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10.1177/1534735405285901Berkson et alIntravenous
!-Lipoic Acid/Low-Dose Naltrexone
Case Report
The Long-term Survival of a Patient With Pancreatic
Cancer With Metastases to the Liver After Treatment
With the Intravenous !-Lipoic Acid/Low-Dose
Naltrexone Protocol
Burton M. Berkson, Daniel M. Rubin, and Arthur J. Berkson
The authors describe the long-term survival of a patient with
pancreatic cancer without any toxic adverse effects. The
treatment regimen includes the intravenous -lipoic acid
and low-dose naltrexone (ALA-N) protocol and a healthy
lifestyle program. The patient was told by a reputable univer-
sity oncology center in October 2002 that there was little
hope for his survival. Today, January 2006, however, he is
back at work, free from symptoms, and without appreciable
progression of his malignancy. The integrative protocol de-
scribed in this article may have the possibility of extending
the life of a patient who would be customarily considered to
be terminal. The authors believe that life scientists will one
day develop a cure for metastatic pancreatic cancer, perhaps
via gene therapy or another biological platform. But until
such protocols come to market, the ALA-N protocol should
be studied and considered, given its lack of toxicity at levels
reported. Several other patients are on this treatment proto-
col and appear to be doing well at this time.
Keywords: pancreatic cancer; naltrexone; lipoic acid; survival
J.A. is a 46-year-old man diagnosed with poorly differ-
entiated adenocarcinoma of the pancreas with
metastases to the liver. In early October 2002, J.A.
started to feel vague abdominal pains as well as com-
plained of symptoms associated with hyperacidity and
indigestion. After his symptoms became more pro-
nounced, he presented to the local emergency depart-
ment where, secondary to his complaint of right lower
quadrant abdominal pain, a computed tomography
(CT) was performed on October 8, 2002. It revealed a
hyperdense mass at the junction of the second and
third portions of the duodenum and uncinate process
of pancreas (Figure 1).
The mass had infiltrative margins, without local
adenopathy. Furthermore, within the liver, there were
at least 3 hyperdense lesions that were thought to pos-
sibly represent hemangiomas; a fourth lesion, 5 to 6
cm in diameter, contained some areas of hypodensity,
thus suggestive of a neoplastic process (Figure 2).
Six days later, an esophagogastroduodenoscopy
was performed, and an ulcerated Ampulla of Vater was
biopsied; the pathology report was significant only for
acute and chronic inflammation. One day later, mag-
netic resonance imaging (MRI) of the liver was per-
formed in an attempt to classify the multiple hepatic
lesions recognized on CT. The MRI suggested the
lesions were not indicative of hemangiomata but
rather of metastatic deposits. Subsequently, a 3.9 !3.9
cm mass was located associated with the head and
Intravenous -Lipoic Acid/Low-Dose Naltrexone
INTEGRATIVE CANCER THERAPIES 5(1); 2006 pp. 83-89 83
BMB is at the Integrative Medical Center of New Mexico and New
Mexico State University, Las Cruces. DMR is in Scottsdale, Ari-
zona. AJB is in the Department of Family Practice, University of Illi-
nois at Chicago, Illinois Masonic Medical Center, and the
Department of Family Practice, Advocate Health Center, Chicago,
Illinois.
Correspondence: Daniel M. Rubin, 4300 North Miller Road, Suite
231, Scottsdale, AZ 85251. E-mail: rubin@rubinmedical.com.
DOI: 10.1177/1534735405285901
Figure 1 Computed tomography scan from October 8, 2002,
shows a hyperdense mass at the junction of the second
and third portions of the duodenum and the uncinate
process of the pancreas (circled).
uncinate process of the pancreas. This prompted a
fine-needle aspiration of the largest liver lesion on
October 22, 2002, and the diagnosis of poorly differ-
entiated adenocarcinoma of pancreatic origin was
made. Laboratory parameters reflecting J.A.’s func-
tional hepatic status were at this time all within refer-
ence range; in addition, a common serum tumor
marker for pancreatic cancer (CA 19-9) was within the
reference range. Furthermore, this common marker
has remained negative throughout the disease course.
