- Email: [email protected]
No Free Lunch: Secondary Neoplasms After Stereotactic Radiation
Perspectives Commentary on: Secondary Neoplasms After Stereotactic Radiosurgery by Patel and Chiang World Neurosurg 81:594-599, 2014
E. Antonio Chiocca, M.D., Ph.D. Professor of Neurosurgery, Harvard Medical School Neurosurgeon-in-Chief and Chairman, Department of Neurosurgery Co-Director, Institute for the Neurosciences at the Brigham and Women’s/Faulkner Hospital Surgical Director, Center for Neuro-oncology Dana-Farber Cancer Institute
No Free Lunch: Secondary Neoplasms After Stereotactic Radiation Muhammad M. Abd-El-Barr and E. Antonio Chiocca
W
hen faced with a brain lesion, treating clinicians must weigh many factors before deciding on a plan of action. They must assess whether this lesion is symptomatic or not. They must assess the importance of tissue diagnosis. They must take into account the patient’s age, functional status, and ability to undergo surgical resection if that is what is needed. They must also consider the lesion’s location and their ability to minimize risks while maximizing surgical resection, if that is what is indicated. There has been a recent emphasis on reducing the invasiveness of neurosurgical procedures and at the same time, not reducing their efficacy. Stereotactic radiosurgery (SRS), or the delivery of high dose radiation in a single treatment, with a steep dose gradient is a proven tool in the armamentarium of treating clinicians for a wide variety of intracranial lesions (3, 7). The indications for SRS are becoming increasingly established and accepted, with reports of SRS efficacy for both benign and malignant lesions, including arteriovenous malformations (4, 13), meningiomas (14), vestibular and nonvestibular schwannomas (8, 9), metastases (6), and primary brain tumors (15). In fact, it may be even true that SRS could become the more cost-effective option for treating such lesions when compared with traditional craniotomy. We have known for quite some time that radiation, as it applies to cranial pathology, is not completely benign. The most robust data detailing the risks of radiation comes from the Israeli experience of scalp radiation for tinea capitis, where subjects were exposed to relatively low levels of radiation (mean dose, 1.5 Gy) (11). Long-term (30 years) data suggested that these doses were associated with close to a 10 times risk of developing new intracranial pathology, with benign lesions developing later than malignant ones (11).
Key words Dedifferentiation - Late complications - Malignant transformation - Secondary neoplasm - Stereotactic radiosurgery -
Abbreviations and Acronyms EBRT: External beam radiotherapy SRS: Stereotactic radiosurgery
WORLD NEUROSURGERY - [-]: ---, MONTH 2014
Similarly, external beam radiotherapy (EBRT) for pituitary tumors or childhood cancers has also been shown to increase the risks of new benign and malignant neoplasms (12, 16). Although retrospective in nature, it has been suggested that even dental roentgenograms may increase the risk of developing meningiomas (2). Although the radiation doses of SRS are considerably higher than those used in these applications, the area of exposed tissue is much less, which the proponents of SRS have argued may decrease the risk of developing new neoplasms (10). Nonetheless, it is not too surprising that numerous reports have reported the development of new intracranial neoplasms after SRS. An important point in trying to define the risk of developing new neoplasms after radiosurgery is that, unlike the cases of tinea capitis, patients that receive SRS already have an intracranial neoplasm. Thus, when a vestibular schwannoma actually increases in size after SRS, which is estimated to occur in w9% of patients (5), does this represent a “new” neoplasm that may have more malignant characteristics or is this the growth that one would expect from the natural history of these lesions? In fact, only those patients who receive a subsequent resection or undergo biopsy and have confirmed pathology, which is different from the original pathology, would be included in the most strict adaptation of Cahan’s criteria for developing novel neoplasms (1). The article by Patel and Chiang in the March/April issue of WORLD NEUROSURGERY aims to review the cases of new intracranial neoplasms after SRS. They discovered 36 such patients in the literature and, although they do not review them individually, they try to find common and salient points. Similar to the EBRT experience, they find that the latency for appearance of new
Department of Neurosurgery, Harvard Medical School, Institute for the Neurosciences at the Brigham and Women’s/Faulkner Hospital, and Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA To whom correspondence should be addressed: E. Antonio Chiocca, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2014). http://dx.doi.org/10.1016/j.wneu.2014.02.016
