bluuebunny/crossref_metadata_2025 huggingface dataset:
JC papovavirus leukencephalopathy in a patient with B-CLL receiving long-term chemotherapy in combination with an anti-CD20-antibody
Authors: Hartmann B. L. , Winder T. , Sandholzer M. , Gasser K. , Jäger I. , Lang A. H. , Längle M. , Hartmann G. , Bartenstein C. , Luger C.
Published: August 2020

e18007

Background: Progressive multifocal leukencaphalopathy (PML) is a rare demyelinating infection of the central nervous system caused by viruses (CMV, JC, BK). It is almost exclusively described in profound immunocompromised patients developed as a primary infection or by reactivation of the virus after a latent infection. PML is typically observed among patients with severe immunodeficiency like HIV or in the setting of autologous or allogenic transplantation. Methods: Our patient was a 64-year-old woman with B-CLL diagnosed in 2000 in state B of Binet treated with 12 cycles of fludarabin until July 2007 in a B-cell and lymphoma-reducing manner. For the reason of progressive disease 3 cycles of rituximab, fludarabin, mitoxantrone, and cyclophosphamide were added (dose reduced causing hematologic toxicity) until October 2007 continuing rituximab once a month up to Mai 2008. Results: In a CT scan mixed response was observed with progressive disease infradiafragmatic and regression supradiafragmatic. Corticosteroids could stop B-symptoms and leads to a distinct shrinkage of the lymphomas within 2 weeks. Later on she presented with confusion and disorientation. An MRI of the brain showed subcortical and periventricular lesions with increased signal on T2-weighted and fluid attentuated inversion recovery (FLAIR) suggestive of a vascular origin. Her symptoms progressed by aphasia and weakness of the right leg corresponding to increased size and number of cerebral lesions. A lumbar puncture showed no malignant cells and no evidence of inflammation. A PCR analysis was negative for Toxoplasma gondii, HSV, VCV, CMV, EBV, and enterovirus but positive for JC-DNA (215.000 copies/ml). A rapid progression leads to death two months after onset of symptoms. Conclusions: Antibody deficiency syndrome corresponding to CLL under treatment with chemotherapy and rituximab lead to a severe immunosuppression enabling unusual viral infections such as PML.

No significant financial relationships to disclose.
MO19390 (SAiL): Incidence of hemorrhage with first-line bevacizumab (Bv)-based therapy in advanced non-small cell lung cancer (NSCLC)
Authors: Thatcher N. , Stroyakovskiy D. , Zhou C. , Bearz A. , Isla D. , Griesinger F. , Pavlakis N.
Published: August 2020

e19000

Background: MO19390 (SAiL) is an international, multicenter, open-label study evaluating the safety of first-line Bv in combination with a range of chemotherapy regimens in over 2,000 patients (pts). We report interim safety data with a focus on the incidence of serious bleeding events, including pulmonary hemorrhage. Methods: Primary endpoint was safety; secondary endpoints included time to disease progression and overall survival. Eligibility criteria included: non-squamous NSCLC with no prior chemotherapy, no uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg) or active cardiovascular disease at baseline, ECOG PS 0–2, no history of grade [g])>2 hemoptysis, and no evidence of tumor abutting or invading major blood vessels. Pts received Bv (7.5 or 15mg/kg) with chemotherapy for up to six cycles, then non-progressors proceeded to receive Bv until disease progression. Results: Interim analyses were available for a safety population of 2,008 pts (data cut-off July 2008). Baseline characteristics for pts were (%): male 60.1; Caucasian/Asian/other 80.1/15.6/4.3; stage IIIB/IV 19.5/80.5 (no data for 3 pts); adenocarcinoma/large cell/other 85.8/7.1/7.1; central tumor location yes/no (Y/N) 27.3/72.7; cavitated tumor Y/N 2.6/97.4; smoking history Y/N 70/30; ECOG PS 0/1/2 38.1/56.1/5.8. The median age was 59 years. Serious bleeding events (g≥3) of any cause were reported in 43 pts (2.1%). Bv-related bleeding events (g≥3) were reported in 16 pts (0.8%), including hemoptysis in 5 pts (0.2%) and gastrointestinal hemorrhage in 3 pts (0.1%). Conclusions: In Bv-treated pts, significant bleeding and hemoptysis are rare events. Our results confirm the well established and manageable safety profile of Bv-based therapy in eligible non-squamous NSCLC pts. Updated results will be presented.

[Table: see text]
MO19390 (SAiL): Incidence and management of hypertension (HTN) during bevacizumab (Bv)-based first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Garrido Lopez P. , Laskin J. , Jiang G. , Barlesi F. , Isla D. , Tsai C.
Published: August 2020

e19002

Background: SAiL is an ongoing, multicenter, international, open-label trial investigating the safety and efficacy of first-line Bv in combination with a range of standard first-line chemotherapy regimens in >2,000 pts with advanced NSCLC. Methods: Eligible pts had locally advanced, metastatic or recurrent non-squamous NSCLC. Pts received Bv (7.5mg/kg or 15mg/kg q3w) with standard first-line chemotherapy for up to 6 cycles, then Bv monotherapy until disease progression. Pts with uncontrolled HTN (systolic >150mmHg and/or diastolic >100mmHg) or active cardiovascular disease at baseline were excluded. The primary endpoint was the incidence of serious adverse events (SAEs) related to Bv, and AEs of special interest, including hypertension. Bv was interrupted for persistent or symptomatic grade 3 HTN and discontinued if blood pressure remained uncontrolled by medication. Bv was discontinued for grade 4 hypertension. Results: This analysis was based on 2,008 pts who received at least 1 dose of study medication (data cut-off July 2008): median age was 59 and ECOG PS 0/1/2 (%) was 38.1/56.1/5.8. Antihypertensive medications at baseline included ACE inhibitors (11.3%), Angiotensin II receptor blockers (6.2%), beta-blockers (10.9%), calcium channel blockers (7.7%) and diuretics (8%). Pts received a median of 5 Bv cycles and 4 chemotherapy cycles. Overall, 388 patients (19.3%) had a total of 487 incidents of HTN (any grade), occurring equally in patients ≤65 and >65 years of age (18.9% and 20.2%, respectively). Only six pts (0.3%) had grade ≥3 HTN events related to Bv meeting the criteria for SAE. The overall incidence of HTN was consistent across the various types of chemotherapy regimens. Conclusions: The incidence of grade ≥3 HTN was low, and the overall HTN incidence was similar across age groups and chemotherapy regimens. Updated results will be presented, including data on HTN management and evolution of HTN events during administration of antihypertensive medication.

