bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-effectiveness analysis of proton versus photon therapy with respect to risk of growth hormone deficiency.
Authors: Mailhot Raymond , Kim Jane , Hollander Abby , Michalski Jeff M. , Tarbell Nancy , Yock Torunn I. , MacDonald Shannon M.
Published: March 2020

e17553

Background: Proton therapy has been endorsed as a radiotherapy (RT) modality with the potential to avert many RT associated comorbidities. Currently, few proton centers exist, and no evidence-based data as yet adequately informs allotment of care. Childhood cancer survivors of central nervous system (CNS) malignancies have high prevalences of growth hormone deficiency (GHD) after hypothalamic exposure, notable for its cost of treatment greater than $10,000/year. We propose methodology to help guide proton referral of pediatric patients with CNS tumors through cost-effective analysis comparisons for proton and photon hypothalamic received dose. Methods: A Markov cohort model was designed to assess the expected costs and effectiveness for specific RT doses to the hypothalamus. Patients entered the model receiving proton or photon RT for CNS tumors at four and twelve years of age and were followed for 60 more years of life. Patients could experience two health states: GHD or healthy. Risk of GHD was based on data by Merchant et al. Costs were measured in USD and captured cost of GHD and cost of RT. Cost of proton course relative to photon was estimated at $160K. Effectiveness was measured in quality-adjusted life years (QALYs). The main outcome measure used for comparison was the incremental cost-effectiveness ratio (ICER). We assumed a societal willingness to pay threshold of $50,000/QALY. Results: Data were used to generate tables incorporating the differential cost of proton RT to project ICERs for different combinations of hypothalamic RT dose as displayed in the Table below. Conclusions: Despite the high cost of proton therapy, the cost of GHD alone can yield proton RT a cost-effective (even cost-minimizing) strategy when compared to photon RT. This work provides a guide for identifying a set of patients for which proton therapy is particularly cost-effective. [Table: see text]
The City of Hope (COH) performance excellence program (PEP): A physician incentive program to improve health care performance (HCP) in an academic medical center.
Authors: Alvarnas Joseph C. , Kassab Tricia , Avanessian Priscilla , Pierce Michael , Levine Alexandra M.
Published: March 2020

e17556

Background: The Affordable Care Act (ACA) introduced a pay for performance model focused on: safety, timeliness, effectiveness, efficiency, patient-centered, equitable care. COH is an NCI sponsored Comprehensive Cancer Center, focused on cancer care. Methods: In 2011, a physician led team with representation from finance, QRRM, nursing and legal identified 13 quality measures (QM) where opportunities for improvement (OFI) existed. Selection criteria included measurability, importance, applicability to ACA, physician impact, return on investment and national importance. The QM include HCAHPS score, Healthcare Associated Infection rate (HAI), quantity of blood products internally produced (BP), coder response rate (RR), use of sepsis bundle orders, time to new patient appointments (NPA), OR 1st case on-time starts, timeliness of adjuvant therapy for breast/colon cancer patients, SCIP composite score and use of VTE prophylaxis orders. HCP for the first 4 QM was assessed based upon institutional performance; 6 QM were assessed upon departmental performance. There were 3 build measures (BM): creating a system to obtain advanced directives (AD) on all new patients, creating a system for effective communication with referring physicians and 4 departmental BM based on best practices. Results: PEP performance was assessed between 5/1/12-12/31/12. 174 physicians in 11 departments were eligible for a $2.05 million incentive pool. QM were evaluated using a tiered bonus structure. Significant improvements were seen in HAI, BP production, SCIP, OR starts and timely adjuvant therapy. There were improvements in the use of VTE orders, but aggregate performance fell below payment threshold. The build measure for AD was completed. Conclusions: (1) PEP is an effective tool for physician engagement in an academic medical center. (2) PEP enhanced alignment between the medical group, hospital, nursing and administration. (3) PEP was effective in improving HCP in less than one year from its inception. [Table: see text]
Time from surgery to first adjuvant chemotherapy: Experiences at two Toronto hospitals.
Authors: Polenz Chanele K. , Manoharan Amanda S. , Sevick Laura , Marchand Christina , Hassan Maha , Burkes Ronald L. , Brezden Christine B.
Published: March 2020

e17557

Background: Optimal treatment of patients with colorectal cancer (CRC) includes the timely administration of adjuvant chemotherapy (AC). While Cancer Care Ontario (CCO) guidelines advise that CRC patients receive their first AC no later than 8 weeks after surgical resection, new data suggests treatment should begin between 4 and 6 weeks. This retrospective study was performed to determine the treatment times and identify barriers at two Toronto hospitals: St. Michael’s Hospital (SMH) and Mount Sinai Hospital (MSH). Methods: Of all 797 patients diagnosed with CRC between January 1, 2005 and April 30, 2012 at SMH and MSH, 483 patients did not meet eligibility criteria. Thus, our sample population of 314 patients had stage II or III CRC, and received both surgical resection and AC at each respective hospital. Data collected included: time from surgery to first AC, patient demographics, and systemic/clinical barriers. Data was analyzed using statistical methods in Excel, assuming p-values <0.05 as significant. Results: The mean ageof the patients was 60.5 years (range 23 – 91); 55% were male and 72% had stage III disease; 75% (237/314) had colon cancer and 75% of AC was the FOLFOX regimen. The mean time from surgery to first AC was 57.4 days (sd = 16.8) or 8.2 weeks (range 4.1-18.7). Referral from surgeon averaged 20 days (sd=29.3). Time from medical oncology consult to first AC averaged 26.5 days (sd=30.8) including 23 days awaiting port-a-cath insertion. Post-operative medical complications affected 23.6% of patients. The presence of a complication was associated with delay in AC (10.6 days, p<0.001). An association between tumour site (eg. colon vs. locally advanced rectal cancer) and delay (p=0.0002) was also observed. Conclusions: Adherence to CCO guidelines can be optimized in CRC patients at SMH and MSH. The presence of a medical complication and tumour site are both factors associated with delays in AC treatment post-surgery. To improve the timeliness of care and achieve greater consistency between hospitals, rapid-cycle improvement of confounding barriers will be adopted.
Oncologists’ perceptions of cost and cancer care in India: A comparison of private practice (PPOs) and non-private practice oncologists (NPPOs).
Authors: Bhattacharya Manisha , Hamilton Erika Paige , Zafar Yousuf
Published: March 2020

