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Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

From the Division of Hematology & Oncology, Vanderbilt University Medical School, Nashville, TN; Department of Thoracic/Head & Neck Medical Oncology, M.D. Anderson Cancer Center, Houston; US Oncology, Sammons Cancer Center, Baylor University Medical Center, Mary Crowley Medical Research Center, Dallas, TX; Kaiser Permanente, Vallejo; Thoracic Oncology Program, University of California San Francisco/Mount Zion Medical Center; Genentech Inc, South San Francisco, CA; and Fox Chase Cancer Center, Philadelphia, PA

Address reprint requests to David H. Johnson MD, Division of Hematology & Oncology, Vanderbilt University Medical School, 777 Preston Research Bldg, Nashville, TN; e-mail: david.johnson{at}vanderbilt.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer.

PATIENTS AND METHODS: 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/m²) 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.

RESULTS: 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.

CONCLUSION: 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.

	INTRODUCTION

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Vascular endothelial growth factor (VEGF) was originally discovered in the 1980s.^1–3 It is a highly conserved, homodimeric, heparin-binding glycoprotein that exists in several isoforms and functions as an endothelial cell specific mitogen.⁴ VEGF mediates its effects by interacting with VEGF receptor-1 (Flt-1) and VEGF receptor-2 (KDR, flk-1) and is considered essential for normal developmental vasculogenesis and angiogenesis.⁴ Transformed cell lines often express VEGF mRNA and secrete VEGF, whereas transfection of Chinese hamster ovary cells with expression vectors encoding VEGF allow these cells to form tumors in nude mice.⁵ Further evidence that VEGF plays an important role in tumor angiogenesis comes from the observation that an antibody to VEGF, alone or in combination with chemotherapy, can inhibit tumor growth in vivo.^6–8 Thus, VEGF serves as a major tumor angiogenesis factor during epithelial carcinogenesis and for this reason it is considered to be a rational therapeutic target.

Bevacizumab (Avastin; Genentech, Inc, South San Francisco, CA) is the recombinant humanized version of the murine antihuman VEGF monoclonal antibody A4.6.1.⁹ In phase I trials, bevacizumab was generally well tolerated and was not associated with a dose-limiting toxicity.¹⁰ When combined with classical cytotoxic chemotherapy agents, there was no exacerbation of expected toxicities.¹¹ Based on these observations, we initiated a randomized phase II trial in patients with advanced non-small-cell lung cancer (NSCLC) in which bevacizumab was combined with carboplatin plus paclitaxel. We opted to use carboplatin and paclitaxel because it is efficacious and generally less toxic than most standard regimens.¹² Furthermore, in preclinical studies, these agents demonstrated enhanced tumor growth inhibition when combined with an antiangiogenic agent.¹³

	PATIENTS AND METHODS

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Patient Eligibility
Patients with histologically confirmed stage IIIB (with pleural effusion), stage IV, or recurrent NSCLC were eligible. Patients with small-cell or mixed histologies were excluded. Additional eligibility requirements included age 18 years, bi-dimensionally measurable disease, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, life expectancy 3 months, and availability for regular follow-up. Patients who had received prior chemotherapy or biotherapy, radiotherapy to an area of measurable disease (unless disease progression had been documented following completion of therapy), or radiotherapy within 2 weeks preceding day 0 were excluded from the trial. Additional exclusion criteria included an absolute neutrophil count 1,500/µL, hemoglobin less than 9 gm/dL, platelet count 100,000/µL, bilirubin > 2.0 mg/dL, AST or ALT 5 times upper limit of normal (ULN) for subjects with metastases, > 2.5 x ULN for those without metastases, and serum creatinine > 1.8 mg/dL. Patients with nonhealing wounds, ulcers, or bone fractures, significant cardiovascular disease (ie, uncontrolled hypertension, myocardial infarction within 6 months, unstable angina, NYHA grade 2 congestive heart failure, or serious cardiac arrhythmia), clinically significant peripheral vascular disease, CNS metastasis, active secondary malignancies (other than basal cell carcinoma of the skin), an active infection, or pregnancy were excluded. In addition, because of the potential for impaired wound healing, major surgery within 4 weeks before day 0, a fine needle biopsy or an open biopsy within 1 week before day 0, a significant recent traumatic injury, or the anticipation of a major surgical procedure were exclusion criteria. Recent or current use of aspirin or oral and/or parenteral anticoagulants (except low-dose coumadin 1 mg) was not allowed. Written informed consent was required. The study was approved by the institutional review boards of all participating centers and conducted in accordance with the United States Food and Drug Administration Good Clinical Practice requirements.

