bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized, phase II trial comparing sequential paclitaxel/cisplatin/gemcitabine/vinorelbine/ (PCGV) with cisplatin/gemcitabine/vinorelbine/ (CGV) in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: De Castro J. , Belda-Iniesta C. , Casado Saenz E. , Feliu J. , Sereno M. , Chacon J. , Martin G. , Madroñal C. , Jara C. , Torrego J. , Gonzalez-Baron M.
Published: March 2020

17008

Background: New effective therapies are needed to improve the outcome of patients with advanced NSCLC. In this regard, new approaches such as cisplatin-based triplets have been explored with promising results but high toxicity. Furthermore, sequential chemotherapy schedules with taxanes followed by cisplatin-based regimens or viceversa could improve activity. A phase II study showed that sequential chemotherapy with weekly paclitaxel followed by CGV was highly active. Methods: A multicenter, randomized phase II trial of PCGV vs CGV in advanced NSCLC patients was conducted. Primary end-point: time to progression and survival. Eligible pts had unresectable, histologically confirmed NSCLC; no prior chemotherapy; PS 0–2; measurable disease. Pts received: Arm A (PCGV): P 150 mg /m2/week × 6, followed 2 weeks later by C 100 mg/m2 on day 1, gemcitabine 1,000 mg/m2 on days 1 and 14, and vinorelbine 25 mg/m2 on days 1 and 14 (CGV), every 28 days for a maximum of six courses. Arm B (CGV): C 100 mg/m2 on day 1, gemcitabine 1,000 mg/m2 on days 1 and 14, and vinorelbine 25 mg/m2 on days 1 and 14 (CGV), every 28 days for a maximum of six courses. Results: 106 Pts were included. Pts baseline characteristics (A/B: 52/54): male 82/79%; median age 60/59 (range 38–75 years); PS 0: 30/33%; 1 63/60%; 2: 7/7%; % squamous carcinoma:44/42%.WHO grade 3–4 toxicities for P were: neutropenia 18%; anemia 10%; thrombocytopenia 2%, peripheral neuropathy 18%. Grade 3–4 toxicities for CGV after P were: neutropenia 31%,nausea-vomiting 20%,thrombocytopenia 7%,anemia 5%,peripheral neuropathy 21%. WHO grade 3–4 toxicities for arm B were: neutropenia 35%,nausea-vomiting 19%, anemia 12%, thrombocytopenia 11% and peripheral neuropathy 15%. After therapy with arm A, 44% achieved a partial response, 15% had stabilization and 41% progressed. Arm B response rate were as follows: partial response 33%, stable disease 24% and progressive disease 43%. Median time to progression was (A/B) 7/6 months (log rank test, p 0.13) and median survival was (A/B): 11/10 months (log rank test, p 0.5). Conclusions: In spite of high response rate in TCGV arm, no survival benefit was detected in advanced NSCLC patients.

No significant financial relationships to disclose.
Phase I study of two different schedules of bortezomib (BORT) and pemetrexed (PEM) in advanced solid tumors
Authors: Metzger A. S. , Lara P. , Lau D. , Mack P. , Gumerlock P. , Gandara D. , Davies A. M.
Published: March 2020

17051

Background: BORT(PS-341) is a small molecule proteasome inhibitor while PEM, a multi-targeted antifolate, inhibits multiple enzymes involved in purine/pyrimidine formation. Both are approved anti-cancer agents. We examined the safety and tolerability of two different schedules of BORT and PEM in patients with advanced solid tumors. Methods: Two dose escalation trials (Arm A and Arm B) were conducted simultaneously. PEM was given every 21 days in both arms (500–600 mg/m2 IV). Arm A: BORT was given D1,4,8 &11 (0.7–1.3 mg/m2). Arm B: BORT was given D1 & 8 (1.0–1.6 mg/m2). All patients received vitamin B12, folic acid and decadron. Dose limiting toxicity (DLT) was defined as: grade (GR) 4 platelets (plts) (≤25K); GR 3 plts (25K-49,999K) with bleeding, requirement for transfusion, or lasting > 7 days; febrile neutropenia; GR3 ANC (ANC ≤1.0 × 109) with documented infection, or any ≥ GR3 non-heme toxicity. Results: 18 patients have been treated on 3 of the 4 planned dose levels. Tumor types included lung (12), prostate (2), breast (1), thymus (1), head & neck (1) and adenoid cystic carcinoma (1). Pt. characteristics: Median age 65 years; Sex M/F = 7/11; Performance Status ≤1/2 = 18/0. There have been no DLTs in either arm (Dose level 3-Arm A: PEM 500 mg/m2, BORT 1.3 mg/m2; Arm B:PEM 500 mg/m2, BORT 1.6 mg/m2). Most common GR3/4 toxicities were: neutropenia 27% and lymphopenia 11%. Of 17 evaluable patients: 1 had partial response, 11 had stable disease, 5 had progressive disease. Mean number of cycles: 4. Arm A had more doses held during the first cycle than Arm B (6 doses held vs. 1 dose held). Accrual to the final dose level in both arms is ongoing. Conclusions: 1) PEM in combination with BORT is feasible and tolerable. 2) Thus far, there are no differences in toxicity between the arms. 3) A randomized, multi-institutional phase II study will examine the efficacy of these two schedules in patients with NSCLC.

