- Email: [email protected]
Vincristine as a treatment for a large haemangioma threatening vital functions
The British Association of Plastic Surgeons (2004) 57, 168–171
CASE REPORT
Vincristine as a treatment for a large haemangioma threatening vital functionsq S.L. Fawcett, I. Grant, P.N. Hall, A.W.R. Kelsall, J.C. Nicholson* Addenbrooke’s NHS Trust, Cambridge, UK Received 25 March 2003; accepted 6 November 2003
KEYWORDS Haemangioma; Vascular anomaly; Vascular tumour; Vincristine
Summary We report the use of vincristine to treat a large steroid resistant haemangioma of the lower face and neck. At the time of treatment the lesion had shown no signs of involution. The haemangioma was not life threatening but extension within the mouth was associated with bleeding and ulceration, which was impairing feeding and speech development. A significant improvement was seen with vincristine treatment. Q 2004 The British Association of Plastic Surgeons. Published by Elsevier Ltd. All rights reserved.
Introduction
Case report
There are anecdotal reports of vincristine being used for the treatment of life-threatening, steroid resistant haemangiomas in cases associated with Kasabach-Merritt syndrome or thrombocytopenia.1 It has also been used for the treatment of haemangiomas causing respiratory distress.1,2 We report a case of the successful use of vincristine for a haemangioma that was not life threatening but was affecting the development of speech and impairing feeding. Administration of vincristine appeared to correct the impairment in speech and feeding caused by the haemangioma.
A baby girl, born at full term following a normal delivery, had no obvious abnormality at birth. The first signs of a cutaneous lesion were noticed at 1 week of age. At 5 weeks the child presented to hospital with a haemangioma in the beard distribution. A MRI scan performed at 2 months of age demonstrated an extensive haemangioma extending below both parotid glands, reaching the level of the mastoids bilaterally. The lesion extended into the parapharyngeal fat, posterior triangle of the neck and encroached upon the nasopharynx. The sternomastoid muscles were compressed bilaterally and displacement of the common carotid artery and internal jugular vein was reported unilaterally on the right. There was neither extension into the superior mediastinum nor any extension through the skull base. Feeding difficulties were encountered within a few weeks of imaging. Treatment with prednisolone was initiated and nasogastric feeding was required. Laser treatment was used for a small pre-auricular ulcerated area.
q This work has not been previously presented nor submitted elsewhere. The authors have not received any funding or other support for this work, and have no commercial interest in the products used. *Corresponding author. Address: Department of Paediatric Oncology, Box 181, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK. Tel.: þ44-1223-216-878; fax: þ 441223-586-794. E-mail address: [email protected]
S0007-1226/$ - see front matter Q 2004 The British Association of Plastic Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjps.2003.11.003
Vincristine as a treatment for a large haemangioma threatening vital functions
During the first year of life, multiple admissions were necessary for respiratory distress secondary to aspiration, high output cardiac failure and feeding difficulties. Steroid therapy continued and diuretic treatment was also required. At 8 months of age a gastrostomy tube was inserted because of persistent feeding difficulties. A second MRI scan was performed at 16 months of age (Fig. 1). This confirmed the clinical impression that the extent of the haemangioma had not changed, and steroids were therefore discontinued, after 8 months of treatment. Surgery was not thought to be a viable treatment option at this stage, based on the MRI findings. The possible role of vincristine was discussed but treatment was deferred in favour of further observation. Within 3 months there was no evidence for any spontaneous resolution, whilst troublesome bleeding and ulceration of the tongue continued to interfere with feeding and speech development was also affected. Therefore the decision was made to start vincristine. At 21 months of age once weekly doses of vincristine (1.5 mg/m2) were administered for four doses. Within two weeks of starting treatment, the child’s parents and clinicians noted a marked improvement in the clarity of speech. Feeding improved sufficiently for the gastrostomy tube to be removed after 4 weeks. There was a visible improvement in the external appearance of the lesion and the component of the lesion under the tongue was less engorged. No side effects attributable to vincristine were reported. Following the encouraging response, a further four doses of vincristine were given at 3-week intervals but these had less clinical impact than the initial
Figure 1 An MRI scan at 16 months of age. The haemangioma has not responded to 8 months of steroid therapy. It involves the tongue, encompasses the parotid glands and vascular structures within the neck and extends into the nasopharynx and infratemporal fossa.
169
course. Fig. 2 shows photographs taken before and after treatment with vincristine.
