bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of irinotecan, carboplatin, and bevacizumab in patients with limited-stage small cell lung cancer
Authors: Zubkus J. D. , Spigel D. R. , Greco F. A. , Yardley D. A. , Burris H. A. , Vazquez E. , Farley C. , Patton J. F. , Hart L. , Hainsworth J. D.
Published: March 2020

18133

Background: In a previously reported phase II trial bevacizumab (B) was used as maintenance therapy following induction with irinotecan (I), carboplatin (C) and radiotherapy (RT) in patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). 1-year progression- free survival (PFS) and overall survival (OS) were 53% and 70%, respectively. In the present multicenter community-based trial B is given with induction chemoradiotherapy and as maintenance therapy. Methods: The primary endpoint is to assess the median PFS. Eligibility criteria: newly diagnosed LS-SCLC, measurable disease, ECOG PS 0–1, and informed consent. Exclusion criteria: hemoptysis and therapeutic anticoagulation. Treatment: I 60mg/m2 IV D1, 8, 15, C AUC=4 IV D1, and B 10 mg/kg IV D1 and 15 every 28D. Pts received concurrent RT to 61.2 Gy starting with the 3rd cycle, and were restaged every 8 weeks. If no progressive disease (PD) or excessive toxicity after 4 cycles, pts received B x 6 months. Prophylactic cranial irradiation was used at M.D. discretion. This 2-stage trial was designed to achieve a 40% improvement in historical median PFS of 12–14 months. Results: 20 pts were enrolled from 4/06 to 12/06 (trial ongoing, n=50 planned). Data are available for 14 pts in this analysis. Baseline features: median age 64 years; male/female, 21%/79%; and ECOG PS 0/1, 64%/36%. The objective response rate was 78% (95% CI 45%-94%) - all partial responses. No pt had PD. 7 pts were not evaluable: too early, 5 pts; off study (toxic megacolon, 1 pt; intercurrent illness, 1 pt). With a median follow-up of 5 months, the median PFS has not been reached. Grade (G) 3/4 non-hematologic toxicity with induction occurring in more than 2 pts: diarrhea (29%) and esophagitis, fatigue, pain (21% each). G3/4 hematologic toxicity: leukopenia (21%), neutropenia (14%), and thrombocytopenia (43%). There have been 2 G3/4 bleeding events with induction: suspected tracheoesophageal fistula with death (possibly treatment-related), 1 pt; and hematochezia, unrelated, 1 pt. Conclusions: This trial continues to be closely monitored for safety. Further accrual and longer follow-up are necessary to assess if B can be safely combined with chemoradiotherapy and improve efficacy.

No significant financial relationships to disclose.
Gefitinib (G) treatment outcome after progression on erlotinib (E) in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Grossi F. , Brianti A. , Defferrari C. , Loprevite M. , Catania G. , Pronzato P.
Published: March 2020

18138

Background: Two case reports describe a response to E after failure of G (Garfield DH, J Clin Oncol 2005) or to G after failure of E (Choong NW et al, Nat Clin Pract Oncol 2006) in patients (pts) with advanced NSCLC. Otherwise, a limited experience in 5 pts suggests that E is not effective in pts progressing on G (Viswanathan A et al, Lung Cancer 2005). Aim of this study was the evaluation of response and time to progression (TTP) in advanced NSCLC pts treated with G after failure of E. Methods: Pts received G 250 mg/day after disease progression (PD) with E 150 mg/day. Pts accrual was stopped on August 2006 after the approval of E for use in Italy and the consequent closure of the G compassionate-use program. Results: From May 2005 to August 2006, 15 pts were enrolled. Median age 65 years (50–85); males= 14 pts (93%); never/former smokers= 4/10 pts (26/67%); adenocarcinoma= 10 pts (67%); PS 0/1= 5/10 pts (33/67%); in 2 pts (13%) E was administered as first-line therapy, 8 pts (53%) received 2 prior lines of chemotherapy (CT) and 3 pts (20%) received CT between E and G. One patient (7%) had a partial response (PR) and 5 pts (33%) had disease stabilization (SD) with E; with G no PR and 6 SD (40%) were obtained. Five out of 6 RP/SD pts with E, had SD with G; 8 out of 9 PD pts with E, had PD with G; 1 SD patient with E, progressed with G and 1 vice versa. TTP in RP/SD pts was 7.2 and 3.4 months for E and G respectively; in PD pts TTP was 1.7 and 1.6 for E and G respectively. Conclusions: Our data suggest that there is a benefit with G in pts who had RP/SD with E and that is associated with a good TTP. Conversely G is not recommended in pts that immediately progressed after E. Moreover these results support the rationale of treating PD pts with an EGFR TKI with another one; it may be worthwhile to collect more data on E.

No significant financial relationships to disclose.
Ca-15.3 antigen as predictor of response to EGFR inhibitors in patients with bronchiolo-alveolar carcinoma
Authors: Bearz A. , Talamini R. , Vaccher E. , Spina M. , Simonelli C. , Berretta M. , Spazzapan S. , Tirelli U.
Published: March 2020