www.WORLDNEUROSURGERY.org
1
PERSPECTIVES
benign neoplasms is longer than that for new malignant neoplasms (14.25 years vs. 7.1 years). Interestingly, these latency times are shorter than those quoted in the EBRT literature. By focusing on patients with vestibular schwannomas, they also show that more than half of the cases of new neoplasms are malignant peripheral nerve sheath tumors, which may represent secondary malignant degeneration and may not be new tumors, especially in those cases with very little latent periods. Reassuringly, Patel and Chiang also point out that the number of case reports of new neoplasms after SRS for brain metastases is exceedingly low (2). Perhaps these patients succumb to their systemic metastatic disease much faster than the latency time to develop these new neoplasms. With these case reports in hand (numerator), Patel and Chiang attempt to quantify the relative risk of developing new neoplasms after SRS by using data on the prevalence of SRS (denominator). Although this method can be heavily criticized, they estimate this risk to be 0.04% at 15 years. This is
REFERENCES 1. Cahan WG, Woodard HQ, Higinbotham NL, Stewart FW, Coley BL: Sarcoma arising in irradiated bone; report of 11 cases. Cancer 1:3-29, 1948. 2. Claus EB, Calvocoressi L, Bondy ML, Schildkraut JM, Wiemels JL, Wrensch M: Dental x-rays and risk of meningioma. Cancer 118: 4530-4537, 2012. 3. Friedman WA: Linear accelerator radiosurgery. Clin Neurosurg 38:445-471, 1992. 4. Friedman WA: Stereotactic radiosurgery of intracranial arteriovenous malformations. Neurosurg Clin N Am 24:561-574, 2013. 5. Friedman WA, Foote KD: Linear accelerator-based radiosurgery for vestibular schwannoma. Neurosurg Focus 14:e2, 2003. 6. Gans JH, Raper DM, Shah AH, Bregy A, Heros D, Lally BE, Morcos JJ, Heros RC, Komotar RJ: The role of radiosurgery to the tumor bed after resection of brain metastases. Neurosurgery 72:317-325 [discussion 325-326], 2013. 7. Hoh DJ, Liu CY, Pagnini PG, Yu C, Wang MY, Apuzzo ML: Chained lightning, part I:
2
www.SCIENCEDIRECT.com
considerably lower than the rates quoted by the Israeli tinea capitis group. Patel and Chiang posit a very interesting hypothesis of why that is, suggesting that the doses of SRS are so high that they push both normal and neoplastic cells toward cytoxicity rather than mutagenesis. This work thus shows that there is an exceedingly small, yet not null, risk of developing new neoplasms after SRS. A final concern may be whether we will see the rates of these secondary neoplasms increase as therapies for cancer improve to the point of allowing longer lives for these patients. As new technologies are added to the armamentarium of treating clinicians, it will be exceedingly important to note the advantages and disadvantages of each. This work is an important first step in analyzing a very specific consequence of one of these tools (SRS). As always, many factors must be carefully weighed and analyzed before a treatment plan is carried out and this must be individualized to each patient.
exploitation of energy and radiobiological principles for therapeutic purposes. Neurosurgery 61: 14-27 [discussion 27-28], 2007. 8. Kimball MM, Foote KD, Bova FJ, Chi YY, Friedman WA: Linear accelerator radiosurgery for nonvestibular schwannomas. Neurosurgery 68: 974-984 [discussion 984], 2011. 9. Kondziolka D, Mousavi SH, Kano H, Flickinger JC, Lunsford LD: The newly diagnosed vestibular schwannoma: radiosurgery, resection, or observation? Neurosurg Focus 33:E8, 2012. 10. Niranjan A, Kondziolka D, Lunsford LD: Neoplastic transformation after radiosurgery or radiotherapy: risk and realities. Otolaryngol Clin North Am 42: 717-729, 2009. 11. Ron E, Modan B, Boice JD Jr, Alfandary E, Stovall M, Chetrit A, Katz L: Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 319:1033-1039, 1988. 12. Salvati M, D’Elia A, Melone GA, Brogna C, Frati A, Raco A, Delfini R: Radio-induced gliomas: 20-year experience and critical review of the pathology. J Neurooncol 89:169-177, 2008.
13. See AP, Raza S, Tamargo RJ, Lim M: Stereotactic radiosurgery of cranial arteriovenous malformations and dural arteriovenous fistulas. Neurosurg Clin N Am 23:133-146, 2012. 14. Starke RM, Nguyen JH, Reames DL, Rainey J, Sheehan JP: Gamma knife radiosurgery of meningiomas involving the foramen magnum. J Craniovertebr Junction Spine 1:23-28, 2010. 15. Taw BB, Gorgulho AA, Selch MT, De Salles AA: Radiation options for high-grade gliomas. Neurosurg Clin N Am 23:259-267 viii, 2012. 16. Tsang RW, Laperriere NJ, Simpson WJ, Brierley J, Panzarella T, Smyth HS: Glioma arising after radiation therapy for pituitary adenoma. A report of four patients and estimation of risk. Cancer 72: 2227-2233, 1993.
