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Cervical Neuropathy Following Mantle Radiotherapy
Clinical Oncology (2002) 14: 468–471 doi:10.1053/clon.2001.0021, available online at http://www.idealibrary.com on
Case Report Cervical Neuropathy Following Mantle Radiotherapy V. J. McFarlane*, G. P. Clein†, J. Cole†, N. Cowley†, T. M. Illidge* *Wessex Radiotherapy Centre, Royal South Hants Hospital, Brintons Terrace, Southampton, SO14 0YG; †Poole General Hospital, Longfleet Road, Poole, BH15 2JB, U.K. ABSTRACT: The majority of newly diagnosed patients with Hodgkin’s lymphoma are expected to survive because of effective therapies established during the last 40 years. Long-term observations from large populations of treated patients have disclosed a variety of late effects of the disease and its therapy that have contributed morbidity and excess mortality to Hodgkin’s lymphoma survivors. As such complications have been recognized treatment approaches have been modified. Here we report a case of cervical neuropathy secondary to mantle radiotherapy, a complication not previously reported in the literature. McFarlane, V. J. et al. (2002). Clinical Oncology 14, 468–471 2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved. Key words: Hodgkin’s lymphoma, neuropathy, radiotherapy Received: 8 January 2001
Introduction
Hodgkin’s lymphoma is an uncommon lymphoid malignancy with an incidence of approximately 3 per 100,000 in Western Europe. With the advent of chemotherapy and modern radiation techniques all presentations of Hodgkin’s lymphoma are potentially curable. The prognostic significance of the Ann Arbour staging system has been well validated and the use of stage-specific therapies is now considered standard practice. Traditionally stages I and IIA supradiaphragmatic Hodgkin’s disease has been treated in the U.K. over the last three decades with extended field radiotherapy. Freedom from relapse of 76% at 10 years has been achieved in patients, who were surgically staged, with supradiaphragmatic stage I and IIA disease treated with radiotherapy alone in the Stanford series [1]. Many of those patients who relapse after radiotherapy can be successfully salvaged with combination chemotherapy. Disease-free survival may, however, be improved by using combined treatment as initial therapy. No survival advantage has yet been demonstrated and studies are ongoing. In view of the relative success of current treatments for Hodgkin’s lymphoma, the complications of therapy have become an important consideration in designing future treatment protocols. Wide-field irradiation is complicated by a number of severe late effects and there has therefore been enthusiasm for the incorporation of chemotherapy with reduced volume and dose of Author for correspondence: V. J. McFarlane, Wessex Radiotherapy Centre, Royal South Hants Hospital, Brintons Terrace, Southampton, SO14 0YG, U.K. Tel: +44(0) 23 80796184. 0936–6555/02/060468+04 $35.00/0
Accepted: 20 September 2001
radiation, or indeed to eliminate radiotherapy altogether [2,3]. Here we report a case of a chronic neuropathic process affecting the cervical muscles of a patient treated with mantle radiotherapy. To our knowledge, such a complication has not previously been reported in the literature.
Case Report
A 29-year-old lady presented in 1976 with a 5-month history of right cervical and bilateral supraclavicular lymphadenopathy. She had no ‘‘B’’ symptoms. In addition, on clinical examination she had a palpable splenic tip. Initial histological examination from a biopsied cervical lymph node confirmed Hodgkin’s lymphoma. A routine staging laparotomy and splenectomy was performed, the histopathology of which demonstrated sarcoid granulomata only in the liver and spleen. A chest x-ray revealed widening of the mediastinum at the level of the aortic arch. Lymphangiogram, IVP, routine biochemistry and haematology, including erythrocyte sedimentation rate (ESR), were normal. The patient was designated as stage IIA, and subsequently treated with total nodal irradiation on a cobalt 60 unit. Anterior and posterior fields were used, the patient lying supine for the anterior field and prone for the posterior field. The infradiaphragmatic region was treated as an inverted ‘‘Y’’ field with standard shielding and a dose of 35 Gy at mid-plane was delivered in 20 fractions over 56 days. The supradiaphragmatic region
2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