Following this diagnosis, chemotherapy was pre-
scribed. On November 7, 2002, J.A. began a 21-day
course of gemcitabine (1000 mg/m2; actual dose =
1800 mg; day 1 and day 8) and carboplatin (AUC 5;
actual dose = 600 mg; half dose on day 1 and half dose
on day 8). The patient, after becoming leukopenic
and thrombocytopenic and demonstrating poor sub-
jective tolerance for the chemotherapy, decided to
seek another opinion and traveled to a well-respected
oncology center. After a complete oncology workup
and review of his previous records, J.A., per his histori-
cal account, was told essentially that, given his situa-
tion, any further treatment would ultimately be
fruitless.
Given this prognosis, on November 25, 2002, J.A.
presented to the Integrative Medical Center of New
Mexico (IMCNM) and was seen in consultation by one
of the authors (B.M.B.). At the time of presentation,
his review of systems was positive for seasonal allergies,
heartburn, tinnitus, decrease in force of urinary
stream, sleeping difficulty, weight loss, abdominal
pain, and severe emotional stress and anxiety. Medica-
tions at arrival were Prevacid 30 mg, trimethoprim/
sulfamethoxazole, Mylanta, Pepto-Bismol, and
Rolaids. B.M.B. added alprazolam 0.25 mg each bed-
time as needed to help relieve J.A.’s nighttime anxiety.
An integrative medical program was then devel-
oped and prescribed for the patient. The purpose of
this program was 3-fold: (1) nutritional support, (2)
comfort and palliation, and (3) immune stimulation.
The key therapeutic agents were intravenous "-lipoic
acid (ALA) 300 to 600 mg 2 days per week and low-
dose naltrexone (LDN), 4.5 mg at bedtime. In addi-
tion, a triple antioxidant regimen consisting of oral
ALA (600 mg/d), selenium (200 #g 2 times per day),
and silymarin (300 mg 4 times a day) was added to scav-
enge the products of oxidative stress that inevitably
result from any serious chronic medical disorder. J.A.
was also placed on a lifestyle program that included
specific dietary advice.
After the first intravenous (IV) administration of
the ALA, the patient improved subjectively, prompt-
ing his volunteered comment, “I have increased
energy and a sense of well-being.” The program was
continued, and J.A. was extremely compliant.
On January 3, 2003, a repeat CT scan was per-
formed using the same machine at the same diagnos-
tic radiology department. Again, the mass at the head
of the pancreas as well as the multiple hepatic lesions
were demonstrated, and all lesions remained un-
changed as compared to the scan of October 8, 2002
(Figure 3); furthermore, no new lesions were identi-
fied. The course of events was relatively uneventful as
the patient continued on this integrative treatment
plan.
On February 24, 2003, a repeat CT scan was per-
formed (Figure 4; same CT machine, 51 days after the
previous CT scan and 138 days after the initial CT
scan), which again demonstrated unchanged pancre-
atic primary and metastatic hepatic lesions; no new
lesions were identified.
As the patient continued on his treatment plan,
follow-up CT scans were ordered at regular intervals.
Both CT scans of April 21, 2003, and June 20, 2003
(Figure 5) revealed no changes in the existing lesions,
nor any new lesions.
Another CT scan performed on August 19, 2003
(this time on a different machine at a different
Berkson et al
84 INTEGRATIVE CANCER THERAPIES 5(1); 2006
Figure 2 Computed tomography scan from October 8, 2002,
shows multiple hyperdense masses within the hepatic
parenchyma (circled).