18151

Background: Bronchiolo-alveolar carcinoma (BAC) is a subtype of non-small cell lung cancer (NSCLC). Incidence of pure BAC ranges between 2% and 5% of NSCLC although a BAC histotype may be present in up to 20%. There is no established treatment for BAC, although promising results have been achieved from the use of inhibitors of the Epidermal Growth Factor Receptor (EGFR). It has been demonstrated that there is a very close relationship between responsiveness to EGFR inhibitors Erlotinib and Gefitinib and some factors, including female gender; adenocarcinoma histotype, with BAC features; Asian origin; and never having smoked. No tumor marker has been validated in the diagnosis and follow-up of lung cancer. Ca 15–3 antigen serum levels are reported to be pathologically abnormal in adenocarcinoma of the lung, although it does not seem to be related to the EGFR pathway. We studied this tumor marker in relation with the treatment with EGFR inhibitors in patients affected by BAC. Methods: We collected data from 16 caucasian, female and never smoker pts with BAC. All pts received EGFR inhibitors as first-line therapy. In compliance with the EAP, dosage of Gefitinib and Erlotinib was 250 mg/day and 150 mg/day, respectively. Results: One (6%) pt had a complete response and 6 (38%) showed a partial response to EGFR inhibitors, 1 (6%) pt remained stable for 4 months, while 8 (50%) pts progressed. All 7 pts with normal Ca 15–3 levels before treatment with EGFR inhibitors’ achieved a partial or complete response, but the 8 pts with abnormal Ca 15–3 levels did not (p=0.0001). Among the responders we noticed an increase of Ca 15–3 serum levels at progression. In particular, 5 pts had an increase of Ca 15–3 serum levels up to normal value when their disease progressed; 2 pts have not progressed yet and Ca 15–3 serum levels remain normal. Conclusions: We suggest that Ca 15–3 levels may be a prognostic factor to predict the response to EGFR inhibitors in pts with BAC. We are studying its role in a larger population with BAC and in other NSCLC subtypes as well.

No significant financial relationships to disclose.
A phase I/II study of pemetrexed plus cisplatin in Japanese patients with malignant pleural mesothelioma
Authors: Gemba K. , Yamazaki K. , Kunitoh H. , Hida T. , Nakagawa K. , Shinkai T. , Ichinose Y. , Nambu Y. , Saijo N. , Fukuoka M.
Published: March 2020

18152

Background: Pemetrexed (pem) is globally used for the treatment of malignant mesothelioma (MPM) in combination with cisplatin (cis). Pharmacokinetic (PK) difference of pem/cis between Western and Asian population (pop) so far remains unknown. To investigate safety/efficacy of pem/cis therapy and PK profiles of pem/cis for Japanese (Jpn) MPM patients (pts), we designed a phase I/II study. Methods: Primary objectives in phase (Ph) I part were to determine a recommended dose (RD), and in Ph II part were to examine the efficacy of the RD and safety. PK profiles were to be analyzed as a secondary objective. A cohort of 6 pts, starting from a dose of pem 500 mg/m2 and cis 75 mg/m2 (level 1: LV1), was used in the dose-escalation Ph I. The efficacy of the RD was to be evaluated in at least 18 pts in the study. Key eligibility criteria were: histologic diagnosis of MPM incurable by surgery, no prior systemic chemotherapy, and a performance status 0–1. Under full vitamin supplementation, pem was administered as a 10-min. infusion on day 1 of a 21-day cycle, followed by cis administration as a 2-hr. infusion 30 min. after pem administration. For comparison of PK profiles, PK data of this study and a Western phase III study were analyzed by pop PK approach. Results: In Ph I, 13 pts were enrolled: 7 in LV1 and 6 in level -1 (LV-1: pem 500 mg/m2 and cis 60 mg/m2). Two dose-limiting toxicities were observed in LV1: pneumonitis and neutropenia. The RD were then determined to be LV1. In Ph II, 12 pts were enrolled in LV1. For safety, one drug-related death was reported among 25 pts due to worsening of underlying pneumonia observed before enrollment. The most common G3/4 toxicities were neutropenia and hemoglobin decrease. For efficacy, a partial response was achieved for 7 of 19 pts who received LV1. Response rate was 36.8% (95% CI: 16.3- 61.6). PK profiles of pem/cis in Jpn pts were similar to those in Western. The results of other secondary objectives, e.g., progression-free survival, QOL, and pulmonary function test, will be presented in the conference. Conclusions: The profiles of efficacy/safety/PK shown in this study are almost comparable to those in Western pts, and indicate that pem/cis therapy will be a promising therapy for Jpn MPM pts.

No significant financial relationships to disclose.
Gemcitabine in combination with oxaliplatin as second-line therapy of advanced and metastatic NSCLC
Authors: Alencar A. J. , Blaya M. , Raez L. , Farfan N. , Lopes G. , Walker G. , Flores A. , Macintyre J. , Rocha-Lima C.
Published: March 2020

18157

Background: Single agent gemcitabine is active as second line therapy in NSCLC. Oxaliplatin may be non-cross resistant with the other platinum-containing agents used as first-line therapy in NSCLC. The combination of gemcitabine and oxaliplatin (GEMOX) is synergistic in pre-clinical models. Methods: A phase II, non-randomized trial was designed to assess the efficacy and tolerability of gemcitabine 1,000 mg/m2 over 100 min in combination with oxaliplatin 100 mg/m2 over 2 hours both given on days 1 and 15 of each 28-day cycle. Patients with NSCLC were eligible if they had progressed after first line treatment. Primary endpoint was tumor response rate. Planned sample size is 30 patients over a period of 2 years. Functional Assessment of Cancer Therapy- Lung (FACT-L) v.4 questionaire was used to assess quality of life of patients on therapy. Results: Twenty-two patients have been enrolled. 13 males (59%) and 9 females (41%). 15 Hispanic (68%), 4 Caucasian (18%), and 3 African-American (13%). Median age is 55 yrs. Histologic subtypes are as follows: adenocarcinoma, 12; NSCLC not otherwise specified 7; squamous cell carcinoma, 3. Nine patients had an ECOG performance status (PS) of 0 (41%) and 13 had a PS of 1 (59%). Two patients were never smokers. A total of 56 cycles have been administered (median 2, range 1 to 6). GEMOX as second-line therapy was given to 18 patients (81%), third-line to 4 patients (18%). Two patients died on study from disease progression leading to respiratory and multi-organ failure. The following Grade 3 and 4 adverse events were seen in 2 patients each: fatigue, dyspnea, anemia, and multi-organ failure. Cancer pain was seen in 1 patient. Twenty patients are available for assessment of response. Two patients had a confirmed partial response (10%) and another eight had stable disease (40%). Preliminary results of FACT-L analysis in 19 pts shows improvement in Lung Cancer Subscale (LCS) score in 25% of the patients after 2 cycles of therapy. Conclusions: Combination gemcitabine and oxaliplatin is active and well tolerated as second line treatment for NSCLC. Improvement of LCS score after 2 cycles suggests a clinical benefit that is beyond the observed response rate of 10%.