Citation: World Neurosurg. (2014). http://dx.doi.org/10.1016/j.wneu.2014.02.016 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2014.02.016
E. Antonio Chiocca, M.D., Ph.D. Professor of Neurosurgery, Harvard Medical School Neurosurgeon-in-Chief and Chairman, Department of Neurosurgery Co-Director, Institute for the Neurosciences at the Brigham and Women’s/Faulkner Hospital Surgical Director, Center for Neuro-oncology Dana-Farber Cancer Institute
No Free Lunch: Secondary Neoplasms After Stereotactic Radiation Muhammad M. Abd-El-Barr and E. Antonio Chiocca
W
hen faced with a brain lesion, treating clinicians must weigh many factors before deciding on a plan of action. They must assess whether this lesion is symptomatic or not. They must assess the importance of tissue diagnosis. They must take into account the patient’s age, functional status, and ability to undergo surgical resection if that is what is needed. They must also consider the lesion’s location and their ability to minimize risks while maximizing surgical resection, if that is what is indicated. There has been a recent emphasis on reducing the invasiveness of neurosurgical procedures and at the same time, not reducing their efficacy. Stereotactic radiosurgery (SRS), or the delivery of high dose radiation in a single treatment, with a steep dose gradient is a proven tool in the armamentarium of treating clinicians for a wide variety of intracranial lesions (3, 7). The indications for SRS are becoming increasingly established and accepted, with reports of SRS efficacy for both benign and malignant lesions, including arteriovenous malformations (4, 13), meningiomas (14), vestibular and nonvestibular schwannomas (8, 9), metastases (6), and primary brain tumors (15). In fact, it may be even true that SRS could become the more cost-effective option for treating such lesions when compared with traditional craniotomy. We have known for quite some time that radiation, as it applies to cranial pathology, is not completely benign. The most robust data detailing the risks of radiation comes from the Israeli experience of scalp radiation for tinea capitis, where subjects were exposed to relatively low levels of radiation (mean dose, 1.5 Gy) (11). Long-term (30 years) data suggested that these doses were associated with close to a 10 times risk of developing new intracranial pathology, with benign lesions developing later than malignant ones (11).
Key words Dedifferentiation - Late complications - Malignant transformation - Secondary neoplasm - Stereotactic radiosurgery -
Abbreviations and Acronyms EBRT: External beam radiotherapy SRS: Stereotactic radiosurgery
WORLD NEUROSURGERY - [-]: ---, MONTH 2014
Similarly, external beam radiotherapy (EBRT) for pituitary tumors or childhood cancers has also been shown to increase the risks of new benign and malignant neoplasms (12, 16). Although retrospective in nature, it has been suggested that even dental roentgenograms may increase the risk of developing meningiomas (2). Although the radiation doses of SRS are considerably higher than those used in these applications, the area of exposed tissue is much less, which the proponents of SRS have argued may decrease the risk of developing new neoplasms (10). Nonetheless, it is not too surprising that numerous reports have reported the development of new intracranial neoplasms after SRS. An important point in trying to define the risk of developing new neoplasms after radiosurgery is that, unlike the cases of tinea capitis, patients that receive SRS already have an intracranial neoplasm. Thus, when a vestibular schwannoma actually increases in size after SRS, which is estimated to occur in w9% of patients (5), does this represent a “new” neoplasm that may have more malignant characteristics or is this the growth that one would expect from the natural history of these lesions? In fact, only those patients who receive a subsequent resection or undergo biopsy and have confirmed pathology, which is different from the original pathology, would be included in the most strict adaptation of Cahan’s criteria for developing novel neoplasms (1). The article by Patel and Chiang in the March/April issue of WORLD NEUROSURGERY aims to review the cases of new intracranial neoplasms after SRS. They discovered 36 such patients in the literature and, although they do not review them individually, they try to find common and salient points. Similar to the EBRT experience, they find that the latency for appearance of new
Department of Neurosurgery, Harvard Medical School, Institute for the Neurosciences at the Brigham and Women’s/Faulkner Hospital, and Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA To whom correspondence should be addressed: E. Antonio Chiocca, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2014). http://dx.doi.org/10.1016/j.wneu.2014.02.016
