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10.1177/1534735405285901Berkson etalIntravenous

-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

Theauthors describe the long-term survivalof 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 healthylifestyleprogram. Thepatientwastoldby a reputableuniver-

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 patientwho would be customarily considered to

be terminal. The authors believe that life scientists will one

day develop a cureformetastaticpancreaticcancer, 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 withmetastases 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 andindigestion. After his symptoms became more pro-nounced, hepresentedto thelocalemergency depart-ment where, secondary to hiscomplaintof right lowerquadrant abdominal pain, a computed tomography(CT) wasperformed on October 8, 2002. It revealed ahyperdense mass at the junction of the second andthird portions of theduodenum anduncinate processof pancreas (Figure 1).

The mass had infiltrative margins, without localadenopathy. Furthermore, within the liver, there wereat least3 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 esophagogastroduodenoscopywas performed,and anulceratedAmpullaofVater wasbiopsied; the pathology report was significant only foracute and chronic inflammation. One day later, mag-netic resonance imaging (MRI) of the liver was per-formed in an attempt to classify the multiple hepaticlesions recognized on CT. The MRI suggested the

lesions were not indicative of hemangiomata butrather of metastatic deposits. Subsequently, a 3.9 3.9cm 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 NewMexico State University, Las Cruces. DMR is in Scottsdale, Ari-zona.AJB is in theDepartment of Family Practice, University of Illi-nois at Chicago, Illinois Masonic Medical Center, and theDepartment of Family Practice, Advocate Health Center, Chicago,Illinois.

Correspondence: Daniel M.Rubin, 4300 North MillerRoad, Suite231, Scottsdale, AZ 85251. E-mail: [email protected]: 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 uncinateprocess of the pancreas (circled).

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institution) revealed stable primary and hepaticlesions with the potential development of 2 newlesions. However, a caveat by the interpreting radiolo-gist read, Two newvisible lesions that were notclearlyevident on the prior scan [June 20, 2003, differentinstitution], but again this could be an artifact of a dif-ferent phase of contrast enhancement rate/hr than adefinite new finding. Otherwise stable CT of theupper abdomen. It isnoted bythe authors thatnoCTscan performed on J.A. has ever demonstrated evi-dence of biliary obstruction nor dilatation.

J.A. continued on his integrative protocol, withoutchanges to his schedule, through March 2004, duringwhich time CT images showed no changes in his dis-ease status. The patient began to feel so well, with nosymptoms of his disease, that he voluntarily discontin-ued his integrative treatment program. A positronemission 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 2004demonstrated evidence of progressive disease at both

the primary and metastatic sites (Figure 6). Thelesion

at the head of the pancreas had increased in size to 5cm transversely, and 8 hepatic lesions became recog-nizable,while the previously identifiedhepatic lesionsshowed a general increase in their sizes. In December2004, because of the unsatisfactory scan results, J.A.resumed the IMCNM program. Since that time, J.A.has continuedto improve subjectively, and he realizedno disease progression in a June 2005 CT scan.

Discussion

The overall prognosis for patients with carcinoma ofthe pancreas is poor: the average length of survival af-

ter diagnosis ranges from 3 to 6 months.

1

Surgical re-section is generally not an option for people withmetastatic pancreatic cancer, and patients with ad-vanced metastatic disease rarely survive more than afewmonths. Thecurrent dogma concerning this issueis thattreatment should concentrateonthealleviationofpain andthe improvementofquality of life with par-ticipation from palliative medical personnel.2

This leaves few options for such patients beyondchemotherapy and clinical trials. In this instance, J.A.chose to follow an integrative medical program thatincludedintravenousALA300 to 600 mg twice a week,LDN3 to4.5mg atbedtime, theoral tripleantioxidant

therapy protocol (developed by B.M.B.) consisting of(1) ALA 300 mg orally 2 times a day, (2) selenium 200mg orally 2 times a day, and (3) silymarin 300 mg 4times a day, along with 3 professional-strength vitaminB complex capsuleseach day. Itwas also suggestedthathe follow the IMCNM lifestyle program including astrict dietary regimen along with a stress-reductionand exercise program.

