bluuebunny/crossref_metadata_2025 huggingface dataset:
A feasibility/phase II study of gemcitabine (G) and split dose cisplatin (C) in advanced or metastatic non-small cell lung cancer (NSCLC) in an outpatient setting
Authors: Hussain S. A. , Palmer D. H. , Swinson D. E. , Riley P. , Brown C. , Wills A. , El-Modir A. , Rea D. W. , Chetiyawardana A. D. , Cullen M. H.
Published: March 2020

17048

Background: This is a feasibility/phase II trial with GC on a 21-day cycle, with G and C split between d1, 8. Split dose C allowed administration in an outpatient setting. Objectives: To document the toxicity and define the objective response rate; and determine progression free and overall survival. Methods: Pts with stage III/IV NSCLC received: G/C 1250/40mg/m2 (G and C given on d1, 8 every 3 wks). Eligibility: ECOG PS 0–2, adequate bone marrow/liver function, calculated GFR > 50 ml/min. Results: 56 pts enrolled, all evaluable for toxicity; 47 evaluable for response; 4 patients too early for response assessment and 5 patients did not complete 1 cycle of chemotherapy. Characteristics: 70% male, median age 66 yrs (41–77), 25% GFR 50- 60 ml/min, 62% Stage IV. Radiotherapy was allowed after completing chemotherapy. 165 cycles have been delivered. Cycles with hematological toxicity: Grade 3: 5 anaemia, 17 neutropenia, 6 thrombocytopenia; Grade 4: 7 neutropenia, 4 thrombocytopenia. There were 3 episodes of febrile neutropenia. Cycles with non-hematological toxicity: Grade 4: 1 myocardial infarction (MI), 1 gastrointestinal (GI) bleed, 1 pulmonary embolism, 1 stroke; Grade 3: 3 nausea, 1 deep vein thrombosis, 4 chest infection, 1 hypomagnesemia; Grade 2: 3 renal toxicity, 2 seizure, 1 hypomagnesemia. Five cycles were deferred due to grade 4 neutropenia; 2 for renal toxicity (in one patient with diabetes and hypertension renal function declined after 1 cycle necessitating discontinuation of chemotherapy). 2 deaths occurred on treatment: 1 MI (patient with a previous history of MI); 1 GI bleed (on aspirin). Overall ITT RR was 33% (17/52: 1 CR+ 16 PR) (36% [17/47] for assessable pts). Median survival is 310-days. 1- year survival rate is 38%. Conclusion: G plus C in a 21-day schedule is active and well tolerated in an outpatient setting. This modified regimen with C split between d1 and d8, and, eligibility criteria of GFR as low as 50mls/min widens the spectrum of patients receiving cisplatin-based chemotherapy. Phase III trial is warranted.

[Table: see text]
Increased levels of inflammatory mediators in lung cancer and their modulation by oral anticoagulant treatment
Authors: Hoppensteadt D. A. , Ciftci A. , Demir M. , Altiay G. , Tobu M. , Iqbal O. , Fareed D. , Bick R. , Fareed J.
Published: March 2020

17050

Background: Venous thromboembolic events (VTE) are associated with lung cancer and significantly contributes to the increased mortality in these patients. While the increased prevalence of VTE is fully recognized in lung cancer, its pathogenesis is not fully understood. Even the patients undergoing therapeutic interventions are at high risk to develop VTE. These patients provide a unique clinical setting to investigate the pathogenesis of lung cancer associated thrombosis. Methods: In a prospective, randomized, controlled study patients with inoperable lung cancer (n = 100) were randomized to receive chemotherapy, radiation and warfarin (INR 1.5–2.5) or chemotherapy, radiation without warfarin (n = 50). Blood samples were drawn prior to and after the second treatment cycle with warfarin. All samples were analyzed for tumor necrosis factor alpha (TNF α), CD 40 ligand (CD 40L), C-reactive protein (CRP), interleukin 1 beta (IL-1β), asymmetric dimethylarginine (ADMA) and nitric oxide (NO). Results: Summarized in the table given below. All of the surrogate markers of inflammation showed a decreased trend (13–50%) in the warfarin treated group, whereas the non-warfarin treated group exhibited an increase (18–46%) in all markers except CRP and ADMA. Conclusions: The levels of various inflammatory markers are upregulated in lung cancer suggesting a pathogenic role of this process in lung cancer. Warfarin down regulated the inflammatory process in contrast to the non-warfarin treated group. The clinical relevance of these observations require additional analysis.

[Table: see text]

No significant financial relationships to disclose.
Phase I-II trial of daily thalidomide in combination with docetaxel in patients with relapsed non-small cell lung cancer: A final analysis
Authors: Seidler C. W. , Scepansky E. , Khanani S. , Rooney J. , Gordon J. , Walsh W.
Published: March 2020

17060

Background: Recent studies have shown that inhibition of vascular endothelium growth factor (VEGF) in combination with chemotherapy can improve the antitumor efficacy of chemotherapy in NSCLC. This study tested the effectivness and toxicity of thalidomide (an inhibitor of VEGF) combined with docetaxel as second-line therapy for progressive NSCLC. Methods: Patients(pts) with recurrent/progressive NSCLC, prior chemotherapy, measurable/evaluable disease, ECOG performance status (PS) 0–2 and adequate hematologic, renal and hepatic function were enrolled. Pts with uncontrolled CNS disease or hypercoagulable state were excluded. Doxetaxel 75 mg/M2 was administered every 3 weeks (maximum of 8 cycles). Thalidomide was administered orally at a starting dose of 50 mg daily escalated by 50 mg every 3 weeks to a maximum dose of 200mg day and continued until disease progression, dose limiting toxicity, or completion of chemotherapy. Primary end-point was overall survival (OS), secondary end points were time to disease progression(TTP) by Kaplan Meyer method and response rate (RECIST criteria). Results: Of 28 enrolled patients, 26 were eligible for treatment and 25 were evaluable for disease progression and survival. For evaluable pts: mean PS = 1, median age 64.5 years, median number of prior chemotherapy regimens + 1.2. Response rate was 19.1% (1 complete response, 4 partial responses). Stable disease was observed in 9 patients (34.6%). TTP was 2.7 months (95% confidence interval [CI] 2.1–5.0+): median OS was 5.4 months (95% CI 3.1–9.3+). One episode each of febrile neutropenia requiring hospitalization and pulmonary embolism was observed. No grade 3–4 neuropathy was shown. Nonhematologic adverse events included constipation, alopecia, nausea and anorexia. Conclusions: These data suggest thalidomide in doses of 200mg/ day may be combined with docetaxel 75 mg/m2 every 3 weeks in the second line treatment of NSCLC. The response rate, TTP and OS compare favorably with previously reported studies with docetaxel in this population.

