bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic literature review of processes and challenges in establishing accurate diagnosis of hematologic malignancies.
Authors: Oberthur Johnson Laura , Zarotsky Victoria , Teitelbaum April H.
Published: March 2020

e17017

Background: Multiple tests are often needed to ensure accurate differential diagnosis (DDX) of hematologic malignancies, particularly for rare/complex conditions. Integration of morphology, immunophenotype, cytogenetic, and molecular results present challenges but is critical to determine prognostic parameters and treatment (tx) decisions. Methods: Systematic literature search was performed (PubMed/MedLine, EMBASE, Cochrane Library) for US-based articles in last 10 yrs regarding DDX of myelodysplastic syndrome, myeloproliferative neoplasm, chronic lymphocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma. Results: 35 articles were identified that addressed methods (n=27) and/or accuracy/timing (n=15) of establishing a diagnosis. Diagnostic (dx) ability improved with use of systematic processes/algorithms (ALG), comparative techniques, and harmonization/central review; few ALG were comprehensive. Updates/revisions of disease-specific dx criteria could result in dx change. Accuracy improved with experienced clinicians (disease-specific knowledge), specialized pathologists (vs. generalists), tissue sample type/quality, and ancillary test availability. A pathologist’s dx ability was related to experience with rare/complex histological subtypes. Dx accuracy was often complicated by inconsistent/overlapping clinical presentation and lack of standardized terminology or reproducible results across facilities. Delays were attributed to lack of dx experience and patient’s health insurance type. Impact of dx delay on clinical outcomes was largely not addressed. Conclusions: With shift from morphologic- to genetic/molecular-based approaches, determination of tests done in parallel/reflexively often requires expert input. Impact of delayed dx on clinical outcomes is lacking. Standardized dx processes/ALG, along with access to expert hematopathologist review and interpretation of test results, may lead to earlier and improved dx accuracy and appropriate/timely tx initiation, thereby avoiding consequences of erroneous dx, especially of benign conditions initially dx as malignant.
Leptomeningeal disease as a manifestation of CLL.
Authors: Zaidi Aisha Salman , Burton Eric Christopher , Lotia Mitesh
Published: March 2020

e17019

Background: Chronic Lymphocytic Leukemia is a lymphoproliferative disorder which can have variable course from being indolent to aggressive. Reported annual incidence of Chronic Lymphocytic Leukemia is 3:100000. The most common manifestation is Lymphadenopathy and Leptomeningeal involvement is very rare with only a few reported cases in literature. Methods: This is an observational case report. Results: We report a case of 57 year old White male who presented with CNS disease as his first manifestation of CLL. He reported a 6 week history of cognitive decline with inability to perform complex tasks, difficulty with calculations, word finding trouble, progressive clumsiness of right arm and leg and a weight loss. MRi revealed Left sided Leptomeningeal enhancement. As part of his work up; patient received LP, PET scans, Infectious and autoimmune studies and eventually brain biopsy which initially showed Lymphocytic predominance.On further review by NIH immunohistochemical stains for CD5, CD20 and CD23 were positive on the leptomeningeal and parenchymal lymphocytes. His bone marrow showed CLL involvement both morphologically and immunophenotypically by means of flow cytometric analysis. He was started on treatment with High dose methotrexate and Rituximab and showed remarkable improvement in his cognitive function by the completion of his second cycle. His bone marrow repeat biopsy showed complete remission and no involvement of lymphoma. Conclusions: CLL is an indolent disease and direct CNS invasion is extremely rare. Our case becomes unique in terms of its presentation. It highlights the importance of timely diagnosis and management of leptomeningeal disease in CLL can lead to resolution of neurologic symptoms.
Baby-step chemotherapy as a way to deliver chemotherapy in poor PS small cell lung cancer.
Authors: Noronha Vanita , Patil Vijay , Joshi Amit , Muddu Vamshi , Prabhash Kumar
Published: March 2020

e17500

Background: Majority of patients with SCLC present with advanced stage and poor ECOG performance status. Hence delivery of adequate dose of chemotherapy is compromised. We hypothesized that initial low-dose chemotherapy might improve PS and enable administration of standard-dose chemotherapy, thus extending benefit of chemotherapy to otherwise ineligible patients. Methods: 30 patients with ECOG performance status 2-4 received low-dose chemotherapy consisting of either single agent carboplatin at AUC 2 or an abbreviated course of platinum-etoposide. Patients whose PS improved got full-dose chemotherapy with the standard regimen of platinum-etoposide. Demographic details, toxicity, time to progression and overall survival were analyzed. Univariate and multivariate analysis was performed to determine factors associated with TTP and OS. Results: Median age was 58 years with male predominance. The PS was IV in 9, III in 20 and II in 1 patient. Extensive-stage and limited-stage disease was seen in 24 and 6 patients respectively.15 patients received single-agent carboplatin, 10 patients abbreviated cisplatin-etoposide, 1 patient each cyclophosphamide and cisplatin-etoposide and 3 patients refused chemotherapy. Major grade 3-4 toxicity was mucositis in 1, loose motions in 1 and hyponatremia in 4 patients. There was no grade 3- 4 haematological toxicity. The median number of dose-reduced cycles was 1 and 3 patients received more than 2 cycles. 22 patients were eligible and willing for full-dose chemotherapy. The median time to start of full-dose chemotherapy was 11.5 days (4-26 days). The median number of cycles of standard-dose chemotherapy was 5 (1-6) with 16 completing planned schedule. Grade 3-4 toxicity was neutropenia in 50%, febrile neutropenia in 25%, loose motions in 25% and hyponatremia in 40%. The overall TTP and OS was 182 days and 263 days respectively. Presence of SIADH (p = 0.02) and completion of standard treatment (p = 0.001) had a positive impact on TTP while completion of treatment (p = 0.01) and normal LDH (p = 0.03) had a positive impact on OS. Conclusions: Low-dose chemotherapy is well-tolerated and might help in extending the benefit of standard-dose chemotherapy to otherwise ineligible patients.
Stage III non-small cell lung cancer: Who passes the threshold?
Authors: Palka Magda , Ruiz-Valdepeñas Andrea , Doger de Speville Bernard Gaston , Ibeas Patricia , Perez Callejo David , Almagro Elena , Huelves Miriam , Mendez Miriam , Maximiano Constanza , Provencio-Pulla Mariano
Published: March 2020

