bluuebunny/crossref_metadata_2025 huggingface dataset:
Self-directed learning module for radiation therapy treatment planning
Authors: Campeau M. , Lasalle S. , Lambert C. , Filion É.
Published: March 2020

17051

Background: Radiation Oncology is a rich and rewarding specialty that requires in-depth understanding of anatomy, physics, dosimetry and oncology. The area of dosimetry is an important and basic fundamental concept to be acquired during residency, and pertinent educational tools are few and far between. The purpose of this project was to develop a self-assessment tool to facilitate radiation therapy treatment planning for non-small cell lung cancer (NSCLC). Methods: We focused our learning module on basic dosimetric and NSCLC treatment planning objectives that radiation oncology residents will encounter during residency. Interactive questions incorporating objective-related concepts were then devised. Treatment planning program templates were developed using the Eclipse software application. Results: A web-based self-directed learning module was developed as the tool's delivery mechanism. The module's questions were divided into the following sections: Chest Anatomy, ICRU Concepts, Beam Modificators, Integrated NSCLC Treatment Plans, Systematic Treatment Planning Approach and Inhomogeneity Corrections. By answering questions via the module, learners receive immediate feedback, corrections and concept-related explanations. A variety of different question techniques were employed, such as multiple choice questions, open-ended questions and associations. Learners are prompted by the system to draw isodoses and volumes on the screen. Other tasks in the module involve identifying structures, setting treatment fields and analyzing dose volume histograms. The website is publicly available in both English and French at: http://www.radiol.umontreal.ca/radio-onco/ . Conclusions: This self-directed learning module is a complementary tool that will help residents gain a solid grasp of NSCLC treatment planning objectives. Other modules covering radiation therapy treatment planning for a variety of anatomical sites, as well as diseases at different stages will eventually be created and added to the website. This educational project aims to facilitate learning and understanding the concepts of treatment planning, according to the different types of cancer.

No significant financial relationships to disclose.
The impact of lymph node dissection in patients with colorectal cancer
Authors: Gentry R. W. , Govindarajan R. , Spencer H. J. , Dykstra-Long G.
Published: March 2020

17055

Background: The role of extended lymphadenectomy on survival of patients with colorectal cancer is unclear. Survival in these patients is inversely proportional to the stage of disease. The prognostic significance of inadequate lymph node dissection is not understood. To understand the impact of the number of lymph nodes removed at the time of surgery on survival, we conducted a retrospective study of patients with colorectal cancer treated at the Central Arkansas Veterans Healthcare System, Little Rock, AR. Methods: Data on 531 patients with a diagnosis of colorectal cancer from January 1991 to October 2005 was obtained from the tumor registry. The number of lymph nodes dissected the number of positive and negative lymph nodes for each patient, treatment received and overall survival was analyzed. The number of resected nodes was grouped as follows: none (LNG0), 1–5 (LNG1), 6–10 (LNG2), and > 10 (LNG3). Log rank test was used to evaluate difference in survival between the groups. Results: There were 451 Caucasians, 80 African Americans, 523 males and 8 females in the study. The median age was 69 yrs (range: 29–100). Rectal cancer patients had fewer nodes dissected compared to colon cancer (p <0.001). There was no survival difference between LNG0, LNG1, LNG2 and LNG3 (p=0.435). The number of lymph nodes removed did not have an impact on survival among those who had node negative disease (0.435) and node positive (0.458) disease. LNG0 patients had the same prognosis as those with node negative disease (P=0.435) who had better survival compared to node positive disease. (p=0.029). However, LNG0 patients had similar survival compared to LNG1 subset of patients and those in LNG3 had a trend towards better survival, though not statistically significant. LNG0 subjects received less chemotherapy (p=0.018) and radiation therapy (p=0.01) compared to those who had lymphadenectomy. Conclusions: The number of nodes removed at the time of surgery did not affect survival in subjects with node negative and node positive disease. Patients who did not have any identifiable nodes at the time of surgery had the same prognosis as those who had node negative disease. Patients with more than 10 negative nodes dissected had a trend towards better survival although not statistically significant.

No significant financial relationships to disclose.
Prescription patterns for metastatic breast cancer patients previously treated with anthracycline and taxane: An assessment in a United States managed care database
Authors: Harris L. A. , Yu Y. , Donato B.
Published: March 2020

17056

Background: There is a scarcity of literature documenting actual prescription patterns for metastatic breast cancer (MBC) patients. The objective of this study was to describe the pattern of dispensing chemotherapy agents among MBC patients previously exposed to anthracycline and taxane in the managed care setting. Methods: Study cohort was extracted from the PharMetrics database between 1/1999 through 6/2005, who were =18 years, enrolled =6 months with =2 ICD-9-CM codes for breast cancer (BC), =1 ICD-9-CM code for distant metastases, and =1 NDC/J-code for anthracycline and taxane. A 21 day treatment interval was assigned to all agents to identify treatment regimens. If types of agents in consecutive intervals were the same, they were collapsed into one regimen disregarding the sequence. Following the reference date, the dispense date of the first anthracycline or taxane prescription, whichever occurred later, the first regimen was treated as reference regimen. Following this regimen, sequential monotherapy or combination therapy was identified in a chronological order. Results: Of the 1,028 who met inclusion criteria, 67% (n=691) did not receive a sequential therapy. Of the 33% (n=337) who did, the first sequential regimen for 177 was monotherapy and 160 combination therapy. The most common agents within the monotherapy regimens were taxanes 28%, capecitabine 20%, and trastuzumab 18%. For combination, taxane/trastuzumab 9.4%, vinorelbine/trastuzumab 9.4%, and carboplatin/taxane 8.8%. Of those who received sequential therapy, 68% were retreated with a taxane; 34% with docetaxel and 46% with paclitaxel. Conclusions: In this study, the majority of the population did not receive sequential therapy. This may have been due to loss to follow up, the duration of the reference regimen (lasting throughout the study period(s) after collapsing), or treatment in the inpatient setting where chemotherapy agents are not identifiable in this claims database. Taxane was the most common agent received in the first sequential therapy, both for monotherapy and combination therapy. A high proportion of patients with sequential therapy were retreated with a taxane.

