bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential budget impact of capecitabine versus 5-FU/LV as adjuvant chemotherapy for stage III (SIII) colon cancer in Canada and its provinces
Authors: Virik K. , Skedgel C. , Younis T.
Published: March 2020

6581

Background: Adjuvant chemotherapy for SIII colon cancer is an accepted standard of care. Oral Capecitabine (CAP) has been shown to be at least equivalent and possibly superior to 5FU/LV (Mayo regimen) with regards to a superior relapse free survival. This new option is associated with a higher drug cost but improved toxicity profile and appears to be cost-effective (CE). An economic analysis was undertaken to examine the potential budget impact for CAP in Canada and its provinces for 2007 onwards. Methods: A previously developed cost-effectiveness model was adapted to a prevalence perspective to project the net budgetary impact of CAP over a 5 year horizon. The projected population and incidence of colon cancer for each Canadian province from 2007–2016 was obtained and the proportion of patients with SIII colon cancer suitable for adjuvant chemotherapy was estimated from the literature. The average budget impact in the first 5 years (start up phase) and subsequent years (steady state) was assessed in Canadian $. Results: The projected average annual impact for Canada is 13.9 million (M) during the start up phase and $11.8 M during the steady state phase (NL $210K, PEI $63K, NS $424K, NB $282K, QC $2.92M, ON $4.66M, MB $464K, SK $336K, AB $993K and BC 1.45M). Budget impact is greater during the initial start-up phase (2007–11), as the steady state impact (2012–16) includes relapses avoided over a 5-year period. Sensitivity analyses for key parameters will be provided. Conclusions: The annual budget impact of CAP decreases over time and reaches a steady state after 5 years when the full impact of decreased recurrences is captured. As CAP appears to be CE, budget impact analysis has the potential to assist in the planning of healthcare funding resources regarding this treatment option.

[Table: see text]
Identifying patients at high risk for neutropenic complications during chemotherapy for metastatic breast cancer (MBC) with doxorubicin or pegylated liposomal doxorubicin: Development of a prediction model
Authors: Reardon G. , Rayson D. , Chang J. , Gelmon K. , Dranitsaris G.
Published: March 2020

6598

Background: Despite the effectiveness of anthracycline (ACH) therapy in the adjuvant and MBC settings, neutropenic complications (NC) remain a common and often unpredictable problem. Consequences may include dose reductions or delays in chemotherapy, or hospitalization for fever or infection. This study describes the development of a cycle-based risk prediction model for NC during chemotherapy with traditional doxorubicin (DOX) or a pegylated liposomal formulation (PLD) for MBC. Methods: Data analyzed was from a randomized clinical trial of MBC patients (n=509), who received chemotherapy with DOX (60 mg/m2 every 3 wks) or PLD (50 mg/m2 every 4 wks) [O'Brien, 2004]. NC were defined as an absolute neutrophil count (ANC) = 1.5 x106 cells/L, febrile neutropenia or neutropenia with infection. Patient, treatment and hematological factors potentially associated with NC were evaluated. Factors with a p-value of ≤ 0.25 within a cycle were included in a generalized estimating equations (GEE) regression model. Using backward elimination, we derived a risk scoring algorithm (range 0–63) from the final reduced model. Results: Risk factors retained in the model included poor performance status, ANC = 2.0 × 106 cells/L at some point in the previous cycle, the first cycle of chemotherapy, DOX vs. PLD and older age. A precycle risk score from = 25 to < 40 for a given patient was identified as being the optimal threshold for sensitivity (58.0%) and specificity (78.7%). Patients with a score at or beyond this threshold would be considered at high risk for developing NC in later cycles. Risk scores below, within, or above this threshold predict a 0.3%–2%, 3%–8% and a 9%–45% probability risk of NC, respectively. Conclusion: This risk prediction tool demonstrated acceptable internal validity and can be readily applied by the clinician prior to a given cycle of chemotherapy. The application of this prediction tool may allow for identification and targeted intervention (such as growth factor support or the use of PLD) for those most likely to experience NC during anthracycline-based chemotherapy for MBC.

No significant financial relationships to disclose.
The quality-of-life impact of osteonecrosis of the jaw: Implications for bisphosphonate use in metastatic breast cancer
Authors: Miksad R. A. , Come S. , Weinstein M.
Published: March 2020

6620

Background: Osteonecrosis of the jaw (ONJ) has been linked to bisphosphonates used to prevent skeletal related events (SREs) in metastatic breast cancer (MBC). The primary aim of this decision-analysis study is to determine the preference threshold at which the quality of life (QOL) impact of ONJ may change bisphosphonate treatment decisions. Methods: We developed a Markov decision- analysis model of bisphosphonate use in MBC that includes the risk of ONJ. For the base case we estimated the QOL impact of ONJ by evaluating published ONJ reports with the Oral Health Impact Profile (OHIP). OHIP scores were transformed to EQ5D utilities and adjusted for MBC (published utility for MBC=0.63). We used published utility values for SRE: 0.46 for the month in which SRE occurs. Based on published data, we estimated that bisphosphonates reduce the incidence of SREs by 41% and that the incidence of SRE rises with increased bisphosphonate exposure: year 1=0.004/month; year 2=0.022/month; year 3=0.034/month. We inspected 2 treatment strategies: treat all patients with bisphosphonates (treat all) and treat no patient with bisphosphonates (treat none). Results: 18 published cases were adequate for evaluation. The mean OHIP score=27 (possible range 14–70), s.d.=1.8. We calculated that patients with MBC and ONJ have a utility=0.53 (s.d.=0.04) for the base-case. The model predicted a mean survival of 22 months for both strategies. In the treat all strategy each patient received a mean of 19 months of bisphosphonates and suffered 2.4 SREs. In the treat none strategy each patient suffered 4.0 SREs. In the base case, the treat all strategy maximized net quality-adjusted life, although by less than 1/2 month per patient. The treat all strategy was optimal for only 33% of patients. The treat all strategy does not maximize net quality-adjusted life if the risk of ONJ is 4.5 times higher than the base case or the ratio of the utility for ONJ to the utility for SRE is less than 0.4 (base-case ratio=1.152). Conclusions: The QOL impact of ONJ alters the decision to use bisphosphonates when 1) the incidence of ONJ is 4.5 times higher than published estimates; or 2) the long-term preference for ONJ is 60% lower than the short-term preference for SRE. Further QOL research may refine these estimates.

