bluuebunny/crossref_metadata_2025 huggingface dataset:
A review of physician preparedness in response to a systemic crisis: The case of Eastern Regional Health Authority, Newfoundland, Canada, estrogen receptor (ER) breast cancer (BC) errors
Authors: Popadiuk C.
Published: August 2020

e17551

Background: From March until October 2008, a Commission of Inquiry was held in St. John's, Canada, investigating systemic errors leading to incorrect ER results in BC patients. 386 ER negative BC samples tested between 1997 and 2005 were incorrect. Of 91 witnesses, 26 physicians testified about their roles in this “crisis.” Physicians have traditionally been trained to respond to individual clinical crises and acute traumatic situations. This study summarizes the physicians’ training and preparedness in response to a systemic organizational crisis. Methods: Inquiry exhibits, submissions, and transcripts of physician testimony were reviewed for evidence of education and experience in crisis management (CM) as applied to a complex organization. Education and experience with organizational health care crisis were tabulated and prevalent themes relevant for physicians summarized. Results: Evidence was reviewed from 5 oncologists, 17 pathologists, 1 health information analyst, and 3 senior physician leaders. 20 physicians held departmental or divisional leadership roles, one had an advanced degree in Public Health and one had direct experience in a complex private organization. 5 out of province expert consultants had direct experience with continuous quality control applied to large organizations. No physicians were formally trained in CM in terms of acute crisis response. Two prevailing concerns were expressed: 1) delayed and incomplete disclosure of information to patients and public, and 2) numerous preceding systems problems identified by physicians that did not translate into necessary systemic changes to prevent the crisis. Conclusions: The practice of CM recognizes the need to eliminate technological and human systems failure and to develop formal communication systems to avoid or to manage crisis situations. Large-scale organizational crisis management is an important concept for physicians to understand and actively participate in their professional roles. At present most physicians do not receive formal training in CM.

No significant financial relationships to disclose.
A cost analysis of treatment with bevacizumab plus cisplatin and gemcitabine (BCG) versus cetuximab plus vinorelbine and cisplatin (CVC) in patients with advanced or recurrent non-small cell lung cancer (NSCLC) in Germany
Authors: Heigener D. F. , Wiesner C. , Aultman R.
Published: August 2020

e17553

Background: Although new treatment options for advanced NSCLC can offer improved survival over standard treatment with chemotherapy (CT) they should also offer value for money. Bevacizumab (BEV), a humanized monoclonal antibody (MAb) directed against vascular endothelial growth factor when combined with CT increases overall survival (median 13.6 months in the AVAiL study) and progression-free survival (PFS) in patients with advanced NSCLC when compared with CT alone. Cetuximab (CTX), an IgG1 MAb which targets the epidermal growth factor receptor achieved a median survival time of 11.3 months when combined with CT in the FLEX study and marketing authorization is anticipated in 2009. The aim of this study was to compare the costs of treating NSCLC with BCG or CVC in Germany. Methods: A Markov model was used to compare drug and administration costs associated with treating advanced or recurrent NSCLC with either BCG or CVC. The model assumes patients move from non-progressive to progressed disease prior to death, according to transition probabilities derived from an indirect comparison of the efficacy of BCG and CVC in terms of PFS using data from the respective pivotal trials and appropriate indirect comparison methodology. Cost data were derived from local sources. Drug costs assumed CT was given for up to 6 cycles, that CTX was administered at an initial dose of 400 mg/m2 followed by 250 mg/m2 weekly until progression and that BEV was administered at 7.5 mg/kg until progression. The model estimated average drug and administration costs per patient treated with either BCG or CVC. Results: The mean total cost of BCG treatment was €4713 less per patient when compared with CVC (€28342 vs. €33055). The addition of BEV to CT was less costly than the addition of CTX to CT (€18796 vs. €29502) and the administration costs were also lower (€391 vs. €1179). Conclusions: Targeted therapy using BEV is less costly than CTX in Germany and thus, from a budget perspective, offers the best value for money strategy for improving outcomes in patients with advanced NSCLC. Furthermore, costs savings with BCG in Germany are likely to be increased when gemcitabine comes off-patent in 2009.

[Table: see text]
Economic evaluation of sunitinib versus other new targeted therapies as first-line treatment of metastatic renal cell carcinoma (mRCC) in the United States
Authors: Benedict A. , Figlin R. A. , Charbonneau C. , Kreif N. , Hariharan S. , Négrier S.
Published: August 2020

e17556

Background: RCC, the most prevalent kidney cancer, is a relatively rare malignancy that carries a poor prognosis. New targeted therapies, such as sunitinib, sorafenib, temsirolimus, and bevacizumab + interferon-alfa (IFN-α), are now available in the US for the treatment of mRCC. In the absence of head-to-head trials, the aim of this analysis was to assess the economic value of these therapies as first-line treatment of mRCC from a U.S. third-party payer perspective, using an indirect comparison based on reported survival data. Methods: An economic model was built to simulate progression-free and overall survival based on each treatment's hazard ratio against IFN-α as reported from phase II and III clinical trials. Clinical model parameters were also derived from these trials and complemented with clinical experts’ opinions. Costs of drugs, routine follow-up, treatment-related adverse events, disease progression, and best supportive care of terminally-ill patients were included in the model. Results, expressed as life-years (LY), progression-free LY (PFLY), and quality adjusted LY (QALY) gained, treatment costs (applied in 2008 USD), and incremental cost-effectiveness ratios (ICER), were obtained through probabilistic analysis over a 10-year time horizon. Since the phase III clinical trial of temsirolimus included the MSKCC (modified) poor risk group patients only, two separate evaluations were carried out: (1) comparison of sunitinib, sorafenib, and bevacizumab + IFN-α in all patients and (2) a similar comparison of sunitinib and temsirolimus in the poor-risk group patients only. Results: In the first comparison model, sunitinib was both more effective (with gains of 0.52 and 0.19 PFLY, and 0.17 and 0.03 QALY) and less costly (by $13,675 and $84,260) than sorafenib and bevacizumab + IFN-α, respectively, over 10 years. Similarly, sunitinib was both more effective (with gains of 0.12 PFLY and 0.07 QALY) and less costly (saving $9,605 over ten years) than temsirolimus in patients in the poor risk group. Conclusions: These model results suggest that sunitinib is a cost-effective alternative to sorafenib, bevacizumab + IFN-α, and temsirolimus as a first-line treatment of mRCC.