No significant financial relationships to disclose.
Economic burden of brain metastases in breast cancer patients in a US managed-care population
Authors: Amonkar M. M. , Pelletier E. M. , Shim B.
Published: March 2020

17069

Background: Limited data are available evaluating health resource use and costs of breast cancer (BC) patients who develop secondary brain metastases (BM). This study estimated the economic burden among BC patients diagnosed with incident BM. Methods: Female BC patients aged 18+ years, newly diagnosed with BM between 1/2002 and 12/2004 were identified from a private payer database (PharMetrics, Inc). The index date was the date of the incident BM diagnosis. BC was identified during a 1-year look-back period. BM patients were matched to a control group of BC patients with no evidence of BM during the study period. Patients not continuously enrolled in a health plan for 1 year before and at least 1 month after the index date and those aged 65+ years and not in Medicare Risk were excluded. Paid claims were used to estimate resource utilization and costs. Results: 775 incident and control patients resulted from a 1:1 match (mean age=54 years). At 6 months follow-up (N=398), BM patients had significantly more hospital stays (mean 1.1 vs. 0.5, p<0.001) and remained hospitalized for a longer period (mean 8.0 days vs. 2.5 days, p<0.001) compared to controls. BM patients also averaged more outpatient services, including physician office visits (32.8 vs. 24.3, p<0.001), as well as pharmacy claims (56.0 vs. 39.1, p<0.001). Similar differences were found at 1 year (N=230), with greater mean inpatient, outpatient, and pharmacy services (p<0.001) in BM patients. Average total costs for BM patients at 6 months were $60,045 compared to $28,193 (p<0.001) for controls; this difference was driven by higher mean inpatient ($17,462 vs. $5,362, p<0.001) and outpatient ($26,209 vs. $11,652, p<0.001) costs among BM patients. At 1 year, higher mean total costs persisted in BM patients ($99,899 vs. $47,719, p<0.001). After adjusting for key variables, mean costs for BM patients were 123% higher than those for control group patients. Conclusions: Patients with BC and secondary BM incurred significantly more healthcare resources following diagnosis compared to those with BC but no BM. Mean total costs for BM patients were more than double those of patients without BM at 6 months and 1 year. These findings underscore important economic implications of BM and the call for new therapies that improve outcomes in patients with BM.

No significant financial relationships to disclose.
A survey of Canadian medical oncologists on internet use for medical information and a needs assessment for an oncology education website
Authors: Verma S. , Horn L. , Chung J. , Vijayaratnam S. , Berry S.
Published: March 2020

17072

Background: The internet offers an innovative resource for medical oncologists to share and discuss important medical information and advances. Despite the existence of many websites with oncology related information, there has not been a comprehensive assessment of how Canadian medical oncologists use the internet to access this information. Purpose: In the first phase of developing a new educational website (OncologyEducation.com), we surveyed Canadian medical oncologists to determine how they used the internet to access information and to assess their needs for a web based educational resource. Method: A structured survey was developed and assessed for face and content validity by medical oncologists from our local institution. The survey had several domains including: comfort level with computers, description of internet use for work, and key features they would want in an educational website. The survey was sent to all medical oncologists in Canada via regular mail and e-mail. Results: 58 % (144/247) of medical oncologists responded to our survey. The number of years in practice varied from <5 yrs (31%) to 5–10 yrs (30%), and 11–20 years (15%) with 85% having an academic appointment. 90% of respondents were comfortable with using a computer. The most common reasons for internet use were email (91%), literature updates (78%), and answering clinical questions (72%). 27% of respondents used the internet for clinical questions daily, and 29% on a weekly basis. 49% accessed the internet for work-related information for 1–5 hours weekly, 26% for 6–10 hours weekly, and 20% for more than 11hrs weekly. Respondents expressed a need for an educational website stressing the following content: (1) Canadian Oncologists Database to improve opportunities for collaboration (2) Key updates by disease sites (3) Access to information about upcoming conferences. Conclusion: The internet plays a major role in the daily clinical activities of Canadian medical oncologists. The development of an education website based on the needs assessed in this survey is warranted. We are currently developing this site (OncologyEducation.com) and plan to evaluate on an ongoing basis.

No significant financial relationships to disclose.
Direct hospital costs of skeletal-related events (SRE) in Portuguese patients (pts) with breast cancer (BC) and bone metastases
Authors: Felix J. , Andreozzi V. , Soares M. , Gervásio H. , Moreira A. , Costa L. , Peralta F. , Furtado I. , Albuquerque C. , Passos- Coelho J.
Published: March 2020