That J.A. has had comparatively stable disease formore than a 3-yearperiod isa remarkable clinical find-ing and prompts this report. It is the opinion of the


INTEGRATIVE CANCER THERAPIES 5(1); 2006 85

Figure 4 Computed tomography scan from February 24, 2003,shows stable hepatic parenchymal lesions ascomparedto January 3, 2003 (arrows).

Figure 5 Computed tomography scan from June 20,2003, showsstable hepatic parenchymal lesions as compared toFebruary 24, 2003 (arrows).

Figure 6 Computed tomography scan from December 2004shows increase in size of the primary pancreatic lesionand increase in the number of the hepatic parenchymallesions as compared to the June 20, 2003 scan (18-month interval).

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authors that the lack of progression of J.A.s diseasecannot be solely attributed to the single dose of che-motherapy he received. It has been reported thatgemcitabines effect on response rate and survival isdisappointing.3 No data exist determining response topartial, 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 theauthors (B.M.B.). This is further evidenced by thequick progression of J.A.s primary andhepatic lesionsafter his voluntary discontinuation of his integrativeand successful treatmentan unfortunate but notuncommon decision. Many patients, despite strongencouragement from their physicians, will discon-tinue their treatments, in whole or in part, when facedwith better health, diminishing financial resources, orboth. The former is a subjective sensation often real-ized by patients when undergoing a treatment plan

aimed at improving their overall healthand as a resultpromoting an autogenous antitumor response. Non-medically trained patients tend to associate improvedsense of well-being and reduction of paraneoplasticsymptoms with thenotion that they areimproving andthat continued treatment may not, indeed, be neces-sary. In addition, because nonconventional medicaltreatments are generally not covered by most insur-ance plans, long-term care of this type can become afinancial burden, forcing a discontinuation of theirtreatments 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 inwhich such treatmentplanshave 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 treatmentof intravenous ALA, his symptoms began to resolve.Improvement in quality of life is a particular strengthof nutritional programs, and its inclusion in a treat-ment plan for someone with advanced pancreaticcancer may be essential.

People with metastatic pancreatic cancer often suf-fer from weight loss. The mechanism behind this isgenerally well understood and involves a complexinterplay of proinflammtory biological response mod-ifiers4; however, such pathways will not be reiteratedherewith. From a clinical point of view, and for J.A.scase in particular, maintenance of body weight andprovision of normal protein-calorie nutritional statusis of paramount importance. As weight loss continues,an individuals appetite generally diminishes, thusaccelerating the loss of lean body mass, which then

leaves thepatientwitheven lessendogenous resourcesto maintain health and fight disease. It is probable,from the course of this case, that had J.A. continuedon his course of chemotherapy, he quite possiblywould have developed frank cachexia followed by thedeleterious consequences of such a syndrome,

including death.The first key component in J.A.s treatment proto-

colwasALA. It is chiefly an antioxidant, which has alsobeen shown to influence a variety of biological pro-cesses associated withoxidative stress including diabe-tes, liver disease, and cancer.5-8 ALA is a naturallyoccurring cofactor that is active in an assortment ofenzymatic complexes that control metabolism. Therehave been a numberofarticles suggesting the utility ofALA in the treatment of various cancers. One articlereported that ALA induced hyperacetylation of his-tones.9 In this study, human cancer cell lines becameapoptotic after being exposed to ALA, while the same

treatment of normal cell lines did not induceapoptosis.