Discussion Haemangiomas present in the neonatal period, grow rapidly during infancy and regress slowly during childhood. During the growth phase, these lesions are characterised histologically by proliferating endothelial cells. For the majority of lesions, no treatment is needed beyond correct diagnosis and reassurance. There are circumstances when treatment is required. Bulky peri-orbital tumours can threaten development of binocular vision. High output cardiac failure may occur with large tumors and is particularly associated with hepatic haemangiomatosis. Life can be threatened by mass effects causing respiratory distress, particularly, in the case of subglottic tumors. Kasabach-Merrit syndrome is a consumptive coagulopathy, with thrombocytopenia and microangiopathic haemolytic anaemia, associated with haemangiomas, and carries a mortality rate of up to 40%.3 There are a variety of treatments reported for problematic haemangiomas requiring therapeutic intervention. Corticosteroids are the commonly accepted first line treatment, but satisfactory results are reported in only 30% of cases.4,5 Numerous side effects are reported with steroid treatment in infants, including irritability, hypertension, immunosuppression, growth retardation and osteoporosis. Most of these are reversible following cessation of treatment.5,6 The use of interferon alpha 2a has been widely reported for corticosteroid resistant haemangiomas but has been limited by the side effects. In the short term these include fever, neutropenia and anemia. Of greater concern is the development of neurotoxicity with up to 20% of cases treated with interferon alpha 2a developing a spastic diplegia.7,8 There has been a recent report of the use of radiotherapy in a steroid resistant case associated with Kasabach-Merritt syndrome that also failed to improve with interferon alpha 2a.9 A second case report has been published in which radiotherapy was successfully used in conjunction with interferon alpha 2a.10 Radiotherapy has been used widely for the treatment of non-life-threatening haemangiomas since before the 1960s. The side effects include scarring, skin atrophy, hyperpigmentation and permanent hair loss. In the long term growth retardation and radiation induced malignancies have also been recognised. For these
170
Figure 2 The child at 21 and 25 months before and after treatment with vincristine. Improvements in feeding and speech were more pronounced than changes in the appearance of the haemangioma.
S.L. Fawcett et al.
reasons radiotherapy has fallen out of favour as a treatment for haemangioma without severe life threatening coagulopathy.10 Other strategies that have been utilised, with varying degrees of success, include embolisation, surgery and sclerotherapy.5,11 None of these could have been applied safely or effectively to our case. The treatment of haemangiomas with vincristine has not been widely reported and has been restricted to cases with life-threatening complications that have failed to respond to steroids. There is considerable experience in the use of vincristine in the treatment of malignancies in adults and children, including an understanding of its safety and side effect profile. It has long been associated with acute neurotoxicity in adults manifesting as constipation, abdominal pain and ileus and also bone pain, particularly in the jaw.12 Neurotoxicity has also been reported in children but is usually mild. The differences between children and adults may relate to the pharmacokinetics of vincristine, which varies according to age.13 However, vincristine is a vesicant and caution needs to be exercised if given peripherally, due to the risk of extravasation. The treatment regimes for childhood malignancies are often prolonged, sometimes over two or more years. Despite this, there are no significant long-term risks associated with the use of vincristine in children.14 In this case a short course of just four doses produced a significant functional improvement and some cosmetic improvement without any side effects. The speed of improvement, particularly in relation to the total duration of the condition in this patient, was strongly suggestive of a response to vincristine, rather than a result of spontaneous involution or compensatory growth of the airways, leading to improved function. The dose of vincristine used was equivalent to that used routinely in the treatment of children with leukaemia and solid tumours, and the intervals between doses of 1 –3 weeks were also consistent with experience with treatment of malignancy. The total cumulative dose was small compared with standard regimens used against malignancies. Our case adds to the limited number of successful reports of vincristine treatment for haemangiomas. We have demonstrated that vincristine warrants consideration in cases with significant morbidity or potential impairment of normal childhood development even if this is not immediately life threatening, particularly when more traditional approaches, such as the use of steroids, have failed. The use of vincristine should be limited to administration under supervision of a paediatric oncologist in a specialist centre. Provided it is given in a
Vincristine as a treatment for a large haemangioma threatening vital functions
safe environment by professionals with appropriate experience, the use of vincristine is unlikely to lead to significant treatment related complications.