No significant financial relationships to disclose.
Phase II trial of weekly docetaxel and gemcitabine as first line therapy for patients with advanced non-small cell lung cancer
Authors: McNeill G. , Kalmadi S. , Davis M. , Peereboom D. , Adelstein D. J. , Bukowski R. M. , Mekhail T.
Published: March 2020

17076

Background: A platinum doublet has been the standard treatment for patients with advanced non-small cell lung cancer (NSCLC) and good performance status. This treatment results in almost a doubling of 1-year survival, along with an improvement in quality of life despite treatment related toxicities. However, platinum based treatment is associated with significant toxicity. Methods: In this trial, we prospectively evaluated a weekly regimen of docetaxel and gemcitabine for advanced NSCLC from December 2001 to January 2005. The endpoints of this study included objective response rate, survival and toxicity. Forty-two patients with previously untreated, advanced NSCLC with PS 0–1 were included. Patients received docetaxel (36 mg/m2) and gemcitabine (600 mg/m2) on days 1,8 and 15 of a 28-day cycle. Responses were assessed every two cycles. Results: The median age was 63 years; with 22 males and 20 females; 67% were >60 years old; and 38 patients had stage IV disease. In the intent-to-treat (ITT) analysis of response, 16 patients had a partial response (38%) and 15 patients had stable disease (36%). The 1-year survival was 48%; median survival for all patients was 11.3 months and the median progression-free survival was 5.1 months. Toxicities (> grade 3) included neutropenia (29%), asthenia (26%), thrombocytopenia (14%), diarrhea (14%), pneumonitis (7%), peripheral neuropathy (5%), peripheral edema (5%), nail changes (2%), and myositis (2%). Conclusions: This study demonstrated that this non-platinum doublet (docetaxel + gemcitabine) given on a weekly schedule for advanced NSCLC was well tolerated with efficacy comparable to platinum based chemotherapy regimens.

[Table: see text]
Health-related quality of life measures in advanced non-small cell lung cancer patients receiving sorafenib
Authors: Gondek K. , Dhanda R. , Simantov R. , Gatzemeier U. , Blumenschein G. R. , Reck M.
Published: March 2020

17085

Background: A multicenter, international, single-arm Phase II study evaluated the efficacy, safety, and tolerability of sorafenib in patients with advanced non-small-cell lung cancer (NSCLC). In addition, patients’ health-related quality of life (HRQL) and symptoms were assessed. Methods: HRQL was measured by the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire that was self-administered at baseline, at every other cycle during the study treatment period, and at the end-of-treatment (EOT) visit. Patients responded to each item on a five-point Likert-type scale ranging from 0 (not at all) to 4 (very much). Five subscale scores and an overall function score were calculated, with higher scores reflecting better function and symptom response. A change of two points, the minimum important difference (MID), in each of the five domains (physical well-being [PWB], emotional well-being [EWB], social well-being [SWB], lung cancer symptoms [LCS], and functional well-being [FWB]) was determined to be clinically meaningful. The total score of the treatment outcome index (TOI) was also assessed. Results: A total of 52 patients were evaluated. Data were collected at baseline, Cycle 2, Cycle 4, and EOT for 50/52 (96%), 42/52 (81%), 21/52 (40%), and 20/52 (38%) of patients, respectively. The mean total FACT-L scores were 99.3, 106.5, and 83.7 at Cycles 2, 4, and EOT, respectively. The mean changes from baseline in the total FACT-L score were -4.6, -0.2, and -14.6 at Cycles 2, 4, and EOT, respectively. The mean change from baseline in the each subscale scores were: -0.6, -1.0, -5.8 for PWB; -0.4, -0.8, -0.6 for SWB; -0.0, 2.1, -1.1 for EWB; -0.7, 0.9, -3.9 for FWB; -0.5, -1.0, -3.6 for LCS; and -2.6, -1.0, -13.2 for TOI, at Cycles 2, 4, and EOT, respectively. An improvement greater than the MID was observed in EWB at Cycle 4. Decreases below MID were observed for EWB at Cycle 2 and EOT, and all other subscales of the FACT-L at Cycles 2, 4, and EOT. Conclusions: These findings are encouraging and suggest that sorafenib did not adversely impact patient-reported outcomes in function and symptom response during the treatment period. As there is no comparator arm, interpretation of results is limited.

