Correspondence

Hearing Improvement after Bevacizumab for Neurofibromatosis Type 2

N Engl J Med 2009; 361:1809-1811October 29, 2009

Article

To the Editor:

Plotkin et al. (July 23 issue)1 report a sustained tumor-volume reduction in 4 of 10 patients and a hearing response in 4 of 10 patients with neurofibromatosis type 2 after bevacizumab treatment. The authors' conclusion that tumor shrinkage and hearing improvement are effects of bevacizumab treatment is not convincing, because the study did not involve a control group. Shrinkage of a vestibular schwannoma, especially in cystic tumors in patients with neurofibromatosis type 2, can also occur during an observation period without any treatment.2 In addition, some patients who have been assigned to wait-and-scan observation show hearing improvement over time without any treatment.3 The nonblinded design of the study might have biased the investigators and patients during the hearing tests. Otherwise, how do Plotkin et al. explain the poor correlation between tumor-volume shrinkage and hearing improvement? Also, how do they explain the poor correlation between pure-tone thresholds and word-recognition results? Instead of only using subjective acoustic hearing tests, it would have been worthwhile to use objective test methods such as brain-stem auditory evoked response.

Orlando Guntinas-Lichius, M.D.
Friedrich Schiller University of Jena, Jena, Germany
orlando.guntinas@med.uni-jena.de

3 References

1. 1

   Plotkin SR, Stemmer-Rachamimov AO, Barker FG II, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med 2009;361:358-367
   Full Text | Web of Science | Medline

2. 2

   Stangerup SE, Caye-Thomasen P, Tos M, Thomsen J. The natural history of vestibular schwannoma. Otol Neurotol 2006;27:547-552
   CrossRef | Web of Science | Medline

3. 3

   Stangerup SE, Caye-Thomasen P, Tos M, Thomsen J. Change in hearing during `wait and scan' management of patients with vestibular schwannoma. J Laryngol Otol 2008;122:673-681
   CrossRef | Web of Science | Medline

To the Editor:

Plotkin et al. report that vascular endothelial growth factor (VEGF) blockade with bevacizumab improved hearing and decreased the volume of vestibular schwannomas in some patients with neurofibromatosis type 2. Dynamic contrast-enhanced magnetic resonance imaging data indicated that bevacizumab normalized the function of tumor vessels. We wonder whether vascular normalization is the real or unique mechanism of anti-VEGF therapy for vestibular schwannomas. In some clinical trials, vascular normalization might provide benefit by killing tumor cells in synergy with chemotherapy; this is accomplished by improving the delivery of cytotoxic agents to tumors. However, in this study, 10 patients received bevacizumab as monotherapy. Otherwise, VEGF inhibition might have had direct cytotoxic effects on tumor cells that express VEGF receptors and that depend on VEGF for survival.1,2 The authors and other groups have detected VEGF and its receptors in schwannomas, and increased levels of these factors correlate with increased rates of tumor growth.3,4 Therefore, it is not known whether the curative effect is due to the direct killing of tumor cells and increase in apoptosis by bevacizumab or to vascular normalization.

Jian-Sheng Diao, M.D.
Wen-Sen Xia, M.D.
Shu-Zhong Guo, M.D.
Fourth Military Medical University, Xi'an, China

4 References

1. 1

   Wey JS, Fan F, Gray MJ, et al. Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer 2005;104:427-438
   CrossRef | Web of Science | Medline

2. 2

   Fan F, Wey JS, McCarty MF, et al. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene 2005;24:2647-2653
   CrossRef | Web of Science | Medline

3. 3

   Caye-Thomasen P, Baandrup L, Jacobsen GK, Thomsen J, Stangerup SE. Immunohistochemical demonstration of vascular endothelial growth factor in vestibular schwannomas correlates to tumor growth rate. Laryngoscope 2003;113:2129-2134
   CrossRef | Web of Science | Medline

4. 4

   Caye-Thomasen P, Werther K, Nalla A, et al. VEGF and VEGF receptor-1 concentration in vestibular schwannoma homogenates correlates to tumor growth rate. Otol Neurotol 2005;26:98-101
   CrossRef | Web of Science | Medline

Author/Editor Response

Guntinas-Lichius raises an important issue about trial design in studies of vestibular schwannomas. Recently, a group of experts endorsed the objective radiographic response rate as the appropriate choice for initial single-group drug trials because the rates of spontaneous tumor shrinkage in untreated vestibular schwannomas are low.1 In the study cited by Guntinas-Lichius,2 extremely few tumors decreased in size during the observation period (0.9%), whereas the majority of tumors were either stable (70.2%) or increased in size (28.9%). In our study, 60% of tumors had a radiographic response; this rate far exceeded the rate of spontaneous tumor shrinkage. Moreover, the median annual growth rate of the tumors before bevacizumab therapy was 63%, whereas many of the tumors in the previous study were not growing at baseline. In a companion study3 to the study cited by Guntinas-Lichius, the rate of spontaneous hearing improvement without treatment was 2.7%, which is far lower than the reported rate of hearing improvement in our study (57%). Together, these findings provide strong evidence that changes in tumor size and hearing after treatment were related to the effects of bevacizumab.

We do not fully understand why word recognition improved more than detection of pure tones. However, we disagree with the assertions that the hearing measurements were subjective and that bias may explain the findings. Standardized methods exist for the determination of pure-tone averages and measurement of word recognition. In hearing loss due to vestibular schwannomas, word recognition typically is affected more than the detection of pure tones.1 Thus, greater improvement might be expected in word recognition than in the ability to hear pure tones after effective treatment of vestibular schwannomas. Although brain-stem auditory evoked response measurements would have been worthwhile, we did not include them because we did not have sufficient data for comparisons among patients.

We agree with Diao et al. that inhibiting VEGF in vestibular schwannomas probably affects both the vasculature and tumor cells. Our data do not permit us to estimate the relative contributions of vascular permeability and direct killing of tumor cells to clinical response. However, these two processes might explain why the effect of bevacizumab on tumor size and hearing was not tightly correlated.

Scott R. Plotkin, M.D., Ph.D.
Massachusetts General Hospital, Boston, MA
splotkin@partners.org

Chris Halpin, Ph.D.
Massachusetts Eye and Ear Infirmary, Boston, MA

Emmanuelle di Tomaso, Ph.D.
Novartis Institutes for BioMedical Research, Cambridge, MA

Since publication of the article, Dr. di Tomaso reports being employed by the Novartis Institutes for BioMedical Research. No other potential conflict of interest relevant to this letter was reported.

3 References

1. 1

   Plotkin SR, Halpin C, Blakeley JO, et al. Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma. J Neurooncol 2009;93:61-77
   CrossRef | Web of Science | Medline

2. 2

   Stangerup SE, Caye-Thomasen P, Tos M, Thomsen J. The natural history of vestibular schwannoma. Otol Neurotol 2006;27:547-552
   CrossRef | Web of Science | Medline

3. 3

   Stangerup SE, Caye-Thomasen P, Tos M, Thomsen J. Change in hearing during `wait and scan' management of patients with vestibular schwannoma. J Laryngol Otol 2008;122:673-681
   CrossRef | Web of Science | Medline