References 1. Perez J, Pardo J, Gomez C. Vincristine—an effective treatment of corticosteroid-resistant life-threatening infantile hemangiomas. Acta Oncologica 2002;41(2):197—9. 2. Moore J, Lee M, Garzon M, et al. Effective therapy of a vascular tumour of infancy with vincristine. J Pediatr Surg 2001;36:1273—6. 3. El-Dessouky M, Azmy AF, Raine PAM, Young DG. KasabachMerritt syndrome. J Pediatr Surg 1988;23(2):109—11. 4. Bartoshesky LE, Bull M, Feingold M. Corticosteroid treatment for cutaneous hemangiomas. How effective? Clin Pediatr 1978;17:625—38. 5. Enjolras O, Riche MC, Merland JJ, Escande JP. Management of alarming hemangiomas in infancy: a review of 25 cases. Pediatrics 1990;85:491—8. 6. Sadan N, Wolach B. Treatment of hemangiomas of infants with high doses of prednisolone. J Pediatr 1996;128:141—6. 7. Barlow CF, Priebe CJ, Mulliken JB, et al. Spastic diplegia as a
8.
9.
10.
11.
12. 13.
14.
171
complication of interferon alfa-2a treatment of hemangiomas of infancy. J Pediatr 1998;132:527—30. Grimal I, Duveau E, Enjolras O, Verrett JL, Ginies JL. Effectiveness and dangers of interferon-alpha in the treatment of severe hemangiomas in infants. Arch Pediatr 2000; 7(2):163—7. Frevel T, Rabe H, Uckbert F, Harms E. Giant cavernous hemangioma with Kasabach-Merritt syndrome; a case report and review. Eur J Pediatr 2002;161(5):243—6. Hesselmann S, Micke O, Marquardt T, et al. Kasabach-Merritt syndrome; a review of the therapeutic options and a case report of successful treatment with radiotherapy and interferon alpha. Br J Radiol 2002;75(890):180—4. Jackson IT, Carreno R, Potparic Z, Hussain K. Hemangiomas, vascular malformations and lymphovenous malformations: classification and methods of treatment. Plast Reconstr Surg 1993;91:1216—30. Arnold AM, Kelleher LH, Rendell SG, Levine MN. Acute vincristine neurotoxicity. Lancet 1985;9(8424):346. Crom WR, de Graaf SSN, Synold T, et al. Pharmacokinetics of vincristine in children and adolescents with acute lymphocytic leukemia. J Pediatr 1994;125(4):642—9. Kissen GDN, Wallace WHB. Long term follow up therapy based guidelines. The United Kingdom Children’s Cancer Study Group (UKCCSG). Late effects group; 1995.
CASE REPORT
Vincristine as a treatment for a large haemangioma threatening vital functionsq S.L. Fawcett, I. Grant, P.N. Hall, A.W.R. Kelsall, J.C. Nicholson* Addenbrooke’s NHS Trust, Cambridge, UK Received 25 March 2003; accepted 6 November 2003
KEYWORDS Haemangioma; Vascular anomaly; Vascular tumour; Vincristine
Summary We report the use of vincristine to treat a large steroid resistant haemangioma of the lower face and neck. At the time of treatment the lesion had shown no signs of involution. The haemangioma was not life threatening but extension within the mouth was associated with bleeding and ulceration, which was impairing feeding and speech development. A significant improvement was seen with vincristine treatment. Q 2004 The British Association of Plastic Surgeons. Published by Elsevier Ltd. All rights reserved.
Introduction
Case report
There are anecdotal reports of vincristine being used for the treatment of life-threatening, steroid resistant haemangiomas in cases associated with Kasabach-Merritt syndrome or thrombocytopenia.1 It has also been used for the treatment of haemangiomas causing respiratory distress.1,2 We report a case of the successful use of vincristine for a haemangioma that was not life threatening but was affecting the development of speech and impairing feeding. Administration of vincristine appeared to correct the impairment in speech and feeding caused by the haemangioma.
A baby girl, born at full term following a normal delivery, had no obvious abnormality at birth. The first signs of a cutaneous lesion were noticed at 1 week of age. At 5 weeks the child presented to hospital with a haemangioma in the beard distribution. A MRI scan performed at 2 months of age demonstrated an extensive haemangioma extending below both parotid glands, reaching the level of the mastoids bilaterally. The lesion extended into the parapharyngeal fat, posterior triangle of the neck and encroached upon the nasopharynx. The sternomastoid muscles were compressed bilaterally and displacement of the common carotid artery and internal jugular vein was reported unilaterally on the right. There was neither extension into the superior mediastinum nor any extension through the skull base. Feeding difficulties were encountered within a few weeks of imaging. Treatment with prednisolone was initiated and nasogastric feeding was required. Laser treatment was used for a small pre-auricular ulcerated area.
