bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I/II study of idarubicin (Ida), high-dose ara-C, and sorafenib (S) in patients (pts) younger than 65 years with acute myeloid leukemia (AML)
Authors: Ravandi Kashani F. , Cortes J. , Faderl S. , Jones D. , Byrd A. , Brandt M. , Garcia-Manero G. , Levis M. , Andreeff M. , Kantarjian H.
Published: August 2020

7018

Background: S is an oral multi-kinase inhibitor with activity against the Raf/ERK/MEK pathway and FLT3. It selectively induces apoptosis in FLT3-mutant human AML cell lines at nM concentrations. Methods: Objectives of this study are to determine the tolerability and efficacy of combination of S with chemotherapy. Ara-C 1.5 g/m2 over 24 hrs daily x 4 (x 3 for pts over 60) and Ida 12 mg/m2 daily x 3 are administered with S. In the phase I part, pts with relapsed AML were treated with escalating doses of S (400 mg qod, 400 mg daily, 400 mg bid) for 7 days during induction, and 400 mg bid was established as safe. Pts achieving CR receive up to 5 courses of consolidation with Ida 8 mg/m2 daily x 2 and Ara-C 0.75 g/m2 daily x 3 in addition to S 400 mg bid for up to 28 days per cycle repeated every 4 to 6 weeks. Maintenance is with S 400 mg bid for up to a year. Results: 10 pts (median age 34, range 21–58) with relapsed AML (median prior therapy 2, range 1–6) were treated in the phase I . 7 were FLT3-ITD positive. 4 achieved CR; 6 failed. In the phase II part, 45 pts (12 with FLT3-ITD and 2 with FLT3-TKD) were treated. Median age is 53 (range 18 - 65). Cytogenetics were diploid in 19, +8 in 5, -5/-7 in 5, 11q23 in 2, other in 14. Median presentation WBC was 4.9 x 109/L (range 0.6 - 122.7 x 109/L). 8 pts were FLT3-ITD+/NPM1-. 40 pts are evaluable for response and 85% achieved CR (n = 30) or CRp (n = 4) (13 of 14 FLT3 mutated pts); 5 pts are too early (1 FLT3 mutated). Most frequent grade 3 and higher related adverse events: hyperbilirubinemia (5), rash and hand-foot syndrome (3), raised transaminases (2), diarrhea (2), hypertension (2). With a median f/u of 5.4 mo (range, 0.5 - 11.3), the probability of survival at 6 mo is 81.6%. 5 pts have relapsed; median CR duration has not been reached, (range; 0.2+ - 10.6+ mo). Among pts with FLT3 mutation, 4 have relapsed and 9 remain in CR. Plasma inhibitory assay was performed using day 7 samples from 10 pts; mutant FLT3 was suppressed by all with 5-fold more potent suppression against mutant versus wild-type FLT3. Conclusions: S can be safely combined with IA; it has a high CR rate in frontline therapy of younger pts with AML, in particular those with FLT3 mutations. Correlative studies confirm potent activity of S against FLT3 signaling.

[Table: see text]
Sibling donor immunization with patient-derived Id-KLH vaccine prior to reduced-intensity allogeneic hematopoietic cell transplantation for multiple myeloma
Authors: Bishop M. R. , Kwak L. W. , Fowler D. H. , Giralt S. , Steinberg S. M. , Bryant K. , Neelapu S. S.
Published: August 2020

7024

Background: Relapse is the most common cause of treatment failure after reduced-intensity allogeneic hematopoietic cell transplantation (RI-alloHCT) for multiple myeloma (MM). To enhance graft-versus-myeloma effects, we investigated the use of patient-specific idiotype (Id) vaccine in both donors and recipients. Methods: Id protein was obtained by plasmapheresis and conjugated to keyhole limpet hemocyanin (Id-KLH) to generate vaccine. Donors received 3 SQ injections of Id-KLH + GM-CSF at 10, 8, and 4 weeks before stem cell donation. MM pts received a reduced-intensity conditioning regimen (Flu/Cy) and GVHD prophylaxis consisted of cyclosporine plus methotrexate. MM pts were vaccinated with the Id-KLH+GM-CSF at 3, 4, and 6 months post-transplant. Humoral responses were determined by ELISA and Th1 (IL-2, IFN-γ, TNF-α, and GM-CSF) and Th2 (IL-4, IL-5, IL-10, and IL-13) cellular immune responses against Id and KLH were determined by multiplex cytokine assay. Results: Ten MM pts (median age: 54 years; IgG = 8, IgA = 2) and their respective donors were enrolled onto study. All 10 donors completed vaccinations without significant complications. Following vaccination, KLH-specific antibody and Th1/Th2 responses were noted in all 10 donors. Id-specific antibody responses were noted in 6 donors; Th1 and Th2 responses were noted in 5 and 6 donors, respectively. All 10 MM pts underwent RI-alloHCT; the median potential follow-up post-transplant is 43.8 months. Id-specific Th1 and Th2 responses were noted in 5 and 3 pts, respectively, prior to post-transplant immunization; antibody response was noted in 1 patient. Nine evaluable MM pts completed their post-transplant vaccinations. KLH-specific antibody and Th1/Th2 responses were detectable in all 9 pts post-transplant. Id and KLH immune responses were further enhanced by post-transplant vaccinations. Median progression-free survival is 27.3 months; median survival has not been reached. Conclusions: The data suggest Id-specific immunity can be safely induced in normal stem cell donors and passively transferred to recipients of RI-alloHCT. Donor vaccination with tumor-specific antigen represents a tactic to potentially reduce relapse after RI-alloHCT.

