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
CANCER April 15 1988
Transfer factor (TF) is a dialyzable extract from the
disrupted peripheral lymphocytes of an antigen-sensi-
tized donor which can passively confer cell-mediated
immunity upon an unimmunized recipient. First de-
scribed in 1955,” TF has since been characterized as a
low molecular weight (less than 12,000 daltons), non-
immunogenic substance with both antigen-dependent
and -independent actions on macrophages and lympho-
cytes.I2 Attempts to employ these effects practically has
led to the use of TF as an antitumor agent. Our prelimi-
nary studies suggested that transfer factor might be ef-
fective as adjuvant therapy for melanoma patients,13 in-
cluding those with surgically resectable lung metas-
tases.14 Its adjuvant use also was supported by the
favorable results of a nonrandomized, historically con-
trolled trial of transfer factor in high-risk Stage I mela-
noma, reported by Blume and coworkers.15
These considerations led us to undertake a random-
ized, double-blind, placebo-controlled trial of TF as ad-
juvant therapy in malignant melanoma treated surgi-
Patients and Methods
Patients participating in the study had histologically
documented malignant melanoma and prognostic indi-
cators suggesting a high risk for disease recurrence. For
patients with Stage I disease inclusion criteria were pri-
mary melanoma with a Clark’s level of 111, IV, or V and
a thickness of 1.25 millimeters or more; mucosal, sub-
ungual, or acral-lentigenous melanoma; or regional cu-
taneous or subcutaneous recurrence of disease. Patients
with Stage I1 disease who had histologic confirmation of
regional lymph node metastasis were likewise eligible.
Patients with Stage 111 melanoma were excluded from
The patients’ referring physicians provided appro-
priate surgical treatment before protocol entry, e.g.,
wide reexcision of the primary lesion, resection of a local
or regional recurrence and/or regional lymph node dis-
section. Radiotherapy or isolated limb perfusion were
employed, when necessary, to ensure clinical disease-
free status prior to study entry. In so far as possible, all
primary melanoma histologic material was reviewed by
a single dermatopathologist. After referral to the Mela-
noma Clinic, confirmation of clinical tumor-free status
was documented by physical examination, complete
blood count, serum chemistry panel (with liver enzyme
determinations), urinalysis, radionuclide scan of the
liver and spleen or abdominal computed tomography
(CT). and either whole-lung tomography or chest CT
scan. Administration of the assigned medication had to
begin within 90 days of the last surgery demonstrating
positive histologic evidence of melanoma. This 90 day
limit allowed time for patient referral, Melanoma Clinic
evaluation, and patient staging in the postoperative pe-
Staging, Stratification, and Randomization
The melanoma staging system accepted by the Inter-
national Union Against Cancer was used for patient
classification. Stage I patients were defined as those with
only regional melanoma, i.c., primary lesions, local cu-
taneous or subcutaneous metastases, or “in transit” skin
metastasis greater than 5 cm from the primary lesion but
not yet spread to regional lymph nodes. Stage I1 patients
had regional nodal tumor involvement or lymph node
disease without a known primary melanoma. Patients
with melanoma dissemination beyond the regional lym-
phatic drainage, to cutaneous, subcutaneous, distant
nodal, or visceral sites were considered to have Stage 1 1 1
disease and were not eligible.
Patients were stratified, depending upon clinical pre-
sentation, into one of the following five patient classes:
1. Primary melanoma Clark’s level 111, IV, or V, 1.25
mm or greater in thickness, with no node dissection
(clinical Stage 1).
2. Primary melanoma Clark‘s level 111, IV, or V, I .25
mm or greater in thickness, with node dissection nega-
tive (histologic Stage I). Volar, subungual, or mucosal
primary melanoma with no lymph node dissection or
node dissection negative (clinical or histologic
3. Primary melanoma Clark’s level 111, IV, or V, 1.25
mm or greater in thickness, with node dissection posi-
tive within 90 days of primary melanoma biopsy (histo-
logic Stage 11).
4. Node dissection positive greater than 90 days from
primary melanoma biopsy (clinical and histologic Stage
11). Nodal metastatic melanoma of unknown primary
(clinical and histologic Stage 11).
