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Comparison of Efficacy of Intralesional Bleomycin and Oral Propanolol in Management of Hemangiomas

Thayal, Piyush Kumar D.N.B.; Bhandari, Padam Singh M.Ch.; Sarin, Yogesh Kumar M.Ch.

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Plastic and Reconstructive Surgery: April 2012 - Volume 129 - Issue 4 - p 733e-735e
doi: 10.1097/PRS.0b013e318245e739
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Sir:

Figure
Figure

The management of hemangiomas has been the subject of much debate ranging from “masterful neglect” to therapeutic intervention either as a pharmacotherapy, radiologic intervention, or surgical resection. Recently, Léauté-Labrèze1 reported β-blockers as a surprise in the management of infantile hemangiomas. The objective of this study was to evaluate the efficacy of oral propranolol, to evaluate the efficacy of intralesional bleomycin injection, and to compare the efficacy of both.

Children aged 6 months to 5 years with cutaneous hemangioma as defined by the International Society for the Study of Vascular Anomalies24 and with no known systemic disorders were included in the study. Children with deep-seated hemangiomas and orbital hemangiomas and those who received some form of treatment earlier were excluded.

Twenty patients were enrolled in this prospective study and divided equally into two groups: group A, those treated with intralesional bleomycin injection; and group B, those treated with propranolol given by the oral route. Laboratory investigations, hemogram, routine urine, and microscopy were recorded. In group A, liver function tests were recorded in addition to the above investigations.

In group A, the patients received intralesional bleomycin injections at a dose of 0.5 mg/kg body weight. A total of three injections were given at intervals of 6 weeks under general anesthesia. Clinical photographs were taken on day 0 before the start of treatment and just before every injection. After 5 months of management, the patients were declared to have completed the therapy. No further injections were given, even if it was necessary so as to have uniformity with group B. In group B, propranolol was administered for 6 weeks according to the schedule in Tables 1 and 2.

Table 1
Table 1:
Propranolol Dosage Schedule Used in the Study
Table 2
Table 2:
Response to Propranolol

Children were monitored for bradycardia, hypotension, and clinical features of hypoglycemia (i.e., lethargy, restlessness). The patients were photographed on day 0, day 5, and day 7; the end of weeks 2, 3, 4, 5, and 6; and during monthly follow-up visits for 5 months.

The efficacy of propranolol was evaluated for regression in the size of the lesion, change in the color of the lesion, epithelialization in case of ulceration, subsidence of pain, complications following therapy, and signs of relapse after therapy. The outcome based on regression in size was graded as follows:

  1. Complete involution, implying greater than 90 percent response.
  2. Response of reduction in size of 75 to 90 percent.
  3. Response of reduction in size of 50 to 75 percent.
  4. Response of reduction in size of 25 to 50 percent.
  5. Response of reduction in size less than 25 percent.

Of 20 patients, five were boys and 15 were girls. Overall, half of the patients enrolled were infants. In group A, 70 percent of the patients were older than 1 year, whereas in group B, 70 percent of the patients were infants.

In group A, the dose of bleomycin administered ranged from 3 to 12 mg. Of the 10 patients, seven received three injections at an interval of 6 weeks and three had a single dose of intralesional bleomycin injection (two patients were lost to follow-up and one child did not require a second dose because of response grade I). The response to intralesional bleomycin injection was noted just before the next dose.

One patient had a grade I response, five had a grade II response, and two had a grade III response at the end of 5 months. Complications noted were febrile episode, superficial ulceration, and raised alkaline phosphatase in 50 percent. In group B, the response was noted in all patients within the first week, with varying degrees of response and with the most common improvement being change in the color of the lesion.

All patients had a decrease in size of the lesion of up to 25 percent by the first week. By the end of the second week, three patients had 60 to 65 percent reduction in the size and six patients had reduction in the size of lesion of up to 50 percent. By the end of the 5 months, two had complete response (grade I) and four had a size reduction of up to 85 to 90 percent, three had a decrease in size by 50 to 75 percent, and one had a 40 to 50 percent size reduction (Figs. 1 and 2). No complications were observed. Further improvement was noted in the size reduction of the lesion during the follow-up, but the change was within the same response grade. Two had an increase in size noted during the third and fourth months of follow-up.