No significant financial relationships to disclose.
BCR-ABL truncation due to premature translation termination as a mechanism of resistance to kinase inhibitors
Authors: Yeh C. , Ma W. , Kantarjian H. , Zhang Z. J. , Cortes J. , Albitar M.
Published: August 2020

7028

Background: The major mechanism underlying imatinib resistance in patients with chronic myeloid leukemia (CML) is clonal expansion of leukemic cells with point mutations in the BCR-ABL tyrosine kinase. We describe three novel ABL premature termination mutations leading to BCR-ABL truncation in leukemia patients with multidrug (imatinib/nilotinib/dasatinib) resistance. Methods: Peripheral blood or bone marrow samples from drug-resistant CML patients were collected. Total nucleic acids were purified and subjected to two rounds of PCR analysis, with the first PCR designed to eliminate amplification of the wild-type, non-translocated ABL gene. Bi-directional sequencing was then performed. HL60 cells (a Ph-negative myeloid leukemia cell line) and peripheral blood of healthy subjects were used as negative controls; a human CML cell line (K562) was used as a positive control. Results: We identified an exon 7 deletion in three CML patients, a 4-nt insertion (908insCAGG) near the exon 5/6 junction in one CML case, and an exon 6 point mutation (997C>T) in one patient with acute lymphoblastic leukemia (ALL). These mutations all create premature stop codons and cause termination at residues 381, 315, and 333, respectively, leading to truncated proteins with only the first quarter of the kinase domain (P-loop) or lacking the C-terminus of ABL including the A-loop. Conclusions: These novel mutations, and the previously documented 35-nt insertion in exon 8, may constitute a new class of mutations that 1) cause truncation of the BCR-ABL kinase; (2) abolish the regulatory element in the ABL kinase domain and the downstream C-terminal region; and (3) confer significant drug resistance.

[Table: see text]
Impact of azacytidine induction chemotherapies on post-transplant outcomes in patients with myelodysplastic syndromes
Authors: Cogle C. R. , Imanirad I. , Scornik J. , Wingard J. R.
Published: August 2020

7032

Background: With the advent of azacytidines for treatment of MDS, disease remissions are achievable; however the disease nearly always relapses. In contrast, allogeneic hematopoietic cell transplantation (HCT) can be curative. Whereas cytotoxic induction chemotherapy in patients with MDS provides no clear benefit after HCT, the effects of azacytidine therapy prior to HCT are unknown. Methods: To address this question, we analyzed post-transplant outcomes in 43 MDS patients, 9 who received an azacytidine before transplant and 34 who did not. Although patients in both groups were equivalent in time to transplant, performance status, and transfusion dependence, patients who received an azacytidine were older (61 vs 48, p < 0.01), more immunosuppressed at HCT (absolute lymphocyte count 815 vs 1339, p = 0.04), and less likely to receive myeloablative conditioning (38% vs 78%, p = 0.03). Azacytidine patients were marginally more likely to have higher disease burden at HCT (WPSS 4 vs 3, p = 0.08) and more likely to have received a graft from an unrelated donor (66% vs 33%, p = 0.07). These patient characteristics reflect the current practice of using an azacytidine as a bridge to transplant for older patients who have no readily available, matched related donors. Results: With a median follow-up of 7 months, the group that received azacytidine pre-transplant demonstrated higher donor chimerism at days 30, 60 and 100 (p < 0.01). Rates of acute and chronic GVHD, and median overall survival (OS) did not differ significantly between groups. There was a trend toward higher relapse in the azacytidine group (44% vs 18%, p = 0.09). Conclusions: Our data indicate that induction with azacytidines results in higher short-term donor chimerism post-transplant. This effect is likely due to increased immunosuppression in an older population after azacytidine therapy. The increased rate of relapse in the azacytidine group likely reflects the progressive nature of chemotherapy-insensitive disease at HCT. Although only randomized controlled trials can establish a definite conclusion regarding use of azacytidines prior to HCT and duration of induction therapy before proceeding to HCT, the data presented support administration of azacytidines to MDS patients prior to HCT.

[Table: see text]
A phase II study with CP-4055 in patients with second salvage AML
Authors: Giles F. J. , O'Brien S. , Rizzieri D. A. , Vey N. , Krug U. , Sekeres M. , Jacobsen T. F. , Nilsson B. I. , Staudacher K.
Published: August 2020

7047

Background: CP-4055 (cytarabine 5'-elaidic acid ester) is a novel derivative of cytarabine, independent of nucleoside transporters to enter the cell. The aim of this study was to assess efficacy and safety of CP-4055 when given as second salvage therapy to patients (pts) with acute myeloid leukemia (AML). Methods: Adult pts who received two previous chemotherapy regimens and who had refractory/relapsed AML (CR after first salvage therapy lasting less than 6 months) were enrolled. CP-4055 2,000 mg/m2/d was administered over 24 h (CIV) in a day (d) 1–5 q3w schedule. After every 20-pts cohort, an Independent Data Monitoring Committee (IDMC) evaluated the results for futility and safety for recommendation of study continuation. Results: Forty pts (28 male and 12 female, median age 48 yrs [range 26–82]) were enrolled. 6 pts had previous transplant, the majority of the pts had previous ara-C based therapy, 12 pts had not obtained CR1 or CR2. Only 1 pt did not receive d1–5 dosing. The first 20-pt cohort (12 male, median age 53 yrs [range 26–82]) was evaluated by the IDMC. Most frequently reported related AE ≥ grade 3 (CTCAE v3.0) were myelosuppression, abdominal pain, colitis, diarrhoea, nausea, fatigue, liver function test (LFT) elevation. Clinical activity (IWG criteria for AML), 2 CR (1 with no CR1 or CR2), and 1 CRp (CR rate 15%), were reported. Toxicity was manageable, clinical activity reported and continuation recommended. Among all 40 patients 7 pts (18%) had LFT elevations of grade 3 or more and 4 pts (10%) had LFT elevations of grade 2. Clinical activity has been reported also among the last 20 pts. Therapy is ongoing. Conclusions: CP-4055 given as second salvage therapy to AML pts show manageable toxicity when administered at 2,000 mg/m2/d, 24 h CIV, in a d1–5 q3w schedule. Clinical activity (2 CR and 1 CRp) has been reported among the first 20 late stage AML pts. Data from 40 patients will be presented.