[Table: see text]
Phase II trial of a 2-hour infusion of gemcitabine plus carboplatin as first-line chemotherapy for advanced non-small cell lung cancer
Authors: Xu N. , Shen P. , Zhang C. X. , Yu F. L. , Bao Y. H. , Shi M. G. , Huang S. , Chen J. , Fang J. W.
Published: March 2020

17099

Background: Prolonged infusion of gemcitabine have shown increased levels of the active triphosphate metabolite that theorically could increase the response rate and toxicity. The objectives of this study were to evaluated the efficacy and safety of this combination of using gemcitabine as a rate infusion of 10 mg/m2 per min with carboplatin in front-line chemonaive patients with advanced NSCLC. Methods: Fifty-four chemonaive patients have been included. 44 were male and 10 female. Median age was 63 years (19–75). 13% had ECOG 0 and 53.7% ECOG 1 and 33.3% ECOG 2. 32 (59.2%) patients had adenocarcinoma, 13 (24.1%) squamous cell, 1 (1.9%) large cell carcinoma, and 8 (14.8%) others. Eight (14.8%) had stage IIIB and 46 (85.2%) stage IV. Treatment was consisted of 1200 mg/m2 gemcitabine given as a 2-hour continuous infusion (10 mg/m2 per min) on days 1 and 8 of each cycle an AUC 5 carboplatin as on day 1, repeating each cycle every 21 days. A total of 223 chemotherapy cycles were administered, with a median of 4 cycles per patient (range 1–6), and 15 (27.8%) patients received all six cycles. Results: Of the fifty-four patients enrolled, all were evaluated for toxicity (according to the WHO scale) and 51 assessed for response (according to the RECIST criteria), the overall response rate (ORR) was 41.2% (95% confidence interval, 28% to 57%), including two complete responses (CRs: 3.9%) and 19 partial responses (PRs: 37.3%). As per the intent-to-treat (ITT) analysis, the ORR was 38.9%. With a median follow-up time of 10.8 months, the median TTP was 5.0 months (range 3.7–6.3 months), median OS time was 11.5 months (range 9.9–13.1 months) and 1-year survival was 41.7% (95% CI 26% to 57%) and 2-year survival was 19.3% (4.4% to 34.2%).The main grade 3–4 toxicity consisted of neutropenia (55.6%) and thrombocytopenia (57.4%).Patients were required platelet transfusion in 27 cycles (12.1%) and haematopoietic growth factors support care in 56 (25.1%) cycles. No bleeding episodes were recorded. Grade 3 nausea/vomiting occurred in 5.6% and grade 1–2 skin rash occurred in 42.6%. Conclusions: Prolonged gemcitabine infusion combined with carboplatin is manageable tolerated and its efficacy is similar to that of other chemotherapeutic schemes used for NSCLC treatment.

No significant financial relationships to disclose.
Phase II pilot study of neoadjuvant cetuximab in combination with cisplatin and gemcitabine in patients with resectable IB-IIIA non small cell lung cancer
Authors: Coate L. E. , Gately K. , Barr M. P. , Meaney J. , O’Connell F. , Nicholson S. , McGovern E. , Young V. , O’Byrne K.
Published: March 2020

17107

Background: Adjuvant and neoadjuvant chemotherapy play a role in optimising long term outcome of patients with resectable non small cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase which is overexpressed NSCLC. Cetuximab is a monoclonal antibody which attaches to the extracellular domain of the EGFR preventing ligand binding. Preclinical data and phase II evidence in advanced NSCLC suggest cetuximab potentiates the effect of conventional cytotoxic agents. Methods: Patients with histologically confirmed resectable stage IB-IIIA NSCLC and adequate end-organ function, giving informed written consent are eligible. Three weekly cycles of cisplatin 80 mg/m2 D1, gemcitabine 1250 mg/m2 D1,D8 and cetuximab loading dose of 400 mg/m2 on first infusion, thereafter weekly 250 mg/m2 are used. The primary endpoint is response rate (radiological and pathological). Secondary endpoints are safety and tolerability of the combination, resection rate following therapy, overall survival and relapse free survival. In addition, molecular prognostic and predictive biomarkers of response are being assessed. Sequential samples of tissue, plasma, serum and white blood cells are being collected before, during and after therapy on all patients. Results: 16 patients have been recruited to date. (10 men, 6 women). Median age 66 (range 29–76). 3 patients stage I, 4 patients, stage II, 9 patients stage III. 11 have completed treatment. Response (RECIST guidelines); PR - 6 patients, SD - 4 patients, PD - 1 patient. The most common toxicity was skin rash (100%). Grade 3/4 toxicities were neutropenia (73%), thrombocytopenia (45%). There were 2 grade 3 and 2 grade 4 cardiovascular toxicities in patients with significant co-morbid cardiovascular histories. Conclusion: The response rate is consistent with that established for neoadjuvant chemotherapy. Ongoing biomarker studies may identify those patients most likely to benefit from induction treatment.

No significant financial relationships to disclose.
PDGFR-β expression in small cell lung cancer patients
Authors: Lu B.
Published: March 2020

17128

Background: Small cell lung cancer (SCLC) carries an extremely poor prognosis and treatment options for this disease remain poor. PDGF and PDGFR-β are expressed and have been found to have prognostic value in several human cancers. Data in non-small cell cancer cell lines have suggested that PDGFR is a therapeutic target for drug development. In the current study PDGFR-β expression and prognostic value in SCLC was investigated. Methods: Paraffin embedded tissue blocks from 53 patients with limited and extensive stage SCLC were obtained for immunohistochemical staining. Tumors from each patient were sampled three times and stained with PDGFR-β specific antibody. Patients were divided into low and high staining groups based on intensity. Results: There was high intensity PDGFR-β staining in 20 patients with SCLC. Another 29 expressed low intensity PDGFR- β staining, with only 4 patients showing no PDGFR- β staining. There was no statistically significant difference in five year overall survival between patients with low levels of PDGFR-β staining versus those with high level staining SCLC tumors (P = 0.538). Conclusions: Though expression of PDGFR-β may not be a predictor of prognosis, due to its high expression in SCLC it may represent an important target for improved tumor control, however, further studies are required to confirm this.