Another indication of a mechanism whereby ALAmight discourage the growth of cancer cells is its abil-ity to stabilize NF-kB transcription factor.10 Th1- andTh2-mediated immune system cells identify and reactto pathogenic insults with various cell membranereceptors. Most of these receptors initiate a cascade ofsignal transduction events that eventually activate themaster transcription factor NF-kB. NF-kB is able tobind to DNAafter the phosphorylation andubiquitin-mediated deactivation of its inhibitor IkB and to

affect the rate of transcription of certain deleteriousgenes that have NF-kB binding sites. Because of this,NF-kB plays a significant role in the regulation ofinflammatory-induced gene function. High doses ofALA, when added to cell culture, have been shown toinhibit the activation of NF-kB.11,12

Additional data have demonstrated evidence of amechanism by which ALA may contribute to the ther-apy for malignant disease: ALA can stimulateprooxidant-driven apoptosis in human colon cancercells. This process is activated by an increased uptakeof oxidizable substrates into the mitochondrion.8 Inanother study, ALA synergistically improved vitamin C

cytotoxicity against cancer cells in tissue culture.13

Unlike ascorbate alone, ALA was equally effectiveagainst proliferating and nonproliferating cells.

One study evaluated an extensive population ofpeople withadvancedcancer forthebiological consid-erations that are relevant to cancer cachexia.14 Theparameters studied were serum levels of proinflam-matory cytokines (IL-1b, IL-6, TNF-a), IL-2, acute-phase proteins (C-reactive protein and fibrinogen),leptin, and others applicable to oxidative stress, suchas reactive oxygen species, endogenous antioxidant

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enzymes such as glutathione peroxidase, andsuperoxide dismutase. The authors observed thatpatients with advanced cancer exhibit a chronicinflammatory state with high-grade oxidative stress.The article also suggests that antioxidant agents suchas ALA can stimulate the development and matura-

tionof cancer-fightinglymphocytes. Therefore, in thisway, ALA can promote the functional restoration ofthe immune system in individuals suffering theoxidative stress that results from advanced cancer.

In another study, ALA was shown to increasehomocysteine concentrations within cancer cells incertain established cancer cell lines.15 The increasedhomocysteine concentrations were toxic to the malig-nant cells.

Another study demonstrated the effects of ALA onthe proliferation of mitogen-stimulated humanperipheral blood lymphocytes in comparison to itseffects on the proliferation of 2 leukemic T-cell lines.16

The discriminating toxicity of ALA toward the cancercell lines was shown by electron microscopy and wasdue to the induction of apoptosis. In addition, ALAnoticeably increased the induction of IL-2 mRNA andIL-2 protein secretionincancercells.Theauthors sug-gested that the differential effects of ALA on normaland leukemic T lymphocytes may specify a new path-way toward development of therapeutic agents forcancer.

AnotherrelevantarticledemonstratedtheabilityofALA to correct the most significant functional defectsof peripheral blood mononuclear cells (PBMC) iso-

lated from advanced-stage cancer patients.

17

Twentypatients (mean age = 64.6 years) with advanced can-cers of the lung, ovary, endometrium, and head andneck were examined. The serum levels of IL-1b, IL-2,IL-6, TNF-a, and sIL-2R were significantly higher inthose with cancer than in patients with no known can-cers. The addition of ALA (0.001 mM) into the PBMCcultures significantly increased the response of PBMCisolated from cancer patients and healthy subjects.After 24 and 72 hours of culture, the expression ofCD25 and CD95 on PBMC isolated from cancerpatients was significantly lower than that of PBMC iso-lated from healthy subjects. The addition of ALA into

these cultures significantly increased the percentageof cells expressing CD25 as well as those expressingCD95. ALAthus had a positive effectonseveral impor-tant T-cell functions in people with advanced-stagecancer.

LDN was the second key ingredient in this case.Nocturnally dosed LDN blocks endogenous opiatereceptors, a short-lasting effect. During this receptorblockade, thebody produces large amounts of opiatesin response to the positive feedback, which becomeavailable to andsaturate said receptors, once the LDN

has been cleared from them. Opiates are powerfulinducers of the Th1 immune response: in this sense,then, LDN produces an indirect immune response.LDN has a stimulatory effect on immune cells via anindirect interaction with their opiate receptors,whereashigh-dose naltrexone hasan inhibitory effect.