[Table: see text]
Interim results of protracted low doses of temozolomide in high-risk acute myeloid leukemia
Authors: Medeiros B. C. , Gotlib J. R. , Coutre S. E. , Jones C. , Khan S. A. , Rajwanshi R. , Rajwanshi R. , Zehnder J. , Zehnder J.
Published: August 2020

7052

Background: High treatment-related mortality and low response rates often discourage elderly patients with acute myeloid leukemia from receiving treatment. Previous data demonstrate that only patients lacking expression of O6-alkylguanine-DNA alkyltransferase (AGAT) in leukemic blasts are sensitive to temozolomide. Protracted exposure to low doses of temozolomide can significantly inhibit AGAT enzymatic activity. Methods: Phase II clinical trial of tailored temozolomide therapy to high-risk AML patients according to AGAT methylation promoter status. Patients demonstrating evidence of AGAT promoter methylation were stratified to conventional doses of temozolomide at 200 mg/m2 orally x 7 days. Patients demonstrating lack of AGAT promoter methylation (unmethylated) received protracted doses of temozolomide (100 mg/m2 orally x 14 days) followed by conventional doses of temozolomide. Patients who achieved CR were given up to 5 consolidation treatments. Results: Fifteen patients have completed treatment to date. The median age was 78 (68–83) and nine were male. De novo AML was diagnosed in eight patients and five patients had s-AML. Nine patients had a normal karyotype and three patients had a complex karyotype. Two patients had only a NPM1 mutation and one had NPM1mut/FLT3-ITD. In 13 patients, the AGAT promoter was found to be unmethylated. AGAT protein was present in 5/11 patients. All patients had an intact mismatch repair pathway. Thirteen patients had HCT-CI scores of 0–2. Six patients (6/13) achieved a complete remission (CR) after 1 cycle of therapy (1/2 for patients with methylated and 5/11 for patients with unmethylated AGAT promoter). Nonhematologic toxicities were minimal. Drug-related hematologic toxicities were difficult to distinguish from disease-related cytopenias. Three patients remain in CR with a median duration of 22 weeks (14–36 weeks). Seven patients have died from disease progression, while two patients died of neutropenic sepsis (early deaths). With a median follow-up of 38 weeks (10–48), the median overall survival for the entire population is 12 weeks (3.5 - 38) weeks (responders 26.5 weeks). Conclusions: These preliminary results suggest that temozolomide therapy may be individually tailored to elderly patients with AML according to AGAT promoter status.

[Table: see text]
Phase I study of pemetrexed in patients with relapsed or refractory acute leukemia or lymphoid blast phase chronic myelogenous leukemia
Authors: Plunkett W. , Thomas D. A. , O'Brien S. M. , Federl S. , Giles F. J. , Nicol S. J. , Gill J. , Zhao L. , Ravandi F. , Kantarjian H.
Published: August 2020

7068

Background: Pemetrexed is a folate antimetabolite that is clinically active in a number of different cancers. The purpose of this phase I trial was to define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of pemetrexed given with vitamin supplementation to patients with relapsed or refractory leukemia. Secondary objectives were pharmacokinetic (PK) and pharmacodynamic (PD) analyses of pemetrexed. Methods: Patients ≥15 years of age were enrolled with relapsed or refractory leukemia, Eastern Cooperative Oncology Group performance status ≤2, adequate renal and hepatic function, and life expectancy of ≥6 weeks. Enrollment was planned using a 3+3 dose escalation design. Intravenous pemetrexed was given at a starting dose of 900 mg/m2 over 1 hour every 3–4 weeks. Doses were escalated to 1,200, 1,500, 2,000, 2,700, and 3,600 mg/m2. Folic acid and Vitamin B12 were given with pemetrexed. Response was assessed by standard blood and bone marrow criteria. Toxicities were assessed using Common Terminology Criteria for Adverse Events, version 3.0. Results: Twenty-two patients entered the trial; median age was 50 years (range: 18–75); 15 patients had acute myeloid leukemia and 7 patients had acute lymphocytic leukemia (ALL). Two patients were ineligible and did not receive study drug. At the 1,200 and 1,500 mg/m2 dose levels, 1 patient per level developed grade (G) 3–4 liver enzyme and bilirubin elevations attributed to sepsis. At the 3,600 mg/m2 dose level, 1 patient had a G3 liver enzyme elevation and 2 added patients also had G3 liver toxicity. In addition, 2 patients in the 3,600 mg/m2 cohort developed G2 liver abnormalities. Based on liver toxicities, the DLT dose level was established at 3,600 mg/m2. Two patients died during the study due to disease progression and 1 patient discontinued due to a subdural hematoma of unknown cause. One patient with ALL achieved a partial response. There were no other objective responses. PK and PD data were not available for this report. Conclusions: The MTD and RP2D of pemetrexed were determined to be 2,700 mg/m2. Due to limited observed efficacy, a planned phase II trial was canceled.

