Correspondence
Bevacizumab for Non–Small-Cell Lung Cancer
N Engl J Med 2007; 356:1373-1375March 29, 2007
- Article
To the Editor:
In their report on chemotherapy plus bevacizumab for non–small-cell lung cancer, as compared with chemotherapy alone, Sandler and colleagues (Dec. 14 issue)1 conclude that the addition of bevacizumab to paclitaxel and carboplatin has a significant survival benefit but is associated with an increased risk of treatment-related death. According to their results, 12 patients need to be treated to prevent one death at 1 year, at the price of an excess of one death from toxic effects for every 24 patients treated. Clearly, the balance between benefit and risk is questionable.
1 ReferencesMarina Chiara Garassino, M.D.
Ospedale Fatebenefratelli e Oftalmico, 20121 Milan, Italy
marina.garassino@fbf. milano. it Lital Hollander, B.Sc.Med.
Valter Torri, M.D.
Istituto Mario Negri, 20157 Milan, Italy1
Sandler A ,Gray R ,Perry MC , et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-2550[Erratum, N Engl J Med 2007;356:318.]
Full Text | Web of Science | Medline
To the Editor:
Sandler et al. show a survival benefit of bevacizumab in non–squamous-cell non–small-cell lung cancer, but pulmonary hemorrhage in their patients is a worrisome complication. Further clarification of the risk factors for this complication is needed. The phase 2 trial reported by Johnson et al.1 showed an association between hemoptysis and centrally located tumors and tumor cavitation; were these features present in the patients in the study reported by Sandler et al.? Some patients with pulmonary hemorrhage had episodes of minor hemoptysis preceding the fatal event; how many other patients in the bevacizumab group had minor (grade 1 or 2) hemoptysis, and can minor hemoptysis truly be used as a warning sign?
1 ReferencesGeoffrey R. Oxnard, M.D.
Massachusetts General Hospital, Boston, MA 021141
Johnson DH ,Fehrenbacher L ,Novotny WF , et al. 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. J Clin Oncol 2004;22:2184-2191
CrossRef | Web of Science | Medline
To the Editor:
Before recommending, as Sandler and colleagues do, the routine use of bevacizumab combined with chemotherapy for non–squamous-cell, non–small-cell lung cancer, we should consider that cisplatin-based chemotherapy is superior, in terms of survival, to carboplatin-based chemotherapy when combined with a third-generation drug.1,2 In addition, Rosell et al. showed that survival was better when paclitaxel was combined with cisplatin, rather than with carboplatin.3
The objective response rate in the control group in the study by Sandler and colleagues was surprisingly low (15%), in contrast to the rates that are usually reported (20 to 30%).4 This point suggests a potential selection bias.
4 ReferencesJean-Paul Sculier, M.D., Ph.D.
Anne-Pascale Meert, M.D.
Marianne Paesmans, M.Sc.
Institut Jules Bordet, 1000 Brussels, Belgium
sculier@bordet.be 1
Hotta K ,Matsuo K ,Ueoka H ,Kiura K ,Tabata M ,Tanimoto M . Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 2004;22:3852-3859
CrossRef | Web of Science | Medline2
Ardizzoni A ,Tiseo M ,Boni L , et al. CISCA (cisplatin vs. carboplatin) meta-analysis: an individual patient data meta-analysis comparing cisplatin versus carboplatin-based chemotherapy in first-line treatment of advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2006;24:Suppl:7011-70113
Rosell R ,Gatzemeier U ,Betticher DC , et al. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol 2002;13:1539-1549
CrossRef | Web of Science | Medline4
Chu Q ,Vincent M ,Logan D ,Mackay JA ,Evans WK . Taxanes as first-line therapy for advanced non-small cell lung cancer: a systematic review and practice guideline. Lung Cancer 2005;50:355-374
CrossRef | Web of Science | Medline
To the Editor:
In the study by Sandler et al., the exclusion criteria were quite restrictive. Were patients who discontinued the use of aspirin, other antiplatelet drugs, nonsteroidal antiinflammatory agents, or anticoagulants included in the trial? “Clinically significant cardiovascular disease” and “medically uncontrolled hypertension” need to be defined clearly, since they are common conditions and were exclusion criteria. In addition, “predominantly” squamous-cell cancer needs to be defined. It would be useful for the practicing oncologist to know the number of patients who had poorly differentiated (not otherwise specified) non–small-cell lung cancer.
