Retrospective review of the toxicities and change in dosing patterns for pegaspargase in patients with acute lymphoblastic leukemia/lymphoma and T-cell lymphoma.

INTRODUCTION: Pegaspargase (PEG) is a key component of standard regimens for acute lymphoblastic leukemia/lymphoma (ALL) and extranodal natural killer/T-cell lymphoma (NKTCL). Emerging evidence suggests an opportunity to decrease incidence of PEG-associated toxicities with dose capping, but evidence is limited. This study aims to evaluate whether a significant difference in PEG-associated toxicities related to dosing strategy exists and to identify patient-specific or regimen-specific factors for PEG-related toxicity. METHODS: A retrospective analysis of PEG-associated toxicities was completed in adult patients with ALL or NKTCL who received PEG within Cancer and Leukemia Group B (CALGB) 10403 or modified dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) regimens at the UW Medical Center/Fred Hutchinson Cancer Center. PEG-associated toxicities that occurred through 8 weeks after PEG doses were noted. RESULTS: Twenty-eight patients received dose-capped PEG, and 29 received noncapped PEG. Fewer all-grade and grade 3/4 toxicities were observed in the dose-capped cohort. Grade 3/4 toxicities observed were hepatotoxicity, hyperglycemia, hypersensitivity, and hypertriglyceridemia. In addition, fewer grade 3/4 pancreatitis and thrombosis events occurred in the dose-capped cohort. Hypertriglyceridemia and hepatotoxicity were associated with the highest cumulative incidence proportions among all toxicities. CONCLUSION: Dose capping of PEG was associated with a similar or later median onset for most toxicities, a less heterogeneic toxicity profile, and a lower recurrence of most toxicities upon PEG rechallenge compared to the non-dose-capped cohort. Standardizing PEG dose capping in the CALGB 10403 and mSMILE regimens may translate to improved tolerance compared to a historical standard of no dose capping PEG.

Avoiding Overtreatment of Women ≥70 With Early-Stage Breast Cancer: A Provider-Level Deimplementation Strategy.

INTRODUCTION: National guidelines recommend against routine axillary staging with sentinel lymph node biopsy (SLNB) and adjuvant radiotherapy (RT) in women ≥70 y with early-stage, hormone receptor-positive, HER2-negative breast cancer and clinically negative axilla; however, these practices remain common. METHODS: We conducted a prospective pilot study from August 2021 to 2022 using an intervention targeting breast surgeons and radiation oncologists in Michigan that aimed to reduce SLNB and RT in eligible patients. The intervention consisted of (1) a geriatric assessment, (2) an assessment of the patient's medical maximizing-minimizing preferences, and (3) a tailored script with counterpoints to reasons patients commonly seek SLNB or RT. At the end of the study period, participants completed a survey providing feedback with the primary outcomes being: acceptability, appropriateness, feasibility, and intention and motivation to use the materials based on validated measures. RESULTS: Participants (n = 23) included 15 breast surgeons and 8 radiation oncologists. Collectively, the materials were used with 115 patients. Considering all materials holistically, acceptability, appropriateness, and feasibility of the intervention were high; participants also intended and were motivated to use the intervention. Scores across all measures were highest for the geriatric assessment and lowest for the tailored script. The major barriers to using the intervention were limited time and instances of disagreement on treatment recommendations among surgeons and radiation oncologists. CONCLUSIONS: The omission of SLNB and adjuvant RT should be discussed in appropriately selected patients. A multifaceted provider-level deimplementation strategy may be an effective means for achieving this goal.

Predicting adjuvant endocrine therapy initiation and adherence among older women with early-stage breast cancer.

