bluuebunny/crossref_metadata_2025 huggingface dataset:
Gemcitabine/docetaxel (GD) vs gemcitabine/cisplatin (GC) in stage IIIB/IV advanced non-small cell lung cancer (NSCLC)
Authors: Casal Rubio J. , Vázquez Estevez S. , Vázquez Rivera F. , Amenedo Gancedo M. , Fírvida Pérez J. , Mel Lorenzo J. , Grande Ventura C. , Lázaro Quintela M. , Álvarez Gómez E. , López López R.
Published: March 2020

17017

Background: This trial was designed to compare, in terms of response rates, the standard regimen gemcitabine/cisplatin versus a non-platin regimen, gemcitabine-docetaxel in NSCLC. Methods: The chemotherapy regimens administered were: Arm A: gemcitabine 1250 mg/m2 d1 & 8 plus cisplatin 75 mg/m2 d1; Arm B: gemcitabine 1000 mg/m2 d1 & 8 plus docetaxel 85 mg/m2 d1 repeated every three weeks. Eligibility criteria were measurable stage IV or stage IIIB with pleural effusion NSCLC (brain metastases eligible if asymptomatic) and PS (ECOG Scale) = 0–2. Results: 108 patients (pts) were included between January 2001 and August 2004, 56 in arm A and 52 in arm B. For arm A median age was 59.9 (69.7–50.1); PS 0–1: 83.3%, PS 2: 16.7; Stage IIIB/IV: 18.2/81.8%, For arm B median age was 61.4 (70.4–52.4); PS 0–1: 84%, PS 2: 16%; Stage IIIB/IV: 14/86%. A median number of 5 cycles in arm A and 4 in arm B were administered. Response rates from the 105 eligible patients were: Arm A (55 pts): CR 3.8%, PR 32.1%, SD 32.1%; Arm B (50 pts): CR 2.3%, PR 44.2%, SD 20.9%. Median overall survival (OS) was the same in both arms, 8.9 months (6.3–10.5) in arm A and 8.9 months (3.9–10) in arm B (p = 0.525); median time to progression disease (TTPD) was 6 months (4.2–7.1) in arm A and 5.5 months (4.1–7.2) in arm B (p = 0.607). Toxicities include, in Arms A and B respectively: Grade 3–4 neutropenia 49.1% and 41.2%, with neutropenic fever in 1.8% and 2%; Grade 3/4 thrombocytopenia 30.9/0% and 3.9/0%; Grade 3/4 anemia 14.5/0% and 3.9/0%. Non-hematological toxicity grades 3–4 were similar in both arms, with the exception of nausea and vomiting, (16.3% and 2% in arm A and B respectively); renal and hepatic toxicity (hepatic 5.6% vs. 12.7% and renal 3.7% vs. 0%). Conclusions: The overall response rate was higher in the combination gemcitabine-docetaxel, although there are no significant differences in OS and TTPD. GD is an active non-platin regimen and a good first treatment option for advanced NSCLC.

No significant financial relationships to disclose.
The predictive factors and patient-selection associated with the survival benefits of gefitinib in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Funada Y. , Satouchi M. , Miyagawa T. , Urata Y. , Shimada T. , Yoshimura S. , Watanabe Y. , Kurata T. , Adachi S. , Takada Y. , Negoro S.
Published: March 2020

17020

Background: Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has shown meaningful antitumor activity for advanced NSCLC. Survival benefit of treatment with gefitinib has not been shown in unselected patients, however heterogeneity in survival outcomes between sub-group (histological types, gender, smoking status and ethnicity) of patients has been observed. The aim of this study was to identify the potential predictive features associated with the survival benefit of treatment with gefitinib. Methods: All NSCLC patients who began taking gefitinib during the period from July 2002 until July 2005 in our institute were retrospectively reviewed. Potential factors analyzed included age, gender, smoking history, performance status (PS), histology, stage, and prior chemotherapy. Results: Overall 221 patients were analyzed. The overall response rate of gefitinib was 26.7%. Median survival time (MST) was 8.0 months. MST of patients whose tumor response was partial response (PR) was 34.5 months. Univariate analysis revealed that the predictive factors of favorable survival were female (p = 0.001), never-smoker (p < 0.0001), good PS (p < 0.0001) and adenocarcinoma (p < 0.0001). Multivariate analysis showed that never-smoking history (p = 0.005), adenocarcinoma (p = 0.004), and better PS (P < 0.001) were significant independent predictors of long survival. The Brinkman index (BI), number of cigarettes per day multiplied by number of years smoked, was associated with survival benefit. MST was 17.6 months in the BI = 0 group (never-smokers), 9.7 months in 1 ≤BI <500, 6.9 months in 500 ≤BI <1000, 4.4 months in 1000 ≤BI <1500, and 4.0 months in BI ≥1500. Conclusion: Never-smokers and adenocarcinoma are predictive factors for prolonged survival. As for smoking status, lower BI is associated with better prognosis after treatment with gefitinib. Therefore, histological factors and smoking status must be considered when treating with gefitinib.

No significant financial relationships to disclose.
Serum levels of administered gefitinib correlate with the time to treatment failure in non small cell lung cancer patients
Authors: Nishio M. , Ohyanagi F. , Horikike A. , Ishikawa Y. , Satoh Y. , Okumura S. , Nakagawa K. , Nishio K. , Horai T.
Published: March 2020

17027

Background: Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, has been shown to have clinical activity against non-small cell lung cancer (NSCLC). The aim of the present study was to clarify the relationship between serum gefitinib levels and clinical efficacy in patients with advanced NSCLCs. Methods and Results: Sera from 89 cases (51 men and 38 women) were obtained after 2 weeks gefitinib (250 mg/day) monotherapy. The average gefitinib level was 429.4 ± 214.8 ng/ml (mean ± SD) with 17-fold variability observed. No significant variation was observed with reference to gender, smoking history or performance status. There was no direct link between gefitinib level and tumor response, but a significant positive correlation was evident with time to treatment failure in 44 patients receiving gefitinib for more than 3 months (R = 0.365, P = 0.0144). Conclusions: These results suggested that a dose response may exist for time treatment failure in the patients who benefit from gefitinib. Dose modification in accordance with the serum gefitinib level may thus improve the efficacy of gefitinib for NSCLCs.