e17502

Background: Objective: The objective of the study is to indentify the patients diagnosed of stage III non-small cell lung cancer (NSCLC) in Puerta de Hierro Madrid Hospital (Spain) between 2000 and 2008, who had longer overall survival rates (more than 24 months) and longer time to progression after completing initial treatment. Methods: We revised all cases of NSLC seen in our hospital, and of those, selected 147, the ones diagnosed, treated and followed completely in our hospital. We reviewed the age at diagnosis, initial staging, modalities of treatment received in each case, time to progression, site of development of metastasis, time to relapse and overall survival. The time of monitoring was from date of diagnosis until death date or, until transferral to palliative care clinics. Results: We revised 966 histories of patients, of which 147 were diagnosed stage III, treated and followed in our hospital. Most common hystological type were Epidermoid Carcinomas (54.3% versus 21.7% of adenocarcinomas), and were diagnosed at older ages. 45.6% underwent surgery, most of them (41.2%) were treated before with neoadyuvant chemo or radiotherapy, with a median survival of 32.4 months, with an overall survival interval very wide, from 20 days until more than 8 years. Among these patients were the ones who survived more than 24 moths after diagnosis, and those had Ps 0 -1 at diagnosis, less comorbidities and had the same proportion of stage IIIA and IIIB stages. 53% of patients were only treated with cisplatin-based chemotherapy or radiotherapy at 60Gy, and in these cases, the median overall survival was shorter: 9.5 months Conclusions: In our study, neoadyuvant therapies and the protocols used are the most accepted in international guidelines. The patients who underwent chemotherapy and surgery lived much more and they had better Performance Status at diagnosis, so we can conclude that chemotherapy and surgery, if possible, are a good treatment option with longer global survival. Definitive chemotherapy and radiotherapy should be better reserved for those patients who are not candidates for surgery.
Impact of asbestos exposure on survival and treatment of patients with malignant mesothelioma.
Authors: Bourgouin Patrick P , Blais Normand , Tehfe Mustapha , Florescu Marie
Published: March 2020

e17507

Background: Malignant mesothelioma is a rare pleural cancer heavily correlated to asbestos exposure. However, the number of mesotheliomas without any known exposure to asbestos is surely increasing. The impact of asbestos exposure on patient survival and response to standard treatment is unknown. We retrospectively analyzed 49 consecutive patients diagnosed with malignant mesothelioma using an unselected SARDO database at Notre-Dame Hospital from 2006 to 2009. Methods: Patients were sorted into 2 groups based on reported asbestos exposure status, mostly on patient’s working exposure. Demographic and treatment data were collected and analyzed with Kaplan-Meier survival plots and log-rank tests. Results: The median survival was 22.6 months for the entire 49 patients, overall survival at 1 year 86.4% and at 2 years 47.3%. Median survival of exposed patients (n = 20) was 22.6 months and that of non-exposed patients (n = 29) was 59.5 months. However, survival was not significantly different between the 2 groups (p = 0.450), despite there was no treatment difference in between 2 cohorts. Most patients were men (n = 42) and women (n=7) generally belonged to the non-exposed group. 3 patients had surgical treatment (pleurectomy with either pneumonectomy or lobectomy), but their survival was not statistically superior (p = 0.091) despite a clear trend. Patients younger than 65 years did not have better survival. Conclusions: Although asbestos exposure clearly increases the risk of mesothelioma, it does not seem to have an impact on the overall survival of patients with malignant mesothelioma neither on the efficiency of their treatment. However, a reliable serum biomarker of asbestos exposure would probably be necessary to make sure patients with no working exposure have really no exposure in other circumstances to asbestos.
Association of second primary malignancies with past and family history of malignancy in patients with small cell lung cancer.
Authors: Kirita Keisuke , Goto Koichi , Umemura Shigeki , Yoh Kiyotaka , Niho Seiji , Ohmatsu Hironobu , Nagai Kanji , Ohe Yuichiro
Published: March 2020

e17526

Background: Based on recent development in the treatment for small cell lung cancer (SCLC) such as chemotherapy and radiotherapy, long-term survivors are frequently observed. Meanwhile, etoposide and radiotherapy, which are key treatments for SCLC, are also known as methods to set up late complication including carcinogenicity. There have been few reports of second primary malignancies (SPM) in patients with SCLC, and risk factor for SPM has not become evident other than smoking continuation. Methods: From July 1992 to December 2009, 900 patients with SCLC were treated in National Cancer Center Hospital East. Medical records of all patients were retrospectively reviewed, and the incidence and risk factor for SPM were investigated. Results: Demographics of all patients with SCLC were as follows: Male/Female, 738/162; median age, 66 years (range 22-87); smoking pack-year (PY) <30/30≤, 155/745; Limited/Extensive, 468/432. Median follow up time was 4.5 years. Three and 5-year overall survival rate were 16.4% and 11.6%, respectively. Twenty-seven patients (3.0%) developed SPM, 15 patients (54%) of whom died due to SPM. Thoracic cancer occupied 52% of them (lung, 11; trachea, 1; esophagus, 4; breast, 1). Three and 5-year cumulative incidence rate (CIR) of SPM were 2.5% and 11.8%. Although there was no significant risk factor for SPM, the groups having past history of malignant disease and heavy smoker (PY ≥30) tended to develop SPM (p=0.11and 0.07). Using etoposide containing regimen and thoracic irradiation were not significant risk factors for the incidence of SPM (p=0.84 and 0.24). Neither serum level of CEA, NSE nor ProGRP were risk factors of incidence of SPM (p=0.51, 0.09 and 0.21). Within over 2-year survivors, there was a significant correlation between family history of cancer within first-degree relatives and CIR of SPM (p<0.01). Conclusions: Five years CIR of SPM was 11.6%, and secondary thoracic cancer accounted for large portion of them. It was concluded that cumulative smoking amount, past history of malignant disease, and positive family history of cancer within first-degree relatives were risk factors for SPM.
Preclinical modeling of the AKT inhibitor MK2206 and topotecan in small cell lung cancer (SCLC).
Authors: Holland William S. , Chinn Danielle C. , Lara Primo , Gandara David R. , Mack Philip C , Kelly Karen
Published: March 2020

