Summary Background Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET) ...tyrosine kinases. In a randomised phase 2 study in patients with previously treated non-small-cell lung cancer (NSCLC), adding vandetanib 100 mg to docetaxel significantly improved progression-free survival (PFS) compared with docetaxel alone, including a longer PFS in women. These results supported investigation of the combination in this larger, definitive phase 3 trial (ZODIAC). Methods Between May, 2006, and April, 2008, patients with locally advanced or metastatic (stage IIIB–IV) NSCLC after progression following first-line chemotherapy were randomly assigned 1:1 through a third-party interactive voice system to receive vandetanib (100 mg/day) plus docetaxel (75 mg/m2 intravenously every 21 days; maximum six cycles) or placebo plus docetaxel. The primary objective was comparison of PFS between the two groups in the intention-to-treat population. Women were a coprimary analysis population. This study has been completed and is registered with ClinicalTrials.gov , number NCT00312377. Findings 1391 patients received vandetanib plus docetaxel (n=694 197 women) or placebo plus docetaxel (n=697 224 women). Vandetanib plus docetaxel led to a significant improvement in PFS versus placebo plus docetaxel (hazard ratio HR 0·79, 97·58% CI 0·70–0·90; p<0·0001); median PFS was 4·0 months in the vandetanib group versus 3·2 months in placebo group. A similar improvement in PFS with vandetanib plus docetaxel versus placebo plus docetaxel was seen in women (HR 0·79, 0·62–1·00, p=0·024); median PFS was 4·6 months in the vandetanib group versus 4·2 months in the placebo group. Among grade 3 or higher adverse events, rash (63/689 9% vs 7/690 1%), neutropenia (199/689 29% vs 164/690 24%), leukopenia (99/689 14% vs 77/690 11%), and febrile neutropenia (61/689 9% vs 48/690 7%) were more common with vandetanib plus docetaxel than with placebo plus docetaxel. The most common serious adverse event was febrile neutropenia (46/689 7% in the vandetanib group vs 38/690 6% in the placebo group). Interpretation The addition of vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy. Funding AstraZeneca.
Epidermal growth factor receptor (EGFR) mutations have been associated with tumor response to treatment with single-agent EGFR inhibitors in patients with relapsed non-small-cell lung cancer (NSCLC). ...The implications of EGFR mutations in patients treated with EGFR inhibitors plus first-line chemotherapy are unknown. KRAS is frequently activated in NSCLC. The relationship of KRAS mutations to outcome after EGFR inhibitor treatment has not been described.
Previously untreated patients with advanced NSCLC in the phase III TRIBUTE study who were randomly assigned to carboplatin and paclitaxel with erlotinib or placebo were assessed for survival, response, and time to progression (TTP). EGFR exons 18 through 21 and KRAS exon 2 were sequenced in tumors from 274 patients. Outcomes were correlated with EGFR and KRAS mutations in retrospective subset analyses.
EGFR mutations were detected in 13% of tumors and were associated with longer survival, irrespective of treatment (P < .001). Among erlotinib-treated patients, EGFR mutations were associated with improved response rate (P < .05) and there was a trend toward an erlotinib benefit on TTP (P = .092), but not improved survival (P = .96). KRAS mutations (21% of tumors) were associated with significantly decreased TTP and survival in erlotinib plus chemotherapy-treated patients.
EGFR mutations may be a positive prognostic factor for survival in advanced NSCLC patients treated with chemotherapy with or without erlotinib, and may predict greater likelihood of response. Patients with KRAS-mutant NSCLC showed poorer clinical outcomes when treated with erlotinib and chemotherapy. Further studies are needed to confirm the findings of this retrospective subset analysis.
Learning Objectives
After completing this course, the reader will be able to:
Identify the role of angiogenesis in non‐small cell lung cancer (NSCLC).
Explain the role of bevacizumab in apparently ...producing greater response, time to progression, and overall survival rates in a randomized phase II trial comparing carboplatin, paclitaxel, and bevacizumab with carboplatin and paclitaxel without bevacizumab and the limitations of this interpretation.
