bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics (PK) and pharmacodynamics (PD) of rituximab administered by faster infusion in patients with previously untreated diffuse large B-cell (DLBCL) or follicular lymphoma (FL).
Authors: Brewster Michael , Hurst Deborah , Chai Akiko , Lee Edward James , Upadhyaya Gargi H. , Dakhil Shaker R.
Published: March 2020

6591

Background: Faster infusion of rituximab (R) can improve patient (pt) convenience and reduce strain on oncology unit resources. To assess the safety, PK and PD of a 90-min infusion rate for R in NHL pts, a prospective, open-label, phase III, multicenter, single-arm trial (RATE) was conducted. Safety results have been previously presented (ASH 2011). Methods: Pts (≥18 yrs old) with untreated DLBCL or FL, without clinically significant cardiovascular disease, received R-chemotherapy. R (375 mg/m2) was given at the standard infusion rate (4–6 h) in Cycle 1. Pts who did not experience Grade 3/4 infusion-related reactions (IRRs) and who had circulating lymphocyte counts ≤ 5000/µl before Cycle 2, received subsequent R (375 mg/m2) infusions at a 90-min rate: 20% over 30 min then 80% over the next 60 min. Pts (n=14) who completed all cycles at the 90-min infusion rate gave further serum samples up to 16 wks after the last cycle for determination of PK parameters, including R terminal half-life (t½), maximum serum concentration (Cmax), systemic clearance (CL) and volume of distribution (V). Results: For pts (n=365) that received the 90-min infusion rate at Cycle 2, serum R concentrations increased over the course of the study. Estimated median values were: CL, 107 ml/d; V at steady state, 3830 ml; t½, 24.6 d. At Cycle 2, 50.5% of pts had undetectable CD19+ levels; this percentage increased during the study (68.3% Cycle 6, 87.5% Cycle 8). Conclusions: Peak R levels were higher than seen in published data of q3w R regimens but comparable with levels seen for q1w R regimens. The estimated median values for CL, V, t½ and B cell (CD19+) depletion with the 90-min infusion rate were similar to previously reported estimates for infusions at the standard rate. These results, in combination with the safety profile previously reported, show that a faster infusion of R can be an acceptable option for selected NHL pts who tolerated the standard infusion rate at Cycle 1 without a severe IRR. [Table: see text]
Azacitidine as induction therapy of elderly patients with acute myelogenous leukemia.
Authors: Khan Cyrus , Rossetti James M. , Hilton Christie , Sadhashiv Santhosh , Khalid Sanaullah , Abid Arifa , Fischer Victoria , Fazal Salman , Sahovic Entezam A. , Shadduck Richard K. , Lister John
Published: March 2020

6620

Background: Effective alternative treatment of elderly patients (aged ≥ 60 years) with acute myelogenous leukemia (AML) remains challenging. Elderly patients with AML respond poorly to standard induction regimens and have high treatment related mortality. In a prior retrospective analysis of elderly patients with AML performed at our institution, azacitidine (AZA) showed an overall response rate (ORR) of 60% with limited toxicity. Methods: This is a prospective, phase II open-label study using AZA in patients ≥60 years with AML. Inclusion criteria: Newly-diagnosed non-M3 AML and ECOG ≤ 2. Patients with circulating blast count ≥30,000/mcl were treated with hydroxyurea until < 30,000/mcl. AZA was administered at 100 mg/m2 subcutaneously for 5 consecutive days every 28 days until disease progression or significant toxicity. Results: In all, 15 patients were enrolled last follow-up being 8/2/11. The mean age of patients is 74 years (range: 64–82). Mean ECOG score was 1. Mean baseline bone marrow blast count was 52% (range: 25–92%). ORR was 46% (n=7) with complete response (CR) in 3 (20%) patients and partial response (PR) in 2 (13%) patients according to NCI response criteria, and hematologic improvement (HI) in 2 (13%) patients according to IWG response criteria. The mean number of days on treatment was 198 (range: 13–724). The mean time to best response among responders was 95 days (range: 44-279). The mean number of days hospitalized for diagnosis plus treatment or disease-related complication was 19 (range: 5–56), with the majority of therapy administered in an outpatient setting. Mean overall survival (OS) from diagnosis for all patients was 355 days (range: 13–908) and mean OS for responders was 532 days (range: 120–908). Non-hematological toxicity was limited to mild injection site skin reaction and fatigue in 73% (11/15). No treatment-related deaths were observed. The dose and schedule of AZA remained constant in a majority of the patients. Conclusions: This study suggests that a 5-day schedule of SC AZA at 100 mg/m2 to elderly patients with newly-diagnosed AML is a feasible, well-tolerated and effective alternative to standard induction chemotherapy.
Association of cytokine levels and reductions in spleen size in COMFORT-II, a phase III study comparing ruxolitinib to best available therapy (BAT).
Authors: Harrison Claire N , Kiladjian Jean-Jacques , Gisslinger Heinz , Passamonti Francesco , Sirulnik L. Andres , Wang Ling , Squires Matthew , Knoops Laurent , Barosi Giovanni , Barbui Tiziano , Cervantes Francisco
Published: March 2020