e17537

Background: Extensive-stage small cell lung cancer (SCLC) is an aggressive and lethal tumor. Despite its exquisite chemosensitivity, median survival is only 9-11 months. Topotecan is the only approved drug for relapsed SCLC and new treatments with demonstrated antitumor activity are urgently needed. Defects in PTEN and PI3KCA are common to SCLC (identified in 10-15% of tumor specimens), suggesting that inhibitors of the PI3K/AKT pathway should be evaluated. MK-2206 is a first- in-class oral allosteric AKT inhibitor that is both potent and highly selective against all AKT isoforms. Our aim is to determine if MK-2206 plus topotecan has superior anticancer activity compared to either agent alone in SCLC cell lines. Methods: Three SCLC cell lines (H526- PTEN/PI3K wild type; H69- PTEN wild type/PI3K mutated; H2196- PTEN mutated/PI3K wild type) were treated with MK2206, topotecan or the combination. Median Effect Analysis was conducted using proliferation assays to test the combination for synergy. Immunoblotting was performed to explore the targeted effect on the PI3K/AKT pathway while flow cytometry was used to determine cell cycle effects. Results: H526 cells were refractory to selective AKT inhibition, but sensitive to topotecan. In contrast, H69 cells were responsive to single-agent MK2206, but two orders of magnitude less sensitive to topotecan. The H2196 cell line was sensitive to both agents. All cell lines showed decreased phosphoAKT (S473) with MK2206. In the combination experiments, additive to moderately synergistic interactions were detected in all cell lines with the greatest synergism observed in the H69 cells. Increased PARP cleavage was observed in response to the combination treatment compared to single-agent topotecan suggesting that AKT inhibition improved the activity of topotecan. In H69, a prolonged G1/S-phase arrest was observed in the combination compared to single-agent treatment. Conclusions: MK2206 demonstrated antitumor activity in SCLC cell lines harboring PI3K or PTEN mutations and enhanced the activity of topotecan in wild type and mutant cell lines. Based on this data, a SWOG clinical trial of topotecan plus MK2206 versus topotecan in relapsed SCLC is in development.
Multicenter institutional experience of surgically resected thymic epithelial tumors (TETs): An observational report.
Authors: Genestreti Giovenzio , Burgio Marco Angelo , Ampollini Luca , Rolli Luigi , Sanna Stefano , Scarpi Emanuela , Burgio Salvatore Luca , Amadori Dino
Published: March 2020

e17546

Background: Thymic epithelial tumors (TETs) consist of a series of neoplasm arising from the anterior mediastinum. Due to its rarity, large-scale prospective trials have been lacking. This retrospective multicenter analysis aimed to evaluate clinical outcome and clinico-pathological features of TETs after surgery resection and adjuvant treatments as chemotherapy and/or radiotherapy. Methods: All medical records about TETs surgically resected between 2000 and 2007 and eventually treated with adjuvant therapies (chemotherapy and/or radiotherapy) were reported. Surgical procedures included complete removal of thymic, mediastinal fat tissue and any suspicious lesions. Histological classification has been made in according to WHO criteria and Masaoka staging system was adopted. Adjuvant chemotherapy was represented by anthracycline and platin-based regimen whereas adjuvant radiotherapy was delivered on irradiation field covered primary tumor bed. Overall survival was calculated from the date of diagnosis until patient death or last follow-up visit. Disease free-survival was defined the interval from operation until date of recurrence. Results: Overall 32 patients were analyzed of whom 12 (37%) male and 20 (63%) female. Median age was 61 years (range: 33 - 86). At the beginning of their oncologic history 14 (42%) patients had miastenia. Overall at clinical staging there were 19 (60%) stage I, 4 (12%) stage II, 4 (12%) stage III, and 5 (16%) stage IVb at radiological staging. The histological exam reported: 5 (16%) A tumor type, 11 (34%) AB type, 3 (10%) B1 type, 3 (10%) B2 type, 8 (24%) B3 type, 2 (6%) C type. At pathological staging there were: 18 (56%) stage I, 7 (22%) stage II, 2 (6%) stage III and 5 (16%) stage IVb. Post-surgical therapies were represented by chemotherapy in 2 (6%) patients and radiotherapy in 13 (41%) patients. Disease relapse was recorded in 1 (3%) patient after 27 months from diagnosis. Overall survival rate at 78 months is 86% (CI: 66-100). Conclusions: TETs are rare and indolent cancer. Surgery offers the good perspectives eventually improved with adjuvant therapies like chemotherapy and/or radiotherapy. Supported by GIPO.
Full-dose irinotecan plus platinum (IP) with concurrent thoracic radiotherapy (C-TRT) in unresectable locally advanced non-small cell lung cancer (LA-NSCLC).
Authors: Zhang Jun , Biswas Tithi , Fried Daniel B , Rosenman Julian , Russo Suzanne M. , Salvador Wenimar , Tiley Stephen , Parent Teresa , Eubanks Susan , Nelson Zenith , Aljumaily Raid , Bowling Mark , Walker Paul R.
Published: March 2020