was treated using a standard mantle technique. The dose delivered was 40 Gy at mid-plane in 20 daily fractions over 33 days. The mid-plane central separation was 13.5 cm, with a maximum midline separation of 17 cm and a minimum midline neck separation of 9 cm. Lung blocks and lead shielding to the oral cavity and cervical spine (to a width of 2 cm) posteriorly were used throughout the treatment. The thoracic spine was shielded posteriorly, and the larynx anteriorly from 20 Gy. Bolus was not used over the neck. No severe acute side effects were reported during the treatment. At the time of reporting, the patient has remained in clinical remission following radiotherapy, but has had numerous complications secondary to that treatment. These have included premature menopause aged 38, carotid stenosis of 60–65% on Doppler ultrasound and hypothyroidism. However, the most serious complication the patient has developed appears to be neurological. In January 1998, 22 years after her radiotherapy, she presented with a hoarse voice and was found to have a left vocal cord palsy, due to damage to the left recurrent laryngeal nerve. Over the same time period she became aware of her neck becoming thinner and weaker with a tendency for her head to fall forward. On examination she had obviously wasted posterior neck muscles, supplied by several cervical nerve roots, with weakness of neck extension and mild weakness of C5 myotomes (Fig. 1). The lower cervical limb muscles and cranial nerves, other than the left recurrent laryngeal nerve, appeared to be normal and there were no sensory signs or upper motor neuron signs. This would clinically support the diagnosis of a cervical peripheral neuropathy rather than a myelopathy. Magnetic resonance imaging (MRI) showed no abnormality of the cervical cord but marked wasting of the paraspinal muscles. Electromyography (EMG) studies have been performed on several muscle groups, and repeated after an 18-month interval. These studies support the diagnosis of a chronic neuropathic process affecting the upper cervical muscles. EMG from erector spinae at C6/7 shows a reduction in interference pattern with increased amplitude of units, which are large and polyphasic, compatible with a chronic neuropathic process. No spontaneous activity was seen here or in other muscles. Trapezius and erector spinae at C3 both show an excess of polyphasic units but were less affected. These neuropathic changes seen in the neck muscles were not apparent in shoulder and arm muscles, suggesting local nerve damage. The lack of sensory symptoms and signs was perhaps a little surprising. Peripheral nerve conduction was normal in the arm (median and ulnar digital sensory nerve action potentials and compound action potentials). Median and ulnar somatosensory evoked potentials were normal on both sides. The normal sensory neurophysiological results support the conclusion that low cervical sensory conduction was normal. The results were compatible with a neuropathic process affecting the nerves to cervical muscles but involve-
469
ment of trapezius and the vocal cord palsy suggested a more widespread involvement. There was no evidence of a more distal brachial plexopathy.
Discussion
This patient presented with a radiation-induced peripheral neuropathy, a complication usually only seen after radiation doses greater than 60 Gy, although there appears to be an increased risk with lower doses where fraction sizes greater than 2 Gy are used [4]. Although cervical neuropathy has not been reported, brachial plexus neuropathy has been reported in two patients as a late complication of mantle radiotherapy to 40 Gy. Both patients had received vinca alkaloids on relapse, which may have contributed to their neurological damage [5]. Dosimetric studies of the mantle technique have been performed, measuring actual dose received at various points in the treatment field. A study by Cilliers used thermoluminescent dosimetry and a RANDO phantom to look at various techniques [6]. Using a similar technique as our patient, treating with a cobalt-60 unit, turning the patient over between fields and using personalized lung blocks, 2 Gy was prescribed at mid-plane on the central axis. The actual dose measured on the neck was 2.84 Gy3.7%. Using the linear-quadratic equation, and assuming an alpha:beta ratio for peripheral nerve of 2 Gy, it can be calculated that the cervical peripheral nerve would have received a biologically equivalent dose of 68.7 Gy in 2 Gy fractions, if 40 Gy was prescribed at mid-plane on the central axis. This may explain the significant late tissue effects seen. Dosimetry can, however, be considerably improved using compensators to adjust for the smaller separation over the neck. Dosimetry was further improved using a 6 MV linear accelerator rather than a cobalt-60 unit. A similar multicentre dosimetry study of the mantle technique was performed in Australia and New Zealand, which suggested that all centres should adopt dose compensation as a standard technique [7], although many centres still do not routinely use tissue compensators in such patients. Despite poor dose homogeneity with this technique, cervical neuropathy is clearly still rare. In this patient there may have been a greater than average difference between the mid-plane and neck separations leading to a higher radiation dose in the neck. She may also be abnormally sensitive to radiation although there is little other evidence to support this. When discussing late complications it is appropriate to re-address the radiation dose used to treat Hodgkin’s lymphoma. Standard doses currently used to treat involved sites of disease vary between 36 and 44 Gy. Moody and Williams have reviewed the literature and found that there is little scientific basis to support the use of such a relatively high dose [8]. Their conclusions were
470
Fig. 1 – Wasted posterior neck muscles 22 years after mantle radiotherapy.