e17562

Background: Cancer incidence is increasing in India, where most patients lack health insurance. Little is known about how out-of-pocket costs affect cancer treatment decision-making by Indian physicians and patients. Methods: We conducted a cross-sectional survey of PPOs and NPPOs in 6 Indian metropolitan areas. Oncologists were surveyed about cost of care and cost discussions with patients. Descriptive statistics and Fisher’s exact tests were used to describe differences in cost perceptions and discussions. Results: 59 oncologists were surveyed (61% response). 78% (n=46) were men. 59% (n=34) were PPOs, and 41% (n=25) were NPPOs. Oncologists routinely discussed cost with their patients (96%, n=57); PPOs and NPPOs were equally likely to do so (p=1.00). According to oncologists, patients seeing NPPOs or PPOs were equally likely to discuss costs before deciding on treatment (p=0.14). 55% (n=32/58) of oncologists discussed cost with patients before prescribing diagnostic tests, and 79% (n=46/58) discussed cost before making treatment decisions. PPOs were more likely than NPPOs to believe that costs may discourage patients from presenting for an initial cancer evaluation (88% vs. 44%; p=0.0009). However, 71% of NPPOs (vs 44% of PPOs; p=0.06) believed that, once diagnosed, more than half of their patients found costs to be a barrier to receiving standard care. Oncologists reported the most costly components of care for their patients to be: 1) chemotherapy; 2) radiotherapy and diagnostic imaging (tied); 4) surgery; 5) indirect costs from lost wages and inpatient admission (tied). When asked about how to reduce costs, oncologists identified: lowering chemotherapy prices (88%, n=52); judicious use/ lowering cost of diagnostics (36%, n=21); optimizing the referral process (22%, n=13). Insurance/subsidies were identified by 15% (n=8). Conclusions: Cost is routinely discussed by Indian patients and oncologists across care settings. Cost can be a deterrent to initial evaluation and a barrier to receiving standard care. Oncologists more commonly suggested reducing costs of diagnostics and therapeutics, rather than expanding insurance or changing referral practices.
Impact of leucovorin shortage on patient treatment.
Authors: Hanna Mina Samir Erian , Kozuch Peter , Thorn Molly , Roitman Janna , Grossbard Michael L. , Becker Daniel Jacob
Published: March 2020

e17566

Background: Shortages of intravenous leucovorin were initially reported in late 2008, and availability plummeted nationally and at Continuum Cancer Centers of New York (CCCNY) in late 2011. NCCN guidelines recommend either the use of levoleucovorin or low dose leucovorin during the shortage. The impact of the leucovorin shortage on patient therapy remains unknown. Methods: We reviewed patient charts for all outpatients treated with leucovorin at CCCNY between April and September of 2010, 2011, and 2012. We recorded patient characteristics, and leucovorin use (dose, number of treatments); and calculated descriptive statistics. We classified each dose as either low (20-40 mg/m2) or high (200-500mg/m2) and compared leucovorin use between years with Chi Square and ANOVA tests. We also reviewed pharmacy purchasing data to evaluate the economic effect of the leucovorin shortage. Results: We identified 55 patients treated with 313 doses of leucovorin in 2010, 99 patients treated with 582 doses in 2011 and 118 patients treated with 742 doses in 2012. No patients received levoleucovorin. Patient characteristics, disease and stage were similar between years with colorectal cancer accounting for 78%, 69%, and 70% of patients in 2010, 2011, and 2012 (p=0.87). Low dose leucovorin was used in 30.0% of doses in 2010, 30.4% in 2011, and 99.1% in 2012 (p<0.0001). The mean dose/treatment (SD) was 459 mg (296), 499 mg (328), and 47 mg (89), in 2010, 2011, 2012, respectively (p<0.0001). Among patients treated for colon cancer we found no association between stage (III vs. IV) and use of low dose leucovorin in 2010 or 2011. Quantity of leucovorin purchased at one hospital decreased by 63% from 171.75 g in 2010 and 157.50g in 2011 to 63.00 g in 2012. The price of leucovorin was similar at 0.017 $/mg in 2011 and 0.013 $/mg in 2012. Conclusions: Worsening leucovorin drug shortage was associated with a profound change in leucovorin use at CCCNY between 2011 and 2012. In accordance with NCCN guidelines, physicians used more low dose leucovorin. The price of leucovorin remained constant despite limited supply. Additional patient follow up is warranted to evaluate the outcomes of patients treated during the shortage.
Content validity of signs and symptoms measures with the EORTC core module in women with locally advanced or metastatic breast cancer (MBC): A phase II trial with eribulin mesylate.
Authors: Simons W. Robert
Published: March 2020

