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CANCER June 1, 1997 / Volume 79 / Number 11
ing, 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).
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.
Dorr RT, Snead K, Liddil JD. Skin ulceration potential of
paclitaxel in a mouse skin model in vivo. Cancer 1996;
Bicher A, Levenback C, Burke TW, Morris M, Warner D,
Dejesus Y. Infusion site soft-tissue injury after paclitaxel administration. Cancer 1995;76:116–20.
Ajani JA, Dodd LG, Daugherty K, Warkentin D, Ilson DH.
Taxol-induced soft-tissue injury secondary to extravasation:
characterization by histopathology and clinical course. J
Natl Cancer Inst 1994;86:51–3.
Dorr RT. Antidotes to vesicant chemotherapy extravasations.
Blood Rev 1990;4:41–60.
Bertelli G. Prevention and management of extravasation of
cytotoxic drugs. Drug Saf 1995;12:245–55.
Bertelli G, Gozza A, Forno GB, Vidili MG, Silvestro S, Venturini M, et al. Topical dimethylsulfoxide for the prevention
of soft tissue injury after extravasation of vesicant cytotoxic
drugs: a prospective clinical study. J Clin Oncol 1995;
Dorr RT, Alberts DS. Vinca alkaloid skin toxicity: antidote
and drug disposition studies in the mouse. J Natl Cancer
Inst 1985;74:113–20.
Bertelli G, Dini D, Forno GB, Gozza A, Silvestro S, Venturini
M, et al. Hyaluronidase as an antidote to extravasation of
Vinca alkaloids: clinical results. J Cancer Res Clin Oncol
Shapiro J, Richardson GE. Paclitaxel-induced ‘‘recall’’ soft
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tissue injury occurring at the site of previous extravasation
with subsequent intravenous treatment in a different limb.
J Clin Oncol 1994;12:2237–8.
10. Mechan JL, Sporn JR. Case report of taxol administration
via central vein producing a recall reaction at a site of prior
taxol extravasation. J Natl Cancer Inst 1994;86:1250–1.
11. Du Bois A, Kommoss FGM, Pfisterer J, Luck HJ, Meerpohl
HG. Paclitaxel-induced ‘‘recall’’ soft tissue ulcerations occurring at the site of previous subcutaneous administration
of paclitaxel in low doses. Gynecol Oncol 1996;60:94–6.
Gianfilippo Bertelli, M.D.
Mara A. Cafferata, M.D.
Andrea Ardizzoni, M.D.
Alberto Gozza, M.D.
Riccardo Rosso, M.D.
Divisione di Oncologia Medica 1
Istituto Nazionale per la Ricerca sul Cancro
Genova, Italy
Dario Dini, M.D.
Servizio di Riabilitazione Oncologica
Istituto Nazionale per la Ricerca sul Cancro
Genova, Italy
Author Reply
am pleased to offer the following comments regarding the report of Bertelli et al. on their clinical study
of hyaluronidase and taxane extravasation.
Bertelli et al. describe putative beneficial effects
of the use of subcutaneous hyaluronidase as a treatment for extravasations of the taxanes paclitaxel and
docetaxel in cancer patients.1 This group has previously provided clinical support for the use of the
preading factor enzyme in treating extravasations of
Vinca alkaloids.2 Their new findings with patients who
experienced inadvertent extravasation of paclitaxel
and docetaxel suggest that hyaluronidase may be useful in this setting. Obviously, the small number of patients treated and the different exposure risks in terms
of the dose and concentration of two different extravasated taxane solutions precluded an unequivocal conclusion about efficacy, as Bertelli et al. state. However,
because controlled studies in this area are notoriously
difficult, these findings have clinical importance and
are clearly compatible with the findings of our prior
animal trial.3
From the few cases of serious soft tissue damage
reported to date, taxane extravasations appear to require the delivery of relatively large amounts of fluid
and/or the exposure of subcutaneous tissues to highly
concentrated solutions for local ulceration to occur.
This is based on the demonstration in a large clinical
W: Cancer
data base that most extravasations of dilute paclitaxel
solutions do not cause serious soft tissue damage
when no local treatment is given.4 – 6 Similar findings
have been established with the more potent anthracycline-based vesicant, doxorubicin.7 Thus, the taxanes
comprise a class of ‘‘weak’’ vesicants, with local toxicity dependent on the subcutaneous delivery of relatively large amounts of the drugs. In this regard, the
taxanes differ significantly from both the anthracyclines and the Vinca alkaloids, which each can cause
extravasation necrosis after the leakage of small
amounts of subcutaneous solution.