6625^

Background: Ruxolitinib is a potent and selective oral JAK1/2 inhibitor that has been approved for the treatment of myelofibrosis (MF). Ruxolitinib has demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms and quality of life (QoL) in 2 phase 3 studies (COMFORT-I and –II) in patients (pts) with primary MF (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). This analysis evaluated associations between cytokine levels and spleen size reductions in the COMFORT-II study. Methods: COMFORT-II is a randomized (2:1), open-label, phase 3 study comparing the safety and efficacy of ruxolitinib with BAT. Spleen volume was measured by MRI every 12 weeks and spleen length by palpation at each study visit. Plasma samples were analyzed using Rules Based Medicines Human MAP v1.6; 89 cytokines were measured at BL and wks 4, 24, and 48. Simple linear regression was used to evaluate the correlation between BL or change from BL in cytokine levels with % change of spleen size. Results: In the ruxolitinib arm, association was found between changes in TNF-α and leptin levels and % spleen volume reduction at wk 24 (TNF-α: N = 93; correlation coefficient [R] = 0.43; false discovery rate adjusted P value [P] < .01; leptin: N = 96; R = -0.28; P = .09) and wk 48 (TNF-α: N = 86; R = 0.43; P < .01; leptin: N = 87; R = -0.34; P = .02) that was not observed with BAT and was independent of JAK2V617F status. For ruxolitinib-treated JAK2V617F+ pts, higher leptin levels at BL were associated with greater % spleen length reductions at wk 48 (N = 45; R = -0.44; P = .11). A clear trend was observed for increased leptin levels that preceded weight gain on ruxolitinib treatment. For ruxolitinib-treated JAK2V617F+ pts, decreased IL-8 at wk 4 was associated with % spleen volume reductions at wk 24 (N = 68; R = 0.28; P = .24) and wk 48 (N = 60; R = 0.38; P = .15). Conclusions: This analysis has shown statistically significant associations between changes in cytokine levels and spleen size reductions. Further analysis is in progress to determine associations between cytokine levels and QoL or symptoms and to confirm these observations in an independent data set.
History of autoimmunity to predict clinical response to DNA methyltransferase inhibitors (DNMTI) in myelodysplastic syndromes (MDS), and MDS-derived acute myeloid leukemias (AML).
Authors: Emadi Ashkan , Sadrzadeh Hossein , Patal Payal , Burns Kathleen H. , Duffield Amy , Ballen Karen K. , Amrein Philip C. , Attar Eyal C. , Smith B. Douglas , Fathi Amir Tahmasb
Published: March 2020

6629

Background: MDS is comprised of a heterogeneous group of clonal myeloid disorders. Chronic immune stimulation has been reported as a trigger for the development of a subset of MDS, with increased autoreactive cytotoxic T cells present in the bone marrow. Autoimmunity has been associated with MDS and other marrow failures. DNMTIs, 5-azacytidine and decitabine, are approved for the treatment of MDS. In addition to epigenetic impacts, these agents may have immunomodulatory effects, including augmentation of MAGE-related anti-tumor response. These reports and clinical observations led us to hypothesize that MDS patients with a history of autoimmunity may be more responsive to DNMTIs. Methods: To identify patients with MDS, a retrospective database review (2007-2011) was performed at Johns Hopkins Hospital (JHH) and Massachusetts General Hospital (MGH). The MGH data also included those with AML whose disease had progressed from MDS. Past medical history of autoimmune disorders, diagnosis, blood counts, flow cytometry and cytogenetics were reviewed. Patients with aplastic anemia, paroxysmal nocturnal hemoglobinuria or non-malignant etiologies of cytopenia were excluded. Patients with MDS were further studied if they were treated with DNMTI. Results: Of 137 patients with MDS or MDS/AML, 23 had a documented history of autoimmunity in the medical record. Of these, 15 (65.2%) experienced a response to therapy as defined by the International Working Group. Of 114 patients without a documented history of autoimmunity, 34 (29.8%) achieved a response during therapy, a significantly lower percentage as compared to those with autoimmune conditions (p-value 0.002, t-test). The majority of responding patients with a history of autoimmunity displayed a normal karyotype (9 of 15 patients). Conclusions: A history or co-presence of an autoimmune disorder may predict a high likelihood of achieving a clinical response to DNMTIs. Correlative studies in this unique population of patients with MDS and MDS/AML and prospective clinical studies are needed to improve our understanding of the possible mechanism of action of DNMTIs in these patients.
Phase III trial of concurrent thoracic radiotherapy (TRT) with either the first cycle or the third cycle of cisplatin and etoposide chemotherapy to determine the optimal timing of TRT for limited-disease small cell lung cancer.
Authors: Park Keunchil , Sun Jong-Mu , Kim Sang-We , Ahn Myung-ju , Ahn Jin Seok , Lee Dae Ho , Suh Cheolwon , Ahn Yong Chan , Pyo Hongryull , Choi Eun Kyung , Song Si Yeol , Lee Se-Hoon , Lee Jung Shin
Published: March 2020

7004

Background: Concurrent thoracic radiotherapy (TRT) with chemotherapy has been regarded as optimal treatment for limited-disease small cell lung cancer (SCLC). However, the issue on how early TRT should be commenced is not yet defined. Methods: A total of 219 patients with limited-disease SCLC, who were enrolled from July 2003 to June 2010, received four cycles of cisplatin plus etoposide (cisplatin 70 mg/m2 on day 1 and etoposide 100 mg/m2 on days 1 to 3 every 3 weeks). We randomly assigned these patients to receive concurrent TRT, beginning with the first cycle (initial arm) or the third cycle (delayed arm) of chemotherapy. In both arms, patients received 2.1 Gy once-daily in 25 fractions over a period of five weeks, with a total dose of 52.5 Gy. Patients with partial or complete response were recommended to receive prophylactic cranial irradiation (PCI). Results: Approximately 82% of patients completed planned four cycles of chemotherapy with 52.5 Gy TRT (81.1% and 82.4% in the initial and delayed arm, respectively). After a median follow-up of 4.9 years (range, 1.2 – 8.1 years), the median overall survivals were 24.1 and 26.8 months (P=0.60) in the initial and delayed arm, respectively. Progression-free survival and complete response rates were 12.2 vs. 12.1 months (P=0.94) and 36.0% vs. 38.0% (P=0.77) in the initial and delayed arms, respectively. PCI was given to 49.5% and 55.6% of patients in the initial and delayed arms, respectively (P = 0.37). Febrile neutropenia was significantly more frequent with the initial arm, occurring in 21.6% of patients, as compared with 10.2% in the delayed arm (P = 0.02). All grade esophagitis occurred in 45.0% and 37.0% of the initial and delayed arms, respectively (p = 0.23). Conclusions: TRT (52.5 Gy, once daily) beginning with the third cycle of chemotherapy showed comparable survival outcomes and complete response rates with TRT beginning with the first cycle of chemotherapy, with a lower frequency of febrile neutropenia.
Prognostic and predictive effects of KRAS mutation subtype in completely resected non-small cell lung cancer (NSCLC): A LACE-bio study.
Authors: Shepherd Frances A. , Bourredjem Abderrahmane , Brambilla Elisabeth , Domerg Caroline , Douillard Jean-Yves , Filipits Martin , Graziano Stephen L. , Hainaut Pierre , Janne Pasi Antero , Le Chevalier Thierry , Le Teuff Gwenael , Pignon Jean-Pierre , Pirker Robert , Seymour Lesley , Soria Jean-Charles , Taron Miquel , Tsao Ming Sound ,   LACE-Bio Collaborative Research Group
Published: March 2020