No significant financial relationships to disclose.
Topotecan and etoposide as salvage chemotherapy in patients with irinotecan- and platinum-failed small-cell lung cancer: A phase II study
Authors: Choi H. , Choi B. , Shin S. , Cheon S. , Cheon S. , Jung J. , Kim Y. , Sohn J. , Kim J. , Kim J.
Published: March 2020

18177

Background: The efficacy and safety of a combined regimen of topotecan and etoposide was tested in patients with relapsed or refractory small-cell lung cancer. Methods: From October 2003 to May 2005, 23 patients who have failed to the previous irinotecan and platinum chemotherapy received intravenous topotecan 1mg/m2 (day 1–5) followed by intravenous etoposide 80mg/m2 (day 1–3). Treatment was repeated every 21 days for a maximum of 6 cycles. Results: Twelve patients were refractory to first-line chemotherapy. Seventeen patients (73.9%) were male and the median age was 63 years. ECOG performance status was 0–1 in 13 (56.5%) patients. The median cycles of chemotherapy was 3. Twenty one patients were assessable for response evaluation. The overall response rate was 17.4% (0 CR, 4 PR, 7 SD, 10 PD) under the intent-to-treat analysis. After a median follow- up of 20.8 months, median progression free survival was 4.7 months and median overall survival was 9.5 months. The estimated 1-year survival rate was 38.7%. In sensitive relapsed patients, 2 achieved tumor response and median progression free survival and overall survival were 5.5 months and 14.5 months. All patients were assessable for toxicity and major toxicities were myelosuppression. Grade 3/4 neutropenia and thrombocytopenia occurred in 18 (78.3%) and 12 (52.2%) patients, respectively. Grade 3/4 febrile neutropenia occurred in 2 patients (8.7 %) and infection in 3 patients (13.0%). There was one treatment-related death due to pneumonia. Conclusions: This salvage regimen failed to demonstrate a considerable response rate compared with monotherapy for relapsed or refractory SCLC. However, the combination of topotecan and etoposide could be further studied for sensitive relapsed patients pretreated with irinotecan and platinum

No significant financial relationships to disclose.
Investigation on the serum antibodies levels against Epstein-Barr virus in pulmonary lymphoepithelioma-like carcinoma
Authors: Niraula S. , Zong Y. S. , Zhai L. Z. , Guo C. C. , Lin T. Y.
Published: March 2020

18186

Background: Pulmonary lymphoepithelioma-like carcinoma (PLELC) belongs to large cell sub-type of non-small cell lung cancer (NSCLC) with just about 160 cases reported previously. Its epidemiology, prognosis and therapeutic approach is evidently different from other NSCLCs. EBV infection is seen in 100% of Asian PLELC patients whenever tested. The aim of this study was to analyze serum antibodies level against EBV in PLELC patients. Methods: Sera of all seven patients with re-confirmed PLELC from a single institute in Canton, China in the past 4 years were collected. Serum levels of 8 different antibodies against EBV (Epstein-Barr virus): EBNA1 (EBV nuclear antigen 1- IgA and IgG), Zta (Bam Z transactivator antigen-IgA and IgG), VCA-p18 (Viral capsid antigen-p18-IgA and IgG), VCA-antigen complex (VCA-IgA) and Early antigen complex (EA-IgA ) were measured in each of these patients using enzyme-linked immunosorbent assay and Immunoenzymatic assay respectively. Results: Out of 7 cases, 6 showed high EBNA-1 level, 4 showed high zta, 3 showed high VCA-p18, 3 showed high titer of VCA complex and 2 showed high EA complex titer ( Table 1 ) Conclusions: Though small sample size, this is the first study in this depth ever to conclude that sera of all Asian patients with pulmonary LELC have high antibody titers against EBV. The infection mainly is latency II type as seen in Nasopharyngeal carcinoma and Hodgkin’s disease as well. A small portion of PLELC express lytic products such as Zta, EA and VCA. The authors assume that pre-therapeutic measurement of serum levels of anti-EBV antibodies (at least 2 kinds) is highly warranted in suspected Asian NSCLC patients. Positive result strongly puts PLELC into differential diagnosis.

[Table: see text]

No significant financial relationships to disclose.
Gemcitabine and cisplatin double as neoadjuvant chemotherapy for operable 1B-IIIB stage NSCLC patients
Authors: Gorbounova V. , Polotsky B. , Marenich A. , Breder V. , Laktionov K. , Gerasimov S. , Dgebuadze E. , Fedenko A. , Kolesnik A. , Rodnikova E.
Published: March 2020

18190

Background: the ongoing open-label, nonrandomized clinical trial on the evaluation of the efficiency and safety of gemcitabine/cisplatin as neoadjuvant chemotherapy of operable NSCLC. Methods: 37 chemonaive patients (male- 30 (81%) and female- 7 (19%), median age 54), ECOG 0–1 with morphologically verified NSCLC recieved gemcitabine 1250 mg/m2 IV on days 1,8 plus cisplatin 75 mg/m2 IV on day 1. The follow-up period was 3 years after the surgery. Results: Most of patients recieved 3 cycles in neoadjuvant setting. IB stage had 5 (13.5%) patients, IIB- 3 (8.1%), IIIA- 23 (62.2%) and IIIB- 6 (16.2%) patients. At baseline 12 (32.3%) patients had ECOG 0 and 25 (67.7%) ECOG 1. CR was registered in 3 (8.1%) patients, PR in 12 (32.3%), SD in 19 (51.3%) and PD in 2 (5.4%) and 1 patient was not assessed. The most common hemotologic toxicity was mild/moderate neutropenia that didn’t need dose reduction or intercycle interval prolongation. 25 patients underwent curative surgery with median survival of 30 months, 1-year survival of 81%, 2-year survival- 60% and 3-year survival - 40%. There was no statistically significant dependance between the level of pathomorphosis and the intensity of clinical response.6 patients recieved explorative thoracotomy and 6 didn’t recieve any surgery. Conclusions: Preliminary results show that gemcitabine/cisplatin combination is an effective and well-tolerable neoadjuvant regimen for patients with operable NSCLC.