[Table: see text]
Variables in the correct subclassification of non-small cell lung cancer (NSCLC)
Authors: Mishra A. , Farghaly H. , Rabinowits G. , Kloecker G. H.
Published: August 2020

e17561

Background: Targeting specific cancer growth pathways has become standard in treating NSCLC. Distinguishing subclasses of NSCLC is therefore increasingly important. However, 20–30% of cases in major clinical trials are categorized as “not otherwise specified” (NOS), similar to our cancer registry at the University of Louisville hospital. This study examines clinical and pathological variables that may affect the probability to accurately specify NSCLC histology. Methods: 147 cases of NSCLC after 2004 were randomly selected and reviewed. The variables examined included time of diagnosis, amount of tissue at diagnosis, use of immuno-histochemistry (IHC), and eligibility for systemic therapy. NOS was defined as unclassified histology, including poorly differentiated carcinoma. Results: NSCLC was confirmed by cytomorphology in all but one case. 69 cases were adeno ca (47%), 45 squamous (31%), 2 large cell (1%), 31 NOS (21%), with the percentage of NOS being constant over the years. The patient's eligibility for systemic therapy was not associated with any particular histology. Only 3/31 (10%) cases of NOS had surgical specimens, whereas 36/116 (31%) with specified histology had surgical specimens (p<0.05). 47 % of adeno ca, 24% of squamous ca, and 41% of NOS cases had IHC. Of all specimens only 39% had IHC performed. Conclusions: Cytomorphology alone is not able to subclassify all cases of NSCLC in FNA specimens. Our study found a significant association between adequate tissue quantity and correct subclassification of NSCLC. IHC helps to subclassify NSCLC, but was not done in most cases. Lack of sufficient tissue is a major reason for absent IHC's and failure to subclassify NSCLC. To retrieve genomic and proteomic information from tissue and target therapy correctly, it becomes important to do core needle biopsies whenever possible. Pathology assistance at time of biopsy to assure adequacy of the sample is another practical measure to decrease the proportion of cases with NOS.

[Table: see text]

No significant financial relationships to disclose.
Interim results of a survey to evaluate use and interest in autologous and allogeneic bone marrow transplant as a treatment option among patients
Authors: Van Hoef M.
Published: August 2020

e17569

Background: A survey was placed on websites inviting patients to provide an opinion about bone marrow transplant as treatment option for their disease. Herein an interim analysis of results is presented. Methods: A survey was developed requesting general information about the responder, the disease, and the experience with and interest in autologous and allogeneic donor transplants as treatment option for disease. The survey was placed on sites in the Netherlands and Belgium (cancer fora and website) and was initially announced in a few magazins. Results: Several cancer fora in the Netherlands initially rejected the survey; in Belgium no restrictions were encountered. At the interim analysis 81 Dutch and 2 English speaking responders have started the survey. 60 Dutch and 1 English speaking responder completed the survey as of December 1, 2008. Of Dutch responders 60.5% accessed the survey from the website, 79.9% were women, 56% were patient. Among responders 18.7% responded related to leukemia, and the remaining to other diseases among which myeloma (10.7%), lymphoma (13.3%) and breast cancer (19.4%). The majority had been diagnosed in 2006 and 2007. The majority of responders had not been treated with autologous or allogeneic transplants (for both 87%), however 43.8% informed to know what and autologous transplant is and 55.2% knew what an allogeneic transplant is. About 25% of responders of either type had spoken about transplant with a doctor and about 35% of responders of either type thought that BMT is a treatment option for their disease. 76% of responders were aware that people can be a bone marrow donor. Conclusions: 20 questions were asked and answered; 75% of responders completed the survey. Interim results gave among others insight in knowledge, treatment. and discussion of transplant as treatment option with doctors. An update and further details will be presented.

No significant financial relationships to disclose.
Allocation of high demand, scarce medical technology: Lessons for proton radiotherapy
Authors: Rakszawski K. , Bekelman J. E.
Published: August 2020

e17570

Background: Proton radiotherapy is a scarce therapeutic resource. To inform policy development on the allocation of proton radiotherapy, we performed a systematic review to investigate the use of high demand, scarce medical technology in three settings: 1) proton radiotherapy; 2) liver transplantation; and 3) intensive care units (ICUs). Methods: Studies were identified by searching MEDLINE (from 1990 to 2008) and references of articles, letters, commentaries, and editorials. We included English-language quantitative and qualitative studies, commentaries and policy papers addressing the methods and effects of resource allocation. A total of 2,304 citations were screened, 197 potentially eligible full articles were retrieved on a basis of abstract review, and 34 studies met our inclusion criteria (1 related to proton radiotherapy, 10 related to liver transplantation, and 23 related to ICUs). Data was extracted from each of the 34 studies into tabular displays, drawing from the balance sheet model for integrating and interpreting multiple types of evidence. Results: A single case report addressed the allocation of proton radiotherapy. Within the liver transplantation setting, the Model for End-Stage Liver Disease (MELD) system utilizes a priority scale based on objective indicators of disease severity. One study showed that use of the MELD system increased transplants among patients with greater disease severity and reduced transplant wait times. Within the ICU system, formal admission guidelines have been developed by committees with input from multiple stakeholders. However, one survey showed that while the majority of hospitals have formal guidelines, only 25% use these guidelines in routine clinical practice. Conclusions: Evidence to inform policy development on the allocation of proton radiotherapy is sparse. The substantial potential benefits and costs of proton radiotherapy underscore the need for an objective, transparent system for proton radiotherapy allocation.