[Table: see text]
Phase I/II study of MKC-1 and pemetrexed (PEM) as second-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Hanna N. H. , Estes D. , Arnott J. , Marcotte S. , Hannah A. , Sidor C. F. , West H. , Clamon G. , Hoang T.
Published: August 2020

e19005

Background: MKC-1 is a novel oral cell cycle inhibitor with preclinical activity against NSCLC cell lines including multi-drug resistant lines, and single agent activity in NSCLC pts. Binding targets of MKC-1 include microtubules, members of the importin-β family and AKT-mTOR. This phase 1/2 study evaluated MKC-1 in combination with PEM as second-line therapy in pts with advanced NSCLC. Methods: Eligible pts had NSCLC previously treated with one regimen for metastatic disease or disease progression within one year following adjuvant and neoadjuvant therapy. Phase 1 dose escalation used 3+3 design. Phase 2 pts were treated with MKC-1 at 75 mg/m2 given p.o. BID for 14 days along with PEM at 500 mg/m2 given i.v. on day 1 of each 21 day cycle. Following 4 cycles of combined treatment, single agent MKC-1 was continued as maintenance therapy. An interim analysis after 17 pts in phase 2 would allow accrual to continue provided one response was confirmed. Results: 27 pts were enrolled (8 in phase 1 and 19 in phase 2). Median age/PS for phase 2 is 64/1 and 89% had adenocarcinoma. Total # of treatment cycles to date for phase 2 pts is 95, with a median of 4 cycles. Of the 19 phase 2 pts, 18 were evaluable for tumor response. The best response was confirmed PR, noted in 3 pts. 5 additional pts (4 confirmed) had minor responses (>10% but <30% shrinkage). One additional pt continues on study with stable disease for >18 months. In phase 2 (n=19), all grade toxicities were anorexia (59%), fatigue (63%), nausea (58%), and dyspnea (48%). Grade 3/4 toxicities included fatigue (26%); neutropenia (22%); dyspnea, anorexia, AST and ALT elevation (11% each); nausea and constipation (5% each). 7 pts had at least one dose reduction of both PEM and MKC-1 and 3 additional pts had only MKC-1 reduced. Median PFS was 86 days with two pts continuing on study (treated for 530+ days and 140+ days, respectively). Conclusions: The phase 2 dose of MKC-1 (75 mg/m2 BID) and PEM (500 mg/m2) has been defined. The combination is well tolerated with 17% of patients achieving a confirmed PR thus far. A decision to proceed with additional accrual in this single arm study versus initiating a randomized phase 2 study of this combination is pending.

[Table: see text]
Evaluation of erlotinib treatment after gefitinib failure in Japanese recurrent non-small cell lung cancer patients
Authors: Hata A. , Nanjo S. , Kaji R. , Hujita S. , Katakami N. , Nishimura T. , Ishihara K. , Yoshioka H. , Hayashi H. , Ishida T.
Published: August 2020

e19008

Background: Both gefitinib (G) and erlotinib (E) belong to the family of epidermal growth factor receptor-tyrosine kinase inhibitors that has shown positive results in the treatment of advanced/recurrent non-small-cell lung cancer (NSCLC). Recent studies suggested a distinction in efficacy between G and E. In fact, there is a subgroup of patients who had clinically meaningful benefit with E therapy after G failure, but little is known about the factors that predict disease control or the risk factors that develop toxicity in these patients. Our aim is to evaluate the efficacy and toxicity of E after G failure in the largest scale study to date. Methods: We retrospectively evaluated the efficacy and toxicity of E therapy and analyzed factors that contributed to disease control in patients had experienced G failure. EGFR mutational analysis was performed in evaluable cases. Results: From January 2008 to December 2008, seventy-seven patients were treated with E after G failure in our institutions. Of these 77 patients, 11 had a partial response (PR) and 21 had a stable disease (SD), resulting in a best response rate of 14% and a disease control rate (DCR) of 42%. Thirty of 56 (54%) patients who had benefited from prior G therapy achieved disease control, while only 2 of 20 (10%) patients who had experienced initial progressive disease to G therapy obtained SD (P<0.001) . Twenty-seven of 48 (56%) patients with performance status (PS) 0/1 achieved disease control, but a DCR of PS 2/3/4 patients was only 17% (5 of 29) (P<0.001). EGFR mutation status, smoking history, and gender had little relationship to disease control. In 4 of 11 patients who achieved PR, E was effective for brain metastases. The most common side effects of E therapy were skin rash and diarrhea, as described in previous studies. Notably in approximately 30% of poor PS patients, grade 3 to 4 non-hematological toxicity including severe general malaise and anorexia was observed. Conclusions: E may be effective as a salvage therapy for some Japanese NSCLC patients after G failure, especially in those who had benefited from prior G treatment and/or those who maintain a good PS. Interestingly, E was effective for brain metastases of some patients after G failure.