No significant financial relationships to disclose.
Multicenter, randomized trial comparing a combined gemcitabine and cisplatin 3-week regimen with a 4-week regimen in non-small cell lung cancer (NSCLC) patients
Authors: Liao M. , Zhu Y. , Li L. , Wan H. , Yu S. , Hall B. J. , Wang L.
Published: March 2020

17062

Background: This multicenter, randomized Phase II study (B9E-GH-JHSE) was aimed to compare the efficacy and safety of a gemcitabine-cisplatin combination over a 3-week schedule versus a 4-week schedule as first line treatment for Chinese patients with advanced NSCLC. Methods: Patients (pts) with pathologically or histologically confirmed stage IIIB/IV NSCLC not amenable to curative surgery, and presenting at least one measurable lesion were eligible for this study. Pts were randomized to receive cisplatin (cis) 75 mg/m2 on Day 1 plus either gemcitabine (gem) 1250 mg/m2 on Day 1 and 8 of a 21-day cycle (3-week arm) or gem 1000 mg/m2 on Day 1, 8, and 15 of a 28-day cycle (4-week arm). Patients received up to 6 cycles of treatment during this study. The primary endpoint was WHO objective response rate (ORR) and secondary endpoints included time to progression (TTP), CTC toxicity, and overall survival. Results: Of the 100 pts who were randomized to treatment, there were 51 pts in the 3-week arm: 14 females; mean age 59±8 yrs; 37% stage IIIB, 63% stage IV. In the 4-week arm, there were 49 pts: 24 females; mean age 56 ± 13 yrs; 33% stage IIIB, 67% stage IV. In the 3-week arm the overall response rate (complete response or partial response) was 24%, compared to 27% in the 4-week arm (Odds ratio: 1.17, 95% CI 0.47– 2.9, p = .819). There were no statistically significant differences between the two treatment arms in median overall survival time (3-week: 12.1 mths, 4-week: 13.8 mths; Hazard ratio (HR): 1.19, 95% CI 0.68–2.1, p = .54) and TTP (3-week: 4.9 mths, 4-week: 6.9 mths; HR: 1.33, 95% CI 0.85–2.1, p = .21). The difference in grade 3/4 hematological toxicities did not reach statistical significance (3-week: 37%, 4-week: 57%, p = .07), while grade 3/4 non-hematological toxicities were statistically significantly reduced in the 3-week arm (33% vs. 63%, p = .005). Grade 3/4 study drug related neutropenia (3-week: 27%, 4-week: 51%, p = .02) and thrombocytopenia (3-week: 8%, 4-week: 31%, p = .005) were reduced in the 3-week arm. Conclusions: While all efficacy endpoints were numerically superior in the 4-week arm, the difference was not statistically significant. However, grade 3/4 toxicities were reduced in the 3-week arm.

[Table: see text]
Cooperative antitumor activity between the retinoid X receptor (RXR)-selective agonist bexarotene and EGFR-tyrosine kinase inhibitors in preclinical models of NSCLC
Authors: Bissonnette R. P. , Fan B. , Roegner K. , Ng S. , Corpuz M. , Prudente R. , Negro-Vilar A. , Yen W.
Published: March 2020

17073

Background: Gefitinib and erlotinib, small molecule inhibitors of the EGFR-tyrosine kinase (EGFR-TKI), can have antitumor activity in patients with advanced NSCLC. However, analysis of clinical samples and in vitro characterization of NSCLC cell lines has revealed EGFR mutations that correlate with the clinical responses. While EGFR-mutant cell lines are hypersensitive to EGFR-TKI-mediated growth inhibition and have a greater tendency to undergo apoptosis in response to EGFR inhibition, wild-type EGFR cell lines undergo growth inhibition only at high concentrations, and are resistant to apoptosis induction. Bexarotene (Targretin) is a RXR modulator with clinical activity enhancing survival in a subset of NSCLC patients. We have shown that bexarotene can suppress the growth of epithelial tumors by modulating the expression and function of the EGFR pathway. This study examined the effect of bexarotene/EGFR-TKI combinations in preclinical models of NSCLC, and evaluated the possible molecular mechanisms for cooperative antitumor activity between these agents. Results: Bexarotene enhanced the activity of gefitinib in most of the cell lines tested, and did so regardless of their EGFR mutation status or intrinsic sensitivity to gefitinib alone. Resistant lines were sensitized by the combination, which decreased gefitinib IC50s to clinically achievable concentrations. Bexarotene increased the pro-apoptotic activity of both gefitinib and erlotinib, an effect which was paralleled by enhanced repression of p-Akt and p-Her2 levels by the combinations. In ex vivo cultures of human NSCLC explant tissue, the addition of bexarotene enhanced the growth inhibitory activity of both gefitinib and erlotinib. Finally, combinations of bexarotene and EGFR-TKI produced growth inhibition of TKI-resistant A427 NSCLC xenograft tumors that was superior to either agent alone. Conclusions: These results indicate that bexarotene can sensitize NSCLC cells which are unresponsive to the effects of EGFR-TKIs, resulting in cooperative growth inhibition and apoptosis induction. Combination therapy using bexarotene in conjunction with EGFR-TKIs may provide a powerful new therapeutic strategy.

[Table: see text]
Analysis of neuroendocrine, signal transduction and adhesion proteins in SCLC tissue to predict the tumor response and the rogression free survival (PFS) in limited stage SCLC (SCLC-LS) patients subjected to chemo-radiation therapy
Authors: Benedetti G. , Damiani S. , Cancellieri A. , Magrini E. , Fedele M. , Tamberi S. , Frezza G. , Crino L.
Published: March 2020

