Does Early Chemotherapy Improve Survival in Advanced Endometrial Cancer? Objectives: In endometrial cancer, the appropriate sequence of adjuvant chemotherapy (aCT) and adjuvant radiation therapy (aRT) is unclear. We aim evaluated whether early chemotherapy is associated with improved overall survival (OS) and cancer-specific survival (CSS). Methods: Endometrial cancer patients that received aCT and aRT were selected from the SEER-Medicare database. Early chemotherapy was defined as receiving aCT before aRT, with or without additional aCT (“sandwich” regimens). All other patients received a full course of aRT before chemotherapy with or without concurrent chemotherapy. Univariate and multivariate Cox proportional hazards regression was utilized to assess the impact of clinical and demographic factors on OS. Results: We selected 597 patients for analysis. Median age and was 72 years; 85% of patients were white. Overall, 68% of women had FIGO (International Federation of Gynecology and Obstetrics) stage III disease and 77% received 4 to 6 cycles of chemotherapy. Five-year OS (66.6% vs. 62.4%, P=0.46) and 5-year CSS (71.1% vs. 71.2%, P=0.88) was not significantly improved among those receiving early chemotherapy. In addition, early chemotherapy did not improve OS (hazard ratio [HR]=0.87; 95% confidence interval [CI]: 0.56-1.34, P=0.53) or CSS (HR=1.21; 95% CI: 0.82-1.79, P=0.34) on multivariate analysis. Compared with 1 to 3 cycles, receiving 4 to 6 (HR=0.48, 95% CI: 0.26-0.87, P=0.02), and ≥7 cycles (HR=0.42, 95% CI: 0.20-0.89, P=0.02) of chemotherapy was associated with improved OS. Conclusion: No differences in OS or CSS were noted among endometrial patients receiving early chemotherapy. However, the number of chemotherapy cycles was associated with prolonged survival.

Paragangliomas of the Head and Neck: Local Control and Functional Outcome Following Fractionated Stereotactic Radiotherapy Objectives: To investigate local control and functional outcome following state-of-the-art fractionated stereotactic radiotherapy (FSRT) for paragangliomas of the head and neck. Methods: In total, 40 consecutive patients with paragangliomas of the head and neck received conventionally FSRT from 2003 to 2016 at the Department of Radiation Oncology of the University Hospital Erlangen. Local control, toxicities, and functional outcome were examined during follow-up. In total, 148 magnetic resonance imaging studies were subjected to longitudinal volumetric analysis using whole tumor segmentation in a subset of 22 patients. Results: A total of 80.0% (32/40) of patients received radiotherapy as part of their primary treatment. In 20.0% (8/40) of patients, radiation was used as salvage treatment after tumor recurrence in patients initially treated with surgery alone. The median dose applied was 54.0 Gy (interdecile range, 50.4 to 56.0 Gy) in single doses of 1.8 or 2 Gy. Local control was 100% after a median imaging follow-up of 52.2 months (range, 0.8 to 152.9 mo). The volumetric analysis confirmed sustained tumor control in a subset of 22 patients and showed transient enlargement (range, 129.6% to 151.2%) in 13.6% of cases (3/22). After a median volumetric follow-up of 24.6 months mean tumor volume had diminished to 86.1% compared with initial volume. In total, 52.5% (21/40) of patients reported improved symptoms after radiotherapy, 40% (16/40) observed no subjective change with only 7.5% (3/40) reporting significant worsening. Conclusions: State-of-the-art FSRT provides excellent control and favorable functional outcome in patients with paragangliomas of the head and neck. The volumetric analysis provides improved evidence for sustained tumor control.