Guru Sonpavde, M.D.
U.S. Oncology Research, Houston, TX 77598
guru.sonpavde@usoncology. com Author/Editor Response
Garassino et al. express concern regarding the balance between risk and benefit with the addition of bevacizumab. Despite a modest increase in treatment-related deaths, the addition of bevacizumab to chemotherapy yielded an absolute improvement in survival of nearly 7% at 1 and 2 years. These data prompted the Food and Drug Administration to approve bevacizumab for the treatment of non–squamous-cell lung cancer.
In reply to Oxnard, episodes of minor hemoptysis were not routinely captured on the case-report forms. To assess for possible risk factors for hemoptysis, we conducted a retrospective case–control study that included patients from both our phase 2 and phase 3 studies.1 In this analysis, baseline hemoptysis and tumor cavitation were noted as risk factors. However, the interpretation of these data is limited by the low incidence of clinically significant pulmonary hemorrhagic events.
We agree that cisplatin may be slightly superior to carboplatin on the basis of recent meta-analyses; however, we observed no survival advantage with cisplatin, as compared with carboplatin, in our randomized trial (E1594), which predated the cited meta-analyses.2 The results of the E1594 trial, coupled with the results of the pilot phase 2 trial,3 led to the selection of carboplatin-based therapy for the phase 3 trial (E4599). In any case, the E4599 trial clearly isolates the additional survival benefit with bevacizumab plus the carboplatin-based regimen. A recently completed European trial of cisplatin and gemcitabine with or without bevacizumab will help address the concern of Sculier et al.
Sonpavde questions the eligibility criteria used in our study. To clarify, patients could not receive any antiplatelet agent (other than aspirin at a dose of less than 325 mg daily) or anticoagulant. The protocol did not specify a washout period for antiplatelet agents; however, in practice, delaying the start of bevacizumab until after the antiplatelet effect has dissipated is reasonable. In the protocol, we defined clinically significant cardiovascular disease as “symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.” On enrollment, blood pressure had to be less than or equal to 150/100 mm Hg while patients were receiving a stable regimen of antihypertensive drugs.
With regard to histologic features, we used the following eligibility criterion in the protocol: “Patients must have histologically or cytologically confirmed non–small-cell lung cancer except squamous-cell carcinoma. Mixed tumors will be categorized by the predominant cell type.” Of our 850 patients, 585 had adenocarcinoma, and 46 had large-cell carcinoma.
3 ReferencesAlan Sandler, M.D.
Vanderbilt University, Nashville, TN 37235
alan.sandler@vanderbilt. edu Robert Gray, Ph.D.
Dana–Farber Cancer Institute, Boston, MA 02115David H. Johnson, M.D.
Vanderbilt University, Nashville, TN 372351
Sandler AB ,Johnson DH ,Brahmer J , et al. Retrospective study of clinical and radiographic risk factors associated with early onset, severe pulmonary hemorrhage in bevacizumab-treated patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2006;24:Suppl:381S-381S
CrossRef | Web of Science2
Schiller JH ,Harrington D ,Belani CP , et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-98
Full Text | Web of Science | Medline3
Johnson DH ,Fehrenbacher L ,Novotny WF , et al. 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. J Clin Oncol 2004;22:2184-2191
CrossRef | Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
Yihai Cao. (2010) Angiogenesis: What can it offer for future medicine?. Experimental Cell Research 316:8, 1304-1308
CrossRef2
S. L. C. Lee, P. Rouhi, L. D. Jensen, D. Zhang, H. Ji, G. Hauptmann, P. Ingham, Y. Cao. (2009) Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model. Proceedings of the National Academy of Sciences 106:46, 19485-19490
CrossRef3
Vittorio Gebbia. (2008) Does an optimal therapeutic sequence exist in advanced non-small cell lung cancer?. Expert Opinion on Pharmacotherapy 9:8, 1321-1337
CrossRef4
Anand Rajeswaran, Andreas Trojan, Bernard Burnand, Massimo Giannelli. (2008) Efficacy and side effects of cisplatin- and carboplatin-based doublet chemotherapeutic regimens versus non-platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: A systematic review of randomized controlled trials. Lung Cancer 59:1, 1-11
CrossRef