No significant financial relationships to disclose.
Interstitial lung disease associated with amrubicin in the treatment of patients with small cell lung cancer
Authors: Yoh K. , Nishiwaki Y. , Kemmotsu H. , Yamaguchi Y. , Kubota K. , Ohmatsu H. , Goto K. , Niho S. , Saijo N.
Published: August 2020

e19018

Background: Amrubicin is a novel anthracycline agent with significant activity against small-cell lung cancer (SCLC). The adverse pulmonary effects of amrubicin are less well known. We investigated the incidence of acute interstitial lung disease (ILD) in SCLC patients receiving amrubicin. Methods: Medical records were used to retrospectively investigate a total of 100 SCLC patients treated with single-agent amrubicin at the National Cancer Center Hospital East between June 2003 and March 2008. The radiographic records and clinical data of these patients were reviewed to find patients who developed acute ILD after being treated with amrubicin. Results: Seven of 100 SCLC patients subsequently developed pulmonary infiltrates without underlying heart disease after receiving amrubicin, and were identified as cases of acute ILD associated with amrubicin. The median time from the start of amrubicin treatment to the development of ILD was 22 days (15–94 days). Among 7 patients who developed ILD, 6 patients received treatment with corticosteroids and ILD improved in 3 patients. However 3 patients died of respiratory failure. The incidence of ILD was 33% (4/12) in patients with preexisting pulmonary fibrosis and 3% (3/88) in patients without preexisting pulmonary fibrosis, and the difference between the two groups was statistically significant (P = 0.0036). Conclusions: Our findings indicate that amrubicin can cause severe ILD, and that the incidence of ILD might be higher in the patients with preexisting pulmonary fibrosis. Physicians need to be alert to the possibility.

No significant financial relationships to disclose.
Effect of genetic polymorphisms on toxicity and survival in advanced non-small cell lung cancer (NSCLC) patients (pts) treated with carboplatin (CBDCA) and pemetrexed disodium regimen
Authors: Ludovini V. , Crinò L. , Pistola L. , Floriani I. , Meacci M. , Chiari R. , Garavaglia D. , Tofanetti F. R. , Mare M. , Giuffrida D. , Gori S.
Published: August 2020

e19028

Background: Identification of genetic polymorphisms which influence chemotherapy outcome may help towards individually optimized therapy. We investigated the influence of ten single nucleotide polymorphisms (SNPs) of 7 genes (P53 Arg72Pro (G/C); XRCC3 Thr241Met (C/T); XPD Lys751Gln (A/C); ERCC1 Asn118Asn (C/T); GARFT C/G, GARFT C/T, DHFR C/G, DHFR A/G, TS 5’UTR, TS 3’UTR involved with metabolism of CBDCA and Alimta regimen in pts with advanced NSCLC. Methods: Genomic DNA was extracted from whole blood samples using the QIAamp DNA estraction kit on Biorobot EZ1 (Qiagen). Polymorphisms were detected with TaqMan-probe based assays using the 7300 Real-Time PCR system (Applied Biosystems, Foster City, CA) or PCR followed by RFLP. The results of SNPs were assessed by Cox model for survival/PFS & logistics regression for response/toxicity. Results: We performed a retrospective analysis in 57 advanced pretreated (2nd or 3th line) NSCLC pts treated with CBDCA(AUC=5) + Alimta (500 mg/m2). Median age was 59 years (range 26–79), M/F:63/37%; Adeno/Squa/other Ca:65/20/15%; ECOG PS:0–1/2–3:96/4%. Overall response rate was 38.6%, stable disease 38.6% and disease progression 21.1%. At median follow-up of 7.9 months, 10 pts (17.5%) died, 47 pts (82.5%) are alive. The median progression free survival (PFS) was 7.4 months, the median survival time not reached. P53 Pro72Pro was significantly associated with shorter survival (HR 5.5, 95%CI 1.01–30.5, p=0.04) when compared to P53 Arg72Arg. None of the analyzed polymorphisms was related to response to therapy. No associations were found between the analyzed polymorphisms and toxicity considered either as the maximum observed grade, or as sum of each toxicity pattern grade, probably due to low number of events observed for toxicity within this data set. Conclusions: P53 Pro72Pro may be associated with shorter survival in pts with advanced NSCLC. Further studies are warranted to validate this finding. Genotype-related differences in common toxicities and in response to therapy were not observed. The small sample size limits interpretation of these data.

No significant financial relationships to disclose.
Role of PET/CT scanning in detecting asymptomatic brain metastases in non-small cell lung cancer
Authors: Virani S. , Almubarak M. , Marano G. , Rogers J. S.
Published: August 2020

e19038

Background: Up to one-third of non-small cell lung cancer (NSCLC) patients are diagnosed with brain metastasis. Our study aims to evaluate the role of whole body and brain FDG-PET/CT in detecting asymptomatic brain metastasis in this population. Methods: We performed a retrospective chart review of 282 consecutive non-small cell lung cancer patients between February of 2005 and June of 2008. 60 patients with brain metastasis were identified. Information regarding tumor histology and presence of neurological symptoms at the time of discovery of brain metastasis was collected. In addition, data was acquired from brain MRI and PET/CT (with IV contrast) reports including: study date, findings and any change in staging secondary to the study. Results: The median age was 63 years (47 % women). 39 (65%) of the patients had neurological symptoms at the time of discovery of brain metastasis. PET/CT scan with IV contrast was performed in 53 patients with brain metastasis. For patients who had a PET/CT scan, the histological types were: adenocarcinoma (58.4%), unclassified (22.6%), squamous (13.2%), large cell (3.8%) and other (1.8%). PET/CT scan had a sensitivity of 97.8% in detecting CNS metastasis seen on brain MRI. 19/53 patients were found to have asymptomatic brain metastasis on PET/CT scan (2 stage I, 1 stage II, 2 stage III and 13 stage IV). Overall, PET/CT scan resulted in upstaging of 5 asymptomatic and 6 symptomatic patients or 11/53 (20.7%). Conclusions: PET/CT scan with IV contrast has a high sensitivity in detecting brain metastasis in patients with NSCLC when compared to brain MRI. It is effective in detecting asymptomatic brain metastasis in this population. Those patients, who initially were thought to have non-metastatic disease, are spared inappropriate aggressive surgery or radiation.