No significant financial relationships to disclose.
Pemetrexed in second-line therapy in patients with malignant pleural mesothelioma
Authors: Serke M. , Bauer T.
Published: March 2020

18198

Introduction: Based on the study of Vogelzang (2003) standard treatment in patients with malignant pleural mesothelioma (MPM) is pemetrexed cisplatin with a medium survival of 12 months compared to 9 months with cisplatin therapy. As this treatment prolongs survival, but is not a curative treatment, many patients will relapse during the course of their disease. In sensitive relapses (within more than 3 months) our policy was to reintroduce pemetrexed therapy in unselected consecutive patients. Methods: Retrospective analysis of 17 consecutive patients treated in our hospital. Patient characteristics: 17 patients (pat), 14 males, 3 females, with MPM were included between April 2004 and November 2006 with an age between 45 and 82 years, with a median age of 65 years. Histologic subtypes were: 16 epithelial, 1 biphasic MPM. Pretreatment: 8 pat. had undergone palliative debulcing surgery (pleurectomy) 1 pat. underwent EPP. All patients were pretreated with platinum /pemetrexed, 5 pat. were pretreated with platinum/Gemcitabine before the availability of pemetrexed. 2nd line chemotherapy: 9 pat. were treated with carboplatin AUC5 / pemetrexed 500 mg/m2, 1 patient had cisplatinum 75 mg/m2/Pemetrexed 500 mg/m2 and 7 patients had pemetrexed single agent therapy (500 mg/m2 d1, WH d21), repeated on day 22 respectively. Results: Response: 6% (n=1) PR, MR: 12% (n=2 )., NC: 47% (n=8)., PD: 35% (n= 6), clinical benefit (PR, MR, NC) was seen in 65% of ou pat. Toxicity: Pemetrexed/Carboplatin or pemetrexed therapy were well tolerated, toxicity was mild: one patient developed mild sensory neurotoxicity (peripheral sensory neuropathy) (WHO II) under 6 cycles pemetrexed, 35% developed mild fatigue (Who I and II), one patient had mild renal impairment, no alopecia was seen. Survival: Only 3 patients had still died, median survival from start of second-line pemetrexed-therapy was not reached, time to progression was between 25 and 630 days, 4 pat. had not progressed until now. Conclusion: Second line therapy in MPM is not yet standard of care. Nevertheless patients with progressive disease following pemetrexed/platinum therapy may benefit from second line pemetrexed reintroduction therapy. Clinical benefit was seen in 65% with low toxicity.

No significant financial relationships to disclose.
Anti-cancer gene expression profile of curcumin identifies new therapeutic targets in squamous cell lung carcinoma in vitro
Authors: Sen S. , Singh A. , Pal A. , Sharma C. , Kar R. , Singh N.
Published: March 2020

18203

Background: Lung cancer is notorious for early metastasis and very high mortality, worldwide. Curcumin, a chemopreventive has also shown chemotherapeutic potential but its mechanisms are still not well understood. In this study, the genes targeted by Curcumin were investigated to identify new targets for the therapy of squamous cell lung carcinoma (SCC) in vitro. Methods: Lung squamous cell carcinoma cells (H520) were cultured in DMEM with 10% FCS. They were treated with Curcumin (25μM) for 24 hours. Apoptosis was detected by morphological examination, MTT assay, flowcytometry and TUNEL assay. Microarray analysis of gene expression profiles on curcumin treatment was done. Real time quantitative RT-PCR confirmed the results. Results: Curcumin (25μM for 24 hours) caused 29.8 ± 2.1% cytotoxicity (MTT assay). Apoptosis was corroborated by flowcytometry (23.7 ± 1.4%) and TUNEL (21.6 ± 1.8%). Using microarray analysis, 34 genes were seen to be upregulated and 31 genes downregulated after curcumin treatment. Several apoptosis related genes were upregulated including GADD45a (3.36 fold), transcription factor Egr-1 (2.2 fold) and Peroxiredoxin-I (2 fold). In addition, Angiopoietin-2 (Ang-2), an angiogenic factor that promotes angiogenesis and tumor invasion was downregulated (1.7 fold). Real time quantitative RT-PCR confirmed the results. Conclusions: This study helps to identify novel putative intervention sites as targets for curcumin in the therapy of squamous cell lung carcinoma (SCC) in vitro and can contribute to better understanding of lung tumorigenesis and anticancer therapy.

No significant financial relationships to disclose.
High incidence of symptomatic methemoglobinemia (metHb) in Asian patients (pts) treated with 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, triapine) and gemcitabine (GEM) in a second-line phase II trial of metastatic non-small cell lung cancer
Authors: Ma B. , Tan E. H. , Mok T. , Lam K. C. , Soo R. , Leong S. S. , Wang L. Z. , Mo F. , Chan A. T. , Goh B. C.
Published: March 2020