e17547

Background: Weekly paclitaxel-carboplatin or cisplatin-etoposide with C-TRT is the standard of care for unresectable LA-NSCLC, with median survival time (MST) of 16-24 months and 3 year overall survival (OS) of 17-27%. Irinotecan plus platinum with C-TRT has been studied in LA-NSCLC with similar outcomes and no undue toxicities (Langer et al J Thorac Oncol 2007; Bastos et al J Thorac Oncol 2010). We reviewed our multi-disciplinary thoracic oncology program experience of full dose IP with C-TRT in LA-NSCLC. Methods: All patients with unresectable LA-NSCLC treated between January 2007 and December 2011 were searched through our program database and included. 26 patients treated with definitive IP and C-TRT were identified. Treatment consisted of irinotecan 65mg/m2, plus cisplatin 30mg/m2 or carboplatin AUC 3, on days 1 and 8, every 21 days for four cycles. C-TRT started on day 22 at 2 Gy/day for 6-7 weeks. (Total 60-70Gy.) Survival curves were estimated by Kaplan-Meier analysis. Primary end point was OS. Secondary endpoints were overall response rate (ORR), progression free survival (PFS), and toxicities. Results: Patient characteristics: Median age 61 (range 44-82); 73% males; 50% squamous, 31% adenocarcinoma, 19% other histology; 30% Stage IIIA/ 62% IIIB/8% IIB. 1 patient died early without evaluation. ORR was 69%, 5 (19%) complete response, 13 (50%) partial response, 7 (27%) stable disease. Median PFS 10.1 months. MST 31.4 months. One year OS 67.8% (95% CI 52-89) and three year OS 35.7% (95%CI 15-87). 12 (46%) patients had G3/4 hematologic toxicities: 7 neutropenia, 6 thrombocytopenia, 6 anemia, 2 lymphopenia. 9 (34.6%) patients had G3/4 non-hematologic toxicities: 4 radiation esophagitis, 3 elevated creatinine, 2 pneumonia, 2 nausea/vomiting. 1 G5 radiation pneumonitis. Two patients died of pneumonia and sepsis. 18 (69%) patients completed 4 cycles IP with concurrent TRT. Conclusions: Definitive treatment with full dose Irinotecan plus platinum and concurrent thoracic radiotherapy is effective and tolerable for unresectable LA-NSCLC with an enhanced MST of 31 months and 3 year OS of 35%.
Phase II study of ADI-PEG 20 in patients with relapsed sensitive or refractory small cell lung cancer.
Authors: Tran Sinhan , Ready Neal , Krug Lee M. , Pietanza Maria Catherine , Jungbluth Achim A , Pan Linda S. , Venhaus Ralph Rudolph , Hoffman Eric W. , Peters Ann-Marie , Dukelow Karen , Bomalaski John S. , Wu Bor-Wen , Old Lloyd J.
Published: March 2020

e17558

Background: Small cell lung cancer (SCLC) is a rapidly progressing malignancy. The majority of patients show relapse after initial therapy. Second-line chemotherapy has limited activity, and alternative therapies are desperately needed. ADI-PEG 20 is pegylated recombinant arginine deiminase which degrades arginine, resulting in growth inhibition of SCLC tumor cells deficient in argininosuccinate synthetase (ASS) in xenografts and in vitro, and induction of sensitivity to cell autophagy. Based on ASS deficiency identified in ~50% of human SCLC, a phase II trial in patients with relapsed SCLC was initiated. Methods: This is an open label, multicenter, phase II study of ADI-PEG 20 in subjects with relapsed SCLC. The primary objective is to determine overall response rate according to RECIST. Secondary objectives are to measure safety, overall survival, pharmacodynamics, and immunogenicity. Patients with histologically documented SCLC, measurable disease, and ASS negative (by immunohistochemistry) or weakly positive (< 5%) tumor are eligible. Patients with severe comorbidities, metastatic disease of the central nervous system, prior treatment with 3 or more lines of chemotherapy, and known allergy to pegylated products are excluded. Patients are enrolled in either Cohort 1 (Sensitive disease—response to first-line therapy maintained ≥ 90 days) or Cohort 2 (Refractory disease—no response to first-line therapy or progression within 90 days, or progression after 2 lines of therapy). All patients receive weekly intramuscular injections of ADI-PEG 20 at a dose of 320 IU/m2 (36.8 mg/m2) until disease progression. The two cohorts will be analyzed separately with a two-stage design. For Cohort 1, if 3/15 patients respond, additional 13 patients will be accrued to the second stage. For Cohort 2, if 1/9 patients responds, additional 8 patients will be accrued to the second stage. Results: Cohort 1 has enrolled 2 of planned 15 patients and Cohort 2 has enrolled 7 of 9 planned patients. Conclusions: Will be published when study is complete.
Usefulness of cytological samples (CS) for the assessment of ALK rearrangements in non-small cell lung cancer (NSCLC).
Authors: Lozano Maria D. , Labiano Tania , Zudaire Maria I. , Gurpide Alfonso , Zulueta Javier , López-Picazo José María , Echeveste Jose Ignacio , Seijo Luis Miguel , Idoate Miguel A. , Martin-Algarra Salvador , Perez-Gracia Jose Luis
Published: March 2020