[Table: see text]
Phase II trial of old age acute myeloid leukemia treatment by arsenic trioxide and low-dose subcutaneous cytosin arabinoside
Authors: Ghavamzadeh A. , Hashemi S. , Alimoghaddam K. , Nasri Moghaddam Z. , Shadpour M. , Jalili M.
Published: August 2020

7075

Background: AML is a disease of old age, but unfortunately due to several factors standard treatment can not be delivered to these patients. Here we tried to achieve to bet possible response to these patients. Methods: Eleven old age patients selected for this trial. Patients couldn't tolerate standard treatment of AML due to old age or comorbid disorders. Treatment consist of best supportive care plus administration of low dose ARA-C (20mg/day as SQ) for 10 days each months and arsenic trioxide 10 mg/day as 2 hour iv infusion each month. Patients followed by CBC and BMA/B when peripheral blood normalized or every other month. Results: This cohort consist of 8 men and 3 women. Median age was 75 y/o (55–80). Median WBC count Hb level and platelet count at presentation were 42,860μl, 8.3g/dl and 30,500/μl, respectively. Complete remission observed in 6 and partial remission in one patient (RR = 63.6%), but remission was short live, after 6 months one patient was in CR and one in PR. After 12 months, only one patient was in PR. Median survival was 6 months and 6 patients survive more than 6 months. Two patients are alive after 12 months. Conclusions: Although prognosis of old age AML remain poor, but with this type of treatment RR is acceptable. In this very high-risk group of very old AML, combination of ATO and ARA-C possibly could improve survival.

No significant financial relationships to disclose.
Role of serum erythropoietin, erythropoietin-independent erythroid colony formation, and bone marrow assessment in the diagnosis of polycythemia vera in patients with JAK2 V617F mutation
Authors: MacKenzie-Feder J. M. , Eaves C. , Lambie K. , Abdi-Ali A. , Ramadan K. M. , Young S. , Horsman D. , Galbraith P. , Eaves A. , Foltz L.
Published: August 2020

7085

Background: The discovery of the JAK2 V617F mutation in over 95% of polycythemia vera (PV) patients has led to the development of the new 2008 World Health Organization diagnostic criteria for PV. These specify a requirement for an elevated hemoglobin (Hb, males: >185 g/L, females: >165 g/L) and either evidence of JAK2-mutant cells plus any one of the following minor criteria: a below normal level of serum erythropoietin (Epo), detectable Epo-independent erythroid colony (EEC) formation in vitro, or panmyelosis in the bone marrow, or two of the latter in the absence of detectable JAK2-mutant cells. However, in patients with an elevated Hb and JAK2V617F positivity, there are few data to determine whether any of the 3 minor criteria actually add an independent contribution to the diagnosis of PV. Methods: We performed a retrospective chart review of 77 patients who had an elevated Hb and were positive for the JAK2 V617F mutation and who also had a test for at least one of the 3 minor criteria (serum Epo level: n = 53; EEC formation: n = 66; bone marrow examination: n = 16) to determine the frequency of cases who might lack one or more of these. Results: Although the number of patients with a complete set of data was limited, the results, nevertheless, were sufficient to show that all 3 minor criteria were highly represented and all 77 of the patients analyzed (100%) were positive for at least one of them; i.e., 47 of 53 tested (89%) had a reduced serum Epo level; 65 of 66 tested (98%) had EECs and 15 of 16 tested (94%) had evidence of bone marrow panmyelosis. Conclusions: Neither the Epo level, nor the presence of EECs nor evidence of bone marrow panmyelosis provided additional diagnostic specificity in a population of 77 patients with both JAK2 V617F-positive cells and an elevated Hb. Consideration should be given to limiting serum Epo, EEC, and bone marrow assessments to JAK2 mutant-negative patients.

No significant financial relationships to disclose.
Comparative efficacy of reduced or standard doses of lenograstim for peripheral blood stem cell mobilization and transplantation: A randomized study in patients undergoing autologous peripheral stem cell transplantation
Authors: Ozturk M. , Arpaci F. , Ataergin S. , Ozet A. , Cetin T. , Kuzhan O. , Ozturk B. , Kilic S. , Komurcu S. , Guler T. , Budakoglu B.
Published: August 2020

7099

Background: 10 microg/kg/day of filgrastim and lenograstim have been recommended for mobilization of CD34+ cells without associated chemotherapy. However,in our previous randomized study we demonstrated that a 7.5 microg/kg/day dose of lenograstim has been as efficacious as 10 microg/kg/day of filgrastim. In this study, we investigated whether a reduced dose of lenograstim is equavalent to standard dose for autologous peripheral blood stem cell (PBSC) mobilization and transplantation. Methods: A total of 49 consecutive patients were randomized to either low dose (7.5 microg/kg/day, n = 24) or standard dose (10 microg/kg/day, n = 25) of lenograstim. These two groups were similar in regard to disease, sex, body weight, body surface area, conditioning regimens, previous chemotherapy cycles and radiotherapy. Each dose of lenograstim was administered for 4 consecutive days. The first PBSC apheresis was done on the 5th day. In the posttransplant period, lenograstim was given at 5 microg/kg/day until leukocyte engraftment. Results: Successful mobilization with the first apheresis, was achieved in 10/24 (42%) patients in low dose group versus 14/25 (56%) patients in standard dose group. No significant difference was seen in the median number of CD34+cells mobilized, as well as the median number of apheresis, median volume of apheresis, percentage of CD34+ cells, and CD34+ cell number. Leukocyte and platelet engraftments, the number of days requiring G-CSF and parenteral antibiotics, the number of transfusions were similar in both groups in the posttransplant period. Conclusions: Lenograstim 7.5 microg/kg/day is as efficious as Lenograstim 10 microg/kg/day for autologous PBSC mobilization and transplantation.

