Skin ulceration potential of paclitaxel in a mouse skin model in vivo (1997)

We have read with interest the recently published article by R. T. Dorr et al.1 about the skin ulceration potential of paclitaxel in a mouse skin model. Taxanes are increasingly being used in the treatment of a variety of solid tumors; soft tissue injury in patients with paclitaxel extravasation has been described,2, 3 but no official recommendation for antidotal treatment has been formulated so far. For other cytotoxic drugs that are irritants or vesicants, recommendations for the use of antidotes after extravasations are largely based on animal studies.4, 5 Only few prospective clinical studies on this subject have been published.6 Hyaluronidase, an enzyme that increases the absorption of locally injected drugs by degrading hyaluronic acid, is recommended as an antidote after extravasation of the Vinca alkaloids vincristine and vinblastine; this recommendation is essentially based on the results obtained in the same mouse skin model.7 Therefore, the recent article by Dorr et al., which reports that intradermal administration of hyaluronidase diluted in saline immediately after an experimental paclitaxel extravasation in the mouse was an effective antidotal manoeuvre,1 may have an impact on daily clinical practice, and we would like to contribute information on the same subject by making a small but encouraging clinical observation. Based on our positive experience using hyaluronidase after Vinca alkaloid extravasations,8 since 1995 we have also been using this antidote after extravasation of taxanes. This practice gave us the opportunity to gather clinical data on seven patients, all of whom seemed to benefit from the manoeuvre. Hyaluronidase (250 units diluted in 6 mL normal saline) was injected subcutaneously into and around the extravasation site with a 25-gauge needle; no hot or cold packs were applied to the site. Five patients had extravasations during the infusion, in a peripheral vein of the forearm, of a solution of paclitaxel diluted in 1 L of normal saline. The final drug concentrations administered to the patients equalled 0.18, 0.195, 0.24, 0.25, and 0.315 mg/mL, respectively. The patients were followed for a median of 21 weeks (range, 10-47 weeks) after the administration of hyaluronidase. In all five of them, local symptoms of extravasation (pain, swelling, and erythema) subsided without the need for further treatment. Two of the patients repeated paclitaxel administration for one more cycle and one patient for three more cycles, in all cases without any observed reaction at the site of previous extravasation. Two other patients had extravasations of docetaxel, which was diluted in 250 mL of 5% dextrose in water and infused over 1 hour into a peripheral vein of the forearm at final concentrations equal to 0.78 and 0.64 mg/mL, respectively. In the first patient, all local symptoms disappeared rapidly, and no skin ulceration was evident until his death of disease progression 8 weeks later. In the second patient, pain, swelling, erythema, and hypoesthesia at the site of extravasation were still evident 1 week after the extravasation (Fig. 1) but slowly subsided in the following days. Three weeks after the extravasation, the patient received another course of docetaxel. After another nine weeks, a nearly complete resolution of local symptoms was documented, with slight dyscromia and hypoesthesia still present (Fig. 2). No ulceration or tissue necrosis occurred during the rest of the follow-up of the patient (a total of 17 weeks). The forearm of Patient 7 from case series is shown. An extravasation of docetaxel occurred during infusion through a peripheral vein of the forearm. This photograph was taken 1 week after the extravasation, when local symptoms (pain, swelling, and erythema) were at their maximum. Hyaluronidase (250 units diluted in normal saline) had been administered subcutaneously as an antidote immediately after the extravasation. The forearm of Patient 7 is shown again, in a later photograph. With no further treatment, the extravasation became resolved without progression to skin necrosis. This photograph was taken 12 weeks after the event, when only slight dyscromia and hypoesthesia were present. Considering the increasing use of paclitaxel and docetaxel in oncology, the need to prevent soft tissue injury after an extravasation may arise relatively frequently. In the future, prescription information regarding these drugs could incorporate the recommendation of using hyaluronidase diluted in saline as a safe, well-tolerated, and probably beneficial antidote. Prompt administration of hyaluronidase, which would absorb extravasated drug from the tissues, would also likely have the additional advantage of preventing possible late "recall" ulceration after further systemic administration of the drug as reported in recent years for paclitaxel.9-11 Although of limited extent, our case series supports the experimental data of R. T. Dorr et al.1 The results may be considered encouraging, as none of the patients had skin ulceration after the extravasation of taxanes or suffered recall reactions when exposed to repeated administrations of the same cytotoxic agent. Gianfilippo Bertelli M.D., Mara A. Cafferata M.D., Andrea Ardizzoni M.D., Alberto Gozza M.D., Riccardo Rosso M.D., Dario Dini M.D.