17084

Background: SRE such as pathological fractures, spinal cord compression, surgery or radiation therapy to bone and tumour- induced hypercalcemia account for substantial health resource utilization (HRU). The objective of this study was to investigate SRE-related direct hospital costs in Portuguese pts with BC and bone metastases. Methods: Pts with BC and at least one SRE within 12 months prior to study entry were eligible for this retrospective medical record review cost analysis study. SRE treatment cost were calculated by multiplying 12 month health resource utilization frequency (hospitalization, clinic visits, diagnostic tests, drugs) by the corresponding unit costs from the Portuguese Ministry of Health costs database. To account for the skewed nature of the data, costs were modelled using generalized linear models with gamma distribution and log link. Results: A total of 121 pts (age at bone metastases, mean 56.8 years, range 21- 89) from six different hospitals in Portugal were included. Median time from BC diagnosis to bone metastases was 38 months [CI95%: 24–57]. ECOG performance status at the time of SRE was 0 in 24.6% of pts, 1 in 45.9%, 2 in 18.0%, 3 in 8.2% and 4 in 3.3%. Total number of SRE over twelve months was 142 (mean 1.2 SRE/pts, SD=0.4) distributed as follows: pathological fractures (12.7%), spinal cord compression (4.9%), surgery to bone (1.4%), radiation therapy to bone (74.7%) and tumour induced hypercalcemia (6.3%) . Mean SRE treatment cost over 12 months was 5,963€ (SD=3,646€): hospitalization 1,312€, clinic visits 36€, diagnostics 103€, radiotherapy 1,481€, drugs 3,031€. According to biphosphonate (Bph) use in the prior 12 months, the mean (SD; pts) unadjusted SRE treatment cost was: no Bph 2,282€ (1,491; n=4), oral Bph 1,579€ (1,123; n=5), zoledronic acid 6,221€ (2,923; n=77), pamidronate 6,766€ (4,476; n=33). When excluding Bph costs, pamidronate pts were 1.8 [95% CI: 1.3–2.7] times more expensive than zoledronic acid when controlling for pts’ clinical characteristics. Conclusions: This study confirms prior data on the high cost of SRE in pts with BC metastatic to bone

[Table: see text]
Phase I trial of gemcitabine (GEM) infused at fixed-dose rate (FDR) with high-dose docetaxel/melphalan/carboplatin (GEM-DMC) and autologous stem-cell transplant (ASCT)
Authors: Nieto Y. , Rifon J. , Perez-Calvo J. , Zafra A. , Zufia L. , Viudez A. , Viteri S. , Sayan O. , Hernandez M. , Aldaz A.
Published: March 2020

17500

Background: More active ASCT regimens are needed. We combined GEM, which inhibits DNA damage repair, with the potent DMC regimen (BBMT 11:297–306,2005). GEM infusions at FDR of 10 mg/m2/min, targeting steady-state concentrations (Css) <20 μM, which in vitro do not saturate its intracellular activation to GEM-triphosphate (GEM-TP), result in greater activity but more myelotoxicity than its usual short infusions. Methods: Pts with advanced, refractory tumors and normal organ function were eligible. Study endpoints: to define the maximum tolerated duration (MTD) of GEM at FDR with ASCT, dose-limiting toxicity (DLT) and regimen-related toxicity (RRT) of GEM-DMC, and pharmacokinetics (PK) of high-dose GEM and docetaxel. Daily GEM FDR infusions (d-5 to d-2) were extended in sequential cohorts (total length: 9 to 20 hr), followed on d-5 by docetaxel (350 mg/m2), on d-4 to d-2 by melphalan (50 mg/m2/d) and carboplatin (333 mg/m2/d), and ASCT on d0. Results: 52 pts accrued (breast ca [N=31], Ewing's [5], germ-cell [4], lymphoma [4], Hodgkin's [3], sarcoma [5]), median age 40 (6–66), 3 median prior chemo regimens and 3 organs involved. GEM MTD: 5 hr/d x 4 (total 20 hr, 12 g/m2). Neutrophils engrafted on d+8 (6–10) and platelets on d+11 (8–33). There were 3 non-RRT deaths (1 aspiration, 2 catheter-related sepsis). At the MTD (N=25), enteritis (20% G3) was DLT; all other RRT were = G3 and reversible (28% stomatitis, 8% ileus, 8% rash). The response rate was 97% (60% complete). At median follow-up of 18 (7–27) months, 58% EFS (median 22 mo) and 85% OS rates (median not reached). All pts had GEM Css <20 μM. The infusion length correlated linearly with the AUC of GEM (r2= 0.65, p<10-5) but not with its clearance (r2=0.03) or t1/2 (r2= 0.02). GEM AUC was associated with G3 RRT (p<10-3). The AUCs of GEM and GEM-TP (/106 mononuclear cells) correlated on d-5 (r2=0.5, p=0.01), but not on d-2 (r2= 0.05) due to late GEM-TP accumulation. Docetaxel had 3–4 fold higher AUC and peak levels and similar clearance compared to its standard-dose population PK. Conclusions: GEM-DMC, markedly extending GEM infusions at FDR, is tolerable and highly active, without saturating the activation of GEM to GEM-TP. High-dose GEM and docetaxel show adequate linear PK.

No significant financial relationships to disclose.
To assess the response and toxicity of imatinib mesylate and low-dose cytarabine in imatinib non-responder chronic myeloid leukemia, chronic phase (CML-CP) patients: A pilot study
Authors: Singh N. , Kumar L. , Kochupillae V. , Raina V. , Sharma A. , Velpandian T.
Published: March 2020

17507

Background: To overcome primary imatinib mesylate (Gleevec ) resistance, we used a combination of imatinib mesylate and low dose cytarabine to treat patients of CML-CP. Methods: Between January 2005 and July 2006, 30 patients (median age 34 years, range 20 to 57 years, M:F ratio 5:1) were enrolled. 2/30 patients had primary hematological and 28/30 had primary cytogenetic resistance. 7 patients had been pretreated with interferon alpha. Treatment consisted of imatinib 400mg daily and cytarabine 10mg subcutaneous daily for 10 days every month. Median of 5 cycles (range 3–6) was administered. Patients were monitored on outpatient basis with weekly blood counts. Bone marrow cytogenetics was done 3 monthly to assess cytogenetic response (CGR). Toxicity was recorded as per NCI CTC (version 2). Primary end points were response and toxicity at the end of 6 cycles. We measured plasma imatinib levels by HPLC in 20 of these patients (J Chromatography B 2004;84:431–34) and compared the levels with 20 patients who were imatinib responders. Results: 11/30 (37%) patients obtained major CGR including complete CGR in 6/30 (20%). None of the patients with primary hematological resistance responded. Grade 3/4 hematological and non hematological toxicities were seen in 3.33% (n=1) and6.66% (n=2) patients respectively. 8/30 (27%) patients discontinued treatment due to reversible cardiac arrest (n=1), hepatitis (n=1), progression to BC/AP (n=2), grade 4 thrombocytopenia (n=1), loss of CHR (n=2), and consent withdrawl (n=1). The mean plasma imatinib levels in non responders were significantly lower, compared to imatinib responders (0.70 micro moles vs 2.34 micro moles, p=0.002). Conclusions: Present study confirms the activity of low dose cytarabine and imatinib in patients having primary cytogenetic resistance. The reasons for low plasma imatinib levels among non responders and methods to circumvent so as to achieve higher plasma levels of imatinib needs further study.