e18008

Background: ALK gene rearrangements define a new molecular subtype of NSCLC with response to Crizotinib, a dual MET and ALK inhibitor. Analysis of ALK rearrangements has been performed in biopsies or surgical specimens. However, advanced NSCLC is often diagnosed by FNA cytology obtained through minimally invasive techniques, and frequently CS are the only tumour sample available. We assessed the feasibility of determining ALK rearrangements in CS. Methods: We studied prospectively ALK rearrangements in 53 CS from 53 NSCLC patients (30 M/23 F) by FISH (Vysis dual colour break apart probe). We considered positive for ALK rearrangement when > 15% of cells show splits signals. Tumor samples were obtained by bronchoscopy -FNA in 26 cases (49.1%), EBUS-FNA in 7 (13.2%), EUS-FNA in 3 cases (5.7%), CT-FNA in 3 (5.7%), and direct FNA in 6 cases (11.3%). Two cavity fluids (3.8%), 4 imprints (7.5%), and 2 cellblocks received for consultation (3.8%) were also studied. FISH was performed on non-stained ThinPrep in 28 cases (52.8%), Papanicolau stained smears in 15 cases (28.3%), cell block in 9 cases (17%), and 1 stained ThinPrep. All cases were tested for EGFR and KRAS mutations. Correlation cytological/paraffin embedded samples was performed in 4 paired cases. Results: Thirty-seven samples(69.8%) were adequate for FISH analysis. Three cases (8.1%) had ALK rearrangements: non-smoker women with adenocarcinoma, two of them with signet ring cells. One case had a concurrent EGFR mutation in exon 21. FISH study was unsuccessful in 16 cases (30.2%):10 Papanicolau stained smears (62.5%), 5 unstained ThinPrep (31.3%), and 1 cell block. Nineteen ThinPrep slides were adequate for FISH analysis (86.4%) as well as 8 out of 9 cell blocks. Concordance rate in paired cases were 100%. Conclusions: Determination of ALK gene rearrangements in CS is feasible. It is mandatory an exquisite management and care of the samples to preserve quality. ThinPrep and cell blocks are the most suitable samples for FISH analysis, while Papanicolau stained smears provide poor results. Coexistence of ALK gene rearrangements and EGFR mutations was observed in one case, indicating that such alterations are not necessarily mutually exclusive.
KRAS mutational status and sensitivity to a reversible epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in EGFR wild type (WT) advanced non-small cell lung cancer (NSCLC) patients (pts).
Authors: Metro Giulio , Duranti Simona , Chiari Rita , Bennati Chiara , Molica Carmen , Currà Maria Francesca , Scafati Chiara , Siggillino Annamaria , Flacco Antonella , Marcomigni Luca , Ludovini Vienna , Minotti Vincenzo , Crinò Lucio
Published: March 2020

e18023

Background: Treatment with a reversible EGFR-TKI may benefit pts with EGFR WT advanced NSCLC, though to a much lesser extent than pts carrying an activating mutation in the EGFR gene. We assessed whether KRAS mutational status would help predict sensitivity to gefitinib or erlotinib in EGFR WT advanced NSCLC pts. Methods: Sixty-seven EGFR WT, advanced NSCLC pts treated with a reversible EGFR-TKI in any line setting were included. Pts were treated from May 2005 to March 2011 at the Medical Oncology of the Perugia Hospital. EGFR (exons 18 to 21) and KRAS (codons 12, 13 and 61) genes were amplified by nested PCR and sequenced in both sense and antisense directions. Results: Median age was 60 years (39-84); 52 pts (77.6%) were PS 0 or 1; 58 pts (86.6%) belonged to the non-squamous subtype and 22 pts (32.8%) were never-smokers. Eighteen pts (26.8%) were KRAS mutant (MUT), of which 14 pts at codon 12 (COD 12 MUT) and 4 pts at codon 13 (COD 13 MUT). Overall, 11 pts (16.4%) responded to treatment and 8 pts (11.9%) achieved stable disease, for a disease control rate of 28.3%. At a median follow-up of 25.2 months, median progression-free survival (PFS) and overall survival (OS) were 2.9 and 29.5 months, respectively. When analyzed according to KRAS status, a significantly shorter PFS was noted for the EGFR WT/KRAS MUT subgroup (N=18) compared with the EGFR WT/KRAS WT population (N=49) (1.6 vs. 3.0 months, respectively, p=0.04). However, no significant difference was observed between the two groups in terms of OS (18.0 vs. 34.8 months, respectively, p=0.42). Within the EGFR WT/KRAS MUT subrgoup a significantly longer PFS was reported for COD 12 MUT pts compared with COD 13 MUT pts (1.7 vs 0.7 months, respectively, p=0.04). Similarly, KRAS COD 12 MUT pts experienced a statistically significant superior OS compared with COD 13 MUT pts (36.2 vs 7.4 months, respectively, p=0.003). Conclusions: EGFR WT/KRAS MUT pts appear to be more resistant to treatment with a reversible EGFR-TKI, the greatest resistance occurring in COD 13 MUT pts. KRAS COD 12 MUT pts may represent a clinically distinct subgroup of KRAS mutants with a particularly favorable prognosis.
Erlotinib as frontline treatment for elderly patients (p) with advanced nonsquamous non-small cell lung cancer (nsNSCLC): GGCP044/09 study.
Authors: Firvida Perez Jose Luis , Vazquez Estevez Sergio , Casal Rubio Joaquin , Alonso Bermejo Miguel , Varela Ferreiro Silvia , Villanueva Silva Maria Jose , Afonso Afonso Francisco J. , Lazaro Quintela Martin , Areses Manrique Carmen , Campos Balea Begona , Huidobro Vence Gerardo , Fernandez Calvo Ovidio , Alvarez Gomez Elena , Grande Ventura Carlos , Fernandez Montes Ana , Castro Gomez Enrique , Mel Lorenzo Jose Manuel ,   Galician Lung Cancer Group
Published: March 2020