Define the main toxicity concerns with the use of bevacizumab in the treatment of NSCLC.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit atCME.TheOncologist.com
There is an urgent need for new therapies to treat non‐small cell lung cancer (NSCLC), as progress with current chemotherapy regimens has been limited. The roles of vascular endothelial growth factor (VEGF) in promoting tumor angiogenesis, maintaining existing vasculature, and contributing to resistance to traditional therapies, together with its negative prognostic significance in NSCLC, make it an appropriate target for therapy. Bevacizumab (AvastinTM; Genentech Inc., South San Fransisco, CA), a monoclonal antibody directed against VEGF, has shown promise in treating a number of different cancers. In a recent phase II trial in patients with advanced metastatic NSCLC, the addition of bevacizumab to standard carboplatin/paclitaxel chemotherapy produced a significantly longer time to progression (32.1 versus 18.4 weeks) and greater response rate (31% versus 19% not significant) than chemotherapy alone. In the subset of patients with nonsquamous histologies, response rates and survival were further enhanced, with a mean survival time of 17.9 months versus 12.3 months with chemotherapy alone.
Bevacizumab was generally well tolerated and did not appear to increase the incidences or severities of the nausea/vomiting, neuropathy, and renal toxicity that are typically associated with carboplatin/paclitaxel chemotherapy. Adverse events in phase I and II studies included hypertension, thrombosis, proteinuria (with occasional nephrotic syndrome), and epistaxis. Serious tumor‐related bleeding episodes (hemoptysis/hematemesis) appear to be the main safety concern in patients with NSCLC, with squamous cell histology as a possible risk factor.
Further work is needed to identify the best way to use bevacizumab in NSCLC, including use in combination with other biologic agents and in the adjuvant setting.
Lung cancer is the most common cause of cancer death worldwide, with most patients dying with metastatic disease. The prognosis for the majority of patients remains poor. It is evident that advances ...in the treatment of this and other tumor types will require new approaches, and recent research has focused on molecular-targeted therapies. A key therapeutic strategy is inhibition of specific processes essential for tumor vascular development (a concept known to be beneficial in colorectal cancer) and a range of such antiangiogenic agents are currently in development. The most promising of these target the proangiogenic vascular endothelial growth factor (VEGF), either by preventing VEGF-receptor binding or inhibiting downstream receptor signaling. However, other more direct approaches against tumor vasculature are also in development. Since antiangiogenic agents often exert an indirect, cytostatic effect, many are being evaluated in combination with conventional chemotherapies in order to optimize the anticancer effects of both strategies. Additionally, the combination of several antiangiogenic agents is also being explored. This has become possible given the large number of agents currently available. As part of this evaluation process, the assessment of surrogate markers of target inhibition and treatment effect is ongoing in the hope of identifying reliable surrogate markers to aid the development of this new generation of anticancer agents.
Cisplatin-based chemotherapy improves survival in appropriately selected patients with stage IV non-small cell lung cancer (NSCLC). However, cisplatin-based regimens have well-known dose-related ...toxicities, particularly renal insufficiency and neurotoxicity. On the basis of prior preclinical and phase I studies, we initiated a phase II study of SPI-77 (STEALTH® Liposomal Cisplatin) in patients with stage IIIB and IV NSCLC who failed previous treatment with platinum. Disease in all subjects had progressed during therapy, failed to respond, or progressed within 3 months after discontinuing the platinum-based chemotherapy. Between January and June 1999, 13 patients were enrolled at our institution. Patient characteristics included: seven women, six men; median age, 61 years; median Karnofsky performance status, 80%; median number of prior chemotherapy regimens, two (range, 1–3). All patients had adequate hepatic and renal function. SPI-77 was administered at a dose of 260 mg/m
2 IV every 3 weeks. A median of two cycles (range 1–6) were given; the total number of cycles was 35. Among the 12 patients evaluable for response, two had (17%) stable disease and ten (83%) had progressive disease. The median survival was 24.3 weeks, and the median follow-up was 43.9 weeks. Toxicity could be evaluated in all subjects. Moderate anemia (46% of cycles, ≤grade 2; 3% of cycles, ≥grade 3) with minimal granulocytopenia and thrombocytopenia (26% of cycles grade 1; 0% of cycles, ≥grade 2) were the most notable manifestations of myelosuppression. Grade 3 nonhematological toxicities included dyspnea (8%), fatigue (8%), and pain (8%). There were no grade 4 toxicities. These data suggest that this liposomal cisplatin formulation does not have appreciable activity in this population of patients with NSCLC who had received prior platinum-based chemotherapy. The lack of encouraging results from SPI-77 use in other phase I and II studies resulted in early closure of this trial by the manufacturer.