No significant financial relationships to disclose.
Can meta-analysis suggest carboplatin/paclitaxel as a reference arm in randomized trials of first-line chemotherapy for advanced non-small cell lung cancer?
Authors: Yamanaka T. , Yamamoto N. , Seto T. , Takahashi T. , Murakami H. , Tsuya A. , Naito T. , Kaira K. , Nakamura Y. , Ichinose Y.
Published: August 2020

e19039

Background: The validity of adapting carboplatin/paclitaxel (CbP) as a reference arm in randomized trials of first-line chemotherapy for advanced non-small-cell lung cancer has not been fully evaluated. Methods: We performed a meta- analysis on trials identified through a literature search. The analysis included randomized trials comparing CbP with cisplatin-based third- generation (3G) regimens. Results: Of 160 articles screened, seven randomized trials were eligible for the analysis. The pooled hazard ratio (HR) for overall survival showed that CbP was not an inferior regimen to cisplatin-based 3G regimens (HR=1.04; 95% confidence interval, 0.96–1.13; p=0.296). On focusing on 3G agents other than vinorelbine, we observed a marginally significant improvement in survival with cisplatin-based regimens (HR=1.08; 95% confidence interval, 0.99–1.18; p=0.080). CbP generally involved a higher risk of thrombocytopenia and peripheral neuropathy but a lower risk of anemia, nausea, and toxic deaths. Conclusions: There is no evidence that CbP was significantly inferior to cisplatin-based 3G regimens in terms of efficacy. However, since CbP was less inclined to result in better survival, the preferred use of CbP as a reference arm in randomized trials instead of cisplatin-based 3G regimens may depend on the purpose of the trial.

No significant financial relationships to disclose.
Staging 18FDG-PET in newly diagnosed small cell lung cancer (SCLC): 15-year institutional experience
Authors: Azad A. , Chionh F. , Scott A. , White S. , Mitchell P. L.
Published: August 2020

e19044

Background: 18FDG-PET is not routinely used in the initial staging of SCLC despite evidence that it alters stage classification and management. Furthermore, the association between stage classification by PET and prognosis of newly diagnosed SCLC has not previously been directly assessed. We aimed to evaluate whether PET altered stage classification, management and prognosis when used to stage newly diagnosed SCLC. Methods: We retrospectively reviewed the medical records of 46 consecutive patients undergoing PET during initial staging for SCLC at Austin Health from 1993 to 2008 inclusive. Data collected included patient demographics, stage classification before and after PET, treatment history and date of death. Statistical analysis included estimation of overall survival (OS) by the Kaplan-Meier method using the log-rank test. Results: PET altered stage classification in 12 of 46 (26%) of patients. Stage alteration led to a change in treatment modality in 9 of these 12 patients. In addition, PET altered the target radiation field in another three patients. Therefore, PET had a significant impact on management in 12 of 46 (26%) of patients. Patients with limited disease (LD) on both conventional imaging and PET had significantly longer OS than patients with LD on conventional imaging that was upstaged to extensive disease (ED) on PET (median 557 days versus 172 days; log-rank p<0.0001). Patients with ED on conventional imaging that was downstaged to LD on PET had significantly longer OS than patients with ED on both conventional imaging and PET (median 328 days versus 177 days; log-rank p=0.037). Conclusions: The use of 18FDG-PET during staging for SCLC had a major impact on stage classification, management and prognostic stratification. The use of staging PET should be considered in patients with newly diagnosed SCLC.

No significant financial relationships to disclose.
Comparison of incidence and pattern of interstitial lung disease (ILD) during erlotinib and gefitinib treatment in Japanese pts with NSCLC
Authors: Hotta K. , Kiura K. , Takigawa N. , Yoshioka H. , Harita S. , Yonei Y. , Fujiwara K. , Maeda T. , Tabata M. , Tanimoto M.
Published: August 2020

e19056

Background: Erlotinib was approved in Dec 2007 in Japan, and incidence and pattern of ILD during its therapy for Japanese pts with NSCLC has not still been determined, although we had previously reported the frequency of ILD through the gefitinib treatment [PASCO2004, #7063]. In this study, we intended to elucidate this issue in pts receiving erlotinib therapy. Methods: We reviewed the clinical records of 159 pts who had initiated erlotinib therapy last year (cohort A), and of 330 pts receiving gefitinib between 2000 and 2003 (cohort B) for comparing the incidence and pattern of ILD during the both TKI treatments. Toxicity data during the first months after the initiation of TKIs were obtained. Results: The demographics of 489 pts were as follows; M:63%, Ad:75%, and PS 0–1:69%. None of pts in the cohort B received erlotinib therapy before the gefitinib treatment, whereas 66 of the 159 cohort A pts (42%) were given gefitinib before the erlotinib therapy. In 23% and 28% of the pts in the cohorts A and B, erlotinib and gefitinb treatments were discontinued within 1 month after the initiation of TKI therapy, respectively. Two pts (1.3%) developed ILD in the cohort A during the first month of erlotinib treatment, while 8 ILD-events (2.4%) were observed in the gefitinib therapy (cohort B) during the same treatment period. Both 2 pts who developed ILD during the erlotinib therapy had not had a history of prior gefitinib treatment. The toxicity grades of ILD were as follows: grades 1 and 2 in 1 each (cohort A) and grades 3, 4 and 5 in 1, 1 and 6 pts, respectively (cohort B). Statistically significant factors affecting the occurrence of ILD by multivariate analysis were presence of prior pulmonary fibrosis (OR=37.3, p<0.01) and poor PS (OR=6.4, p=0.02), but type of TKIs was not a significant risk factor for ILD. Conclusions: In this setting, the type of TKIs did not affect the incidence of ILD although its incidence after the initiation of erlotinib was somewhat low as compared with that during gefitinib therapy. In addition, the grade of ILD was less severe in the cohort A. These might be partly due to a patient selection based on the recent awareness of Japanese physicians regarding the risk factors for ILD events who learned it through the gefitinib treatment.