No significant financial relationships to disclose.
Cost-effectiveness (CE) analysis of CHOP and rituximab for diffuse large B-cell lymphoma (DLBCL) in British Columbia (BC)
Authors: Loh G. W. , Taylor S. C. , Peacock S. , Moravan V. , Krahn M. , Sehn L.
Published: March 2020

6623

Background: The BC Cancer Agency (BCCA) provides province-wide, population-based care. Outcomes are monitored to verify therapeutic effectiveness and justify funding for systemic treatment policies. The CE of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) (CHOP-R) for DLBCL was compared to its predecessor, CHOP alone. Methods: This was a pragmatic population-based CE analysis based on the original cohort of advanced DLBCL patients described by Sehn et al (JCO 2005) who received either CHOP or CHOP-R between Sept 1999 and Aug 2002 (18-months pre and post availability of rituximab in BC) according to standard BCCA treatment policy at the time. The primary endpoint was CE in terms of life-expectancy (LE) at a median follow-up of 4 years (cost-per-life-year-gained). Costs were incorporated into a decision analysis including primary systemic therapy and downstream chemotherapy, radiotherapy, and stem-cell transplant (SCT). Actual incidence of each downstream therapy was converted to a probability for each group. Downstream therapy costs were then multiplied by these probabilities and added to the respective primary treatment costs. The CE analysis took the BCCA perspective which includes all direct costs for active cancer treatment, and hospitalization for SCT, but not ambulatory supportive care. Sensitivity analyses varying LE to the extremes of its 95% CI, modeling out to 15 years and discounting at 0, 3, and 5% were performed. Results: 292 patients were included and categorized to treatment received: 148 CHOP and 144 CHOP-R (median follow- up 5.4 and 4 years respectively). LE to 4 years was 30.18 months for CHOP and 39.44 for CHOP-R. OS at 4 years was 48.8% and 70.1% for CHOP and CHOP-R respectively (p<0.0001) Respective costs of primary and downstream therapy were $4,682 and $7,198 for CHOP versus $26,366 and $6,228 for CHOP-R. The incremental CE ratio at 4 years median follow-up was $26,844 CDN per life year gained. Results were robust across univariate sensitivity analyses conducted. Conclusions: At 4 years median follow-up, CHOP-R improves LE and appears to be economically attractive at conventional thresholds. CE is an increasingly useful tool for the BCCA in making decisions about new cancer therapies.

No significant financial relationships to disclose.
Overhead costs (OC) associated with quality oncology care (QOC) monitoring to ensure compliance with national treatment guidelines (TG)
Authors: Vakil R. , Bosserman L. D. , Presant C. , McNatt W. , Der A. , Greenburg A. , Estrella A. , Upadhyaya G. , Vakil M.
Published: March 2020

6637

Background: QOC is a goal of all oncology practices (op), healthcare insurance plans (hip), HMOs, and payers for health insurance. In order to ensure compliance with TG and maintain QOC in a multi-site op, we adapted an electronic medical record (EMR) to evaluate tumor and stage specific compliance in oncology treatments. This report evaluates the OC associated with development and operation of that monitoring system and its application to an HMO patient population of 75,000 covered lives. Methods: OC included 25% (proportion of HMO to total patients )of the emr system developmental costs (DC) and operational costs (OpC). Personnel time included entering data and treatments, training, data coordination, and data analysis. Salaries were based on regional averages for physicians, administrators, clerks, and nurses. Time estimates were made for monitoring quality data only, excluding standard patient care. Compliance data is reported separately. Results: 1,250 patients over 18 months were treated by 5 of the op physicians. DC for this program included computer hardware $25,000, personnel training $10,900, and EMR licensing $12,500. Annualized operational costs (OpC) included emr maintenance fees $1000, IT consultants $4500, physician time to enter individual patient data at first consultation and follow up visits $58,000, nursing time to enter treatment data and continued training $7650, physician continued training $11,250, senior administrator coordination $30,000, administrative supervision $17,900, clerical data analysis $22,500, and senior physician supervision $50,000. Costs per covered life for DC were $0.645 and for OC were $2.704 per year. Conclusions: The costs to maintain QOC and ensure TG compliance are substantial and must be reimbursed by hips and HMOs. Understanding these costs is essential to negotiating care contracts with hips that will monitor care appropriately. Investing in EMR methods to ensure QOC will be important to patients and op, as well as hips. Monitoring continuing OC to determine if they decrease with additional experience is essential. Standardizing EMR data sets aad op methodologies for compliance monitoring will further improve efficiencies and cost efficacy in documenting delivered QOC.