No significant financial relationships to disclose.
The rationale for the NEOCOR study: A new paradigm in locally advanced non-small cell lung cancer
Authors: Mitra S. S.
Published: March 2020

17146

Background: Most patients with locally advanced NSCLC die of systemic disease. (Chevalier et al JNCI 1991). Concurrent chemoRT + adjuvant chemotherapy is the standard of care based on a metaanalysis comparing sequential chemoRT and Concurrent chemoRT, with median survival increased by 3 months. (Hak Choy ASCO 2003) The aim is to critically review all the sequential trials and the metaanalysis against a scientifically valid criteria. Methods: A scientifically valid trial comparing the two approaches: sequential chemoRT versus Concurrent chemoRT needs to have equivalent chemotherapy in both arms. It also needs to have equivalent chemoRT in both arms. There needs to be an adequate course of neoadjuvant chemotherapy (at least 4 cycles) in the sequential chemoRT arm. All the relevant sequential chemoRT versus concurrent chemoRT trials are critically reviewed. Results: The sequential chemoRT trials had an average of 2 cycles of chemotherapy before radiation. (Dillman et al CALGB B 8433, Sause et al ECOG 4588, Schaakee - Koning et al NEJM 1992). The Hak Choy metaanalysis is not a comparison of the two approaches: sequential chemoRT versus concurrent chemoRT. The WJLCG Furuse trial had more intensive chemotherapy in the concurrent arm. The GLOT-GFPC study had Etoposide chemotherapy on the concurrent arm. The LAMP study, Zatloukal - Zemanova study & RTOG 9410 all had 2 cycles of chemotherapy followed by radiotherapy or concurrent chemoRT. SWOG 9504 using Cisplatin + Etoposide concurrent with Radiotherapy and adjuvant Docetaxel suggests that systemic treatment is important along with concurrent chemoRT. Betticher et al ( JCO 2003) showed that neoadjuvant chemotherapy with Docetaxel + Cisplatin achieves a 19% complete pathological response & overall 66% response rate. Conclusions: Most patients with locally advanced NSCLC still die of systemic disease. Sequential chemoRT trials did not have adequately intensive chemotherapy regimens.Concurrent ChemoRT is a better form of RT. The author proposes a phase II trial of Neoadjuvant Chemotherapy with 4 cycles of Docetaxel 85 mg/m2 D1+ Cisplatin 50 mg/m2 D1 & 2 followed by 2 cycles of Concurrrent Chemoradiotherapy with Cisplatin 50 mg/m2 D1 & D8 + Etoposide 50 mg/m2 D1–5 concurrent with 61 Gy of Radiotherapy as a new paradigm in Locally advanced NSCLC.

No significant financial relationships to disclose.
ECOG 1503: A phase II trial of triapine (NSC#663249) with gemcitabine (T/G) as 2nd line treatment of non-small cell lung cancer (NSCLC)
Authors: Traynor A. M. , Levy D. E. , Bayer G. K. , Tate J. M. , Thomas S. P. , Mazurczak M. A. , Graham D. L. , Kolesar J. M. , Schiller J. H.
Published: March 2020

17151

Background: Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) is a novel chelator of the ribonucleotide reductase (RR) subunit M2. Triapine was shown to enhance cellular uptake and DNA incorporation of gemcitabine in tumor cell lines. Preclinical evidence suggested that cells with the wild-type (wT) MDR1 gene may have lower intratumoral concentrations of Triapine. Objectives: Primary objective was response rate (RR). Secondary objectives included rate of stable disease (SD), progression free survival (PFS), overall survival (OS), and safety of T/G in the 2nd line treatment of advanced NSCLC. Correlative objectives were to examine the effects of MDR1 polymorphisms, RRM1, RRM2, and p53R2 protein and gene expression, and germline and tumor mutations of p53 on clinical outcomes. Methods: Pts with relapsed NSCLC who failed one prior cytotoxic regimen were eligible; prior gemcitabine was excluded. Treatment: Triapine 105 mg/m2 IV on days 1, 8, and 15 and gemcitabine 1000 mg/m2 on days 1, 8, and 15, of a 28 day cycle. Results: 18 pts enrolled from 11/04–1/05. Stage: IIIB (1 pt); IV (17 pts). PS: 0 (4 pts); 1 (14 pts). Median number of cycles administered: 2. No objective antitumor responses were seen. 5 pts experienced SD (range 7–135 days). Median OS: 5.4 mo (95%CI 3.98, not yet reached); median PFS: 3.2 mo (95%CI 1.7, 6.4); estimated 1 yr OS: 39% (SE 13%). Worst Gr 3/4 toxicities: leucopenia (Gr 3–8 pts; Gr 4–1 pt), neutropenia (Gr 3–8 pts; Gr 4–2 pts), hypoxia (Gr 3–4 pts), vomiting (Gr 3–2 pts). Genotyping for MDR1 polymorphisms C1236T, G2677T, and C3435T was performed on all pts. None of the 5 pts with SD were wTs. Pts with wT MDR1 had increased GI and pulmonary toxicity. Additional correlative data will be available for the meeting. Conclusions: T/G did not demonstrate clinically relevant activity in relapsed NSCLC. Genotyping for MDR1 polymorphisms may predict both efficacy and toxicity.