No significant financial relationships to disclose.
Docetaxel-carboplatin chemotherapy in combination with cetuximab in patients with locally advanced or metastasized non-small cell lung cancer (NSCLC): Interim results of the nonrandomized phase II study TaxErb
Authors: Fischer J. R. , Griesinger F. , Fink T. , Buchholz E. , Salm T. , Marseille A. , Wolf M.
Published: August 2020

e19062

Background: Combination chemotherapy with carboplatin-docetaxel has been shown to be effective and safe for patients with locally advanced or metastasized NSCLC. The monoclonal anti-EGRF antibody cetuximab has the potential to improve response rates and survival without a substantial increase in toxicity when given in combination with chemotherapy. Methods: Open, non-controlled phase II study with a planned sample size of 70 pts. Pts with locally advanced or metastasized NSCLC, ECOG performance status ≤ 2 and no prior systemic chemotherapy were treated with carboplatin AUC5 (d 1) q4w for 4–6 cycles and docetaxel 35 mg/m2 (d1, 8, 15) q4w; cetuximab 400 / 250 mg/m2 (d 1) q1w until progression or intolerable toxicity (12 month max.). The primary endpoint was response rate defined as complete or partial remission according to RECIST. Secondary endpoints were toxicity, 1 year survival, median and progression free survival. Results: Subject of the interims analysis were 27 pts (25 stage IV, 2 stage IIIb). ECOG 0/1/2 was 33.3%/59.3%/3.7% (1 no data). 63% had prior surgery, 93% prior radiotherapy and all had adjuvant or inductive chemotherapy. Pts received a mean of 3 ± 1.4 cycles docetaxel-carboplatin-cetuximab. 49 adverse events were grade 1–2 and 12 grade 3–5. Skin toxicity (49%; 95%CI: 30%-68%; 41% G1/2, 8% G3/4), dyspnoea (35%; 95%CI: 17%-53%) and diarrhoea (23%; 95%CI: 7 %-39%; 19% G1/2, 4% G3) were most frequent. 11 pts (41%) had toxicity leading to dose reduction. 0 pts had complete and 11 pts had partial remission resulting in a response rate of 40.7% (95%CI: 22%-59%) based on intention to treat. 6 pts had stable disease (22.2%; 95%CI: 7%-38%). 5 pts were not evaluable for response. Conclusions: The combination of carboplatin-docetaxel-cetuximab has an overall acceptable tolerability. With a preliminary response rate of 40.7% the benefit risk assessment was found to be favourable and the study was continued.

[Table: see text]
A phase I trial of intravenous therapy with tumor suppressor FUS1-nanoparticles for recurrent/metastatic lung cancer
Authors: Lu C. , Stewart D. J. , Ji L. , Ramesh R. , Jayachandran G. , Erasmus J. , Lee J. J. , Templeton N. S. , McMannis J. D. , Roth J. A.
Published: August 2020

e19065

Background: The tumor suppressor gene FUS1 is frequently inactivated early in lung cancer development. FUS1 mediates apoptosis in cancer cells but not normal cells through its interaction with Apaf1. DOTAP:cholesterol nanoparticles encapsulating a FUS1 expression plasmid showed selective uptake by cancer cells and activity in mouse xenograft metastatic lung cancer models. Methods: Patients with recurrent/metastatic lung cancer previously treated with platinum-based chemotherapy were treated with escalating doses of intravenous DOTAP:cholesterol FUS1 nanoparticles. Nanoparticle-DNA complexes were manufactured in GMP facilities to meet specifications of OD400, size, appearance, and transfection efficiency. Results: Patients have received doses ranging from 0.01–0.09 mg/kg at 3 week intervals. To date 23 patients have been entered on study at 6 dose levels, with 21 patients currently evaluable for the primary endpoint of cycle 1 toxicity. 70% of subjects had received 2 or more prior chemotherapy regimens. Among 4 patients treated without premedications, all 4 developed grade 2 or higher fevers within 24 hours of treatment. Among the 17 patients premedicated with dexamethasone and diphenhydramine, 4 developed grade 1 fever. There have been no other grade 2 or higher drug-related toxicities. Four patients received only one dose because of rapidly progressing disease at a site requiring local treatment. Fifteen patients received two or more doses and are evaluable for response, with 4 patients achieving stable disease and 11 patients progressing. Median survival time for all patients is 10.3 months. A maximum tolerated dose (MTD) has not been reached. Pre and 24 hour posttreatment tumor biopsies were obtained from 4 patients. A quantitative real time reverse transcriptase PCR (RT-PCR) analysis using a plasmid FUS1 sequence-specific probe have been performed on 3 paired-samples blinded to time of biopsy. A high level of plasmid FUS1 expression was detected in all 3 posttreatment samples but not in three pretreatment samples and negative controls by RT-PCR. Conclusions: DOTAP:cholesterol FUS1 nanoparticles can be safely administered intravenously in lung cancer patients with demonstrable gene expression in posttreatement tumor biopsies.