Figure 3 Computed tomography scan from January 3, 2003,
shows stable hepatic parenchymal lesions as compared
to October 8, 2002 (arrows).
institution) revealed stable primary and hepatic
lesions with the potential development of 2 new
lesions. However, a caveat by the interpreting radiolo-
gist read, “Two new visible lesions that were not clearly
evident on the prior scan [June 20, 2003, different
institution], but again this could be an artifact of a dif-
ferent phase of contrast enhancement rate/hr than a
definite new finding. Otherwise stable CT of the
upper abdomen.” It is noted by the authors that no CT
scan performed on J.A. has ever demonstrated evi-
dence of biliary obstruction nor dilatation.
J.A. continued on his integrative protocol, without
changes to his schedule, through March 2004, during
which time CT images showed no changes in his dis-
ease status. The patient began to feel so well, with no
symptoms of his disease, that he voluntarily discontin-
ued his integrative treatment program. A positron
emission tomography (PET)/CT fusion scan was per-
formed on July 20, 2004, the results of which demon-
strated disease advancement. Unfortunately, a subse-
quent CT scan performed in December 2004
demonstrated evidence of progressive disease at both
the primary and metastatic sites (Figure 6). The lesion
at the head of the pancreas had increased in size to 5
cm transversely, and 8 hepatic lesions became recog-
nizable, while the previously identified hepatic lesions
showed a general increase in their sizes. In December
2004, because of the unsatisfactory scan results, J.A.
resumed the IMCNM program. Since that time, J.A.
has continued to improve subjectively, and he realized
no disease progression in a June 2005 CT scan.
Discussion
The overall prognosis for patients with carcinoma of
the pancreas is poor: the average length of survival af-
ter diagnosis ranges from 3 to 6 months.1Surgical re-
section is generally not an option for people with
metastatic pancreatic cancer, and patients with ad-
vanced metastatic disease rarely survive more than a
few months. The current dogma concerning this issue
is that treatment should concentrate on the alleviation
of pain and the improvement of quality of life with par-
ticipation from palliative medical personnel.2
This leaves few options for such patients beyond
chemotherapy and clinical trials. In this instance, J.A.
chose to follow an integrative medical program that
included intravenous ALA 300 to 600 mg twice a week,
LDN 3 to 4.5 mg at bedtime, the oral triple antioxidant
therapy protocol (developed by B.M.B.) consisting of
(1) ALA 300 mg orally 2 times a day, (2) selenium 200
#g orally 2 times a day, and (3) silymarin 300 mg 4
times a day, along with 3 professional-strength vitamin
B complex capsules each day. It was also suggested that
he follow the IMCNM lifestyle program including a
strict dietary regimen along with a stress-reduction
and exercise program.
That J.A. has had comparatively stable disease for
more than a 3-year period is a remarkable clinical find-
ing and prompts this report. It is the opinion of the
Intravenous -Lipoic Acid/Low-Dose Naltrexone
INTEGRATIVE CANCER THERAPIES 5(1); 2006 85
Figure 4 Computed tomography scan from February 24, 2003,
shows stable hepatic parenchymal lesions as compared
to January 3, 2003 (arrows).
Figure 5 Computed tomography scan from June 20, 2003, shows
stable hepatic parenchymal lesions as compared to
February 24, 2003 (arrows).
Figure 6 Computed tomography scan from December 2004
shows increase in size of the primary pancreatic lesion
and increase in the number of the hepatic parenchymal
lesions as compared to the June 20, 2003 scan (18-
month interval).
authors that the lack of progression of J.A.’s disease
cannot be solely attributed to the single dose of che-
motherapy he received. It has been reported that
gemcitabine’s effect on response rate and survival is
disappointing.3No data exist determining response to
partial, moreover a single dose, of this drug either
alone or in combination.