Study Design and Treatments
Eligible patients were randomly assigned to carboplatin/paclitaxel alone or carboplatin/paclitaxel plus low-dose (7.5 mg/kg) or high-dose (15 mg/kg) bevacizumab using an interactive voice response system. In an earlier phase I trial, bevacizumab doses of 0.1, 0.3, 1.0, 3.0, and 10 mg/kg yielded no identifiable dose limiting toxicity.¹⁰ We thus selected the 7.5 and 15 mg/kg doses based on pharmacokinetic modeling that predicted these doses would result in steady-state trough antibody concentrations of approximately 70 to 140 µg/mL respectively. Importantly, inhibition of tumor growth was observed at antibody serum concentrations between 10 and 30 µg/mL in mice. Also, in a separate phase I trial, various combinations of chemotherapy plus bevacizumab were assessed for safety.¹¹ Bevacizumab in combination with carboplatin plus paclitaxel appeared to be safe and well tolerated in this patient population. Randomization was stratified by ECOG PS (0 or 1 v 2) but not histology or stage. Patients received up to six cycles of carboplatin/paclitaxel. Paclitaxel (200 mg/m²) was administered over 3 hours every 3 weeks. Carboplatin dosing was based on the Calvert formula¹⁴ with a target area under the curve of 6 mg/mL x min and glomerular filtration rate (GFR) estimated for males as GFR = (140-age) x weight/72 x (serum creatinine). For females, a correction factor of 0.85 was used. Carboplatin was administered over 15 to 30 minutes, beginning 60 minutes after completion of the paclitaxel. Dose reductions were permitted for febrile neutropenia or absolute neutrophil count less than 1,000/µL for 5 days, any clinically significant bleeding ( grade 2), grade 3 nausea/vomiting not controlled by antiemetic medication, evidence of hepatic (AST > 5 x ULN or bilirubin > 3 x ULN), cardiovascular (symptomatic arrhythmia, hypotension [< 90/60 mmHg or fluid replacement] or chest pain), neurologic ( grade 2) or other grade 3 or 4 toxicity. Bevacizumab was administered by intravenous infusion over 90 minutes, 1 hour after each cycle of chemotherapy. If the initial infusion was well tolerated, subsequent infusion times were shortened to 30 to 60 minutes. The bevacizumab dose was not modified during this study. On completing the planned chemotherapy, nonprogressing patients were allowed to continue on bevacizumab at the same dose and schedule for up to a maximum of 18 doses. Patients in the control arm were permitted to receive bevacizumab (15 mg/kg) on disease progresssion.

All patients received standard supportive care, including blood and platelet transfusions, antibiotics, and antiemetics, as appropriate. Granulocyte colony-stimulating factor was administered only if there was persistent neutropenia despite dose reductions during the previous cycle. Patients were followed for survival information every 2 months until death or loss to follow-up.

Study Parameters
Baseline evaluation included assessment of ECOG PS, standard hematology, chemistry, electrolytes, urinalysis, INR/aPTT, and physical examination. Baseline tumor assessments, with prospective identification of sentinel lesions to be followed over the course of the study, included a chest x-ray, computed tomography scans of head, chest, abdomen, and bone scans. Tumor status was assessed after cycles 3, 6, 10, 14, and 18 using standard ECOG tumor response criteria. Tumor responses required confirmation 4 weeks after initial documentation. Responses were independently determined by the investigator and an independent review facility (IRF) blinded to treatment assignment. Safety evaluations including physical examination, laboratory tests, and vital sign monitoring were performed before, during, and after bevacizumab infusions (before chemotherapy for patients in the control arm).