[Table: see text]
Impact of the income-based health service types on survival in patients with metastatic gastric cancer
Authors: Oh S. , Oh H. , Yoon S. , Shin D. , Lee K. , Kim I.
Published: August 2020

e17574

Background: Subscription to National Health Insurance (NHI) is a national obligation for South Korean people. For low-income citizens (about lower 3% of population), Medicaid is applied. Many recipients of Medicaid are vulnerable people such as old age singles, the homeless or the handicapped. These populations are suspected to have worse prognosis. According to one report, on the other hand, patients with Medicaid were more likely to receive chemotherapy than patients with NHI despite the uniform health insurance coverage within the two types of health cost financing. Owing to these conflicting findings, we investigated the relationship between health insurance type and prognosis. Methods: Patients are stage IV advanced gastric cancer patients who received palliative chemotherapy. Medical records were reviewed from January 2006 to November 2008 in Seoul Medical Center (municipal teaching hospital). Results: Total 37 patients were found. Median age was 61 years (range 31–85) and male constituted 75.7%. Platinum (cisplatin or oxaliplatin) combined with 5-FU was the most frequently used regimen (78.4%). Twelve patients (32.4%) were recipients of Medicaid. Median PFS and OS of NHI group were 6.9 (95% CI, 1.7–12.0) and 7.8 (95% CI, 3.4–12.1). And that of Medicaid were 5.6 (95% CI, 2.6–8.6) and 7.8 (95% CI, 3.4–12.2) months. The difference from two groups were not statistically different (p = 0.739 for PFS and 0.466 for OS). When patients were divided into longer or shorter survivors according to mean OS (14.1 ±2.6 months), NHI recipients had more probability for survival (odds ratio 0.72, 95% CI 0.56–0.92). Conclusions: The question is raised whether recipients of Medicaid have poorer prognosis than patients with NHI in metastatic gastric cancer in South Korea. Although it seems that NHI recipients has better prognosis, still we cannot sure. It should be cleared in large scale cohort study whether this is related to low socio-economic status or other uncontrolled confounder.

No significant financial relationships to disclose.
Febrile neutropenia during acute myeloid leukemia therapy: Single institution experience from a developing country
Authors: Gupta A. , Singh M. , Singh H. , Kumar L. , Sharma A. , Bakhshi S. , Raina V. , Thulkar S.
Published: August 2020

e18000

Background: Febrile neutropenia poses a major challenge during treatment of acute myeloid leukaemia (AML). Methods: Episodes of febrile neutropenia in 104 consecutive patients of AML admitted to the medical oncology ward between May 2001 and December 2006 were studied. There were 62 males and 42 females, median age 28 years (2–61 years). Results: 402 febrile episodes including 363 episodes of febrile neutropenia (180 in induction, 183 in consolidation) and 39 non-neutropenic episodes (18 in induction, 21 in consolidation) occurred. Clinical, microbiological and radiological foci could be detected in 51.1%, 22.2 %, and 31.1% episodes of febrile neutropenia during induction and 31.1%, 19.1% and 12.7% episodes during consolidation. Rates of documented infections during induction and consolidation were 74% and 52%. Respiratory (39.2%) and ear, nose, and throat ( 23.9%) were the commonest clinical sites during induction. Respiratory (21%) and central line infections (19.2%) were commonest during consolidation. Gram negative infections predominated (Pseudomonas aeruginosa, Klebsiella pneumoniae: major isolates). 32.5% of microbiologically proven infections during induction and 14.2% during consolidation were polymicrobial. Bronchopneumonia was the commonest radiological focus. There were 60 episodes of fungal infections (47 in induction, 13 in consolidation). There were: 1 definite: mucormycosis, 3 probable (1 case each: Candida krusei, Candida tropicalis in blood, 1 chronic disseminated hepatosplenic candidiasis), and 56 possible infections. Halo sign was seen in 18, sinusitis with bone erosion in 7. Infections accounted for 85% of the 20 deaths (induction: 18). Fungal infections and bronchopneumonia were major causes of mortality (p = 0.001). 3/4 enterococcal bacteremias were associated with mortality (p = 0.001). 6 cases of tuberculosis (5 pneumonias with necrotic mediastinal nodes, 1 Pott's spine) and 3 cases of malaria (1 cerebral malaria) were also detected. Conclusions: Induction was associated with greater morbidity and mortality. Prompt and proper institution of antibiotics and antifungals besides considering alternative diagnosis peculiar to the region (e.g. tuberculosis, malaria) may aid in better management.

No significant financial relationships to disclose.
A phase II feasibility study of cytarabine and idarubicin combination in relapsed or refractory adult acute lymphoblastic leukemia
Authors: Hafeez M. , Shaharyar A. , Zia N. , Rasheed H.
Published: August 2020

e18002

Background: Most patients with adult ALL eventually relapse. Salvage regimens in these patients and in patients with primary refractory disease are generally based on cytarabine in combination with other agents. Exact merit of each combination remains undefined as these continue to be tested in non randomized trials. This study was conducted with the objectives to find out the efficacy and toxicity of cytarabine and idarubicin combination. Methods: From December 2006 to March 2008, 30 patients were enrolled in this prospective, nonrandomized single institution phase II feasibility study. It was empirically decided that the study will only be considered feasible if more then ten patients achieve a complete remission. Patients who relapsed during maintenance therapy or were refractory and were at least 16-years-old were considered eligible provided they have received at least vincristine and prednisone as induction. No prior cytarabine was allowed. Cytarabine 100 mg/m2 continuous infusion for seven days along with idarubicin 12 mg/m2 day 1 to 3, IV bolus was given. Bone marrow examination was done 15 days after the completion of chemotherapy. Results: All thirty patients completed planned treatment. Five patients died of infection during treatment. Eleven patients achieved complete remission. All patients relapsed within eight months. Conclusions: The regimen of cytrarabine and idarubicin is feasible and sufficiently effective in relapsed or refractory adult ALL with manageable toxicity.