[Table: see text]
Neoadjuvant weekly paclitaxel/cisplatin chemotherapy (WTP) with concurrent thoracic chemoradiation followed by surgical resection for stage IIIA (pN2) non-small cell lung cancer (NCLC): Phase II study
Authors: Kim S. , Sohn H. , Suh C. , Ryu J. , Choi E. , Kim Y. , Kim D. , Park S. , Kim W. , Lee J.
Published: March 2020

17036

Background: To investigate the role of weekly chemotherapy with paclitaxel/cisplatin and concurrent thoracic radiation (RT) as neoadjuvant therapy before surgical resection for patients with N2-IIIA NSCLC. Methods: Patients with pathologically proven N2 (pN2) and operable stage IIIA NSCLC were eligible. Six weekly chemotherapy with paclitaxel (50 mg/m2)/cisplatin (20 mg/m2) was given with concurrent thoracic RT (1.8 Gy/fraction once a day, 45 Gy) during 5 weeks. Chest CT, whole body PET were checked before and 3 weeks after chemoradiation. For the patients without clearing pN2 nodes or with pT3 after surgical resection, boost RT (20 Gy) was given. Results: From Jan. 2002 to Nov. 2005, 38 patients were enrolled. Median follow-up time was 20 months: gender (male: female, 30:8,), age (median 56, 42–67). Of them, 31 patients underwent surgical resection. Three patients showed brain metastasis during chmoradiation. Two patients refused surgical resection after chemoradiation. One patient showed severe radiation pneumonitis and was not fit for the operation. One patient showed lung to lung metastases before surgical resection. Of the 31 patients who underwent surgical resection, 14 (45.2%) showed pN0–1, and 7 (22.6%) showed pathologic complete remission (CR). Three year overall survival rate of all patients was 37.7% (median 35.9 months) and 3 year progression free survival was 34.2% (median 18 months). In univariate analysis, clearing N2 node and pathologic CR after surgery were the factors that could predict long-term survival. And the 2nd PET after chemoradiaiton could not expect clearing N2 nodes after surgical resection: sensitivity 44%, specificity 46%. As toxicities of WTP, hypersensivity reaction to paclitaxel and pneumonia with neutropenia were noted in 1 patient each. Severe radiation pneumonits was noted in 4 (of them 3 were given 65 Gy). Conclusions: WTP followed by surgical resection for N2-stage IIIA NSCLC was feasible. Clearing N2 nodes or pathologic CR after surgical resection were the factors of long-term survival. The usefulness of 2nd PET to expect the clearing N2 nodes was not adequate.

No significant financial relationships to disclose.
mRNA expression of signal transducer and activator of transcription (STAT5), disheveled-3 (Dvl-3) and dicer in early-stage non-small-cell lung cancer (NSCLC)
Authors: Cecere F. , Rosell R. , Taron M. , Ceribelli A. , Milella M. , Mendez P. , Cuello M. , Visca P. , Facciolo F. , Cognetti F.
Published: March 2020

17038

Background: STAT5 plays a role in angiogenesis and metastasis. Activation of STAT5 occurs through dysregulation of growth factor receptor tyrosine kinases (TK) (including EGFR TK mutations), non-receptor TKs or Janus kinases. Dvl-3, a critical mediator of the Wingless-type (Wnt) signaling pathway, contributes to self-renewal of stem cells. Dicer has a key role in processing microRNAs required for stem cell regulation. We assessed mRNA expression of STAT5, Dvl-3 and Dicer in early-stage NSCLC. Methods: cDNA was derived from paraffin-embedded primary tumors of 47 surgically resected, early-stage NSCLC patients. Real-time quantitative reverse transcriptase PCR was used to measure STAT5, Dvl-3 and Dicer mRNA levels relative to the internal reference gene β-actin. Results: Median expression levels were: STAT5, 0.66 (0.15–6.03); Dvl-3, 3.69 (1.02–25.83); Dicer, 4.53 (1.22–21.96). STAT5 levels for squamous cell carcinoma (SCC) were 0.57 vs 0.89 for non-SCC (P=0.01), while Dicer levels were higher in SCC (4.25) than in non-SCC (2.60) (P = 0.01). A strong correlation between the levels of Dvl-3 and Dicer was found (rho = 0.49; P < 0.001). 90% of females had low Dicer mRNA levels (P = 0.01). No other correlation between mRNA levels and patient characteristics was found. Conclusions: High levels of Dvl-3 are associated with SCC. The close correlation between Dvl-3 and Dicer levels may indicate that Dicer could process a class of microRNA that activates the Wnt pathway. In non-SCC, overexpression of STAT5 could be involved in tumor angiogenesis. These 3 transcripts could be potential predictors of metastasis and ideal targets for individualized treatment.