e17576

Background: The EORTC-QLQ30 is the core quality of life (QOL) instrument developed by the European Organization for Research and Treatment in Cancer. We assessed content validity for the signs and symptoms component in an investigational trial. Methods: We use a Phase II clinical trial where 291 women with locally advanced or MBC were required to have received prior treatment with an anthracycline, a taxane, and capecitabine. EORTC-QLQ30 was collected every second cycle, before drug administration and before patients were informed of their tumor assessment. We use the reported adverse events (AE) for those signs and symptoms to test the correlation between reported AEs and responses to the QoL questionnaire. The sum of the incidence by patient is generated as well as average scores for each sign and symptom. An endpoint for respondents positively reporting signs and symptoms without any AE is also evaluated (False-Positive). Statistically significant positive correlations between AEs and signs and symptoms as well as negative correlations for False-Positive establish content validity. Results: 283 women provided 1068 QOL assessments. Their general health status was 68.88 (P<0.0001) on a 100 point scale, improving by 7.90 (P=0.0153) when responding to eribulin. Nausea and vomiting were positively correlated with the reported incidence of nausea as AEs, 0.126 (P=0.03) and vomiting (P<0.01); false positives were negatively correlated, (-0.329; P<0.01 and -0.352; P<0.01, respectively). Constipation also satisfied the criteria for content validity, 0.189 (P<0.01) for correspondence and (-0.394; P<0.01) for lack of False-Positives. Diarrhea had a correspondence of 0.292 (P<0.01) and specificity of (-0.260; P<0.01). Dyspnea had a 0.226 (P<0.01) correspondence and (-0.349; P<0.01) specificity. Insomnia failed the criteria. Upset by hair loss was weakly correlated with alopecia but very specific (-0.479; P<0.01). Conclusions: Signs and symptoms as measured by the EORTC-QLQ-BR32 questionnaire have content validity in an investigational setting and they contribute clinically meaningful information to reported AE incidence data. Clinical trial information: NCT00246090.
Is comparative effectiveness research emphasized in oncologic residency training programs? Results of a national survey.
Authors: Zaorsky Nicholas George , Hess Jordan , Den Robert Benjamin , Bar-Ad Voichita , Filicko Joanne , Dicker Adam , Showalter Timothy Norman
Published: March 2020

e17577

Background: Comparative effectiveness research (CER) is informally defined as an assessment of all available efficacious options for a specific medical condition, with intent to estimate effectiveness and efficiency in specific subpopulations. The American Recovery and Reinvestment Act of 2009 allocated $1.8 B to increase CER and train physicians in its practice. Although program directors (PDs) of medical oncology (MO) and radiation oncology (RO) training programs know that CER is emphasized nationally, it is unknown if CER is emphasized in oncological training programs themselves. We examine the emphasis of CER in MO and RO training programs. Methods: A web-based, anonymous survey was sent to RO PDs (n = 85) and chief residents (CRs; 98); and MO PDs (99), asking them to forward a link to fellows (Fs; 160). Mean weighted Likerts (MWLs ± standard deviations [SDs]) were calculated from scales (1, strongly disagree; 3, neutral; 5, strongly agree). Results: The response rates for RO PDs, RO CRs, MO PDs, and MO Fs were 20%, 21%, 11%, and 10% (combined, 15%, 68/442). Respondents had mixed beliefs in having a clear definition of CER (MWL, 3.1 ± 1.2); their programs encouraging CER (3.2 ± 1.2); including a course on CER (2.3 ± 0.9); or discussing the differences among efficacy, effectiveness, and efficiency (2.9 ± 0.9). Retrospective cohort studies were easy to perform at institutions (4.3 ± 0.8), but less so CER (3.1 ± 1.3). Respondents believed their programs’ research integrated some core values of CER, including comparing treatments to influence clinical decision making (4.6 ± 0.7). Respondents believed CER was important (4.3 ± 0.7); 47% would divert funding from other types of research toward CER; 35% would, only if funding for other research was unaffected. Conclusions: CER is not emphasized in oncologic training programs, and most PDs and trainees cannot clearly define CER. In the era of health care reform and potential future payment reforms, it is anticipated that CER will become an increasingly important component of evidence-based medicine and continuous quality improvement. This study identifies a need for oncology training programs to incorporate education about CER into their curricula.
Adult participation in oncology clinical trials by indication, race, and age.
Authors: Combest Austin James , Reitsma Dirk J. , Moseley Angelena , Steele Savanna D. , Bonneterre Marie-Edith Anne
Published: March 2020

e17586

Background: According to the National Cancer Institute (NCI), approximately 3 percent of adult cancer patients participate in clinical trials despite the NCCN guidelines frequently recommending clinical trials as standard of care in many circumstances (Mooney, 2010). In a large analysis of NCI Cancer Therapy Evaluation Program (CTEP) trials, 40 percent of trials failed to achieve minimum enrollment, including 3 of 5 phase III trials (Cheng, 2010). Additionally, concerns about unequal access to clinical trials led Congress to enact the National Institutes of Health (NIH) Revitalization Act 20 years ago (June 10, 1993). Using data from Ipsos’ Tandem Oncology Monitor, a robust, nationwide system that collects actual prescriptions and clinical trial participation by indication from 500 oncologists and hematologists from the United States, we evaluated current participation and ethnic diversity in clinical trials. Methods: We assessed adult clinical trial participation from October 2011 to September 2012. Age, ethnicity and practice type were also collected to identify descriptive trends. Results: With regards to indication, clinical trial participation ranged from 1 percent (prostate, renal cell and head and neck) to 12 percent (thyroid) averaging between 2 and 3 percent. We observed a decline in first-line metastatic melanoma participation between pre- and post- vemurafenib/ipilimumab approval (9%-pre versus 2%-post). Patient diversity results are included in the Table. Conclusions: Despite efforts to increase oncology clinical trial participation, we have observed overall low clinical trial participation. Additionally, we observed better trial participation in the youngest age groups and minor differences between ethnic categories. Continued focus on increasing trial participation and patient diversity is still needed. [Table: see text]
How breast cancer care is coordinated in hospitals serving predominantly minority women.
Authors: McAlearney Ann Scheck , Moss Alexandra , Franco Rebeca , Bickell Nina A.
Published: March 2020