The choice of hyaluronidase for treating taxane
extravasations does make pharmacologic sense in that
it should promote the local dilution of extravasated
solution and thereby lessen the risk of subsequent serious necrosis. The safety of such low doses of hyaluronidase is also clear; this agent has been used at much
higher dose levels systemically8 and is known to be
extremely well tolerated locally when used as an antidote for Vinca alkaloid extravasations.2 Thus, there is
very little to argue against using 150 – 250 units of hyaluronidase to treat taxane extravasations when there is
reason to believe a serious extravasation has occurred.
The current clinical findings of Bertelli et al., although
limited by the small number of patients, suggest that
hyaluronidase, without topical heating or cooling
(which did not work in the mouse model), should be
considered as a clinical treatment for large, inadvertent extravasations of the taxanes.
Bertelli G, Cafferata MA, Ardizzzoni A, Gozza A, Dini D,
Rosso R. Skin ulceration potential of paclitaxel in a mouse
skin model in vivo [correspondence]. Cancer 1997;79:2266–
Bertelli G, Dini D, Forno GB, Silvestro S, Venturini M, et
al. Hyaluronidase as an antidote to extravasation of Vinca
alkaloids: clinical results. J Cancer Res Clin Oncol 1994;
Dorr RT, Snead K, Liddil JD. Skin ulceration potential of
paclitaxel in a mouse skin model in vivo. Cancer 1996;
McGuire WP, Rowinsky EK, Rosenshein NB, Grumbine FC,
Ettinger DS, Armstrong DK, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian
epithelial neoplasms. Ann Intern Med 1989;111:273–9.
Murphy WK, Fossella FV, Winn RJ, Shin DM, Hynes HE,
Gross HM, et al. Phase II study of Taxol in patients with
untreated advanced non-small-cell lung cancer. J Natl Cancer Inst 1993;85:384–8.
Wiernik PH, Schwartz EL, Einzig A, Strauman JJ, Lipton RB,
Dutcher JP. Phase I trial of Taxol given as a 24-hour infusion
every 21 days: responses observed in metastatic melanoma.
J Clin Oncol 1987;5:1232–9.
Larson DL. Treatment of tissue extravasation by antitumor
agents. Cancer 1982;49:1796–9.
Maroko PR, Hillis LD, Muller JE, Tavazzi L, Heyndrickx GR,
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05-14-97 13:42:05
Ray M, et al. Favorable effects of hyaluronidase on electrocardiographic evidence of necrosis in patients with acute
myocardial infarction. N Engl J Med 1977;296:898–903.
Robert T. Dorr, Ph.D., R.Ph.
Pharmacology Research Program
Arizona Cancer Center
Tucson, Arizona
The National Cancer Advisory Board
25 Years Later
s Chair of the National Cancer Advisory Board
(NCAB), I was pleased that a recent issue of Cancer
focused on the 25th anniversary of the National Cancer Act. I was particularly interested in the distinguished Dr. Lawrence’s observations on the evolution
of the National Cancer Advisory Board.1 Dr. Lawrence
invoked the earlier days of the NCAB, and he expressed
concern that the Board had diminished in effectiveness. He identified several areas of potential NCAB
weakness, and I will address each of these, although
in a somewhat different order than his commentary.
Dr. Lawrence commented on the following topics: the
role of the NCAB in proactive planning, membership,
the NCAB’s role in secondary review, and its involvement in the bypass budget.
Let me assure Dr. Lawrence that no one is more
concerned with reviewing the performance of the
NCAB and its roles than the Board itself. To that end,
we devoted a Board retreat in June 1996 and a followup meeting in September to an examination of the
appropriate roles of the Board. We agreed that the
Board’s main roles are in several areas: secondary review of grants, budget and planning, stewardship, and
advisory oversight and advocacy. Each of these categories has been defined.
Different times call for different boards. The current National Cancer Institute (NCI) budget is more
than $2 billion higher than the budget in 1972. 1971
and the years that immediately followed were a time
of dramatic expansion at the NCI; the current era is
one of more modest growth in the face of increased
competition for all government dollars, and external
forces in academia and medicine that preclude massive new programs. And even if the budget were available, today’s philosophy at the National Institutes of
Health (NIH) relies much more on investigator-initiated rather than Institute-directed research. These
changes in the scope, magnitude, and maturity of pro-
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