No significant financial relationships to disclose.
Efficacy and safety profile of oxaliplatin and docetaxel in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Santos E. S. , Raez L. E. , Rosado M. , Lopes G. , Roman E. , Kumar P. , Tolba K. , Silva O. , Rocha-Lima C. , Hamilton K.
Published: March 2020

17061

Background: Platinum-based doublets are used as treatment for advanced or metastatic non-small cell lung cancer (NSCLC), but chemotherapy must be tailored to decrease side effects. Oxaliplatin is more potent than cisplatin, requiring fewer DNA adducts to provide equivalent cytotoxicity in vitro studies. Oxaliplatin was active as a single agent and in combination with vinorelbine, paclitaxel, and gemcitabinein phase II studies of patients with NSCLC. A phase II study was conducted to evaluate the efficacy and safety of oxaliplatin combined with docetaxel for NSCLC. Methods: Patients with stage-IIIB or -IV, chemotherapy-naive NSCLC received docetaxel 70 mg/m2, oxaliplatin 130 mg/m2, and pegfilgrastim 6 mg every 21 days for up to 6 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints were progression-free and overall survival (PFS and OS), and safety. Results: Twenty-nine patients were treated; 15 (51.7%) were women, 25 (76%) were white, 17 (58.6%) were hispanic, 21 (72.4%) had adenocarcinomas, 24 (83%) had a PS ECOG 1, 93% had stage-IV disease and 28% had brain metastases. There were 10 partial responses in 27 evaluable patients for an ORR of 37% (90% confidence interval [CI], 21.7%–54.7%). Median PFS for 29 treated patients was 4.6 months (95% CI, 2.6–6.5 months); 12-month PFS was 14.8% (95% CI, 3.4%– 34.0%). Median OS was 10.9 months (95% CI, 8.9–16.8 months); 12-month OS was 40% (95% CI, 18.5%–60.8%) and 18-month OS was 16% (95% CI, 1.4%–45.7%). There were no unusual or unexpected adverse events. The most common grade-3 and -4 toxicities were anemia (14% of patients) and hyperglycemia (10%). There were only 2 reports of neutropenia; both were grade 1 or 2. Conclusions: These phase II findings suggest that the combination of oxaliplatin and docetaxel is active and well tolerated, and offers a feasible treatment alternative for patients with advanced or metastatic NSCLC.

[Table: see text]
Phase I/II trial of doranidazole (PR-350) and concurrent thoracic radiotherapy (TRT) in patients (pts) with locally advanced (LA) non-small cell lung cancer (NSCLC)
Authors: Takeda K. , Negoro S. , Nakagawa K. , Segawa Y. , Nishimura Y. , Fukuoka M. , Ariyoshi Y.
Published: March 2020

17064

Background: PR-350 was a nitoroimidazole derivative as a hypoxic cell radiosensitizer with low toxixity, developed by POLA Chemical Industries Inc.(Yokohama, Japan). We undertook this phase I/II trial to characterize the safety, pharmacokinetics (PK), and antitumor activity of the combination chemotherapy of platinum agent and paclitaxel followed by PR-350 and concurrent TRT in pts with LANSCLC. This trial was conducted by West Japan Thoracic Oncology Group (WJTOG). Methods: Major eligibility included 20–74 years old, histologically or cytologically proven NSCLC, surgically unresectable stage IIIA and IIIB, no prior therapy, ECOG performance status of 0 to 1, and adequate organ functions. All pts received two cycles of cisplatin of 80 mg/m2 and paclitaxel of 180 mg/m2 before radiotherapy with PR-350. The radiation dose was 60 Gy in 30 fractions of 2 Gy over 6 weeks. PR-350 dose of 2000 mg/m2 was administered as a 25 minutes intravenously prior to irradiation daily. The starting consecutive days were 10 times with daily TRT, and the times were escalated in increments of 10 times for successive groups of 6 new pts. PK studies of PR-350 were performed on the first day and the end. Induction chemotherapy of carboplatin (AUC = 6) and paclitaxel (200mg/m2) was also permitted in phase II portion. Results: 37 pts were enrolled into this trial. Major severe toxicity was radiation pneumonitis, which developed 2 treatment related deaths (TRD). Grade 3 or more esophagitis was not developed in this trial. PR-350 was able to administered 30 consecutive days with concurrent TRT. Overall response rate was 67.6% (95% CI: 50.2–82.0%). Median survival time was 16.8 months (95% CI: 12.1–21.9 months), and 1 and 2 year survival rate were 64% and 21%, respectively. No cumulative effect was demonstrated among 3 dose levels by PK studies. Conclusions: Induction chemotherapy followed by TRT with 30 times of PR-350 was well tolerated and promising for the treatment of LANSCLC.

[Table: see text]

No significant financial relationships to disclose.
Role of (18) F-FDG PET scanning in detecting osseous metastases in non-small cell lung cancer (NSCLC) in a community setting: A retrospective data analysis
Authors: Pulagam S. R. , Johnson J. , Nelson K. , Kim B. , Kirchner L. , Mamounas E.
Published: March 2020

17067

Background: Metastasis from a distant site is the most common neoplastic process involving bone. Accurate staging of NSCLC is critical for effective management. Bone scans have been traditionally used for diagnosing bone metastases in NSCLC. Recently, PET scanning has been shown to be effective in detecting bone metastases in several studies. In NSCLC, using a single PET scan to evaluate both the primary tumor and bone metastases might be more cost-effective and if the accuracy of PET scanning for detection of bone metastases can be established, the need for bone scanning may be obviated. We performed a retrospective comparison between PET scan and bone scan in NSCLC patients diagnosed and treated in a community hospital setting. Methods: 50 patients who were diagnosed with NSCLC between January 1, 2002 and December 31, 2004 and who had both PET scan and Bone scan done within 3 months of each other were included in the study. 47 patients had both investigations within 40 days duration. Data regarding all the lesions found on bone and PET scan were collected. Results: The median age of the patients was 70.5 years. Total of 20 patients were diagnosed with bone metastases by one or the other test. Of these 15 were identified with bone scan with a sensitivity of 75% (95% Confidence interval CI 56.2%–97.1%). 17 patients were identified by PET scan with a sensitivity of 85% (95% CI 45.5%–92%), p-value -0.48 compared to bone scan. 3 patients who had positive bone scan had a negative PET scan. 5 patients who had positive PET scan had a negative bone scan. Conclusions: PET scan appears to be as good as bone scan in detecting bone metastases. Unless very high clinical suspicion exists regarding bone metastases, negative PET-Scan for bone metastases should obviate the need for bone scan.

