- Email: [email protected]
Nasal septal perforation secondary to systemic bevacizumab
Nasal Septal Perforation Secondary to Systemic Bevacizumab Mathew Geltzeiler, Toby O. Steele PII: DOI: Reference:
S0196-0709(16)30611-1 doi:10.1016/j.amjoto.2017.01.018 YAJOT 1799
To appear in:
American Journal of Otolaryngology–Head and Neck Medicine and Surgery
Received date:
19 December 2016
Please cite this article as: Geltzeiler Mathew, Steele Toby O., Nasal Septal Perforation Secondary to Systemic Bevacizumab, American Journal of Otolaryngology–Head and Neck Medicine and Surgery (2017), doi:10.1016/j.amjoto.2017.01.018
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
RI
Mathew Geltzeiler, MD1,2, Toby O. Steele, MD3
PT
Nasal Septal Perforation Secondary to Systemic Bevacizumab
1
Potential Conflicts of Interest: None
MA
Correspondence:
NU
SC
Department of Otolaryngology- Head and Neck Surgery, Oregon Health & Science University, Portland, OR 97239, USA. 2 University of Pittsburgh Medical Center, Pittsburgh, PA 15213 USA 3 Department of Otolaryngology – Head and Neck Surgery, University of California Davis, Sacramento, CA 95817 USA
Mathew Geltzeiler, MD,
AC CE P
TE
D
University of Pittsburgh Medical Center Department of Otolaryngology Suite 500 Eye and Ear Institute 200 Lothrop St. Pittsburgh, PA 15213 E-mail: [email protected]
MeSH Key Words: avastin, bevacizumab, chemotherapy, nasal septum, perforation, septal perforation, sinonasal pathology, ovarian cancer, hereditary hemorrhagic telangiectasia
Word Count: 1,098
ACCEPTED MANUSCRIPT
SC
RI
PT
Abstract: Importance: A case of nasal septal perforation secondary to systemic bevacizumab therapy for ovarian cancer is reported. Bevacizumab is a vascular endothelial growth factor A (VEGF-A) inhibitor that is becoming more widely utilized in the oncologic community. There is only one prior report of septal perforation secondary to bevacizumab in the Otolaryngology specific literature. The purpose of this report is: 1) to raise awareness and discuss the literature surrounding the sinonasal complications of bevacizumab and 2) provide workup and treatment recommendations based on the sum of the available literature.
MA
NU
Observations: We review the clinical record of a 59 year old patient who presented with an anterior septal perforation while taking bevacizumab therapy for ovarian cancer. She had mild symptoms. Her oncologist held bevacizumab and topical moisture therapy was started. After several weeks, the perforation remained stable and bevacizumab was restarted for her ovarian cancer.
AC CE P
TE
D
Conclusion and Relevance: Bevacizumab is associated with both septal perforation and more widespread sinonasal toxicity. These lesions tend to produce only mild symptoms and can usually be managed conservatively. The decision to hold bevacizumab therapy should be made in conjunction with the patient and medical oncologist. Otolaryngologists should be aware of the toxicity from this increasingly common oncologic therapy.
ACCEPTED MANUSCRIPT
Introduction:
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PT
Bevacizumab is a monoclonal antibody inhibitor of vascular endothelial growth factor A (VEGF-A) which is currently FDA approved several late stage, solid tumor malignancies.1 The medication is also approved for epistaxis secondary to Hereditary Hemorrhagic Telangiectasia (HHT).2 Over the last 10 years, several reports of bevacizumab induced nasal septal perforations have been described in patients treated for breast3 and colorectal cancer.4 More recently, bevacizumab has been associated with not only perforations but more widespread sinonasal toxicity.5 Despite these publications in the medical oncology literature, there is relatively sparse data in the Otolaryngology literature.6 The aims of this study are two-fold. First, this report will serve to raise awareness of the potential nasal toxicities secondary to systemic bevacizumab through case presentation and literature discussion. Secondly, based on the review of the literature, recommendations for work up and treatment are presented.
TE
D
MA
Report of Case: A 59 year old female presents with an anterior septal perforation. This lesion occurred approximately 4 months prior. The patient blew her nose and removed several large crusts, after which she noticed the perforation. She was taking systemic bevacizumab for ovarian cancer. She had mild rhinorrhea but no other rhinologic symptoms. She had no history of prior nasal surgery, systemic inflammatory disease or cocaine abuse. No family history of autoimmune diseases. Her exam revealed a 0.5 cm anterior perforation with crusting (Figure 1). Bevacizumab was held for several weeks and topical moisture (nasal gel) was applied. The perforation remained stable and she re-started bevacizumab for her ovarian cancer.