No significant financial relationships to disclose.
Factors affecting the hematological and nonhematological toxicities in B-cell lymphoma patients during treatment
Authors: Karimi P. , Shokri A. , Etemadi L. , Negar Rezania N.
Published: August 2020

e18004

Background: Despite recent improvements, toxicities in B-cell lymphoma patients during treatment remains a major challenge for leukemia community. The aim of this study was to determine factors affecting the hematological and non-hematological toxicities in B-cell lymphoma patients during treatment. Methods: This multicentral cross-sectional study was performed on 68 diagnosed B-cell lymphoma patients (17–72 y/o, mean age 53y/o) admitted in three cancer centers for treatment during 2003–2008. Patients with other malignancies, serious illness or infection were not included. Demographic data, clinical and para clinical manifestations were recorded during treatment. Results: 31 (45%) patients developed grade 2 or greater non-hematological toxicities: 11:fever, 8:chills, 6:vomiting, 4:rash, and 3:pruritus. Moreover, 7 patients developed grade 3 non-hematological toxicities. 42 (62%) patients developed grade 2 or greater hematological toxicities. Non-hematological toxicities were more frequent in patients with BM (Bone Marrow) involvement [15/32 (47%) versus 21/60 (35%), p = 0.01] and with extranodal disease [23/48 (48%) versus 11/42 (26%), p = 0.008]. The incidence of grade 3 or 4 hematological toxicity was higher in females than males [17/43 (40%) versus 13/50 (26%), p = 0.001]. Furthermore, being female was significantly associated with the development of grade 3 or 4 neutropenia [17/49 (35%) versus 8/53 (15%), p = 0.003]. In addition, high LDH was also associated with grade 3 or 4 leukopenia [7/27 (26%) versus 9/58 (16%), p = 0.01], but not with neutropenia. Conclusions: Multivariate analysis demonstrate that some factors like female gender, BM involvement, and serum LDH level could be useful for predicting the hematological and nonhematological toxicities in B-cell lymphoma patients during treatment.

No significant financial relationships to disclose.
Bevacizumab (Bv) single-agent maintenance following Bv-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): Results from an exploratory analysis of the AVAiL study
Authors: Mezger J. , von Pawel J. , Reck M.
Published: August 2020

e19001

Background: The significant survival benefits observed with Bv plus chemotherapy in pivotal NSCLC trials were generated using treatment to progression. Given that little data on the use of single-agent Bv as maintenance therapy are currently available, we report here the results of an analysis focused on the maintenance phase of the AVAiL study. Methods: AVAiL, a randomized, international, placebo-controlled phase III trial, evaluated Bv plus cisplatin-gemcitabine (CG) in pts with previously untreated advanced, non-squamous NSCLC, with performance status 0/1. 1,043 pts (age 20–83) were randomized to C 80mg/m2 and G 1,250mg/m2 q3w for up to 6 cycles plus either Bv 7.5mg/kg q3w (Bv 7.5; n=345), Bv 15mg/kg q3w (Bv 15; n=351) or placebo (Pl; n=347). Bv/Pl was administered until disease progression. This retrospective analysis focused on progression-free survival (PFS) and overall survival (OS) of the 376 patients who received blinded Bv (n=174 and n=162 for Bv 7.5 and 15) or Pl monotherapy (n=41) after completing 6 cycles of CG + Bv or CG + Pl (as specified in the protocol; most patients received 6 cycles). PFS was measured from last day of last cycle of CG + Bv/Pl to disease progression or death. Results: In the overall population, Bv reduced the risk of progression or death by 25% vs Pl (PFS primary endpoint (HR=0.75 [0.64–0.87] and 0.85 [0.73–1] for Bv 7.5 and Bv 15, respectively). When analyzing the outcome of the post chemotherapy maintenance phase, the use of Bv as single agent yielded median PFS of 3.2 months (95%CI [3–5]) for Pl, 4.6 months (95%CI [4–6]) for Bv 7.5 and 4.6 months (95%CI [4–5]) for Bv 15.The OS results for this maintenance analysis are consistent with those from the overall population in which the PFS findings were not associated with an OS benefit. Conclusions: This post-hoc analysis, focused on the maintenance phase of AVAiL, suggests that Bv used as single-agent maintenance therapy appears to confer clinical benefit beyond the chemotherapy phase. This finding warrants further exploration in future studies.