e17592

Background: Underuse of adjuvant breast cancer treatment results from system failures and occurs more commonly in minority women. We assessed organizational processes associated with care coordination prior to implementing an intervention. Methods: We interviewed 29 clinical and 20 administrative key informants from 6 hospitals with high volumes of minority breast cancer patients. We analyzed qualitative interview data using the constant comparative method. Results: Hospitals varied in approaches to coordinate adjuvant therapy delivery. All hospitals made a “basic” effort to follow up with patients who missed appointments (e.g., certified letters), but some sites included “extra” efforts such as clinician calls. Processes to coordinate handoffs among providers involved use of clerical staff to reach out across specialties in most sites; several sites also explicitly involved clinicians. Effective tracking and handoffs were hindered where electronic health record (EHR) systems were not fully integrated. A critical distinction was whether breast cancer care delivery was integrated within the hospital. Better integration appeared to facilitate communication among clinicians, as well as promote service coordination. Accountability was an important factor contributing to integration, particularly in sites that were less integrated. Conclusions: Appropriate delivery of adjuvant therapies to breast cancer patients appears to be facilitated by better integration of care and services within the hospitals we studied. A fully integrated EHR and enhanced processes for tracking no shows and supporting handoffs seemed to increase integration in these hospitals. Integration was further facilitated when there was accountability for results. Strong clinical leadership can promote integration, but its impact may be lessened if hospitals’ processes are integrated. [Table: see text]
Impact of the distance from a radiation oncology treatment facilty on initiation of therapy and its influence on survival in patients with stage III and IV NSCLC.
Authors: File Danielle M. , Arce-Lara Carlos Eduardo , Whittle Jeffrey C. , Gore Elizabeth , Santana-Davila Rafael
Published: March 2020

e17594

Background: Patients with stage III and IV lung cancer require multidisciplinary care. The Milwaukee VA is the only center within the Veterans Health Administration in the state that has a radiation oncology facility. Patients frequently travel from across the state to receive treatment here. We conducted a retrospective review of cases seen in our institution to determine if the distance from the patients’ home to our center influenced their outcome. Methods: Patients with NSCLC treated between 2000 and 2012 were identified from our internal registry. Type of treatment was identified from the registry and confirmed in a chart review.. SAS 9.2 was used for statistical analysis and to measure distance between the patients’ home address and our center. Results: We included 230 patients with stage III disease treated with radiation therapy and 139 patients with stage IV treated with chemotherapy. Of those with Stage III (53% with IIIA and 47% IIIB) 41.3% (n=95) received concurrent radiation therapy and chemotherapy, 14% received sequential therapy, 40% received radiation therapy alone and 5% were treated with chemotherapy followed by palliative radiation. In those with metastatic disease 61% received palliative radiation at some point during their treatment. Median distance between the patients’ home and the Milwaukee VA was 57miles (IQR 10-109) in patients with stage III disease and 22 (IQR 5-84) in those with metastatic disease. There was no correlation between the distance travelled and the time to first treatment in either stage (r=0.008 in stage III and r=0.05 in stage IV). In a univariate analysis living further than 50 miles did not appear to influence survival in stage III (median OS 14.6 vs. 16.4 months p=0.25) nor stage IV disease(9.7 vs 8 p=0.55). In a multivariate analysis when controlling for age, time to first treatment and distance as a continuous variable was not associated with survival in patients with stage III(HR 1.01, 95% CI 0.99-1.02 p=0.15) or stage IV disease (HR 1.01, 95%CI 0.98-1.04 p=0.35). Conclusions: Distance traveled to a radiation oncology treatment facility in this cohort did not influence survival in patients with stage III and IV NSCLC.
A prospective single center study from a developing country to evaluate the prevalence of vitamin-D deficiency in patients with de novo hematologic malignancies.
Authors: Shetty Nishitha , Sengar Manju , Menon Hari , Dangi Uma Bhaskar , Ghadge Meera , Inamdar Nitin , Shinde Bhoopal , Kumar Santhosh , Ghosh Joydeep , Rajamanickam K. Deepan , Sheth Vipul , Philip Deepa susan , MV Chandrakant
Published: March 2020