that 32.5 Gy should be adopted as a standard radiation dose as there was no evidence to suggest a dose response above this. This dose may reduce long-term side-effects and is unlikely to impact on local disease-free survival or to reduce overall survival because of the effectiveness of salvage chemotherapy. It appears therefore, that our patient developed a cervical peripheral neuropathy as a result of mantle radiotherapy using standard techniques and dosage in 1972. In many centres there has been little change to the technique or dosage used over the last 30 years and it is therefore possible that we may see others presenting with such late neurological complications. In order to improve such profound long-term morbidity optimal radiotherapy techniques should be used including tissue compensation, reduced radiation dose and treatment volume reduction, with the use of combination chemotherapy to prevent the long-term sequelae of radiotherapy.
471
References 1 Hoppe RT. Radiation therapy in the management of Hodgkin’s disease. Semin Oncol 1990;17:704–715. 2 Mauch P. Controversies in the management of early stage Hodgkin’s Disease. Blood 1994;83:318–329. 3 Horning SJ, Williams J, Bartlett NL, et al. Assessment of the Stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkin’s disease: Eastern Cooperative Oncology Group pilot study E1492. J Clin Oncol 2000;18:972–982. 4 Gillette EK, Mahler PA, Powers BE, et al. Int J Radiat Oncol Biol Phys 1995;31:1309–1318. 5 Wadd NJ, Lucraft HH. Brachial plexus neuropathy following mantle radiotherapy. Clin Oncol 1998;10:399–400. 6 Cilliers GD, Cilliers C, Browde S. A study of the mantle technique for Hodgkin’s disease using thermoluminescent dosimetry. Radiother Oncol 1987;10:321–326. 7 Amies C, Rose A, Metcalfe P, et al. Multicentre dosimetry study of mantle treatment in Australia and New Zealand. Radiother Oncol 1996;40:171–180. 8 Moody AM, Williams MV. Radiation dose in Hodgkin’s disease: are we overtreating? Clin Oncol 1997;9:15–57.
Case Report Cervical Neuropathy Following Mantle Radiotherapy V. J. McFarlane*, G. P. Clein†, J. Cole†, N. Cowley†, T. M. Illidge* *Wessex Radiotherapy Centre, Royal South Hants Hospital, Brintons Terrace, Southampton, SO14 0YG; †Poole General Hospital, Longfleet Road, Poole, BH15 2JB, U.K. ABSTRACT: The majority of newly diagnosed patients with Hodgkin’s lymphoma are expected to survive because of effective therapies established during the last 40 years. Long-term observations from large populations of treated patients have disclosed a variety of late effects of the disease and its therapy that have contributed morbidity and excess mortality to Hodgkin’s lymphoma survivors. As such complications have been recognized treatment approaches have been modified. Here we report a case of cervical neuropathy secondary to mantle radiotherapy, a complication not previously reported in the literature. McFarlane, V. J. et al. (2002). Clinical Oncology 14, 468–471 2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved. Key words: Hodgkin’s lymphoma, neuropathy, radiotherapy Received: 8 January 2001
Introduction
Hodgkin’s lymphoma is an uncommon lymphoid malignancy with an incidence of approximately 3 per 100,000 in Western Europe. With the advent of chemotherapy and modern radiation techniques all presentations of Hodgkin’s lymphoma are potentially curable. The prognostic significance of the Ann Arbour staging system has been well validated and the use of stage-specific therapies is now considered standard practice. Traditionally stages I and IIA supradiaphragmatic Hodgkin’s disease has been treated in the U.K. over the last three decades with extended field radiotherapy. Freedom from relapse of 76% at 10 years has been achieved in patients, who were surgically staged, with supradiaphragmatic stage I and IIA disease treated with radiotherapy alone in the Stanford series [1]. Many of those patients who relapse after radiotherapy can be successfully salvaged with combination chemotherapy. Disease-free survival may, however, be improved by using combined treatment as initial therapy. No survival advantage has yet been demonstrated and studies are ongoing. In view of the relative success of current treatments for Hodgkin’s lymphoma, the complications of therapy have become an important consideration in designing future treatment protocols. Wide-field irradiation is complicated by a number of severe late effects and there has therefore been enthusiasm for the incorporation of chemotherapy with reduced volume and dose of Author for correspondence: V. J. McFarlane, Wessex Radiotherapy Centre, Royal South Hants Hospital, Brintons Terrace, Southampton, SO14 0YG, U.K. Tel: +44(0) 23 80796184. 0936–6555/02/060468+04 $35.00/0
Accepted: 20 September 2001
radiation, or indeed to eliminate radiotherapy altogether [2,3]. Here we report a case of a chronic neuropathic process affecting the cervical muscles of a patient treated with mantle radiotherapy. To our knowledge, such a complication has not previously been reported in the literature.