5. Isolated limb perfusion or radiation required after
surgery to ensure elimination of all evident disease
(clinical or histologic Stage I or 11).
There was no further stratification; other factors im-
portant in determining prognosis, eg., sex, age, and pri-
mary tumor thickness, were reserved as covariates in the
analysis of results.
Randomization within each class was done in bal-
anced sets of six patients to ensure approximately equal
numbers of participants in either the TF or placebo
study arms. Neither study participants nor the investi-
gators knew the nature of the individual medication as-
signments, whether TF or placebo, during the course of
TRANSFER FACTOR THERAPY
FOR MELANOMA -
Miller et al.
Study participants received either a three milliliter (5
x 1 O8 lymphocyte equivalents) subcutaneous injection
of TF or three milliliters of placebo. Injections were
administered either at the Melanoma Clinic or by the
patients' primary physicians under the direction of the
principal investigators. Injections were given every three
weeks. This schedule was chosen based on past experi-
ence demonstrating that skin test reactivity following TF
administration lasts three weeks in cancer patients.I6
Treatment was continued until the earliest event: pa-
tient death, appearance of an unresectable disease recur-
rence, tumor-free survival for 2 years or protocol termi-
nation. The 2 year standard treatment period was cho-
sen because of the knowledge that in very high risk Stage
I patients and in Stage I1 patients the likelihood of recur-
rence approaches 50% during this time.'
Interval evaluation of disease status was performed at
the Melanoma Clinic every 3 months until the patient
had been disease free for 2 years. Study observations
were continued semiannually thereafter. These evalua-
tions consisted of history, physical examination, com-
plete blood count, serum chemistry panel, chest radio-
graph and urinalysis. More frequent examinations or
additional testing were performed if warranted.
Any recurrence date was documented as the earliest
appearance of a lesion subsequently confirmed to be
melanoma. Whenever possible, histologic confirmation
of recurrence was obtained. For visceral metastasis, re-
currence was considered present when, in the opinion of
the investigators, lesions were almost certainly mela-
noma, e.g., when radiographic studies demonstrated
new pulmonary, hepatic, or brain metastasis.
Times to first disease recurrence, Stage 111 dissemina-
tion, and death were analyzed using the Kaplan-Meier
life table meth~d.'~ The statistical significance of life
table endpoint differences between TF and placebo
groups was determined using both the Gehanl' and log-
rank (Mantel)" tests. Specified P-values are two tailed
and are considered significant for P I
Study Medication Preparation
Transfer factor was prepared using a modification of
previously described methods2' In brief, normal healthy
volunteers were selected as donors. Donor leukocytes
were harvested by leukophoresis using an Aminco Cell-
trifuge and were further separated from remaining
plasma by centrifugation. The cells were counted,
washed, lysed by repeated freezing and thawing, lyophy-
lized, and dialyzed. The dialysate was lyophylized and
TABLE 1. Distribution of Patient Characteristics
No. of patients
~ ~~ ~
TF: transfer factor.
then suspended in enough sterile, distilled water to ob-
tain a final concentration of 1.67 X lo8 lymphocyte cell
equivalents per milliliter or 5 X 10' lymphocyte equiva-
lents per 3 milliliter dose. This dose was selected based
on previous knowledge of its success in the transfer of
cellular immunity to patients with pulmonary mela-
noma metastases.14 Placebo consisted of carmelized glu-
cose having a similar appearance and irritative quality as
TF. Both TF and placebo were stored at -70" in coded,
3 milliliter, single-use vials until used.
One hundred and eighty patients were randomized to
the study; of these, 89 were entered into the TF arm and
91 into the placebo arm. Twelve patients were subse-
quently excluded from the analysis; five were realized to
have had active disease at time of entry (one patient, TF;
four patients, placebo), one patient did not meet histo-
logic criteria (placebo) and six candidates either never
started treatment or had a therapy trial of less than 3
months (three patients, TF; three patients, placebo). Ex-
clusion of these patients was performed before knowl-
edge of their treatment regimen was available to the
investigators. A total of 168 evaluable patients remained
(85 patients, T F 83 patients, placebo).