No significant financial relationships to disclose.
Dasatinib phase I/II study of patients with chronic myeloid leukemia (CML) resistant or intolerant to imatinib: Results of the CA180031 study in Japan
Authors: Sakamaki H. , Ishizawa K. , Taniwaki M. , Fujisawa S. , Morishima Y. , Tobinai K. , Okada M. , Ando K. , Ueda K. , Ohno R.
Published: March 2020

17515

Background: Dasatinib is a potent, orally active, multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases. Studies outside Japan have shown dasatinib to be highly effective in overcoming resistance and intolerance to imatinib, inducing durable cytogenetic (CyR) and hematologic responses (HR) in this population. The maximum tolerated dose was not reached in the Phase-I trial outside Japan and a 70-mg BID dose was determined to provide the optimal benefit-risk profile. Methods: This Phase-I/-II study was designed to assess the safety and efficacy of dasatinib in Japanese patients with imatinib-resistant or -intolerant CML or Ph+ALL. In the 4-week Phase-I portion in patients with chronic-phase (CP) CML, three dose levels were evaluated: 50 mg, 70 mg, and 90 mg BID. The Phase-II portion is currently evaluating the CyR of dasatinib in patients with CP-CML at 24 weeks, and the HR rate in accelerated- (AP) or blast-phase (BP) CML and Ph+ ALL at 12 weeks. Results: As of December 2006, 17 eligible patients have been treated in Phase I. Six patients (4F, 2M; median age 43 y [range 27–56]) were treated with 50 mg BID and 1 dose-limiting toxicity (DLT) was observed (Grade 4 thrombocytopenia). Two patients experienced transient Grade 3 ALT elevations but as treatment was uninterrupted, these were not considered DLTs. Six patients (6M; median age 42 y [range 27–55]) were treated with 70 mg BID and again 1 DLT was observed (Grade 4 thrombocytopenia). No DLT has been observed among 4 patients (3M, 1F; median age 41 y [range 27–64]) at the 90-mg BID dose. Major CyRs have been achieved in all three cohorts in the Phase-I segment of the trial. Thirty six patients were enrolled and treated in the Phase-II part of the trial (12 CP-CML, 7 AP- CML, 4 BP-CML, and 13 Ph+ALL). Efficacy and safety data as well as the baseline BCR-ABL mutation data are currently being assessed and will be presented. Conclusions: Dasatinib can be safely administered at doses of up to 90 mg BID to Japanese patients with imatinib-resistant or -intolerant CP-CML.

No significant financial relationships to disclose.
Pattern of extramedullary relapse in latin patients with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and chemotherapy
Authors: Casanova L. A. , Quintana S. M. , Neciosup S. P. , Samanez C. A.
Published: March 2020

17520

Background: Extramedullary relapse (EMR) is a rare event in APL and reports have suggested a possible rol of ATRA in its pathogenesis. Our study intent to determine the pattern of EMR in Latin patients treated whit trans-retinoic acid (ATRA) and chemotherapy (CT). Methods: We evaluated 87 patients diagnosed of APL from January 2001 to December 2005. They were treated with ATRA and chemotherapy. Results: 74/87 received ATRA plus chemotherapy. Median age was 28 (5–68). 39/74 (53%) patients were female. Subtype M3v constituted 21/74 (28%). 76% presented disseminated intravascular coagulation (DIC). Extramedullary deposit was observed in 7 cases, more frequent was central nervous system (CNS). According the Sanz Index, 32/74 (32%) were High Risk, 40/74 (54%) Intermediate Risk, 2 Low Risk. 31/55 (56%) presented t(15,17). 52/74 (70%) patients had complete response. EMR was documented in 8 (15%) (CNS: 5, External Auditory Foramen: 3), 4 were High Risk. Median time to EMR was 11.5 months (7.03–27.3). 55% are alive at date. The following median was 36 months, 41 months of Disease Free Survival (DFS), rate was 62 % to 3 years. Overall survival was 44 months; rate was 83% to 3 years. Conclusions: EMR incidence was 8%, higher report that other series, this event was presented in CNS and external auditory foramen. It suggest to establish EMR risk factors and to include CNS prophylactic treatment.