18207

Background: Triapine (Vion Pharmaceuticals) is an inhibitor of ribonucleotide reductase that can enhance GEM uptake in GEM- resistant cell lines. Clinically significant metHb has been rarely reported with triapine & G6PD-deficient pts maybe more susceptible. This multicenter study evaluated the activity & safety of combined triapine-GEM in pts with metastatic NSCLC who had progressed despite prior response or disease stabilization to 1st line platinum-GEM regimen. Methods: Eligible pts were treated with triapine (105mg/m2) as 4-hr IV infusion, followed by GEM (1g/m2) over 30-min on days 1, 8 & 15, repeating every 28 days for 6 cycles. G6PD-deficient pts were excluded. Results: 6 males & 6 female Asian pts (median age: 65 yrs) received a median no. of 2 cycles (range 1–6 cycles). At a median follow-up of 4.6 mos, no response was seen. 4 pts had stable disease. Median time to progression was 3 mos (95% CI: 1.7–9.1 mos). Gr 3–4 toxicities included neutropenia (gr 3, 2 pts), hypoxia (gr 3, 3 pts) & dyspnea (gr 3, 1 pt). There were no treatment-related deaths & all pts remained alive at analysis. 4 pts developed symptomatic metHb during, or ≤ 4 hrs of stopping triapine. This was manifested as dyspnea &/or hypoxia, associated with an oxygen saturation of ≤90% at room air. Arterial metHb assay performed during the hypoxic episode showed a metHb level of up to 15% of total concentration of hemoglobin ([Hb]), which fell to < 5% of [Hb] within 4–6 hrs of stopping triapine. All pts recovered with conservative treatment & none required reversal with methylene blue. 3 out of the 4 pts were able to continue treatment after dose-reduction of triapine. Conclusions: The cause of the relatively high incidence of triapine-related symptomatic metHb was unclear in this Asian cohort. This study was terminated prematurely due to lack of response.

No significant financial relationships to disclose.
Correlation between anemia before treatment with survival in patients with advanced non-small cell lung cancer
Authors: Bella S. R. , Richardet M. E. , Gomez Storniolo P. , Celiz P. , Lingua A. , Mascheroni B. , Mangeaud A. , Richardet E. A.
Published: March 2020

18211

Background: Prognostic factors identified in advanced non small cell lung cancer are: age, gender, PS, h. SWOG univariable analysis in patients with chemotheraphy; confirmed these factors and show a relationship between the hemoglobin level and the overall survival; in addition the metastasic site number and cisplatin- based chemotheraphy (7). To analyse and compare the hemoglobin level before cisplatin- based chemotheraphy with survival in patients with advanced non- small cell lung cancer. Methods: Retrospective study conducted at the IONC of the 179 clinical record were analized, over a 5 year period. The collected data were: age, gender, PS, histologic type, stage, chemotheraphy cycles number, smooke history, number and metastasic site. We analyzed median and overal survival using Kaplan Meier, and the anemia as a prognostic implication factor with univariable and multivariable Cox regression analysis. Istologic type and TNM (1–6). Results: The mean age was 59 (40–79); 146 (81.5%) male and 33 (18.5%) women; histological types found were squamous cell carcinomas in 66 (37%), and adenocarcinoma in 113 (63%); stage IIIB in 61 (34%) and IV in 118 (66%). 147 (82%) were smokers and 32 (18%) were never smokers. All the patients had PS 0–1. Median overall survival time was 11.53 months and 13.88 months in the haemoglobin level < or > 11 gr/ 100 ml, respectively. (p=0.3). In univariable Cox regression analysis, smoking rates and chemotheraphy cycles number were predictors of survival (p=0.05 y p=0.018, respectively). Hemoglobine (p=0.55). In multivariable Cox regression analysis, only the number of cycles was predictor of survival (p=0.026). Hemoglobine (p=0.34). Conclusions: In our experience, a greater survival tendency was observed in patients with advanced non- small cell lung cancer who presented levels of Hemoglobine greater than 11 gr/dl, previous to cisplatin- based chemotherapy without statistical significance.

[Table: see text]
Autologous transplantation for relapsed non-Hodgkin lymphoma using intravenous busulfan and cyclophosphamide as conditioning regimen: A single center experience
Authors: Stefanovic A. , Escalon M. P. , Pereira D. L. , Santos E. S. , Goodman M. , Byrnes J. J. , Fernandez H. F.
Published: March 2020

18508

Background: High-dose chemotherapy followed by autologous stem cell transplanatation has become standard of care for patients with relapsed, chemosensitive non-Hodgkin’s lymphoma (NHL). In an effort to improve safety and efficacy of this therapeutic approach, new conditioning regimens are being developed. Methods: We retrospectively reviewed the clinical data of 44 consecutive patients with relapsed NHL who had been treated with intravenous Busulfan and Cyclophosphamide (BU/CY) as conditioning regimen for autologous stem cell transplantation between January 2000 and April 2005. Busulfan was administered at a total dose of 3.2 mg/kg on days -7 to -4 (given in two or four divided doses), followed by Cyclophosphamide at a dose of 120 mg/kg intravenously on days -3 and -2. We determined treatment-related morbidity and mortality, event-free survival (EFS, defined as time period between transplantation and occurrence of serious morbidity, disease relapse, disease progression, or death), disease-free survival (DFS), and overall survival (OS). Results: The distribution by histologic type of the 44 patients was as follows: 29 diffuse large B-cell lymphoma, 8 follicular lymphoma, 4 mantle cell lymphoma, and 3 peripheral T-cell lymphoma. Median age was 50 (range 20 to 68 years). At the time of transplantation, 27 patients had attained a complete response (CR or CRu) to salvage chemotherapy, 13 had achieved a partial response, and 4 had stable disease. Median time to neutrophil recovery post transplantation was 11 days. Treatment-related toxicities included nausea/vomiting (77%), diarrhea (43%), and mucositis (66%), which were mild in the majority of cases. Neutropenic fever occurred in 82% of patients. The 100-day mortality rate was 4 (9%) of patients: sepsis (n=1), pneumonia (n=1), and hepatic veno-occlusive disease (n=2). After a median follow-up of 52 months, 3-year Kaplan-Meier estimates of EFS, DFS, and OS were 35%, 41% and 44% respectively. Conclusions: Intravenous BU/CY is a safe and effective conditioning regimen as part of autologous transplantation for relapsed NHL. Our outcomes are comparable to those of other published regimens. Further investigation of this treatment approach is warranted.