AC CE P
Discussion: Bevacizumab is a monoclonal antibody inhibitor of VEGF-A indicated for multiple malignancies including colorectal, lung, breast, renal, neurologic and GYN. A rare complication of systemic therapy is septal perforation. While several prior reports of this complication exist in the medical oncology literature, this is the second report in an Otolaryngology journal. The true incidence of septal perforation secondary to bevacizumab is still being elucidated. In the two largest case series, Mailiez et. al.3 found an incidence of 7% in their cohort of 70 breast cancer patients while Ramiscal and Jatoi 4 noted an incidence of 1% in their cohort of 100 consecutive colorectal cancer patients. Mailliez et. al. reported a median time to presentation of 21 weeks (range 9-45) with three of five patients (60%) receiving combination chemotherapy with taxanes.3 Bevacizumab has also been associated with more widespread sinonasal toxicity.5 D’Amico et. al. reported on their cohort of 47 patient receiving bevacizumab for a variety of malignancies. Overall, 96% of patients showed some nasal mucosal lesions with mild epistaxis and sinonasal irritation being the most common symptoms. In their multivariable analysis, bevacizumab dose, concomitant taxane therapy and digital self manipulation were all significantly associated with worse sinonasal disease. No perforations were found in this group.
ACCEPTED MANUSCRIPT
PT
Beviziamab is also utilized for recurrent HHT. Drug dosing was presumed to play a role in the high rate of perforations found when the drug was injected directly into the cartilaginous septum.2 Based on these findings, bevacizumab is typically administered topically in the setting of HHT or injections are based laterally in the inferior and middle turbinates.
SC
RI
The mechanism of bevacizumab toxicity is not clearly defined and likely multifactorial. Inhibition of VEGF-A with associated reduction in angiogenesis is one possible cause.4 Additionally, mucositis from bevacizumab itself or secondary to concomitant taxane therapy is a possible contributing factor.5 Bevacizumab has also been associated with poor wound healing7 and spontaneous bowel perforation.8 Infection, immunosuppression and trauma are other potential etiologies.
AC CE P
TE
D
MA
NU
The workup for sinonasal toxicity in the setting of bevacizumab use is undefined. All patient should undergo a complete history and physical exam with focus on prior sinonasal disease, trauma, intranasal drug use and systemic inflammatory disease. Laboratory testing for autoimmune diseases and routine biopsy of perforations or mucosal lesions should be guided by clinical suspicion. Given that taxane therapy is associated with immunosuppression, tissue biopsy and tissue culture may be considered. No reports of secondary malignancy, invasive fungal sinusitis, septal infection or autoimmune disease have been discovered by these additional tests in this clinical context. Because bevacizumab induced sinonasal toxicity is becoming increasingly well recognized, we recommend that medical symptom management without additional workup can be appropriate if the time course and presentation are otherwise straightforward. The management of bevacizumab induced perforation and mucositis is still being defined. Conservative treatment with topical moisture is adequate in the majority of cases as disease severity tends to be minimal.3,5,7 In the studies reporting nasal perforations as a result of bevacizumb, perforations that were discovered tended to not progress over time, although no long term studies exist. There have also been no reports of saddle nose deformity. Besides topical moisture, septal buttons have been used with success.6 We suspect that surgical management would also be appropriate if the perforation remained symptomatic many months after completion of oncologic therapy. Many reports describe stopping bevacizumab when the perforation was discovered. We feel that this decision should be made carefully with the patient and medical oncologist. As the symptoms from the perforations tend to be mild, we do not recommend routinely holding oncologic therapy, especially if outcomes may be compromised. Lastly, medical oncologist may consider prophylactically starting topical nasal moisture with bevacizumab given the high rate of sinonasal mucositis. Conclusion: Bevacizumab in an increasingly common medication that is associated with septal perforation and more widespread sinonasal toxicity. Otolaryngologists should be aware of these complications.
Author Contributions:
ACCEPTED MANUSCRIPT Mathew Geltzeiler, MD: Study design, drafting and revision, final approval, agreement to accountability.
AC CE P
TE
D
MA
NU
SC
RI
PT
Toby Steele, MD: Study design, drafting and revision, final approval, agreement to accountability.
ACCEPTED MANUSCRIPT References: Shih T, Lindley C. Bevacizumab: An angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther. 2006;28:1779-1802. doi:10.1016/j.clinthera.2006.11.015.