No significant financial relationships to disclose.
Impact of number of resected and involved lymph nodes (LN) at the time of surgical resection on the survival of non-small cell lung cancer (NSCLC)
Authors: Saji H. , Tsuboi M. , Miyajima K. , Shimada Y. , Ohira T. , Ikeda N.
Published: August 2020

7514

Background: Total number of lymph-nodes has recently proven prognostic in early breast and colorectal cancer. In this study we retrospectively evaluated the prognostic impact of the number of resected and involved lymph-nodes on the survival of stage I-III NSCLC. Methods: A series of 928 consecutive NSCLC pts who underwent complete lobectomy, bilobectomy or pneumonectomy with lymph-nodes dissection from 1/2000 to 11/2007 at Tokyo Medical University was eligible. Log rank and Cox proportional hazard model was used to estimate survival rates and relative risks. Results: Demographics are as follows: median age: 65.0 (22–87yrs), sex: 547 males and 381 females, median follow-up time: 2.5 yrs, clinical stage: 765 stage I, 84 stage II and 76 stage III, histology: 684 adenocarcinoma, 182 squamous cell carcinoma, and 62 others, operation: 870 lobectomy, 42 bilobectomy and 16 pneumonectomy, mean number of resected LN: 15 (1–49), mean number of involved LN: 0.9 (0–22). We observed a statistically significant increasing trend in overall survival (OS) between 0–3 and 4 and more of number of involved LN (P<0.001). Although a significant increasing in OS of 0–9 of number of resected LN cases compared with 10 and more was observed in all stages (P=0.024), no significant differentiation was observed in clinical stage I cases. Conclusions: This data suggests that there is a significant decrease in OS with 10 and more number of resected LN examined at surgery in NSCLC pts. However, there is no significant different in stage I pts, which implies that selected LN sampling is enough in clinical stage I cases. Further study such as LN dissection vs LN sampling in clinical stage I will be needed.

No significant financial relationships to disclose.
CALGB 140803—Association between cardiorespiratory fitness and overall survival in operable lung cancer patients: Ancillary analysis of protocol 9238
Authors: Kohman L. , Watson D. , Herndon J. , Eves N. , Haithcock B. , Loewen G. , Jones L.
Published: August 2020

7518

Background: Cardiorespiratory fitness is a well-established independent predictor of all-cause mortality in a broad range of adult populations. The association between cardiorespiratory fitness and mortality has not been investigated among individuals diagnosed with cancer. We examined the association between cardiorespiratory fitness and all-cause mortality in 398 patients with non-small cell lung cancer (NSCLC). Methods: Using a prospective, observational design, patients with known or suspected NSCLC enrolled in CALGB 9238 were studied. Prior to pulmonary resection, all participants performed an incremental exercise test with expired gas analysis to assess cardiorespiratory fitness (i.e., peak oxygen consumption; VO2peak) and were observed for death or until June 2008. Cox proportional hazards models were used to estimate the risk of all-cause mortality according to cardiorespiratory fitness category defined by VO2peak (<0.96 / 0.96–1.29 / >1.29 L.min-1) with adjustment for age, gender, and performance status. Results: Of the 398 patients, 335 underwent surgical resection and 63 were deemed not eligible for resection. Median follow-up was 30.8 months, 294 deaths were reported during this period. For the entire sample, mortality rates declined across increasing VO2peak categories (adjusted Ptrend= 0.012). Compared with patients achieving a VO2peak <0.96 L.min-1, the adjusted hazard ratio (HR) for all-cause mortality was 0.64 (95% CI, 0.46 to 0.88) for a VO2peak of 0.96–1.29 L.min-1, and 0.56 (95% CI, 0.39 to 0.80) for a VO2peak of >1.29 L.min-1. The corresponding HRs for surgical patients were 0.65 (95% CI, 0.44 to 0.96) and 0.62 (95% CI, 0.42 to 0.90) relative to the lowest VO2peak category (ptrend=0.03), respectively. For non-surgical patients, the HRs were 0.74 (95% CI, 0.32 to 1.75) and 0.43 (95% CI, 0.18 to 1.00) relative to the lowest category (ptrend<0.04). Conclusions: Low VO2peak is associated with poorer survival among surgical candidates with NSCLC. Further work is required to investigate the prognostic value of objective measures of functional capacity in NSCLC and other cancer populations.

No significant financial relationships to disclose.
Biomarker analysis from completely resected NSCLC patients enrolled in an adjuvant erlotinib clinical trial (RADIANT)
Authors: Richardson F. , Richardson K. , Sennello G. , Young D. , Orlov S. , Pápai-Székely Z. , Keshavjee S. , Kim J. , Cerfolio R. , Shepherd F. A.
Published: August 2020

7520

Background: RADIANT is a phase III trial comparing erlotinib 150 mg daily vs. placebo (2:1) in stage IB-IIIA NSCLC patients with EGFR-positive tumors (IHC and/or FISH), following complete surgical resection. Planned accrual is 945 patients. Correlative biomarker studies on primary tumor tissue, whole blood, and serum are key components of the study. Methods: Tumor tissue was evaluated by IHC for protein expression of EGFR (PharmDx Kit, Dako with + ≥ 1% positive tumor cells), by FISH for gene expression of EGFR (Vysis, Abbott), and by Wave HS for EGFR and Kras mutations. Results: Among 655 tissue samples analyzed, 96% were EGFR IHC+ and 74% EGFR FISH+. Of the 476 tissue samples analyzed to date for mutations (mut), 12% had activating EGFR and 19% had Kras mut. Preliminary comparisons suggest that EGFR mut rate increased while Kras mut rate decreased with tumor stage. EGFR mut occurred in 29/178 (16%) females (F) vs. 23/271 (8%) males (M), 19/57 (33%) Asians (A) vs. 33/392 (8%) non-Asians (NA), and 29/66 (44%) never smokers (NS) vs. 23/383 (6%) current or former smokers (S). The differences between A vs. NA and NS vs. S were significantly different (P <0.0001) for all comparisons made. Kras mut occurred in 40/180 (22%) F vs. 48/280 (17%) M, 4/57 (7%) A vs. 84/403 (21%) NA, and 3/68 (4%) NS vs. 85/392 (22%) S. The difference between A vs. NA and NS vs. S were significantly different (P ≤0.0389) for all comparisons made. In adenoca, 51/254 (20%) had EGFR and 79/261 (30%) had Kras mut, and in SCC, 0/157 (0%) had EGFR and 3/162 (2%) had Kras mut. One tumor sample demonstrated both an activating EGFR and Kras mut. Conclusions: Ongoing comprehensive biomarker assessment in the RADIANT population indicates successful sample collection and analysis. FISH positivity rates are greater than observed in late-stage tumors. Remaining results in this early-stage population are consistent with those observed in advanced-stage disease. Once complete, this study will provide a robust biomarker dataset on which to evaluate predictive and prognostic response markers, which may help determine who may benefit from treatment with erlotinib in the adjuvant setting.