[Table: see text]
Phase II study of irinotecan plus S-1 combination for previously untreated advanced non-small cell lung cancer: Hokkaido Lung Cancer Clinical Study Group 0601
Authors: Oizumi S. , Akie K. , Ogura S. , Shinagawa N. , Fukumoto S. , Harada M. , Kojima T. , Kinoshita I. , Dosaka-Akita H. , Isobe H. , Nishimura M.
Published: August 2020

e19012

Background: Platinum-containing therapy is a standard first-line treatment for advanced non-small cell lung cancer (NSCLC). Platinum-free regimens can be alternative if they can provide similar efficacy with better tolerability. This study evaluated the efficacy and safety for combination of irinotecan and S-1, a newly developed oral 5-fluorouracil derivative, for chemotherapy-naïve advanced NSCLC. Methods: In this multicenter phase II trial, we initially planned to enroll 40 patients. Chemotherapy consisted of 4-week cycles of irinotecan (100 mg/m2 IV, day 1 and 15) and S-1 (80 mg/m2 orally, day 1–14). Primary end point was response rate; secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. Association of UGT1A1 genotypes (*6 and *28) with frequency of severe toxicity was also examined. Results: A total of 112 cycles was administered into 40 patients (median, 3 cycles: range, 1–6). Median age was 64 years (range, 42–75); 29 patients (73%) had adenocarcinoma, and 8 patients (20%) had squamous cell carcinoma. Majority of the patients (32 cases, 80%) had stage IV disease. Twelve patients exhibited partial response (PR), and 17 patients exhibited stable disease (SD), resulting in response rate of 30% [95% confidence interval (95% CI), 16.6–46.5] and disease control rate of 72.5% (95% CI, 56.1–85.4). Median OS and PFS were 13.8 months (95% CI, 10.7–16.9) and 4.7 months (95% CI, 3.4–6.0), respectively. Hematological toxicities of grade 3 or 4 were neutropenia (32.5%) and anemia (5.0%). The most common non-hematologic toxicities of grade 3 or 4 included diarrhea (15.0%) and anorexia (17.5%). There were no treatment-related deaths. Among the 40 patients, there were 1 homozygous and 8 heterozygous for UGT1A1*6, whereas 7 heterozygous for UGT1A1*28; none of the patients had both genotypes. Patients with homozygous or heterozygous for UGT1A1*6 showed a trend for high incidence of grade 3 diarrhea (p = 0.055). No association of UGT1A1*28 with severe toxicity was observed in this study. Conclusions: Irinotecan and S-1 combination is an alternative treatment with tolerable toxicity for previously untreated advanced NSCLC.

No significant financial relationships to disclose.
Concurrent chemotherapy immediately following erlotinib (E) or gefitinib (G) induced apoptosis in previously untreated patients with advanced or metastatic non-small cell lung cancer (NSCLC)
Authors: Natale R. B. , Natale R. B.
Published: August 2020

e19014

Background: The EGFR-TKIs, E and G, block EGFR-mediated proliferative and anti-apoptotic signaling. The predominance of anti-proliferative effects over the latter mechanism is postulated as the reason that no additional benefit was observed when either agent was given concurrently with 1st line chemotherapy in unselected NSCLC pts (INTACT 1 & 2, TALENT & TRIBUTE trials). However, a subset analysis of TRIBUTE pts with a never smoking history suggested that improved survival may occur when the pt population is partially enriched to increase the proportion with an EGFR-TKI induced apoptotic effect (Miller VA. Proc ASCO, 2004). We therefore hypothesized that pts demonstrating rapid tumor regression within a 3–4 week exposure to E or G represented a population highly enriched for the apoptotic effect and that immediate concurrent administration of chemotherapy would produce prolonged survival. Methods: Forty-one stage IIIB/IV pts, including 27 women and 14 men, median age 67 (range 41 to 88) with limited smoking history (21 never smokers, 20 former light smokers) were treated with E 100–150 mg/day (39 pts) or G 250 mg/day (2 pts) for an average of 26 days (range, 21–34) before response assessment. Twenty-two pts achieved objective tumor responses (2 CRs, 20 PRs) and immediately received 4–6 cycles of platinum-based chemotherapy concurrently with continued E or G (group A). E or G was discontinued in 19 pts not achieving objective response and platinum-based chemotherapy alone was given after a 10–14 day washout. Results: With a median follow-up of 24 mos, the median TTPs are 21+ mos and 7 mos and the median survivals are 31+ and 12 mos in groups A and B, respectively. Thus far, only 5 deaths have occurred in 22 group A pts. Results of EGFR mutation and other analyses in tumor tissue from 27 pts will be presented. Conclusions: These data suggest that EGFR-TKI induced apoptosis may act synergistically with concurrent 1st line chemotherapy in pts with advanced or metastatic NSCLC and a new paradigm for incorporation of biologically targeted agents into chemotherapy regimens.

[Table: see text]
Phase II study of dasatinib in non-small cell lung cancer (NSCLC)
Authors: Johnson F. M. , Tang X. , Tran H. , Saigal B. , Erasmus J. , Kurie J. , Hwang L. , Oh Y. , Lippman S. , Stewart D. J.
Published: August 2020

e19015

Background: Lung cancer is the leading cause of cancer-related deaths. Better systemic therapies are needed. One potential therapeutic target is c-Src which is expressed and activated in NSCLC patient tumors where it can mediate invasion, angiogenesis, and proliferation. Additionally, epidermal growth factor receptor (EGFR) and c-Src cooperate to promote NSCLC survival. We are conducting a phase II study of dasatinib, a tyrosine kinase inhibitor of c-Src, Abl, c-Kit, PDGFR, Btk, and EphA2. The primary objective is to determine the rate of progression free survival at 12 weeks in patients with metastatic NSCLC treated with dasatinib as front line therapy. Methods: Patients with metastatic NSCLC were treated with dasatinib (100 mg BID), with PET/CT scans every 6 weeks. KRAS and EGFR mutations, EGFR copy number, and pSrc expression were measured in pre-treatment biopsies. Blood was collected pretreatment and on day 21 to measure drug exposure (PK), pharmacodynamics (PD), and serum cytokine levels. Results: Twenty five patients have enrolled on study. Of the 16 patients evaluable for response: 1 had a partial response (PR) with no evidence of recurrence for at least 18 months (male smoker with adenocarcinoma and KRAS mutation); 6 patients had stable disease (SD) which includes 3 patients with prolonged stable disease for 4, 6, and 18 months; 9 had progressive disease (PD). Only 4 patients had a significant change in SUV (>25%): decreased in 2 with PR and SD and increased in 2 with PD and SD. There is currently no clear association between EGFR and KRAS mutational analysis and response, although the sample number is small. Only 2 patients have activating EGFR mutations: one with SD and one with PD. PK, PD, and cytokine data will be presented. The most common grade 3/4 toxicity is dyspnea/pleural effusion that has led to a reduced dasatinib starting dose in subsequent patients. Conclusions: Dasatinib as a single agent has activity in a subset of patients with NSCLC. Planned correlative studies may lead to the discovery of biomarkers that predict response. Toxicities observed were consistent with prior dasatinib phase I studies in solid tumor patients. Supported by NCI/CTEP (NIH contract N01-CM-62202), The Commonwealth Foundation for Cancer Research and Bristol-Myers Squibb.