Comparisons of the treatment and control groups re-
vealed similar characteristics in terms of patient sex, age,
stage, and stratification (Table 1). Important pathologic
prognostic indicators also proved comparable (Table 2).
CANCER April 15 1988
Vol. 6 1
TABLE 2. Distribution of Pathologic Characteristics
No. of patients
Primary lesion Clark's level
No known primary
Primary lesion depth
No known primary
Primary lesion location
No known primary
TF: transfer factor.
* Patients entered trial after resection of nodal metasases (stratifica-
tion Group 4).
The median follow-up period for all patients was 24.8
months (TF: 22.3 months, placebo: 26.5 months) with a
range of 0.5 to 59.3 months (TF: 6.0 to 49.3 months,
placebo: 0.5 to 55.3 months). Follow-up for all patients
Three endpoints were selected for evaluation: time to
first recurrence, time to first Stage III disease, and sur-
vival. Time to first Stage 111 disease was included in the
analysis because progression to disseminated melanoma
provides an early indication of fatal outcome. A therapy
capable of slowing the onset of Stage I11 melanoma, even
if it did not have an effect on local-regional recurrence,
might favorably influence survival.
The differences in disease-free intervals between
treatment and placebo groups approached statistical sig-
nificance (Fig. IA): patients receiving TF tended to ex-
perience first recurrences more rapidly than controls (P
= 0.1004, Gehan; P = 0.0534, logrank). Times to first
recurrence were comparable for the Stage I groups (P
= 0.5005, Gehan; P = 0.3878, logrank) (Fig. IB). The
adverse trend appeared most pronounced among the
Stage I1 patients (P = 0.1541, Gehan; P = 0.0673, log-
rank) (Fig. 1C).
Time to first Stage 111 disease (Fig. 2A) was signifi-
cantly shorter for TF-treated participants than for those
receiving placebo (P = 0.0164, Gehan; P = 0.01 58, log-
rank). No significant differences were noted when only
Stage I patients, treatment and control, were compared
(P = 0.2146, Gehan: P = 0.4225, logrank) (Fig. 2B), the
Stage I1 patients contributing most prominently to the
disparity between the groups (P = 0.0531, Gehan; Y
= 0.0 184, logrank) (Fig. 2C).
Significant survival differences between TF and pla-
cebo groups were not observed, no matter whether com-
parison was made among all patients (P = 0.1882.
Gehan; P = 0.1218, logrank) (Fig. 3A), Stage I subjects
(P = 0.0988, Gehan; P = 0.2397, logrank) (Fig. 3B), or
participants with Stage I1 disease (P = 0.4997, Gehan; P
= 0.2374, logrank) (Fig. 3C). A more favorable outcome
in the placebo-treated group was still suggested by the
When analyses were performed incorporating survival
and recurrence data from the 12 excluded patients, no
material impact on the study results could be found. No
side effects of TF were observed except for occasional
injection site tenderness. One placebo-treated patient
and two patients given TF died with no evidence of
Historically controlled therapy trials often suffer from
inadvertant exaggeration of poor outcome in the control
group and favorable biases in the selection of the treat-
ment group.2' Seemingly effective therapies, when eval-
uated in a randomized fashion, frequently provide less
encouraging results. The potential benefit and minimal
toxicity of TF observed in early open ~tudies'~-'~
cated the need for this larger randomized, controlled
double-blind trial to thoroughly assess TF efficacy.
However, like previous well designed evaluations of ba-
cillus calmette guenn vaccine (BCG)22-24 and levamis-
ole25 as adjuvant immunotherapy, this study proved TF
to be disappointing in the prevention of melanoma re-
currences. These most recent results in fact demonstrate
favorable trends in the placebo-treated patients as com-
pared to those receiving transfer factor when patients
were evaluated for time to first recurrence, time to first
Stage 111 disease, and survival. The difference with re-
gard to one endpoint, time to first Stage 111 disease, was
statistically significant with a more rapid disease pro-
gression rate noted in the treatment group, particularly
among patients receiving TF after surgical resection of
nodal metastases. The increased recurrence rate in the
TRANSFER FACTOR THERAPY
FOR MELANOMA -
MilZer et al.