No significant financial relationships to disclose.
Prognostic factors for response to second induction course in patients showing persistent disease after first course of standard induction chemotherapy for de novo acute myeloid leukemia (AML)
Authors: Lee J. , Sym S. , Choi S. , Lee J. , Lee Y. , Seol M. , Ryu S. , Lee J. , Kim W. , Lee K.
Published: March 2020

7056

Background: Standard induction chemotherapy for AML consists of cytarabine plus daunorubicin or idarubicin (‘7+3' regimen). For patients showing persistent leukemia after first induction course (IND1) of the induction, usual practice is to give a second course (IND2) of similar regimen (‘7+3' or 5+2'). This strategy, however, has not been well evaluated. We investigated prognostic factors for response to IND2. Methods: We performed a retrospective study in 110 patients with de novo AML. All patients received cytarabine (100 or 200 mg/m2/d) for 7 days plus daunorubicin (45–60 mg/m2/d) or idarubicin (12 mg/m2/d) for 3 days as IND1. Patients who showed persistent leukemia after IND1 were given the same doses and drugs as ‘5+2’ (n = 85) or ‘7+3’ (n = 25) for IND2. We collected the clinico-pathologic data of the patients at diagnosis and at IND2, and analyzed prognostic factors for response to IND2. Results: Sixty-one (55.5%) of 110 patients, who received IND2, achieved complete remission (CR). The causes of treatment failure were resistant disease in 35, complication of aplasia in 8, and indeterminated in 6. Five-year probabilities of overall and relapse-free survival were 25% and 21%, respectively. Multivariate analysis demonstrated that cellularity at interim BM biopsy > 30% (p = 0.015), blast percentage at interim BM aspiration > 30% (p = 0.031), presence of circulating blasts at IND2 (p = 0.011), and unfavorable chromosomal abnormalities (p = 0.014) were independent risk factors for failure to induce CR. The CR rates were significantly different according to the number of the risk factors: 73% for 0–1 factor, 48% for 2 factors, and 11% for 3–4 factors (p< 0.001). Conclusions: We identified 4 independent poor risk factors for CR in patients who showed persistent disease after standard induction chemotherapy and who received similar second induction course. Other treatment strategies such as high-dose cytarabine rather than standard regimens seem to be needed for the patients with 3–4 risk factors before IND2.

No significant financial relationships to disclose.
Older-age AML: Disease biology and dose response
Authors: Buchner T. , Berdel W. E. , Haferlach C. , Haferlach T. , Schnittger S. , Serve H. L. , Sauerland M. C. , Heinecke A. , Wörmann B. , Hiddemann W.
Published: March 2020

7058

Background: In 2602 pts entering two sequential trials the 47% pts of 60+y compared to the younger pts achieved 55 vs 71% CR, 19 vs 41% OS and 77 vs 54% RR (relapse risk) at 3 years. While the trials addressed various options for both de-novo and secondary AML understanding the age related biology of AML required restriction to pts comparable in history, therapy and availability of risk factors. Methods: We therefore selected from the two trials pts with de-novo AML and known karyotype assigned to one of two different intensity induction regimens, either TAD-HAM (HAM, high-dose araC 3(age <60) and 1(age 60+) g/m2x6), or HAM-HAM. All pts received TAD consolidation and monthly reduced TAD maintenance. Results: In the 1284 selected pts the CR rate is 60% in pts of 60+y and 70% in those of 16 −<60y (p<.001), the OS is 23 vs 41% (log rank p<0.001) and the RR is 73 vs 50% (p<.001). There are advantages for younger pts in favorable (16 vs 7%) and unfavorable (18 vs 24%) karyotypes (p<.001) whereas WBC (p=.002) and LDH (p=.002) are lower in the older pts. Among normal karyotypes (52%) the favorable NPM mutation in absence of Flt3 mutation account for 33% of NPM/Flt3 combinations in older and 37% in younger pts (n.s.). The inferior CR, OS and RR in the older vs younger pts is seen in all prognostic subgroups. Thus, the OS at 3 years is 36 vs 62% in favorable (p=.001), 2 vs 14% in unfavorable karyotypes (p=.001), 25 vs 42% in low WBC (p<.001), 21 vs 38% in high WBC (p<.001), 23 vs 42% in low LDH (p<.001), 16 vs 38% in high LDH (p<.001), 30 vs 43% in low day 16 blasts (p<.001), 19 vs 38% in high day 16 blasts (p<.001) and even 50 vs 63% in pts with NPM+/Flt3- mutation (p=.020). In contrast, outcome does not vary by randomization for TAD-HAM vs HAM-HAM chemotherapy. Conclusions: The lack of dose response and the modest age related differences in defined risk profiles suggest hitherto unknown determinants of the poor outcome in older age AML across all subsets. These experiences may indicate the way toward novel experimental options instead of further escalation.

No significant financial relationships to disclose.
A phase I study of the combination of a DNA topoisomerase inhibitor, idarubicin, with the histone deacetylase inhibitor vorinostat, in advanced acute leukemia
Authors: Kadia T. M. , Borthakur G. , Wierda W. , Ravandi F. , Faderl S. , Newsome W. , Zwiebel J. , Egorin M. , Garcia-Manero G.
Published: March 2020

7066

Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor (HDACi) with single agent activity in patients with advanced leukemia. HDACi lead to the acetylation of histones and facilitate an open chromatin configuration. Idarubicin potently inhibits DNA topoisomerase (topo) II by forming stable complexes with it, and eventually leading to ds-DNA breaks and apoptosis. Because of their effect on the chromatin of dividing cells, we postulated that the pairing of an HDACi with a topo II inhibitor, would have antileukemia activity. We tested this in vitro in leukemia cell lines and have shown that the combination of idarubicin and SAHA is synergistic. Methods: To test this clinically, we developed a phase I trial of the combination of idarubicin and SAHA, given in 2 different schedules, in advanced leukemia. In schedule A, idarubicin 12 mg/m2 daily for 3 days is given concurrently with SAHA, orally TID for 14 days (starting at 100 mg). In schedule B, SAHA is only given for 3 days. Only SAHA was dose-escalated, following a classic 3+3 schema, with the plan to treat 10 patients at the MTD. If both schedules were open at any given time, patients were randomized among them. Results: So far, 20 patients have been treated: 8 in schedule A and 12 in B. Median age of the patients is 56 (21–80). Of the patients enrolled thus far, 19 (95%) had relapsed, refractory AML, 1 had MDS, and 8 out of the 20 (40%) had diploid cytogenetics. In schedule A, a dose of idarubicin at 12 mg/m2 and SAHA at 100 mg was found to be above the MTD, with the DLT's being myelosuppression, encephalopathy, and dysphagia. Dose escalation of schedule B continues currently at a dose of SAHA at 400 mg. No severe grade 3 or 4 toxicities have been observed on this schedule. No cardiac toxicity has been observed. So far, 2 CR and 2 complete marrow responses have been observed. All of these patients had failed previous anthracycline-based chemotherapy. Induction of γ-H2AX, histone acetylation, and induction of topo II and p21CIP1 mRNA expression are being evaluated, as well as pharmacokinetic characteristics of both agents. Conclusion: The combination of idarubicin with SAHA is safe and active, and SAHA could be incorporated in the treatment of front-line AML.