[Table: see text]
Expression of telomerase enzyme as predictive factor of response to first line chemotherapy with gemcitabine/carboplatin in advanced non-small cell lung cancer (IIIB and IV)
Authors: Pluma-Jimenez M. , Castillo-Medina S. , Murillo-Ortiz B. , Labastida S. , Alvarado I. , Olivares-Beltran G. , Silva J. A. , Astudillo-De La Vega H.
Published: March 2020

17156

Background: Non-small cell lung cancer (NSCLC) is the most frequent neoplasia in the world and the main cause of death for cancer. The palliative chemotherapy is the elected treatment for patients in stage III and IV. The telomerase enzyme is expressed in 82% of neoplasias and its activity is implied in the genomic instability, apoptosis inhibition and cell immortalization. Objective: To determine the predictive value of the expression of the telomerase enzyme with the first line regimen gemcitabine (1 gr/m2 SC, days 1 and 8) and carboplatino (AUC of 5 in day 1) every 28 days in patients with NSCLC clinical stages IIIB and IV. The response and toxicity rate was also determined. Methods: Patients were recruited in a period between 04/01/2004 and 11/30/2004, ages between 18 and 80, ECOG ≤ 2, measured disease (RECIST), virgin to treatment, permissible hematic biometry for chemotherapy and optimal kidney function. A total of 17 patients with an average age of 61 (range 44 to 77 years old) 9/17 (53%) males and 8/17 (47%) females, 4/17 with clinical stage IV (23%) and 13/17 with clinical stage IIIB (77%) from which: 8/13 (61%) presented pleural effusion. From the total number of patients, 1/17 presented ECOG 0 (6%), 14/17 ECOG 1 (82%) and 2/17 ECOG 2 (12%). The histopathologic diagnosis was adenocarcinoma in 12/17 (70%) and epidermoid carcinoma in 5/17 (30%). A rabbit polyclonal antibody was used to asses the expression of the telomerase enzyme by the immunohistochemical method. Results and Conclusions: It was demonstrated in 11/17 patients that the high expression of telomerase enzyme is directly correlated to the lack of response to treatment (3/11 patients stable disease and 4/11 with progressive disease); and a low or absent expression (4/11 patients) was correlated to a response higher than 30% (p = 0.045). The obtained response rate was lower that the previous ones reported with the regimen gemcitabine (days 1, 8 every 21 days and 1, 8 and 15 every 28 days) presenting a minimum hematologic toxicity. This analysis suggests that the telomerase enzyme could be a response predictive marker in the NSCLC with this therapeutic regimen.

No significant financial relationships to disclose.
A dose dense low toxicity salvage regimen for histologically aggressive non-Hodgkin’s lymphoma (NHL): Gemcitabine, rituximab, oxaliplatin combination (GROC) plus pegfilgrastim
Authors: Cabanillas F. , Liboy I. , Rodriguez-Monge E. , Pavia O. , Robles N. , Maldonado N. , Rivera E. , Suau L.
Published: March 2020

17513

High dose chemo/autologous stem cell transplant (ASCT) is standard treatment for relapsed aggressive NHL. However many are unable to receive ASCT because they are refractory to salvage therapy, too old or too sick. More effective, less toxic salvage regimens are needed prior to ASCT. Gemcitabine (G) and Oxaliplatin (O) are active agents in NHL and exhibit synergism so their combination is attractive to explore together with Rituximab (R). We hereby report the results of a phase I-II trial designed to explore the GROC regimen administered every 14 days with Pegfilgrastim support. After the first 6 pts were entered, the phase I portion was completed; recommended dose: R = 375 mg/m2 on day 1, G = 1,250 mg/M2 on day 2, O = 100 mg/m2 on day 2 and Neulasta 6 mg day 3. So far we have entered 21 pts of which 19 are currently evaluable. Median age = 58 (range = 27–88); 9 were refractory to 1st line therapy, 5 were on 1st relapse, 3 on 2nd and 2 >2 relapses, 12 had high LDH, 10 high Beta-2-M. Using IWG/PET criteria ORR = 79%, CR = 42%, PR = 37%. There was a correlation between response to preceding chemo regimen and response to GROC ( table ). In 6 the response to GROC was better than to preceding regimen while only in 2 was the response worse. At 1 year the projected OS is 49% and PFS 34%. So far, only 5 of 15 responders have relapsed. An intriguing finding is that in 6 of 15 responders, PFS has been longer with GROC than with preceding regimen and shorter in only 1. Grade 4 hematologic toxicity occurred only once. No neutropenic fevers seen. Most common toxicity was reversible transaminitis in 13 (grade 1–2 in 10, grade 3 in 3), neuropathy in 9 (grade 1–2 in 8, grade 3 in 1), diarrhea in 3 (grade 4 in 1). We could deliver courses at a median interval of 14 days. Conclusions: 1- GROC is an effective dose dense salvage regimen. 2- It appears effective even in pts with poor prognostic features including primary refractory disease. 3-Hematologic toxicity is very low and non-hematologic toxicity acceptable.

[Table: see text]

[Table: see text]
A phase II study of R-CHOP in treatment of diffuse large B-cell lymphoma (DLBCL) subgroups
Authors: Cao Y. , Lin T. , Wang S. , Fu X. , Xiao J. , Yi J. , Lin H. , Guan Z.
Published: March 2020

17540

Background: Recent studies with genes expression profiling and tissue microarray have divided the diffuse large B cell lymphoma (DLBCL) into prognostically important subgroups with germinal center B cell like (GCB) and non-GCB. However, these results are based on the samples of patients who were received standard CHOP regimen. Combination with CHOP and Rituximab (R-CHOP) has been proved to improve the survival of patients with DLBCL. To evaluate the efficacy of R-CHOP in different subgroups of DLBCL, this phase II study has been conducted. Methods: Previously untreated patients with DLBCL were enrolled in this study. No upper age limit was specified. Patients received six cycles of R-CHOP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, and prednisone 40 mg/m2 for 5 days) every 3 weeks. Immunohistochemical stains on paraffin-embedded tissues from diagnostic biopsies from these patients with antibodies against GCB cell (CD10 and Bcl-6) and activation (MUM1). These patients are divided into GCB and non-GCB groups according to the expression of antibodies against CD10, BCL-6 and MUM1. Results: A total of 64 patients were evaluated, 19 in GCB group and 45 in non-GCB group. Complete Remission (CR) rate was achieved 57.9% and 53.3%, in GCB group and in non-GCB group, respectively. (p = 0.737). A median follow-up of 2.2 years, the two-year failure free survival was no different between two groups (p = 0.566). Conclusions: In patients with GCB group or non-GCB group of DLBCL, addition of Rituximab in CHOP regimen, preliminary result was showed in similar response and survival.