The stability of J.A.’s disease is thus attributable to
the integrative program developed by one of the
authors (B.M.B.). This is further evidenced by the
quick progression of J.A.’s primary and hepatic lesions
after his voluntary discontinuation of his integrative
and successful treatment—an unfortunate but not
uncommon decision. Many patients, despite strong
encouragement from their physicians, will discon-
tinue their treatments, in whole or in part, when faced
with better health, diminishing financial resources, or
both. The former is a subjective sensation often real-
ized by patients when undergoing a treatment plan
aimed at improving their overall health and as a result
promoting an autogenous antitumor response. Non-
medically trained patients tend to associate improved
sense of well-being and reduction of paraneoplastic
symptoms with the notion that they are improving and
that continued treatment may not, indeed, be neces-
sary. In addition, because nonconventional medical
treatments are generally not covered by most insur-
ance plans, long-term care of this type can become a
financial burden, forcing a discontinuation of their
treatments despite their desires or those of the treat-
ing physician. Thus, it becomes the duty of integrative
physicians to bring to public attention, via publica-
tion, cases in which such treatment plans have demon-
strated success.
When J.A. first presented to the clinic (IMCNM),
his quality of life was poor. He was losing weight,
exhausted both physically and emotionally, and expe-
riencing almost constant abdominal pain and nausea.
However, as mentioned above, after only 1 treatment
of intravenous ALA, his symptoms began to resolve.
Improvement in quality of life is a particular strength
of nutritional programs, and its inclusion in a treat-
ment plan for someone with advanced pancreatic
cancer may be essential.
People with metastatic pancreatic cancer often suf-
fer from weight loss. The mechanism behind this is
generally well understood and involves a complex
interplay of proinflammtory biological response mod-
ifiers4; however, such pathways will not be reiterated
herewith. From a clinical point of view, and for J.A.’s
case in particular, maintenance of body weight and
provision of normal protein-calorie nutritional status
is of paramount importance. As weight loss continues,
an individual’s appetite generally diminishes, thus
accelerating the loss of lean body mass, which then
leaves the patient with even less endogenous resources
to maintain health and fight disease. It is probable,
from the course of this case, that had J.A. continued
on his course of chemotherapy, he quite possibly
would have developed frank cachexia followed by the
deleterious consequences of such a syndrome,
including death.
The first key component in J.A.’s treatment proto-
col was ALA. It is chiefly an antioxidant, which has also
been shown to influence a variety of biological pro-
cesses associated with oxidative stress including diabe-
tes, liver disease, and cancer.5-8 ALA is a naturally
occurring cofactor that is active in an assortment of
enzymatic complexes that control metabolism. There
have been a number of articles suggesting the utility of
ALA in the treatment of various cancers. One article
reported that ALA induced hyperacetylation of his-
tones.9In this study, human cancer cell lines became
apoptotic after being exposed to ALA, while the same
treatment of normal cell lines did not induce
apoptosis.
Another indication of a mechanism whereby ALA
might discourage the growth of cancer cells is its abil-
ity to stabilize NF-$B transcription factor.10 Th1- and
Th2-mediated immune system cells identify and react
to pathogenic insults with various cell membrane
receptors. Most of these receptors initiate a cascade of
signal transduction events that eventually activate the
master transcription factor NF-$B. NF-$B is able to
bind to DNA after the phosphorylation and ubiquitin-
mediated deactivation of its inhibitor I$B and to
affect the rate of transcription of certain deleterious
genes that have NF-$B binding sites. Because of this,
NF-$B plays a significant role in the regulation of
inflammatory-induced gene function. High doses of
ALA, when added to cell culture, have been shown to
inhibit the activation of NF-$B.11,12
Additional data have demonstrated evidence of a
mechanism by which ALA may contribute to the ther-
apy for malignant disease: ALA can stimulate
prooxidant-driven apoptosis in human colon cancer
cells. This process is activated by an increased uptake
of oxidizable substrates into the mitochondrion.8In
another study, ALA synergistically improved vitamin C
cytotoxicity against cancer cells in tissue culture.13
Unlike ascorbate alone, ALA was equally effective
against proliferating and nonproliferating cells.