Prognosis and Management of Thick and Ultrathick Melanoma Objectives: Thick melanomas, defined as ≥4 mm in thickness, represent ~5% of new melanoma diagnoses and have been associated with poor overall survival (OS). Ultrathick melanomas, those lesions ≥8 mm in thickness, have been associated with worse survival. We sought to compare prognostic factors for thick and ultrathick melanoma. Methods: Retrospective analysis of a prospective database of all patients receiving an operation for melanoma, June 2005 to December 2016 was performed. Multivariate Cox proportional hazards regression analyses were performed to identify predictors of progression-free survival (PFS) and OS. Results: Of 95 patients with thick melanoma, 37 (39%) had ultrathick tumors (≥8 mm thick). Thick and ultrathick lesions were not significantly different on the basis of tumor location, ulceration, mitotic rate, lymphovascular invasion, or performance or positivity of sentinel node biopsy or therapeutic lymphadenectomy. Disease recurrence was identified in 38 patients overall (40%), more commonly in ultrathick disease (55% vs. 29%, P=0.008). Serum neutrophil to lymphocyte ratio (NLR) was available for 36 patients, of whom 23 (64%) had high NLR (>3.0). Decreased PFS was independently associated with ultrathick tumors (HR, 2.9; P=0.003), head/neck location (HR, 2.6; P=0.023), and positive lymph nodes (HR, 3.3; P=0.004). Decreased OS was independently associated with high NLR (HR, 5.0; P=0.042). Conclusions: Disease progression was higher in the ultrathick melanoma group. Thicker tumors, head/neck location, and positive lymph nodes were associated with decreased PFS. High NLR was associated with decreased OS. Ultrathick melanomas represent advanced malignancy; however, patients may derive benefit from surgical treatment to achieve locoregional control.

National Burden of Hospitalization Due to Cutaneous Melanoma in Adolescents and Young Adults Objectives: Although adolescents and young adults (AYA) suffer disproportionately from cutaneous melanoma (CM), little is known regarding the burden of CM leading to hospitalization in AYA. The objective of this study was to elucidate sociodemographic/hospitalization characteristics of AYA CM inpatients, determine which factors lead to the greater length of stay (LOS) and cost of care for AYA CM inpatients, and evaluate trends in the prevalence, LOS, and cost of care for AYA CM hospitalizations. Materials and Methods: A retrospective cohort study of nationally representative data from the 2009 to 2015 National Inpatient Sample. Multivariable survey-weighted logistic regression models were used to determine sociodemographic factors associated with AYA CM hospitalization. Multivariable survey-weighted linear regression models were used to determine characteristics associated with the greater cost of care and LOS in AYA CM inpatients. Results: A total of 8986 AYA CM inpatients were included in this study. The prevalence of AYA CM hospitalizations is decreasing over time while the cost of care is increasing. On average, AYA CM hospitalizations were 3.3 days long and cost $38,018.40. Controlling for all covariates, male sex, older age, non-Hispanic white race, higher income, private insurance, and elective admissions were associated with AYA hospitalization due to CM (P<0.0001). Male sex was associated with longer LOS (P=0.007) and cost of care (P=0.01) among AYA hospitalized for CM. Conclusions: Despite a decreasing prevalence of CM hospitalizations in AYA inpatients, the economic burden of these hospitalizations is increasing. Substantial sex-based differences exist in the inpatient burden of AYA CM. Further research is required to elucidate the causes of these differences and prevent AYA hospitalization due to CM.

Cost-Effectiveness Analysis of Upfront SBRT for Oligometastatic Stage IV Non–Small Cell Lung Cancer Based on Mutational Status Objectives: Current National Comprehensive Cancer Network (NCCN) guidelines support systemic therapy based on mutational status in stage IV non–small cell lung cancer (NSCLC), with stereotactic body radiation therapy (SBRT) reserved for oligoprogression. We aimed to evaluate the cost-effectiveness of the routine addition of SBRT to upfront therapy in stage IV NSCLC by mutational subgroup. Materials and Methods: A Markov state transition model was constructed to perform a cost-effectiveness analysis comparing SBRT plus maintenance therapy with maintenance therapy alone for oligometastatic NSCLC. Three hypothetical cohorts were analyzed: epidermal growth factor receptor or anaplastic lymphoma kinase mutation-positive, programmed death ligand-1 expressing, and mutation-negative group. Clinical parameters were obtained largely from clinical trial data, and cost data were based on 2018 Medicare reimbursement. Strategies were compared using the incremental cost-effectiveness ratio with effectiveness in quality-adjusted life years (QALYs) and evaluated with a willingness to pay threshold of $100,000 per QALY gained. Results: SBRT plus maintenance therapy was not cost-effective at a $100,000/QALY gained threshold, assuming the same survival for both treatments, resulting in an incremental cost effectiveness ratio of $564,186 and $299,248 per QALY gained for the epidermal growth factor receptor or anaplastic lymphoma kinase positive and programmed death ligand-1 positive cohorts, respectively. Results were most sensitive to the cost of maintenance therapy. A large overall survival gain with SBRT could potentially result in upfront SBRT becoming cost-effective. For the mutation-negative cohort, upfront SBRT was nearly cost-effective, costing $128,424 per QALY gained. Conclusion: Adding SBRT to maintenance therapy is not a cost-effective strategy for oligometastatic NSCLC compared with maintenance therapy alone for mutation-positive groups. However, this should be validated via randomized trials.