7007

Background: We reported previously that KRAS is weakly prognostic and not significantly predictive of benefit from adjuvant chemotherapy (ACT) in NSCLC (Tsao et al. Proc ESMO 2012, Abst 4217). In colorectal cancer (CRC), KRAS mutation predicts resistance to EGFR monoclonal antibodies, but recent reports suggest that this may not be true for all mutation subtypes (De Roock et al. JAMA 2010). Smoking-related KRAS mutations in NSCLC differ from those of CRC. To explore the influence of KRAS mutation subtype, we undertook an analysis of KRAS subtype in LACE-Bio. Methods: KRAS mutation was determined in blinded fashion in 3 laboratories by direct sequencing. Exploratory analyses were performed to identify relationships between mutation status and subtype, overall (OS) and disease-free survival (DFS) using a Cox model stratified by trial and adjusted for covariates. Results: KRAS subtype was available in 1,532 patients (756 observation [OBS], 776 ACT). There were 300 mutations (275 codon 12, 24 codon 13, 1 codon 14). In the OBS arm, there was no difference in prognosis for OS for codon 12 (Hazard Ratio [HR] mutation v wild-type [WT] KRAS 1.04, CI .77-1.4) or codon 13 (HR 1.01, CI 0.47-2.17) mutations. A trend for benefit from ACT was observed in WT (HR ACT v OBS 0.89 CI 0.76-1.04, p=0.15) but not in patients with codon 12 mutations (HR 0.95, CI .67-1.35, p=0.77). In patients with codon 13 mutations, chemotherapy was deleterious (HR 5.78, CI 2.06-16.2, p<0.001), test for equality among 3 HRs p=0.002. Results were similar for DFS. Among codon 12 mutations, there was no prognostic effect based on specific amino acid substitution. Patients with G12A or G12R mutations appeared to derive greater benefit from ACT (HR 0.66 p=0.48) compared to those with G12C or G12V (HR 0.94 p=0.77) or G12D or G12S (HR 1.39 p=0.48) or WT, but the differences were not significant (comparison of 4 HRs p=0.76). Conclusions: In this study, patients with KRAS codon 13 mutations had significantly poorer outcomes with ACT. These results require further confirmation and should be interpreted with caution in view of the small number of patients with codon 13 mutations. Supported by unrestricted grants from Sanofi Aventis and LNCC.
Pilot SCAT trial: Spanish customized adjuvant chemotherapy (CT) based on BRCA1 mRNA expression levels (l) in resected stage II-IIIA non-small cell lung cancer (NSCLC) patients (p).
Authors: Sanchez Jose Miguel , Cobo Manuel , Arrabal Rafael , Massuti Bartomeu , Rodriguez Paniagua Jose Manuel , Moran Teresa , Astudillo Julio , Jimenez Ulpiano , Pun Yat Wa , Aguiar Bujanda David , Freixenet Jorge , Gonzalez-Larriba Jose-Luis , Hernando-Trancho Florentino , Gómez-Codina Jose , Penalver Juan-Carlos , Martinez Banaclocha Natividad , Lopez-Vivanco Guillermo , Pac Joaquin , Taron Miquel , Rosell Rafael ,   Spanish Lung Cancer Group
Published: March 2020

7011

Background: Surgical resection is the standard treatment in early stages of NSCLC. Nonetheless, long-term survival rate even after surgical resection is disappointing. Several randomized trials and meta-analyses confirmed the survival benefit of adjuvant cisplatin-based CT for stage II and IIIA. BRCA1 is a component of multiple DNA repair pathways, functions as a molecular determinant of response to cytotoxic chemotherapeutics agents, and is an independent prognostic variable in resected p. Since BRCA1 mRNA expression has been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 expression may provide additional information for customizing adjuvant CT. Methods: Completely resected p with pathological lymph node involvement (N1, N2) received 4 cycles of customized adjuvant CT according BRCA1 l. Low l: gemcitabine-cisplatin, intermediate l: docetaxel-cisplatin, high l: docetaxel. Overall survival (OS) was the primary endpoint. Multivariate analysis for time to relapse (TTR) and survival was performed. Results: Eighty-three p were elegible. Most of the patients were male (83%). Type of surgery: 23% pneumonectomy, and 77% lobectomy or bilobectomy. Fifty-three per cent had low BRCA1 l, 33,7% intermediate l, and 13,3% expressed high l. Most of the tumors with adenocarcinoma histology had low l (71%). With a median follow-up of 41.6 months (m), median TTP for the whole group was 22.9 m (13.4-32.5): 20.3 m for low l, 56.5 m for intermediate l, and 51.9 m for high l (P=0.31). Median OS for the whole group was 63.6 m (33.3-93.9): 55 m for low l, and not reached for intermediate and high l (P=0.58). Forty-three p (51.8%) are still alive. Conclusions: Selection of customized CT based on BRCA1 expression l is feasible and could increase time to relapse and survival in resected N1-N2 p. No statistical differences for survival: 55 months for gemcitabine-cisplatin, and not reached for docetaxel-cisplatin and for docetaxel as single agent. Randomized phase III SCAT trial with the addition of a non-pharmacogenomic control arm is ongoing (372 patients included).
Comparison between diameters of the whole nodule and solid area and the proportion of GGO in the tumor shadow on HRCT in predicting less-invasive lung cancer and recurrence after complete resection in patients with clinical N0 NSCLC.
Authors: Matsuguma Haruhisa , Nakahara Rie , Suzuki Haruko , Kasai Takashi , Kamiyama Yukari , Igarashi Seiji , Mori Kiyoshi , Kodama Tetsuro , Yokoi Kohei
Published: March 2020