1 3 ! 3
- - Placebo
0 5 -
- - Placebo
- - Placebo
p = 0.2146 (Gehan)
p = 0.4225 (logrank)
p = 01004 (Gehan)
p = 0 0534 (logrank)
Disease-Free Interval (months)
- - Placebo
p = 0.1541 (Gehan)
p = 0.0673 (logrank)
12 24 36 48
Disease-Free Interval (months)
p = 0.0164 (Gehan)
p = 0 0158 (logrank)
Time to Stage 111 Disease (months)
, . .
p = 0.0531 (Gehan)
p = 0.0184 (logrank)
' - Placebo
p = 0 5005 (Gehan)
p = 0.3878 (logrank)
24 36 48
Disease-Free Interval (months)
FIGS. 1A-1C. Disease-free intervals for (A) all, (B) Stage I, and (C)
Stage I1 melanoma patients treated with transfer factor or placebo.
Numbers represent number of patients disease-free during interval/
number of patients entering each interval. Vertical bars represent
standard errors of the mean.
y o 5
24 36 48
Time lo Stage 111 Disease (months)
FIGS. 2A-2C. Times to progression to Stage 111 disease for (A) all, (B)
Stage I, and (C) Stage I1 melanoma patients treated with transfer factor
or placebo. Numbers represent number of patients without Stage 1 1 1
disease during interval/number of patients entering each interval.
Vertical bars represent standard errors of the mean.
I I I
12 24 36 48
Time to Stage Ill Disease (months)
CANCER April15 1988
p = 0.1882 (Gehan)
p = 0.1218 (logrank)
Survival Time (months)
Transfer Factoi n
p = 0.4997 (Gehan)
p = 0.2374 (logrank)
SuNlval Time (months)
treatment cohort had not translated into significantly
increased mortality at the time of data analysis, but an
unfavorable trend was apparent.
The study observations extend the tentative conclu-
sions drawn from an earlier Cleveland Clinic random-
ized TF therapy protocol26 under which 3 6 melanoma
patients with regional skin and/or node metastases were
assigned to receive either surgery followed by TF or sur-
gery alone. An improved median survival time of 40.6
months in the TF patients contrasted with 27 month
median control group survival but statistical signifi-
cance was not shown (P = 0.17). Small study size, prog-
nostic differences between patient cohorts, the use of
both unselected and patient-related donors, and the
unblinded nature of this trial cast uncertainty upon the
findings, but TF benefit seemed unlikely.
Randomized trials evaluating adjuvant TF therapy in
other types of malignancy have provided mixed results.
Patients with nasopharyngeal carcinoma given TF after
radiotherapy for local tumor extension showed an unfa-
vorable mortality trend, but statistical significance was
not shown.27 Adjuvant treatment of o~teosarcoma,~~~~~
mycosis f~ngoides,~' and recurrent, low-grade bladder
tumors3' have also demonstrated the inefficacy of TF for
these disorders. By contrast, TF benefit has been
claimed in the treatment of invasive cervical carci-
p = 0 0988 (Gehan)
p = 0.2397 (logrank)
Survival Time (months)
FIGS. 3A-3C. Survival times for (A) all, (B) Stage I, and (C) Stage I1
melanoma patients treated with transfer factor or placebo. Numbers
represent number of survivors/number of patients entering each inter-
val. Vertical bars represent standard errors of the mean.
n ~ m a ~ ~ and, in two separate trial^.,^^,^^ an advantage was
suggested to its use after primary lung cancer therapy.
The reasons for these disparate findings remain elusive.
The use of selected TF donors (household contact, cured
patients) has not convincingly influenced outcome; TF
from specified donors has given both p o ~ i t i v e ~ ~ , ~ ~
negati~e~',~~ results in randomized trials. Differences in
TF preparation, doses and dosing schedules, the method
of primary tumor control, and the simultaneous use of
chemotherapy and TF also complicate analysis of the
Certainly, it is clear, based on our findings, that TF is
ineffective as surgical adjuvant therapy for melanoma.