Case Report
A 29-year-old lady presented in 1976 with a 5-month history of right cervical and bilateral supraclavicular lymphadenopathy. She had no ‘‘B’’ symptoms. In addition, on clinical examination she had a palpable splenic tip. Initial histological examination from a biopsied cervical lymph node confirmed Hodgkin’s lymphoma. A routine staging laparotomy and splenectomy was performed, the histopathology of which demonstrated sarcoid granulomata only in the liver and spleen. A chest x-ray revealed widening of the mediastinum at the level of the aortic arch. Lymphangiogram, IVP, routine biochemistry and haematology, including erythrocyte sedimentation rate (ESR), were normal. The patient was designated as stage IIA, and subsequently treated with total nodal irradiation on a cobalt 60 unit. Anterior and posterior fields were used, the patient lying supine for the anterior field and prone for the posterior field. The infradiaphragmatic region was treated as an inverted ‘‘Y’’ field with standard shielding and a dose of 35 Gy at mid-plane was delivered in 20 fractions over 56 days. The supradiaphragmatic region
2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
was treated using a standard mantle technique. The dose delivered was 40 Gy at mid-plane in 20 daily fractions over 33 days. The mid-plane central separation was 13.5 cm, with a maximum midline separation of 17 cm and a minimum midline neck separation of 9 cm. Lung blocks and lead shielding to the oral cavity and cervical spine (to a width of 2 cm) posteriorly were used throughout the treatment. The thoracic spine was shielded posteriorly, and the larynx anteriorly from 20 Gy. Bolus was not used over the neck. No severe acute side effects were reported during the treatment. At the time of reporting, the patient has remained in clinical remission following radiotherapy, but has had numerous complications secondary to that treatment. These have included premature menopause aged 38, carotid stenosis of 60–65% on Doppler ultrasound and hypothyroidism. However, the most serious complication the patient has developed appears to be neurological. In January 1998, 22 years after her radiotherapy, she presented with a hoarse voice and was found to have a left vocal cord palsy, due to damage to the left recurrent laryngeal nerve. Over the same time period she became aware of her neck becoming thinner and weaker with a tendency for her head to fall forward. On examination she had obviously wasted posterior neck muscles, supplied by several cervical nerve roots, with weakness of neck extension and mild weakness of C5 myotomes (Fig. 1). The lower cervical limb muscles and cranial nerves, other than the left recurrent laryngeal nerve, appeared to be normal and there were no sensory signs or upper motor neuron signs. This would clinically support the diagnosis of a cervical peripheral neuropathy rather than a myelopathy. Magnetic resonance imaging (MRI) showed no abnormality of the cervical cord but marked wasting of the paraspinal muscles. Electromyography (EMG) studies have been performed on several muscle groups, and repeated after an 18-month interval. These studies support the diagnosis of a chronic neuropathic process affecting the upper cervical muscles. EMG from erector spinae at C6/7 shows a reduction in interference pattern with increased amplitude of units, which are large and polyphasic, compatible with a chronic neuropathic process. No spontaneous activity was seen here or in other muscles. Trapezius and erector spinae at C3 both show an excess of polyphasic units but were less affected. These neuropathic changes seen in the neck muscles were not apparent in shoulder and arm muscles, suggesting local nerve damage. The lack of sensory symptoms and signs was perhaps a little surprising. Peripheral nerve conduction was normal in the arm (median and ulnar digital sensory nerve action potentials and compound action potentials). Median and ulnar somatosensory evoked potentials were normal on both sides. The normal sensory neurophysiological results support the conclusion that low cervical sensory conduction was normal. The results were compatible with a neuropathic process affecting the nerves to cervical muscles but involve-
469
ment of trapezius and the vocal cord palsy suggested a more widespread involvement. There was no evidence of a more distal brachial plexopathy.
