Off-label Drugs – An Intro

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The off-label use of a drug is the prescription or taking of a medicine for other than what it was originally intended for as described or approved by the US FDA or similar regulatory body. Simply put, medication usage for what is not on the official label of the drug is “Off-Label”.

Although hardly uncommon, there are distinct reasons why off-label prescribing is not as common as it ought to be if based on scientific evidence of efficacy alone. Firstly, it is unlawful to market, advertise or promote the off-label use of drugs (See an example of the intricacies and complexities as well as the conundrum of off-label regulation by FDA, US Congress and the Courts as evidenced by the recent saga of the Neurontin case in this 2004 paper by Robert Kaufman of the Harvard Law School).

Secondly, the insurance industry frequently invoke the off-label nature of a prescription to decline payment (ie they will not pay if they can find a reason not to pay, why would they? See illustrative story here), although Medicare in recently expanded its coverage of off-label treatments for cancer (See related news here), although it mainly applies to the use of an agent already approved for the coverage of some form of cancer to be covered when used for a different cancer, which is quite different from the drugs presented here ( approved for some other condition than cancer, to be applied for use as an anti-cancer), ie it is off-label use of a cancer drug rather than off-label use of a drug for cancer.

Finally, although the FDA does not regulate the individual physician’s prescription of a drug as long as it has been approved,  the legal liability for the physician is deemed higher especially if harm arises out of the course of its use and if it seems to deviate from “standards of care” which is how physicians are legally judged. Furthermore, physicians may be deemed to be engaged in human experimentation when prescribing drugs off-label (See a balanced discussion by Maxwell Mehlman JD on the legality and bioethics issues of off-label prescribing here)

It is because of potential legal risk on the part of the prescribing physician, limitations of insurance reimbursement, as well as the lack of knowledge about the potential off-label usefulness that limits the broader use of such drugs.  The unlawfulness of pharma related marketing or promotion and their lack of interest in investing in new clinical trials to demonstrate new indications when a drug has already gained FDA approval is often a factor limiting the broader use off-label treatments.

Back to the cancer patient: my purpose here is just to broaden the awareness of the science behind the usefulness of some very common and some not so common drugs that could jointly or otherwise enhance a patient chances of overcoming cancer, and to disentangle the healing process from insurance red-tapes and legal suffocation (See Disclaimer).

More useful info on Off-label Drugs for cancer can be found at the NCI site here.

Urso as Chemopreventative

Off-label therapeutic inspirations sometimes come from my patients.

And this one came from Noreen T.  Noreen has advanced metastatic breast cancer refractory to almost all treatments and has just started on an investigational Dendritic vaccine + Zadaxin (thymosin) but her disease is progressing rapidly with rising markers and an obstructive jaundice caused by liver metastases.  External drainage and internal stenting was out of the question and she was offered lactulose as we need to buy time for the immune treatments to work.  In my searches, I came across Ursodiol (Urso) which I am familiar with in its use in preventing gallstones or for primary biliary cirrhosis and other cholestatic conditions.  Its just that its not usually used in oncology.  Researching deeper led to the interesting discovery for me that it is also an anti-cancer (which I doubt that most my hepatology or GI colleagues are aware). Even more interesting was a converse (vis-a-vis this blog) discovery, that Tamoxifen which is traditionally used for breast cancer, may be useful as an off-label treatment for primary biliary cirrhosis (Reddy et al. Liver Int., 2004 Jun;24(3):194-7)!  So thank you Noreen for leading me to a treasure trove of discoveries!

What is Urso?

Ursodiol or Ursodeoxycholic (Actigall, URSO) is a naturally derived bile acid that decreases the amount of cholesterol produced by the liver and absorbed by the intestines. Interestingly, ursodiol is found in large quantities and the major therapeutic ingredient in bear bile, which is an established if controverial member of traditional Chinese medicine’s pharmacopoeia. Ursodiol helps break down cholesterol that has formed into stones in the gallbladder and is also hepatoprotective. Ursodiol also increases bile flow, which is why it is useful in cholestatic conditions such as biliary cirrhosis.  Since the 1980’s, Urso has been in widespread clinical use for biliary conditions. But what surprised me when researching the potential application of Urso for Noreen’s case is the anti-cancer properties of Urso.