2.
Chen IV S, Karnezis T, Davidson TM. Safety of intranasal Bevacizumab (avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis. Laryngoscope. 2011;121(March):644-646. doi:10.1002/lary.21345.
3.
Mailliez A, Baldini C, Van JT, Servent V, Mallet Y, Bonneterre J. Nasal septum perforation: a side effect of bevacizumab chemotherapy in breast cancer patients. Br J Cancer. 2010;103:772-775. doi:10.1038/sj.bjc.6605828.
4.
Ramiscal JAB, Jatoi A. Bevacizumab-Induced Nasal Septal Perforation: Incidence of Symptomatic, Confirmed Event(s) in Colorectal Cancer Patients. Acta oncologica (Stockholm, Sweden) 50, 578-581 (2011). doi:10.3109/0284186X.2010.537692.
5.
M. D’Amico, M. Pagano, A. Pasa, M. Puntoni, M. Clavarezza, A. Gennari, A. Gozza, S. Zanardi, C. Defferrari, N. Provinciali, E. Campazzi, S. Campora, L. Paleari, D. Marra, M. Petrera M AD. An observational study of nasal cavity toxicity in cancer patients treated with bevacizumab. Expert Opin Drug Saf. 2014;13(11):1437-1442.
6.
Burkart CM, Grisel JJ, Hom DB. Spontaneous nasal septal perforation with antiangiogenic bevacizumab therapy. Laryngoscope. 2008;118(September):1539-1541. doi:10.1097/MLG.0b013e31817c4296.
7.
Ramiscal JAB, Jatoi A. Nasal septal perforation from bevacizumab: A discussion of outcomes, management, and pharmacovigilance. Curr Oncol Rep. 2012;14:307-310. doi:10.1007/s11912-012-0236-x.
8.
Qi WX, Shen Z, Tang LN, Yao Y. Bevacizumab increases the risk of gastrointestinal perforation in cancer patients: A meta-analysis with a focus on different subgroups. Eur J Clin Pharmacol. 2014;70:893-906. doi:10.1007/s00228-014-1687-9.
AC CE P
TE
D
MA
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SC
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PT
1.
ACCEPTED MANUSCRIPT
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Figure 1:
Figure Legend:
Figure 1: Endoscopic photograph of caudal nasal septal perforation secondary to bevacizumab taken from the right naris.
S0196-0709(16)30611-1 doi:10.1016/j.amjoto.2017.01.018 YAJOT 1799
To appear in:
American Journal of Otolaryngology–Head and Neck Medicine and Surgery
Received date:
19 December 2016
Please cite this article as: Geltzeiler Mathew, Steele Toby O., Nasal Septal Perforation Secondary to Systemic Bevacizumab, American Journal of Otolaryngology–Head and Neck Medicine and Surgery (2017), doi:10.1016/j.amjoto.2017.01.018
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
RI
Mathew Geltzeiler, MD1,2, Toby O. Steele, MD3
PT
Nasal Septal Perforation Secondary to Systemic Bevacizumab
1
Potential Conflicts of Interest: None
MA
Correspondence:
NU
SC
Department of Otolaryngology- Head and Neck Surgery, Oregon Health & Science University, Portland, OR 97239, USA. 2 University of Pittsburgh Medical Center, Pittsburgh, PA 15213 USA 3 Department of Otolaryngology – Head and Neck Surgery, University of California Davis, Sacramento, CA 95817 USA
Mathew Geltzeiler, MD,
AC CE P
TE
D
University of Pittsburgh Medical Center Department of Otolaryngology Suite 500 Eye and Ear Institute 200 Lothrop St. Pittsburgh, PA 15213 E-mail: [email protected]
MeSH Key Words: avastin, bevacizumab, chemotherapy, nasal septum, perforation, septal perforation, sinonasal pathology, ovarian cancer, hereditary hemorrhagic telangiectasia
Word Count: 1,098
ACCEPTED MANUSCRIPT
SC
RI
PT
Abstract: Importance: A case of nasal septal perforation secondary to systemic bevacizumab therapy for ovarian cancer is reported. Bevacizumab is a vascular endothelial growth factor A (VEGF-A) inhibitor that is becoming more widely utilized in the oncologic community. There is only one prior report of septal perforation secondary to bevacizumab in the Otolaryngology specific literature. The purpose of this report is: 1) to raise awareness and discuss the literature surrounding the sinonasal complications of bevacizumab and 2) provide workup and treatment recommendations based on the sum of the available literature.