Fig. 1
Fig. 1:
Patient 1 before treatment.
Fig. 2
Fig. 2:
Patient 1 at 4-month follow-up.

The propranolol therapy was completed by the time patients in group A received the second dose of bleomycin. The response obtained by 6 weeks with propranolol therapy was far better than the response in those treated with bleomycin. At the end of 5 months, 62.5 percent of patients had a grade II response in group A, whereas 60 percent of patients in group B had a grade II response. In group B, size reduction was more than 85 percent in comparison with group A, where the response was up to 80 percent.

  • A 75 percent reduction in the size of the hemangioma was achieved with three injections administered at 6 weekly intervals in comparison with other series (i.e., Pienaar et al.5 and Omidvari et al.6) that reported similar results with an average of four intralesional injections administered at an interval of 3 weeks.
  • Raised serum alkaline phosphatase was noted in our study, in contrast to other studies where liver function tests remained normal.
  • There was no other drug added along with propranolol, and no child had received any other treatment previously. This is in contrast with the rest of the studies, where duration of therapy had been greater than 5 months. In all studies,710 patients had received prednisolone along with the propranolol. We had achieved a good result with shorter duration of propranolol therapy without a combination of drugs in comparison with others.
  • A comparative analysis between the two groups did highlight the efficacy of propranolol in the management of the hemangiomas with a shorter duration of therapy and slightly better response in achieving up to 90 percent regression of the lesion in comparison with the intralesional bleomycin injection.

We would like to propose that propranolol be the choice of pharmacotherapy in the management of hemangiomas, provided that the safety profile of the propranolol is well established because:

  1. Complete regression of the lesion can be achieved if given during the proliferative phase, even with shorter duration of therapy.
  2. Oral propranolol does not require any anesthesia and requires monitoring only for the initial few doses.
  3. Bleomycin, which is the second line of therapy, also likely ranks behind propranolol, as evident from our study, but needs to be established after a larger, age-matched, randomized controlled trial.

The nonrandomized method of our study has been the only limitation to ascertain the complete comparison of the drugs in early infancy, and a long-term randomized controlled study would be helpful for ascertaining our findings of propranolol being better than other drugs.

Piyush Kumar Thayal, D.N.B.

Padam Singh Bhandari, M.Ch.

Department of Burns and Plastic Surgery

Yogesh Kumar Sarin, M.Ch.

Department of Pediatric Surgery, Lok Nayak Hospital and, Maulana Azad Medical College, New Delhi, India

DISCLOSURE

There was no funding for this study. The authors received no financial benefit for the use of the drugs mentioned, which are freely available in the hospital drug supply.

REFERENCES

1. Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649–2651.
2. Enjolras O, Mulliken JB. Vascular tumors and vascular malformations (new issues). Adv Dermatol. 1997;13:375–423.
3. Blei F. Basic science and clinical aspects of vascular anomalies. Curr Opin Pediatr. 2005;17:501–509.
4. Enjolras O, Wassef M, Chapot R. Introduction: ISSVA Classification. Color Atlas of Vascular Tumors and Vascular Malformations. New York: Cambridge University Press; 2007:1–13.
5. Pienaar C, Graham R, Geldenhuys S, Hudson DA. Intralesional bleomycin for the treatment of hemangiomas. Plast Reconstr Surg. 2006;117:221–226.
6. Omidvari S, Nezakatgoo N, Ahmadloo N, Mohammadianpanah M, Mosalaei A. Role of intralesional bleomycin in the treatment of complicated hemangiomas: Prospective clinical study. Dermatol Surg. 2005;31:499–501.
7. Bonifazi E, Colonna V, Mazzota F, Balducci G, Laforgia N. Propranolol in rapidly growing hemangiomas. Eur J Pediatr Dermatol. 2008;18:185–192.
8. Sans V, de la Roque ED, Berge J, et al. . Propranolol for severe infantile hemangiomas: Follow up report. Pediatrics 2009;124:e423–e431.
9. Arneja JS, Pappas PN, Shwayder TA, et al.. Management of complicated facial hemangiomas with beta blocker (propranolol) therapy. Plast Reconstr Surg. 2010;126:889–895.
10. Truong MT, Chang KW, Berk DR, Heerema-McKenney A, Bruckner AL. Propranolol for the treatment of a life-threatening subglottic and mediastinal infantile hemangioma. J Pediatr. 2010;156:335–338.

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