However, the adverse trends noted in the treatment
group are more difficult to interpret. It is conceivable
that TF could produce untoward results. Relatively re-
cently the presence of immunologic suppressor sub-
stances in TF dialysates has been reported.35 Such sup-
pressors have been claimed to have potentially detri-
mental clinical effects when administered as therapy for
isolated immune defects in patients with certain chronic
infection^,^^ but their impact on the course of mela-
noma, or cancer in general, remains unknown. Because
random variation, rather than a true TF effect, remains
an alternate explanation for the negative trends, further
patient entry and longer follow-up would have been nec-
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.
1. Day CL, Mihm MC, Lew RA, Kopf AW, Sober AJ, Fitzpatrick
TB. Cutaneous malignant melanoma: Prognostic guidelines for physi-
cians and patients. CA 1982; 32:113-122.
2. Mastrangelo MJ, Rosenberg SA, Baker AR, Katz HR. Malignant
melanoma. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer:
Principles and Practice of Oncology. Philadelphia: J. B. Lippincott,
1982; 1124-1 170.
3. Hill GJ, Moss SE, Golomb FM ef al. DTIC and combination
therapy for melanoma: I1 DTIC (NSC 45388) Surgical Adjuvant Study
CO (7 Protocol 7040). Cancer 1981; 47:2556-2562.
4. Balch CM, Murray D, Presant G, Bartolucci AA. Ineffectiveness
of adjuvant chemotherapy using DTIC and cyclophosphamide in pa-
tients with resectable metastatic melanoma. Surgery 1984; l 1:454-
5. Creagan ET, Cupps RE, Ivins JC ef al. Adjuvant radiation ther-
apy for regional nodal metastases from malignant melanoma: A ran-
domized, prospective study. Cancer 1978; 42:2206-22 10.
6. Little JH. Partial regression in primary cutaneous malignant mel-
anoma. Pathology 1971; 352.
7. McGovern VJ. Etiology of melanoma. In: Malignant Melanoma
of the Skin and Mucus Membrane. London: Churchill Livingstone,
8. Bulkley GB, Cohen MH, Banks PM, Char DH, Ketcham AS.
Long-term spontaneous regression of malignant melanoma with vis-
ceral metastases: Report of a case with immunologic profile. Cancer
9. Kopf AW. Host defenses against malignant melanoma. Hosp
Pract 1971; 6:116-124.
10. Lewis MG. Immunology and the melanomas. In: Current
Topics in Microbiology and Immunology. New York Springer-Ver-
lag, 1974; 49-84.
I 1. Lawrence HS. The transfer in humans of delayed skin sensitiv-
ity to streptococcal M substance and to tuberculin with disrupted
leukocytes. J Clin Invest 1955; 34:2 19-230.
12. Kirkpatrick CH. Transfer factor. CRC Crit Rev CIin Lab Sci
13. Spitler LE, Levin AS, Wybran J. Combined immunotherapy in
malignant melanoma. Cell Imrnunol 1976; 2 1: 1-19.
14. Gonzalez R, Wong P, Spitler L. Adjuvant immunotherapy with
transfer factor in patients with melanoma metastatic to the lung.
Cancer 1980 45:57-63.
15. Blume M, Rosenbaum E, Cohen R, Gershow J, Glassberg AB,
Shepley E. Adjuvant immunotherapy of high risk stage I melanoma
with transfer factor. Cancer 1981; 472382-888.
16. Solowey AC, Rapaport FT, Lawrence HS. Cellular studies in
neoplastic diseases. In: Curtoni ES, Mattinz PL, Tosi RM, eds. Histo-
compatibility Testing 1967: Report of a Conference and Workshop,
Torino and Saint Vincent, Italy. Baltimore: Williams and Wilkins,
17. Kaplan EL, Meier P. Nonparametric estimation from incom-
plete observations. J Am Stat Assoc 1958; 53:457-481.
18. Gehan EA. A generalized Wilcoxon test for comparing arbi-
trarily single-censored samples. Biometrika 1965; 52:203-223.
19. Mantel N. Evaluation of survival data and two new rank order
statistics arising in its consideration, Cancer Chemolher Rep 1966;
50: 163-1 70.
20. Spitler LE, Levin AS, Fudenberg HH. Human lymphocyte
transfer factor. In: Busch H, ed. Methods in Cancer Research, vol. 8.