MA
NU
Observations: We review the clinical record of a 59 year old patient who presented with an anterior septal perforation while taking bevacizumab therapy for ovarian cancer. She had mild symptoms. Her oncologist held bevacizumab and topical moisture therapy was started. After several weeks, the perforation remained stable and bevacizumab was restarted for her ovarian cancer.
AC CE P
TE
D
Conclusion and Relevance: Bevacizumab is associated with both septal perforation and more widespread sinonasal toxicity. These lesions tend to produce only mild symptoms and can usually be managed conservatively. The decision to hold bevacizumab therapy should be made in conjunction with the patient and medical oncologist. Otolaryngologists should be aware of the toxicity from this increasingly common oncologic therapy.
ACCEPTED MANUSCRIPT
Introduction:
NU
SC
RI
PT
Bevacizumab is a monoclonal antibody inhibitor of vascular endothelial growth factor A (VEGF-A) which is currently FDA approved several late stage, solid tumor malignancies.1 The medication is also approved for epistaxis secondary to Hereditary Hemorrhagic Telangiectasia (HHT).2 Over the last 10 years, several reports of bevacizumab induced nasal septal perforations have been described in patients treated for breast3 and colorectal cancer.4 More recently, bevacizumab has been associated with not only perforations but more widespread sinonasal toxicity.5 Despite these publications in the medical oncology literature, there is relatively sparse data in the Otolaryngology literature.6 The aims of this study are two-fold. First, this report will serve to raise awareness of the potential nasal toxicities secondary to systemic bevacizumab through case presentation and literature discussion. Secondly, based on the review of the literature, recommendations for work up and treatment are presented.
TE
D
MA
Report of Case: A 59 year old female presents with an anterior septal perforation. This lesion occurred approximately 4 months prior. The patient blew her nose and removed several large crusts, after which she noticed the perforation. She was taking systemic bevacizumab for ovarian cancer. She had mild rhinorrhea but no other rhinologic symptoms. She had no history of prior nasal surgery, systemic inflammatory disease or cocaine abuse. No family history of autoimmune diseases. Her exam revealed a 0.5 cm anterior perforation with crusting (Figure 1). Bevacizumab was held for several weeks and topical moisture (nasal gel) was applied. The perforation remained stable and she re-started bevacizumab for her ovarian cancer.
AC CE P
Discussion: Bevacizumab is a monoclonal antibody inhibitor of VEGF-A indicated for multiple malignancies including colorectal, lung, breast, renal, neurologic and GYN. A rare complication of systemic therapy is septal perforation. While several prior reports of this complication exist in the medical oncology literature, this is the second report in an Otolaryngology journal. The true incidence of septal perforation secondary to bevacizumab is still being elucidated. In the two largest case series, Mailiez et. al.3 found an incidence of 7% in their cohort of 70 breast cancer patients while Ramiscal and Jatoi 4 noted an incidence of 1% in their cohort of 100 consecutive colorectal cancer patients. Mailliez et. al. reported a median time to presentation of 21 weeks (range 9-45) with three of five patients (60%) receiving combination chemotherapy with taxanes.3 Bevacizumab has also been associated with more widespread sinonasal toxicity.5 D’Amico et. al. reported on their cohort of 47 patient receiving bevacizumab for a variety of malignancies. Overall, 96% of patients showed some nasal mucosal lesions with mild epistaxis and sinonasal irritation being the most common symptoms. In their multivariable analysis, bevacizumab dose, concomitant taxane therapy and digital self manipulation were all significantly associated with worse sinonasal disease. No perforations were found in this group.
ACCEPTED MANUSCRIPT
PT
Beviziamab is also utilized for recurrent HHT. Drug dosing was presumed to play a role in the high rate of perforations found when the drug was injected directly into the cartilaginous septum.2 Based on these findings, bevacizumab is typically administered topically in the setting of HHT or injections are based laterally in the inferior and middle turbinates.
SC
RI
The mechanism of bevacizumab toxicity is not clearly defined and likely multifactorial. Inhibition of VEGF-A with associated reduction in angiogenesis is one possible cause.4 Additionally, mucositis from bevacizumab itself or secondary to concomitant taxane therapy is a possible contributing factor.5 Bevacizumab has also been associated with poor wound healing7 and spontaneous bowel perforation.8 Infection, immunosuppression and trauma are other potential etiologies.