PURPOSE: The CALGB 9343 trial demonstrated that women age 70 or older with early-stage, estrogen receptor positive (ER +) breast cancer (BC) may safely forgo radiation therapy (RT) and be treated with breast conserving surgery followed by adjuvant endocrine therapy (AET) alone. However, most patients in this population still undergo RT in part because AET adherence is low. We sought to develop a predictive model for AET initiation and adherence in order to improve decision-making with respect to RT omission. METHODS: Women ages 70 and older with early-stage, ER + BC were identified using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Comorbidities, socioeconomic measures, prescription medications, and demographics were collected as potential predictors. Bivariate analysis was performed to identify factors associated with AET initiation and adherence. Stepwise selection of significant predictors was used to develop logistic regression classifiers for initiation and adherence. Model performance was evaluated using the c-statistic and other measures. RESULTS: 11,037 patients met inclusion criteria. Within the cohort, 8703 (78.9%) patients initiated AET and 6685 (60.6%) were adherent to AET over 1 year. Bivariate predictors of AET initiation were similar to predictors of adherence. The best AET initiation and adherence classifiers were poorly predictive with c-statistics of 0.65 and 0.60, respectively. CONCLUSIONS: The best models in the present study were poorly predictive, demonstrating that the reasons for initiation and adherence to AET are complex and individual to the patient, and therefore difficult to predict. Initiation and adherence to AET are important factors in decision-making regarding whether or not to forgo adjuvant RT. In order to better formulate treatment plans for this population, future work should focus on improving individual prediction of AET initiation and adherence.

Long-term Impact of CALGB 9343 on Radiation Utilization.

BACKGROUND: The results of the Cancer and Leukemia Group B (CALGB) 9343 trial showed that radiation therapy (RT) did not improve survival for women older than 70 y with early-stage estrogen receptor + breast cancer treated with breast conserving surgery and adjuvant endocrine therapy. In 2005, guidelines were modified to allow for RT omission; however, minimal change in clinical practice has occurred. The aim of this study was to determine if CALGB long-term follow-up data have affected RT utilization, and to characterize the population still receiving RT after breast conserving surgery. METHODS: The Surveillance, Epidemiology, and End Results-Medicare database was used to identify women diagnosed with early-stage breast cancer from 2004 to 2015 who matched the CALGB 9343 inclusion criteria. Multivariate logistic regression was carried out to identify the factors that affect the receipt of radiation therapy. We also plotted the overall use of RT over time juxtaposed with the temporal trends of CALGB 9343 clinical trial data, guideline recommendations, and publishing of long-term survival data. RESULTS: The study cohort included 25,723 Medicare beneficiaries, of whom 20,328 (79%) received RT and 5395 (21%) did not receive RT. In a multivariate model, the frequency of RT omission increased over time, with those diagnosed in year 2015 being 2.72 times more likely to omit RT compared with those diagnosed in 2004 (95% confidence interval 2.31-3.19). CONCLUSIONS: This study investigated the impact of long-term CALGB 9343 data on clinical practice. The results of this study support results from previous studies, extend the dates of analysis, and indicate that after long-term follow-up of CALGB 9343 data, RT was less used, but overall trends did not dramatically decrease.

The evolving role of adjuvant radiotherapy for elderly women with early-stage breast cancer.

BACKGROUND: Elderly patients with early-stage breast cancer (ESBC) derive a local control benefit from radiotherapy (RT) after lumpectomy, without any apparent effect on overall survival. Therefore, the use of RT is controversial. In the current study, the authors characterized updated trends in RT for elderly patients with estrogen receptor (ER)-positive ESBC. METHODS: Patients aged ≥70 years with ER-positive ESBC measuring ≤2 cm after lumpectomy with negative resection margins and known RT details were identified in the National Cancer Data Base. Patients were classified by year of diagnosis and segregated into 3 groups relative to the initial publication and updated presentation of the Cancer and Leukemia Group B (CALGB) 9343 trial. RT use overall, prescription of hypofractionated RT, and use of boost RT were compared between groups using logistic regression analysis, and the influence of clinicopathologic covariates was determined with multivariable logistic regression analysis. RESULTS: A total of 122,796 elderly patients with ER-positive ESBC who were diagnosed between 1998 and 2011 were identified. Overall, 84,649 patients (68.9%) received adjuvant RT, with a decline observed between successive cohorts (71.3% in the pre-initial publication cohort, 69.5% in the pre-update cohort, and 64.7% in the post-update cohort; P <.001). Hypofractionated RT use increased among treated patients over time (P<.001). Boost RT was used in 67.5% of patients, with a decline noted between the pre-update and post-update cohorts (68.7% vs 57.7%; P<.001). Overall RT use as well as use of boost RT were found to be lower among older patients and those with lower-grade or smaller tumors (P<.001), whereas hypofractionated RT was used more commonly in these groups (P<.001). CONCLUSIONS: RT use appears to have declined in elderly patients with ER-positive ESBC, a finding that is reflective of evidence-based practice integrating mature trial data. Further research is needed to develop tools to aid in the decision-making process regarding the delivery or avoidance of RT in this setting.