No significant financial relationships to disclose.
Oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in relapsed diffuse large B-cell lymphoma (DLBCL): Final results of a phase II trial
Authors: Crump M. , Coiffier B. , Jacobsen E. D. , Sun L. , Ricker J. L. , Xie H. , Frankel S. R. , Randolph S. S. , Cheson B. D.
Published: March 2020

18511

Background: Vorinostat (Zolinza™) is a histone deacetylase inhibitor (HDACI) approved in the US for the treatment of cutaneous manifestations in patients (pts) with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following 2 systemic therapies. Clinical responses with vorinostat have been reported in other lymphoma subtypes. Methods: Open-label, single-arm, nonrandomized Phase II trial of oral vorinostat 300 mg bid (initially 14 d/3 wks; amended to 3 d/wk) until disease progression or intolerable toxicity. Eligibility: measurable, relapsed/refractory DLBCL; = 2 prior systemic therapies; adequate hematologic, hepatic and renal function. Pts who had prior HDACI treatment, allogeneic transplant, or had failed > 3 prior therapies were excluded. Primary endpoint: objective response rate (ORR) measured by CT/PET. Secondary endpoints: assessment of response duration (DOR), time to progression (TTP), time to response (TTR) and safety. Results: Eighteen pts (median age, 66 y [range, 59–86 y]; median 2 prior systemic therapies) were enrolled from 5/05 - 3/06 at 8 centers. Seven pts were initially treated with 300 mg bid 14 d/3 wks, but 4 had DLT (Gr 3 muscle spasms; Gr 4 thrombocytopenia, n = 3). The schedule was amended to 300 mg bid 3 d/wk and no other pt had DLT. One pt on the 3d/wk schedule achieved a CR (TTR = 85 d; DOR = 225+ d) and the ORR was 5.6%. One pt had SD for 301 d. Sixteen pts discontinued (DC) due to PD; median TTP for all pts was 44 d. Median number of treatment cycles was 2 (range, 1–14+). Two pts received > 6 cycles (126 d). Common drug-related adverse experiences (AE; mostly = Gr 2) were diarrhea (61%), fatigue (50%), nausea (39%), anemia (33%) and vomiting (33%). Three pts had dose reduction (300 -> 200 mg bid 14 d/3 wks) and none DC due to a drug-related AE. Drug-related AE = Gr 3 included thrombocytopenia (n = 3; 300 mg bid 14 d/3 wk) and asthenia (n = 2; 300 mg bid 3 d/wk). Two pts died on study of causes unrelated to drug: PD + GI hemorrhage (d 40) and acute myocardial infarction (d 95). Conclusion: Vorinostat has modest activity in pts with relapsed DLBCL and is well tolerated at 300 mg bid 3 d/wk or 200 mg bid 14 d/3 wks. The optimal dose/schedule and predictive response biomarkers require further study.

No significant financial relationships to disclose.
A phase I-II study to assess the safety, pharmacokinetics, and potential efficacy of intravenous SB-743921 on days 1 and 15 of a 28-day cycle in patients with non-Hodgkin lymphoma
Authors: Goy A. , Feldman T. , Dessanti M. , Hainsworth J. , Weaver C. , Ungerleider R. , Wolff A. , Escandon R.
Published: March 2020

18516

Background: Kinesin spindle protein (KSP) is required for mitotic spindle bipolarity and cell cycle progression. SB-743921 (SB- 921), a selective KSP inhibitor, blocks mitotic spindle assembly, causing cell cycle arrest in mitosis and subsequent cell death. Neutropenia was the dose-limiting toxicity (DLT) in the first-in-humans study of SB-921 given Q21 days. Methods: Cohort 1 of the Phase I portion of a study determining the safety, pharmacokinetics and MTD of SB-921 without prophylactic GCSF in patients (pts) with Non-Hodgkin’s Lymphoma (NHL) or Hodgkin’s Disease is reported. Pts with relapsed or refractory disease were eligible if they had received at least one prior chemotherapy regimen, had failed high-dose therapy with autologous stem cell transplant (ASCT), or were not candidates for ASCT. SB-921 is given to dose-escalating cohorts of 3 pts as a 1 hr IV infusion, Q14 days. Dosing began at 2 mg/m2 and escalated in 1 mg/m2 increments after 3 pts tolerated 1 cycle. Pts without dose-limiting toxicity (DLT) not completing Cycle 1 are replaced. Cohort expansion to 6 pts occurs if 1/3 pts experiences DLT, defined as any drug-related toxicity = grade 3 or drug-related grade 4 hematologic toxicity. Results: Cohort 1 (2 mg/m2) enrolled 6 NHL pts (5 indolent, 1 aggressive). 4 were female; median age = 59 (52–73); 5 Caucasian, 1 African-American; median no. of cycles = 2 (1–6). 5/6 pts were evaluable; 1 dropped out before dosing. The most common Grade 1–2 AEs, in decreasing order, were fatigue, dysgeusia, paresthesia, leukopenia, and diarrhea. Grade 3 AEs of note were 1 each of hemolytic anemia, leukopenia, thrombocytopenia and dyspnea; 1 Grade 4 anemia was reported. Conclusions: SB-921 was well tolerated without prophylactic GCSF in Cohort 1 of the Phase I portion of this study, which continues to dose-escalate. If neutropenia is the DLT, dose escalation will continue with prophylactic GCSF.