No significant financial relationships to disclose.
Imatinib mesylate in newly diagnosed patients of chronic myeloid leukemia chronic phase: A comparative study
Authors: Jacob L. A. , Bapsy P. P. , Govindbabu K. , Lokanatha D.
Published: March 2020

17521

Background: Two single centre experiences from India on the use of Imatinib mesylate in the treatment of chronic myeloid leukemia chronic phase (CML-CP) have shown somewhat similar results. While complete hematological response (CHR) achieved in the two studies was comparable to Western data, major cytogenetic response (MCR) and complete cytogenetic response (CCR) were much lower. Both studies had included newly diagnosed as well as previously treated patients. This study was undertaken to evaluate the efficacy and safety of imatinib mesylate, only in newly diagnosed patients of CML-CP and to compare the results obtained with those reported in literature. Methods: The study population included 100 newly diagnosed patients of CML-CP. Therapy was initiated with imatinib mesylate 400mg orally daily and patients monitored carefully for any adverse effects. After 6 months of treatment, bone marrow aspiration and cytogenetics were repeated to ascertain the response. In patients not achieving a MCR, the dose of imatinib was increased to 600mg daily and therapy continued. Results: In the present study, although imatinib produced CHR in 90% of the patients; only 50% achieved a MCR at 6 months and 55% at 12 months as compared to the 86- 87% reported in major trials involving newly diagnosed patients of CML-CP. The drug was safe and well tolerated. A comparison of patient characteristics with those in the Western studies revealed that majority of the Indian patients probably presented late in the disease course. A higher incidence of adverse genomic factors at diagnosis leading to rapid progression of disease could be the probable explanation for this. Conclusions: Thus based on our present study, we conclude that there is a difference in the efficacy profile of imatinib in Indian patients as compared to the West, the reasons for which needs to be investigated and validated.

No significant financial relationships to disclose.
Outcome of prophylactic cranial radiotherapy in children with ALL
Authors: Ozden S. , Ozyurt H. , Ozgen Z. , Ozseker N. , Parlak C. , Mayadagli A.
Published: March 2020

17532

Background: The aim of this study was to evaluate influence of prophylactic cranial radiotherapy (RT) and prognostic factors on overall survival (OS) in patients with acute lymphoblastic leukemia (ALL), retrospectively. Methods: Forty nine children referred to Dr. Lutfi Kirdar Kartal Education and Research Hospital to undergo prophylactic cranial RT for the diagnosis of ALL between years 1997–2003 were analyzed retrospectively to determine cranial recurrence rate. Eleven patients were considered as loss due to loss of contact. Survival analyses were carried out by Kaplan Meier. Results: Median follow-up time was 49 months. Of the 49 cases, 30 (61,2%) were male, and 19 (38,8%) were female. Median age was 6 years (2–18). Moderate to high risk patients who revealed remission after chemotherapy (CT) had been referred to our clinic for RT. At the time of presentation, 5 patients had CNS involvement, and one patient had mass in his right eye. Craniospinal RT was performed to 4 patients while others received total cranial RT including C1–2 vertebra. RT was given with Co 60 in various dose and fractionation schedules (120–200cGy/fx) to total doses ranging from 11,4 to 24 Gy in 7–16 fractions. There was a statistically significant survival difference between cases treated at doses <18 Gy (n:15) and those treated at doses >18 Gy (n:23) in favor of higher RT doses (OS: 35,5 vs. . 44,1 months, p=0.01). Cases with no CNS involvement at presentation revealed a significant overall and disease free survival (DFS) advantage over cases with involvement (OS: 44,2 vs. 22,5 months, DFS:40,7 vs. 19,5 months, p=0.001). OS analyses of 24 cases whose leukocyte counts (LC) were determined at the time of diagnosis revealed OS of 57,5, 35,6, 36,2 months for those with LC of <10000 (n:9), 10000–50000 (n:5) and >50000 (n:10), respectively (p=0,01). There was no notable influence of sex or age on survival. CNS recurrence was seen in only 2 male patients. No morbidity related to RT was experienced in any of the patients that are still alive. Conclusions: Prophylactic cranial RT of 18 Gy is a well-tolerated treatment option for children with the diagnosis of ALL, and optimal dose for better outcome should be identified.

No significant financial relationships to disclose.
Multivariate dimensions of hemotologic chaos indices for responders versus non-responders of patients with myelodysplastic syndromes (MDS) after treatment with ptx/cipro/decadron: A qualitative study
Authors: Huang R. R. , Raza A.
Published: March 2020

17540

Background: In our clinical study of 35 MDS patients who were treated with PTX/Cipro/Decadron, there was an 80% response rate in terms of achieving improved hematopoiesis (responders) during a 4-week period. The primary question of interest was, “What were the hematologic dynamic patterns that transpired between patients who responded versus those who did not?” The purpose of this study was an attempt to answer this question by applying chaos theory to peruse the underlying patterns that may have prognosis utility. Methods: Responders and non-responders were identified and were matched by age, sex, and FAB type. Only those patients who have sufficient and complete hematologic evaluations after treatment with at least 6 months follow-up to derive stable chaotic indices were included. The resulted sample was 3 patients from the non-responded group and 4 patients from the responded group. The three selected hematoloic parametes were white blood count, hemoglobin and platelets. The selected chaos index to indicate its magnitude of across time was the fractal dimension that has three components, namely capacity, information and correlational. Results: The mean ages for the non-responders and responders were 68 and 65, respectively. The median number of weeks evaluated was 38 for the non-responders and 35 weeks for the responders. The three hematologic parameters were analyzed simultaneously in the form of 3-dimensional space. Table indicates the chaos fractal indices for the two groups. Conclusion: Across the three indices, non-responders have an average of 7.4 % larger than responders, suggesting the former exhibited a relatively higher degree of “chaos” than the latter. For prognosis purpose, this result also suggests that patients who exhibit lower magnitude of the chaotic phenomena, will have a higher probability of responding to therapy. This work was done while the authors were at Rush-Presbyterian-St.Luke’s Medical Center.