Intrapatient Molecular and Histologic Heterogeneity After First-generation or Second-generation TKI Therapy of NSCLC Patients: Potential Clinical Impact on Subsequent third-generation TKI Treatment Objectives: The discovery of tyrosine kinase inhibitors (TKI) has remarkably improved the clinical course of patients with non–small cell lung cancer driven by Epidermal Growth Factor Receptor (EGFR) mutations. However, virtually in all cases, the disease resurfaces in a TKI-resistant form that is mainly linked to an acquired EGFR-T790M mutation, a MET amplification, or small cell lung cancer (SCLC) transformation. Third-generation TKIs are able to block tumor growth through an irreversible binding to the T790M-mutated receptor. Such new treatments require the diagnostic analysis of new pathologic tissue or a liquid biopsy to detect the presence of the T790M mutation. Materials and Methods: Pre-TKI and post-TKI biopsies from 27 patients with an activating EGFR mutation were collected and analyzed for EGFR-T790M mutation, MET amplification, and SCLC transformation. Results: The T790M mutation was found in 16 patients (59%) whereas MET gene amplification was found in 2 (10.5%) of 19 evaluated cases. The histologic transformation from adenocarcinoma (ADC) to SCLC was identified in 3 patients (11%). In one of them reversal from SCLC back to adenocarcinoma was observed. One patient had the T790M mutation concordantly detected in 2 synchronous lesions whereas another patient showed T790M positivity only in one of 2 specimens. In 4 patients longitudinal biopsies revealed T790M gains and losses not always according to biological expectations. Conclusions: Intrapatient molecular or histologic heterogeneity may be frequently found during routine treatment of non–small cell lung cancer patients. This biological aspect may have profound repercussions on subsequent therapeutic decisions, and therefore requires in-depth investigation.

A Matter of Comprehensive Informed Consent: Short-Term Mortality Rates With Definitive Treatment Options in Elderly Stage I NSCLC Background: Although lobectomy is the standard of care in stage I non–small cell lung cancer (NSCLC), medical comorbidities increase surgical risk in elderly patients. No population-based studies compare short-term mortality (STM) for surgery (STM-S), radiation (STM-R), and observation (STM-O) in elderly patients with stage I NSCLC. Methods: A total of 60,466 biopsy-proven stage I NSCLC cases diagnosed between 2004 and 2012 were retrieved from the Surveillance, Epidemiology, and End Results Program. Patient characteristics were compared using χ2 test. Age was divided into 5-year subsets (60 to 64 to 90+ y) for analysis. Similar to other series, STM was defined as death within 2 months of diagnosis. Univariate and multivariate analysis for STM was performed using odds ratio, Kaplan-Meier actuarial method, and Cox proportional hazard ratio. Results: In younger patients, STM-S rates are lower compared with STM-R (1.6% vs. 3.4% in patients 60 to 64 y, P<0.001). However, STM-S rates surpass STM-R with increasing age (up to 8.1% vs. 2.3% in patients 90+ y, P<0.001) becoming significant in the 75- to 79-year age group (4.7% vs. 2.2%, P<0.001). There is an inflection point in the 65- to 69-year age group where STM-S and STM-R rates are similar (2.6% vs. 3.0%, P=0.090). STM for observation reflected the poor health of this cohort with high STM rates in all age groups (19.5% for age 60 to 64 y to 25.3% for age 90+ y, P=0.005). Sex, race, Hispanic ethnicity, age group, and treatment were associated with higher STM on the multivariable analysis (all P<0.001). Conclusion: STM in elderly stage I NSCLC patients treated with surgery increases with advancing age but remains stable for patients receiving radiation. Given the success of stereotactic body radiation therapy, radiation should be considered for patients with high STM risk associated with surgery.