[Table: see text]

No significant financial relationships to disclose.
Salvage vinorelbine (VNR) in the 2nd to 4th line setting in advanced non-small cell lung cancer (NSCLC): A retrospective review at the Fox Chase Cancer Center (FCCC)
Authors: Devlin J. G. , Langer C. J.
Published: March 2020

17072

Background: Published literature has demonstrated minimal activity for VNR in the salvage treatment of NSCLC, with response rates of only 0.8% (Fossella, et al, JCO 2000; 18(12), 2354–2362). However, in our clinical experience, we have observed a number of patients (pts) with clinical benefit. Methods: Retrospective evaluation was performed of all pts with NSCLC who had received VNR at FCCC from 6/02–6/05 in the salvage setting. Pts were evaluable if full medical records (including radiographic imaging for disease assessment) were available, had received ≥2 cycles of VNR, and had advanced, recurrent or metastatic NSCLC. Primary endpoint was response rate (RR); secondary endpoints included safety, median overall survival (OS), and median time to progression (TTP). Results: 52 pts were included, 28 pts were ultimately evaluable (13 pts received <2 cycles of VNR, 7 pts did not have NSCLC, and 4 pts received VNR with RT or other agents). Median age was 64 yrs, 64% were female; ECOG-PS 0–18%, 1–50%, 2–28.5%, 3–3.5%. 82% exhausted 2 lines of systemic therapy before VNR; 32% exhausted 3; 21.4% received prior EGFR-TKI; 18% received other prior protocol therapies. 96.3% of pts had stage IV, stage IIIB, or recurrent disease. 21.4% had bone mets; 25% had brain mets; and 42.8% had visceral metastases. 85.8% had significant comorbidities. Median number of VNR cycles was 4. RR:PR 10.7%, SD/MR 35.7%, and PD 50%. 25% required dose reductions, predominantly for gr 4 hematologic toxicities. Non-hematologic toxicities were generally mild, and included neuropathy, fatigue and GI distress; there were no Tx-related deaths. 32% were able to receive other systemic therapy after VNR. Median OS was 5 months, and median TTP was 3 months. Conclusions: Vinorelbine is active and relatively well-tolerated in the salvage treatment of NSCLC, including heavily pretreated pts. Response rates exceed that observed in the literature.

[Table: see text]
Prognostic quantification of non-small cell lung cancer metastases to the lung
Authors: Oh Y. , Srivastava G. , Rana V. , Munden R. , Bekele B. N. , Karp D.
Published: March 2020

17080

Background: Lung is the most frequent organ site of metastases from non-small cell lung cancer (NSCLC), yet the impact of these metastases on the natural history of the disease has not been well elucidated. Part of the difficulty of evaluating the prognosis of lung metastases in NSCLC patients is the effect of metastases to other organ sites. Here we have studied the survival of patients with lung as the solitary or dominant site of metastases and correlated it with number and maximal size of tumors. Methods: Data from the M.D. Anderson Cancer Center Tumor Registry during 1998 to 2002 was interrogated. Of 1280 patients registering as new patients, 87 were evaluable as having lung as the only site of metastases on initial staging evaluation. Excluding 13 patients who had bronchioloalveolar carcinoma (BAC) or BAC features on histology, the remaining 74 patients’ baseline CT scans were reviewed and scored for 1) the maximal linear measurement of the largest lung tumor and 2) the number of lung nodules that were growing and consistent with lung metastases. Results: In non-BAC patients with lung only metastases, an inverse correlation is seen between maximal linear measurement of a patient’s largest lung metastasis on baseline staging and their subsequent survival. A similar inverse correlation is seen between the number of lung metastases and survival. When patients with subsequent development of other metastatic sites are excluded from the analysis, these correlations are strengthened. Also, in BAC patients with lung only metastases, a trend toward longer survival with fewer metastases was seen, but only 13 patients were evaluable. Formal statistical analysis of these results is pending. Conclusions: The number and size of lung metastases from NSCLC appear to be independent predictors of survival. This might be explained by lead-time bias where fewer lesions represent an earlier stage of metastatic disease, however, increasing number and size of metastases may also be multiplying the source for further metastatic spread of disease. This interpretation of data may justify the local therapy of individual lung metastases in oligometastatic disease by surgery, stereotactic radiosurgery, or radiofrequency ablation.

No significant financial relationships to disclose.
Clinical outcomes of a phase I/II study of stereotactic radiotherapy for metastatic lung cancer
Authors: Nagata Y. , Hiraoka M. , Norihisa Y. , Takayama K. , Matsuo Y. , Mizowaki T. , Sakamoto M.
Published: March 2020

17081

Background: The clinical significance of three-dimensional stereotactic radiotherapy (SRT) for primary lung cancer has been demonstrated by a few studies. This study was performed to evaluate the clinical outcomes of SRT for treating metastatic lung cancer using a stereotactic body frame. Methods: Of the forty-one patients who were treated between October 1998 and December 2004, thirty-four patients were evaluated in this study. All patients had less than two lung solitary metastases without any other metastases and primary recurrence. Fifteen patients were metastasis from primary lung cancer. The other 9 had metastasis from colo-rectal cancer, 5 from head and neck cancer, 3 from renal cancer, 1 from breast cancer, 1 from osteosarcoma of femur. All tumor size was less than 4 cm in diameter. Three-dimensional treatment planning using 5 to 8 non-coplanar beams was performed to maintain the target dose homogeneity and to decrease the irradiated lung volume >20 Gy. All patients were irradiated using a stereotactic body frame and 18 received 4 single 12 Gy, 16 recieved 5 single 12Gy of radiation at the isocenter over a period of 4–18 (median = 12) days. Results: Four patients (4/34%) completely disappeared after treatment (CR) and nine (9/34%) decreased in size by 30% or more (PR), eighteen had no tumor progression in clinically (SD). Three had progress disease (PD). Twenty-eight (82%) of 34 tumors were locally controlled during the follow-up period. Local recurrences and new metastase occurred in one and six of lung cancer patients, one and three of colo-rectal cancer patients, respectively. For recurrent primary lung cancer, the overall survival rates after one and three years were 100 and 63%, respectively, while for secondary lung cancer from colorectal cancer, the overall survival rates were 100 and 71%, respectively. During the follow-up of 10.5–80.6 (median = 27.3) months, no pulmonary complications greater than an CTC-AE V3.0 criteria of grade 4 were noted. Conclusions: Sterotactic radiotherapy using a stereotactic body frame was useful for the treatment of metastatic lung tumors.