[Table: see text]
Randomized trial of adjuvant chemotherapy (Cx) with cisplatin plus gemcitabine (CG) versus cisplatin plus docetaxel (CD) in patients (pts) with completely resected non-small cell lung cancer (NSCLC) with quality of life (QoL) as the primary objective
Authors: Barlesi F. , Chouaid C. , Crequit J. , Lecaer H. , Pujol J. , Bérard H. , Vergnenegre A. , Letreut J. , Fabre-Guillevin E. , Loundou A.
Published: August 2020

7532

Background: Adjuvant Cx with vinorelbine plus cisplatin (VC) improves survival of resected NSCLC but has an immediate negative impact on QoL (Bezjak, JCO 2008). In advanced stages NSCLC, GC and DC have comparable efficacy and might be superior to VC in QoL outcomes. This trial was designed to provide with data on other adjuvant Cx regimens for pts with resected NSCLC. Methods: Pts with stage IB to III resected (R0) NSCLC, without major postoperative complication, were eligible. Surgery has to be standardized. Cx consisted of cisplatin (75 mg/m2, D1) plus gemcitabine 1,250 mg/m2 (D1,8) or docetaxel (75 mg/m2 D1) for 3 cycles. The primary endpoint was QoL (EORTC QLQC30) and the trial was designed to detect a 10 points difference in QoL scores (α=0.05; power 80%). Relapse-free survival, overall survival (OS), safety profile and costs were the secondary endpoints. Results: 136 pts (median age: 57 yrs, 74% males, pTNM: 32% IB, 34% II, 34% III; histology: 55% ADC, 23% SCC) were included. 67 and 69 pts were randomized in the GC and DC arms, respectively. Surgery was a (bi)lobectomy in 85% of cases. No imbalance was found between arms regarding major pts characteristics. Overall, a Gr3/4 hematological toxicity occurs for 33.8% and 21.7% of pts (p=0.11) and a Gr3/4 non-hematological toxicity occurs for 33.8% and 26.1% of pts (p=0.33), in the GC and DC arms. Compliance to QoL assessment was good (93%). At inclusion, global health status (GHS) scores (/100) were comparable between arms (mean score, 63.5 and 62.7, in the GC and DC arms, p=0.8). At the end of treatment (3rd month), GHS scores have slightly improve (mean score, 64.5 and 65.4, in the GC and DC arms, p=0.8). At the time of analysis, 15 pts (7 GC, 8 DC) have died. At 1 year, 100 and 96.8% of the pts were alive in the GC and DC arms; At 2 years, 92.9 and 89.8% of the pts were alive in the GC and DC arms (log-rank, p=0.88). Conclusions: Adjuvant GC and DC have comparable effect on post-operative QoL and equivalent efficacy among pts with resected NSCLC. The GC and DC efficacy, safety profiles and QoL outcomes favorably compare with the results reported for the VC regimen. Detailed analyses will be presented at the meeting.

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A phase I study of pemetrexed plus carboplatin or cisplatin with concurrent chest radiation therapy (CRT) for patients with locally advanced non-small cell lung cancer (LANSCLC)
Authors: Heinzerling J. H. , Hughes R. S. , Govindan R. , Bradley J. D. , Schiller J. , Peng G. , Treat J. , Obasaju C. , Tran T. , Choy H.
Published: August 2020

7545

Background: Pemetrexed is a multi-targeted antifolate that inhibits the synthesis of both pyrimidines and purines. Pemetrexed is an effective new chemotherapeutic agent in advanced non-small cell lung cancer. Pemetrexed has also shown preclinical activity as a radiosensitizer in lung cancer. A phase I study was performed to establish the maximum tolerated dose (MTD) and phase 2 dose of carboplatin or cisplatin given with pemetrexed and CRT in LANSCLC. Methods: Patients (pts) with LANSCLC were enrolled. Initial intent was to establish the MTD of both weekly cisplatin and weekly carboplatin in combination with pemetrexed and CRT as an alternating two-arm phase I trial. Subsequently and based on early results from the CALGB 30407 trial (also evaluating the MTD of carboplatin), the protocol was amended to establish the safety of the planned phase II doses of cisplatin and carboplatin combined with pemetrexed 500 mg/m2 and given every 3 weeks with concurrent CRT. Dose limiting toxicity (DLT) was defined as ≥ Grade 3 hematologic or nonhematologic toxicity based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. MTD was determined by occurrence of 2 DLTs among 6 pts in each cohort. Results: 22 pts were enrolled on 3 cohorts. All pts received pemetrexed, 9 with carboplatin AUC=2, 9 with cisplatin 30 mg/m2, and 4 with cisplatin 75 mg/m2. One DLT occurred in each of the carboplatin and cisplatin 30 mg/m2 cohorts, prompting enrollment of 3 additional patients. No DLTs were seen in the cisplatin 75 mg/m2 cohort. Conclusions: The MTD of cisplatin in combination with pemetrexed and CRT was not reached. Based on these results and those from CALGB 30407, either carboplatin AUC=5 or cisplatin 75 mg/m2 in combination with pemetrexed 500 mg/m2 given every 3 weeks with CRT appears to be well tolerated, and are currently being studied in a randomized phase II trial in pts with LANSCLC.