AC CE P
TE
D
MA
NU
The workup for sinonasal toxicity in the setting of bevacizumab use is undefined. All patient should undergo a complete history and physical exam with focus on prior sinonasal disease, trauma, intranasal drug use and systemic inflammatory disease. Laboratory testing for autoimmune diseases and routine biopsy of perforations or mucosal lesions should be guided by clinical suspicion. Given that taxane therapy is associated with immunosuppression, tissue biopsy and tissue culture may be considered. No reports of secondary malignancy, invasive fungal sinusitis, septal infection or autoimmune disease have been discovered by these additional tests in this clinical context. Because bevacizumab induced sinonasal toxicity is becoming increasingly well recognized, we recommend that medical symptom management without additional workup can be appropriate if the time course and presentation are otherwise straightforward. The management of bevacizumab induced perforation and mucositis is still being defined. Conservative treatment with topical moisture is adequate in the majority of cases as disease severity tends to be minimal.3,5,7 In the studies reporting nasal perforations as a result of bevacizumb, perforations that were discovered tended to not progress over time, although no long term studies exist. There have also been no reports of saddle nose deformity. Besides topical moisture, septal buttons have been used with success.6 We suspect that surgical management would also be appropriate if the perforation remained symptomatic many months after completion of oncologic therapy. Many reports describe stopping bevacizumab when the perforation was discovered. We feel that this decision should be made carefully with the patient and medical oncologist. As the symptoms from the perforations tend to be mild, we do not recommend routinely holding oncologic therapy, especially if outcomes may be compromised. Lastly, medical oncologist may consider prophylactically starting topical nasal moisture with bevacizumab given the high rate of sinonasal mucositis. Conclusion: Bevacizumab in an increasingly common medication that is associated with septal perforation and more widespread sinonasal toxicity. Otolaryngologists should be aware of these complications.
Author Contributions:
ACCEPTED MANUSCRIPT Mathew Geltzeiler, MD: Study design, drafting and revision, final approval, agreement to accountability.
AC CE P
TE
D
MA
NU
SC
RI
PT
Toby Steele, MD: Study design, drafting and revision, final approval, agreement to accountability.
ACCEPTED MANUSCRIPT References: Shih T, Lindley C. Bevacizumab: An angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther. 2006;28:1779-1802. doi:10.1016/j.clinthera.2006.11.015.
2.
Chen IV S, Karnezis T, Davidson TM. Safety of intranasal Bevacizumab (avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis. Laryngoscope. 2011;121(March):644-646. doi:10.1002/lary.21345.
3.
Mailliez A, Baldini C, Van JT, Servent V, Mallet Y, Bonneterre J. Nasal septum perforation: a side effect of bevacizumab chemotherapy in breast cancer patients. Br J Cancer. 2010;103:772-775. doi:10.1038/sj.bjc.6605828.
4.
Ramiscal JAB, Jatoi A. Bevacizumab-Induced Nasal Septal Perforation: Incidence of Symptomatic, Confirmed Event(s) in Colorectal Cancer Patients. Acta oncologica (Stockholm, Sweden) 50, 578-581 (2011). doi:10.3109/0284186X.2010.537692.
5.
M. D’Amico, M. Pagano, A. Pasa, M. Puntoni, M. Clavarezza, A. Gennari, A. Gozza, S. Zanardi, C. Defferrari, N. Provinciali, E. Campazzi, S. Campora, L. Paleari, D. Marra, M. Petrera M AD. An observational study of nasal cavity toxicity in cancer patients treated with bevacizumab. Expert Opin Drug Saf. 2014;13(11):1437-1442.
6.
Burkart CM, Grisel JJ, Hom DB. Spontaneous nasal septal perforation with antiangiogenic bevacizumab therapy. Laryngoscope. 2008;118(September):1539-1541. doi:10.1097/MLG.0b013e31817c4296.
7.
Ramiscal JAB, Jatoi A. Nasal septal perforation from bevacizumab: A discussion of outcomes, management, and pharmacovigilance. Curr Oncol Rep. 2012;14:307-310. doi:10.1007/s11912-012-0236-x.
8.
Qi WX, Shen Z, Tang LN, Yao Y. Bevacizumab increases the risk of gastrointestinal perforation in cancer patients: A meta-analysis with a focus on different subgroups. Eur J Clin Pharmacol. 2014;70:893-906. doi:10.1007/s00228-014-1687-9.
AC CE P
TE
D
MA
NU
SC
RI
PT
1.
ACCEPTED MANUSCRIPT
AC CE P
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MA
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Figure 1:
Figure Legend:
Figure 1: Endoscopic photograph of caudal nasal septal perforation secondary to bevacizumab taken from the right naris.