[Table: see text]
The correlation between the expression of ABH and Lewis A histo-blood group antigens and the biological behavior of primary pulmonary adenocarcinoma
Authors: LI J. , Zhou X. , Liu Q. , Wang Z. , LI Y. , LI Y.
Published: August 2020

e19066

Objective: To investigate the correlation between the expression of ABH and Lewis A histo-blood group antigens and the differentiation, tumorigenesis, progression, metastasis and prognosis of primary pulmonary adenocarcinoma. Methods: The expression of ABH and Lewis A histo-blood group antigens were detected in normal tissue (n=30), primary adenocarcinoma (n=103) and corresponding metastatic lesion (n=41) with immunohistochemistry S-P method. Results: The positive expression of A, B, H antigens was found in normal corresponding pulmonary tissue. While in cancer tissue, such expression was absent. The absence in poorly differentiated tumor was significantly higher than in moderate and highly differentiated cell (P<0.001). And the absent expression was statistically higher in tumor with metastasis than in without metastasis (P=0.036),higher in N2 than in N1 group, higher in secondary tumor in than primary focus(P=0.008).There was significantly statistical difference on the absent expression rates among normal pulmonary tissue, primary tumor and metastatic tumor (P<0.001), and having a tendency of increased absence rate. The expression of Lewis A antigen was markedly higher in pulmonary adenocarcinoma than in normal tissue (P=0.024). Concerning Lewis A expression, the significant difference was found in Stage I,II and III+IV cancers (P=0.001), while the positive expression rate in advanced cancer (StageII+III+IV) was remarkably higher than in early cancer (Stage I) . The 5-year survival of positive expression of ABH antigen was 25%, higher than that in negative expression group (P<0.0001). The 5-year survival in positive expression of Lewis A antigen was 7%, lower than in negative group (P=0.0002). Conclusions: The absence of ABH antigen is closely correlated with tumorigenesis, poor differentiation, and metastasis of primary adenocarcinoma. The detection of ABH, Lewis A antigen may be of vital significance for the prognosis.

No significant financial relationships to disclose.
A phase II study of S-1 for previously treated small cell lung cancer (SCLC)
Authors: Kudo K. , Ohyanagi F. , Horiike A. , Miyauchi E. , Motokawa I. , Horai T. , Mun M. , Sakao Y. , Okumura S. , Nakagawa K. , Nishio M.
Published: August 2020

e19074

Background: S-1 is a novel oral 5-fluorouracil derivative that exhibits obvious activity against various tumor types including NSCLC. However, the effects of S-1 against SCLC have not been reported. The present phase II trial assesses the efficacy and safety of S-1 in previously treated SCLC patients. Methods: Eligible patients had pathologically documented SCLC that relapsed after platinum-based chemotherapy, ECOG performance status (PS) 0–2, and adequate bone marrow, kidney and liver function. Patients with untreated or symptomatic brain metastasis were excluded. Treatment comprised the oral administration of S-1 at 40 mg/m2 twice each day for 28 days every 6 weeks. The primary end point was the objective tumor response rate (RECIST). Secondary endpoints included progression-free survival and overall survival. Results: Twenty-six evaluable patients were enrolled (Simon's two-stage optimal design; α = 0.1; β = 0.1; P0 = 0.05; P1 = 0.25) with the following characteristics: male: female, 22/4; median age, 68 (33 - 79) y; PS0–1, n = 21; PS2, n = 5. The median number of prior treatment regimens was 2 (1–3). S-1 was administered for a mean of 1.3 cycles (1 - 5). One patient (3.8%) partially responded, 10 (38.5%) had stable and 15 (57.7%) had progressive disease. The overall response rate was 3.8% and the disease control rate was 42.3%. The median time to progression was 33 days. The median survival time was 8.0 months and the 1-year survival rate was 23%. This regimen was well tolerated. The common grade 3/4 toxicities included neutropenia (7.7%), leukopenia (7.7%), anemia (7.7%), hyponatremia (7.7%), rush (7.7%), infection (7.7%), and diarrhea (3.8%). None of the patients developed febrile neutropenia and no deaths were attributed to treatment. Conclusions: S-1 is well tolerated but has low activity as a single agent in previously treated patients with SCLC.

No significant financial relationships to disclose.
Outcomes of small cell lung cancer (SCLC) patients treated with second-line chemotherapy (SL): A retrospective analysis of 166 patients
Authors: Garassino M. C. , Michetti G. , Lo Dico M. , Califano R. , Aglione S. , Borgonovo K. , Mancuso A. , Galetta D. , Gallerani E. , Collovà E. , Torri V.
Published: August 2020

e19093

Background: Patients with SCLC progressed after first-line chemotherapy (FL) have a poor prognosis and the evidence of a benefit of SL is still limited.This retrospective analysis evaluates the clinical outcomes of patients who received a SL treatment after failure of a FL for SCLC Methods: Retrospectively we reviewed 166 consecutive patients who failed a FL and received a second or third-line treatment, between 1993 and 2008 in 17 institutions. We divided patients for analysis in four subgroups, according to the type of SL administered: 1) Platinum-based (P) rechallenge 2) Non-platinum-based polichemotherapy 3) Non-topotecan monochemotherapy 4) topotecan monochemotherapy. Our endpoints were Overall survival (OS), Progression free survival (PFS) and Response Rate. Survival curves were designed with Kaplan-Meier method and Cox proportional hazard model was used for investigating factors which influence survival Results: Median age was 63 (range 25–86). Median OS from the SL was 6.2 months and PFS 2.9. 163 patients received a platinum based chemotherapy as FL, among them 67% obtained a response (CR=14%, PR=53.7%) and 19% had a progressive disease. 74% of patients had a PS 0–1 when started on SL. Moreover, 50 patients underwent also a third-line chemotherapy. Of the 23 CR at FL, 7 patients achieved a response in SL(30%), of the 85 PR only 19 (22%) and of the PD+SD only 6 (16%) (test for trend p=.03). No statistical differences among regimens groups were found; however, patients rechallenged with P went better then others when a long PFS in FL was demonstrated (p=.02) Conclusions: The clinical benefit of SL therapy for SCLC is poor and strictly dependent on response and on duration of response with FL treatment. Our retrospective analysis confirms that median OS for patients receiving SL is about 6 months and median PFS 2.9 months. A rechallenge with platinum should be the best options in patients with a long PFS in FL. Single agent topotecan, the most investigated agent in the literature, did not show evidence of superiority against other chemotherapy regimens