No significant financial relationships to disclose.
Treating the anemia of MDS with erythropoietin: Impact of higher dose compared to combination with G/GM-CSF
Authors: Moyo V. M. , Lefebvre P. , Duh M. , Yektashenas B. , Mundle S.
Published: March 2020

7082

Background: Recombinant human erythropoietin (EPO) is extensively used to improve erythropoiesis and reduce transfusions in anemic MDS pts. The addition of G/GM-CSF to EPO alfa or beta has been associated with higher erythroid response (ER) rates vs. EPO alone. Studies suggest higher ER rates could be achieved with EPO monotherapy if higher initiation doses were used. To study this question a meta-analysis was performed on studies of MDS pts treated with EPO alfa or beta + G/GM-CSF. Methods: Data extraction was performed on studies from PubMed, ASCO and ASH proceedings from 1990–2006 in MDS pts treated with EPO (alfa or beta) ± G/GM-CSF. To allow for cross comparisons, only studies including IWG or IWG-like ER criteria were selected for analysis. Pooled estimates of ER rates were calculated using fixed-effect (F-E) meta-analysis methods. Results were stratified by: (i) EPO-alfa at standard doses, (ii) EPO- alfa at high doses, (iii) EPO-alfa + G/GM-CSF, and (iv) EPO-beta + G/GM-CSF. Results: From 39 studies identified, 19 met inclusion criteria. Most pts (>55%) had RA/RARS. Studies using EPO-alfa at standard doses showed comparable ER rates to studies using EPO- alfa + G/GM-CSF (49.0% vs. 50.6%; p=0.731) ( Table ). Among EPO-alfa studies, those using higher EPO doses had higher ER rates vs. studies using standard EPO doses (p<0.001) or EPO + G/GM-CSF combination (p=0.007). Overall ER rates were not available for studies using EPO- beta + G/GM-CSF, however, 52 pts (37.7%) had major ER, similar to that observed in all EPO-alfa monotherapy studies (195/589=33.1%). Conclusions: These findings suggest increasing EPO-alfa dose may have a greater impact on ER than addition of G/GM-CSF. Further validation is warranted.

[Table: see text] [Table: see text]
Correlation of high CD49d expression with disease progression and need for therapy in chronic lymphocytic leukemia (CLL) patients
Authors: Gattei V. , Bulian P. , Del Principe M. I. , Zucchetto A. , Niscola P. , Bomben R. , Dal Bo M. , Buccisano F. , Amadori S. , Del Poeta G.
Published: March 2020

7091

Background: CD49d mediates interaction of lymphocytes with microenvironmental components. We and others reported the correlated expression of CD49d and CD38 by CLL cells, and the complementary value of these molecules in predicting overall survival for CLL patients. However, nothing is known on the relationship of CD49d with other prognosticators and its impact in predicting disease progression and need for therapy in CLL. Methods: The study includes 232 CLLs (median age 64 yrs), all characterized for Rai stages, lymphocyte doubling time (LDT), CD49d, CD38 and ZAP-70 expression, serum levels for sCD23 and beta2-microglobulin (beta2-m), IgVH mutations (139/232), cytogenetics (151/232; FISH for 17p, 11q, 13q, 12). CD49d was measured in CD19/CD5 cells by three-color flow cytometry, choosing a 30% cut-off to discriminate CD49d-low vs. CD49d-high CLLs. NCI-working group criteria were used for CLL diagnosis, progression and therapy need. Results: Median time-to-progression (TTP) was 136 and 56 months in CD49d-low and CD49d-high CLL patients (p=0.00008), respectively; similarly, median time-to-treatment (TTT) was 108 and 46 months for the same patient groups (p=0.000008). Correlations were also observed among CD49d and CD38 (p=2.2x10exp-16) or ZAP-70 (p=0.00009) expression, sCD23 serum level (p=0.0017), LDT (p=0.0037), Rai stages (p=0.019), cytogenetics (p=0.011), IgVH mutations (p=0.00008). TTT and TTP were significantly shorter in CLLs in advanced Rai stages, or with high CD38 and ZAP-70 or low IgVH mutations. Within these cases, significantly longer TTP/TTT were observed in subsets expressing low CD49d. Serum levels of sCD23 and beta2-m, LDT, and FISH analyses had also predictive value for progression and treatment in our series. Within the better prognosis groups (i.e. <70 U/ml sCD23, 12 months, or a normal karyotype), high CD49d expression identified a subset of patients with significantly shorter TTP/TTT. Overall, the capability of CD49d to predict disease progression and need for therapy was statistically significant in younger patients (<64 y.o.; 115 cases; p=0.0001), but not in those older than 64 yrs (117 cases; p=0.09). Conclusions: We propone to include evaluation of CD49d expression in the prognostic assessment of CLL patients.