17075

Background: Most of SCLC-LS patients (pts) relapse within 12 months because of chemo and radio resistance. This phenomenon seems related to the induction of morphologically variant cells, which lack the neuroendocrine expression proteins and seem to trigger Akt-dependent inhibition of apoptosis. We analyzed neuroendocrine, signal transduction and adhesion molecules on tumor tissue from pts treated with chemoradiation therapy for SCLC-LS. Methods: We treated twenty-two pts with cisplatin/etoposide and concurrent thoracic irradiation. Paraffin blocks of the tumor obtained from each pt were used in the immunohistochemical analysis (IHA). Sections were stained with antibodies against phospho-Akt (p-Akt), phospho-MAP Kinase (p-MAPK), by a routine IHA method. Sections were stained in parallel with an automated immunostainer with antibodies against chromogranin A (ChrA), Neuron Specific Enolase (NSE), E-cadherin (Cad). Results: A preliminary IHA analysis obtained in ten out of twenty-two pts demonstrated that 9 out of 10 (9/10) tumor were NSE-positive; 6/10 ChrA-positive; 8/10 Cad-positive; 3/10 p-MAPK-positive; 5/10 p-Akt-positive. The correlation with tumor response and progression free survival (PFS) showed that the five patients with prolonged (10–60 months) complete remission (CR) had a p-Akt-positive, on the opposite the pts with short CR (6–18 months ) or partial remission (PR) had a p-Akt-negative staining. The two patient with prolonged and mantained CR (30+ and 60+ months) had a p-Akt-positive and Cad-negative profile. Conclusions: The expression of p-Akt and the absence of E-cadherin seems predict a prolonged CR after chemo-radiation therapy in SCLC-LS pts. Conclusive analysis will be presented at the meeting.

No significant financial relationships to disclose.
Induction chemotherapy with paclitaxel and cisplatin followed by concurrent chemoradiation therapy for Stage IIIB non-small cell lung cancer
Authors: Lee G. , Kang K. , Kang J. , Kim H. , Jang J. , Lee J.
Published: March 2020

17090

Background: We conducted a phase II study of Induction chemotherapy with paclitaxel and cisplatin followed by concurrent chemoradiation in patients with stage IIIB non-small-cell lung cancer to evaluate the response and toxicity profiles. Methods: All enrolled patients were scheduled to receive 2 cycles of induction chemotherapy with paclitaxel (175 mg/m2) intravenous infusion on day 1 and cisplatin (75 mg/m2) intravenously on day 1 every 3 weeks. All non-progressing patients were subsequently treated with concurrent chemoradiation. Concurrent chemoradiation included paclitaxel (60 mg/m2) plus cisplatin (25 mg/m2) intravenously for 6 weeks on day 43, 50, 57, 71, 78, and 85 and once-daily thoracic irradiation. Results: Between July 2000 and October 2005, 39 patients diagnosed as stage IIIB non-small cell lung cancer were enrolled in this study. Four patients achieved a complete response (10.3%) and 21 patients achieved a partial response (53.8 %), for an overall response rate of 64.1% [95% C.I. (49.4%–79.2 %)]. The 1, 2, and 3 year overall survival rate of all 39 patients were 66.7%, 40.6%, and 27.4% respectively, with a median survival time of 20 months. The median progression free survival was 10.7 months [95% C.I. (4.5%–16.9%)]. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 18 patients (45%). Conclusions: Induction chemotherapy with paclitaxel and cisplatin followed by concurrent chemoradiation for stage IIIB non-small cell lung cancer seems to be effective treatment. However, Physicians should also be aware of severe esophagitis to require inpatient parenteral nutrition support and pain control.

No significant financial relationships to disclose.
K-ras and EGFR mutations in 24 Chinese patients with non-small-cell lung cancer (NSCLC) treated with gefitinib
Authors: Wang Z. , Wu Y. , Zhang G. , Lin J. , Zhou Q. , Xu C. , Guo A.
Published: March 2020

17109

Background: It was previously reported that K-ras mutations could behave as a resistance marker for response to gefitinib while EGFR mutations make NSCLC more responsive to this medication. And it is known that Asians and Westerners have different responses to gefitinib. Therefore, we are to identify the mutational status of K-ras and EGFR in the group of Chinese patients with NSCLC especially adenocarcinoma treated with gefitinib to find some helpful information. Methods: Genomic DNA was extracted from tumor specimens, including liquid nitrogen frozen tumor, paraffin blocks and fine needle biopsies from 24 patients with advanced NSCLC, who failed at least one platinum-based regimen, treated with gefitinib. Nested polymerase chain reaction products of codons 12, 13, 59, and 61 of K-ras and exon 18 through 21 of EGFR were directly sequenced at least twice. Results: Patients’ age ranges from 24 to 71 years (54.8 ± 10.2). Male/female was 14/10. Thirteen patients were smokers and 11 were non-smokers. Eighteen were adenocarcinomas, 2 were bronchioloalveolar carcinomas, 2 were squamous cell carcinomas and 2 were large cell carcinomas. The disease control (CR+PR+SD) rate was 79.2% (19/24) and the objective response (CR+PR) rate was 50.0% (12/24). No K-ras gene mutation was found in all patients. Fifteen patients (62.5%, 15/24) harbored EGFR mutations, which were delE746-A750 (8), delE746-A751 (1), delE746-A751insA (1), L861Q (1), L858R (5) and A871G (1). Two patients had double mutations (delE746-A750 and L858R). The disease control rate for wild type and mutant EGFR were 66.7% (6/9) and 86.7% (13/15), and the objective response rate were 33.3% (3/9) and 60.0% (9/15). Median time to progress (TTP) for wild type and mutant EGFR were 439 days (SE 249.8) and 367 days (SE 108.8). However, no statistically significant differences were found between these two groups regarding the response rates and TTP. Conclusions: K-ras mutation may occur at a low frequency in Chinese NSCLC groups despite the pathology, status of smoking, gender and EGFR mutations. And the relationship between the response to gefitinib and K-ras mutation might still remain to be determined at least in Chinese NSCLC. And the role of EGFR mutations in prediction of response to gefitinib should be further studied.