No significant financial relationships to disclose.
The pre-treatment PET scans SUV inversely correlates with overall survival (OS) of high grade NHL
Authors: Sukari A. , Wong O. , Balasubramaniam M. , Decker D.
Published: March 2020

17543

Background: Parling-Lynch (Blood 2003; Abs, 102(11):4805). report a high discriminative power of maximum standard uptake value (SUV) in differentiating high and low grade lymphoma. This study examines the relationship between the pre-treatment (18)F-2-deoxy-2-fluoro-D-glucose Positron emission tomography (18-FDG PET) scans, SUV, overall survival (OS) and disease free survival (DFS) in high grade non-Hodgkin’s lymphoma (NHL). Methods: 33 patients with pathological diagnosis of aggressive NHL but without other malignancies were included; the patients had a pre treatment 18-FDG PET scan with calculated SUV. NHL was classified using WHO classification, IPI score was calculated using International Non-Hodgkin’s Lymphoma Prognostic Factors Project criteria. Cox Proportional Hazards Regression analysis was used to assess the effect of SUV and the grouped IPI Score on both overall survival and disease-free survival. Results: 29 patients have diffuse large B-cell lymphoma (DLBCL), 2 have Mantle cell lymphoma (MCL) and 2 have peripheral T-cell lymphoma (PTCL). Over a median follow up of 2.6 years (0.6–4.6), OS and DFS were 76% and 82%, respectively. Median SUV was 18.6 (1.6–55.9). Patients with higher SUV have higher risks of dying after adjusting for their IPI Score (p-value = 0.0038). Specifically, each additional unit of SUV is associated with a 9.8% increase in the hazard of death. Patients with higher IPI Score have higher risks of dying after adjusting for their SUV (p-value = 0.0017). Specifically, each additional level of IPI Score is associated with a 274.9% increase in the hazard of death. SUV is not a significant predictor of disease-free survival once IPI Score is already known/adjusted for (p-value = 0.0731). Patients with higher IPI Score have higher risks of relapse after adjusting for their SUV (p-value = 0.023). Conclusions: Pre-treatment PET scan SUV significantly affects overall survival in high grade NHL. Our data indicate statistically non significant correlation between SUV and DFS. These findings could be secondary to small study sample or short median follow up.

No significant financial relationships to disclose.
Treatment of newly diagnosed, inner-city multiple myeloma patients with low-dose thalidomide and dexamethasone and zoledronate
Authors: Klueppelberg U. H. , Kahn D. M. , Braunstein M. , Smith E. L. , Shapira I. , Batuman O.
Published: March 2020

17555

Background: The incidence of multiple myeloma (MM) is high in African Americans (AA), who are underrepresented in clinical trials. This Phase II trial assessed thalidomide (100 mg/day), dexamethasone (10–40 mg for 4 days/week x3 for 6 months, then 4 days/month), and zoledronate (4 mg/4 weeks) (TDZ) in newly diagnosed AA patients with MM. TDZ was designed to be non-myelotoxic and compatible with HAART because of the high HIV infection rate in our patients. Because it mitigates tumor growth and angiogenesis and bone resorption, zoledronate was expected to boost the therapeutic effects of thal and dex. All newly diagnosed patients were eligible. Methods: Of 45 enrollees, 38 (22F/16M; median age = 61 years) were evaluable. All had bone disease, and baseline serum beta2-microglobulin (4.9 mg/dL) and albumin (3.3 mg/dL) indicated advanced disease. Eight patients (21%) were HIV+ (7F/1M; median age = 47 years). Patients with HIV were younger (P < .001) and had higher β2-microglobulin levels (P = .003), and 6 were on HAART. Patients were treated for 24 months or until disease progression. Results: Mean duration of treatment was 18 months (range = 3–24). Age-adjusted one-year survival was 74.4%, identical to SEER data (73.7%). Near-CR was achieved in 30% (7 HIV-/4 HIV+) and partial remission in 68% (22 HIV-/3 HIV+) of patients. Median time to maximum response was 4.5 months in HIV- patients and 2.5 months in HIV+ patients (P < .05). Overall cumulative survival at 24 months was 68% by Kaplan-Meier analysis, and was unaffected by HIV status, age, or sex. Creatinine clearance both for HIV+ and HIV- patients was normal, and was unaffected by TDZ. Despite daily ASA, thromboembolism occurred in 13% of patients. No other significant toxicity was observed. Ten patients died (9 HIV- and 1 HIV+); deaths were due to MM progression (n = 3), MM complications (n = 3), and causes unrelated to MM (n = 4). Conclusions: TDZ is safe and effective in the long-term management of MM, and is comparable to high-dose chemotherapy with stem cell rescue for both HIV- and HIV+ patients. TDZ is without renal or osteonecrotic side effects. The faster response to TDZ in HIV+ MM patients on HAART suggests a cooperative interaction between the two regimens.

No significant financial relationships to disclose.
Multiple primary cancers in patients with non-Hodgkin’s lymphoma
Authors: Song H. , Do Y. , Lee W. , Lee J.
Published: March 2020