7021

Background: Prediction of less-invasive lung cancer is important in selecting candidates for limited surgical resection. A greater proportion of ground-glass opacity (%GGO) is well-known to be strongly associated with less-invasive lung adenocarcinoma. Recently, the diameter of the solid area (SolidØ) has been reported to also be a simple and better marker for the same purpose compared to the diameter of the whole nodule (NoduleØ). The aim of this study was to confirm that SolidØ can completely replace %GGO in predicting less-invasive lung cancer. Methods: From 1987 to 2009, 433 patients with clinical T1a-2bN0 NSCLC underwent complete resection, and their preoperative HRCT images were preserved in DICOM format. NoduleØ and SolidØ were precisely measured using software. %GGO was calculated using the method we previously published (Eur J Cardiothorac Surg 25:1102-6, 2004). Less-invasive lung cancer was defined as having no vascular, lymphatic, nor pleural invasion. We compared the three parameters with regard to predicting less-invasive lung cancer and recurrence. Results: Among the 433 patients, 220 were male, 367 had an adenocarcinoma histology, and 58 experienced recurrence. Table shows percentages and numbers of non-less-invasive lung cancer cases. Among each category of SolidØ, greater %GGO is associated with less-invasive lung cancer. ROC analysis also showed that the area under the curve of %GGO was the highest (0.859, 95% CI 0.824 – 0.893), followed by SolidØ (0.806, 0.767 – 0.846), and NoduleØ (0.671, 0.620 – 0.721). Regardless of SolidØ, no patient with a greater %GGO (> 50%) experienced recurrence. Conclusions: Although SolidØ is a better prognostic indicator of non-invasiveness compared to NoduleØ, %GGO remains important. [Table: see text]
Use of a proliferation-based mRNA signature to predict outcome in early-stage non-small cell lung adenocarcinoma.
Authors: Behrens Carmen , Lombardi Francesca , Wagner Susanne , Fujimoto Junya , Raso Maria G , Spaggiari Lorenzo , Galetta Domenico , Huges Elisha , Reid Julia E. , Sangale Zaina , Swisher Stephen , Kalhor Neda , Moran Cesar , Gutin Alexander , Lanchbury Jerry S. , Kim Edward S. , Barberis Massimo , Wistuba Ignacio I.
Published: March 2020

7023

Background: Adjuvant treatment of patients with early-stage lung adenocarcinoma is based on post-surgical pathological staging and patient performance status. Disparate outcomes within each staging group suggest that additional prognostic markers could improve our understanding of risk-benefit and potentially lead to better treatment decisions. A proliferation-based, mRNA expression profile was applied to public microarray data of surgically treated lung adenocarcinomas and a cohort of FFPE samples to test its potential prognostic utility. Methods: Public expression data (Director’s Consortium, DC) were derived from Affymetrix HG-U133A arrays. Clinical FFPE samples were assayed by quantitative PCR. A cell cycle progression (CCP) score was calculated from the expression average of 31 cell cycle genes normalized by 15 housekeeper genes. The prognostic value of the CCP score to predict stage I and II patient outcomes was evaluated by Cox proportional hazards analysis with disease-related death as the primary outcome measure. Results: In 256 DC cases, the CCP score was a significant predictor of death in univariate (p=0.0001) and multivariate analysis (p=0.001, HR 1.57, 95%CI 1.20-2.05) using age, stage, gender, smoking status and treatment as covariates. Similarly, in a second data set (GSE31210, n=204) the CCP score was highly associated with death (univariate, p=0.001; multivariate analysis, p=0.003, HR 1.81, 95% CI 1.24-2.66). Using quantitative PCR, the signature was applied to 381 FFPE samples with a median follow-up of 5 years collected at the MD Anderson Cancer Center and the European Institute for Oncology. In the presence of clinical covariates (as above and tumor size and pleural invasion), the CCP score remained the most significant predictor of death in univariate (p=0.0003) and multivariate analysis (p=0.007, HR 1.50, 95% CI 1.11-2.02). Conclusions: A 46 gene mRNA signature is a significant predictor of disease-related death in early-stage lung adenocarcinoma, providing independent prognostic value in the presence of clinical variables. This molecular predictor of cancer survival will be studied in additional cohorts for its ability to impact clinical treatment decisions.
Predictors of survival after resections of synchronous lung cancers located in mutiple lobes: A multi-institutional pooled analysis.
Authors: Tanvetyanon Tawee , Finley David J. , Fabian Thomas , Riquet Marc , Voltolini Luca , Fulp William J , Kocaturk Celalettin , Park Bernard J. , Robinson Lary
Published: March 2020