[Table: see text]

No significant financial relationships to disclose.
A phase II study of carboplatin (C) and weekly paclitaxel (P) with a selective cyclooxygenase-2 (COX-2) inhibitor, meloxicam, in advanced non-small cell lung cancer (NSCLC)
Authors: Suzuki R. , Yamamoto M. , Saka H. , Taniguchi H. , Shindo J. , Tanikawa Y. , Nomura S. , Oishi T. , Hasegawa Y. , Shimokata K.
Published: March 2020

18007

Background: COX-2 overexpression is seen in many malignancies including lung cancer. Recent pre-clinical studies have shown that selective COX-2 inhibitors have demonstrated promising results when used with chemotherapy. Based on these observations, we are assessing the efficacy and tolerability of the combination chemotherapy consisting of C and P with meloxicam, a selective COX-2 inhibitor. Methods: Patients with stage IIIB or IV, ECOG PS 0 or 1, who had adequate organ function, were eligible. Patients received P 70 mg/m2 weekly for 3 of 4 weeks with C (AUC 6) on day 1, as well as daily meloxicam (10 mg/day). Response rate was the primary endpoint. Secondary endpoints were overall survival, toxicity profile and QOL (Using EORTC QLQ-C30 and LC13). Results: From March 2005 until September 2006, forty-four patients were evaluated in this study. Gender M/F; 31/13, median age; 64 yr (range, 34–75), stage IIIB/IV; 11/33, PS0/1; 22/22, histology Ad/Sq/Others; 29/6/9. Partial response was observed in 19 patients (43%), and no complete response, yielding an overall response rate of 43% (95% confidence interval, 28.5%-57.8%). Nineteen patients (43%) had stable disease. Seven patients (16%) had grade (G) 3 and three (7%) had G4 neutropenia. Three patients (7%) had G3 thrombocytopenia. As for non-hematological toxicities, one G4 toxicity (perforation of jejunum) was observed, but the other toxicities were mild (one muscle pain, 2 liver dysfunction, 1 fatigue and 1 nausea G3). Grade 2 peripheral neuropathy was observed in only one patient. Using EORTC QLO questioner, the global health status did not changed significantly during this therapy (before and 4 and 8 weeks later). Median follow-up was 9.6 months (range, 1.8–22.7 months). At the time of the final analysis (January 2007), 16 patients had died. The one-year survival rate was 70% and MST was not reached till now. Conclusions: Meloxicam in combination with C and weekly P chemotherapy showed promising activity with encouraging survival. This therapy is relatively well-tolerated in advanced NSCLC.

No significant financial relationships to disclose.
Meta-analysis of pemetrexed (P) plus gemcitabine (G) in first-line, advanced (adv) non-small cell lung cancer (NSCLC)
Authors: Ye Z. , Treat J. A.
Published: March 2020

18015

Background: Clinical trials with varying schedules and doses of P and G have demonstrated anti-tumor activity in NSCLC. Methods: This report summarizes best response and toxicity data of 4 clinical trials using PG regimens in 1st-line, adv NSCLC. Pt populations were similar and included measurable or evaluable Stage IIIB-IV disease. Results: *Excludes 1 pt considered inevaluble for neutropenia **One pt died due to thrombocytopenia. Conclusion: Based on the results of these 4 trials, PG was efficacious and well tolerated as 1st-line therapy for pts with adv NSCLC. A low incidence of alopecia and Gr 4 thrombocytopenia are noted.

[Table: see text] [Table: see text]
Initial safety results of an open-label phase II trial of erlotinib in non-small cell lung carcinoma (NSCLC)
Authors: García-Velasco A. , Pérez-Carrión R. , de Castro J. , Garrido P. , García R. , González-Larriba J. L. , Martín G. , Provencio M. , Amador M. L. , Paz-Ares L.
Published: March 2020

18038

Background: Erlotinib is an orally selective and reversible inhibitor of HER1/EGFR tyrosine kinase. Erlotinib has demonstrated to be effective in the treatment of advanced non-small-cell lung cancer, in terms of longer survival, better quality of life and delayed symptom progression. The TargeT trial is a large open-label, non-randomized, phase II study carried out in 101 Spanish institutions. Methods: Eligibility criteria included stage IIIB-IV previously treated patients (p) with confirmed NSCLC. Patients harboring mutations in EGFR gene or p unsuitable for chemotherapy were also allowed to enter the study and received erlotinib as first line treatment. Subjects were treated with 150 mg/day po until disease progression or unacceptable toxicity. Dose reductions were allowed. Primary end-point was time to progression. Results: By the time of this analysis, data from 1,522 p were available. Median age: 65 y (range 26–95); most p were male (71.9%); active/former a smoker (78.3%). Around half of the p had adenocarcinoma histology, including bronchioloalveolar carcinoma (53%) and 81.8% exhibited stage IV. ECOG PS 0/1/2 were (%) 21/54/25. The % p receiving erlotinib as 1st/2nd/3rd-line treatment were 29/38/33. Safety data were available for 1,255 p. 6.9% p did not experience any adverse event. As expected most common adverse events were rash (any grade: 61%; gr. 3/4: 11%), and diarrhea (any gr.: 31%; gr. 3/4: 4%) 5.6% p withdrew prematurely the trial due to AE. Erlotinib-related AEs leading to treatment discontinuation were cutaneous toxicity in 21 p (17 gr. 3/4), diarrhea in 6 p (4 gr. 3/4), hepatic toxicity in 1 p, cholestasis in 1 p, and interstitial pneumonitis in 1 p. No unexpected toxicities were reported. 10% of p had dose reductions mainly due to rash and diarrhea. Response rate in these p was 18.7%; time to progression 3.8 months (95% CI: 3.5–4.2); and overall survival 6.0 months (95% CI: 5.5–6.4). Conclusions: These initial interim safety results of erlotinib in real-life clinical setting in a large number of unselected patients with advanced non-small-cell lung cancer confirm the favorable toxicity profile and good tolerability of erlotinib.