Discussion
This patient presented with a radiation-induced peripheral neuropathy, a complication usually only seen after radiation doses greater than 60 Gy, although there appears to be an increased risk with lower doses where fraction sizes greater than 2 Gy are used [4]. Although cervical neuropathy has not been reported, brachial plexus neuropathy has been reported in two patients as a late complication of mantle radiotherapy to 40 Gy. Both patients had received vinca alkaloids on relapse, which may have contributed to their neurological damage [5]. Dosimetric studies of the mantle technique have been performed, measuring actual dose received at various points in the treatment field. A study by Cilliers used thermoluminescent dosimetry and a RANDO phantom to look at various techniques [6]. Using a similar technique as our patient, treating with a cobalt-60 unit, turning the patient over between fields and using personalized lung blocks, 2 Gy was prescribed at mid-plane on the central axis. The actual dose measured on the neck was 2.84 Gy3.7%. Using the linear-quadratic equation, and assuming an alpha:beta ratio for peripheral nerve of 2 Gy, it can be calculated that the cervical peripheral nerve would have received a biologically equivalent dose of 68.7 Gy in 2 Gy fractions, if 40 Gy was prescribed at mid-plane on the central axis. This may explain the significant late tissue effects seen. Dosimetry can, however, be considerably improved using compensators to adjust for the smaller separation over the neck. Dosimetry was further improved using a 6 MV linear accelerator rather than a cobalt-60 unit. A similar multicentre dosimetry study of the mantle technique was performed in Australia and New Zealand, which suggested that all centres should adopt dose compensation as a standard technique [7], although many centres still do not routinely use tissue compensators in such patients. Despite poor dose homogeneity with this technique, cervical neuropathy is clearly still rare. In this patient there may have been a greater than average difference between the mid-plane and neck separations leading to a higher radiation dose in the neck. She may also be abnormally sensitive to radiation although there is little other evidence to support this. When discussing late complications it is appropriate to re-address the radiation dose used to treat Hodgkin’s lymphoma. Standard doses currently used to treat involved sites of disease vary between 36 and 44 Gy. Moody and Williams have reviewed the literature and found that there is little scientific basis to support the use of such a relatively high dose [8]. Their conclusions were
470
Fig. 1 – Wasted posterior neck muscles 22 years after mantle radiotherapy.
that 32.5 Gy should be adopted as a standard radiation dose as there was no evidence to suggest a dose response above this. This dose may reduce long-term side-effects and is unlikely to impact on local disease-free survival or to reduce overall survival because of the effectiveness of salvage chemotherapy. It appears therefore, that our patient developed a cervical peripheral neuropathy as a result of mantle radiotherapy using standard techniques and dosage in 1972. In many centres there has been little change to the technique or dosage used over the last 30 years and it is therefore possible that we may see others presenting with such late neurological complications. In order to improve such profound long-term morbidity optimal radiotherapy techniques should be used including tissue compensation, reduced radiation dose and treatment volume reduction, with the use of combination chemotherapy to prevent the long-term sequelae of radiotherapy.
471
References 1 Hoppe RT. Radiation therapy in the management of Hodgkin’s disease. Semin Oncol 1990;17:704–715. 2 Mauch P. Controversies in the management of early stage Hodgkin’s Disease. Blood 1994;83:318–329. 3 Horning SJ, Williams J, Bartlett NL, et al. Assessment of the Stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkin’s disease: Eastern Cooperative Oncology Group pilot study E1492. J Clin Oncol 2000;18:972–982. 4 Gillette EK, Mahler PA, Powers BE, et al. Int J Radiat Oncol Biol Phys 1995;31:1309–1318. 5 Wadd NJ, Lucraft HH. Brachial plexus neuropathy following mantle radiotherapy. Clin Oncol 1998;10:399–400. 6 Cilliers GD, Cilliers C, Browde S. A study of the mantle technique for Hodgkin’s disease using thermoluminescent dosimetry. Radiother Oncol 1987;10:321–326. 7 Amies C, Rose A, Metcalfe P, et al. Multicentre dosimetry study of mantle treatment in Australia and New Zealand. Radiother Oncol 1996;40:171–180. 8 Moody AM, Williams MV. Radiation dose in Hodgkin’s disease: are we overtreating? Clin Oncol 1997;9:15–57.