The widely recognized pharmacologic effect of nal-trexone is the competitive inhibition of membrane-based opiate receptors that consequently produce anopiateblockade. Asa resultof this action, patientswhoare addicted to opiates or are chronic ethyl alcoholusers will not feel the normal high and should beinclined to discontinue these recreational activities.For this reason, naltrexone is considered an opiateantagonist.

Zagon and McLaughlin18 reported that very low-dose naltrexone slowed the growth of neuroblastomacells in culture and suggested that it therefore mayhave a role in the treatment of certain cancers. In a

2003 article, thesame authors suggestedthat the mod-ulation of cancer cell growth in tissue culture was notthe result of alterations in apoptosis or necrosis butfrom some other pathway.19

Malignant astrocytomas are believed to be incur-able; therapy forsuch isaimed atpalliation andoverallsurvival. Lissoni et al20 reported on the treatment ofmalignant astrocytomas with the administration ofnaltrexone plusradiotherapy (RT).Thetumor regres-sion rate in patients treated with RT plus naltrexonewas slightly higher than that of those treated with RTalone, but the percentage of those surviving at 1 year

was significantly higher in patients treated with RTplus naltrexone than in those treated with RT alone(5/10 vs 1/11, P< .05).

In a later article, Lissoni et al21 reported escalationof IL-2-dependent anticancer immunity by the admin-istration of melatonin (MLT) plus naltrexone. Theresearchers found that these 2 agents were able tostimulate the Th1 and suppress the Th2 lymphocyteresponse.Theresults of their study also suggestedthatNTX amplified the lymphocytosis obtained by IL-2plus MLT. Inaddition, theauthorswrote that inview ofthe fact that lymphocytosis represents themost 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 thetreatment of people with cancer. Over the years, headministeredLDNto 450 patients withcancer, most ofwhom had failed the standard treatments.23,24Accord-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



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125 others were reported to have stabilized andappeared 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 treatedwith a standard chemotherapy regimen. Aftera singletreatment of gemcitabine andcarboplatin, thepatientbecame leukopenic and thrombocytopenic andcouldnot tolerate any further chemotherapy. In addition,

even with the standard chemotherapy protocol, hiscancer progressed.J.A. then arrived at the office of one of the authors

(B.M.B.) and was promptly started on a program ofintravenous ALA, LDN, and a healthy lifestyle pro-gram. During the period from October 2002 to pres-ent (December 2005), J.A.s pancreatic cancer withmetastases to the liver was followed closely by regularoffice visits and CT and PET scans, and he hasremained mostly stable (Figure 7). It is interesting tonote that J.A.s disease progressed rapidly when he

went off the ALA-LDN therapy; however, it stabilizedquickly when he resumed the treatment.

J.A. went back to work soon after he started theALA-LDNintegrative treatment protocol andremainsfree of symptomsat3 years and 3 months. The authorsbelieve that since most people with metastatic pancre-

atic cancersuccumbtotheirdiseasemiserablywithinavery short time, the 39-month survival time with non-progressive disease reported here represents a bench-mark in oncology. People with metastatic pancreaticcancer more oftendie from their disease or complica-tions thereof within 6 months and usually after a verystressful and painful course. The report above is thusof great importance.

In summary, the integrative therapy described inthis article may have the possibility of extending thelife 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 thatcan stimulate an endogenous immune response. Theauthors believe that biomedical science will one daydevelop a cure for metastatic pancreatic cancer, per-haps via gene therapy or another biological-type plat-form. But until such protocols come to market, andmoreover evolve and become realized, the ALA/LDNtherapy should be considered given its lack of toxicityat levels reported herein, ready availability, and itseffect on J.A., the true subject of this report.

B. Berkson declares no financial interest in thesub-

stances discussedin this paper butuses lipoic acid andnaltrexone in his medical practice.

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Figure 7 Computed tomography scan from June 2005 showssta-ble primary metastatic hepatic lesions (top) and stableshrunken primary pancreatic lesions (bottom) as com-pared to October 2002.

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Berkson et al (2006)