e18004

Background: Vitamin-D deficiency is a global problem due to lack of sunlight exposure or dietary deficiency. Few studies have correlated vitamin-D deficiency with poor outcome in patients with diffuse large B-cell lymphomas and chronic lymphocytic leukemia. Expression of vitamin-D receptors on both normal and malignant hematopoietic cells suggests its possible role in pathogenesis, response to therapy and as a potential therapeutic target in haematological cancers. Given the high prevalence of malnutrition in our country and the potential impact of vitamin-D deficiency in haematological malignancies we conducted this prospective study to identify its prevalence in this subset of patients. Methods: Consecutive patients (15-50 years) with de novo haematological cancers who were registered at our centre over a three months period were evaluated. Patients who had received bisphosphonates or calcium and vitamin-D supplementation were excluded. Demographic variables, performance status, lifestyle (sedentary or non-sedentary), diet (vegetarian or mixed), consumption of milk products, serum 25 (OH) D, albumin and calcium levels were recorded. Levels <30ng/ml and <20ng/ml were considered as insufficient and deficient respectively. Results: A total of 126 patients (70% males) were enrolled. Median age was 35 years. Distribution as per histology was acute leukemia-59, lymphomas-53, chronic myeloid leukemia-14. 78% patients had non-sedentary life style and were consuming mixed diet and milk. 90% patients had performance status ≤2. Serum albumin>3.5 gm/dL and normal calcium levels were seen in 90%. Vitamin-D deficiency was seen in 12% patients whereas 73% patients were vitamin D insufficient. Keeping the cut-off <25 ng/mL, 82% patients were deficient. Deficiency did not correlate with age, underlying diagnosis, lifestyle or dietary habits. Conclusions: Our study identified a very high prevalence of vitamin-D deficiency in patients with haematological malignancies. This could be one of the factors responsible for the aggressive nature of disease and poor outcome in our patients.
BCL3 and NSCLC: Are they related?
Authors: Dimitrakopoulos Fotinos-Ioannis D , Kottorou Anastasia E , Antonacopoulou Anna G , Marousi Stella , Koukourikou Ioulia , Scopa Chrisoula D , Dougenis Dimitrios , Papadaki Helen , Kalofonos Haralabos
Published: March 2020

e18507

Background: NFkB pathways have become objects of detailed research in the last years, although, little is known of the possible role of BCL3 in lung carcinogenesis. The aim of this study was to define the relation of the BCL3 single nucleotide polymorphism rs8100239 with NSCLC and its association with BCL3 protein expression. Methods: Using Tagger and Sysnps programs, we chose the rs8100239 polymorphism of BCL3.We used 294 blood and FFPE normal tissue specimens from patients with NSCLC and 280 blood specimens from healthy donors. DNA isolation was performed using the Qiagen DNA blood and the QIAamp DNΑ FFPE Tissue kits. Samples were genotyped using real-time PCR. Immunohistochemical analysis for BCL3 was performed on 90 FFPE specimens (80 tumors and 10 tumor-adjacent normal tissues) from NSCLC patients. Results: Approximately half of the healthy donors (45.5%) were AT heterozygotes, 36.6% were TT and 17.9% were AA homozygotes. The respective frequencies in patients were 43.8%, 33.1% and 23.1%. There was no statistically significant difference in allele frequencies between healthy controls and patients (p=0.297). However, patients of stage II carrying a T allele displayed two and five-year survival benefit compared to patients with AA genotype (p<0.001). Immunohistochemical analysis for BCL3 protein revealed a statistically significant difference between malignant and normal lung tissue (p<0.001). More specifically, BCL3 was detected in both the cytoplasm and nucleus in neoplastic tissues with strong intensity, whereas in non neoplastic tissue no immunostaining was noticed. BCL3 protein levels were not associated with the polymorphism. However, cytoplasmic expression of BCL3 was correlated with age (p=0.009), histological subtype (p=0.031) and disease stage (0.038). Furthermore, tumors with smaller diameter had higher BCL3 nuclear expression levels than larger tumors (p=0.009). Conclusions: Patients of stage II carrying a T allele had improved two and five-year survival. BCL3 expression is not correlated with rs8100239 status. However, it is related to histological subtype, stage and maximum diameter while it differs between malignant and normal lung tissue. This research has been co-financed by the EU and Greek national funds (Heracleitus II Program).
Treatment-free interval (TFI) after first-line therapy (FLT) and disease control rate (DCR) on second-line therapy (SLT): Impact on overall survival (OS) in relapsed malignant pleural mesothelioma (MPM).
Authors: Viganò Maria G , Gregorc Vanesa , Ghio Domenico , Bulotta Alessandra , Rossoni Gilda , Sallemi Claudio , Colombi Scialini , Rossoni Gloria , Lambiase Antonio , Bordignon Claudio
Published: March 2020

e18528

Background: Both TFI (the time elapsing from FLT completion to SLT initiation) and DCR (the rate of nonprogression at first tumor evaluation) have been found to predict OS in other tumor types. Methods: The impact on outcome of TFI after FLT and DCR on SLT was tested in an individual patient pooled analysis of 261 MPM patients (pts) who had radiologic progressive disease (PD) after a pemetrexed-based FLT before entering a ph 2 trial with single-agent NGR-hTNF (n=50) and a ph 3 trial with single-agent gemcitabine, vinorelbine or doxorubicin plus NGR-hTNF/placebo (n=211). In both trials, response to SLT was assessed every 6 weeks by MPM-modified RECIST. Progression-free survival (PFS) and OS were computed from SLT start. By ROC analysis, the cutpoint for estimating TFI in relation to OS was set at 6 months (AUC=0.59; p=.009). Results: After FLT, 60 pts (23%) had partial response (PR), 135 (52%) stable disease (SD), for a DCR of 75%, and 66 (25%) early PD. Median time to PD was 7.0 months (95% CI, 6.2-7.4) and median TFI was 4.4 months (3.8-5.0), with 97 pts (37%) having a TFI > 6 months. Among baseline factors (age, sex, PS and histology) used in logistic regression, only younger age was related to higher odds to attain a TFI > 6 months (OR=1.9; 95% CI, 1.2-3.3). A TFI > 6 months (vs ≤ 6) was weakly related to DCR (Spearman's r=0.16; p=.01) and strongly associated with longer PFS and OS, with HR of 0.48 (0.36-0.65) and 0.59 (0.42-0.83), respectively. After SLT, 9 pts (3%) had PR, 130 (50%) SD, for a DCR of 53%, and 122 (47%) early PD. Of 60 pts responding to FLT, 23 (38%) progressed early on SLT, while of 66 pts progressing early during FLT, 32 (48%) experienced disease control on SLT. Baseline factors did not relate with DCR at week 6. On landmark analysis set at the 6-week time point, DCR (vs PD) was associated with OS benefit (HR=0.46; 0.32-0.65), which persisted after adjusting for baseline factors (HR=0.40; 0.27-0.57). Conclusions: With a smaller HR, an early-look measure such as 6-week DCR on SLT shows some advantage over TFI after FLT in predicting subsequent OS. In relapsed MPM, TFI as stratification factor and DCR as surrogate endpoint may be considered. Clinical trial information: NCT00484276-NCT01098266.
Sensitivity of malignant mesothelioma lacking Merlin to the FAK inhibitor VS-6063: Evaluation of merlin/NF2 status in clinical samples.
Authors: Pachter Jonathan A. , Shapiro Irina M , Weaver David T. , Vidal Christian M. , Ring Jennifer E. , Keegan Mitchell , Xu Qunli , Menges Craig , Testa Joseph R. , Paterson Daniel
Published: March 2020