New York: Academic Press, 1973; 59-106.
2 1. Sacks H, Chalmers TC, Smith H. Randomized versus historical
controls for clinical trials. Am J Med 1982; 72:223-240.
22. Cunningham TJ, Schoenfeld D, Nathanson L, Wolter J, Patter-
son WB, Cohen MH. A controlled study of adjuvant therapy in pa-
tients with stage I and I1 malignant melanoma. In: Terry WD, Wind-
horst D, eds. Immunotherapy of Cancer: Present Status of Trials in
Man. New York Raven Press, 1980; 19-26.
23. Morton DL, Holmes EC, Eilber FR, Sparks FC, Ramming KP.
Adjuvant immunotherapy of malignant melanoma: Preliminary re-
sults of a randomized trial in patients with lymph node metastases. In:
Terry WD, Windhorst D, eds. Immunotherapy of Cancer: Present
Status of Trials in Man. New York Raven Press, 1978; 57-64.
24. Pinsky CM, Hirshaut Y, Wanebo HJ et al. Randomized trial of
Bacillus Calmet-Guerin (percutaneous administration) as surgical ad-
juvant immunotherapy for patients with stage I1 melanoma. Ann NY
AcadSci 1976; 277:187-194.
25. Spitler LE, Sagebiel R. A randomized trial of levamisole versus
placebo as adjuvant therapy in malignant melanoma. N Eng/ J Med
26. Bukowski RM, Deodhar S, Hewlett JS, Greenstreet R. Ran-
domized controlled trial of transfer factor in stage I1 malignant mela-
noma. Cancer 1983; 51:269-272.
27. Goldenberg GJ, Brandes LJ, Lau WH, Miller AB, Wall C, Ho
JHC. A cooperative trial of immunotherapy of nasopharyngeal carci-
noma with transfer factor from donors with Epstein-Barr virus anti-
body activity. Cancer Treat Rep 1985; 69:161-767.
28. Ivins JC, Ritts RE, Pritchard DJ, Gilchrist GS, Miller GC, Tay-
lor WF. Transfer factor versus combination chemotherapy: A prelimi-
nary report of a randomized postsurgical adjuvant treatment study in
osteogenic sarcoma. Ann NY Acad Sci 1976; 277:558-574.
29. Gilchrist GS, Pritchard DJ, Dahlin DC, Ivins JC, Taylor WF,
Edmonson JH. Management of osteogenic sarcoma: A persepctive
based on the Mayo Clinic experience. NCIMonogr 198 I; 56: 193-1 99.
30. Thestrup-Pedersen K, Grunnet E, Zachariae H. Transfer factor
therapy in mycosis fungoides: A double-blind study. Acta Durn Vene-
reol 1982; 62:47-53.
31. Tarkkanen J, Grohn P, Heinonen E, Alfthan 0, Pyrhonen S.
Transfer factor immunotherapy of recurrent non-infiltrative papillary
bladder tumors. Cancer Immunol Immunother 1981; 1025 1-255.
32. Wagner G, Gitsch E, Haveler L, Knapp W, Rainer H, Selander
S. Transferfaktor als adjuvante Immuntherapie beim invasiven Zer-
vixkarzinom: Bericht uber eine Doppelblindstudie. Wien Klin Wo-
chenschr 1983; 95:738-742.
33. Fujisawa T, Yamaguchi Y, Kimura H, Arita M, Baba M, Shiba
M. Adjuvant immunotherapy of primary resected lung cancer with
transfer factor. Cancer 1984; 54:663-669.
34. Kirsh MM, Omnger MB, McAuliffe S, Schock MA, Katz B,
Silva J. Transfer factor in the treatment of carcinoma of the lung. Ann
ThoracSurg 1984; 38:140-145.
35. Lawrence HS, Borkowsky W. A new basis for the immunoregu-
latory activities of transfer factor: An arcane dialect in the language of
cells. CellImmunol 1983; 82:102-116.
36. Wilson GB, Fudenberg HH, Keller RH. Guidelines for immu-
notherapy of antigen-specific defects with transfer factor. J Clin Lab