Early Exploratory Analysis for Patient-reported Quality of Life and Dosimetric Correlates in Hypofractionated Stereotactic Body Radiation Therapy (SBRT) for Low-risk and Intermediate-risk Prostate Cancer: Interim Results from a Prospective Phase II Clinical Trial Objectives: Given the relative novelty of stereotactic body radiation therapy as a treatment modality low-risk and intermediate-risk prostate cancer, little data exist evaluating dosimetry and its impact on patient-reported quality of life (PR-QOL) metrics. Herein, we present an interim analysis of a phase II clinical trial of PR-QOL and dosimetric correlates. Methods: Patients with biopsy-proven low-risk or intermediate-risk prostate cancer, prostate volume ≤100 cm3, and life expectancy ≥10 years were enrolled. Expanded Prostate Cancer Index Composite (EPIC) scores were tabulated by domain and evaluated in relation to dosimetry. Paired t test was performed to compare differences in scores from baseline. Minimally important differences were established using the anchor-based approach and correlations made using the χ2 test. Results: A total of 95 patients were analyzed with a median follow-up of 18.1 months (range, 3.0 to 76.9 mo). There were no cases of acute or late grade 3+ GI or GU toxicities. Expanded Prostate Cancer Index Composite scores in urinary obstructive/irritative domain at 1 month (−4.8, P=0.03) and bowel domain at 1, 6, and 12 months (−10.8, −6.1, and −5.2) were significantly different from pretreatment, with both returning to nonsignificant differences around 24 months. Higher bladder V37Gy (≥3.35%) was associated with both late urinary incontinence and obstructive/irritative declines. Both higher rectal D5% and rectal V36Gy >0.6 cm3 were correlated with an enhanced proportion of patients with late minimally important difference declines. Conclusions: Higher dose volumes for the bladder and rectum predicted for poorer PR-QOL. In contrast to prostate brachytherapy data, neither prostate volume nor urethral dosimetry at this dose schedule correlated with urinary symptoms.

Phase I Study of IGF-Methotrexate Conjugate in the Treatment of Advanced Tumors Expressing IGF-1R Objectives: Insulin-like growth factor-methotrexate (IGF-MTX) is a conjugate of methotrexate and 765IGF, a variant of IGF-1 with high affinity for insulin-like growth factor type 1 receptor. The study aim was to determine the maximum tolerated dose of IGF-MTX in refractory solid organ and hematologic malignancies expressing insulin-like growth factor type 1 receptor. Materials and Methods: This phase I trial used a modified toxicity probability interval design with 5 cohort dose levels, and expansion cohort at maximum tolerated dose. IGF-MTX was given intravenously over 90 minutes on days 1, 8, and 15 of a 28-day cycle. Results: A total of 17 patients were enrolled. The highest tolerated dose tested was 0.80 µEq/kg with dose-limiting toxicity of grade 3 hypoglycemia. Drug-related grade 3 and 4 toxicities included abdominal pain (26%), hypoglycemia (10%), and hypotension (10%). Of the 15 evaluable for response, 3 patients (20%) had stable disease, including the patient with Hodgkin lymphoma with stable disease for 12 cycles of therapy. IGF-MTX concentrations declined rapidly, with half-lives of 5.2 to 14 minutes for the initial distribution phase and 6.5 to 7.5 hours for the terminal elimination phase. Higher IGF-R1 expression did not correlate with better outcome. Conclusions: IGF-MTX is well tolerated. IGF-MTX pharmacokinetics suggest rapid cellular uptake. The activity of IGF-MTX in Hodgkin lymphoma should be explored.

Determining the Impact of a Cancer Diagnosis on Diabetes Management: A Systematic Literature Review Objectives: Cancer patients with comorbid diabetes have a 50% increased risk of all-cause mortality compared with cancer patients without diabetes. Less attention to diabetes management (glucose control, medication adherence, and diabetes self-management behaviors) during active cancer treatment is hypothesized as an explanation for worse outcomes among diabetic cancer patients. The objective of this systematic review is to determine and quantify how a cancer diagnosis impacts diabetes management. Methods: Quantitative and qualitative studies evaluating diabetes management among patients were identified by searching 4 databases: MEDLINE, EMBASE, The Cochrane Library, and Web of Science. Two independent reviewers extracted data and summarized results from eligible studies. Study quality was formally assessed. Results: Thirty-six studies met all inclusion criteria. We observed heterogeneity across studies in terms of study design, sample size, cancer site, type of diabetes management evaluated, and quality. Numerous articles discussed that overall, glucose control, medication adherence, and diabetes self-management behaviors declined following a cancer diagnosis. However, findings were inconsistent across studies. Conclusions: Although the effects of a cancer diagnosis on diabetes management are mixed, when results across studies were synthesized together, diabetes management appeared to generally decline after a cancer diagnosis. Declines in diabetes management seem to be primarily due to shifts in the priority of care from diabetes management to cancer. A next critical step in this line of work is to identify patient and provider level predictors of better or worse diabetes management to design and test interventions aimed at improving effective diabetes management for cancer patients.