7024

Background: Surgical resection is a treatment option for patients with multiple primary lung cancers. However, for synchronous disease, it is often difficult to differentiate this condition from metastatic disease, especially when cancers are distributed in multiple lobes or in both lungs. Some people believe that surgery should be avoided when patients have bilateral cancers or when all cancers have the same histology. To date, however, available evidences are limited by small sample size. Methods: Studies (published 2008-2011) of curative resection for patients with synchronous (< 2-year interval) multiple lung cancers located in ≥ 2 lobes, but without radiographic evidence of distant metastasis, were identified from literature. Corresponding authors were contacted and individual patient data were obtained. Patients with multiple cancers, but localized only to one lobe, were not included. Databases were pooled and multi-variable Cox Proportional Hazard models were fit to adjust for confounders. Results: There were 467 patients included from 6 studies. Median overall survival was 52.0 months (95% CI: 45.6-63.7). Postoperative (30-day) mortality rate was 1.9%. In a multivariable model, study site or having pneumonectomy did not independently impact on survival. However, age, gender, nodal stage, tumor location, and histological similarity were independent predictors of survival. Advanced age increased mortality (p=0.012). Male sex increased mortality compared with female: HR 1.64 (95% CI: 1.23-2.19, p=0.0008). N2 or N1 increased mortality over N0: HR 1.85 (95% CI 1.29-2.66, p=0.0008) and 1.97 (1.43-2.73, p=0.0001), respectively. Unilateral location increased mortality over bilateral location: HR 1.62 (95% CI 1.23-2.13, p=0.0002). Different histology increased mortality over similar histology: HR 1.45 (95% CI 1.11-1.90, p=0.0069). Conclusions: In this largest multi-institutional database of resected multiple lung cancers of multiple lobes to date, we found no evidence of inferior survival among patients having bilateral cancers or having all cancers with the same histology. In fact, the survival among such patients appears superior to their counterparts.
Randomized phase III study comparing etoposide and cisplatin (EP) with irinotecan and cisplatin (IP) following EP plus concurrent accelerated hyperfractionated thoracic radiotherapy (EP/AHTRT) for the treatment of limited-stage small-cell lung cancer (LD-SCLC): JCOG0202.
Authors: Kubota Kaoru , Hida Toyoaki , Ishikura Satoshi , Mizusawa Junki , Nishio Makoto , Kawahara Masaaki , Yokoyama Akira , Imamura Fumio , Takeda Koji , Negoro Shunichi , Harada Masao , Okamoto Hiroaki , Yamamoto Nobuyuki , Shinkai Tetsu , Sakai Hiroshi , Matsui Kaoru , Nakagawa Kazuhiko , Shibata Taro , Saijo Nagahiro , Tamura Tomohide ,   Japan Clinical Oncology Group
Published: March 2020

7028

Background: Four cycles of EP plus AHTRT is the standard treatment for LD-SCLC. IP demonstrated statistically significant overall survival (OS) improvement compared to EP for extensive-stage SCLC (JCOG9511; Noda, et al.NEJM, 2002). EP plus AHTRT followed by 3 cycles of IP is feasible with acceptable toxicities for LD-SCLC (Kubota, et al. CCR,2005). Methods: Eligibility criteria included patients with previously untreated LD-SCLC with measurable lesion, ECOG PS of 0-1, age: 20=<, =<70 years old. Eligible patients received one cycle of EP (etoposide 100 mg/m2 on days 1-3 and cisplatin 80mg/m2 on day 1) plus AHTRT (1.5 Gy b.i.d. total 45 Gy/3 weeks). Patients who achieved CR, good PR, PR or SD with induction EP/AHTRT were randomized to receive either 3 cycles of consolidation EP or IP (irinotecan 60 mg/m2 and cisplatin 60 mg/m2 on days 1, 8, 15). Patients with CR or good PR after consolidation chemotherapy received prophylactic cranial irradiation. The primary endpoint is OS after the randomization. The planned sample size for randomization is 250 with a one-sided alpha of 2.5% and at least 70% power to detect a difference between gruops, 30% in EP versus 42.5% in IP group in 3-year survival. Results: From Sep 2002 to Sep 2006, 281 patients from 36 institutions were registered. After the induction EP/AHTRT, 258 patients were randomized to consolidation EP (n=129) or IP (n=129). Patient demographics were well balanced between the two groups. At the final analysis, the superiority of IP in OS was not demonstrated (hazard ratio of IP to EP, 1.085 [95%CI: 0.80-1.46]; one sided p=0.70, stratifield log-rank test). Grade 3/4 neutropenia (95%/78%), anemia (35%/39%), thrombocytopenia (21%/5%), neutropenic fever (17%/14%), diarrhea (2%/10%) were observed in EP and IP groups, respectively. Conclusions: EP plus AHTRT followed by 3 cycles of IP failed to demonstrate survival advantage over 4 cycles of EP plus AHTRT which still is the standard treatment for LD-SCLC. [Table: see text]
Predictors for locoregional recurrence for clinical stage III-N2 non-small cell lung cancer with nodal downstaging after induction chemotherapy and surgery.
Authors: Lou Feiran , Amini Arya , Correa Arlene M , Baldassarre Randall L , Rimner Andreas , Roth Jack A. , Swisher Stephen , Huang James , Vaporciyan Ara A. , Lin Steven H.
Published: March 2020

7043

Background: Pathologic downstaging following induction chemotherapy in patients with stage III-N2 NSCLC is a well-known positive prognostic indicator. However, the predictive factors for locoregional recurrence (LRR) in these patients are largely unknown. Methods: Between 1998-2008, 153 patients with clinically or pathologically-staged III-N2 NSCLC from two cancer centers in the United States were treated with induction chemotherapy and surgery. All patients had pathologic N0-1 disease, and no one received postoperative radiotherapy. LRR were defined as disease recurrence at the surgical site, lymph nodes (levels 1-14 including supraclavicular) or both. Overall survival (OS) was calculated using the Kaplan and Meier method and comparisons were made using the log-rank test. Univariate and multivariate Cox proportional hazards model were used to assess the association of LRR and risk factors. Results: The median follow up time for survivors was 39.3 months. Baseline pretreatment N2 nodal involvement was staged by either pathologic confirmation (18.2%) or PET/CT (81.8%). Overall, the 5 year LRR rate was 30.8% (n=38), with LRR being the first site of failure in 51% (22 of 43). The 5 year OS for patients with LRR compared to those without was 21% versus 60.1%, respectively (p<0.001). Using multivariate analysis, significant predictor for LRR was pN1 versus pN0 disease at time of surgery (p<0.001, HR 3.43, 95% CI 1.80-6.56) and trended for squamous histology (p=0.072, HR 1.93, 95% CI 0.94-3.98). The 5-year LRR rate for N1 versus N0 disease was 62% versus 20%, respectively. Neither single versus multistation N2 disease (p=0.291) nor initial staging by mediastinoscopy versus PET/CT (p=0.306) were predictors for LRR. We found that N1 status was also predictive for higher distant recurrence rate (p=0.021, HR 1.91, 95% CI 1.10-3.30) but only trended for poorer OS (p=0.123, HR 1.48, 95% CI 0.90-2.44). Conclusions: LRR remains high in resected stage III-N2 NSCLC patients after induction chemotherapy and nodal downstaging, particularly in patients with persistent N1 disease. Postoperative radiotherapy may be needed for these high-risk patients.
A phase II trial of induction gefitinib monotherapy followed by cisplatin-docetaxel and concurrent thoracic irradiation in patients with EGFR-mutant locally advanced non-small-cell lung cancer (LA-NSCLC): LOGIK0902/OLCSG0905 intergroup trial.
Authors: Hisamoto Akiko , Sasaki Jiichiro , Takigawa Nagio , Shioyama Yoshiyuki , Kishimoto Junji , Takemoto Mitsuhiro , Hotta Katsuyuki , Tanimoto Mitsune , Ichinose Yukito , Kiura Katsuyuki ,   Lung Oncology Group in Kyushu and Okayama Lung Cancer Study Group
Published: March 2020