e18541

Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung often resulting from prior exposure to asbestos. MPM patients are usually diagnosed at an advanced stage of disease and the prognosis is poor. Median survival after diagnosis is 9 to 12 months and standard-of-care agents such as cisplatin and pemetrexed have only a modest impact on median survival time for MPM patients. New therapeutic modalities are urgently needed to improve the prognosis of MPM patients. 40-50% of MPM patients exhibit homozygous disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Methods: Proliferation of drug-treated mesothelioma cell lines in 3-dimensional (3D) Matrigel culture was assessed by MTS, and MPM xenograft growth was measured in vehicle- vs. FAK inhibitor-treated SCID mice. Since absence of merlin expression can theoretically result from several mechanisms including NF2 mutation and chromosome 22 abnormalities, we assessed NF2 gene deletion by FISH and merlin protein levels by IHC in the same human mesothelioma tumor samples. Results: Among a panel of mesothelioma cell lines in 3D culture, MPM lines lacking expression of merlin protein were found to be especially sensitive to the selective FAK inhibitor VS-6063. In contrast, MPM cell lines with wildtype merlin were less sensitive with EC50 values greater than 1 μM. Accordingly, oral dosing with a FAK inhibitor induced significant tumor growth inhibition in a merlin-negative mesothelioma model in mice. To enable the planned stratification of MPM patients by merlin status, an immunohistochemistry (IHC) assay has been optimized to quantify merlin protein levels. A merlin IHC H-score below the defined cutoff was associated with loss of at least one copy of chromosome 22, indicating that chromosomal deletion is an important mechanism of merlin loss in mesothelioma patients. Conclusions: These data support the clinical development of VS-6063 for treatment of malignant pleural mesothelioma patients stratified by merlin/NF2 status. A potentially pivotal mesothelioma trial is set to initiate in 2013.
Comparison of toxicity and outcomes of concurrent radiotherapy with carboplatin/paclitaxel (PC) or cisplatin/etoposide (PE) in stage III non-small cell lung cancer (NSCLC).
Authors: Liew Mun Sem , Sia Joseph , Harris Samuel John , Tafreshi Alireza , Starmans Maud HW , Feigen Malcolm , Boutros Paul C , White Shane , Zimet Allan Solomon , Lambin P. , Mitchell Paul , John Tom
Published: March 2020

e18559

Background: Concurrent chemoradiotherapy (CCRT) has become the standard of care for patients (pts) with unresectable stage III NSCLC. Although 60Gy of radiotherapy is accepted as the standard radiation dose, the concurrent chemotherapy regimen is idiosyncratic to the institution with PC generally reserved for older and less fit pts. We retrospectively reviewed outcomes and toxicity of two widely used regimens at our institution (Austin Health, Melbourne): weekly PC (Belani et al, 2005) versus (vs) PE given weeks 1 and 5 (SWOG 9019) each with concurrent chest radiotherapy. Methods: Charts from stage III NSCLC pts treated with radical dose CCRT between 2000-2011 were reviewed. Clinical data including demographics, toxicity, and response were reviewed. Results: A total of 83 (PC: 50, PE: 33) pts were treated. PC pts were older [median age (range) 70 year (44-83) vs 63 year (32-76); p=0.001]. Other characteristics were comparable in PC and PE groups (Table). Increased grade (gr) ≥3 neutropenia was seen with PE (39% vs 12%, p=0.008). Other gr ≥3 toxicities were similar including febrile neutropenia, esophagitis and pneumonitis. With a median follow up of 17.2 months (mo), no statistical difference in overall survival (OS) (median PC 21.3 mo vs PE 13.7 mo; p=0.690) and relapse free survival (median PC 12.0 mo vs PE 11.1 mo; p=0.934) were observed. In multivariate analysis, where treatment type and age were included in the model, only more advanced stage predicted poorer OS (p=0.045). Conclusions: PC was more likely to be used in elderly pts. Despite this, PC resulted in significantly less hematological toxicity but achieved similar survival outcomes compared to PE. PC is an acceptable CCRT regimen especially in older pts. [Table: see text]
Predicting factors for early and long-term mortality after thoracotomy in patients with primary lung cancer.
Authors: van Arkel Cynthia , Dumoulin Daphne , van Straten Bart , ter Woorst Joost , Houterman Saskia , van den Borne Ben
Published: March 2020