No significant financial relationships to disclose.
Vascular endothelial growth factor (VEGF) is a survival factor for neuropilin-1-expressing lung tumour cells
Authors: Barr M. P. , Pidgeon Dr G. P. , O’Byrne Dr K. J.
Published: March 2020

17084

Background: Lung cancer is the leading cause of cancer mortality in Ireland. The formation of new blood vessels, angiogenesis, is essential for tumour growth and metastasis and is induced by several angiogenic factors, including vascular endothelial growth factor (VEGF). Several studies have suggested a role of VEGF as a survival factor for endothelial and some tumour cells. We investigated the effect of VEGF on lung tumour cell survival and examined the VEGF receptor profile of these cells. Methods: A panel of lung cancer cell lines, H460, H647, A549 and SKMES1 were treated with recombinant VEGF (100 ng/ml). Tumour cell survival was assessed using the BrdU proliferation assay. Apoptosis was examined by flow cytometry using Annexin-V and PI staining. VEGF receptor profiles for Flt-1 (VEGFR-1), KDR (VEGFR-2), Neuropilin-1 (NP1) and Neuropilin-2 (NP2) were examined at the mRNA and protein level by RT-PCR and Western blotting, respectively. Tumour cell expression of the Plexin family of signalling receptors was investigated, in addition to the class III Semaphorins which have been shown to bind the Neuropilin receptors. Results: All lung cancer cells expressed NP1 with the exception of the H460 cell line. Using endothelial cells as a positive control, neither VEGFR-1 or VEGFR-2 were identified on the panel of lung cancer cell lines examined at the mRNA and protein level. A dose-response in tumour cell proliferation was observed with the addition of VEGF at 10ng and 100ng/ml. This increase in tumour cell proliferation was significant in all NP1-positive cells, with no effect on NP1-negative H460 cells. VEGF decreased apoptosis in cells expressing NP1, with no effect observed in H460 cells. Our preliminary data show that in addition to NP1, lung cancer cells also express NP2, Plexin-A1, Sema-3A and Sema-3C mRNA which are potential mediators of the NP1 signalling cascade. Conclusions: These results demonstrate that VEGF promotes survival of lung cancer cells, potentially through NP1 signalling. We are currently examining VEGF/VEGFR signalling and the downstream anti- and pro-apoptotic pathways activated in response to VEGF on lung cancer cells. Blockade/inhibition of VEGF and its receptors may offer potential as a therapeutic biological strategy in lung cancer.

No significant financial relationships to disclose.
Phase II study of gemcitabine and carboplatin plus bevacizumab for stage III/IV non-small cell lung cancer: Preliminary safety data
Authors: Kraut M. J.
Published: March 2020

17091

Background: The current standard of care for stage III/IV non-small cell lung cancer (NSCLC) is platinum-based chemotherapy. Bevacizumab (BV) is a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody that improves survival when used in combination with chemotherapy. In a randomized, phase II study of patients (pts) with advanced NSCLC, the addition of bevacizumab 15 mg/kg to paclitaxel/carboplatin (PC) resulted in prolonged survival and progression-free survival compared with PC alone (Sandler AB et al, ASCO 2005). In the present study, we are using BV 15 mg/kg in combination with gemcitabine/carboplatin (GC) for the treatment of NSCLC. Preliminary safety findings are summarized. Methods: Eligible pts with stage IV NSCLC, PS 0–1, and adequate hematologic, renal and hepatic function, were enrolled; pts with squamous cell carcinoma, tumor in the central airways, baseline hemoptysis, or brain metastases were excluded. GC/BV treatment was given in q 3-weekly cycles for 6 cycles, with BV continued in stable and responding patients. G 1250 mg/m2 was given on days 1 and 8 and C AUC 5 was given on day 1. BV 15 mg/kg was given on day 1. After 7 pts were enrolled, the study was amended to reduce the dose of G to 1000 mg/m2 on days 1 and 8 due to unacceptable neutropenia. Primary endpoint of the study is time to progression. Results: To date, 9 pts have received treatment; we report here the hematologic toxicity of the first 8, and non-hematologic toxicity of the first 7. There are 6 men and 2 women, median age 61.5 years. There was one episode of grade 4 thrombocytopenia, and Grade 3 events have been reported a number of patients: leukopenia (5 pts); neutropenia (4 pts); thrombocytopenia (4 pts); infection (1 pt); hemoglobin toxicity (1 pt); fatigue (1 pt); diarrhea (1 pt); dyspnea (1 pt); and dehydration (1 pt). Adverse events possible related to BV include Grade 3 hypertension (1 pt) and Grade 1 epistaxis (2 pts). No thrombosis or proteinuria has been reported. There have been no fatal toxicities. Conclusions: To date, the addition of BV to GC in pts with NSCLC is generally well tolerated and no unexpected adverse events possibly related to BV were observed. Enrollment is ongoing.