The use of adjuvant radiotherapy in elderly patients with early-stage breast cancer: changes in practice patterns after publication of Cancer and Leukemia Group B 9343.

BACKGROUND: The Cancer and Leukemia Group B (CALGB) 9343 randomized phase 3 trial established lumpectomy and adjuvant therapy with tamoxifen alone, rather than both radiotherapy and tamoxifen, as a reasonable treatment course for women aged >70 years with clinical stage I (AJCC 7th edition), estrogen receptor-positive breast cancer. An analysis of the Surveillance, Epidemiology, and End Results (SEER) registry was undertaken to assess practice patterns before and after the publication of this landmark study. METHODS: The SEER database from 2000 to 2009 was used to identify 40,583 women aged ≥70 years who were treated with breast-conserving surgery for clinical stage I, estrogen receptor-positive and/or progesterone receptor-positive breast cancer. The percentage of patients receiving radiotherapy and the type of radiotherapy delivered was assessed over time. Administration of radiotherapy was further assessed across age groups; SEER cohort; and tumor size, grade, and laterality. RESULTS: Approximately 68.6% of patients treated between 2000 and 2004 compared with 61.7% of patients who were treated between 2005 and 2009 received some form of adjuvant radiotherapy (P < .001). Coinciding with a decline in the use of external beam radiotherapy, there was an increase in the use of implant radiotherapy from 1.4% between 2000 and 2004 to 6.2% between 2005 to 2009 (P < .001). There were significant reductions in the frequency of radiotherapy delivery over time across age groups, tumor size, and tumor grade and regardless of laterality (P < .001 for all). CONCLUSIONS: Randomized phase 3 data support the omission of adjuvant radiotherapy in elderly women with early-stage breast cancer. Analysis of practice patterns before and after the publication of these data indicates a significant decline in radiotherapy use; however, nearly two-thirds of women continue to receive adjuvant radiotherapy.

CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer.

BACKGROUND & AIMS: The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL). METHODS: We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated. RESULTS: Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P = .07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P = .049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P = .01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses. CONCLUSIONS: Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.

Biomarkers and prognostic factors for malignant pleural mesothelioma.

The increasing incidence and the dismal prognosis of malignant pleural mesothelioma calls for the identification of biomarkers that will allow a timely diagnosis; display prognostic value; and, predict the response to pharmacological agents employed for the treatment of the disease. Biomarkers associated with early diagnosis currently include mesothelin in combination with miRNA miR-103a-3p. As for prognostic biomarkers, the Cancer and Leukemia Group B (CALGB) and the European Organization for Research and Treatment of Cancer (EORTC) scores take into account different hematological and clinical parameters that distinguish patients with good prognosis from those with inferior outcomes. Fluorodeoxyglucose-PET, microarray expression data, neutrophil-to-lymphocyte ratios, c-MET expression, Ki-67 ratios and fibulin-3 levels have also been associated with disease outcome. Finally, thymidylate synthase protein cutoffs may predict mesothelioma response to the association of pemetrexed with a platinum derivative.

A phase II study of cixutumumab (IMC-A12, NSC742460) in advanced hepatocellular carcinoma.

BACKGROUND & AIMS: IGF-IR is implicated in hepatic carcinogenesis. This and preliminary evidence of biological activity of anti-IGF-1R monoclonal antibody cixutumumab in phase I trials prompted this phase II study. METHODS: Patients with advanced HCC, Child-Pugh A-B8, received cixutumumab 6mg/kg weekly, in a Simon two-stage design study, with the primary endpoints being 4-month PFS and RECIST-defined response rate. Tissue and circulating markers plus different HCC scoring systems were evaluated for correlation with PFS and OS. RESULTS: As a result of pre-specified futility criteria, only stage 1 was accrued: N=24: median age 67.5 years (range 49-83), KPS 80% (70-90%), 20 males (83%), 9 stage III (37%)/15 stage IV (63%), 18 Child-Pugh A (75%), 11 HBV (46%)/10 HCV (42%)/11 alcoholic cirrhosis (46%)/2 NASH (8%), 11 (46%) diabetic. Median number of doses: 7 (range 1-140). Grade 3/4 toxicities >10% included: diabetes, elevated liver function tests, hyponatremia, and lymphopenia. Four-month PFS was 30% (95% CI 13-48), and there were no objective responses. Median overall survival was 8 months (95% CI 5.8-14). IGF-R1 staining did not correlate with outcome. Elevated IGFBP-1 correlated with improved PFS (1.2 [95% CI 1-1.4]; p 0.009) and OS (1.2 [95% CI 1.1-1.4]; p 0.003). CONCLUSIONS: Cixutumumab monotherapy did not have clinically meaningful activity in this unselected HCC population. Grade 3-4 hyperglycemia occurred in 46% of patients. Elevated IGFBP-1 correlated with improved PFS and OS.