e18040

Background: NSCLC is primarily a disease of older people with a median age of approximately 70 years (y) at diagnosis. Platinum combination chemotherapy (CT) has shown to be more effective than single agents but it is associated with more toxicity. Erlotinib is an EGFR TK inhibitor with a favourable toxicity profile and its oral administration makes it suitable to treat elderly p. No much is known about its efficacy and toxicities in this subpopulation, often under-represented in clinical trials. This Galician study aims to evaluate the efficacy and safety of erlotinib as 1st-line treatment (Tx) for elderly p with advanced nsNSCLC. Methods: Elderly p (≥70 years old) with stage IIIB/IV nsNSCLC were included in this prospective observational study. Erlotinib was orally administered at a dose of 150 mg daily until disease progression or intolerable toxicity. PFS (primary objective) and OS were measured from time of diagnosis. Results:A total of 31 p were enrolled. Baseline characteristics: Mean age 78 y (range 70-85); female 67.7%; adenocarcinoma (including BAC) 90.3%; never/current/former smokers (%): 54.8/16.1/22.6 (6.5% unknown), stage IV 84%; ECOG PS 0/1/2 (%): 6.4/45.2/48.4. The median PFS was 6.4 and the median OS was 9.9 months. Out of 26 evaluable p, 8 had PR and 8 SD, for an ORR of 30.8% and a DCR of 61.6%. The most common adverse event was skin rash, 38.7% (9.6% grade 3-4), diarrhoea, 25.8% (3.2% gr. 3-4) and asthenia, 19.3% (no gr 3-4 were reported). 5 p (16.1%) needed dose reduction and 3 p withdrew the Tx due to grade 3 diarrhoea, eye perforation and esofaghitis, respectively. EGFR mutational status was available for 10 p (32.2%); 4 p harboured activating mutations: 3 p achieved PR and 1 p SD. SLP of 31 (ongoing), 22.4 (ongoing), 13.6 and 9.8 months. Conclusions: These results in real-life settings confirm that erlotinib is an active and well tolerated agent as frontline Tx in elderly p (≥70) in nsNSCLC. Response rate is similar to that achieved with CT in younger people; benefit in PFS is modest, but median OS is acceptable, taking into account that half of the p had a PS of 2 EGFR mutation testing should be strongly encouraged among elderly p.
Efficacy and safety of IMO-2055, a novel TLR9 agonist, in combination with erlotinib (E) and bevacizumab (bev) in patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed following prior chemotherapy.
Authors: Smith David A. , Conkling Paul , Richards Donald A. , Flores Maria Regina C. , Nemunaitis John J. , Boyd Thomas E. , Mita Alain C. , de La Bourdonnaye Guillaume , Wages David , Bexon Alice Susannah
Published: March 2020

e18047

Background: IMO-2055 is a novel TLR-9 agonist with potential to enhance the efficacy of biologics and small molecules through immune stimulation. Xenograft data show anti-tumor synergy between IMO-2055, E and bev; E-bev has been evaluated in 2nd line NSCLC. Methods: Primary objective was to determine the recommended dose (RD) of IMO-2055 (dose range 0.08-0.48 mg/kg/w s.c.) with E 150mg/day p.o. and bev 15mg/kg q3w i.v. in a standard 3+3 design. An expansion cohort at the RD further determined safety and efficacy. Pts had AJCC stage 3/4 inoperable, histologically proven NSCLC where standard chemotherapy was not an option. Treatment was until progression (PD) or toxicity. Results: 36 pts were enrolled at 10 US sites from Nov ‘07 to Mar '11. 35 were treated/evaluable for safety; 33 for efficacy. Median age was 64, 58% were men, 81% white, 81% PS 1 with 69% adenocarcinomas and median 17 months since diagnosis. 44% pts were >2nd line. Pts received a median of 4.3 3-week cycles. 19 pts entered dose-escalation: 4 at 0.08 mg/kg, 6 at 0.16 mg/kg, 6 at 0.32 mg/kg, and 3 at 0.48 mg/kg IMO-2055. Two pts had DLTs: 1 grade 3 dehydration at 0.16 mg/kg, and 1 grade 3 fatigue at 0.48 mg/kg. RD was 0.32 mg/kg based on pharmacodynamic and clinical data: 17 more pts were treated at this dose. The most common AEs were diarrhea, nausea, fatigue and rash; most frequent grade 3-4 AEs were fatigue (9%), diarrhea (9%), anemia and dyspnea (both 6%), with no clear dose-relationship to IMO-2055. G3-4 hypertension was 0%, ATE 6% and hemorrhage 3%. Five pts died of PD on or within 30 days of study drug administration. Response rate was 12% with 79% disease control (SD+PR). Median PFS was 5.6 months (95% CI 3.9-7.2) and OS 16 months (95% CI 7.5-17.8) with 55% pts alive at 1 year. Conclusions: Addition of IMO-2055 to E-bev was well tolerated with no unexpected toxicity. The RD of IMO-2055 with E-bev is 0.32 mg/kg/w s.c.  Median PFS and OS in this heavily pretreated population compare favorably with published E-bev data.  IMO-2055 should be further explored in NSCLC.
Long-term survivors with advanced nonsquamous non-small cell lung cancer (nsNSCLC) treated with first-line (1L) chemotherapy (CT) plus bevacizumab (B) and maintenance (mtc) B.
Authors: de Castro Javier , Isla Dolores , Gonzalez Larriba Jose Luis , Vazquez Estevez Sergio , Massuti Bartomeu , Sanchez Torres Jose Miguel , Domine Manuel , Calles Antonio , Cardona Jose Vicente , Garrido López Pilar
Published: March 2020

e18055

Background: B plus CT followed by mtc B has been shown to improve outcomes in patients (pts) with nsNSCLC. In the clinical setting, some pts are able to receive prolonged mtc treatment (Tx) with B. The aim of our research was to explore their clinical characteristics, in order to assess the behavior of these pts who benefit most from B. Methods: In 30 Spanish institutions we studied retrospectively data from 104 pts with advanced nsNSCLC receiving long-time mtc B defined by a PFS ≥ 9 months (m), which represents an increase in PFS of approximately 50%, as compared with historical data. Clinical and histological characteristics, Tx received, ORR, median PFS and OS, and safety data were recorded. Results: Pts characteristics: median age 57 years (yr); caucasian: 98%; ECOG PS 0/1/2 (%): 61/38/2; male: 61%; current/former/never smokers (%): 36/45/19; baseline hypertension (HTN)/cardiovascular disease (%): 24/9; adenocarcinoma: 82%; stage IV: 84%; 84% of pts presented ≤2 metastatic sites; central tumor location: 30%; tumor cavitation: 4%; among 40 pts tested, 8% presented activating EGFR mutations. 1L CT was: carboplatin/cisplatin doublets (%): 57/43; median no. of cycles for CT/B and mtc B was 6 and 18, respectively. Median B dose was 7.5 mg/kg. ORR: 83%. Of 71% of pts who had evidence of PD to 1L, 90% received second-line (2L) Tx. 77% of pts who progressed to 2L, received a third-line (3L). B was maintained in 26% and 24% of pts receiving 2L and 3L. Median PFS: 15 m (CI 95%:14-16); median OS: 31 m (95% CI: 22-39). 1 and 2 yrs survival rates (%): 97 (95% CI: 93 - 100) and 62 (95% CI: 51 - 73). Most frequent B related toxicities (%): gr 1/2 epistaxis (22/0), gr 1/2 HTN (12/6), grade 1/2/3 asthenia (2/6/4) and gr 1/2/3 proteinuria (3/3/1). Conclusions: To our knowledge, these are the first data reported of long-term survivors with advanced nsNSCLC treated with 1L CT/B plus long-time mtc B. Although prospective evaluation is required, the outstanding median OS (31 m) and 2-yr survival (62%) point out the importance of selecting Tx and the role of mtc B after 1LB. B was very well tolerated, without significant life-threatening toxicities. Subgroup analyses will be presented.
Characteristics of advanced NSCLC patients with at least 6 months erlotinib treatment duration in Czech Republic.
Authors: Coupkova Helena , Skrickova Jana , Hejduk Karel , Zbynek Bortlicek , Kadlec Bohdan , Salajka Frantisek , Pesek Milos , Kolek Vitezslav , Koubkova Leona , Sixtova Dimka , Zatloukal Petr , Roubec Jaromir , Zemanova Milada , Vyzula Rostislav , Spelda Stanislav
Published: March 2020