[Table: see text]
Phase II study of UFT, vinorelbine and gemcitabine as first-line treatment in advanced non-small-cell lung cancer
Authors: Atagi S. , Kawahara M. , Takada M. , Kawasaki M. , Tamura A. , Saitou R. , Fukai S. , Komatsu H.
Published: March 2020

17100

Background: Vinorelbine (VNR)/gemcitabine (GEM) is active and well tolerated chemotherapy regimens for the treatment of patients (pts) with advanced non-small-cell lung cancer (NSCLC). UFT is composed of uracil and tegafur in a molar ratio of 4:1, and tegafur is a prodrug of 5-FU. Sequential exposure to 5-FU followed by GEM has been reported to give additive effects in vitro. For these reasons, we conducted a phase II study of triple treatment with these 3 drugs for advanced NSCLC. The objectives were to determine the tumor response rate, survival, safety and toxicity of this combination chemotherapy. Methods: Eligible pts were required to have histologically or cytologically comfirmed measurable or evaluable stage IIIB or IV NSCLC, age <75 years, no previous chemotherapy, a Karnofsky performance status (PS) 0–1, and adequate organ function and bone marrow reserve. In this study, pts received UFT (300 mg/m2 orally on days 1-5, 8–12) plus VNR (25 mg/m2 IV on days 6 and 13) and GEM (1000 mg/m2 IV on days 6 and 13). Treatment was repeated every 3 weeks. Results: Between September 2002 and November 2004, 32 pts were enrolled on this study. Characteristics of this study were as follows: male/female = 20/12; median age = 65 years (range 46–74); PS 0/1 = 11/21; stage IIIB/IV = 5/27. Median # of cycles = 2 (range 1–10). Response: PR = 7 (21.9%), SD = 14, PD = 10, NE = 1. Median survival time was 13.9 mos. 1-year survival rate was 56.7% (95% confidence interval, 38.9–74.4%). Gr 3/4 toxicity (% of pts) was as follows: leukocytes 40.6%, neutrophils 56.3%, platelets 3.1%, infection 9.4%, hypoxia 6.3%, dyspnea 3.1% and ALT/AST 3.1%. There were no treatment-related deaths. Conclusions: The combination of UFT, VNR and GEM appears effective with acceptable toxicity.

No significant financial relationships to disclose.
A multicentric phase II trial of gemcitabine (Gem), oxaliplatin (Oxa) and vinorelbine (VNB) in untreated stage IIIB and IV non-small cell lung cancer (NSCLC) patients (pts): Preliminary results of GON triplet regimen
Authors: Tredaniel J. , Becht C. , Bekradda M. , Culine S. , De Cremoux H. , Misset J. , Alexandre A. , Goldwasser F. , Chomy F. , Ecstein-Fraisse E. , Cvitkovic E.
Published: March 2020

17104

Background: Oxa, Gem and VNB are active agents against NSCLC and have shown synergy in combination. VNB plus Gem showed efficacy comparable to platinum combinations with a more favorable toxicity profile, while Oxa/VNB and Oxa/Gem combinations have established recommended doses. Platinum given on day 2 after Gem appears safer and more active. A fixed Gem infusion rate of 10 mg/m2/min is a pharmacologically optimized dosing intended to provide plasma concentrations (≈20 μmol/L) sufficient to maximize the rate of Gem triphosphate accumulation. The aim of the trial was to assess the efficacy (response rate) and safety of GON regimen. Methods: Chemo naive pts with stage IIIB and IV NSCLC received VNB 25 mg/m2, 20-min IV followed by Gem 700 mg/m2 in 10 mg/m2/min IV on day 1, and Oxa 85 mg/m2, 2h IV, on day 2, cycles repeated every 2 weeks. 88 pts are planned in a two-stage design. Results: From February 2004 to November 2005, 39 pts were eligible and treated: 26M/13F; median age: 58 (36–75) years; PS 0/1: 17/22; stage IIIB/IV: 6/33; 21 adenocarcinoma, 9 squamous, 9 large cell carcinoma. Metastatic sites were 67% lung, 21% liver, 36% bone. 229 cycles (cyc) were administered; median cycles/pt 8. Relative dose intensity: Oxa 89%, VNB 94%, Gem 100%. Thirty-four pts were assessable for response (RECIST, external radiological panel review), 5 pts too early: 1 CR, 14 PR (44% ORR, 95% CI 27–62%) with a median OR duration of 12.5 months (range: 3.1–19+), 9 SD, 10 PD. Median follow-up of 6 months (1–21) with median TTP of 4.6 months (95% CI: 1.0–8.3, range: 1–19+); estimated 6-month survival: 80%. Safety is assessable in 38 pts with grade 3–4 toxicities (pts/cyc): neutropenia 6/18, febrile neutropenia 1/1, anemia 1/2, neurotoxicity 3/4, diarrhea 2/3, vomiting 1/1, transaminitis 2/3. Conclusions: The GON triplet is a safe and active outpatient regimen in advanced NSCLC. If these promising results are confirmed in the full cohort, the regimen warrants comparison with standard doublet regimens.

[Table: see text]
Percutaneous laser-induced thermoablation (LIT) of non-resectable lung metastases and primary lung tumors: A preliminary evaluation of technical aspects and local efficiency
Authors: Sponza M. , Aprile G. , Gasparini D. , Iaiza E. , De Pauli F. , Giovannoni M. , Meduri S. , Piccoli G. , Morelli A. , Fasola G.
Published: March 2020

17106

Background: Surgical resection remains the standard of care for solitary lung metastasis from colorectal cancer or primitive lung tumors. Nevertheless only a small part of patients can be radically resected. Thermal ablation is a mini-invasive local treatment that can be considered an alternative approach in non-resectable lesions or inoperable patients. Methods: We present a consecutive series of thirteen patients treated with LIT from March 2004 to March 2005. Nine patients had a small (maximum diameter smaller than 5 cm) non-resectable lung carcinoma while four patients had a solitary metastasis from colorectal cancer. Median age was 70-yrs (range 55–87), male-female ratio was 2:1. After mild sedation and local anaesthesia, optical fibers were inserted directly into the tumor with CT-guided percutaneous needle placement. Each optical fiber was connected to a neodymium:yttrium-aluminium-garnet (ND:YAG) laser, which delivers concentrated light at a wave-length of 1064 nm, with a 5-Watt power and a 1800-Joule energy per single fiber. A minimum of two and a maximum of four needles were used, with a 5 to 8 mm distance from one needle to another. Results: All the patients tolerated LIT procedure well, developing a minimal pneumothorax, which did not require any treatment. Easy manageable local side-effects occurred in two cases (a mild self-limiting haemoptysis and a pleural empyema). Post-treatment CT-scan demonstrated complete thermonecrosis in all the lesions smaller than 3 cm and almost complete in the bigger ones (3 to 5 cm). All the patients are still alive, with a local tumor control rate of 100% at radiological follow-up: no local progression was observed in 10 pts with a follow-up of at least 12 months and in 3 pts with a follow-up of at least 6 months. Conclusions: Percutaneous LIT permitted a complete ablation of lung metastases and lung carcinomas with an optimal local tumor control rate at 1-year and a low complication rate. Complete necrosis was achieved only in lesions with maximum diameter smaller than 3 cm.