e18562

Background: To determine factors predicting early and long term mortality in patients who underwent a thoracotomy because of primary lung cancer. Methods: Data of patients who underwent a thoracotomy in the Catharina Hospital Eindhoven between 1 January 1995 and 1 January 2011 have been collected retrospectively from the medical files. Early mortality was defined as mortality <30 days after surgery. Last date of follow up was 1 January 2013. Patients were divided in three periods according to date of surgery (1: 1995-1999, 2: 2000-2004 and 3: 2005-2010). Predicting factors for early mortality were assessed with uni- and multivariate logistic regression analysis. For long term mortality and survival predicting factors were assessed using the Cox proportional hazards model and Kaplan-Meier survival curves. Results: In total 501 patients underwent a thoracotomy due to primary lung cancer. Overall 30 day mortality was 5.8% (n=29). Early mortality was 3.0% for lobectomy (n=289), 0.2% for bilobectomy (n=29) and 11% for pneumonectomy (n=109). Multivariate analysis showed that age over 70 (p=0.002), pneumonectomy (p=0.008) and a pre-operative VO2max of <15 ml/kg/min (p=0.02) were significant predictors of early mortality. With respect to long term survival, 308 (62%) patients had died at the end of the follow-up period. Median survival time was 44 months, with an overall 5- and 10- year survival of 45% and 27% respectively. The 5- and 10-year survival for stage I, II and III-IV was 61% and 37%; 46% and 30%;16% and 6.6%, respectively (p<0.0001, log rank test). Finally Cox regression analysis showed that stage (stage I (HR 0.30; 95% CI 0.22-0.42), stage II (HR 0.38; 95% CI 0.26-0.57) compared to stage III-IV, FEV1% ≤70% (HR 1.57; 95% CI 1.61-2.11), a history of cerebrovascular disease (CVD) (HR 1.97; 95% CI 1.20-3.23) and surgery in an earlier time period (1 (HR 1.50; 95% CI 1.04-2.17); 2 (HR 1.46; 95% CI 1.05-2.02) compared to 3) were significant predictors of long term mortality. Conclusions: In this cohort age, pneumonectomy and pre-operative VO2max are significant predictors of early mortality. Significant predictors of long term mortality are disease stage, FEV1%, a history of CVD and surgery in an earlier time period.
Post-progression survival after treatment with epidermal growth factor receptor-tyrosine kinase inhibitor for advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutations.
Authors: Kogure Yoshihito , Kitagawa Chiyoe , Oki Masahide , Saka Hideo
Published: March 2020

e19005

Background: Non-small cell lung cancer (NSCLC) patients harboring the epidermal growth factor receptor (EGFR) mutation show a survival benefit on treatment with EGFR-tyrosine kinase inhibitor (EGFR-TKI); however, few studies report on post-progression tumor behavior after treatment with EGFR-TKI. Methods: We retrospectively reviewed clinical data of stage IV or recurrent NSCLC patients harboring the EGFR mutation, who received EGFR-TKI as first-line treatment in our institute from 2009 to 2011. Results: Thirty-six patients received EGFR-TKI as first-line therapy. Thirty of these patients with recurrent NSCLC were enrolled in this study. The median age of the patients was76 years (range, 38–97), and the male/female ratio was 4/26. The median progression-free survival (PFS) after EGFR-TKI treatment was 8.2 months. Sites of relapse in patients with progressive disease (PD) were the brain, pleural effusion, bone, and lung (n=5, 13, 6, and 8, respectively). Twenty-one patients received sequential therapy: 11 patients received continued EGFR-TKI treatment beyond PD and 10 patients received second-line therapy. Second-line therapies were platinum-based doublet therapy, monotherapy, and another cycle of EGFR-TKI (n = 6, 2, and 2 patients, respectively). Post-progression survival (PPS) of all the patients after treatment with EGFR-TKI was 9.2 months, whereas that of patients who received EGFR-TKI as second-line chemotherapy was 14 months. Subgroup analysis according to the site of relapse showed that after first-line EGFR-TKI treatment, PFS tended to be higher for patients with a relapse in the brain (11.6 months) than for patients with sites of relapse other than the brain (8.2 months). Conclusions: PPS after EGFR-TKI therapy in patients treated with second-line chemotherapy was similar to the OS of NSCLC patients without an EGFR mutation. Subgroup analysis showed that patients with a relapse in the brain might survive longer.
Radiographic parameters in predicting outcome of patients with nonsquamous non-small cell lung cancer (NSCLC) treated with bevacizumab.
Authors: Kaufman Michael R , Salem Mohamed E. , Aoun Hussein , Kalemkerian Gregory Peter , Kunz Sara , El-Refai Sherif , Ranganath Praveen , Sukari Ammar , Gadgeel Shirish M. , Wozniak Antoinette J.
Published: March 2020