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Phase II study of induction chemotherapy with cisplatin (Cis) and gemcitabine (Gem) followed by concomitant Cis-Gem and thoracic radiation (RTX) for unresectable locally advanced non-small cell lung cancer (LA-NSCLC)
Authors: Driesen P. , Verbeke L. , Lonchay C. , Lambrechts M. , Mentens Y. , Carestia L. , Rosier J. , Colinet B. , Chouaki N. , Kraaij K. J.
Published: August 2020

7550

Background: In the CALGB Study Cis with Gem followed by concomitant chemoradiation for inoperable LA-NSCLC was effective, however with significant toxicity (E. Vokes et al; JCO 20: 2002). The aim of this study was to improve tolerability by reducing the Gem dose during radiotherapy and adding one cycle of induction chemotherapy. Methods: Patients with histological proven stage IIIA and IIIB NSCLC were included in this study from 8/04 to 9/07. All patients were to receive 3 induction cycles (21 days) of Cis 80 mg/m2 d1 plus Gem 1250 mg/m2 over 30 minutes d1, 8. After a 3 weeks rest period, 2 cycles of concomitant chemoradiation Cis 80 mg/m2 d1, Gem 300 mg/m2 d1, 8 and RTX (about 60 Gy; 5 times 1,8 Gy fractions / week) were given. Results: A total of 49 patients, median age 63.4 yrs, 73.5% male, with Karnofsky performance status 80/85/90/100: 16.3% / 2.0% / 49.0% / 32.7% were entered. Disease stage IIIA/IIIB: 28.6% / 71.4%. Median dose intensity during chemoradiation Gem 98.4%, Cis 99.0% and radiation median total dose was 63 Gy. Number of grade 3/4 toxicities during induction chemotherapy (N=49): neutropenia 9/9, thrombocytopenia 4/1. Acute grade 3/4 toxicities during chemoradiation phase (N=31): neutropenia 4/0, thrombocytopenia 5/1, radiation esophagitis 4/0 and radiation pneumonitis 1/0. No toxic death. Tumor Response Rate of enrolled patients was 22 (44.9%) (95% CI: 30.7–59.8). Conclusions: Concurrent Cis Gem chemoradiation after Cis Gem induction is an active treatment for LA-NSCLC with managable toxicity.

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Involved-field radiotherapy for patients with limited small cell lung cancer: Patterns of local-regional failure and feasibility
Authors: Xia B. , Fu X. , Cai X. , Chen G. , Yang H. , Fan M. , Zhao K.
Published: August 2020

7554

Background: To investigate the feasibility of the involved-field radiotherapy in patients with limited-stage small cell lung cancer (LSCLC) according to the patterns of local failure, focused on the first local-regional failure. Methods: Two clinical phase II studies for patients with LSCLC treated at our institute between 1997 and 2007 were reviewed. All patients received combined chemotherapy (CHT) with cisplatin and etoposide, and thoracic RT (TRT) was generally delivered sequentially following one to three cycles of CHT and consisted of either 56 Gy in 40 fractions for 4 weeks or 55 Gy in 22 fractions for 4–5 weeks. TRT fields encompassed primary tumor volume (post-CHT) and the involved nodal areas (pre- and post-CHT) without elective node irradiation. The local-regional failure was defined as failure within thoracic cavity and supraclavicular fossa except for pleural effusion, which was then divided into two subtypes: in-field and out-field failure according to the first occurred site in the planning target volume or not. Results: There were 89 patients completed the planed regimen and eligible for evaluating patterns of failure, 54 patients (57%) in 56 Gy cohort and 35 patients(43%) in 55 Gy cohort. The media cycles of CHT were 6 (4–8). The overall survival and local progression-free survival rates for 89 patients at 2 years were 56% and 71%, respectively, with a median survival of 25.6 months. 56 patients (63%) developed distant metastases and 21 patients (24%) developed local-regional failures: 12 in-field and 9 out-field. 8 out of 9 out-field failures occurred in the ipsilateral supraclavicular fossa, and the media duration to the end of TRT was 6 mouths (5–14). Comparing the 56 Gy and 55 Gy cohorts, the rates of any thoracic, in-field and out-field failures were no difference significantly. Conclusions: Thoracic radiotherapy using involved-field technique in patients with LSCLC resulted in a high failure rate of the supraclavicular fossa. Whether improving accuracy for the initial evaluation of clinical stage could reduce out-field failure in supraclavicular fossa need to be investigated.