No significant financial relationships to disclose.
A phase II study of vinoreline (VNR) and carboplatin (CBDCA) in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Takatani H. , Kinoshita A. , Fukuda M. , Soejima Y. , Nagashima S. , Narasaki F. , Soda H. , Oka M. , Kohno S.
Published: March 2020

17108

Background: VNR is one of standard drugs for elderly NSCLC. The role of platinum- based combination chemotherapy for elderly pts is controversial. Methods: Based on our phase I study (Fukuda, et al, abstract 2763, ASCO 2002), we conducted a phase II single arm study of VNR combined with CBDCA for elderly NSCLC pts. Primary endpoints were response and toxicity. Eligibility criteria included: chemotherapy-naïve, good performance status (PS: 0–2), age ≥75, stage IIIB-IV, and adequate hematological, hepatic and renal function, written informed consent. Treatment consisted of VNR 20 mg/m2 i.v. on days 1 and 8 and CBDCA target AUC = 4 (Chatelut formula, Jaffe method) on day 1 of every 4 weeks. Planned sample size was 40. Results: A total of 40 pts were enrolled. Pts characteristics: male/female = 30/10, PS 0/1 = 18/22, median age (range) = 78 (75–86), Ad/Sq/Others = 30/9/1, stage IIIB/IV = 14/26. Forty pts were eligible and assessable for toxicity and survival, and 37 pts were assessable for response on the submission of this abstract. Thirty-three pts were treated with two or more courses of treatment. Overall response rate was 13.5% (95% CI, 4.5%-28.8%); CR= 0, PR= 5, SD = 23, PD = 9. Grade 3 or 4 leukopenia, neutropenia, and anemia were observed in 31.6%, 50.0%, and 7.1%, respectively. Treatment-related death did not occurred. Non-hematological toxicity was mild. The median survival time was 392 days (95% CI, 311–474) and the median time to progression was 114 days. Conclusions: This combination is well-tolerated and modest activity in pts with elderly NSCLC.

No significant financial relationships to disclose.
Pemetrexed and carboplatin plus bevacizumab as first-line therapy for advanced non-squamous non-small cell lung cancer: preliminary safety results of a phase II trial
Authors: Patel J. D. , Hensing T. A. , O’Keeffe P. , Frantonius K. , Hart E. , Bonomi P.
Published: March 2020

17111

Background: Bevacizumab is a novel antiangiogenic agent that has been shown to improve response rates and survival of patients with advanced non-squamous NSCLC when added to paclitaxel and carboplatin. Pemetrexed is a multitargeted antimetabolite that has shown activity in NSCLC as a single agent and when combined with carboplatin. Because the combination of pemetrexed and carboplatin has activity comparable to that of other standard platinum doublets and promising toxicity profile (Zinner, 2005), the addition of bevacizumab to this regimen is investigated. Methods: This single cohort, phase 2 study evaluates the safety and efficacy of the combination of pemetrexed and carboplatin plus bevacizumab in patients with untreated non-squamous NSCLC. Eligibility requires ECOG performance status 0–1, Stage IIIB (malignant effusion) or Stage IV non- squamous NSCLC, no evidence of CNS metastases, no anticoagulation. Treatment consists of pemetrexed 500 mg/m2 over 10 minutes, carboplatin AUC 6 over 30 minutes, and bevacizumab 15 mg/kg over 30–90 minutes. Treatment is repeated every 21 days for 6 cycles. For patients who have either stable disease or partial response, pemetrexed 500 mg/m2 and bevacizumab 15 mg/kg are continued every 21 days until progression of disease or toxicity. All patients receive folic acid, vitamin B12 and steroid prophylaxis. Tumor response is assessed using RECIST every 2 cycles during treatment with carboplatin and then every 3 cycles during treatment with pemetrexed and bevacizumab alone. Results: From 8/2005 to 12/2005, 10 (of planned 50) patients with Stage IIIB and IV non-squamous NSCLC have been enrolled and treated. Patient characteristics are: median age: 65 (48–71), 20% female, 80% male, 30% stage IIIB, 70% stage IV. Median number of cycles delivered is 5 (range 1–9). No patient has discontinued therapy secondary to progressive disease or toxicity to date. 6 patients are evaluable for response: 1 PR, 1 minor response (24% reduction), 4 SD. No grade 3/4 toxicities have been experienced. Conclusions: This is a highly tolerable and active regimen with little toxicity to date. Updated response and toxicity data will be forthcoming. Supported by Genentech Inc and Lilly Pharmaceuticals.