No significant financial relationships to disclose.
Phase II trial of CAT-3888 (BL22) in chemo-resistant hairy cell leukemia
Authors: Kreitman R. J. , Wilson W. H. , Stetler-Stevenson M. , Noel P. , FitzGerald D. J. , Pastan I.
Published: March 2020

7095

Background: CAT-3888 (BL22) is a recombinant anti-CD22 immunotoxin which showed phase I activity in chemo-resistant hairy cell leukemia (HCL). Methods: Eligible patients had relapsed HCL < 4-years after prior cladribine (CdA) and needed additional treatment based on blood counts. Patients were stratified into 2 groups by most recent CdA response of < 1 year or 1–4 years. A 3rd group was added for patients with uncontrolled infection. The study used a 2-stage design of 10 patients each for the first two strata with expansion to 17–30 if hematological remission (HR, i.e. ANC, platelets and Hgb at least 1.5, 100, and 11, respectively) was achieved in at least 3/10. The third strata allowed up to 5 patients. Patients received 40 ug/Kg every other day (QOD) ×3 on cycle 1. Those achieving HR were observed. Patients without a HR and no neutralizing antibodies were retreated at 30 ug/Kg QOD ×3 every 4 weeks beginning at least 8 weeks after cycle 1. Results: 35 patients were enrolled including 25, 9 and 1 in groups 1–3, respectively. CR (44% vs 48%) and overall response (ORR)(64% vs 89%) were similar in strata 1 and 2 with 16 (47%) CRs and 8 (24%) partial responses (PRs) overall. Response was particularly high in 22 with baseline spleen size < 200 mm (95% ORR; 59% CR, 36% PR) compared to patients with spleen height > 200 (ORR 20%, p = 0.001) or patients post-splenectomy (ORR 25%, p = 0.0003). The only serious toxicity was completely reversible grade 3 hemolytic uremic syndrome, not requiring plasmapheresis, in 1 (3%) patient on cycle 2. Neutralizing antibodies which prevented additional cycles were observed in 4 (11%) patients. Conclusions: The activity of CAT-3888 (BL22) in HCL is confirmed in this phase II trial. Toxicity may be limited by retreating only those who do not respond to 1 cycle. Optimal response to CAT-3888 (BL22) following CdA failure may be achieved before the occurrence of massive splenomegaly or splenectomy.

No significant financial relationships to disclose.
Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced non- small cell lung cancer (NSCLC)
Authors: Acharya C. , Hsu D. , Balakumaran B. , Walters K. , Vlahovic V. , Riedel R. , Garst J. , Febbo P. , Nevins J. , Potti A.
Published: March 2020

7501

Background: Standard treatment for advanced non-small lung cancer (NSCLC) includes platinum-based therapy. Response is however suboptimal and unpredictable. Newer agents, such as pemetrexed, have shown significant activity in the second-line setting, but their role in the first-line setting is unknown. Methods: Using in vitro drug sensitivity data, coupled with Affymetrix microarray data, gene expression signatures predicting sensitivity to cisplatin and pemetrexed were developed, using methods previously described (Nature Medicine, 2006). Signatures were validated with response data from 32 independent ovarian and lung cancer cell lines as well as 59 patient samples. Results: Genomic-derived signatures of cisplatin and pemetrexed sensitivity were shown to accurately predict response in vitro and, in the case of cisplatin, in 59 samples obtained from advanced disease patients previously treated with cisplatin. The accuracy of the cisplatin predictor, using clinical response as the endpoint, was 83.1% (Sensitivity: 100%, Specificity: 57%). In comparison, determination of ERCC1 status (IHC) had a predictive accuracy of 62% (Sensitivity: 82.8%, Specificity: 33.3%). Interestingly, a significant inverse correlation (p = 0.004) was found between the likelihood of cisplatin and pemetrexed sensitivity in the NSCLC cell lines. This relationhip was further validated in another indepedent cohort of 91 patients with NSCLC (p < 0.01). Finally, using novel cell proliferation experiments, we show that tumors from cisplatin refractory patients that are initially sensitive to pemetrexed, if treated with a taxane (docetaxel or paclitaxel) prior to pemetrexed therapy, develop resistance to subsequent pemetrexed therapy. Conclusions: The use of gene expression signatures that predict cisplatin and pemetrexed sensitivity can be incorporated into strategies to refine the selection of chemotherapeutic drugs chosen as first-line therapy in advanced NSCLC. It is critical for future prospective studies to validate the use of pharmacogenomic predictors of chemosensitivity in NSCLC, to optimize response rates and survival benefit.

No significant financial relationships to disclose.
Surgery (S) and radiotherapy (RT) plus adjuvant chemotherapy (CT) versus surgery and radiotherapy in non-small cell lung cancer (NSCLC): A meta-analysis using individual patient data (IPD) from randomised clinical trials (RCTs)
Authors: Le Pechoux C. , Tribodet H. , Pignon J. P. , Burdett S.
Published: March 2020

7521

Background: Our previous IPD meta-analysis of CT (BMJ 1995;311:899) suggested that CT may have a role in the treatment of various stages of NSCLC. However, the results in the S + RT setting were uncertain because of the small number of patients in this setting. We have updated this meta-analysis, including trials and outcomes not available in 1995. We report here on the effectiveness of S+RT+CT compared to S+RT. Methods: Systematic searches for RCTs were followed by the central collection, checking and re-analysis of updated IPD. Results from individual trials were combined using the stratified (by trial) log rank test to calculate pooled hazard ratios (HRs). Previously included old trials using long-term alkylating agents were excluded from this analysis. Results: IPD were obtained from 2,626 patients (12% with incomplete resection) from 11 RCTs. This represents 86% of all known randomised patients and adds a further 5 trials and 1,956 patients to the 1995 analyses. Median follow-up is 6.3 years. Ten trials used sequential RT-CT. 8 RCTs used cisplatin + vinca alkaloid/ etoposide, 1 used cisplatin + tegafur and 2 used other platinum regimens. There is a significant benefit of CT on survival (HR=0.88, 95% CI=[0.80–0.96], p=0.0062), with an absolute benefit of 4.7% (from 29% to 34%) at 5 years. The HRs for older (0.93 [0.79–1.10]) and more recent trials (0.89 [0.81–0.97]) were comparable (test for interaction p=0.49). Results were similar for recurrence-free survival (0.84, [0.77–0.93], p=0.0006), local (0.79 [0.67–0.94], p=0.0075) and distant recurrence-free interval (0.75 [0.66–0.87], p<0.0001) (data available for 7 trials). There was no clear evidence of a difference in effect by type of CT given. Also, there was no clear evidence that any patient subgroup defined by age, sex or stage benefited more or less from CT. Conclusion: These results demonstrate now a benefit of adjuvant chemotherapy in resected lung cancer associated with radiotherapy. These results are very similar to those of the meta-analysis without radiotherapy. They provides robust estimates for future policy and research. Unrestricted grants from PHRC, LNCC and sanofi-aventis.