No significant financial relationships to disclose.
Studies of pemetrexed and gemcitabine, alone and in combinations, in human lung cancer models
Authors: Chan D. C. , Chen V. J. , Zhang Z. , Helfrich B. , Hirsch F. R. , Ma D. , Bunn P. A.
Published: March 2020

17114

Background: Gemcitabine (GEM) is a deoxycytidine analog that inhibits DNA synthesis. Pemetrexed (ALIMTA, PEM) is a novel antifolate inhibiting multiple enzymes targets, including thymidylate synthase (TS). This study aimed at evaluating the antitumor effects of these antimetabolites against NSCLC and SCLC tumor models. Methods: In vitro growth inhibition (IC50) studies were done by 6-days MTT assays against a panel of 20 NSCLC and 17 SCLC cell lines. In vivo studies used only NSCLC H2122 tumor line, implanted either subcutaneously in athymic nude mice or orthotopically in athymic nude rats. Drugs were given via the ip route at the designated schedules. Results: Against NSCLC and SCLC cell lines, the averaged IC50s of GEM were 0.015 ± 0.008 μM and 0.055 ± 0.04 μM respectively. The corresponding averaged IC50s for PEM were 0.65 ± 0.2 μM and 0.091±0.018 μM respectively. When H2122 tumors reached 50–100mg, mice were treated with 10 daily doses of PEM at 100, 200 and 300 mg/kg, or three doses of GEM every 4 days at 30, 60 and 120 mg/kg. PEM delayed tumor growth by 12 to 18 days, and GEM delayed by 10 to 14 days, relative to vehicle control. Results of three combination regimens with GEM (30 mg/kg) and PEM (100 mg/kg) were: (1) GEM → PEM gave intermediate activities between the two single agents, but was toxic to animals; (2) PEM and GEM given concurrently were more active than single agents alone and delayed tumor growth by 12 days with some toxic side effects; (3) PEM → GEM was better than the single agents alone, and delayed tumor growth by ∼14 days without toxicity. Athymic nude rats bearing orthotopic H2122 tumors given PEM daily at 50, 100 and 200 mg/kg for 21 days had significantly prolonged survival, but not in a dose-dependent manner. PEM at 50 mg/kg was more effective than doses at 100 or 200 mg/kg. GEM was toxic to nude rats due to poor plasma deamination of GEM. Conclusions: In vitro, PEM was more potent against SCLC than NSCLC cell lines, but GEM had similar activities against all lung lines tested. Studies of H2122 xenografts in rodent supported PEM → GEM as the preferred sequence for the combined administration of these two drugs.

[Table: see text]
A phase II study of BAY 43–9006 (Sorafenib) in patients with relapsed non-small cell lung cancer (NSCLC)
Authors: Liu B. , Barrett T. , Choyke P. , Maynard K. , Wright J. , Kummar S. , Murgo A. , Doroshow J. , Gutierrez M.
Published: March 2020

17119

Background: Sorafenib is an inhibitor of multiple kinases including Raf-1 (C-Raf), b-Raf and pro-angiogenic tyrosine kinases (VEGFR-2/3 and PDGFR-β) and showed preclinical activity against NSCLC cell lines. Its anti-tumor activity may be attributable to inhibition of proliferative signaling through the RAS/Raf/MEK/ERK pathway and its anti-angiogenic effects. In NSCLC, the proliferation signaling of the Ras/Raf/MEK/ERK pathway is increased due to the increase in K-ras mutations. We initiated a single agent sorafenib trial in patients (pts) with relapsed NSCLC to assess clinical response and translational endpoints in tumor biopsies. Methods: This phase 2 trial uses a two-stage design targeting an objective response rate (RR) which can rule out 5% in favor of a more desirable 20% RR. Eligibility criteria: Pts with recurrent NSCLC with measurable disease who have received only one prior chemotherapy regimen, ECOG 0–1. Pts receive Sorafenib 400 mg bid continuously on 28-day cycle. Responses were evaluated every 8 weeks (wks) according to RECIST criteria. Dynamic contrast enhanced MRI (DCE-MRI) and tumor biopsy are performed before cycle 1 and at C1D15 to study early changes in tumor vascularity and translational endpoints. Results: 6 pts are evaluable for toxicity and 5 pts are evaluable for response. Best Response: 1PR (41% tumor reduction at wk 8, remained in PR until wk 28), 1 PR (unconfirmed) at wk 3, 2SD (16 and 19 wks respectively) and 1PD after 8 wks of treatment. Skin toxicity: Acne like drug-related rash (5 pts), hand-foot syndrome (6 pts), keratoacanthoma (1pt) and vasculitis (1pt). All skin toxicities are G1 or G2 and have responded to temporary withdrawal of Sorafenib and supportive care. Hypertension occurred in 1 pt (G2). No G4 toxicities have been observed. G3 toxicities include: anemia (1 pt), hyponatremia (2 pts), and nausea (1 pt). DCE-MRI results: 1 pt on C1D15 showed decrease in permibility parameters (ktrans and kep) and tumor size. DCE-MRI from the other 2 pts (1 PD, 1 SD for 16 weeks) showed no decrease in the permeability parameters. Conclusions: Sorafenib appears to be well-tolerated and active against relapsed NSCLC. Preliminary evidence of objective response warranting second stage accrual.

No significant financial relationships to disclose.
Curative-intent resection for bronchogenic carcinoma in patients with prior spinal cord injury: The Department of Veterans Affairs experience
Authors: Brunworth L. S. , Dharmasena D. , Virgo K. S. , Johnson F. E.
Published: March 2020

17127

Background: There are approximately 250,000 people with spinal cord injury (SCI) in the US, and they have a high prevalence of smoking. A literature search yielded no published information concerning the clinical course of SCI patients who subsequently develop bronchogenic carcinoma and undergo pulmonary resection for this condition. We hypothesized that poorer outcomes of surgery would be observed in this population, as compared to neurally-intact patients. Methods: We conducted a study of all veterans at Department of Veterans Affairs (DVA) Medical Centers during fiscal years 1993–2002 who were diagnosed with SCI, subsequently developed non-small cell lung cancer and were then surgically treated with curative intent. Inclusion criteria included American Spinal Injury Association type A injury (complete loss of neural function distal to the injury site) and traumatic etiology. Data were compiled from national DVA datasets and supplemented by operative reports, pathology reports, progress notes, and discharge summaries. Results: Of 12,634 patients who underwent surgery for bronchogenic carcinoma, 55 also had codes for prior SCI; 7 were evaluable. The mean age was 64. Five (71%) had one or more co-morbid conditions in addition to their spinal cord injuries. All 7 underwent pulmonary lobectomy. Post-operative complications occurred in 4 patients (57%). Two patients died post-operatively on days 29 and 499, yielding a 30-day mortality rate of 14% and an in-hospital mortality rate of 29%. Conclusions: We believe this isthe only report in the English language literature on this topic. SCI patients with resectable bronchogenic carcinoma have a high incidence of co-morbid conditions. Those who undergo curative-intent surgery have high morbidity and mortality rates. This evidence suggests that SCI should be considered a risk factor for adverse outcomes of surgery for primary lung cancer, strengthening the case for alternative treatments.