7045

Background: We previously reported efficacy and safety of cisplatin-docetaxel and concurrent thoracic radiotherapy (TRT) for LA-NSCLC (Segawa Y and Kiura K. JCO 2010). However, its cure rate remains unsatisfied, and further improvement in the treatment outcome is strongly warranted. Recently, systemic chemotherapy has been individualized by intensive anti-cancer researches through the discovery of certain molecular targets in the metastatic NSCLC. Especially, gefitinib, EGFR tyrosine kinase inhibitor, is quite active and now one of the standard chemotherapy for untreated metastatic EGFR-mutant NSCLC (Maemondo M and Inoue A. NEJM 2010). Even in the locally advanced setting, approximately 30% of Japanese NSCLC patients possess EGFR-mutant tumors. Given all of these backgrounds, investigation on the role of adding gefitinib monotherapy to the standard concurrent chemoradiotherapy might cause a new paradigm shift in this setting. Methods: Patients have to meet the following eligibility criteria: LA-NSCLC; active tumor EGFR mutations (exons 19 and 21) but without 790M; measurable lesions; performance status (PS) of 0 or 1; age < 75 years; and V20 ≤ 35%. The primary endpoint is set as 2-year progression-free survival (PFS) rate; assuming that 75% in eligible patients would indicate potential usefulness, whereas 60% would be the lower limit of interest (α = 0.05, ß = 0.20), the estimated accrual number is 46 patients. The secondary endpoint includes toxicity, response rate and overall survival. Patients will receive the induction treatment, specified as gefitinib monotherapy (250 mg/body) for 8 weeks. Patients who have not progressed during the induction therapy will receive cisplatin and docetaxel (40 mg/m2; days 1, 8, 29, 36, each) and concurrent three-dimensional conformal TRT (2-Gy, single, daily fractions for 5 consecutive days each week to provide a total dose of 60 Gy). Enrollment began in 2010, and will complete by 2015. UMIN registration number of 000005086.
5-day dosing schedule of temozolomide in relapsed sensitive or refractory small cell lung cancer (SCLC) and methyl-guanine-DNA methyltransferase (MGMT) analysis in a phase II trial.
Authors: Drilon Alexander Edward Dela Cruz , Kyuichi Kadota , Huberman Kety H , Sima Camelia S. , Fiore John Joseph , Yu Helena Alexandra , Varghese Anna M. , Sumner Dyana K. , Travis William D , Heguy Adriana , Ginsberg Michelle S. , Holodny Andrei , Chan Timothy An-thy , Rizvi Naiyer A. , Azzoli Christopher G. , Riely Gregory J. , Kris Mark G. , Krug Lee M. , Pietanza Maria Catherine
Published: March 2020

7052

Background: MGMT promoter methylation and loss of MGMT activity are associated with improved sensitivity to alkylating agents. We recently reported that the oral alkylating agent temozolomide is active in 2nd- and 3rd-line treatment of relapsed SCLC at 75mg/m2/day for 21 out of 28 days (Pietanza et al, Clin Can Res 2012). Here we evaluate the 5-day dosing schedule of temozolomide in a second cohort of patients and analyze MGMT activity in both cohorts of patients on the same study. Methods: Patients with disease progression after 1 or 2 prior chemotherapy regimens received temozolomide at 200mg/m2/day for 5 out of 28 days (n=25). Those with sensitive (S-SCLC, n=16) and refractory (R-SCLC, n=9) disease were enrolled to assess safety. Available tumor tissue from patients treated according to either schedule was assessed for MGMT promoter methylation status by PCR and MGMT expression by immunohistochemistry (IHC). Results: An overall response rate of 12% was noted (3 partial responses: 1 S-SCLC, 2 R-SCLC). 4 patients had stable disease for at least 3 cycles. Median progression-free survival and overall survival for all patients were 1.3 months and 7.9 months, respectively. Grade ≥3 thrombocytopenia and neutropenia was observed in 20% with a shorter mean duration of myelosuppression compared to the 21-day schedule. Results from MGMT evaluation of tumor samples from both dosing schedules were combined. Promoter methylation of MGMT was not significantly associated with response (p=0.23). However, patients that lacked MGMT expression by IHC had a higher response rate compared to those with MGMT-positive tumors (43% vs. 13%, p = 0.052; see table). Conclusions: The 5-day dosing schedule of temozolomide is both active and safe in patients with relapsed SCLC. A strong trend toward increased response was demonstrated in patients with MGMT-negative tumors compared to patients with MGMT-positive tumors by IHC. A trial combining temozolomide with the PARP inhibitor, ABT888, is planned. [Table: see text]
Prognostic role of FOXP3/CD4 ratio in resectable NSCLC.
Authors: Usó Marta , Sirera Rafael , Jantus-Lewintre Eloisa , Sanmartin Elena , Gallach Sandra , Blasco Ana , Martinez Nieves , Hernando Cristina , Figueroa Santiago , Rolfo Christian Diego , Martorell Miguel , Guijarro Ricardo , Camps Carlos
Published: March 2020

