 [40.2%] female), 228 (47.2%) received IMRT, and 255 (52.8%) received 3D-CRT (median [IQR] follow-up, 5.2 [4.8-6.0] years). IMRT was associated with a 2-fold reduction in grade 3 or higher pneumonitis AEs compared with 3D-CRT (8 [3.5%] vs 21 [8.2%]; P = .03). On univariate analysis, heart V20, V40, and V60 were associated with worse OS (hazard ratios, 1.06 [95% CI, 1.04-1.09]; 1.09 [95% CI, 1.05-1.13]; 1.16 [95% CI, 1.09-1.24], respectively; all P < .001). IMRT significantly reduced heart V40 compared to 3D-CRT (16.5% vs 20.5%; P < .001). Heart V40 (<20%) had better OS than V40 (≥20%) (median [IQR], 2.5 [2.1-3.1] years vs 1.7 [1.5-2.0] years; P < .001). On multivariable analysis, heart V40 (≥20%), was associated with worse OS (hazard ratio, 1.34 [95% CI, 1.06-1.70]; P = .01), whereas lung V5 and age had no association with OS. Patients receiving IMRT and 3D-CRT had similar rates of developing secondary cancers (15 [6.6%] vs 14 [5.5%]) with long-term follow-up. Conclusions and Relevance: These findings support the standard use of IMRT for locally advanced NSCLC. IMRT should aim to minimize lung V20 and heart V20 to V60, rather than constraining low-dose radiation bath. Lung V5 and age were not associated with survival and should not be considered a contraindication for chemoradiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT00533949.

The Emerging Role of Immunotherapy in Resectable Non-Small Cell Lung Cancer.

BACKGROUND: Despite surgical resection, long-term survival of patients with resectable non-small cell lung cancer (NSCLC) remains poor. Adjuvant chemotherapy, the standard of care for locally advanced NSCLC, provides a marginal 5.4% benefit in survival. Immune checkpoint inhibitors (ICIs) have shown a significant survival benefit in some patients with advanced NSCLC and are being evaluated for perioperative use in resectable NSCLC. METHODS: We conducted a literature search using the PubMed online database to identify clinical trials of immunotherapy in resectable NSCLC and studies analyzing biomarkers and immune priming strategies. RESULTS: Building on previous phase I and II trials, randomized phase III trials have shown efficacy of neoadjuvant nivolumab, perioperative pembrolizumab, adjuvant atezolizumab, and adjuvant pembrolizumab in the treatment of NSCLC with improvement of event-free/disease-free survival of 24% to 42%, leading to United States Food and Drug Administration approval of these drugs in the treatment of resectable NSCLC. Three additional phase III trials have also recently reported the use of immunotherapy both before and after surgery, with pathologic complete response rates of 17% to 25%, significantly better than chemotherapy alone. Perioperative ICI therapy has comparable perioperative morbidity to chemotherapy alone and does not impair surgical outcomes. CONCLUSIONS: Perioperative immunotherapy, in combination with chemotherapy, is safe and improves outcomes in patients with resectable NSCLC. Questions regarding patient selection, the need for adjuvant ICI therapy after neoadjuvant chemoimmunotherapy, and the duration of perioperative immunotherapy remain to be answered by future trials.