q This work has not been previously presented nor submitted elsewhere. The authors have not received any funding or other support for this work, and have no commercial interest in the products used. *Corresponding author. Address: Department of Paediatric Oncology, Box 181, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK. Tel.: þ44-1223-216-878; fax: þ 441223-586-794. E-mail address: [email protected]
S0007-1226/$ - see front matter Q 2004 The British Association of Plastic Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjps.2003.11.003
Vincristine as a treatment for a large haemangioma threatening vital functions
During the first year of life, multiple admissions were necessary for respiratory distress secondary to aspiration, high output cardiac failure and feeding difficulties. Steroid therapy continued and diuretic treatment was also required. At 8 months of age a gastrostomy tube was inserted because of persistent feeding difficulties. A second MRI scan was performed at 16 months of age (Fig. 1). This confirmed the clinical impression that the extent of the haemangioma had not changed, and steroids were therefore discontinued, after 8 months of treatment. Surgery was not thought to be a viable treatment option at this stage, based on the MRI findings. The possible role of vincristine was discussed but treatment was deferred in favour of further observation. Within 3 months there was no evidence for any spontaneous resolution, whilst troublesome bleeding and ulceration of the tongue continued to interfere with feeding and speech development was also affected. Therefore the decision was made to start vincristine. At 21 months of age once weekly doses of vincristine (1.5 mg/m2) were administered for four doses. Within two weeks of starting treatment, the child’s parents and clinicians noted a marked improvement in the clarity of speech. Feeding improved sufficiently for the gastrostomy tube to be removed after 4 weeks. There was a visible improvement in the external appearance of the lesion and the component of the lesion under the tongue was less engorged. No side effects attributable to vincristine were reported. Following the encouraging response, a further four doses of vincristine were given at 3-week intervals but these had less clinical impact than the initial
Figure 1 An MRI scan at 16 months of age. The haemangioma has not responded to 8 months of steroid therapy. It involves the tongue, encompasses the parotid glands and vascular structures within the neck and extends into the nasopharynx and infratemporal fossa.
169
course. Fig. 2 shows photographs taken before and after treatment with vincristine.
Discussion Haemangiomas present in the neonatal period, grow rapidly during infancy and regress slowly during childhood. During the growth phase, these lesions are characterised histologically by proliferating endothelial cells. For the majority of lesions, no treatment is needed beyond correct diagnosis and reassurance. There are circumstances when treatment is required. Bulky peri-orbital tumours can threaten development of binocular vision. High output cardiac failure may occur with large tumors and is particularly associated with hepatic haemangiomatosis. Life can be threatened by mass effects causing respiratory distress, particularly, in the case of subglottic tumors. Kasabach-Merrit syndrome is a consumptive coagulopathy, with thrombocytopenia and microangiopathic haemolytic anaemia, associated with haemangiomas, and carries a mortality rate of up to 40%.3 There are a variety of treatments reported for problematic haemangiomas requiring therapeutic intervention. Corticosteroids are the commonly accepted first line treatment, but satisfactory results are reported in only 30% of cases.4,5 Numerous side effects are reported with steroid treatment in infants, including irritability, hypertension, immunosuppression, growth retardation and osteoporosis. Most of these are reversible following cessation of treatment.5,6 The use of interferon alpha 2a has been widely reported for corticosteroid resistant haemangiomas but has been limited by the side effects. In the short term these include fever, neutropenia and anemia. Of greater concern is the development of neurotoxicity with up to 20% of cases treated with interferon alpha 2a developing a spastic diplegia.7,8 There has been a recent report of the use of radiotherapy in a steroid resistant case associated with Kasabach-Merritt syndrome that also failed to improve with interferon alpha 2a.9 A second case report has been published in which radiotherapy was successfully used in conjunction with interferon alpha 2a.10 Radiotherapy has been used widely for the treatment of non-life-threatening haemangiomas since before the 1960s. The side effects include scarring, skin atrophy, hyperpigmentation and permanent hair loss. In the long term growth retardation and radiation induced malignancies have also been recognised. For these
170
Figure 2 The child at 21 and 25 months before and after treatment with vincristine. Improvements in feeding and speech were more pronounced than changes in the appearance of the haemangioma.