Statistical Considerations
The primary efficacy end points were time to progression (TTP) and tumor response rate. Secondary efficacy end points were overall survival and duration of response. Efficacy analyses were based on an intent-to-treat analysis. Standard survival analysis using a Kaplan-Meier approach was performed. The log-rank test was used to provide a formal statistical assessment of the differences between treatment arms. The Cox proportional hazards model was used to estimate the hazard ratio. A two-sided ² test was used to compare tumor response for each bevacizumab arm with the control arm. Exploratory analyses included multivariate adjustments to assess TTP using the Cox model, and for the impact of several baseline factors on the estimates of treatment effect for TTP and survival. The study was designed to have approximately 80% power to detect an increase in the response rate of 25% (ie, from 27% to 52%) in the pooled bevacizumab treated arms. For comparing a single bevacizumab arm with control, the study had 80% power to detect a 30% improvement. The study had 80% power to detect a 100% improvement in the median TTP between the control arm and the pooled bevacizumab-treated arms, or a 150% improvement in TTP between the control arm and any single bevacizumab arm. A single interim analysis was planned for the purpose of assessing safety. Results of significance tests at the interim analyses were not to be considered significant unless P values were less than .0001.

	RESULTS

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Patient Characteristics and Disposition
The study was conducted in 12 centers in North America. Patient characteristics are presented in Table 1. In general, the three arms were reasonably well balanced for usual prognostic features, although there were some imbalances observed. For example, the high-dose bevacizumab arm enrolled a higher percentage of women, whereas squamous histology and stage IV disease were more frequent in the low-dose cohort. One patient assigned to the high-dose bevacizumab arm did not receive protocol therapy because of the discovery of a CNS metastasis just before initiating treatment.

Efficacy Results
The overall response rate showed a trend toward improved response for patients receiving bevacizumab, with the highest response noted in the high-dose group (31.5%) and the lowest in the control group (18.8%; Table 2). Based on the investigator assessment, 85 patients experienced disease progression, 27 of 32 patients (five censored) in the control arm, 29 of 32 patients (three censored) in the low-dose bevacizumab arm, and 29 of 34 patients (five censored) in the high-dose arm. Median TTP was longer in the high-dose bevacizumab arm compared with the control arm (7.4 v 4.2 months; P = .023; Fig 1). This translates to a 46% reduction in the hazard of progressing (Cox proportional hazard model). The IRF findings affirm the investigator-determined results (TTP, 7.0 v 5.9 months; P = .185; hazard of progression, 33%). TTP in the low-dose bevacizumab and control arms were similar (Table 3). Survival for the high-dose bevacizumab arm was modestly longer than the control arm (17.7 v 14.9 months; P = .63; Fig 2).

View larger version (16K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curve showing time to progression according to independent review facility/investigator assessment for carboplatin/paclitaxel (control), bevacizumab 7.5 mg/kg and 15 mg/kg arms, respectively.

View larger version (20K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curve showing overall survival for carboplatin/paclitaxel (control), bevacizumab 7.5 mg/kg and 15 mg/kg arms, respectively.

Safety and Toxicity Results
Nine patients died as the result of an adverse event (AE) not directly related to progressive disease; four in each of the bevacizumab arms and one in the control arm. The causes of death for low-dose bevacizumab included hemorrhage of unknown origin (probable hemoptysis), hemoptysis, unknown cause, and liver failure. In the high-dose arm, the deaths were attributed to aspiration pneumonitis, pulmonary hemorrhage, Aspergillus lung abscess, and chronic obstructive pulmonary disease. The death in the control arm was as a result of sepsis.

Eleven patients discontinued treatment as a result of a nonfatal AE. Discontinuations occurred as a result of: hemorrhagic event (three patients) in the low-dose bevacizumab arm; a hemorrhagic event (one patient); Aspergillus lung abscess (one patient); aspiration pneumonia (one patient); thrombotic stroke (one patient); vertebral fracture (one patient); and peripheral neuropathy (paclitaxel-related; one patient) in the high-dose arm. In two cases, bevacizumab was discontinued following initiation of anticoagulant therapy. Bevacizumab was withheld from one patient with subclavian vein thrombosis.

The addition of bevacizumab to carboplatin and paclitaxel resulted in only modest changes to the expected toxicity profile of chemotherapy alone (Table 3). Nausea and/or vomiting, renal toxicity, and peripheral neuropathy did not appear to be increased with bevacizumab. A trend toward slightly greater toxicity was noted in leucopenia, diarrhea, and minor systemic events such as fever, headache, rash, and chills. AEs observed in patients who received bevacizumab following failure of chemotherapy were generally similar in incidence to those observed in patients treated concurrently, with the possible exception of hemoptysis and epistaxis. These AEs both appeared to be less common (11% each) in this patient group, and only one thrombotic event (deep thrombophlebitis) was reported.