No significant financial relationships to disclose.
Rituximab maintenance after R-CHOP in the first-line treatment of follicular lymphoma: A GOTEL phase II trial
Authors: Rueda A. , Provencio M. , Abrio M. , Gómez-Codina J. , Llanos M. , Delgado J. , Rifá J. , Sabin P. , Vélez de Mendizabal E. ,   Grupo Oncológico para el Tratamiento y Estudio delos Linfomas, Baz V.
Published: August 2020

e19502

Background: Rituximab maintenance have demonstrated improvements in progression-free and overall survival in relapsed patients with follicular lymphoma (FL). Ongoing trials are evaluating the benefit of rituximab maintenance following treatment of therapy-naive patients (pts) treated with rituximab-containing chemoinmunotherapy induction regimens. Methods: The current study evaluated the activity and toxicity of rituximab maintenance after chemoinmunotherapy in the first line treatment of advanced-stage FL. Pts with advanced stage FL were eligible. The induction treatment consisted in 8 courses of chemoinmunotherapy with R-CHOP (rituximab 375 mg/m2; cyclophosphamide 750 mg/m2; doxorubicin 50 mg/m2 and vincristine 2 mg). Pts entering a complete (CR) or partial remission (PR) received maintenance with 6 doses of rituximab (375 mg/m2/d) to be given every two months after the end of induction therapy. Results: From December 2004 to November 2006, 52 pts were included. Median age was 52 years (range, 36–85) and 26 pts were women. At baseline 32 (62%) pts had stage IV and 20 (38%) stage III. According to the Follicular Lymphoma International Prognostic Index (FLIPI), 8 pts (15%) had low risk disease, 24 pts (46%) intermediate risk, and 20 pts (39%) high risk disease. Six (12%) pts did not receive maintenance (3 pts progressed during induction, 2 pts refused maintenance and 1 pt had severe toxicity to induction). Of the 46 pts included in the maintenance phase, 32 (69%) were in CR/CRu and 14 pts (31%) in PR after induction therapy. Rituximab was well tolerated in the maintenance phase. Only 5 pts didn´t receive the 6 scheduled courses (toxicity: 1; progressive disease: 2; cardiovascular events: 2). Grade 3–4 toxicity occurred as follow: neutropenia in 4 pts (9%), and fever in 1 pt (2%). No severe infections were seen. After maintenance, 40 (87%) pts were in CR/CRu, 4 pts (9%) in PR and 2 (4%) progressed. With a median follow-up of 27 months, progression-free and overall survival at 30 months were 82% and 92%, respectively. Conclusions: Rituximab maintenance after first-line R-CHOP is safe and increase the complete remission rate obtained in the induction phase.

No significant financial relationships to disclose.
A phase II trial of sorafenib in patients with relapsing and resistant multiple myeloma (MM) previously treated with bortezomib (S0434)
Authors: Srkalovic G. , Hussein M. , Bolejack V. , Hoering A. , Zonder J. , Barlogie B.
Published: August 2020

e19517

Background: The multikinase inhibitor sorafenib targets several serine/threonine and receptor tyrosine kinases by blocking RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway regulated by the Ras oncogene, which is mutated both in primary patient samples and in human MM lines (35–50%). As the frequency of these mutations increases with advancing disease and increasing drug resistance, inhibition of the RAF/MEK/ERK signaling pathway, as well the angiogenic VEGFR-2/PDGFR beta cascade by sorafenib may be a useful new approach for the treatment of MM. Methods: SWOG evaluated the effect of sorafenib as a single agent in relapsed/refractory MM patients. In this phase II study we assessed response rate, overall (OS) and progression-free survival (PFS) as well as toxicities associated with this treatment. Twenty-three heavily pretreated MM patients were enrolled in the study. Sorafenib was started at oral dose of 400 mg daily until progression or toxicity. This dose was based on the label for metastatic renal cell carcinoma. Results: The study was closed as planned due to lack of efficacy in first 18 patients who were assessable for toxicity and response. Three patients experienced Grade 4 toxicity consisting of thrombocytopenia, anemia and renal failure. 8 cases suffered Grade 3 toxicities including thrombocytopenia, neutropenia, anemia, hand-foot syndrome, diarrhea and dyspnea. No responses were observed. 3 patients had stable disease (2.4–15.9 months) and the remainder progressed. Median PFS is one month, and OS at 12 months is 50%. Conclusions: Thus, single agent sorafenib did not show activity in this group of heavily pretreated MM patients previously exposed to bortezomib. As the frequency of RAS oncogene mutations increases resulting in resistance to traditional chemotherapeutic agents as well as possibly supporting cytokine resistance to immune modulators, sorafenib might have a supportive role in combination therapy with bortezomib, lenalidomide or everolimus in relapsed/refractory MM which is currently being evaluated in ongoing studies.