No significant financial relationships to disclose.
Preliminary results of second-line chemotherapy with vinorelbine and gemcitabine after docetaxel and carboplatin failure in advanced non small cell lung cancer (NSCLC)
Authors: Abou Yared J. , Chahine G. , Kattan J. , Farhat F. , Moukadem W. , Nasr F. , Younes F. , Ghosn M.
Published: March 2020

17130

Background: To evaluate the efficacy and safety of a doublet platinum-free therapy based on Vinorelbine and Gemcitabine in the salvage treatment of patients with advanced NSCLC, previously treated with Carboplatin and Docetaxel. Methods: We conducted a phase II study with the combination of vinorelbine 30 mg/m2 and gemcitabine 1000 mg/m2 d1 d8 / 3w. Eligible were patients with histologically proven advanced or metastatic NSCLC who were refractory or progressed after first-line chemotherapy combining Docetaxel and Carboplatin. Results of this first-line therapy were already reported (Proc. Am. Soc. Clin. Oncol. 2005, abstr 7330). Patients must have measurable disease, PS ≤ 2, life-expectancy ≥ 3 months, adequate hematologic, liver and renal functions. Response to therapy was evaluated according to RECIST guidelines. Toxicities were assessed according to the national cancer institute (NCI) common toxicity criteria 3.0. Results: From August 2004 to September 2005, 28 patients were enrolled. Median age was 63 years (range, 44 to 77) with 18 males and 10 females. A total of 109 cycles were delivered with a median of 4 cycles per patient (range, 1 to 9). Mean metastatic sites were lymph nodes in 9 pts, liver in 6 pts and pleura in 5 pts. 26 patients were evaluable for response (1 patient too early and 1 pt lost of follow-up). 6 patients responded partially (23%), one of them was initially resistant to the first-line therapy. 11 patients had stable disease (42%). Mean objective response duration was 7 months (range, 5 to 10+). Main toxicities (grade 3/4) were: anemia in 4 patients, neutropenia in 7 patients, leucopenia in 8 patients and lymphopenia in 4 patients. Neutropenic fever was encountered in only one patient. Non-hematological toxicities grade 3/4 were universally absent. No dose reduction or treatment delay related to toxicity was necessary. Conclusion: The study is still ongoing and more patients are expected to define time to progression and survival. However, these preliminary results were encouraging with low toxicity profile.

No significant financial relationships to disclose.
Second line therapy with cetuximab in NSCLC
Authors: Buosi R. , Gatti A. , Carnio S. , Sponghini A. , Olympios C. , Alabiso O.
Published: March 2020

17145

Background: EGFR is overexpressed in different solid tumors and in 50–80% of NSCLC. The neoplastic growth and metastatic process is correlated with EGFR overexpression, so that it became the target of a new therapeutic approach. The monoclonal antibody (Mab) against the extracellular domain represent the most innovated method of EGFR inaction. Methods: From May to October 2005 10 patients (8 M and 2 F) of median age 62 years with NSCLC in stage IIIB-IV (7 adenocarcinomas and 3 squamocellulars) have been treated with the association of chemotherapy and Cetuximab. All patients presented a strumental PD after a first line of platinum-based chemotherapy. At the basic valuation, 7 presented ECOG 0 and 3 ECOG 1. Before treatment EGFR expression has been valued by immunohistochemical analysis. Carboplatinum AUC6 + Paclitaxel 175 mg/mq D1 every 3 weeks was chosen as schedule in 5 patients, Paclitaxel 80 mg/mq/w (4/6 weeks) administered in 3 patients while Vinorelbine 25 mg/mq D1, 8 every 3 weeks administered in 2 patients with moderated cardiac disease. All patients received Cetuximab 400 mg/mq at first week followed by 250 mg/mq weekly until PD. Results: Till now 7 patients valued for OR after three months of treatment: 1 RC, 3 RP, 1 SD, 2 PD; none presented an ECOG worsening. Gr 4 hematological toxicity with febrile neutropenia registered in 1 patient treated with vinorelbine. Alopecia reported in all patients treated with paclitaxel and Gr 3 neurotoxicity reported in 1 patient. No other Gr > 2 toxicity has been registered. Skin rash has been checked in all patients. Conclusions: according to our experience the administration of Cetuximab seems to be well tolerated and does not modify the chemotherapy toxicity profile. The combination with vinorelbine is the most toxic. At the moment our data do not allow us to express any judgment on the treatment efficacy, but till today all patients are alive and only one of them presents clinical signs of PD.