17562

Background: Multiple primary malignant tumors have been documented with increased frequency over the last two decades. An analysis of other primary cancers in individuals with non-Hodgkin’s lymphoma (NHL) can help to elucidate this cancer epidemics and etiology. Methods: The occurrence of multiple malignancy was studied in patients with NHL from 1985 to 2005. Results: One or more additional cancers were observed in 19 patients. Seven were diagnosed prior to, 5 concomitantly with, and 7 after the diagnosis of NHL. The diagnosis of 5 synchronous primary cancer were rectal cancer, squamous cell esophageal cancer, prostatic cancer, transitional cell bladder cancer, and non-small cell lung cancer. Each cases of colon cancer, breast cancer, hepatoma, small cell lung cancer, stomach cancer, cervical cancer, and rhabdomyosarcoma were diagnosed prior to NHL, and the second primary cancers were two squamous skin cancer and each cases of melanoma, colon cancer, thyroid cancer, adenocarcinoma of the salivary gland, and cholangiocarcinoma. The mean age of synchronous cases was 68.2 ± 4.8 years-old, and all 5 cases were primary extranodal NHL (2 gastric, 1 nasopharynx, 1 nasal, 1 rectal) and pathologic diagnosis were diffuse large cell in 4 cases and extranasal NK/T cell type in one case. The mean age of the second primary NHL was 57.6 ± 11.4 years-old, and 5 of 7 cases were extranodal origin (each one case of colon, tonsil, tongue, stomach, and CNS), and were diagnosed 11, 19, 24, 72, 73, 101, 168 months after the diagnosis of variable cancers. The mean age of the second primary cancer was 46.9 ± 15.9 years-old, and 3 of 7 cases were extranodal origin (2 gastric and 1 tonsil), and were diagnosed 55, 73, 75, 99, 144, 156, 161 months after the diagnosis of NHL. Conclusions: The synchronous cases of NHL were more older and more frequent extranodal manifestations than metachronous cases.

No significant financial relationships to disclose.
Immunophenotypic diversity and prognosis of adult T-cell leukemia/lymphoma
Authors: Carrasco A. , Beltran B. , Malaga J. , Ferrel G. , Rios H. , Castillo J. , Huamani J. , Rodriguez M. , Flores D. , Falcon S.
Published: March 2020

17565

Background: Adult T-cell leukaemia/lymphoma (ATLL) is an aggressive disease associated with human T-cell lymphotropic virus type-I (HTLV-I) with heterogeneous clinical presentation and outcomes, described in Southern Japan, Europe, Caribbean and previously on Pacific coast of South America including Peru (EHA 2001, abst. 304). Shimoyama’s ATLL classification (BHJ 1991:79), includes four types: acute, lymphomatous, chronic and smouldering; recently a new clinical cutaneous type had been described (BJD 2005:152). Methods: We described our experienced previously (ASH 2005, abst. 4797). Herein we analyzed immunophenotypically our ATLL patient population by flow cytometry looking for aberrant phenotypes and their correlation with overall survival. The statistical method was descriptive and survival was calculated using the Kaplan-Meier method. Results: From July 1997 to March 2005 our registry had 69 cases, 37 had flow pre-treatment: acute type (n = 31) and lymphomatous (n = 6). Over our 37 flow done we were able to analysis only 33. The incidence of the typical (CD4+/CD8-) phenotype, the double-negative (CD4-/CD8-), the double-positive (CD4+/CD8+), and the CD8 positive (CD4-/CD8+) phenotypes was 58%, 12%, 15%, and 12% respectively. The median overall survival (OS) for the 33 patients was 4.1 months (range: 0.5–46.1). The patients with typical phenotypes had a median OS of 4.1 months better than the patients with the double-negative phenotype whom median OS was 2.0 (range: 1.5–9.7) but not significant. Median OS in the double positive and the CD4-/CD8+ phenotype population were 15.2 and 4.8 months respectively with no significance Conclusions: ATLL has a diversity of immunophenotype, our data suggest that there is not any correlation with survival, major accrual will gave us a final conclusion.

No significant financial relationships to disclose.
Higher persistency with i.v. bisphosphonates in patients with bone metastasis
Authors: Mangiapane S. , Hoer A. , Gothe H. , Barghout V. , Haeussler B.
Published: March 2020

18623

Background: Patients with advanced cancer are at high risk for bone metastasis, leading to accelerated bone resorption and skeletal related events and a loss of autonomy. Bisphosphonates can reduce the risk of skeletal complications, provided that patients remain on therapy. The aim of our study was to compare the persistency rates of oral and intravenous (i.v.) bisphosphonate therapy regimes in patients with bone metastasis in a natural setting. Methods: Claims data from a German sickness fund (2002 to 2004) were used. Patients had ICD-10 diagnoses for bone metastasis, were receiving oral or i.v. bisphosphonates (exclusively with a specific approval for patients with bone metastasis) and could be followed-up at least 7 months after their index prescription. Persistency was defined as the continuous prescription refill without an interruption of longer than 30 days. Medication Possession Ratio (MPR) was calculated after 180 days of follow-up and Kaplan Meier curves were analyzed. Results: We identified 233 patients who met our inclusion criteria, 85.8 % getting i.v. and 14.2 % getting oral therapy regime (prescribed bisphosphonates: zoledronate (60.5 %), pamidronate (27.5 %), clodronate (18 %), ibandronate (13.7 %)). Most of them had breast cancer (46.4 %) or prostate cancer (31.8 %). By the end of 6 months, only 64.4 % of all patients on bisphosphonate therapy were defined to be compliant, as they had a MPR ≥ 0.8 (36.4 % of the oral group and 92 % of the i.v. group). Kaplan Meier curves for oral and i.v. bisphosphonate therapy regime differed significantly (p = 0.0012). Conclusions: Persistency rates with oral bisphosphonates are significantly lower than with i.v. bisphosphonates in patients with bone metastasis (36.4 % vs. 92 %). Given the importance of preventing skeletal complications, persistency must be considered when selecting the optimum treatment regime for patients with advanced cancers.