e18062

Background: Erlotinib is approved for NSCLC treatment in Czech Rep since 2005. This analysis was performed to analyze the profile of pts treated with erlotinib longer than 6 months. Methods: This retrospective analysis evaluates data from Czech Tarceva Registry of pts treated outside clinical trials. Survival (mOS, mPFS) was evaluated by the Kaplan-Meier method, survival comparison was performed by Log Rank test. Results: Up to October 2011, 430 out of 2121 pts with completed data in registry were treated with erlotinib for 6 months and longer. Median age 65 years, 54.4% men; 29.8% smokers, 37.9% former smokers, 32.3 % non-smokers; 77% pts ECOG PS 0-1. 74.7% stage IV pts, 21.4% stage IIIB. 43.5% adenoca, 31.9% squamous ca,11% non-specific NSCLC, 6% bronchioloalveolar ca. Erlobinib administered as 1st line treatment in 13% pts, 2L in 50.9%, 3L in 34.9%. Till October 2011, 322 pts (74.9%) finished the treatment, 108 pts (25.1%) still on erlotinib therapy. Treatment discontinued due to progression in 75% pts, death in 15%, toxicity in 3%. The entire group results (n=430): CR in 2.3%, PR in 17.7%, SD in 65.8%, PD in 2.6%. mPFS and mOS from erlotinib initiation 12.4 and 21.4 months respectively. mOS from diagnosis was 43.5 months. Statistical difference in mOS (from the erlotinib initiation) was observed between groups with PS ECOG 0-1 and PS 2-3, 22.0 vs 16.4 months (p=0.001), although there was no difference in both groups in mPFS (12.9 vs. 10.6 months). mPFS and mOS in pts with adenoca (n=187) from erlotinib initiation 14.4 and 23.7 months respectively. mOS from diagnosis was 45.6 months. mPFS and mOS in pts with squamous ca (n=137) from erlotinib initiation was 11.3 and 17.6 months respectively. mOS from diagnosis was 42.2 months. Conclusions: This analysis documented good activity of erlotinib in both adeno and squamous cell carcinoma. The difference in mOS and mPFS between both groups was statistically significant when measured from erlotinib initiation (mOS: p= 0.017, mPFS: p=0.022), however not statistically significant when measured from the date of diagnosis (p=0.361). Patients with PS 0-1 have statistically significantly greater mOS than patients with worse PS (p=0.001).
Differences in utilization of ALK rearrangement FISH analysis and EGFR assay.
Authors: Lathan Christopher S. , Lynch Julie Ann
Published: March 2020

e18067

Background: This study examined institutional and regional factors associated with use of ALK rearrangement FISH diagnostic test compared to the EGFR assay. Previous research presented at AACR Cancer Disparities conference illustrated substantial underutilization of the EGFR assay. Disparities existed in access by institutional and regional factors. Methods: We linked proprietary industry data for clinical diagnostic assays (EGFR mutation and ALK rearrangement) provided by Genzyme Genetics and Abbott Molecular to public datasets which provided institutional and regional characteristics of US hospitals. Individual orders were aggregated and summarized to the hospital. Each hospital’s Medicare provider number (known as the OSCAR number) was obtained and recorded. OSCAR number and zip code were used to link the proprietary and public datasets. Public datasets included Census files, CMS/NCI Provider of Service (POS) files, among others, all current as of 2011. Logistic and multiple regression analysis were conducted. Results: Initial analysis of data suggests higher utilization of the ALK rearrangement FISH analysis when compared to EGFR Assay. However, even with incorporation of both assays into clinical practice guidelines, significant institutional and regional differences existed in access to tumor tissue analysis. 7800 EGFR assay tests were sold in 2010. First 5 months post approval; approximately 12,000 Vysis tests were sold. A reasonable approximation of the testable population of NSCLC patients, given histology and tissue availability is approximately 114,000 patients. This suggests a 7% penetration rate for the EGFR mutation analysis and a 10% penetration rate for ALK rearrangement assay, though EGFR mutations have a 15% incidence rate compared to 5% incidence rate of EML-ALK4 rearrangement. Conclusions: Uptake of the ALK rearrangement assay is likely higher due to the linkage of crizotinib to the FISH diagnostic test. Utilization patterns show regional underutilization that could contribute to disparities.
Evaluation of relationship between progression-free survival and overall survival in first-line treatment of advanced non-small cell lung cancer.
Authors: Buzoianu Manuela , Hong Dr Shengyan , Shi Li , Viner Jaye
Published: March 2020