No significant financial relationships to disclose.
Neuropilin-1 expression in adenocarcinoma and squamous cell carcinoma of the lung is differentially regulated by hypoxia
Authors: Pidgeon G. P. , Barr M. P. , Cathcart M. C. , Gray S. , O’Byrne K. J.
Published: March 2020

17152

Background: Neuropilin-1 (NRP-1) is an isoform-specific receptor for VEGF165 and semaphorin3A, initially discovered on migrating neurons. NRP-1 expression has been reported on a number of tumour cell lines in the absence of the other VEGF receptors, where it mediates survival signals. In this study we examined the regulation of NRP-1 by hypoxia, its effect on survival in a panel of lung cancer cell lines and its potential as a biomarker in retrospective human lung tumours. Methods: A549, SK-MES1, H460 and H647 cells were grown in serum depleted media (0.5%) in normoxic or hypoxic (0.1% O2) conditions and screened for NRP-1 expression by western and immunocytochemistry analysis. Cell survival and apoptosis was determined using BrdU and Annexin-V/PI staining respectively following treatment with an antibody to the extracellular NRP-1 domain. A panel of 100 retrospective resected lung tumours and matched normal samples were stained for NRP-1 expression by immunhistochemistry. Results: A549, SKMES-1 and H647 cell lines all expressed NRP-1 and displayed reduced survival following treatment with NRP-1 antibody (1ug/ml) compared to controls (A549 46%, SKMES-1 61%, H647 53%). H460 did not express NRP-1 and no survival inhibition was seen in the cell line (104%). Reduced survival was accompanied by increased apoptosis in all NRP-1 positive cell lines. Hypoxia strongly increased NRP-1 expression in the A549 adenocarcinoma (AC) cell line, while NRP-1 was decreased in SKMES-1 squamous cell carcinoma (SCC) following hypoxia. Neutralisation of NRP-1 had a greater effect in A549 cells under hypoxia (37%), with a lesser effect in SKMES-1 cells (82%). Western analysis of matched frozen normal and lung cancer biopsies showed NRP-1 overexpression in AC and decreased expression in SCC relative to normal. High NRP-1 expression was confirmed in AC and large cell carcinoma by immunohistochemistry, relative to normal. However, SCCs had a lower level of NRP-1 staining, supporting the results by western analysis and following hypoxia in vitro. Conclusions: These results implicate NRP-1 as an important survival pathway in lung cancer. Hypoxia differentially regulated NRP-1 mediated survival implicating this pathway as a potential therapeutic strategy in AC.

No significant financial relationships to disclose.
The influence of HAART on HIV-associated primary cerebral lymphoma: Declining incidence and improving survival
Authors: Bower M. , Mazhar D. , Newsom Davis T. , Powles T. , Mandalia S. , Gazzard B. , Stebbing J.
Published: March 2020

17512

Background: The risk of primary central nervous system lymphoma (PCL) is increased in individuals infected with the human immunodeficiency virus type-1 (HIV-1). As highly active anti-retroviral therapy (HAART) has reduced morbidity and mortality secondary to HIV, we investigated the effect of HAART on the presentation and outcome of HIV infected individuals with PCL. Methods: From a single centre cohort of 9,621 HIV infected individuals, patients with PCL were identified. We compared pre-HAART and HAART era clinico-pathologic variables and investigated whether exposure to anti-retrovirals with differing CNS penetrations, protected from the development of this AIDS-defining illness. Results: In 61 patients diagnosed with PCL and a median survival of 1.3 months, we observed a decreased incidence of PCL in the HAART era compared to the pre HAART era (χ2 p = 0.0001), and a significantly improved overall survival (Log rank p = 0.032). In the HAART era there were fewer patients with prior AIDS defining illnesses (χ2 p = 0.015) and patients were significantly more likely to have the diagnosis confirmed histologically or by CSF PCR examination (χ2 p < 0.0001). Exposure to specific anti-retrovirals did not protect from the development of PCL, regardless of cerebro-spinal fluid (CSF) penetration. Conclusions: Although the prognosis remains dismal, the HAART era has decreased the incidence and prolonged the survival of individuals with HIV-1 associated PCL.

No significant financial relationships to disclose.
Addition of bortezomib to thalidomide, dexamethasone and zoledronic acid (VTD-Z regimen) significantly improves complete remission rates in patients with relapsed/refractory multiple myeloma
Authors: Teoh G. , Tan D. , Hwang W. , Koh L. P. , Chuah C. , Ng H. J.
Published: March 2020

17537

Background: We previously treated 26 patients with relapsed/refractory multiple myeloma (MM) with thalidomide (Thal), dexamethasone (Dex) and zoledronic acid (Zol); dtZ regimen; and demonstrated an overall response rate of 75.0%. However, the rate immunofixation (IF)-negative complete remissions (CR) was only 7.7%. Recently, the bortezomib (Velcade) has been shown to be effective against MM. In this study, we added bortezomib (Vel) to dtZ (VTD-Z regimen) in a subgroup of patients to determine whether the CR rate can be improved. Methods: A non-randomized, single-arm study was conducted. Consecutive patients (n = 14) who either failed to achieve a partial response (PR) after 3 cycles; or CR after 9 cycles of dtZ were treated with 2 to 11 three-weekly cycles of VTD-Z; comprising: Vel 1.3 mg/m2 on days 1, 4, 8 and 11; Thal 50 mg ON; Dex 20 mg OM on days 1 to 4, 8 to 11, 15 to 18; and Zol 4 mg on day 1. The primary study objective was to determine the maximal response rates (RR). The end-point of the study was maximum response, graded by Bladè’s criteria. Results: Fourteen patients (3 males, 11 females; median age 63.3 years) were studied. Complex karyotypes, including 5 patients with deletion of chromosome 13 (del(13)), were present in 11 patients at diagnosis. The overall RR was 92.9% (13 out of 14), of which 42.9% (6) achieved CR (p < 0.001, chi-squared test). In addition, 21.4% (3) achieved near-CR (nCR), and 28.6% (4) achieved PR. There were no minimal responders (MR) and 1 (7.1%) non-responder (NR). Two patients who achieved CR had del(13). Painful grade 3 peripheral neuropathy was observed in 2 (14.3%) patients. Grade 1 and 2 peripheral neuropathy was observed in another 4 (25.0%) of patients; transient grade 3 thrombocytopenia was observed in 5 (35.7%) patients; and papular rashes were observed in 3 (21.4%) patients. The single NR was the only death that occurred during the period of study. Conclusions: Our study demonstrates that the VTD-Z regimen is exceptionally effective and safe in patients with relapsed/refractory MM. Addition of Vel to dtZ significantly increases the CR rate from 7.7% to 42.9%. These data suggest that combination of these 4 drugs may be at least additive, if not, even synergistic.