[Table: see text]
Final analysis of a multi-center, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin (GC) plus bevacizumab (B) or placebo (P) in patients (pts) with malignant mesothelioma (MM)
Authors: Karrison T. , Kindler H. L. , Gandara D. R. , Lu C. , Guterz T. L. , Nichols K. , Chen H. , Stadler W. M. , Vokes E. E.
Published: March 2020

7526

Background: In phase II trials in MM, GC on a 21-day (D) schedule has response rates of 16%–26% and median overall survival (OS) of 9.6–13 months (mo). Since VEGF has a key role in MM biology, we added anti-VEGF antibody B to GC in a multi-center, double- blind, placebo-controlled randomized phase II trial. Methods: Eligible pts had unresectable MM; no prior chemotherapy; PS 0–1; no thrombosis, bleeding, or major vessel invasion. Primary endpoint: progression-free survival (PFS). Statistics: 90% power to detect HR 0.57. Stratification: PS (0/1), histology (epithelial/other). G 1,250 mg/m2 D 1, 8 Q21D, C 75 mg/m2 D1 Q21D, and B 15 mg/kg or P D1 Q21D was given × 6 cycles, then B or P Q21D until progression. Baseline plasma VEGF was measured. 115 pts enrolled 12/01- 07/05 at 11 sites, 108 (GCB/GCP) 53/55 were evaluable. Male 74%/84%; median age 62/65 (range 44–78/20–84); PS 1 55%/47%; epithelial 74%/67%; pleural 93%/91%; thrombocytosis 40%/40%. Results: Cycles: total 458/424, median 7/6, range 1–42/2–39. Statistically significantly different (SSD) toxicity (p <0.05), any grade: alopecia 60%/38%; epistaxis 62%/24%; hypertension 45%/22%; non-neutropenic infection 15%/4%; proteinuria 62%/47%; stomatitis 23%/7%. There were no SSD toxicities = grade 3. Median PFS 6.9/6.0 mo (HR 0.93, p=0.88). Median OS 15.6/14.7 mo (p=0.91). 1-year survival 59%/57%. Partial response 25%/22%; stable disease 51%/60%. Median VEGF (N=56) 131/154 pg/ml (range 31–1760/5–1786). Higher VEGF was associated with shorter PFS (p=0.02) and OS (p=0.0066). In pts with VEGF = the median, PFS (p=0.043) and OS (p=0.028) were significantly greater for GCB than GCP; in high VEGF strata this was not SSD. Conclusion: Adding B to GC in MM pts does not yield statistically significant differences in PFS, OS, response, or grade ¾ toxicity. GCB-treated pts with low VEGF levels had longer PFS and OS. Supported by NCI grant N01-CM-17102.

No significant financial relationships to disclose.
A randomized phase 3 trial of gemcitabine with or without carboplatin in performance status 2 (PS2) patients (pts) with advanced (stage IIIB with pleural effusion or stage IV) non-small cell lung cancer (NSCLC)
Authors: Obasaju C. K. , Conkling P. , Richards D. , Fitzgibbons J. , Arceneau J. , Boehm K. A. , Asmar L. , Cunneen J. , Peng G. , Reynolds C.
Published: March 2020

7533

Background: The optimal treatment of patients with advanced NSCLC and PS2 has not been resolved. A retrospective analysis of 99 pts with PS2 in CALGB 9730 (Lilenbaum, JCO 2005) demonstrated improved survival associated with combination carboplatin- paclitaxel versus paclitaxel alone (median overall survival=4.7 vs. 2.4 mos., p=.019). Gemcitabine-carboplatin (GC) is an active doublet in advanced NSCLC and is at least as active as paclitaxel-carboplatin (PC) in PS2 pts (ECOG 1599, Tester ASCO 2004). A prospective validation of the activity of GC is needed, which is addressed by comparing GC versus gemcitabine (G) alone in this setting. Methods: 161 chemonaïve pts with advanced NSCLC and PS2 were randomly assigned to G 1250 mg/m2 alone on Days 1,8 or GC (G 1000mg/m2 Days 1,8 followed by C AUC 5 on Day 1). Cycles were repeated every 21 days for 6 cycles or until disease progression or intolerable toxicity. Primary endpoint was median survival. Conclusions: GC resulted in an improved response rate among NSCLC pts with PS2 over G alone. As expected, G3–4 toxicities were greater with GC. Overall survival data will be reported at the time of the meeting.

[Table: see text] [Table: see text]
Phase III randomized study of oral vinorelbine (oV) and gemcitabine (G) (oVG) versus docetaxel (D) and gemcitabine (DG) as first-line treatment of patients with advanced non-small cell lung cancer (NSCLC): A preliminary report
Authors: Agelaki S. , Androulakis N. , Agelidou A. , Agelidou M. , Kotsakis A. , Kakolyris S. , Polyzos A. , Kentepozidis N. , Ziras N. , Mavroudis D.
Published: March 2020