[Table: see text]
Amrubicin (AMR) and cardiotoxicity in second-line treatment of small cell lung cancer (SCLC): A pooled analysis of left ventricular ejection fraction (LVEF) in two phase II trials
Authors: Spigel D. R. , Shah C. , Lorigan P. , McNally R. , Renschler M. , Oliver J.
Published: August 2020

e19019

Background: Amrubicin (AMR) is a third-generation synthetic anthracycline and a potent topoisomerase II inhibitor approved in Japan for the treatment of lung cancer. In Japanese pre and postmarking studies, AMR treatment was not associated with cardiotoxicity. The purpose of this analysis was to determine if AMR treatment of Western patients (pts) is associated with anthracycline-induced cardiomyopathy. Methods: To evaluate risk of cardiomyopathy, LVEF was measured by echocardiogram or by multiple gated acquisition (MUGA) scan and pooled from pts enrolled in 2 trials of IV AMR, 40 mg/m2/day x 3 days q 21 days for second-line treatment of sensitive or refractory SCLC. Pts with measurable disease, ECOG PS 0–2, LVEF ≥50%, and prior platinum-based treatment were assessed at baseline (BL), cycles 3, 6, then every 2 cycles, and end of treatment. Pts were to be assessed by the same method (ECHO or MUGA) throughout the study. Pts with a persistent ≥20% decrease in LVEF during treatment were to be removed from the study. Results: 112 patients were treated (sensitive n=43, median 6 cycles; refractory, n=69, median 5 cycles) and had at least 1 LVEF assessment. Median age was 63 years and median BL LVEF was 60%. Changes in LVEF from baseline were minimal ( Table ) and similar across cumulative dosing groups including 15 pts who received a cumulative dose of >1,000 mg/m2 AMR. Two refractory pts (1.8%) experienced drops in LVEF >20%. One had BL LVEF of 85%, then 60% at cycle 3, and 70% subsequently with ongoing therapy. The second, with a history of cardiomegaly, had LVEF of 55% at BL, cycle 3, and 5 by ECHO, and 29% at the time of progression after cycle 9 (cumulative AMR dose 840 mg/m2) by MUGA. The patient died due to progressive disease with no evidence of CHF. Conclusions: In this pooled analysis of SCLC pts, LVEF remained stable even in pts with cumulative AMR dosing >1,000 mg/m2. AMR for second-line treatment of SCLC does not appear to cause anthracycline-related cardiomyopathy.

[Table: see text]

[Table: see text]
Urine PGE-M to assess prostaglandin E2 (PGE2) levels in non-small cell lung cancer (NSCLC)
Authors: Horn L. , Milne G. , Sandler A. , Morrow J. , Carbone D. , Shyr Y. , Hayes A. , Campbell N. , Johnson D. H.
Published: August 2020

e19026

Background: COX-2 is often overexpressed in NSCLC leading to high systemic PGE2 levels that in turn play a role in NSCLC pathogenesis. Changes in urine PGE-M (the major PGE2 metabolite) reflect changes in systemic & intratumoral PGE2 [Csiki et al. Clin Cancer Res 11:6634, 2005]. A ≥70% decline in PGE-M in NSCLC patients (pts) treated with celecoxib (C) (400 mg bid) + docetaxel (D) was associated with an apparent survival benefit [Ibid]. To effect maximum COX-2 inhibition we tested a higher C dose in a subsequent phase II trial. Methods: Eligibility: previously treated NSCLC, PS 0–2, evaluable/measurable disease, adequate marrow, renal & hepatic function, no current NSAID or sulfa allergy. Urine PGE-M measured prior to & 5–10 days after C 600 mg PO bid. Pts with ≥70% decline in PGE-M continued on C + D 75 mg/m2 or pemetrexed 500 mg/m2 q3wk x 4 cycles followed by maintenance C 400 mg PO bid until PD or drug intolerance. Results: 21 pts enrolled; F=7, M=14; 2 ineligible (1 carcinoid; 1 elevated LFT); 2 stopped C early (1 ARF; 1 pruritus). Mean PGE-M levels decreased from 38.9 to 7.8 ng/mg Cr pre- & post-C (mean change = 80%; P=0.002). The mean decline was greater in current & former smokers (81%; P=0.002) compared to never smokers (46%; P=0.19). Males had higher pre- treatment PGE-M (44 vs. 28.8 ng/mg Cr; P=0.21). Males had a significant decrease in mean PGE-M levels after C (78%; P=0.011); a similar albeit not significant change occurred in females (P=0.12). 12 screened pts (57%) had a ≥70% decline in PGE-M & received treatment with C + chemotherapy; 8 pts are evaluable for response; SD = 6; PD = 2. Treatment was well tolerated with no cardiac toxicities noted. Conclusions: These preliminary data indicate C 600 mg bid effectively inhibits intratumoral COX-2 in >50% NSCLC pts, a higher percentage than our previous trial using C 400 mg bid. The effect is greatest in former & current smokers & males compared to never smokers & females. Toxicities are acceptable. Accrual is ongoing. [Funding: VICC Lung Cancer SPORE CA90949].