No significant financial relationships to disclose.
Combined treatment with high-dose methotrexate and whole brain radiation improves survival in primary central nervous system lymphoma (PCNSL)
Authors: Abdelsalam M. A. , Hussainy G. , Akhtar S. , Maghfoor I. , Elweshi A. , Khafaga Y. , Alhuseini H. , Rahal M. , Alshabana M.
Published: March 2020

18520

Background: Primary CNS lymphoma (PCNSL) is an aggressive primary brain tumor, cranial irradiation alone rarely result in long term disease control or prolonged survival. We analyzed our data for the impact of adding high dose methotrexate (HDMTX) prior to whole brain irradiation (WBI). Methods: All patients with PCNSL diagnosed and managed during 1991–2004 were identified from Oncology Data Unit. Patient’s characteristics, prognostic factors, details of treatment and outcome were reviewed. Sixty-two patients were identified, 10 were excluded (4 had WBI < 40 Gy and 6 had no treatment). Radiation alone was considered curative with a dose ≥ 40 Gy. Combined modality therapy included 3–4 cycles of HDMTX (3gm/m2) followed by WBI Results: 52 patients were analyzed for outcome. 36 had WBI, dose ≥40 Gy, 16 received 3–4 cycle of HDMTX followed by WBI (chemo-radiotherapy (CRT)). Median age was 48.2 years; 42 years in CRT group, 51 years in WBI. Patients characteristics were comparable between two groups except for higher multifocal tumor in CRT group (92% vs. x22%, p=0.029). Median follow is 12.83±6.4 months. Results are shown in Table . HR for event is 0.64 (95% CI was 0.52–0.98) and for death 0.58 (95% CI was 0.48–0.92), both in favor of CRT. Univariate regression analysis using one-way analyses of variance (ANOVA) and multivariate Cox regression analysis for prognostic factors including age (< 60 vs. ≥60), ECOG PS (0–2 vs. 3–4), extent of surgery (biopsy vs. debulking), solitary vs mutifocal tumor and dose of radiation therapy (< 50Gy vs. ≥50Gy) failed to identify any prognostic factor. Conclusions: This retrospective comparison supports other phase II trials results that high dose methotrexate followed by WBI in PCNSL improves outcome.

[Table: see text]

No significant financial relationships to disclose.
Cyclooxygenase-2 inhibition induces oxidative stress and decreases intracellular glutathione to reduce survival of human B lymphoma/leukemia cells
Authors: Ryan E. P. , Rahman I. , Phipps R. P.
Published: March 2020

18522

We recently reported that inhibition of Cox-2 reduced human B-CLL proliferation and survival. Herein, we investigated the mechanisms whereby a small molecule Cox-2 selective inhibitor (SC-58125) blunts survival of human B cell lymphomas and chronic lymphocytic leukemia B cells. SC-58125 (a celecoxib analogue) and OSU03012 (a celecoxib analogue that lacks Cox-2 inhibitory activity) both decreased intracellular glutathione (GSH) content in malignant human B cells, as well as in Cox-2 deficient mouse B cells. This new finding supports Cox-2 independent effects of SC-58125. Interestingly, SC-58125 also significantly increased B cell reactive oxygen species (ROS) production, suggesting that ROS are a pathway that reduces malignant cell survival. Addition of GSH ethyl ester protected B lymphomas from the increased mitochondrial membrane permeability and reduced survival induced by SC-58125. Moreover, the SC-58125-mediated GSH depletion resulted in elevated steady-state levels of the glutamate cysteine ligase catalytic subunit mRNA and protein. These new findings of increased ROS and diminished GSH levels following SC-58125 exposure support novel mechanisms whereby a Cox-2 selective inhibitor reduces malignant B cell survival. These observations also support the concept that certain Cox-2 selective inhibitors may have therapeutic value in combination with other drugs to kill malignant B lineage cells.

No significant financial relationships to disclose.
Ocular adnexal lymphoma subtyped according to the REAL classification: A 12-year experience from a single institution
Authors: Herrada J. , Campos-Gines A. F. , Gupta A. , Vazquez C. W.
Published: March 2020

18541

Background: The Revised European and American Lymphoma (REAL) classification (1994) provided a useful and practical tool to define lymphomas. The aim is to report our experience with this unusual malignancy diagnosed since the REAL classification was implemented. Methods: Retrospective review was performed on patients (pts) with ocular adnexal lymphoma between 1994 and 2006. Medical records, diagnostic imaging procedures, and pathology reports, including immunophenotyping studies, were reviewed. Histologic definition of lymphoma was based on the REAL Classification. Results: 10 pts were identified. All but one were females. Median age at diagnosis was 69 years (54–84). Primary sites included conjunctiva (5), orbital soft tissue (3), and eyelid (2). No lacrimal gland location was found. Ann Arbor stage at diagnosis was IE in most cases (7). One patient (pt) had stage IIE (conjunctival and maxillary sinus) and 2 pts had simultaneous bone marrow involvement (stage IV). 6 pts had marginal zone B-cell subtype, and the remaining 4 pts had small lymphocytic B-cell lymphoma. Radiation as single treatment modality was given to all 7 pts with stage IE, and all those achieved a complete remission (CR). CR was also achieved using chemotherapy with cyclophosphamide (C), vincristine (V), doxorubicin, prednisone (P), and rituximab followed by radiation in the pt with stage IIE. Of the 2 pts with stage IV, 1 achieved a CR with rituximab-based chemotherapy, and 1 never achieved a CR despite chemotherapy (chlorambucil, CVP). With a median follow-up of 23 months (9–70), the 9 pts that achieved a CR after initial treatment remain alive and disease-free. The only pt that did not achieve a CR lost follow-up at 18 months. Conclusions: In our patient population, radiation alone appears to be an effective treatment modality for stage IE. Achieving a CR seems to be a crucial factor for long-term control of the disease.