[Table: see text]
A phase II study with gemcitabine and split-dose cisplatin in patients with advanced non-small cell lung cancer
Authors: Jang H. , Park J. , Kwon J. , Jung J. , Kim H. , Song H. , Zang D. , Lee J. , Park Y. , Kim J.
Published: March 2020

17115

Background: The combination of gemcitabine and cisplatin is among the most active regimens for the treatment of NSCLC. However, the optimal dose and schedule for administration of the two drugs has not yet been determined. We investigated the activity and toxicity of a gemcitabine and split-dose cisplatin regimen in an outpatient setting for patients with advanced non-small cell lung cancer (NSCLC). Methods: From June 2004 to May 2005 patients with stage IIIB or IV who had not had prior chemotherapy entered the study. Treatment consisted of gemcitabine 1,250 mg/m2 and cisplatin 35 mg/m2, both given intravenously on days 1 and 8 every 21 days. Results: Forty-three patients were entered this study. Patient characteristics were as follows: male/female, 32/11; median age (range), 63 (30–76) years; ECOG PS 0/1/2, 7/28/8; stage IIIB/IV, 17/26. A total of 160 cycles were delivered, with a median of 4 cycles (range, 1–6). All patients were evaluable for toxicity. Grade 3 & 4 toxicities according the NCI toxicity criteria included included neutropenia in 7 patients (17%), anemia in 3 (7%), thrombocytopenia in 6 (14%), and emesis in 1 (2%). Of 40 patients assessable for response, one (2.5%) had CR and 22 (55%) had PR. On intent-to-treat basis, the overall response rate was 53% (95% CI, 39–68%). Median time to progression was 6.0 months (range, 1.2–12.0 months) and median overall survival was 13.1 months (range, 1.4–17 months). Conclusions: This regimen with gemcitabine and split-dose cisplatin using a 21-day schedule appears to be active and very well-tolerated in an outpatients setting for patients with advanced NSCLC.

No significant financial relationships to disclose.
Analysis of drug delivery and outcome differences in platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC)
Authors: Radosavljevic D. Z. , Kezic I. , Jelic S. , Tomasevic Z. , Golubicic I.
Published: March 2020

17120

Background: Dose intensity (DI) is the dominant treatment design variable with respect to the degree of therapeutic response while total dose (TD) correlates best with the duration of response in an incurable patient population. To further explore the nature of the relationship of response to treatment (RR) and stable disease (SD) with median survival in advanced NSCLC, we performed an analysis of dose intensity and total dose of platinum compounds in first-line treatment of advanced NSCLC. Methods: Individual patient data from three phase 2/3 studies conducted at the Institute for Oncology and Radiology of Serbia from 1990 to 2001 were reviewed to perform an analysis of DI and TD for responding patients (CR+PR) and stable disease ones (SD). All patients were treated with cisplatin (120 mg/m2) or carboplatin (500 mg/m2 and thereafter AUC 6) based doublets or triplets, every four weeks (second-generation regimens). Results: 109 case records were analyzed, 93 patients received cisplatin-based and 16 carboplatin-based regimens. For responding patients (N=36) median DI of cisplatin was 29.84 mg/m2/wk (range 24.17–36.42) and for stable disease patients (N = 57) median DI was 29.94 mg/m2/wk (range 27.11–40.91). Wilcoxon rank sum test p = 0.28. In percentage, responders had DI of 0.985 of planned dose, and stabilizations had DI 0.99 of planned dose. Regarding TD, responders received median of 577.5 mg/m2 of cisplatin (236.1–1070) while stable disease patients received median of 475 mg/m2 (231.3–929.4), Wilcoxon p=0.0045. Median survival for responders was 9.5 months and for SD patients 6.0 months (log-rank test, p = 0.021). For carboplatin-receiving patients (N = 16) median DI was 122.85 mg/m2/wk (111.91–141.04) and median TD 1900.30 mg/m2/wk (1000–3000). Conclusions: Received DI of cisplatin was the same for responders and stable disease patients, but responders received more drug than stable-disease patients and lived significantly longer. The optimal duration of treatment for stable disease patients as probably the most frequent advanced NCSLC population requires careful consideration, especially while we are still in the era of platinum-based chemotherapy.

No significant financial relationships to disclose.
Induction chemoradiotherapy and surgical resection for non-small cell lung carcinomas of the superior sulcus (pancoast tumors): Mature results of National Cancer Institute (INCa)-Brazil
Authors: Amaral C. , Small I. , Olmedo D. B. , Sousa A. , Toscano E. , Sousa P. , Pelluso H. , Ferreira C. G. , Sales A. , Zukin M.
Published: March 2020

17124

Background: The established treatment for T3 Pancoast tumors, radiation plus surgery, leads to a 50% R0 resection rate and a 30% 5 year survivals. T4 tumors are usually unresectable and incurable. Our group retrospectively analyzed the feasibility and efficacy of induction chemoradiotherapy plus surgery for T3 and T4 tumors. Methods: Eligible patients (pts) had biopsy proven, untreated, T3–4N0–1 Pancoast tumors. Induction therapy was cisplatin (50 mg/m2, days 1,8,29,36) and etoposide (50 mg/m2, days 1–5, 29–33) (PE) given concurrently with radiation (45 Gy, 25 daily fractions). Thoracotomy was done within 5 weeks of induction therapy for stable or responding disease. All pts were to receive postoperative chemotherapy (PE ×2). Median follow up was 19 months. Results: From 4/01–6/05, 13 eligible pts were enrolled: 6 men, 7 women, median age 53 years; 9 T3, 4 T4. All pts (100%) completed induction therapy. Grade 3–4 toxicities were neutropenia (n = 2), anemia (n = 1), fatigue (n = 1), esophagitis (n = 5). All pts had thoracotomy, 13 had R0 resection. Pathologic CR was found in 3 (23.1%), minimal microscopic disease in 1 (7.7%). Postoperative chemotherapy completed by only 1/13 pts. Median survival was not reached and Median Disease free (DFS) and 2 year overall survivals (OS) were 26 months (CI 95% 13.6–38.4) 67% for all pts, respectively. Relapse sites were brain only (n = 3) and local only (n = 1). Conclusion: This combined modality therapy was well tolerated and leads to high rates of complete resection, OS and local control that are strikingly better than with radiation and surgery. These results obtained in a population with T3 and T4 tumors reproduced those of the SWOG study in terms of resectability, safety and short-term survival Of note is the poor adherence to postoperative chemotherapy in this population.

No significant financial relationships to disclose.