7538

Background: Non-platinum based doublets are effective treatments for advanced NSCLC. We performed a multicenter phase III trial to compare the efficacy and tolerance of oVG and DG in NSCLC patients (pts). Methods: Chemotherapy-naive pts with stage IIIB/IV NSCLC and PS (WHO) 0–2 and adequate organ function were eligible. Pts received oV 70 mg/m2 combined with G 900 mg/m2 on days 1, 15 of a 4-week cycle or D 75 mg/m2 on day 1 combined with G 1,000 mg/m2 on days 1, 8 of a 3-week cycle. Primary endpoint was OS and secondary endpoints were response rate (RR), time to progression (TTP) and toxicity. Stratification was done for age, stage and PS. Results: 254 pts received oVG (n=121) or DG (n=133). Median age was 64 and 63 years, and PS was 0–1 in 94.2% and 94%, for oVG and DG, respectively. Most patients had disease stage IV and were =70 years (80.9% vs 74.4% and 74% vs 77%, in oVG and DG, respectively). After a median follow-up time of 6.1 months, median OS was 9.0 vs 10.7 months and 1-yr survival was 38% vs 46% for oVG and DG, respectively (p=0.486). Significantly more responders were observed in the DG arm (11% vs 23%, p=0.018). Median TTP was 3.1 vs 3.9 for oVG and DG, respectively (p=0.335). A similar toxicity profile was observed except for a trend for higher neutropenia grade 3–4 in DG compared to oVG (p= 0.066). There was no difference with respect to neutropenic infections (p= 0.124). An analysis of the influence of age (=70 and = 70) on OS and toxicity revealed that OS was similar for both arms in the two age groups but grade 3–4 neutropenia was lower in the oVG arm for pts =70 years. Conclusions: A higher RR that was not translated to a survival benefit was recorded for the DG arm. Both regimens were well tolerated without significant differences in toxicity.

No significant financial relationships to disclose.
Increased BRCA1 mRNA: An independent prognostic variable in completely resected chemo-naive non-small cell lung cancer (NSCLC) patients (p)
Authors: Rosell R. , Jassem E. , Skrzypski M. , Taron M. , Mendez P. , Perez L. , Szymanowska A. , Rzyman W. , Gulida G. , Jassem J.
Published: March 2020

7551

Background: Following surgical resection in operable NSCLC, 5-year survival is 60% in stage I, 39% in stage IIB and 23% in stage IIIA, with relapse commonly as distant metastases. The average benefit of adjuvant chemotherapy is 5%, ranging from nil in stage I to 15% in stage II-IIIA. Caretaker genes involved in keeping genetic alterations to a minimum include the nucleotide excision repair genes ERCC1 and myeloid zinc finger 1 (MZF1), which mediates ERCC1 expression, and other stability genes, such as BRCA1, which control processes involving large portions of chromosomes. Thioredoxin-1 (TRX1) is a redox protein overexpressed in NSCLC that is correlated with poor prognosis, and TWIST contributes to metastasis by promoting epithelial-mesenchymal transition. Methods: In order to identify p with a high risk of relapse, we investigated the expression of these 5 transcripts in frozen resected tumors from 126 resected NSCLC p by real-time quantitative PCR. Gene expression was normalized using β-actin and 18SrRNA expression as internal references. Results: Adenocarcinoma (adeno), 33 p; squamous cell carcinoma (SCC), 93 p. Stage: IA, 18 p; IB, 53 p; IIB, 33 p; IIIA, 22 p. Tumoral transcript expression with β-actin: ERCC1, 1.23; MZF1, 0.53; BRCA1, 3.65; TRX1, 1.82; TWIST, 7.75. A strong correlation was observed between the expression of ERCC1, MZF1 and BRCA1 (P<0.001). Expression of each of the 5 transcripts was higher in SCC than in adeno (P<0.001). Median survival (MS): low ERCC1 (<1.5) = not reached (NR), high ERCC1 = 33 months (m) (P=0.21); low MZF1 (<0.5) = NR, high MZF1 = 33 m (P=0.04); low BRCA1 (<5) = NR, high BRCA1 = 22 months (m) (P=0.01); low TRX1 (<0.8) = NR, high TRX1 = 39.5 m (P=0.02); no differences in MS according to levels of TWIST. In a multivariate Cox model for survival, BRCA1 and stage emerged as independent prognostic variables ( Table ). Conclusion: Increased BRCA1 is associated with shorter survival, and BRCA1 assessment could be useful for customizing adjuvant chemotherapy.

No significant financial relationships to disclose.

[Table: see text]
Mortality risk for stage I NSCLC with poor histologic grade, tumor size ≥4 cm, and non-upper lobe tumor location: An epidemiologic study of 19,702 patients in the California Cancer Registry from 1989 to 2003
Authors: Ou S. I. , Zell J. A. , Ziogas A. , Anton-Culver H.
Published: March 2020

7558

Background: Platinum-based adjuvant chemotherapy in randomized trials has failed to provide a survival benefit in stage I non-small-cell lung cancer (NSCLC). Using data from California Cancer Registry (CCR), we explored factors that have detrimental effect on survival in stage I NSCLC to identify a subset of patients at high risk for relapse and subsequent mortality. Methods: 19,702 stage I NSCLC cases in the CCR from 1989 to 2003 were identified and subgrouped into stage IA & IB disease. Patient demographic factors, tumor characteristics and treatment delivered were examined. Kaplan-Meier survival curves were calculated to estimate survival rates. Cox proportional hazards ratios were used to identify independent prognostic factors for survival. Results: Advanced age at diagnosis, male sex, low socioeconomic status (SES), non-surgical treatment & poorly-differentiated histologic grade (stage IA: hazard ratio [HR] = 1.14; 95% confidence interval [CI]: 1.08–1.19 & stage IB: HR = 1.11; 95% CI: 1.07–1.16) were factors identified with increased mortality risk on multivariate analysis. Non-upper lobe tumor location (RML/RLL/LLL) and tumor size ≥ 4 cm (vs < 4 cm; HR = 1.22; 95% CI: 1.15–1.30) were additional factors with increased mortality risk among stage IB patients. Conversely, bronchioloalveolar carcinoma (BAC)(vs adenocarcinoma: stage IA: HR = 0.81; 95% CI: 0.72–0.91 & stage IB: HR = 0.87, 95% CI: 0.77–0.98) & Asian ethnicity (vs Caucasian: stage IA: HR = 0.81, 95% CI: 0.70–0.94 & stage IB: HR = 0.80, 95% CI: 0.72–0.90) were associated with decreased mortality risk in stage I NSCLC. Lobectomy had the lowest HRs for death among all surgical techniques for both stage IA & IB NSCLC in the Cox proportional hazards model. Conclusions: Poorly-differentiated stage IA & IB NSCLC and stage IB NSCLC located in non-upper lobes or tumor size ≥ 4 cm carried an increased mortality risk on adjusted analysis.