No significant financial relationships to disclose.
Multicenter study of intravenous busulfan, cyclophosphamide, and etoposide (IV Bu/Cy/VP-16) as conditioning regimen for autologous stem cell transplantation in patients with non-Hodgkin’s lymphoma
Authors: Kim J. , Chae Y. , Kim D. , Baek J. , Yang D. , Lee J. , Kim H. , Shin H. , Jung J. , Bae S.
Published: March 2020

17544

Background: The current study aimed to evaluate the efficacy and toxicity of the combination of intravenous busulfan, cyclophosphamide, and etoposide (IV Bu/Cy/VP-16) as a preparative regimen prior to autologous hematopoietic stem cell transplantation (ASCT) in patients with non-Hodgkin’s lymphoma (NHL). Methods: Forty patients with relapsed (n = 24) or high-risk (n = 16) lymphoma were enrolled into the study. High-dose chemotherapy consisted of intravenous busulfan (0.8 mg/kg i.v. q 6 hr from day-7 to day-5), cyclophosphamide (50 mg/kg i.v. on day-3 and day-2), and etoposide (400 mg/m2 i.v. on day-5 and day-4). Results: The median age of patients was 34 years (range, 17–63 years), and 21 (52.5%) patients were male. Pathologic subtypes were as follows: diffuse large B cell (n = 20), peripheral T cell, unspecified (n = 8), extranodal NK/T cell (n = 4), angioimmunoblastic T cell (n = 3), anaplastic large cell (n = 4), nodal marginal zone B cell (n = 2), and lymphoblastic (n = 3). The median dose of infused CD34+ cells and MNC was 3.95 (range, 0.7–20.6) × 106 and 8.12 (range, 3.0–13.6) × 108, respectively. WBC and platelet were successfully engrafted after ASCT in all patients, and the median days of engraftment of WBC and platelet was 12 (range, 9–48) and 27 (range, 8–263) days, respectively. After the ASCT, 34 complete responses (CR; 85.0%) and 4 partial responses (PR; 10.0%) were confirmed. Thirty-three (82.5%) patients experienced a fever without documented infection, while 2 patient developed fungal infection. However, there was no treatment-related death. After median follow-up duration of 360 (range, 83–639) days, 33 patients are in continuous complete remission, 4 patients are alive in relapse, and 3 patients died of disease. The estimated event-free and overall survival rate at 1.5-year was 80.9 ± 10.0 % and 92.5 ± 5.7 %, respectively. Conclusions: IV Bu/Cy/VP-16 was found to be well-tolerated and effective as a conditioning regimen in patients with NHL. Accordingly, this regimen can be regarded as an alternative high-dose treatment option in the ASCT for NHL.

No significant financial relationships to disclose.
A randomized phase I trial of melphalan + bortezomib as conditioning for autologous transplant for myeloma
Authors: Kaufman J. L. , Waller E. K. , Torre C. , McMillan S. , Langston A. , Flowers C. , Lechowicz M. , Tighiouart M. , Lonial S.
Published: March 2020

17550

High dose chemotherapy and autologous transplant (HDT) clearly benefits most patients with myeloma, but the addition of chemotherapy or TBI to melphalan (M) does not improve outcomes. Bortezomib (B) is a proteasome inhibitor which synergizes with chemotherapy due to its effects on DNA repair enzymes. Recent data has shown that B upregulates the anti-apoptotic protein MCL-1, which would suggest that B followed by M is inferior to M followed by B. We designed a randomized phase I trial combining B and Melphalan 200 mg/m2 (Mel200) in order to determine the toxicity, optimal dose and sequence of administration. Patients were randomized to receive either B 24 hours before Mel 200 or B 24 hours after Mel 200. Standard transplant criteria were used with the addition of requiring measurable numbers of plasma cells at the time of transplant. Enrolled patients underwent BM aspirate on day -4 (before B) and day 0 (before PBSC infusion). Bone marrows were tested for apoptosis, and myeloma cells were sorted for protein analysis. Age range was 48–74 years. Prior therapy has included Velcade (n = 2, both responsive) thalidomide (n = 2) and prior melphalan in 2 (1 HDT). Time to WBC and Plt engraftment were not different from historical cohorts receiving MEL 200 alone. Four patients have been randomized to date with 3 in the B “before“ arm, and 1 in the B “after” arm. Of the 3 patients who received B before M, day 0 bone marrow revealed minimal changes in marrow myeloma cell apoptosis in two patients, and in one patient a >20 fold increase in myeloma cell apoptosis on the day 0 marrow sample when compared to the day - 4 marrow. In the patient enrolled in the B after M arm, there was a 10 fold increase in the day 0 marrow myeloma cell apoptosis. Western blot analysis for DNA repair enzymes and MCL-1 on sorted tumor cells are planned, as is ELISA for secreted cytokines before and after therapy. Toxicity and response data with an update of the molecular correlates will be presented. The combination of B and M as conditioning for HDT is feasible. The optimal dose and sequence of administration remains unknown. Accrual continues.

