A Randomized, Double-Blind, Placebo-Controlled Trial of
Transfer Factor as Adjuvant Therapy for Malignant Melanoma
LANGDON L. MILLER, MD,’rt$ LYNN E. SPITLER, MD,*.t-$ ROBERT E. ALLEN, MD,§
AND DAVID R. MINOR, MDt*$
One hundred and sixty-eight evaluable patients participated in a randomized, double-blind study of
transfer factor (TF) versus placebo as surgical adjuvant therapy of Stage I and Stage I1 malignant
melanoma. Eighty-five patients received TF prepared from the leukocytes of healthy volunteer donors;
eighty-three participants received placebo. Therapy was initiated within 90 days of resection of all
evident tumor and continued until 2 years of disease-free survival or the occurrence of unresectable
dissemination of melanoma. Known prognostic variables were similarly distributed in the treatment and
control groups, documenting the randomization efficacy. Three endpoints were analyzed: disease-free
interval, time to Stage 111 metastasis, and survival. After a median follow-up period of 24.75 months,
there was a trend in favor of the placebo group with regard to all three endpoints and this was significant
(P 5 0.05) for time to Stage I11 metastasis. These findings indicate that TF is not effective as surgical
adjuvant therapy of malignant melanoma.
Cancer 61 :1543-1549, 1988.
D level, in conjunction with other factors of disease
stage, patient sex, and primary tumor location, make
possible predictions of considerable accuracy regarding
the eventual course of malignant melanoma.’ Beyond
surgical removal of obvious tumor, however, little can
be done to improve the prognosis for patients at high
risk for tumor recurrence.2 Adjuvant chemotherapy has
proved ineffective and has demonstrated considerable
ETERMINATIONS OF primary tumor thickness and
Presented in part at the International Symposium on Immunoactive
Products in Oncology and Persistent Viral Infections, Bologna, Italy,
From the *Paul M. Aggelar Memorial Laboratory and the ?Depart-
ment of Medicine, Children’s Hospital of San Francisco, San Fran-
cisco, and the Departments of $Medicine and §Surgery, University of
California Medical Center, San Francisco, California.
Supported by the Melanoma Research Fund of Children’s Hospital,
a private fund comprised of generous contributions from patients,
their friends, and family members.
The authors thank Drs. B. William Brown and Kenneth Resser for
assistance in the statistical analysis of the data; Christopher O’Connor
for review and tabulation of the patient clinical information; Dr. Rich-
ard Sagebiel for interpretation of the pathology of the primary mela-
noma biopsies; the other members of the Melanoma Consulting
Board; Drs. Thomas Drake and Andrew Kneir for assistance in the
care of these patients; the numerous clinical fellows who also partici-
pated in the care of the patients; Drs. Randolph Lippert, Julio Pineda,
and Charles Scott; the physicians who referred patients for study par-
ticipation and took responsibility for their primary care; Christine
Suquet for technical assistance; and the many patients who were will-
ing to help in the assessment of this investigational therapeutic
Address for reprints: Lynn E. Spitler, MD, Biotherapeutics, Suite
201, 2220 Livingston, Oakland, CA 94606.
Accepted for publication August 25, 1987.
in melanoma management.5 As a result, emphasis has
continued to be placed on the development of an effec-
tive, nontoxic, therapeutic adjunct to surgery in order to
suppress the growth of the residual, microscopic tumor
metastases which account for disease recurrence and
Malignant melanoma has been considered a disease
well suited to immunotherapeutic intervention based on
the postulate that it represents a particularly immuno-
genic tumor. Histologic regression within primary mela-
nomas has been noted to occur in as many as 16% of
cases6; an associated dense lymphocytic infiltrate is
often present within regressing tumor^.^ Spontaneous
regression of widespread disease has also been docu-
mented,* it having been estimated that melanoma ac-
counts for 15% of reported regressions of malignancies,
though it represents only 1% to 3% of cancers.’ The
regional waxing and waning of subcutaneous mela-
nomas in patients with limited disease, and the ex-
tremely slow progression of disease in certain individ-
uals is well known.” Though proof of immune mecha-
nisms has been lacking, these unusual but significant
findings have been attributed to host immune respon-
siveness or changes in host immunologic status (brought
on by concurrent infection, for example’). Further sup-
port for immunotherapy of melanoma is provided by
the intradermal and lymphatic locations of the disease,
locations ideal for attempts at cellular immune modula-
Adjuvant radiation therapy has a limited role
FOR MELANOMA - Miller et aZ.
essary to determine whether or not TF really influences
the outcome adversely in patients with melanoma; pre-
sumably a true TF effect would have persisted and
would have induced a statistically significant survival
difference whereas adventitious findings would have
been negated by randomization of larger numbers of
patients to both study arms. However, the obvious lack
of TF benefit demonstrated by the results made continu-
ation of the trial in order to resolve this question unjus-
In summary we conclude that TF has no role in the
management of malignant melanoma and that efforts to
develop beneficial treatment for this disorder should
pursue other approaches.
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