7058

Background: Tregs play a critical role in immune tolerance to tumor cells and have been related to prognosis. The aim of this study was to determine the expression of Tregs makers genes by RT-PCR and to correlate them with clinico-pathological and prognostic variables in NSCLC. Methods: RNA was isolated from frozen lung specimens (tumor and normal lung) from resectable NSCLC patients (n=175). RT-PCR was performed to analyze the expression of: CD4, CD8A, CTLA-4, FoxP3, IL-10, CD25, CD127 and TGFβ-1. Relative expression was normalized by an endogenous gene (GUSB) using the Pfaffl formulae. Statistical analyses were considered significant at p<0.05. Results: Tumor samples had significantly lower expression of CD127 (x0.45) and a tendency toward higher expression of CD25 (x1.81), FoxP3 (x1.57) and CTLA-4 (x1.53) compared to normal lung tissues, reflecting a Treg phenotype infiltrating the tumor. Survival analyses revealed that patients with higher FoxP3 expression had reduced OS (median 29.8 vs 67 months, p= 0.026). We also found that those patients with high levels FoxP3/CD4 ratio had worse TTP and OS (median 22.1 months vs NR, p= 0.021 and 29.8 vs NR months, p=0.003, respectively). A multivariable Cox regression model for TTP and OS was built using variables that were found significant in the univariate analysis (nodal involvement, histology, tumor size, PS, and FoxP3/CD4 ratio). This analysis revealed that FoxP3/CD4 ratio was an independent prognostic marker for both TTP and OS (see table). Conclusions: FoxP3 is a transcription factor necessary and sufficient for induction of the immunosuppressive functions in Tregs. In concordance, our results indicate that higher levels of FoxP3/CD4 ratio in tumor samples is a poor prognostic markers for TTP and OS. Furthermore, the multivariable COX regression analysis showed that FoxP3/CD4 ratio is an independent prognostic marker. Therefore, this ratio could be used as a new biomarker of prognosis in resectable NSCLC. Supported by grants PS09-01149 and RD06/0020/1024 from ISCIII. [Table: see text]
A systematic analysis of high-dose radiation in the treatment of surgically unresectable, locally advanced non-small cell lung cancer.
Authors: Behera Madhusmita , Beitler Jonathan Jay , Bhimani Chandar , Higgins Kristin , Chen Zhengjia , Kim Sungjin , Deng Xingming , Curran Walter J. , Khuri Fadlo Raja , Ramalingam Suresh S. , Owonikoko Taofeek Kunle
Published: March 2020

7059

Background: The 5-year survival rate for locally advanced non-small cell lung cancer (NSCLC) is < 25% with concomitant chemoradiotherapy. High-dose radiation appears to confer additional benefit based on surrogate endpoints from relatively small clinical trials. However, survival advantage of higher-dose radiation delivered by conventional fractionation of 1.8-2 Gy is unclear. We conducted a systematic review of pooled outcome data from published results of studies that evaluated the role of high-dose radiation in the management of locally advanced NSCLC. Methods: A detailed search of published clinical trials was conducted using computerized databases (MEDLINE, EMBASE, Cochrane library) and meeting proceedings. Single arm studies using high dose (>66Gy) or randomized trials of high versus standard radiation dose (60-63Gy) for locally advanced NSCLC were selected. A systematic analysis of extracted data was performed using Comprehensive Meta Analysis (Version 2.2.048) software under the random effect model. Clinical outcome in patients treated with high versus standard radiation dose was compared using point estimates for weighted values of median overall survival (OS), progression free survival (PFS), and response rate (RR). Treatment-related toxicities data between the two arms was compared using T-test and chi-square test. Results: Analytic data was retrieved from the results of 44 eligible studies reported between 1994 and 2012. The studies enrolled 3699 patients, 62% males, 2095 and 1604 treated with standard and high dose radiation respectively. The weighted median age was 63 and 61 years (p=0.66) for standard and high dose patients respectively. The weighted median OS was 19.1 vs. 16.4 months (p= 0.97); weighted RR of 76% vs. 70% (p=0.79) and survival rates after up to 3 years of follow up of 39% vs. 46% (p=0.45) for standard and high dose arms respectively. There was no significant difference in the rate of grade ≥3 toxicities between the two treatment groups. Conclusions: High-dose radiation therapy does not result in improved survival over standard radiotherapy dose in patients with locally advanced NSCLC.
SOX2 and FGFR1 gene copy number in surgically resected non-small cell lung cancer (NSCLC).
Authors: Toschi Luca , Finocchiaro Giovanna , Nguyen Teresa T. , Skokan Margaret , Giordano Laura , Gianoncelli Letizia , Perrino Matteo , Siracusano Licia , Destro Annarita , Infante Maurizio , Alloisio Marco , Terracciano Luigi , Roncalli Massimo , Santoro Armando , Varella-Garcia Marileila
Published: March 2020