Evaluating the utility of ZNF331 promoter methylation as a prognostic and predictive marker in stage III colon cancer: results from CALGB 89803 (Alliance).

While epigenomic alterations are common in colorectal cancers (CRC), few epigenomic biomarkers that risk-stratify patients have been identified. We thus sought to determine the potential of ZNF331 promoter hypermethylation (mZNF331) as a prognostic and predictive marker in colon cancer. We examined the association of mZNF331 with clinicopathologic features, relapse, survival, and treatment efficacy in patients with stage III colon cancer treated within a randomized adjuvant chemotherapy trial (CALGB/Alliance89803). Residual tumour tissue was available for genomic DNA extraction and methylation analysis for 385 patients. ZNF331 promoter methylation status was determined by bisulphite conversion and fluorescence-based real-time polymerase chain reaction. Kaplan-Meier estimator and Cox proportional hazard models were used to assess the prognostic and predictive role of mZNF331 in this well-annotated dataset, adjusting for clinicopathologic features and standard molecular markers. mZNF331 was observed in 267/385 (69.4%) evaluable cases. Histopathologic features were largely similar between patients with mZNF331 compared to unmethylated ZNF331 (unmZNFF31). There was no significant difference in disease-free or overall survival between patients with mZNF331 versus unmZNF331 colon cancers, even when adjusting for clinicopathologic features and molecular marker status. Similarly, there was no difference in disease-free or overall survival across treatment arms when stratified by ZNF331 methylation status. While ZNF331 promoter hypermethylation is frequently observed in CRC, our current study of a small subset of patients with stage III colon cancer suggests limited applicability as a prognostic marker. Larger studies may provide more insight and clarity into the applicability of mZNF331 as a prognostic and predictive marker.

PD-L1 expression complements CALGB prognostic scoring system in malignant pleural mesothelioma.

Background: Programmed death ligand-1 (PD-L1) expression is a predictive biomarker in patients with lung cancer, but its role in malignant pleural mesothelioma (MPM) remains unclear. Evidence suggests that higher PD-L1 expression is correlated with worse survival. CALGB is the main scoring system used to predict the benefit of chemotherapy treatment. This study aimed to determine the prognostic value of PD-L1 expression and its addition to CALGB scoring system in patients with MPM. Methods: In this retrospective analysis, we evaluated samples with confirmed locally advanced or metastatic MPM. PD-L1 Tumor Proportional Score (TPS) was determined by immunohistochemistry at diagnosis. Results: 73 patients were included in this study. A cutoff value of 15 was set for a high or low PD-L1 TPS. In total, 71.2% (n=52) and 28.8% (n=21) of individuals harbored low or high PD-L1 expression, respectively. PD-L1High was associated with worse median progression-free Survival (mPFS) [4.9 vs. 10.8 months; HR 2.724, 95% CI (1.44-5.14); p = 0.002] and Overall Survival (OS) [6.0 vs. 20.9 months; HR 6.87, 95% CI (3.4-8.7); p<0.001] compared to patients with PD-L1Low. Multivariate analysis confirmed that PD-L1 expression was an independent factor for PFS and OS in patients with MPM and CALGB score of 5-6. Conclusion: PD-L1 addition to CALGB scale improves its prognostic estimation of MPM survival and should be considered in future research.

Does chemotherapy regimen matter in the neoadjuvant treatment of esophageal cancer?