Several bevacizumab-associated AEs may be mechanism-based and warrant special emphasis including hypertension, proteinuria, and bleeding. Hypertension was reported for patients in both the low- and high-dose bevacizumab arms (five and six patients, respectively), and rarely in the control arm (one event). Grade 3 hypertension (defined as requiring new or increased antihypertensive medical therapy) was observed in the high-dose arm (two patients). The greatest increases from baseline in systolic blood pressure were also recorded in this dose group (range, +7.46 to 14.29 mmHg on day 42). Of the 12 patients reported to have a hypertensive AE, seven had a history of hypertension and eight required treatment with oral antihypertensive therapy. No patient in the trial discontinued bevacizumab because of hypertension. Asymptomatic proteinuria, as determined by dipstick analysis, was observed in 21 bevacizumab patients (seven low-dose and 14 high-dose patients) and two patients in the control arm. One patient in the low-dose arm developed clinically apparent nephrotic syndrome. A renal biopsy revealed cryoglobulinemic glomerulonephritis.

Two distinct clinical patterns of bleeding were observed during the study; minor mucocutaneous hemorrhage and major hemoptysis. The most common mucocutaneous bleeding was grade 1 or 2 epistaxis, which was reported in 31% of low-dose bevacizumab patients and 44% of high-dose patients compared to 6% of control patients. None required a change in bevacizumab administration. Six patients experienced a major life-threatening bleeding described as hemoptysis or hematemesis. Four events were fatal. All six patients had centrally-located tumors close to major blood vessels. Five cases had cavitation or necrosis of tumors, either at baseline or developing during bevacizumab therapy (Fig 3). Four of the severe hemorrhages occurred in patients with squamous carcinomas and five occurred in the low-dose bevacizumab arm. We conducted an exploratory analysis excluding squamous histology patients. This subset analysis suggested that bevacizumab improves response rate (20%; 31.8%; 50%), TTP (4.0 months; 6.3 months; 7.1 months), and survival (12.2 months; 14.0 months; 17.8 months) in nonsquamous carcinomas with only a small increased risk of serious bleeding (4%; Table 4 and Fig 4).

View larger version (81K): [in this window] [in a new window]   Fig 3. Area of tumor necrosis and cavitation following three cycles of treatment. (A) Tumor before treatment; (B) necrosis and cavitation.

View larger version (19K): [in this window] [in a new window]   Fig 4. Kaplan-Meier curve showing overall survival in patients with non-small-cell lung cancer of nonsquamous cell histology.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

Our data suggest that the addition of bevacizumab to carboplatin and paclitaxel results in higher response rates, longer time to disease progression, and improved overall survival relative to this chemotherapy regimen without bevacizumab.^12,18 Although numerically these improvements appeared to be greatest in the high-dose bevacizumab arm as compared to the low-dose arm, the study lacks sufficient power to make any definitive conclusions regarding a possible relationship between dose and treatment effect. Recognizing the potential for investigator bias in this open label trial design, we used an IRF to perform a separate, blinded assessment of the response rates and time to progression. Except for the overall response rate in the control arm, the results of the IRF assessment were virtually identical to that recorded by the participating investigators. Notably, patients in all three treatment arms experienced a median survival of approximately 1 year or longer (Fig 1). Patients in the control arm experienced a particularly impressive median survival of 14.9 months. This compares to median survivals of approximately 8 months in similar patient populations reported in recently completed cooperative group phase III trials.^12,18 The fact that 19 of the 32 control patients crossed over to single agent bevacizumab on disease progression may have impacted on the median survival of this cohort. Although none of the cross-over patients demonstrated an objective response, five maintained stable disease for more than 6 months. The median survival of cross-over patients was 10 months, which compares quite favorably to that observed in patients receiving second line docetaxel therapy.^19,20 This observation also is consistent with the data derived from numerous preclinical models that suggest antiangiogenic therapy is cytostatic rather than cytocidal.²¹