No significant financial relationships to disclose.
Phase I study of lapatinib, a dual-tyrosine kinase inhibitor, and pemetrexed in the second-line treatment of advanced or metastatic non-small cell lung cancer
Authors: Ramlau R. , Thomas M. , Plummer R. , Reck M. , Heussel C. P. , Lau M. , Parikh R. , Kaneko T. , Oliva C. , Novello S.
Published: August 2020

e19027

Background: Lapatinib is an oral, reversible small-molecule inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). EGFR overexpression is very common in non-small-cell lung cancer (NSCLC), ranging from 30% to 83%, whereas HER2 overexpression occurs in about 20%. Pemetrexed is currently given as second-line therapy and achieves a 9% response rate. The rationale for EGFR/HER2 inhibition in combination with pemetrexed is to demonstrate clinical synergy as previously shown with gemcitabine, another fluoropyrimidine pathway inhibitor. Methods: Eligible patients included those with stage IIIB or IV NSCLC and European Cooperative Oncology Group performance status of 0–2 following 1 previous chemotherapy treatment. Patients were treated in 3 escalating dose levels (DLs) of pemetrexed (given intravenously every 21 days) and daily lapatinib (DL 0: 400 mg/1,250 mg; DL 1: 500 mg/1,250 mg; DL 2: 500 mg/1,500 mg, respectively). A standard phase 1, 3+3 trial design was used. The primary objective was to determine the optimal treatment regimen. Results: Eighteen patients were treated (DL 0: n=4, DL 1: n=8; DL 2: n=6). The most common adverse events (any grade) were diarrhea (61%), rash (44%), fatigue (28%), nausea (28%), anemia (28%), anorexia (22%), vomiting (22%), dyspnea (17%), and neutropenia (17%). Grade 3/4 adverse events were lymphocytopenia (n=5) and neutropenia (n=5). Other related grade 3 events were diarrhea (n=2), nausea (n=1), decreased ejection fraction (n=1), and increased alkaline phosphatase (n=1). The optimal treatment regimen was determined as lapatinib 1250 mg given with 500 mg pemetrexed after occurrence of 3 dose-limiting toxicities during the first cycle in DL 2 (grade 3 diarrhea, grade 4 lymphocytopenia, and grade 3 mucositis). No further dose-limiting toxicities were observed in DL 0 or DL 1. Preliminary evidence of clinical activity was encouraging, with 3 patients showing partial response. Conclusions: The combination of lapatinib with pemetrexed is well tolerated; encouraging activity has been demonstrated in pretreated NSCLC patients and warrants further studies.

[Table: see text]
Multidisciplinary management of brain metastases from non-small cell lung cancer: A retrospective study of 251 patients
Authors: Shenglin M. , Yaping X. , Xinmin Y. , Yang Y.
Published: August 2020

e19030

Background: The detection of brain metastasis(BM) is becoming increasingly common in patients with non-small cell lung cancer (NSCLC). The aim of this study was to evaluate clinical course, prognostic significance, and treatment efficacy in patients with brain metastasis. Methods: The records of all patients with BM from December 2003 to January 2007 were reviewed, and a retrospective study of 251 patients with cytologically and histologically diagnosed NSCLC and brain metastasis detected by cranial computed tomography or magnetic resonance imaging was performed. Variables analyzed included the recursive partitioning analysis (RPA) grouping, weight loss, LDH in blood serum, sex, age, time of brain metastasis (synchronous vs. metachronous), number of brain metastases, maximum diameter of largest brain lesion, Karnofsky performance status, histologic type (adenocarcinoma vs. other types of NSCLC), TNM stage (without consideration of brain involvement), and the treatment modality used for both the primary NSCLC tumor and brain metastasis. Results: The overall 1-, 2- and 3-year survival rates were 34.1%, 13.7% and 8.7% with a median survival time of 9.0 months (95% CI 8.04–9.97 months). On multivariate analysis, RPA grouping, weight loss, LDH in blood serum and treatment were independent prognostic factors. The median overall survival (OS) time of chemotherapy alone, whole brain radiotherapy (WBRT) alone, surgery alone, WBRT with chemotherapy, surgery with chemoradiation, WBRT with Gefitinib and others management was 6.0, 9.0, 12.0, 9.0, 22.0, 13.0 and 4.0 months, respectively, which were significantly different (X2=43.104, P=0.000). The stratify analysis indicated the median OS of patients received concurrent WBRT/chemotherapy (13.0 months) was longer than it of patients received sequential WBRT/chemotherapy (9.0 months) (X2=3.89,P=0.049). Conclusions: The main prognostic factors of BM from NSCLC of pretreatment are RAP grouping, weight loss and LDH in blood serum. The effect of combined treatment of surgery with chemoradiation is favorable and the choice of the patient is important. The survival are prolonged by active multidisciplinary management of brain metastases.