www.WORLDNEUROSURGERY.org
1
PERSPECTIVES
benign neoplasms is longer than that for new malignant neoplasms (14.25 years vs. 7.1 years). Interestingly, these latency times are shorter than those quoted in the EBRT literature. By focusing on patients with vestibular schwannomas, they also show that more than half of the cases of new neoplasms are malignant peripheral nerve sheath tumors, which may represent secondary malignant degeneration and may not be new tumors, especially in those cases with very little latent periods. Reassuringly, Patel and Chiang also point out that the number of case reports of new neoplasms after SRS for brain metastases is exceedingly low (2). Perhaps these patients succumb to their systemic metastatic disease much faster than the latency time to develop these new neoplasms. With these case reports in hand (numerator), Patel and Chiang attempt to quantify the relative risk of developing new neoplasms after SRS by using data on the prevalence of SRS (denominator). Although this method can be heavily criticized, they estimate this risk to be 0.04% at 15 years. This is
REFERENCES 1. Cahan WG, Woodard HQ, Higinbotham NL, Stewart FW, Coley BL: Sarcoma arising in irradiated bone; report of 11 cases. Cancer 1:3-29, 1948. 2. Claus EB, Calvocoressi L, Bondy ML, Schildkraut JM, Wiemels JL, Wrensch M: Dental x-rays and risk of meningioma. Cancer 118: 4530-4537, 2012. 3. Friedman WA: Linear accelerator radiosurgery. Clin Neurosurg 38:445-471, 1992. 4. Friedman WA: Stereotactic radiosurgery of intracranial arteriovenous malformations. Neurosurg Clin N Am 24:561-574, 2013. 5. Friedman WA, Foote KD: Linear accelerator-based radiosurgery for vestibular schwannoma. Neurosurg Focus 14:e2, 2003. 6. Gans JH, Raper DM, Shah AH, Bregy A, Heros D, Lally BE, Morcos JJ, Heros RC, Komotar RJ: The role of radiosurgery to the tumor bed after resection of brain metastases. Neurosurgery 72:317-325 [discussion 325-326], 2013. 7. Hoh DJ, Liu CY, Pagnini PG, Yu C, Wang MY, Apuzzo ML: Chained lightning, part I:
2
www.SCIENCEDIRECT.com
considerably lower than the rates quoted by the Israeli tinea capitis group. Patel and Chiang posit a very interesting hypothesis of why that is, suggesting that the doses of SRS are so high that they push both normal and neoplastic cells toward cytoxicity rather than mutagenesis. This work thus shows that there is an exceedingly small, yet not null, risk of developing new neoplasms after SRS. A final concern may be whether we will see the rates of these secondary neoplasms increase as therapies for cancer improve to the point of allowing longer lives for these patients. As new technologies are added to the armamentarium of treating clinicians, it will be exceedingly important to note the advantages and disadvantages of each. This work is an important first step in analyzing a very specific consequence of one of these tools (SRS). As always, many factors must be carefully weighed and analyzed before a treatment plan is carried out and this must be individualized to each patient.
exploitation of energy and radiobiological principles for therapeutic purposes. Neurosurgery 61: 14-27 [discussion 27-28], 2007. 8. Kimball MM, Foote KD, Bova FJ, Chi YY, Friedman WA: Linear accelerator radiosurgery for nonvestibular schwannomas. Neurosurgery 68: 974-984 [discussion 984], 2011. 9. Kondziolka D, Mousavi SH, Kano H, Flickinger JC, Lunsford LD: The newly diagnosed vestibular schwannoma: radiosurgery, resection, or observation? Neurosurg Focus 33:E8, 2012. 10. Niranjan A, Kondziolka D, Lunsford LD: Neoplastic transformation after radiosurgery or radiotherapy: risk and realities. Otolaryngol Clin North Am 42: 717-729, 2009. 11. Ron E, Modan B, Boice JD Jr, Alfandary E, Stovall M, Chetrit A, Katz L: Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 319:1033-1039, 1988. 12. Salvati M, D’Elia A, Melone GA, Brogna C, Frati A, Raco A, Delfini R: Radio-induced gliomas: 20-year experience and critical review of the pathology. J Neurooncol 89:169-177, 2008.
13. See AP, Raza S, Tamargo RJ, Lim M: Stereotactic radiosurgery of cranial arteriovenous malformations and dural arteriovenous fistulas. Neurosurg Clin N Am 23:133-146, 2012. 14. Starke RM, Nguyen JH, Reames DL, Rainey J, Sheehan JP: Gamma knife radiosurgery of meningiomas involving the foramen magnum. J Craniovertebr Junction Spine 1:23-28, 2010. 15. Taw BB, Gorgulho AA, Selch MT, De Salles AA: Radiation options for high-grade gliomas. Neurosurg Clin N Am 23:259-267 viii, 2012. 16. Tsang RW, Laperriere NJ, Simpson WJ, Brierley J, Panzarella T, Smyth HS: Glioma arising after radiation therapy for pituitary adenoma. A report of four patients and estimation of risk. Cancer 72: 2227-2233, 1993.
Citation: World Neurosurg. (2014). http://dx.doi.org/10.1016/j.wneu.2014.02.016 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2014.02.016