In general, the addition of bevacizumab to carboplatin and paclitaxel was well tolerated. The incidence and severity of nausea and vomiting, renal toxicity, and neuropathy were not increased relative to chemotherapy alone.^12,18 The trends suggesting slightly higher rates of neutropenia and diarrhea will need to be more fully evaluated in larger randomized trials. Minor mucosal bleeding (eg, epistaxis), hypertension, and proteinuria are AEs that have been observed in other clinical trials of bevacizumab.^10,11,22,23 These events were also observed in this trial, but were minor in severity and did not require discontinuation of bevacizumab. Of much greater concern, however, was the occurrence of six life-threatening pulmonary hemorrhages in patients receiving bevacizumab. These events were more common in the low-dose bevacizumab arm (five of six patients), occurred both early ( 60 days) and late ( 180 days) during treatment and were more frequent with squamous carcinomas (four of 13 patients) compared with adenocarcinomas (two of 54 patients). Pulmonary hemorrhage also appeared to be associated with centrally located tumors, tumors closely adjacent to major blood vessels, and the presence or development of tumor cavitation. Because squamous cell tumors are more frequently centrally located and have a greater tendency to cavitate as compared to adenocarcinoma, it is not clear whether histology alone is the central risk factor for bleeding, or simply a surrogate for other risk factors. An exploratory response and survival analysis in patients with nonsquamous histology revealed an apparent improvement in response rate, time to progression and median survival in the bevacizumab arms. In this cohort of nonsquamous carcinomas, the overall risk of severe hemorrhage was approximately 4%. Additional investigation of potential risk factors and strategies to further reduce the incidence of this serious AE are underway.

Although the incidence of severe hemorrhage in this trial is problematic, one might also view these events as pyrrhic victories. Indeed, in preclinical models, antiangiogenic agents can induce central tumor necrosis similar to that observed in this trial²⁴ (Fig 3). One might envision such an event taking place following bevacizumab in a patient harboring a centrally located large squamous carcinoma with pre-existing cavitation. The poorly developed neovessels, lacking a well-formed musculature, might be more prone to hemorrhage into the resulting necrotic tumor cavity. This scenario supports a strategy of combined chemotherapy and an antiangiogenic drug since the former targets the viable rim of tumor that is resistant to the antiangiogenic compound. Somewhat paradoxically perhaps, antiangiogenic agents may also result in normalization of tumor vessels with resultant reduction in intratumoral interstitial pressure, thereby enhancing cytotoxic drug delivery to the malignant cells.¹⁵ Finally, while antiangiogenic drugs are less prone to development of resistance, it should come as no surprise that cancer cells are fully capable of circumventing the growth inhibitory effect of a single agent simply by production of an alternative proangiogenic factor.^15,21 In such a situation, combination antiangiogenic therapy could prove advantageous.^25,26 In summary, these data suggest that bevacizumab in combination with carboplatin and paclitaxel improves response rate, time to progression, and overall survival in patients with advanced NSCLC. To validate these provocative results, a prospective, randomized comparison of carboplatin and paclitaxel ± bevacizumab is underway in patients with nonsquamous carcinomas (E4599). Of note, the recently reported results of a completed phase III trial evaluating bevacizumab in first-line metastatic colorectal cancer validates this general approach to cancer therapy.²⁷

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): William F. Novotny, Genentech; Russell F. DeVore, Genentech; Jacques Gaudreault, Genentech; Eric Homgren, Genentech. Acted as a consultant within the last 2 years: David H. Johnson, Genentech; John J. Nemunaitis, Genentech. Performed contract work within the last 2 years: John J. Nemunaitis, Genentech. Received more than $2,000 a year from a company for either of the last 2 years: David H. Johnson, Genentech; William F. Novotny, Genentech; Jacques Gaudreault, Genentech; Eric Holmgren, Genentech; Fairooz Kabbinavar, Genentech.

	NOTES

 
Research support provided by Genentech, Inc, South San Francisco, CA.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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12. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98, 2002[Abstract/Free Full Text]

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24. Huang X, Molema G, King S, et al: Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science 275:547–550, 1997[Abstract/Free Full Text]

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Submitted November 5, 2003; accepted March 12, 2004.

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				H. S. Friedman, M. D. Prados, P. Y. Wen, T. Mikkelsen, D. Schiff, L. E. Abrey, W.K. A. Yung, N. Paleologos, M. K. Nicholas, R. Jensen, et al. Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma J. Clin. Oncol., October 1, 2009; 27(28): 4733 - 4740. [Abstract] [Full Text] [PDF]

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				C. Schettino, M. A. Bareschino, A. Rossi, P. Maione, V. Castaldo, N. Mazzeo, P. C. Sacco, M. L. Ferrara, G. Palazzolo, F. Ciardiello, et al. Review: The potential role of bevacizumab in early stages and locally advanced non-small cell lung cancer Therapeutic Advances in Medical Oncology, July 1, 2009; 1(1): 5 - 13. [Abstract] [PDF]

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