[Table: see text]
Hepatocyte growth factor as inducer of gefitinib resistance in non-small cell lung cancer harboring EGFR activating mutations
Authors: Yano S. , Wang W. , Li Q. , Yamada T. , Matsumoto K. , Mitsudomi T. , Yatabe Y. , Hanibuchi M. , Nishioka Y. , Sone S.
Published: August 2020

e19034

Background: Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations (EGFRmu) responds favorably to the EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib. However, 25–30% of patients with EGFRmu show intrinsic resistance, and the responders invariably acquire resistance to EGFR-TKIs. Here, we examined the role of hepatocyte growth factor (HGF), a specific ligand of MET, in gefitinib resistance of NSCLC with EGFRmu. Methods: NSCLC cells, PC-9 and HCC827, with EGFRmu, but not T790M second mutation in EGFR or MET amplification, were used in this study. Sensitivity to gefitinib was determined by MTT assay. Phosphorylation of MET, EGFR, ERBB3, and the PI3K/Akt pathway were examined by Western blotting. HGF expression in 20 tumors from 16 NSCLC patients with EGFRmu who were treated with gefitinib was determined by immunohistochemistry. Results: HGF induced resistance to gefitinib by restoring Akt phosphorylation independently of ErbB3. Specific down-regulation of MET, but not ErbB3, reversed gefitinib resistance and Akt phosphorylation induced by HGF. Importantly, high levels of immunoreactivity for HGF were detected in cancer cells of 3 of 3 intrinsic resistant tumors and in one of 2 tumors with acquired resistance without T790M second mutation or MET amplification. Conclusions: The findings indicate that HGF-mediated MET activation is a novel mechanism of intrinsic and acquired gefitinib-resistance in NSCLC with EGFRmu. Therefore, inhibition of HGF-MET signaling may be considerable strategy for more successful treatment with EGFR-TKIs.

[Table: see text]
A phase II study of gemcitabine and vinorelbine combination followed by sequential gefitinib monotherapy in elderly patients with non-small cell lung cancer
Authors: Kasahara K. , Kita T. , Shibata K. , Nishi K. , Ishiura Y. , Araya T. , Tambo Y. , Sakai A. , Kimura H. , Fujimura M. ,   Kanazawa Lung Cancer Study Group
Published: August 2020

e19040

Background: Gemcitabine (GEM) and vinorelbine (VNR) combination have demonstrated activity as a 1st-line treatment in elderly patients with advanced non-small-cell lung cancer (NSCLC). Gefitinib (GEF) is effective as a 2nd-line treatment for NSCLC. We conducted a multicenter phase II trial to evaluate the efficacy and toxicity for treatment of GEM+VNR followed by sequential GEF in elderly patients (pts) with advanced or metastatic NSCLC. Primary endpoint is response rate, secondary endpoints were safety, progression-free survival (PFS), and overall survival (OS). Methods: Eligibility required hitologically or cytologically comfirmed NSCLC, no prior therapy, measurable lesion(s), ECOG PS 0–2, age equal to or over 70 years, and adequate organ functions. Patients were received 3 cycles, each at 4-week intervals, of GEM (1000 mg/m2, d 1, 15) and VNR (25mg/m2 d 1, 15), followed by 250 mg of GEF daily until disease progression or unacceptable toxicity. Results: Between June 2004 and November 2007, 60 pts were enrolled and 2 pts withdrew consent. Fifty-eight pts (35 male and 23 female, median age 77 years) were evaluated. Median number of GEM+VNR administrations was 3 (range 1–3). Median duration of GEF was 101 days (range 9–652 days). Grade 3/4 toxicities included leucopenia (29%), neutoropenia (40%), anemia (12%), febrile neutropenia (9%), and anorexia (9%) during GEM+VNR, anorexia (2%), and constipation (2%) during GEF. Best response rate of GEM+VNR was 17% and that after sequential GEF was 31%. Median PFS and median OS were 4.2 months and 12.6 months, respectively. Response rate, PFS, and OS were significantly favorable in female and never-smoker. Conclusions: Sequential treatment consisted with GEM+VNR and GEF was feasible with acceptable toxicities in elderly patients with NSCLC.

[Table: see text]
Treatment and outcomes of elderly versus younger patients with advanced NSCLC at Mayo Clinic Arizona (MCA)
Authors: Paripati H. , Tong W. , Karlin N. J. , Dueck A. C. , Ross H. J.
Published: August 2020

e19047

Background: Non-small cell lung cancer (NSCLC) is predominantly a disease of the elderly. Most patients (pts) present with incurable advanced disease, but chemotherapy for good performance status (PS) pts improves quality and quantity of life. Despite good PS, many elderly pts with metastatic NSCLC do not receive chemotherapy. This study compared treatment, outcomes, and survival in elderly vs younger pts with stage IV NSCLC. Methods: All analytic MCA Cancer Registry pts with stage IV NSCLC from 1998–2007 were retrospectively reviewed for type of therapy and outcome. Pts were analyzed by age: <75 vs ≥75 years old. Categorical variables were compared using chi-squared tests and survival was compared by Cox regression. Results: 344 pts with stage IV NSCLC were identified. 234 (68%) pts were <75 years old, and 110 pts (32%) were ≥75 years old. Median survival for all pts was 7 months. Among 302 pts with treatment data available, 60.8% of pts <75 years old received some form of systemic therapy (chemotherapy/targeted therapy) compared to only 32% of pts ≥ 75 years old (p <0.0001). Among pts with PS 0–1, pts <75 years old more frequently received systemic therapy than elderly patients (88.5% vs 32.1%, p<0.0001); whereas a difference was not evident in pts with PS 2–4 (34.1% vs 41.7%, p=0.49). Median survival in the <75 age group was 7 months vs. 3.4 months in the ≥75 age group (p=0.048). In the <75 age group, median survival was 12 months in pts who received chemotherapy vs. 2 months in the other or no treatment group (p<0.0001). In the elderly group, median survival was 10 months in the chemotherapy group vs. 2 months in the pts who received other or no treatment (p=0.0003). Thus, the median survival was significantly improved among the pts who received systemic therapy independent of age. Statistical significance persisted when stratifying by PS. Conclusions: Pts with stage IV NSCLC have improved survival with systemic therapy independent of age. Our results confirm that despite an improvement in survival similar to younger pts, elderly patients with metastatic NSCLC are often undertreated. Prospective trials should be designed to include metastatic NSCLC patients without age discrimination

No significant financial relationships to disclose.