No significant financial relationships to disclose.
Vinorelbine (VRB) plus gemcitabine (GEM) as first-line treatment for elderly patients (p) with advanced non-small cell lung cancer (NSCLC): Molecular correlates
Authors: Maestu I. , Isla D. , Diz P. , Muñoz J. , Oramas J. , Garcia R. , del Barco S. , Provencio M. , Taron M. , Rosell R.
Published: March 2020

18040

Background: The clinical benefit of non-cisplatin doublets vs a single agent in elderly or unfit p is still controversial. The present study focuses on clinical outcome with VRB/GEM in elderly p and the role of functional status and comorbidities. Genetic predictive markers of response to VRB/GEM will also be examined in genomic and cDNA from tumor and circulating tumor DNA. Methods: 145 chemonaive p with stage IIIB (pleural effusion or supraclavicular lymph nodes)-IV or recurrent NSCLC and age > 70 years were accrued at 32 sites between April 2004 and January 2006. Treatment consisted of VRB 25 mg/m2 IV or 60–80 mg/m2 oral plus GEM 1200 mg/m2, days 1, 8 every 21 days. Activities of daily living (ADL), instrumental activities of daily living (IADL) and comorbidities were evaluated. DNA samples were collected from primary tumors for the assessment of microtubule associated protein 4 (MAP4) and from serum for the checkpoint with forkhead-associated and ring finger (CHFR) methylation. Results: Data on 130 p is available. Median age 76 years (69–83); males: 86.8%; smokers: 70.5%; PS 0–1: 83.9%; adenocarcinoma: 34.4% / squamous: 48%; stage IIIB: 22.7%, IV: 77.3%. Self-sufficiency in ADL and IADL was 77.4% and 45.2% of the p analyzed. 68% of the p had comorbidities. Median cycles: 3 (1–8). Hematological toxicities (%p): grade 3/4 neutropenia, 7.8%/4.7%; grade 3/4 thrombocytopenia, 2.3%/0.8%; grade 3 anemia, 3.1%. Efficacy in evaluable population: PR, 23.2% (95% CI, 15.1% to 32.9%); SD, 41.1%. 24 p died during the treatment period (non toxicity related) and 21 p were not evaluable. With a median follow up of 5.8 months, median survival for the whole population was 4.97 months (m), progression free survival 4.53 m, event free survival 3.43 m, 1-year survival 26.6%. Statistically significant differences in median survival were observed among subgroups: PS 0–1/2, 6.5/2.3 m (p<0.001); sex male/female, 4.5/9.7 m (p 0.027); ADL <6/=6, 3.4/7.1 m (p 0.023). Conclusions: This trial confirms that VRB/GEM is effective, presenting a favorable toxicity profile in elderly p with advanced NSCLC. Complete data on genetic markers will be presented.

No significant financial relationships to disclose.
The relationship between pemetrexed exposure (AUC) and clinical outcome in Japanese NSCLC patients
Authors: Adachi S. , Tamura T. , Nakagawa K. , Falcoz C. , Musib L. , Calvert H.
Published: March 2020

18041

Background: The efficacy of pemetrexed (PEM) 500 mg/m2 administered with vitamin B12 and folic acid (FS) has been established in previously treated NSCLC. The 500 mg/m2 dose is based on the MTD determined for PEM without FS. Recently completed phase I studies have shown the recommended dose of PEM single agent with FS to be 900–1,000 mg/m2. A randomized phase II study conducted in Japan (ASCO 2007) showed PEM 500 mg/m2 and 1,000 mg/m2 with FS to have similar efficacy for patients with 2nd and 3rd line NSCLC. PEM is renally excreted and a PK model characterizing the relationship between CrCL and PEM AUC has been previously established. The exposure response relationships (ERRs) between AUC and progression free survival (PFS), individual patient’ tumor response, and toxicity were explored in these analyses. Methods: Eligible patients had a histologic or cytologic diagnosis of NSCLC, had been previously treated by 1 or 2 chemotherapy regimens, and were randomized to 500 mg/m2 (N = 108 pts) or 1,000 mg/m2 (N = 108 pts) of PEM once every 3 weeks. A previously established PK model was used to estimate AUC based on patient CrCL and dose administered. AUCs were linked to clinical outcome to identify ERRs. Efficacy models assumed a distribution of events with hazard dependent on prognostic factors and mean AUC at cycle over the treatment period. The AE model assumed probability of toxicity as a function of AUC at each cycle. Results: Median CrCL for patients in 500 mg/m2 and 1,000 mg/m2 groups were 85 ml/min (42–167) and 83 ml/min (38–146), respectively; median estimated PEM AUCs were 158 mg.h/L (107–221) and 318 mg.h/L (215–468). The relationship between model-estimated AUC and PFS was not significant. This is consistent with the clinical findings: PFS for the 500 mg/m2 and 1,000 mg/m2 groups of 3.0 months and 2.4 months, respectively; overall response rate (RR) of 18.5% and 14.8%, respectively. ERR analyses for individual patient tumor response, neutropenia and thrombocytopenia are ongoing at this time. Conclusions: Estimated PEM AUCs, based on CrCL, does not correlate with PFS for pretreated NSCLC at 500 mg/m2 and 1,000 mg/m2. The ERRs for individual tumor response and toxicity are ongoing and will be presented at the meeting.