Background: Neoadjuvant chemoradiotherapy has become the mainstay of treatment for locally advanced esophageal cancer. CALGB 9781 trial established cisplatin and 5-flourouracil (5-Fu) with radiotherapy as superior to surgery alone while the CROSS trial established paclitaxel, carboplatin, and radiotherapy as superior to surgery alone. Previous data has been unclear as to which regimen provides a superior pathologic response. This study aims to look at this. This study aims to look at this. Methods: A retrospective chart review at a single institution of patients who underwent esophagectomies after neoadjuvant chemoradiotherapy with either cisplatin and 5-Fu or carboplatin and paclitaxel between 2012-2020 was performed. Demographics as well as staging, response rates, and modified Ryan scores were collected. Univariate analysis between the two groups was performed. Results: A total of 82 patients were identified between 2012-2020 who underwent esophagectomy after neoadjuvant chemoradiotherapy. In total, 74 (90.2%) received carboplatin and paclitaxel while 8 (9.8%) received 5-Fu and carboplatin. Both groups included patients with squamous cell carcinoma (SCC) and adenocarcinoma. No significant factors were found in terms of patient comorbidities or pathologic staging. There was no significant difference in modified Ryan score between the two groups (P=0.745). Conclusions: This study evaluates the degree and presence of pathologic response between the two neoadjuvant chemoradiotherapy modalities used for esophageal cancer. Our results, in contrast to other studies, suggest no significant difference with regards to pathologic response rate. Furthermore, our findings suggest that use of the least toxic regimen would make sense.

Evaluation of methylated DCR1 as a biomarker for response to adjuvant irinotecan-based therapy in stage III colon cancer: cancer and leukaemia Group B 89803 (Alliance).

Aberrantly methylated genes contribute to the landscape of epigenetic alterations in colorectal adenocarcinoma. The global CpG Island methylator phenotype (CIMP) and individually methylated genes are potential prognostic/predictive biomarkers. Research suggests an association between methylated DCR1 (mDCR1) and lack of benefit with irinotecan (IFL) treatment. We assessed the association between DCR1 methylation status and survival in patients receiving adjuvant fluorouracil/ leucovorin (5-FU/LV) or IFL. We analysed data from patients with stage III colon adenocarcinoma randomly assigned to adjuvant 5-FU/LV or IFL in CALGB 89803 (Alliance). The primary endpoint was overall survival (OS), and the secondary endpoint was disease-free survival (DFS). Using tumour sample DNA, we evaluated the association between survival, DCR1 methylation status, and molecular subgroups (BRAF, KRAS, mismatch repair status, CIMP status) using Kaplan-Meier estimator and Cox proportional hazard model. mDCR1 was observed in 221/400 (55%) colon cancers. Histopathologic features were similar between mDCR1 and unmethylated DCR1 (unDCR1) colon cancers. There was no difference in OS (p = 0.83) or DFS (p = 0.85) based on DCR1 methylation status. There was no association between methylation status and response to IFL . In patients with unDCR1 and KRAS-wildtype tumours, those who received IFL had a nearly two-fold worse DFS compared to patients who received 5-FU/LV (HR = 1.85, 95% CI (0.97-3.53, p = 0.06). This relationship was not notable among other subgroups. In stage III colon cancer patients, mDCR1 status did not associate with response to irinotecan. Larger studies may suggest an association between the iridocene response and molecular subgroups.

Treatment of adult Burkitt lymphoma with the CALGB 1002 protocol: a single center experience in Jordan.

BACKGROUND: The treatment of adult Burkitt lymphoma with pediatric-based chemotherapy protocols usually results in high cure rates, although with significant toxicity. We report our experience with the Cancer and Leukemia Group B1002 (CALGB 1002) protocol. METHODS: The files of adult patients diagnosed with Burkitt lymphoma and treated with the CALGB 1002 protocol at King Hussein Cancer Center between 2008 and 2017 were reviewed. Baseline demographics, clinical laboratory features, treatment details, and responses were collected. The correlations between clinical and laboratory variables with event-free survival (EFS) and overall survival (OS) were determined by univariate and multivariate analyses using backward stepwise Cox regression models. EFS and OS were plotted using Kaplan‒Meier curves. RESULTS: This study included 19 patients with a median age of 33 years (range, 19‒65). Eleven (58%) and two (10.5%) patients had advanced-stage and central nervous system disease, respectively. Among 106 administered cycles, the median interval between cycles was 23 days (range, 19‒84 days). Sixteen patients (84%) achieved a complete response. After a median follow-up of 40.8 months, the 3-year EFS and OS rates were 78.95%. Patients with a low-risk International Prognostic Index (IPI) had better survival than those with intermediate-or high-risk IPI. Grade III‒IV hematological toxicities occurred in 88% of patients, while 73% had grade III‒IV mucositis. CONCLUSION: In adult Burkitt lymphoma, the CALGB 1002 protocol provides high cure rates and can be administered promptly, but is associated with significant toxicity. Risk-adapted approaches and other, less toxic, chemotherapeutic regimens should be considered.