e19009

Background: Bevacizumab has increased survival in NSCLC patients (pts) when added to standard chemotherapy. However, whether radiographic features at baseline and/or post-treatment can predict benefit from addition of anti-angiogenic therapy to standard chemotherapy remains unknown. In addition, the impact of VEGF-targeted therapy on CT parameters is not fully characterized. Methods: A retrospective review was performed using CT scans of pts enrolled into a prospective phase II clinical trial of pemetrexed, gemcitabine and bevacizumab in stage IV chemo-naïve, non-squamous, NSCLC pts (Wozniak A, et al. IASLC2011). Treatments were repeated every 2 wks (1 cycle). CT scans were obtained at baseline and at the end of every 4 cycles. The radiographic CT features of the primary tumors were retrospectively reviewed at baseline and after first 4 cycles. RECIST 1.1 and Morphology, Attenuation, Size, and Structure (MASS) criteria were used to assess tumor radiographic response. Results: Twenty-four pts (43% males; median age, 62 y [range: 41-82]), were evaluable for this analysis. On baseline CT, median tumor size was 2.9 cm (range: 1.6. to 6.3 cm), median attenuation was 56 HU (range: 31 to 87 HU), 81% of tumors had heterogeneous enhancement, and 50% of tumors demonstrated invasion of adjacent structures. Well-defined margins were noted in 43% of tumors and 81% had < 30% necrosis. On post-4 cycle CT, 63% of tumors had decreased long diameter (median 15% decrease), 81% had decreased attenuation (median 21% HU reduction) and 50% had increased necrosis. RECIST-defined PR was seen in 37%, SD in 56%; and PD in 1 (4%) based on size despite > 75% necrosis. MASS criteria response was favorable in 25% and non-favorable in 75% of tumors. Pts with tumors that demonstrated FR response by MASS after 4 cycles were more likely to have prolonged progression free survival (HR 2.94; p= 0.175). Conclusions: In tumors treated with anti-angiogenic therapy, imaging response criteria that include changes in tumor morphology, attenuation, and size may capture anti-tumor effect more accurately than size-based RECIST criteria alone. These results support the need for prospective investigation of the efficacy of MASS criteria.
Review of 200 consecutive patients with mutation profiling in a lung cancer individualized medicine clinic.
Authors: Asiedu Michael , Molina Julian R. , Jen Jin , Jang Jin Sung , Roden Anja , Aubry Marie-Christine , Peikert Tobias , Maldonado Fabien , Thomas Charles , Edell Eric , Lifeng Wang , Yang Ping , Allen Mark S. , Deschamps Claude , Nichols Francis C , Cassivi Stephen D. , Shen Robert , Wigle Dennis A.
Published: March 2020

e19013

Background: Mutation profiling to assess for potentially druggable mutations in NSCLC is being offered at an increasing number of cancer centers throughout North America and internationally. Although data continue to accumulate for the potential value of mutation testing in designing chemotherapeutic regimens, the treatment impact of obtaining information beyond assessment of EGFR and ALK status remains unclear. How best to obtain and clinically utilize these data, including information from exome and whole genome sequencing, also remains unclear. Methods: Patients were reviewed electronically in a multidisciplinary conference regarding indications for testing and results of mutation profiling from various methods, including the mass-spec based LungCarta test, targeted NexGen sequencing, exome, and whole genome sequencing. Outcomes of the multidisciplinary review were communicated back to treating physicians. Results: Mutation testing was performed on 200 patients using a variety of approaches. The majority (>150) were surgically resected stage I and II tumors. Mutations in at least 1 major cancer driver gene, including EGFR, KRAS, MET, BRAF and PIK3CA, were found in 47% of all patients tested. EGFR mutations were present in 14.8% of patients tested, KRAS 21.3%, BRAF 2.6%, PIK3CA 3.2%, and MET 4.5%. A total of 8 patients underwent either exome or whole genome sequencing. A limited number of patients (<10) had mutation results that impacted treatment decisions from this cohort. Conclusions: Mutation profiling can influence treatment decisions in NSCLC, but at a low frequency. The role of exome and or whole genome sequencing for patients with NSCLC is evolving and remains undefined.
Prospective cohort study of serum sialylated glycoprotein (KL-6) as a prognostic marker in patients (pts) with non-small cell lung cancer (NSCLC) receiving gefitinib monotherapy: Okayama Lung Cancer Study Group 0703.
Authors: Yoshioka Hiroshige , Hotta Katsuyuki , Oze Isao , Fujiwara Yoshiro , Hayashi Hidetoshi , Nishiyama Akihiro , Korogi Yohei , Takigawa Nagio , Tanimoto Mitsune , Kiura Katsuyuki ,   Okayama Lung Cancer Study Group
Published: March 2020

e19023

Background: Gefitinib is now crucial in the treatment of EGFR-mutant NSCLC. Its anti-tumor activity could be modulated by MUC1 mucins [Cancer Res 2006], similar to KL-6 in the biochemical property, currently used as an indicator for interstitial lung diseases (ILDs). Our preliminary retrospective study showed the elevated serum KL-6 level is a potential negative prognostic value in pts with advanced NSCLC receiving gefitinib therapy [Lung Cancer 2008]. We conducted an observational study to evaluate this issue prospectively. Methods: Consecutive, EGFR-TKI-naïve NSCLC pts who were to receive gefitinib were enrolled and stratified by pretreatment KL-6 levels (< 500 U/ml: normal group [NG] and ≥ 500 U/ml: abnormally elevated group [EG]). The primary endpoint was overall survival (OS). The planned accrual number of pts was 150, assuming an estimated HR of 2.0, α=0.05, ß=0.10). We also evaluated ILD events during the gefitinib treatment. Results: Between 2007 and 2012, 154 pts were registered (NG: 89 [58%] and EG: 65 [42%] with median KL-6 score of 305 and 1,050 IU/mL, respectively). Those with pretreatment pulmonary fibrosis were similarly distributed between the groups. Median follow-up time was 13.7 months. The EG had significantly worse OS in the univariate analysis (log-rank p=0.0011), which was retained in the multivariate analysis (hazard ratio [HR]: 1.95, 95% confidence interval [95% CI]: 1.34-2.81). Exploratory analyses showed an interaction between EGFR-mutation status and KL-6; HR of KL-6 for OS: 1.96, [1.30-2.97], and HR: 4.80, [1.05-21.95] in pts with EGFR-mutant and wild-typed tumors, respectively (interaction p=0.07). As for ILD event it occurred similarly during the gefitinib therapy (HR: 2.76, [0.62-12.33]). Conclusions: The elevated KL-6 level could predict a poor prognosis in NSCLC pts with gefitinib therapy, and this association seemed modulated by EGFR-mutation status. Further studies are needed to clarify the biological behavior of KL-6 expression on tumor progression especially in the EGFR pathway.