No significant financial relationships to disclose.
Low incidence of brain metastasis as first site of relapse in patients with stage II and III non-small cell lung cancer
Authors: Moazzam N. , Kratzke R.
Published: March 2020

18051

Background: Lung cancer remains the leading cause of cancer mortality in both women and men in the United States. Despite recent advances in treatments, many patients with stage II and III non-small cell lung cancer (NSCLC) die of recurrent disease. Methods: A retrospective review was conducted to determine the incidence of brain metastasis as first site of relapse as well as other patterns of failure in patients with stage II and III NSCLC. From 1995 to 2003, 239 patients were identified from Minneapolis Veterans Affairs Medical Center tumor registry. Data was collected on the following variables to identify prognostic factors for brain metastasis and others patterns of failure: patient’s age, tumor histology, tumor size, nodal status, use of adjuvant chemotherapy, and type of adjuvant chemotherapy. Results: Of the 239 patients, only 12 (5%) had brain metastasis as first site of relapse. Median survival for patients with brain metastasis was 0.9 year (95% CI, 0.75–1.50). Out of 12 patients, 8 (67%) developed brain metastasis between 6 and 12 months after the initial diagnosis, 3 (25%) developed brain metastasis between 12 and 18 months and 1 (8%) developed brain metastasis as first site of relapse more than 18 months after initial diagnosis. Other patterns of failure were as follows: Thorax 36%, primary site 22%, primary + thorax 14% and distant metastasis 32%. Among 88 patients who underwent surgery as a part of definitive therapy, thorax was again the most common site of relapse (23%). Multivariate analysis showed that use of non-platinum based chemotherapy is a significant risk factor for relapse (p=0.02). Conclusion: Brain metastasis as first site of relapse is uncommon in patients with stage II and III NSCLC. Due to very low incidence of brain metastasis in this cohort of patients, prophylactic cranial radiation (which is the focus of few ongoing clinical trials) may cause more harm than good.

No significant financial relationships to disclose.
P63 in cytologic material is helpful for detection of squamous differentiation in non-small cell carcinomas of lung and treatment selection
Authors: Jorda M. , Mousavi F. , Gomez-Fernandez C. , Maleki Z. , Walker G. , Ganjei-Azar P.
Published: March 2020

18052

Background: Bevacizumab in combination with carboplatin and paclitaxel improves overall response and survival in patients with advanced or recurrent non-small cell lung carcinoma. However, this drug is not recommended in patients with carcinomas with squamous differentiation. Therefore, identification of squamous cell component is desirable. In many instances, cytology is the diagnostic tool of choice; however, routine cytomorphology is limited in classification of non small-cell carcinomas into squamous and non-squamous subtypes. The aim of this study is to identify the value of immunocytochemistry for p63 in this distinction. Methods: Review of cytology records identified 51 consecutive pulmonary specimens with the diagnosis of non-small cell carcinoma (9 squamous cell carcinomas and 42 carcinomas without squamous differentiation). Histologically, they proved to be 26 squamous cell carcinomas and 25 non-small cell carcinomas without squamous differentiation. P63 immunocytochemical stain was performed on archival alcohol-fixed Papanicolaou stained cytology slides, using standard immunocytochemical methods. Results: Twenty-three (88 %) of the 26 histologically proven squamous cell carcinomas were positive for p63 on cytologic smears. Using p63, we detected 14 carcinomas with squamous differentiation not identified by cytomorphology. Smears from all carcinomas with squamous differentiation were positive for p63. Sensitivity of cytology for the detection of squamous differentiation increased from 35% to 88% using p63 immunocytochemistry (p=0.001, McNemar’s test). Four carcinomas with squamous differentiation were detected only in cytologic and not in corresponding histologic samples. Conclusions: 1- p63 is a useful marker for the detection of squamous differentiation in cytologic pulmonary samples; 2- p63 immunocytochemistry significantly increases the sensitivity for the identification of squamous cell carcinomas of lung from 35% to 88% (p=0.001); 3- p63 immunocytochemistry should be used in all pulmonary cytologic samples with a diagnosis of non-small cell carcinoma to improve therapeutic selection of patients; 4- Cytologic sampling may provide better representation of tumor subtypes.

No significant financial relationships to disclose.
A phase I and pharmacologic study of belotecan in combination with cisplatin in patients with previously untreated extensive-stage disease small cell lung cancer
Authors: Lee J. , Lee D. , Bae K. , Kim S. , Suh C. , Shin J. , Hong J. , Kang Y.
Published: March 2020

18053

Background: Belotecan (CKD602) is a novel camptothecin derivative antitumor agent. This phase I study was designed to determine the maximum-tolerated dose (MTD), toxicity profile, and dose-limiting toxicity (DLT) of belotecan in combination with cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer (ED SCLC). Furthermore, pharmacokinetics (PK) and preliminary antitumor activity of belotecan against SCLC were evaluated. Methods: Patients with ED SCLC, age 18–70, ECOG PS 0–2, no prior chemotherapy and adequate organ function were eligible. Cisplatin with fixed dose of 60 mg/m2 was administered intravenously (i.v.) over 2 hours on day 1. Belotecan was administered iv as intermittent 30-minute infusions on days 1 to 4, starting dose of 0.40 mg/m2/day with increment of 0.05 mg/m2/day. Modified Fibonacci escalation was used (3 to 6 patients per cohort) and intra-patient dose escalation was not allowed. PK of belotecan was determined during the first treatment using non-compartmental pharmacokinetic analysis. Results: Seventeen patients were treated at 4 dose levels (0.40 to 0.55 mg/m2/day). At 0.55 mg/m2/day of belotecan, the DLT of grade 4 neutropenia with fever occurred in 2 of 5 patients, and therefore the MTD was 0.50 mg/m2/day. Interestingly, out of 17 patients, there were 14 partial responses (82.4%; 95% CI, 63.4% to 100.0%). PK analysis revealed that at 0.50 mg/m2/day, plasma clearance of belotecan was 5.78 ± 1.32 L/hr and terminal half-life was 8.55 ± 2.12 hr. Fraction of excreted amount in urine was 37.36 ± 5.55 %. PK of belotecan were not altered by administration of cisplatin, as compared with historical control. Conclusions: The MTD of belotecan was 0.50 mg/m2/day for intermittent 30-min i.v. infusion for 4 days in combination with cisplatin 60 mg/m2 on day 1 every 3 weeks. Furthermore, very promising antitumor activity against SCLC was observed. The phase II study is being conducted now.

No significant financial relationships to disclose.