No significant financial relationships to disclose.
Varying recurrence rates and risk factors associated with different definitions of local recurrence in patients with surgically resected stage I non-small cell lung cancer
Authors: Medford-Davis L. N. , Varlotto J. , Recht A. , Flickinger J. C. , DeCamp M. M.
Published: August 2020

7583

Background: To examine the effects of different definitions of local recurrence on the reported patterns of failure and associated risk factors in patients undergoing potentially curative resection of Stage I non-small cell lung cancer (NSCLC). Methods: The study included 306 consecutive patients treated from 2000–2005 without radiotherapy. Local recurrence was defined as either: “radiation” (i.e., recurrences confined to the post-operative radiotherapy fields used in the Phase III trial of adjuvant radiotherapy by Trodella et al) (LRR), including the bronchial stump, staple line, the ipsilateral hilum, and ipsilateral mediastinum; or “comprehensive” (LRC), including these sites plus the ipsilateral lung and contralateral mediastinal and hilar nodes. Results: The median follow-up was 33 months. Proportions of LRC and LRR at 2, 3 and 5 years were 14%, 21% and 29%; and 7%, 12%, and 16%, respectively. Significant risk factors for LRC on multivariable analysis were diabetes, lymphatic vascular invasion and tumor size; significant factors for LRR were resection of less than a lobe and lymphatic vascular invasion. Distant (non-local) relapse proportions using these definitions at 2, 3 and 5 years were 10%, 12%, and 18%; and 14%, 19%, and 29%, respectively. Significant risk factors for distant failure were histology when using the LRC definitions and tumor size using the LRR definition. Conclusions: Local recurrence increased nearly two-fold when a broad definition was used, rather than a narrow one. The definition also affected which factors were significantly associated with both local and distant failure on multivariate analysis. Comparable definitions must be used when analyzing different series.

No significant financial relationships to disclose.
Effect of lobectomy on survival in early-stage small cell lung cancer: A retrospective analysis
Authors: Varlotto J. M. , Recht A. , Flickinger J. C. , Dyer A. , Medford-Davis L. , DeCamp M.
Published: August 2020

7585

Background: Small cell lung cancer (SCLC) rarely presents as I/II Disease. In order to assess the incidence, treatment and prognosis of this early-stage SCLC, we used the Surveillance, Epidemiology and End Results database. Furthermore, since some investigators are irradiating growing and/or PET Scan positive nodules without biopsy, presenting characteristics of surgically-resected Stage I SCLC were compared to those of non-small cell lung cancer (NSCLC). Methods: The SEER 17 Database from 1988–2003 was accessed for all patients with early-stage SCLC. Presenting characteristics of surgically-resected Stage I SCLC were compared to those of resected Stage I NSCLC using chi-square and Wilcoxon Rank Sum tests. The logrank test was used to compare the differences in Survival(S) resulting from the various treatments options for early-stage SCLC. Results: 1,615 patients were identified with early-stage SCLC with greater than 3 months of follow-up. The median S was 20 months for the entire group. Over the time period of our study, the incidence of early stage SCLC as a percentage of all SCLCs and all lung cancers (SCLCs and NSCLCs) remained stable and ranged from 3.00–4.96% and 0.09–0.16% respectively. Surgically-resected Stage I SCLC did not differ from NSCLC in regards to patient characteristics (age, sex, race) or tumor location, but SCLC was found to have significantly smaller tumor size (p< 0.0001). Lobectomy or greater resections without radiotherapy were associated with a greater median S than those treated with segmental/wedge resections and those treated with radiotherapy alone (44 vs 29 months, p=0.03 and 20 months, p <0.0001). Furthermore, when lobectomy or greater resection was performed, adjuvant radiotherapy was associated with a shorter, but not significantly different median S (32 vs 44 months, p = 0.17). Segmental/wedge resections without radiotherapy were associated with significantly better S than patients who received radiotherapy alone, but no difference in S was found with the use of adjuvant radiotherapy (29 vs 20 months, p =0.003, and 35 months, p=0.31). Conclusions: The incidence of stage I/II small cell lung cancer was stable over the years of our study. Anatomic lobectomy without adjuvant radiotherapy appears to be the optimal therapy for patients without mediastinal nodal metastases.

No significant financial relationships to disclose.
Sublobar resection with I-125 brachytherapy for early-stage non-small cell lung cancer (NSCLC) using prefabricated mesh
Authors: Manning M. A. , Mohamed M. , Burney D. P.
Published: August 2020

7586

Background: Lobectomy is standard of care for stage I NSCLC, but it reduces pulmonary reserve. Patients with pulmonary dysfunction may tolerate curative wedge resection with a permanent I-125 mesh implant. We report results using this technique with and without a novel prefabricated mesh device. Methods: Between 7/06 and 5/08, 56 patients with clinical stage I NSCLC had wedge resection and brachytherapy. All had PET-CT staging and were ineligible for lobectomy. Median age was 72 (48–87) and median FEV-1 was 1.3 liters (0.6–3.4 liters). At surgery, a significant proportion were upstaged. Pathologic staging confirmed 60.7% to be stage IA and 23.2% stage IB. Others were IIA (3.6%), IIB (5.4%), IIIA (1.8%), IIIB (1.8%), and IV (3.6%). All implants consisted of absorbable polyglactin mesh containing a median of 40 (30–50) I-125 seeds with a median seed activity of 0.536 mCi (0.47 - 0.63 mCi). Half of the patients received mesh prepared intraoperatively, while the second half received patient-specific prefabricated mesh (BrachyMESH - Oncura). Results: The median hospital stay was 5 days. All were immediately extubated. Common toxicities included air leak delaying chest tube removal, leukocytosis, paroxysmal atrial fibrillation, and increased secretions. Two required repeat chest tube placement for subsequent pneumothorax. Two patients with severe pre-op pulmonary dysfunction (pre-op FEV-1 of 0.6 and 0.68 liters) experienced respiratory failure and expired following prolonged hospital stays. With a median follow-up of 7 months (0–23 months), overall survival is 87.5% and disease free survival is 89%. The local control was 96.4% with the intraoperative mesh and 100% with the prefabricated mesh. Conclusions: Wedge resection with permanent I-125 mesh implant is a generally well-tolerated procedure leading to acceptable early local control in patients ineligible for lobectomy. This technique may not be suitable for patients with pre-op FEV-1 < 0.7 liters; but, it provides accurate surgical staging conferring a diagnostic advantage over non-invasive treatment modalities. The prefabricated device offers similar results to manually prepared devices.

No significant financial relationships to disclose.