One study evaluated an extensive population of
people with advanced cancer for the biological consid-
erations that are relevant to cancer cachexia.14 The
parameters studied were serum levels of proinflam-
matory cytokines (IL-1%, IL-6, TNF-"), IL-2, acute-
phase proteins (C-reactive protein and fibrinogen),
leptin, and others applicable to oxidative stress, such
as reactive oxygen species, endogenous antioxidant
Berkson et al
86 INTEGRATIVE CANCER THERAPIES 5(1); 2006
enzymes such as glutathione peroxidase, and
superoxide dismutase. The authors observed that
patients with advanced cancer exhibit a chronic
inflammatory state with high-grade oxidative stress.
The article also suggests that antioxidant agents such
as ALA can stimulate the development and matura-
tion of cancer-fighting lymphocytes. Therefore, in this
way, ALA can promote the functional restoration of
the immune system in individuals suffering the
oxidative stress that results from advanced cancer.
In another study, ALA was shown to increase
homocysteine concentrations within cancer cells in
certain established cancer cell lines.15 The increased
homocysteine concentrations were toxic to the malig-
nant cells.
Another study demonstrated the effects of ALA on
the proliferation of mitogen-stimulated human
peripheral blood lymphocytes in comparison to its
effects on the proliferation of 2 leukemic T-cell lines.16
The discriminating toxicity of ALA toward the cancer
cell lines was shown by electron microscopy and was
due to the induction of apoptosis. In addition, ALA
noticeably increased the induction of IL-2 mRNA and
IL-2 protein secretion in cancer cells. The authors sug-
gested that the differential effects of ALA on normal
and leukemic T lymphocytes may specify a new path-
way toward development of therapeutic agents for
cancer.
Another relevant article demonstrated the ability of
ALA to correct the most significant functional defects
of peripheral blood mononuclear cells (PBMC) iso-
lated from advanced-stage cancer patients.17 Twenty
patients (mean age = 64.6 years) with advanced can-
cers of the lung, ovary, endometrium, and head and
neck were examined. The serum levels of IL-1%, IL-2,
IL-6, TNF-", and sIL-2R were significantly higher in
those with cancer than in patients with no known can-
cers. The addition of ALA (0.001 mM) into the PBMC
cultures significantly increased the response of PBMC
isolated from cancer patients and healthy subjects.
After 24 and 72 hours of culture, the expression of
CD25 and CD95 on PBMC isolated from cancer
patients was significantly lower than that of PBMC iso-
lated from healthy subjects. The addition of ALA into
these cultures significantly increased the percentage
of cells expressing CD25 as well as those expressing
CD95. ALA thus had a positive effect on several impor-
tant T-cell functions in people with advanced-stage
cancer.
LDN was the second key ingredient in this case.
Nocturnally dosed LDN blocks endogenous opiate
receptors, a short-lasting effect. During this receptor
blockade, the body produces large amounts of opiates
in response to the positive feedback, which become
available to and saturate said receptors, once the LDN
has been cleared from them. Opiates are powerful
inducers of the Th1 immune response: in this sense,
then, LDN produces an indirect immune response.
LDN has a stimulatory effect on immune cells via an
indirect interaction with their opiate receptors,
whereas high-dose naltrexone has an inhibitory effect.
The widely recognized pharmacologic effect of nal-
trexone is the competitive inhibition of membrane-
based opiate receptors that consequently produce an
opiate blockade. As a result of this action, patients who
are addicted to opiates or are chronic ethyl alcohol
users will not feel the normal “high” and should be
inclined to discontinue these recreational activities.
For this reason, naltrexone is considered an opiate
antagonist.
Zagon and McLaughlin18 reported that very low-
dose naltrexone slowed the growth of neuroblastoma
cells in culture and suggested that it therefore may
have a role in the treatment of certain cancers. In a
2003 article, the same authors suggested that the mod-
ulation of cancer cell growth in tissue culture was not
the result of alterations in apoptosis or necrosis but
from some other pathway.19
Malignant astrocytomas are believed to be incur-
able; therapy for such is aimed at palliation and overall
survival. Lissoni et al20 reported on the treatment of
malignant astrocytomas with the administration of
naltrexone plus radiotherapy (RT). The tumor regres-
sion rate in patients treated with RT plus naltrexone
was slightly higher than that of those treated with RT
alone, but the percentage of those surviving at 1 year
was significantly higher in patients treated with RT
plus naltrexone than in those treated with RT alone
(5/10 vs 1/11, P< .05).
