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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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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-
W: Cancer
CANCER June 1, 1997 / Volume 79 / Number 11
grams and extramural institutions call for a more focused and selective role for the NCAB.
Although part of the mission of the NCAB in 1971
was to help establish a course for the NCI in the face
of a dearth of knowledge and expanding resources,
one of the most important roles for the NCAB today
is to maintain the needed oversight to keep the NCI
on course and to advise when the course itself needs
Thus, part of the NCAB’s role in recent years has
been to be an integral, if not leading player, in major
reviews of the Institute. For example, the NCAB, under
Dr. Paul Calabresi’s leadership, produced the Subcommittee to Evaluate the National Cancer Program (SENCAP) report, with major recommendations regarding
directions for the national cancer program. Dr. Michael Bishop and Dr. Calabresi nimbly led a major
review of the intramural program at NCI, which resulted in a landmark report leading to substantial
changes in the intramural program, a program that
now is stronger than ever. The Board, led by Ms. Zora
Brown, Dr. Charles Wilson, and others, took leadership
in hosting a conference on minority recruitment and
retention to clinical trials and worked with NCI staff
to create a guide that has been distributed throughout
the country as well as an initiative to provide money
for regional conferences to address unique local or
regional needs. The Board asked for a review of behavioral research at the NCI and participated actively in
both a conference that was held and in making subsequent recommendations. Board members are serving
as members of all the working groups and review
groups constituted by Dr. Klausner to review major
aspects of the NCI and its programs. After each of
these reviews, the Board will participate in issues of
implementation, just as it is doing for the first of these
reports, the one on cancer centers, and in late winter
1997, the NCAB led the process that resulted in NCI’s
revised mammography recommendations.
Yes, the role is different but no less important or
needed than the earlier Board role in program initiation. The evolution of the NCAB’s role is highly appropriate considering the progress and maturity of our
collective efforts against cancer over this period. As an
example, the remarkable discoveries in cancer biology
and cancer genetics could barely have been imagined
in 1971.
Dr. Lawrence observed that the secondary review
role of the NCAB has become perfunctory and suggested that perhaps it is no longer needed or could be
done by another group. He also questioned the ability
of current members, especially those without scientific
training, to perform secondary review. It would be up
to Congress to determine whether the law charging
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advisory councils with this function should be
changed. I, for one, do not believe there is a more
appropriate group to perform the review, and the current NCAB takes the secondary review function very
seriously. However, the task has grown dramatically
in the years since the Act was passed. For example, in
fiscal year 1972, there were 322 competing RO1
awards; in 1996, there were 771 awards, comprised of
670 RO1s and 101 R29 awards. This gives some idea
of the magnitude of growth. Members continuously
evaluate how best to do secondary review in the face
of continued growth in the number of applications
reviewed every year. Most recently, increased focus
and attention have been given to highlighting those
applications with scores around and just beyond the
expected paylines, to search for those applications that
might have special relevance to the NCI, and for cases
in which administrative remedies might be identified
to prevent ongoing productive research programs
from undergoing disruption.
Dr. Lawrence may have forgotten that Congress,
in its wisdom, never intended that the NCAB or other
Advisory Council simply apply the same criteria to applications as primary review panels. It is true that the
nonscientific members do not review the grants as
scientists; they cannot. It is their expertise as nonscientists that is brought to bear in the review. However,
I have been impressed with the diligence of their reviews, and the fact that they often ask insightful, valuable questions that lead to appropriate discussion of
concerns. It is the responsibility of the initial review
groups to conduct scientific review. The NCAB function is one of oversight and, occasionally, asking
broader questions about applications. The legislation
mandates a mix of scientific and nonscientific appointments. I believe this diversity is healthy and, ultimately, results in appropriate review. It is part of a
much more open, inclusive, multidisciplinary process
that characterizes the best science today.