e18073

Background: There is increasing interest in assessing progression-free survival (PFS) as a potential surrogate for overall survival (OS) in many tumor types. However, such an assessment has yet to be adequately performed for non-small cell lung cancer (NSCLC). We assessed the relationship between 1st line treatment effects on PFS or OS in advanced NSCLC utilizing published data from clinical trials. Methods: The estimated PFS hazard ratio (HR) and OS HR from 43 randomized trials published between 2000 and 2010 were used to estimate Pearson correlation coefficient and to model the linear relationship between PFS HR and OS HR. Three approaches were considered in fitting the linear model, reflecting different ways of handling the variability of HR estimates used in the model fitting. The analysis was performed on add-on trials and head-to-head trials separately as well as jointly. Results: For add-on trials, the Pearson correlation coefficient r was 0.831 based on the observed HR data weighted by trial size. The R2 was 0.791 for the linear model after Bayesian adjustment of variability in the observed HR data. All showed strong relationship between PFS HR and OS HR for add-on therapies. The relationship is weak for head-to-head therapy (r=0.288 and R2=0.202). The overall relationship, when jointly considering add-on and head-to-head therapies, is moderate (r=0.653 and R2=0.577). Conclusions: Our analysis supports the use of PFS as a reasonable surrogate for OS if an add-on therapy is developed, but not if a head-to-head therapy is developed as 1st line treatment of advanced NSCLC.
Comparison of bevacizumab versus pemetrexed in combination with platinum-based doublets in first-line treatment of advanced non-small cell lung cancer.
Authors: Pereira Augusto Akikubo Rodrigues , Martins Sandro José , Lessa Rafael Costa , Pinto Flavio Augusto Ismael , Gagliato Debora De Melo , Santos Elizabeth S. , Rodrigues Newton Augusto Ferreira , Freitas Paulo Henrique Aires , Padua Fernando Vidigal , Alves Marclesson S. , Lima Geraldine Eltz , Fanelli Marcello Ferretti , Rinck Jose A. , Dettino Aldo A. , Nicolau Ulisses Ribaldo , Pereira Jose Rodrigues , Cruz Marcelo Rocha De Sousa , Lima Vladmir C.
Published: March 2020

e18078

Background: First-line treatment of advanced nonsquamous non-small cell lung cancer (NSCLC) with platinum-based doublets, including pemetrexed (P) or bevacizumab (B), has achieved more than 12 months of survival. At the moment, there are no phase III head-to-head comparisons of these combinations. Methods: We retrospectively analyzed, from 05/2007 to 02/2011, in a single institution, all pts with stage IIIB or IV nonsquamous NSCLC treated with B or P combined with platinum compounds in first-line treatment to determine differences in OS, PFS, ORR and toxicity. We performed multivariate analysis to identify prognostic factors for survival. Results: Of the 82 pts included, 40 pts (48,8%) received carboplatin/paclitaxel or cisplatin/gemcitabine combined with B (BEV group), while 42 pts (51,2%) received cisplatin or carboplatin combined with P (PEM group). BEV had significantly fewer pts with age > 70 years (p=0,01) and CNS metastases (p<0,001) than PEM. Maintenance therapy was administered in 65,0% and 52,4% of pts in BEV and PEM groups, respectively (p=0,17). Significantly more pts in BEV received second-line treatment (72,5% vs. 52,4%; p=0,04) than in PEM, prevailing P as drug of choice (79,3%). ORR (60,0% vs. 35,7%; p=0,04) and median survival (26,4 vs. 16,4 months; p=0,009) were significantly superior for BEV. Median PFS were not different between BEV and PEM (10,5 vs. 7,7 months; p=0,06). In multivariate analysis, ECOG 2 (p=0,005), bone (p=0,01) and adrenal metastases (p=0,005) were independent prognostic factors for worst survival, while treatment with BEV did not reach statistical significance (p=0,07). Grade 3-4 neutropenia (27,5% vs. 9,5%; p=0,03) and neuropathy (17,5% vs. 0%;p=0,005) were more frequent in BEV. Conclusions: First-line treatment of advanced nonsquamous NSCLC patients with platinum-based doublets combined with B resulted in better ORR and higher rate of toxic effects as compared with P-based regimens. ECOG 2, bone and adrenal metastases were independent prognostic factors for poor survival. Although there was a survival benefit at univariate analysis, use of B combination was not an independent prognostic fator.
KRAS mutation in lung cancer patients: A poor prognostic factor but not a predictive factor of EGFR-TKI and chemotherapy?
Authors: Guan Jilin , Zhong Wenzhao , An Shejuan , Su Jian , Chen Zhihong , Huang Ying , Huang Zhimin , Zhang Xuchao , Yang Jinji , Wu Yi Long
Published: March 2020

e18090

Background: At present, prognostic and predictive value for KRAS mutation in lung cancer patients remains to be controversial. Biases in disease stage, treatment regimens and small scale patient population led to inconsistent results in previous studies. Methods: we collected 91 consecutive lung cancer patients with KRAS mutation detected in Guangdong Lung Cancer Institute from January 2007 to may 2010. And each patient with mutant KRAS was paired randomly to a patient with KRAS/EGFR wild-type and a patient with mutant EGFR according to the identical TNM stage. All patients were followed up for treatment regimes, tumor response, progression-free survival (PFS) and overall survival (OS). Results: The patients with KRAS mutation were associated with a significantly shorter overall survival compared with patient without KRAS mutation (P=0.0005), and the same trend of disease free survival was also found in R0 resected lung cancer patients (P=0.039). Multivariate analyses proved the status of KRAS mutation was an independent prognostic factor (HR=2.69, 95%CI: 1.91-3.80, P=0.0005). No difference was found in PFS and tumor response between the first or second line EGFR-TKI treated patients harboring KRAS mutation and KRAS/EGFR wild-type (The first line: P=0.23, 0.82; The second line: P=1.00, 0.48). In the first and second line chemotherapy, there was no significant difference for PFS among the three groups (P=0.15, 0.52). Conclusions: KRAS mutation was a poor prognosis factor, but not an independent predictive factor for EGFR-TKI and chemotherapy in lung cancer patients. EGFR wild-type is major reason for resistant to EGFR-TKI in patients with KRAS mutation.