In a later article, Lissoni et al21 reported escalation
of IL-2-dependent anticancer immunity by the admin-
istration of melatonin (MLT) plus naltrexone. The
researchers found that these 2 agents were able to
stimulate the Th1 and suppress the Th2 lymphocyte
response. The results of their study also suggested that
NTX amplified the lymphocytosis obtained by IL-2
plus MLT. In addition, the authors wrote that in view of
the fact that lymphocytosis represents the most impor-
tant favorable prognostic variable predicting the
anticancer efficacy of IL-2 immunotherapy, the addi-
tion of MLT and naltrexone to IL-2-containing regi-
mens warrants further testing.
Bihari22 first used LDN to treat people with AIDS:
given his promising results, he later used LDN for the
treatment of people with cancer. Over the years, he
administered LDN to 450 patients with cancer, most of
whom had failed the standard treatments.23,24 Accord-
ing to Bihari, of 354 patients who had regular follow-
ups, 86 showed signs of noteworthy tumor shrinkage
(at least a 75% reduction in tumor bulk), and at least
Intravenous -Lipoic Acid/Low-Dose Naltrexone
INTEGRATIVE CANCER THERAPIES 5(1); 2006 87
125 others were reported to have stabilized and
appeared to be moving toward remission.
Conclusion
In this case report, we describe the treatment of a 46-
year-old man who was diagnosed with metastatic pan-
creatic cancer in October 2002. He was initially sur-
veyed and staged by a local oncology team and treated
with a standard chemotherapy regimen. After a single
treatment of gemcitabine and carboplatin, the patient
became leukopenic and thrombocytopenic and could
not tolerate any further chemotherapy. In addition,
even with the standard chemotherapy protocol, his
cancer progressed.
J.A. then arrived at the office of one of the authors
(B.M.B.) and was promptly started on a program of
intravenous ALA, LDN, and a healthy lifestyle pro-
gram. During the period from October 2002 to pres-
ent (December 2005), J.A.’s pancreatic cancer with
metastases to the liver was followed closely by regular
office visits and CT and PET scans, and he has
remained mostly stable (Figure 7). It is interesting to
note that J.A.’s disease progressed rapidly when he
went off the ALA-LDN therapy; however, it stabilized
quickly when he resumed the treatment.
J.A. went back to work soon after he started the
ALA-LDN integrative treatment protocol and remains
free of symptoms at 3 years and 3 months. The authors
believe that since most people with metastatic pancre-
atic cancer succumb to their disease miserably within a
very short time, the 39-month survival time with non-
progressive disease reported here represents a bench-
mark in oncology. People with metastatic pancreatic
cancer more often die from their disease or complica-
tions thereof within 6 months and usually after a very
stressful and painful course. The report above is thus
of great importance.
In summary, the integrative therapy described in
this article may have the possibility of extending the
life of a patient who is customarily considered termi-
nal. This was accomplished with a program of univer-
sal antioxidants, one that bears known antitumor
activity (ALA) and an opiate-blockading agent that
can stimulate an endogenous immune response. The
authors believe that biomedical science will one day
develop a cure for metastatic pancreatic cancer, per-
haps via gene therapy or another biological-type plat-
form. But until such protocols come to market, and
moreover evolve and become realized, the ALA/LDN
therapy should be considered given its lack of toxicity
at levels reported herein, ready availability, and its
effect on J.A., the true subject of this report.
B. Berkson declares no financial interest in the sub-
stances discussed in this paper but uses lipoic acid and
naltrexone in his medical practice.
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