Similarly, Dr. Lawrence questioned the credentials
of recent appointments. Not wishing to denigrate the
impressive membership of the first Board, I nevertheless would call attention to certain facts. The current
Board has two Nobel Prize winners, two current directors and a former head of cancer centers, and the President and CEO of a pharmaceutical company with a
major interest in cancer therapies, along with outstanding scientific leaders in epidemiology. This is in
addition to other excellent members known for their
accomplishments in clinical research and excellent
nonscientific members who contribute their expertise
from the business community and from years of
involvement in the cancer enterprise. An examination
of the photograph of the earlier Board that was con-
W: Cancer
tained in the same issue of Cancer shows how different
the Boards were then and now. The current Board is
much more diverse in race, gender, and age. That, too,
reflects the times. Something may have been lost, but,
I believe, much more has been gained. Certainly, as
Dr. Lawrence noted, vigilance is required to make certain that the best appointments are made. The issue
of how to assure outstanding appointments is a critical
one, especially given the various channels through
which nominations occur, and the fact that appointments ultimately are made by the President.
Dr. Lawrence suggested that the NCAB should be
more involved in developing broad scientific policy.
At the recent retreat and subsequently, we have been
examining the appropriate role of the NCAB in policy.
There is little disagreement that this is important, but
most of us would probably agree that this needs to be
policy qua the NCI, not all cancer activities in the U.S.
This larger role, to which Dr. Lawrence alluded, is simply too big for one group or even one Institute to
manage on a four meetings per year schedule in addition to other responsibilities. In addition, the President’s Cancer Panel has been expected to play a major
role in cancer policy. The NCAB has no desire to usurp
that role although we have a strong commitment to
collaborate with the Panel. Most recently, a National
Cancer Policy Board has been established to play a
role in larger issues of cancer policy. How the activities
of the Policy Board and the NCAB will intersect still
remains to be seen.
Dr. Lawrence wrote that the NCAB role of late has
been to provide outside support for the bypass budget
rather than playing a significant role in development
or presentation. This is not accurate. In recent years,
the NCAB expressed its concern regarding the format
and content of the bypass presentation. Under the
leadership of Dr. Ellen Sigal, of the Board, a number
of recommendations were made to Dr. Klausner to
streamline and refocus the bypass report. NCAB members worked side by side with NCI staff and were integrally involved in all facets of the latest and much
improved bypass document, and are already at work
on the next one. Although consensus will never be
universal on all priorities, the Board is proud of its role
and will undoubtedly exercise its option of continuing
discussion of bypass issues as a regular part of its
Dr. Lawrence also recommended that the NCAB
be more involved in presentation of the budget. Although we would welcome the opportunity to meet
with the President and his staff, we also recognize the
largely ceremonial value of such events. The bypass
budget is not only for the President; it is also an educational tool for Congress, the many cancer-concerned
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organizations, and the interested public, and the
NCAB plays an important role in interfacing with these
Finally, Dr. Lawrence argued that the NCAB
needs to function more as a Board of Directors, with
the additional task of reviewing the Director. Again,
this is not how Congress has conceived Institute
Councils and the NCAB. According to the legislation, the councils ‘‘advise, assist, consult with and
make directions to the Secretary and the Institute
Director.’’ That means that an effective, collaborative and collegial relationship with the Director is
essential. That does not mean mindless obeisance.
There is always a tension between the oversight responsibility and the advise/assist roles of NIH
councils. Dr. Varmus has established guidelines for
the review of Institute Directors, and has made it
plain that this is to be done on a regular basis. However, the NCI is not a corporation, and the NCAB
is not a Board of Directors in the classic sense. The
fact that advisory is part of the name is no accident.
Parenthetically, recent discussions in the press
have questioned whether corporate Boards of Directors any longer have the intimate knowledge of
organizations needed to perform their intended
Today’s NCAB is different from the first NCAB.
Twenty years from now, the times will be different
and so should the Board. That is a sign of the vibrancy of our scientific enterprise and of the times.
I am grateful to you and the other scientific and
public leaders who have contributed so much of
their time to so important an effort.
Lawrence W Jr. The National Cancer Advisory Board: 25
years later. Cancer 1996;78:2603–6.
Barbara K. Rimer, Dr.P.H.
National Cancer Advisory Board
National Cancer Institute
National Institutes of Health
Bethesda, Maryland;
Professor, Community and Family Medicine
Duke University Medical Center
Durham, North Carolina
Author Reply
have been asked to respond to Dr. Rimer’s letter,
which expresses a number of her concerns regard-
W: Cancer
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