Are Providers and Patients Following Hormonal Therapy Guidelines for Patients Over the Age of 70? The Influence of CALGB 9343.

BACKGROUND: The Cancer and Leukemia Group B (CALGB) 9343 clinical trial proved that omission of radiotherapy (RT) in patients 70 and older with T1cN0M0, estrogen receptor-positive tumors who undergo breast conservation therapy (BCT) and receive 5 years of endocrine therapy (ET) had no change in overall survival, distant disease-free survival, or breast preservation. We examined our institution's practice with this patient subset. PATIENTS AND METHODS: A single-institution retrospective chart review was performed on patients 70 years and older with T1N0M0, estrogen receptor-positive tumors, and who underwent BCT between April 2010 and October 2015. RESULTS: A total of 123 patients met inclusion criteria: 46% received RT and 73% received ET. The ET group had a mean age of 76.2 years, whereas the non-ET group had a mean age of 80.2 years (P = .00006). Race did not influence if patients received ET (P = .4). In patients who received ET, mean age at time of diagnosis for those that completed 5 years of therapy was 75.5 years, whereas those who stopped therapy early had a mean age of 77.6 years (P = .053). In patients who received ET but stopped early, reasons for cessation included side-effect profile (67%), death (22%), and noncompliance (11%). Of the 27% of patients that did not receive ET, 62% were not offered therapy, 24% refused, and 14% were lost to postoperative follow-up. CONCLUSION: Increasing age showed significant association to not receive ET. Contraindication to ET and provider's assessment of minimal benefit are the most common reasons why patients are not prescribed ET. If patients are non-compliant with ET, RT should be reconsidered.

Choosing wisely after publication of level I evidence in breast cancer radiotherapy.

BACKGROUND: Recent trials in early-stage breast cancer support hypofractionated whole-breast radiotherapy (WBRT) as part of breast-conserving therapy (BCT). Evidence also suggests that radiotherapy (RT) omission may be reasonable for some patients over 70 years. Among radiation-delivery techniques, intensity-modulated RT (IMRT) is more expensive than 3-dimensional conformal RT (3DCRT). Based on this evidence, in 2013, the American Society for Radiation Oncology (ASTRO) recommended hypofractionated schedules for women aged ≥50 years with early-stage breast cancer and avoiding routine use of IMRT for WBRT. To assess response to level I evidence and adherence to ASTRO recommendations, we evaluated the pattern of RT use for early-stage breast cancer at our National Comprehensive Cancer Network institution from 2006 to 2008 and 2011 to 2013 and compared the results with national trends. METHODS: Data from a prospective database were extracted to include patients treated with BCT, aged ≥50 years, with histologic findings of invasive ductal carcinoma, stage T1-T2N0M0, estrogen receptor-positive, and HER2 normal. We retrospectively reviewed the medical records and estimated costs based on 2016 Hospital Outpatient Prospective Payment System (technical fees) and Medicare Physician Fee Schedule (professional fees). RESULTS: Among 55 cases from 2006 to 2008, treatment regimens were 11% hypofractionated, 69% traditional schedule, and 20% RT omission (29% of patients were aged >70 years). Among 83 cases from 2011 to 2013, treatment regimens were 54% hypofractionated, 19% traditional schedule, and 27% RT omission (48% of patients were aged >70 years). 3DCRT was used for all WBRT treatments. Direct medical cost estimates were as follows: 15 fractions 3DCRT, $7,197.87; 15 fractions IMRT, $11,232.33; 25 fractions 3DCRT, $9,731.39; and 25 fractions IMRT, $16,877.45. CONCLUSION: Despite apparent resistance to shorter radiation schedules in the United States, we demonstrate that rapid practice change in response to level I evidence is feasible. Wider adoption of evidence-based guidelines in early-stage breast cancer may substantially lower health care costs and improve convenience for patients without sacrificing oncologic outcomes.