No significant financial relationships to disclose.
Prognostic role of interim 18FDG-PET in Hodgkin lymphoma: A single-center experience
Authors: Cocorocchio E. , Vanazzi A. , Botteri E. , Alietti A. , Negri M. , Bassi S. , Preda L. , Travaini L. , Peccatori F. A.
Published: August 2020

e19520

Background: The role of FDG-PET for staging and response assessment in Hodgkin lymphoma (HL) is still evolving. We report our experience with the intent of evaluate prognostic role of 18FDG-PET in terms of long term complete remission (CR). Methods: We retrospectively analysed 65 consecutive pts affected by newly diagnosed HL. Median age was 36 yrs. Histology included 50 classical and 10 lymphocyte predominance HL. According to Hasenclever index, 58 out of 65 pts were considered at low risk, 5 at intermediate and 2 at high risk. 30/65 pts showed good prognosis (defined as IA-IIA, < 3 nodal sites, ERS < 50) and received 4 cycles of VBM followed by involved field (IF) radiotherapy (RT); the remaining 35 pts received hybrid ChlVPP/ABVVP for 6 cycles followed by IF RT in case of bulky disease. All patients underwent 18FDG-PET scans at diagnosis, after the fourth cycle in the VBM group, after the third cycle in the ChlVPP/ABVVP (interim 18FDG-PET), at the end of treatment in all patients. Fisher exact test was used to compare percentages between groups. Results: CR was recorded in 60 (92%) pts. Interim 18FDG-PET was negative in 52 out of 65 pts (80%), all in CR at the end of treatment. Eight out of 13 pts with positive interim 18FDG-PET obtained a CR at the end of treatment (100% versus 62%, Fisher exact text p<0.01). Six out of 65 pts relapsed: interim 18FDG-PET was negative in 5 of them, positive in 1 case. Two deaths occurred, one among pts with negative and one with positive interim 18FDG-PET. After a median follow-up of 30 months, 3-year freedom from treatment failure was 83% and 62% in pts with negative and positive interim 18FDG-PET, respectively (Log-rank test p<0.01, Hazard Ratio 4.9 (95%CI 1.4–16.1)). Conclusions: In our experience interim 18FDG-PET demonstrate a predictive role regarding the achievement of CR and treatment failure, at least as relevant as Hasenclever index, but failed to predict clinical result in 12 (18%) pts. Its role in defining the best therapeutical approach in HL pts must be further investigated in randomized clinical trials.

No significant financial relationships to disclose.
Role of fine needle aspiration (FNA) cytology in assessment of cervical lymphadenopathy
Authors: Khillan R. , Sidhu G. S. , Axiotis C. , Braverman A.
Published: August 2020

e19525

Background: The ability of FNA specimens to provide a definitive lymphoma diagnosis is controversial. Otolaryngolists routinely employ FNA for cervical lymph nodes which may have arisen from head and neck carcinomas, since incisional procedures may interfere with potentially curative surgery. Methods: The charts of 176 patients referred to the Kings County Hospital Center since 1996 for confirmed lymphoma were reviewed. All patients with cervical adenopathy are initially referred to the Otolaryngology service for biopsy, which is routinely FNA. Results: Of the 123 patients for whom pathological data was available, 37 had initial FNAs; 10 more FNAs (total 47) were done when the first was not diagnostic. Cervical adenopathy was the presentation in 27 of 37 patients (73%), 6 of whom also had disseminated adenopathy. Upper aerodigestive tract (UAT) fiberoscopy had been negative in 16 and not performed in 7. The FNA specimens contained interpretable material in 42 of 47 cases (89%). Five FNA specimens were diagnostic of lymphoma (11%), but the type was classifiable in only one. Thus, 32 initial FNA specimens were not diagnostic, nor were 10 repeat FNA's on the same patients. Of the 32 patients who initially had non-diagnostic FNAs, a lymphoma diagnosis and classification was ultimately established by a single excisional lymph node biopsy. Lymphoma diagnosis was delayed in 19 patients because of FNA by 10–941 days; median 38, mean 68 days. Conclusions: Though 90% were not diagnostic, FNA was routinely, and sometimes repeatedly performed in patients with cervical adenopathy, most of whom had no evidence of UAT neoplasms, and some of whom had disseminated adenopathy. Significant delays in diagnosis were the result. Decisions concerning biopsy technique in patients with cervical adenopathy should be made in the context of clinical presentation.

No significant financial relationships to disclose.
Impaired endothelial function in Hodgkin lymphoma survivors receiving mediastinal radiation
Authors: Chen B. , Mahmud F. , Mangel J. , Vujovic O. , Rieder M. , Zelcer S.
Published: August 2020

e19526

Background: Mediastinal radiation (RT) is a cause of premature coronary artery disease (CAD) in Hodgkin lymphoma survivors (HLS). Early detection of atherosclerosis may allow for improved health outcomes. Peripheral arterial tonometry (PAT) is a non-invasive technique that measures endothelial function (EF), as a surrogate marker of sub-clinical atherosclerosis. The objective of our study was to evaluate EF in HLS and age-matched controls using PAT and to determine the association of mediastinal RT. Methods: Cross sectional evaluation of 26 HLS age 12–30 years and within a minimum of two years from the completion of therapy and matched controls. Evaluation for CAD risk factors included measurement of body mass index and blood pressure, fasting lipoproteins and hsCRP. A standardized activity questionnaire (HAES, habitual activity estimation score) was completed by all participants. EF was measured using PAT hyperemia ratios (PAT-HR) in all subjects. Results: HLS and controls were similar for baseline variables (mean age 23.2 ± 5 yrs; 23.4 ± 4.6 yrs, p=0.35). HLS were on average 9.9 ± 3.9 yrs post treatment. No differences in EF or cardiovascular risk factors were observed between HLS survivors and controls. However impaired EF, as evidenced by lower PAT-HR (1.66 ± 0.18 vs. 2.08 ± 0.38, p<0.01) was seen in HLS (n=13) who received mantle/mediastinal RT (mean RT dose 2657 ± 971 cGy) compared to controls. Mean cumulative anthracycline dose did not differ between HLS who did or did not receive RT (224.1 ± 65.4 vs. 253 ± 70.3 mg/m2 p=0.18). These differences were not explained by alterations in lipoproteins or hsCRP, however activity scores were significantly lower in HLS compared with young adult controls (2.01 ± 1.1 vs. 3.6 ± 1.2 hrs daily, p=0.02). Conclusions: Impaired EF was observed in a small group of HLS who received mediastinal RT as compared to those who did not. Cancer survivors at risk may benefit from early assessment of EF as a sub-clinical marker of CAD.

No significant financial relationships to disclose.