No significant financial relationships to disclose.
Phase II: Combination of cladribine, cyclophosphamide, mitoxantrone, rituximab (R-CCM) in patients with relapsed and refractory follicular and mantle cell lymphoma, results of a prospective study at Kitasato University
Authors: Suzuki Y. , Danbara M. , Hayama M. , Togano T. , Ohsaka M. , Miyazaki K. , Horie R. , Higashihara M.
Published: March 2020

18542

Background: Indolent non-Hodgkin’s lymphoma (I-NHL) account for 20% of all of NHL in Japan, and they are increasing in number. More than 80% of the patients who achieve a complete remission with the initial treatment, will require salvage therapy. Recently, cladribine (2-CdA), a purine analogue is receiving much attention, because, even as a single agent, it has shown a high efficacy for I-NHL. The aim of our study was to determine the effectiveness and toxicity of combined chemotherapy consisting of 2-CdA, cyclophosphamide (CYP), mitoxantrone (MIT), rituximab (R-CCM) in the treatment of refractory or relapsed I-NHL. Methods: Patient eligibility criteria were: Previously treated patients with I-NHL, refractory or relapsed disease, no chemotherapy or irradiation within 4 weeks prior to the study, life expectancy of at least 3 months, age: 20–75, perfomance status of 0–3, adequate function ( bone marrow, liver, kidney, lung, heart) and written informed consent. The treatment regimen was: 2-CdA given at a dose of 0.09 mg/kg/day in a 2-h intravenous infusion from day 2–4, CYP 200 mg/m2/day from day 2–4, MIT 8 mg/m2/day on day 2 and rituximab 375 mg/m2/day on day .Primary end point was overall response rate. Results: 9 patients were enrolled, 7 (2 with mantle cell lymphoma, MCL; and 5 with follicular lymphoma, FL) were eligible. Mean Age was 63(51–72). The mean observation time was 121 days(47–314). Overall response rate (complete and partial) just after this therapy was 85.7%, one was progressive disease. One of PR one relapsed and died ten months after this regimen. The major toxicity was myelosuppression. Grade-III and -IV neutropenia was seen in 7 patients, grade-III thrombocytopenia in one and grade-III hemorrhagic cystitis in one, but all of them recovered from these toxicity. After the treatment, Grade-IV pneumonia and grade-III left-ventricular diastolic dysfunction was seen in the PD patient and passed away. Conclusions: the R-CCM is effective and safe in a combined regimen for relapsed and refractory I-NHL patients. We have just begun this new regimen, therefore, further investigations with larger population are warranted.

No significant financial relationships to disclose.
Usefulness of low-dose thalidomide for Japanese patients with refractory and relapsed multiple myeloma
Authors: Kanamori H. , Hashino S. , Takahashi S. , Onozawa M. , Kahata K. , Kondo T. , Asaka M.
Published: March 2020

18543

Background: Thalidomide is not licensed in Japan, and many patients with multiple myeloma (MM) are therefore taking thalidomide that is imported from other countries. In this study, the effectiveness and side effects of thalidomide in patients with MM who took the drug from 2003 to November 2006 were retrospectively analyzed. Methods: Forty-one patients with refractory and relapsed MM were treated with thalidomide. The median age of the patients was 67.6 years (range,48 to 90 years) Most patients (88%) were treated at a dose of 100 mg/day, but the dose was later modified due to toxities, responses and monetary matters. Thalidomide was administered alone (n=21) and in combination with other drugs (n=20) such as dexamethasone. Results: Seventeen patients (41%) responded to thalidomide (nine patients (22%) showed a reduction in myeloma protein of over 50% and eight patients (19%)showed a reduction of 25–50%.). Kaplan-Meier estimates of overall survival were 68.6% at 1 year and 38.4% at 2 years.The 2-year overall survival rate was higher in ten patients who underwent autologous stem cell transplantation(P<0.001). Low-dose thalidomide was tolerated well but thalidomide treatment had to be discontinued in two patients because of life-threatening interstitial pneumonitis (Onozawa et al. JCO 2005,23). Conclusions: Low-dose thalidomide is useful for treatment of advanced myeloma and can improve prognosis. However, thalidomide, even when administered at a low dose, can caese life-threatening toxicities, and attention must therefore be given to safe use of the drug.

No significant financial relationships to disclose.
A phase 2 study to evaluate the efficacy of darbepoetin-alfa administered using an extended dose schedule versus weekly dosing in cancer patients with chemotherapy-induced anemia
Authors: Rearden T. , Schwartzberg L. , Yee L. , Mirtsching B. , Charu V. , Lam H. , Lillie T. , Burkes R. , Silberstein P.
Published: March 2020

19501

Background: Chemotherapy-induced anemia (CIA) can be effectively treated with darbepoetin alfa (DA) using different dosing schedules. Since chemotherapy (CTX) regimens involve various dosing schedules, the ability to synchronize DA dose with CTX could be beneficial. Methods: This phase 2, 25-week (wk), randomized, open-label study compares the efficacy and safety of DA administered using an extended dose schedule (EDS) (every 2 wks [Q2W] or every 3 wks [Q3W]) vs weekly (QW) dosing in patients (pts) with CIA. Pts were randomly assigned to receive DA EDS (either 300 mcg Q2W [with CTX QW, Q2W, or Q4W] or 500 mcg Q3W [with CTX Q3W]) vs 150 mcg DA QW (with CTX QW, Q2W, Q3W, or Q4W). Randomization was stratified by length of CTX cycle, screening hemoglobin (Hb) (< 10 vs = 10 g/dL), and type of cancer (lung/gynecological vs other cancers). The primary endpoint was the change in Hb from baseline (BL) to wk 13; other endpoints included the change in Hb from BL to end of study (EOS), percentage of pts with = 1 transfusion (TFN) from BL to wk 13 and EOS, and safety. Results: Final data for the total 25-wk study period will be presented. Results from a planned interim analysis for all pts who were enrolled in the study and received = 1 dose of DA (n = 752) are shown for wk 13 endpoints (Table). The groups had similar mean change in Hb from BL to wk 13, with a difference (QW minus EDS) (95% CL) of 0.2 (-0.1, 0.4) g/dL. The % pts who achieved target Hb were also similar (difference [95% CL] = 0 [-7, 6]). At the time of the interim analysis, the incidence and types of adverse events were similar between the groups. Ten (3%) EDS and 15 (4%) QW pts had thromboembolic events, 5 (1%) EDS and 2 (1%) QW pts had cerebrovascular accidents, and 19 (5%) EDS and 22 (6%) QW pts had died. Conclusions: This is the first trial synchronizing DA dosing (Q2W and Q3W) with CTX schedules. The interim results suggest that DA administered once per CTX cycle is well-tolerated and efficacious in these patients.

[Table: see text]

No significant financial relationships to disclose.