The number and variety of novel, molecular-targeted agents offers realistic hope for significant advances in cancer treatment. The potential of these new treatment approaches is unquestionable, but ...the reality is something that only thorough clinical evaluation and experience can reveal. Clinical experience of targeted therapies is at an early stage but it is likely that we will have an increasing number of treatment options available to us in the near future. This manuscript explores our current understanding of molecular-targeted therapies and considers: What approach should be used? (single vs multitarget agents); When should they be administered? (identifying the optimal point for intervention); How should they be used? (monotherapy or combination therapy regimens); and Who should we be giving them to? (acknowledging the need for patient selection).
To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer.
In a phase II trial, 99 patients were randomly ...assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m(2)) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks.
Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels.
Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.
A synergistic extraction mixture containing chlorinated cobalt dicarbollide (CCD), carbamoylmethyl phosphine oxide (CMPO), and polyethylene glycol (PEG) has been investigated for the simultaneous ...recovery of cesium, strontium, lanthanides, and actinides from highly acidic media. The extraction properties of this mixture depend on the concentration ratio of the components. For recovery of all major radionuclides, the optimal ratio of CCD:PEG: CMPO = 5:1:1 should be used. The use of diphenyl-N,N-dibutylcarbamoylmethyl phosphine oxide and PEG-400 provides the most efficient recovery of cesium, strontium, lanthanides, and actinides. The possibility of using polyfluorinated ethers, esters, ketones, and sulfones as diluents was examined. Phenyltrifluoromethyl sulfone was the most suitable diluent tested. The use of this diluent allows good extraction properties, chemical and radiation stability, excellent explosion/fire-safety properties, and favorable hydrodynamic characteristics. The extraction of radionuclides from HNO
3
media by mixtures of CCD:PEG:CMPO in phenyltrifluoromethyl sulfone and the subsequent stripping behavior were evaluated.
Preclinical studies indicate that gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, may enhance antitumor efficacy ...of cytotoxics, and combination with paclitaxel and carboplatin had acceptable tolerability in a phase I trial. Gefitinib monotherapy demonstrated unparalleled antitumor activity for a biologic agent, with less toxicity than docetaxel, in phase II trials in refractory, advanced non-small-cell lung cancer (NSCLC). This phase III, randomized, placebo-controlled, double-blind trial evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC.
Patients received paclitaxel 225 mg/m(2) and carboplatin area under concentration/time curve of 6 mg/min/mL (day 1 every 3 weeks) plus gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. After a maximum of six cycles, daily gefitinib or placebo continued until disease progression. End points included overall survival, time to progression (TTP), response rate (RR), and safety evaluation. Results A total of 1,037 patients were recruited. Baseline demographic characteristics were well balanced. There was no difference in overall survival (median, 8.7, 9.8, and 9.9 months for gefitinib 500 mg/d, 250 mg/d, and placebo, respectively; P =.64), TTP, or RR between arms. Expected dose-related diarrhea and skin toxicity were observed in gefitinib-treated patients, with no new significant/unexpected safety findings from combination with chemotherapy. Subset analysis of patients with adenocarcinoma who received > or = 90 days' chemotherapy demonstrated statistically significant prolonged survival, suggesting a gefitinib maintenance effect.
Gefitinib showed no added benefit in survival, TTP, or RR compared with standard chemotherapy alone. This large, placebo-controlled trial confirmed the favorable gefitinib safety profile observed in phase I and II monotherapy trials.
The finite element method is implemented to determine solutions for buoyancy-driven flow in a square cavity. We consider cases with no extended surface, only one extended surface, and an extended ...surface on walls opposite and adjacent to the cold wall. An investigation of the Péclet number provides an estimate for the amount of artificial diffusion to be added to the Boussinesq and heat transfer equations for stable numerical solutions to be obtained. The importance of the characteristic length on the flow in the square cavity is investigated in detail. We show grid convergence by computing the grid convergence index (GCI). The impact of the boundary conditions and extended surfaces on the isotherms, velocity streamlines and flux are plotted and discussed. We find that the case with insulated boundary conditions on the sidewalls gives a 31 and 33 percent decrease in the flux when we have two and three extended surfaces, respectively.
•Artificial diffusion is added to the system of equations to ensure stability.•The grid convergence index (GCI) is used to study the convergence of the FEM method.•The temperature of the sidewalls is shown to have a significant impact on the flow.
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