No significant financial relationships to disclose.

[Table: see text]
A multicenter U.S. trial of neoadjuvant pemetrexed plus cisplatin (PC) followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation (RT) for stage I-III malignant pleural mesothelioma (MPM)
Authors: Krug L. M. , Pass H. , Rusch V. W. , Kindler H. L. , Sugarbaker D. , Rosenzweig K. , Friedberg J. S. , Pisters K. , Obasaju C. K. , Vogelzang N. J.
Published: March 2020

7561

Background: The optimal management for fit patients with early stage MPM remains controversial. One approach involves neoadjuvant chemotherapy followed by EPP and hemithoracic RT and prior trials using gemcitabine and cisplatin have been reported (Weder JCO 2004, Flores JTO 2006). We administered PC, followed by EPP and RT to further assess feasibility and survival of trimodality therapy in a larger, multicenter study. Methods: Eligibility criteria: Stage T1–3 N0–2, no prior surgical resection, adequate organ function (including predicted post-op FEV1 >35%) and PS 0–1. Pts received pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 with vitamin supplementation for 4 cycles. Pts without disease progression underwent EPP followed by RT (54 Gy). The primary endpoint was pathologic complete response (pCR) rate. Enrollment was completed in March, 2006. Results: 77 patients were enrolled and 72 are evaluable. Median age 63.5 (range 34–78), M:F = 51:21, Clinical stage I:II:III:IV = 5:31:33:1, epithelial:nonepithelial = 58:15, ECOG PS 0:1:2 = 28:42:2. 83% of patients completed all four cycles of PC. Grade 3/4 events related to chemotherapy included: neutropenia (4%), febrile neutropenia (3%), nausea (1%), vomiting (3%), pneumonia (6%), pulmonary embolism (1%), and chest pain (3%). Of 73 pts assessed for radiologic response, 3 CRs, 21 PRs, 36 SDs, 3 PDs, and 10 were unevaluable; (RR= 33% [95% CI, 0.22, 0.45]). Of 54 pts who underwent surgery, EPP completion rate was 87% (47/54); that is 47/77 (61%) by ITT. Pathologic stage I:II:III:IV:NE = 4:12:24:3:11. One pCR was confirmed. 35/39 completed RT. Preliminary TTP =13.1 mo (95% CI=9.6, 15.9; 48% censored) and median survival=16.6 mo (95% CI=13.9, 19.3; 55% censored;1-yr survival = 68%). Conclusions: This multicenter trial testing trimodality therapy in MPM showed that it is feasible with a high rate of chemotherapy delivery. One pCR was observed. Preliminary survival is below that reported by single institutions for patients undergoing EPP but with a high censorship rate at this early time point. Further analyses are necessary to identify a cohort of patients most likely to benefit. This study was sponsored by Eli Lilly & Company.

No significant financial relationships to disclose.
A phase II study of cisplatin (P) plus etoposide (E) plus bevacizumab (B) for previously untreated extensive stage small cell lung cancer (SCLC) (E3501): A trial of the Eastern Cooperative Oncology Group
Authors: Sandler A. , Szwaric S. , Dowlati A. , Moore D. F. , Schiller J. H.
Published: March 2020

7564

Background: Scientific evidence supports the concept that the growth of solid tumors, including SCLC, is dependent on angiogenesis. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), has been shown to improve survival when combined with chemotherapy in non-small cell lung cancer. PE is a standard regimen for use in SCLC. Thus, we proposed this study of PE plus B in patients (pts) with previously untreated extensive stage SCLC. Methods: Pts with previously untreated extensive SCLC with a performance status 0–2, received P (60 mg/m2) IV followed by E (120 mg/ m2) IV followed by B (15 mg/kg) IV infusion on day 1, with E repeated on days 2 and 3 of a 21-day cycle for 4 cycles or until progressive disease (PD). Pts not experiencing PD continued bevacizumab until disease progression or unacceptable toxicity. The primary endpoint was per cent of patients alive at 6 months. Results: From 6/8/04 to 8/18/06 (includes a ten month accrual suspension to evaluate data), 64 eligible pts were accrued. Patient characteristics: median age of 65.5 years (range: 45–83), 44% males, 95% Caucasian and 9% were performance status = 2. A median of 6 cycles of treatment were administered (range: 1–12). There is toxicity data on 58 pts. The most common treatment-related grade 3 & 4 toxicities were: neutropenia (7 & 26 pts), thrombocytopenia (8 & 2 pts), fatigue (10 pts, grade 3 only), hypertension (4 pts, grade 3 only), febrile neutropenia (2 pts) and dehydration (3 pts, grade 3 only). Two pts experienced grade 5 toxicities (hypotension and infection with grade ¾ neutropenia). There were no grade ≥3 hemorrhagic events. Response information is available on 39 pts. There have been 4 complete responses and 23 partial responses for an overall response rate of 69% (90% exact CI: (55%, 81%). The proportion of pts alive and progression- free at 6 months was 33% (95% CI: 17%, 49%). Conclusions: Preliminary results indicate that the addition of B to the combination of PE in patients with previously untreated extensive stage SCLC appears promising. A randomized phase III trial comparing PE to PE + B is under consideration.

No significant financial relationships to disclose.