7061

Background: SOX2 is a member of the SRY-related HMG-box family of transcription factors and has been shown to be frequently amplified and overexpressed in squamous cell lung cancer, with conflicting results regarding its prognostic relevance. Similarly, FGFR1, a transmembrane tyrosine kinase receptor belonging to the fibroblast growth factor receptor family, has been recently reported to be amplified in squamous cell lung carcinomas, suggesting a potential role for FGFR1 as a therapeutic target in NSCLC. Aim of the present study is to evaluate SOX2 and FGFR1 gene copy number in surgically resected NSCLCs, to investigate their prognostic relevance and their association with clinico-pathological characteristics. Methods: SOX2 and FGFR1 gene copy number was assessed by fluorescence in situ hybridization (FISH) in tissue microarray cores from 447 surgically resected NSCLCs. Each patient was given a score ranging from 1 to 6 according to increasing mean copy number per cell of each gene, with 6 indicating true gene amplification. Results: SOX2 and FGFR1 FISH was successfully performed in 445 patients (pts), which were grouped as + (score 5-6) and - (score 1-4). Using this scoring system 105 (23.6%) pts tested SOX2+, while 74 (16.6%) pts resulted FGFR1+. True gene amplification for SOX2 and FGFR1 was observed in 19 (4.3%) and 37 (8.3%) cases, respectively. SOX2+ and FGFR1+ status was significantly associated with squamous histology (p<.001). Additionally, SOX2+ pts had a significantly higher chance of being former/current smokers, male and FGFR1+. FGFR1 gene status had no prognostic impact in the whole population and in the squamous cell carcinoma subgroup. Conversely, SOX2+ pts had significantly longer overall survival compared with SOX2- pts (HR 0.68, p=.020). When restricting survival analysis to squamous cell histology, stage I-II SOX2+ pts had a significant survival advantage compared with SOX2- group (HR 0.38, p=.006), while no difference was observed in stage III-IV pts. Conclusions: Increased SOX2 and FGFR1 gene copy number is a common event in lung cancer pts with squamous cell histology. SOX2 gene gain is a favorable prognostic factor in surgically resected pts, particularly in early stage squamous cell cancers.
Survival following segmentectomy and lobectomy for stage I non-small cell lung cancer.
Authors: Smith Cardinale B. , Wisnivesky Juan P.
Published: March 2020

7064

Background: Although lobectomy is considered the standard surgical treatment forstage IA non–small cell lung cancer (NSCLC), limited resections are frequently performed for patients with poor lung function or high operative risk. Recent studies suggest that segmentectomy may be the superior limited resection procedure. The objective of this study was to compare survival among patients with stage IA (≤3cm) NSCLC undergoing lobectomy vs. segmentectomy. Methods: Using the Surveillance, Epidemiology and End Results registry we identified 15,180 cases of stage IA NSCLC that underwent lobectomy or segmentectomy. We used logistic regression to determine propensity scores for patients undergoing segmentectomy based on the patient’s preoperative characteristics. Overall and lung cancer-specific survival of patients treated with lobectomy versus segmentectomy was compared after adjusting, stratifying, or matching patients based on their propensity score. We also performed secondary analyses in subgroups of age (≤70 vs. >70 years) and tumor size ≤2 cm. Results: Overall, 1,200 (8%) patients underwent segmentectomy. Among the entire cohort, analyses adjusting for propensity scores did not demonstrate a difference in outcomes among patients treated with lobectomy versus segmentectomy, (adjusted hazard ratio [HR] for overall survival 1.11, 95% confidence interval [CI]: 0.94 – 1.30 and lung cancer-specific survival 1.11, 95% CI: 0.98 – 1.25). Similarly, secondary analyses showed no difference in overall (HR: 1.12, 95% CI: 0.90 – 1.40) and lung cancer-specific survival (HR: 1.04, 95% CI: 0.88 – 1.24) among patients with tumors ≤2 cm (T1a tumors). For patients ≤70 years of age, no difference in overall survival was observed (HR: 0.97, 95% CI: 0.73 – 1.28); however, a lung cancer-specific survival advantage of lobectomy was observed (HR: 1.19, 95% CI: 1.00 – 1.40). Finally, among those >70 years overall survival (HR: 1.03, 95% CI: 0.87 – 1.22) and lung cancer-specific survival (HR: 1.18, 95% CI: 0. 97 – 1.44) showed equivalence of the two surgical groups. Conclusions: Segmentectomy and lobectomy may lead to equivalent survival rates among patients with stage IA NSCLC. These study findings should be confirmed in prospective studies.
Circulating tumor cell (CTC) as a significant clinical marker in epithelioid-type malignant pleural mesothelioma (MPM).
Authors: Yoneda Kazue , Tanaka Fumihiro , Fukuda Shunichi , Orui Hayato , Hashimoto Masaki , Takuwa Teruhisa , Okumura Yoshitomo , Matsumoto Seiji , Kondo Nobuyuki , Sato Ayuko , Tsujimura Tohru , Tsubota Noriaki , Fukuoka Kazuya , Nakano Takashi , Hasegawa Seiki
Published: March 2020

7080

Background: Circulating tumor cell (CTC) is a surrogate of distant metastasis, and our preliminary study suggested that CTC detected by an EpCAM-based immuno-magnetic separation system (“CellSearch”) was a useful clinical marker in the diagnosis of malignant pleural mesothelioma (MPM) (Tanaka F. et al ASCO 2008). Methods: Patients who presented at our institute to receive pleural biopsy with suspicion of MPM were prospectively enrolled. CTCs in 7.5mL of peripheral blood were quantitatively evaluated with the CellSearch system. Results: Among 136 eligible patients, 104 were finally diagnosed with MPM, and 32 were with non-malignant diseases (NM). CTC was positive (CTC≥1) in 32.7% (37/104) of MPM pts, and in 9.4% (3/32) of NM pts (p=0.011). CTC-count was significantly higher in MPM (range, 0-9) than in NM (range, 0-1; p=0.007). According to a ROC curve analysis, the CTC-test provided a significant diagnostic performance in discrimination between MPM and NM (AUC= 0.623; P=0.036). Among MPM pts, CTC-positivity and CTC-count were significantly increased with tumor progression (p=0.026 and p=0.008, respectively). For all MPM pts, there was no significant difference in overall survival between CTC-positive and negative pts. However, in a planned subset analysis, CTC was a significant factor to predict poor prognosis (median survival time, 8.0 months for CTC-positive pts, and 20.3 months for negative pts; p=0.012) in pts with epithelioid-type MPM in which CTC was exclusively positive; a multivariate analysis confirmed that CTC, along with PS, was an independent prognostic factor (HR=2.38; P=0.006). Conclusions: CTC was a significant diagnostic marker in discrimination between MPM and NM. CTC-positivity was a significant and independent prognostic factor to predict a poor prognosis of epithelioid MPM. [Table: see text]