Contemporary Analysis of Prognostic Factors in Patients with Unresectable Malignant Pleural Mesothelioma.

INTRODUCTION: Previous prognostic scoring systems for malignant pleural mesothelioma (MPM) included patients managed surgically and predated the use of pemetrexed. We analyzed prognostic factors in a contemporary cohort of patients with unresectable MPM who received pemetrexed-based chemotherapy. METHODS: This single-institution analysis included patients with MPM who were managed nonsurgically from 2000 to 2013. Variables correlated with overall survival (OS) included sex, performance status (PS), asbestos exposure, tumor laterality, histology, clinical stage, initial positron emission tomography maximum standardized uptake value, hemoglobin level, platelet count, lymphocyte count, white cell and neutrophil counts, treatment type, and clinical benefit from treatment. OS was analyzed by the Kaplan-Meier method, and significance (p < 0.05) of prognostic factors was analyzed by the log-rank test and Cox regression. RESULTS: A total of 191 patients met the study criteria: median age 71 years (range 46-90), 147 men (77%), 128 epithelioid tumors (67%), and 157 cases of stage III or IV MPM (82%). Median OS for all patients was 13.4 months. According to a univariate analysis, histology (p < 0.001), platelet count (< or = 450,000 versus >450,000, p < 0.001), initial PS (0-1 versus > or = 2), maximum standardized uptake value (< or = 8.1 versus >8.1, p = 0.037), and lymphocyte counts (p = 0.019) were associated with OS. According to a multivariable analysis, only histology, platelet count, and PS were independent prognostic factors. Epithelioid histology, PS, and elevated lymphocyte count at diagnosis were significantly associated with clinical benefit from first-line chemotherapy. CONCLUSIONS: Our results confirm the significance of elements of the Cancer and Leukemia Group B and European Organisation for Research and Treatment of Cancer prognostic scoring systems, identify factors associated with clinical benefit from chemotherapy, and emphasize the impact of histology and clinical benefit of chemotherapy on outcomes.

Validation of EORTC and CALGB prognostic models in surgical patients submitted to diagnostic, palliative or curative surgery for malignant pleural mesothelioma.

BACKGROUND: To assess the trend of our surgical patients affected by malignant pleural mesothelioma (MPM) and submitted to diagnostic/palliative or curative surgical procedures and to validate the European Organisation for Research and Treatment of Cancer (EORTC) prognostic score in our patient population. METHODS: This is a cohort study of patients submitted to surgery for MPM from January 2007 to December 2013. Primary outcome was overall survival (OS). Univariate and multivariate-adjusted comparisons by EORTC prognostic score for OS were accomplished using Cox method. Adjusted models included the following clinical variables: kind of procedure, smoking habit, asbestos exposure, Charlson's Comorbidity Index (CCI), clinical tumor stage, adjuvant chemotherapy, dyspnoea, chest pain and haematological variables according to the score features. Nomenclature of the surgical procedures matches the International Association for the Study Lung Cancer (IASLC)/International Mesothelioma Interest Group (iMIG). RESULTS: One-hundred sixty-six consecutive cases were collected: the median age at surgery was 73 years and 123 patients (75%) had a history of asbestos exposure. Ninty patients (54%) were submitted to a palliative/diagnostic thoracoscopy, 30 to pleurectomy/decortication (P/D), and 6 to extra-pleural pneumonectomy (EPP). Clinical TNM stages were as follows: 99 (60%) stage I-II, 34 (20%) stage III and 33 (20%) stage IV. The median follow-up (FU) was 19 months [interquartile range (IQR), 9-31 months] and the FU-completeness was 98%. By the end of the study 130 patients died (78%). One- and 3-year OS was 60% and 36%, respectively. Patients submitted to EPP and P/D showed a better survival (P=0.013). Multivariable model showed an independent prognostic value of EORTC score (HR =2.86, P<0.001). CONCLUSIONS: In selected patients, aggressive surgical approaches, although not radical, may still be beneficial. The EORTC prognostic index proved to be an independent prognostic factor in our cohort of patients and therefore is a reliable and valid instrument that may be implemented in the daily practice.