[Table: see text]
Analysis of five-year survival rate in patients with proximal femoral tumours after total hip replacement
Authors: Saravanan S. A. , Sokolovski V. , Voloshin V. , Aliev M. , Zybikov V. , Nisichenko D.
Published: March 2020

19508

Background: To analyse the five-year survival rate in patients with proximal femoral tumours after total hip replacement. Methods: Between the period of 1994–2003, 50 patients were operated (Total Hip Replacement) for proximal femoral tumours at the Department of General Oncology (Bone & Soft tissue tuomurs), N. N. Blokhin Cancer Research Institute & Moscow Regional Clinical Research Institute, Moscow, Russian Federation. The histological diagnoses included 14 - metastases, 10 - osteosarcoma, 8 - chondrosarcoma, 4 - Ewing’s sarcoma, 4 - Giant cell tumor, 3 - malignant fibrous histiocytoma, 2 paraosteal and 2 periosteal osteosarcoma, and 1 each from primary neuroectodermal tumor, myeloid disease, and aneurysmal bone cyst. The follow-up ranged from 1–9 years (mean follow-up 5 years). 21 patients (45.7%) had pathological fracture. The cause of the pathological fracture was metastasis in 12 patients (26%). 28 patients (60.8%), had soft tissue invasion. All the survival analyses were done using Kaplan-Meier survivorship analysis method. Functional outcome was estimated using Enneking’s evaluation criteria. Results: The overall survival rate of patients was 66.7% at 5 years. 2 patients had local recurrence.12 patients had metastases after surgery. In that 11 patients were died. There was no evidence of disease in 32 patients. In 3 patients, we performed disarticulation of the hip joint because of the local recurrence. The overall survival rate of limb was 92.7% at 5 years. The overall survival rate of prostheses was 84.2% at 5 years. At the latest follow up, functional outcome was excellent in 15 (30%) patients, good in 27 (54%) patients, fair in 5 (10%) patients, poor in 3 (6%) patients. Conclusions: Though the extent of the muscle and bone resection is large, there is no doubt that endoprosthetic replacement of the proximal femur provides a good functional and oncological outcome when compared with the various other reconstructive surgeries.

No significant financial relationships to disclose.
Evaluation of HER-2 expression in breast cancer using image analysis incorporating automatic feature recognition
Authors: Murray C. , Maddison J. , Anderson C. , Challender D. , Palmer S. , Rodgers J.
Published: March 2020

20007

The currently favoured method for evaluation of HER-2 in routine clinical practice and research studies is immunohistochemistry (IHC). As standardised scoring of protein expression, using a scale of 0 - 3+, generates a significant number of false positives, fluorescent in situ hybridisation (FISH) is used to confirm the presence of gene amplification. Both techniques are laborious, and in the case of by-eye scoring of IHC, semi-quantitative at best. We have developed a high-throughput platform for the quantitative analysis of immunostained slides, based on fast, high-resolution scanning followed by analysis of digitised images (IA) using proprietary software, and in this study compared results obtained using this platform with those obtained using conventional methods. Archival sections of primary breast cancers collected at Nottingham City Hospital in 2004 and 2005 were stained for HER-2 (Herceptest, Dako), and evaluated by eye. Equal numbers of slides from scoring categories 0–3+ were then selected for further image analysis. The digitised images were subjected to automatic delineation to define areas of tumour parenchyma, and these areas further analysed using colour segmentation. Between 100 and 2000 fields were quantified on each section. Staining was expressed as a product of field fraction of coloured pixels and optical density. The results of IA demonstrate a continuum of staining values over the four conventional by-eye categories, with a non-linear correlation to by-eye scores. Inter-sample variation was greatest in the 3+ category, although the mean was much higher than that of the 2+ samples. The 2+ samples showed some variation, with several values not rising above baseline. To further investigate the relationship between FISH scores and IA results in the 2+ category, we analysed an additional set of slides in this group, and found a correlation between FISH and automated IA scores. We conclude that automated image analysis is sensitive to small differences in protein expression, has a wide dynamic range, and provides data superior to conventional by-eye scoring. In undecided cases HER-2 protein expression correlates with FISH data; therefore ultimately IA of HER-2 protein expression alone may provide a basis for clinical decisions.

[Table: see text]
Tissue-dependent and tissue-independent gene expression changes in metastatic colon cancer
Authors: Shen P. , Hellmann G. M. , Gmeiner W. H.
Published: March 2020

20014

Background: Changes in gene expression that occur during cellular transformation and establishment of metastases provide valuable information that may help determine prognosis and direct treatment. We have obtained gene expression profiles from primary colon tumors and metastases to the liver (V), lung (L), and peritoneum (P). Methods: Ten cases, with matched controls, were profiled for the expression of >18,000 human transcripts using Affymetrix U133A chips. Data were filtered using GeneSifter analysis software to identify genes with 2-fold or greater differences in expression relative to the control group. Gene expression levels for primary colon samples were compared to normal colon while metastatic tissues were compared to primary colon samples. Differentially regulated genes were then associated with KEGG pathways for additional analysis. Results: Relative to normal colon samples, primary colon samples displayed high positive z-score values for genes involved in nitrogen and sulfur metabolism (7.30 and 8.10, respectively). Expression level changes for individual genes in each cluster were statistically significant (e.g. p = 0.014 for carbonic anhydrase I in the nitrogen metabolism cluster). Metastatic tissue from liver, lung and peritoneum all displayed substantially decreased expression for genes involved in butanoate and propanoate metabolism, valine, leucine and isoleucine degradation, and moderately decreased expression for genes involved in JAK-STAT signaling. For example, L-3-hydroxyacyl-Coenzyme A dehydrogenase (short chain), a gene involved in both butanoate metabolism and valine, leucine and isoleucine degradation, was down-regulated in tissue from all three metastatic sites relative to primary colon tumor tissue [p = 0.024 (V), p = 0.022 (L), p = 0.005 (P)]. In addition, genes involved in phosphatidylinositol signaling were down-regulated in liver metastases but not in lung or peritoneal metastatic tissue. Conclusions: These results demonstrate that changes in expression levels for genes involved in basic metabolism and cell signaling occur during the course of metastasis. The changes that occur during development of the metastatic phenotype can be independent of, or specific to, the site of metastasis.

No significant financial relationships to disclose.