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Lymphomas and multiple myeloma in rural Kenya: A cross-sectional survey
Authors: Aluoch J. R.
Published: March 2020

17558

Background: Prevalence of lymphomas and multiple myeloma in rural referral centers and far isolated district hospitals in Kenya was unknown apart from the teaching hospital, the Kenyatta National Hospital in Nairobi. Methods: A questionnaire on which disease code according to the WHO international diagnostic index (IDIC) numbers was used for data collection for a ten year period from 1991 to 2000. Care was taken to avoid double entry of patients who might have been seen in more than one center. Disease codes were entered for Burkit Lymphoma (BL), Hodgkin’s Lymphoma (HL), Non-Hodgkin’s Lymphoma (NHL), Unclassified Lymphomas and Other Lymphomas (OL) and Multiple Myeloma (MM). Seven rural referral centers, known as Provincial Hospitals (PGH), namely Coast, Nyanza, Western, Central, Eastern, North Eastern and Rift Valley were used for data collection. Results: There were no data from the semi-arid North Eastern province. A total of 1,027 lymphomas were recorded from the six remaining centers. 40.7% were BL, 36% NHL, 12.6% HL and 10.7% UL. There were 133 cases of MM. 87% of BL were from oceano-lacustrine centers. The same applied to 61% of NHL. 43.4% of HL were from Rift Valley, the rest being spread over the other five centers. The same applied to 69% of UL. 81.2% of MM cases were from the high altitude areas of Rift Valley and the mountain region. Conclusions: Although predominance of BL in oceano-lacustrince regions is accouneted for in association with malaria endemicity, we cannot so far account for high prevalence of MM in high altitude regions of Kenya. We also cannot fully account for the absence of any case from the semi-arid North Eastern Province.

[Table: see text]
Quality assurance of radiotherapy in the Japan Clinical Oncology Group trial 0211 concerning concurrent chemoradiotherapy for localized nasal NK/T-cell lymphoma: The individual case review
Authors: Oguchi M. , Kagami Y. , Ishikura S. , Nihei K. , Ito Y. , Yamaguchi M. , Tobinai K. , Wasada I. , Hotta T. , Oshimi K.
Published: March 2020

17561

Background: It is challenging to conduct a high quality multi-institutional clinical trial for localized nasal NK/T-cell lymphoma due to the anatomical complexity and its rarity. The purpose of this study was to evaluate the compliance with protocol guidelines in concurrent chemoradiotherapy for this disease among radiotherapy institutions participating in a multi-center phase I/II JCOG trial 0211. Methods: The treatment consisted of radiotherapy 50 Gy and 3 cycles of DeVIC chemotherapy [carboplatin, etoposide, ifosfamide, dexamethasone] (Yamaguchi M, et al.: Proc ASH, 2005). CT-based three-dimensional treatment planning was required to cover adequately target volumes and to minimize doses to organs at risk such as the eyes, the brain stem and the spinal cord. Patient data were sent to the review center after the treatments have been finalized. The following parameters were evaluated by the quality assurance review board: treatment records and charts; simulation films; portal images; prescribed dose; dose fractionation and overall treatment time; dose distributions; and dose to risk organs. Results: At the time of phase I analysis, 10 patients were enrolled in this study. In 2 of 10 cases, process of treatment planning was not available. There was no protocol violation. Major deviations were identified as follows: Delineation of clinical target volume (< 2 cm from the edge of the gross tumor volume at any direction), 2/10; dose distribution (not covered by 90%-115% isodose line), 1/10; and dose to optic chiasm (>40 Gy), 1/10. All cases were compliant in prescribed dose, dose fractionation, and overall treatment time. In the last 4 of 10 cases, attending radiation oncologists at the participating institutions were contacted by the radiation oncology study chair and they discussed the treatment planning just after patient enrollment. These 4 cases were all protocol compliant compared to 6 cases with 4 major deviations. Conclusions: Individual case review is essential in a multi-center clinical trial to keep enrolled cases protocol compliant and minimize inter-institutional variations. We expect that our quality assurance program will maintain the quality of the JCOG trial 0211.

No significant financial relationships to disclose.
Development of CMRF-56 blood dendritic cell preparations for immunotherapy of multiple myeloma
Authors: Vari F. , Rossetti T. , Munster D. , Hart D.
Published: March 2020

17572

Background: Despite advances in therapy for multiple myeloma, such as the use of proteosome inhibitors or stem cell transplantation, it is usually incurable. One promising therapeutic approach is to eradicate residual disease after stem cell transplantation by immune therapy. Method: The CMRF-56 monoclonal antibody detects an antigen expressed on blood dendritic cells (BDC) that is expressed after a short in vitro culture period. With clinical trail applications in mind, we have developed a procedure for isolation of CMRF-56+ BDC using CliniMACS. Cell culture, antibody staining and immunoselection occur in a closed system, compatible with regulatory requirements for cell therapy. Simultaneously, our team has developed of a bioprocess for production of the murine biotinylated CMRF-56 antibody for clinical trials. The bioprocess incorporates components that remove contaminating DNA, host cell proteins, viral particles and endotoxin. Results: Positive immunoselection using this antibody produces a BDC population containing some contaminating CMRF-56 positive B cells and monocytes. CliniMACS selection of PBMC from an apheresis produces enough BDC for a vaccination program with an average recovery of 1%, purity of 38%, yield of 48% and viability of 70%. These CMRF-56 dendritic cell preparations have been used to generate strong T cell responses to influenza matrix peptide and the putative tumour antigen MART-1. In order to discover and validate additional antigens capable of inducing effective immune responses against multiple myeloma, we have tested numerous of potential target antigens. It has been possibe to generate moderate specific immune responses against HM1.24 and mucin 1 peptides in normal HLA A2 donors. Using the CMRF-56 dendritic cell preparation as antigen presenting cells, it is possible to generate strong cytotoxic T cell responses against a lysate of the myeloma cell line U266. Indicating the potential usefulness of a whole cell lysate in generating anti-myeloma T cells for immunotherapy. Conclusions: These studies have provided the necessary pre-clinical data to commence a Phase I Clinical Trial in 2006 using CMRF-56 BDC preparations loaded with myeloma and control antigens in myeloma patients with minimal residual disease.

No significant financial relationships to disclose.