S.L. Fawcett et al.
reasons radiotherapy has fallen out of favour as a treatment for haemangioma without severe life threatening coagulopathy.10 Other strategies that have been utilised, with varying degrees of success, include embolisation, surgery and sclerotherapy.5,11 None of these could have been applied safely or effectively to our case. The treatment of haemangiomas with vincristine has not been widely reported and has been restricted to cases with life-threatening complications that have failed to respond to steroids. There is considerable experience in the use of vincristine in the treatment of malignancies in adults and children, including an understanding of its safety and side effect profile. It has long been associated with acute neurotoxicity in adults manifesting as constipation, abdominal pain and ileus and also bone pain, particularly in the jaw.12 Neurotoxicity has also been reported in children but is usually mild. The differences between children and adults may relate to the pharmacokinetics of vincristine, which varies according to age.13 However, vincristine is a vesicant and caution needs to be exercised if given peripherally, due to the risk of extravasation. The treatment regimes for childhood malignancies are often prolonged, sometimes over two or more years. Despite this, there are no significant long-term risks associated with the use of vincristine in children.14 In this case a short course of just four doses produced a significant functional improvement and some cosmetic improvement without any side effects. The speed of improvement, particularly in relation to the total duration of the condition in this patient, was strongly suggestive of a response to vincristine, rather than a result of spontaneous involution or compensatory growth of the airways, leading to improved function. The dose of vincristine used was equivalent to that used routinely in the treatment of children with leukaemia and solid tumours, and the intervals between doses of 1 –3 weeks were also consistent with experience with treatment of malignancy. The total cumulative dose was small compared with standard regimens used against malignancies. Our case adds to the limited number of successful reports of vincristine treatment for haemangiomas. We have demonstrated that vincristine warrants consideration in cases with significant morbidity or potential impairment of normal childhood development even if this is not immediately life threatening, particularly when more traditional approaches, such as the use of steroids, have failed. The use of vincristine should be limited to administration under supervision of a paediatric oncologist in a specialist centre. Provided it is given in a
Vincristine as a treatment for a large haemangioma threatening vital functions
safe environment by professionals with appropriate experience, the use of vincristine is unlikely to lead to significant treatment related complications.
References 1. Perez J, Pardo J, Gomez C. Vincristine—an effective treatment of corticosteroid-resistant life-threatening infantile hemangiomas. Acta Oncologica 2002;41(2):197—9. 2. Moore J, Lee M, Garzon M, et al. Effective therapy of a vascular tumour of infancy with vincristine. J Pediatr Surg 2001;36:1273—6. 3. El-Dessouky M, Azmy AF, Raine PAM, Young DG. KasabachMerritt syndrome. J Pediatr Surg 1988;23(2):109—11. 4. Bartoshesky LE, Bull M, Feingold M. Corticosteroid treatment for cutaneous hemangiomas. How effective? Clin Pediatr 1978;17:625—38. 5. Enjolras O, Riche MC, Merland JJ, Escande JP. Management of alarming hemangiomas in infancy: a review of 25 cases. Pediatrics 1990;85:491—8. 6. Sadan N, Wolach B. Treatment of hemangiomas of infants with high doses of prednisolone. J Pediatr 1996;128:141—6. 7. Barlow CF, Priebe CJ, Mulliken JB, et al. Spastic diplegia as a
8.
9.
10.
11.
12. 13.
14.
171
complication of interferon alfa-2a treatment of hemangiomas of infancy. J Pediatr 1998;132:527—30. Grimal I, Duveau E, Enjolras O, Verrett JL, Ginies JL. Effectiveness and dangers of interferon-alpha in the treatment of severe hemangiomas in infants. Arch Pediatr 2000; 7(2):163—7. Frevel T, Rabe H, Uckbert F, Harms E. Giant cavernous hemangioma with Kasabach-Merritt syndrome; a case report and review. Eur J Pediatr 2002;161(5):243—6. Hesselmann S, Micke O, Marquardt T, et al. Kasabach-Merritt syndrome; a review of the therapeutic options and a case report of successful treatment with radiotherapy and interferon alpha. Br J Radiol 2002;75(890):180—4. Jackson IT, Carreno R, Potparic Z, Hussain K. Hemangiomas, vascular malformations and lymphovenous malformations: classification and methods of treatment. Plast Reconstr Surg 1993;91:1216—30. Arnold AM, Kelleher LH, Rendell SG, Levine MN. Acute vincristine neurotoxicity. Lancet 1985;9(8424):346. Crom WR, de Graaf SSN, Synold T, et al. Pharmacokinetics of vincristine in children and adolescents with acute lymphocytic leukemia. J Pediatr 1994;125(4):642—9. Kissen GDN, Wallace WHB. Long term follow up therapy based guidelines. The United Kingdom Children’s Cancer Study Group (UKCCSG). Late effects group; 1995.