Urso and Cancer

Earnest DL et al. from the U. of Arizona reported as early as 1994 that Urso is a potential chemopreventative agent in experimental colon cancer and highlighted a role of bile salts in modulating gastrointestinal cancer development, and it wasn’t long before Urso became a recognized chemopreventative agent against colon cancer in those with inflammatory bowel disease (See Itzkowitz SH, Gastroenterol Clin North Am. 2002 Dec;31(4):1133-44).  In 1997, the Korean team Park YH et al. reported that Urso induced apoptosis (suicide) of liver cancer cells in vitro (Arch Pharm Res. 1997 Feb;20(1):29-33) and the same team further demonstrated derivatives of Urso had efficacy against prostate and breast cancers in later studies. Im and Martinez more recently demonstrated that Urso induced apoptosis in colon cancer partly via modulation of EGFR/Raf-1/ERK signaling (Nutr Cancer. 2005;51(1):110-6.) A most recent review of Urso as an apoptotic is found in a review by Amaral JD et al. in J Lipid Res. 2009 May 5.

Granted, clinical data for Urso as a cancer treatment is not available and its main potential seems to be the use as chemopreventative in those at high risk for colon or liver cancers to reduce the risk, but attempts to synthesize Urso and other bile salt derivatives for cancer treatment is already on the way.

Noscapine near perfect?

Solid science, potential efficacy, minimal toxicity and low cost – that would be a nearly perfect anti-cancer, wouldn’t it?

This is not an entirely new one.  Noscapine (also, see NCI drug dictionary) a naturally derived and existing ingredient of OTC cough medicines in some countries, it has more data backing its usefulness against cancer than its relative Naltrexone (a fellow off-label anti-cancer candidate which is opiate derived) and works like the chemo drug paclitaxel (Taxol) but without many of the nasty side-effects, all of which has been known for some time.

So, what is Noscapine?  It is a non-opiate alkaloid from plants of the poppy family that makes up 1-10% of opium’s alkaloid content, but without significant pain killing properties. This agent is primarily used for its antitussive (cough-suppressing) effects, and is approved for use as such in some countries, but not in the US.

Mechanism of Action

A review by Ye et al. from Emory, where much subsequent in vitro and in vivo research on its anti-cancer effects were done, presented as early as 1998 (Proc Natl Acad Sci, 17;95(4):1601-6.) demonstrated elegantly how Noscapine may inhibit cancer by interfering with microtubular function at the cellular level, thereby arresting cell growth and  inducing cellular suicide or apoptosis, much like taxanes and the vinca alkaloids do. Noscapine binds to tubulin and alters its conformation, resulting in a disruption of the dynamics of microtubule assembly (by increasing the time that microtubules spend idle in a paused state) unlike other tubulin inhibitors such as the taxanes and vinca alkaloids which affect microtubule polymerization. Perhaps more importantly, Noscapine was able to inhibit cancer at doses which produced little or no toxicity, including no adverse effects on the primary immune response (Ke Y et al. Cancer Immunol Immunother. 2000 Jul;49(4-5):217-25).  More recently, Newcomb et al. from New York also demonstrated potential anti-angiogenic activity of Noscapine as an alternate anti-cancer mechanism (Int J Oncol. 2006 May;28(5):1121-30)

In Vitro

Noscapine inhibits paclitaxel resistant ovarian cancer cells (Zhou, J et al. J Biol Chem. 2002 Oct 18;277(42):39777-85); C6 rat glioma when administered alone, (as well as augmented the cytotoxicity of radiation and chemotherapy upon C6 rat glioma cells when administered concomitantly – Surg Neurol. 2006 May;65(5):478-84), HL60 and K562 myelogenous leukemic cells Anticancer Drugs. 2007 Nov;18(10):1139-47),

In Vivo

Noscapine inhibits murine lymphoid tumors,  human breast and bladder in nude mice murine (Ye, 1998), prolonged survival in melanoma (Landen et al. Cancer Res. 2002 Jul 15;62(14):4109-14), crosses the blood brain barrier and inhibited implanted C6 glioma in the rat model (Landen, Clin Cancer Res. 2004 Aug 1;10(15):5187-201), and has potent anti-cancer activity in the non-small cell lung cancer model Cancer Chemother Pharmacol. 2008 Dec;63(1):117-26).

Generating the most buzz was the last year’s demonstration by Dr. Barken of San Diego of Noscapine’s ability to inhibit progression and metastates (60% and 65% respectively) inPC3 human prostate cancer-bearing immunodeficient mice Anticancer Res. 2008 Nov-Dec;28(6A):3701-4.)

Clinical (human) Studies

Unfortunately, although a phase I/II clinical trial of Noscapine (CB3304) for patients with refractory non-Hodgkin’s lymphoma and chronic lymphocytic leukemia at USC / Norris Cancer Center was planned in 2003, it was terminated early because of apparent funding issues.  However, interim results in 2005 on 12 patients recruited thus far suggested that one out of ten patients evaluable did have a partial response, and two other patients demonstrated stable disease.  The research team stated that they were encouraged by the results. Cougar Biotech Inc. currently has a phase I trial of noscapine in patients with multiple myeloma ongoing at the Center for Lymphoma and Myeloma/Weill Cornell Medical College and Columbia University Medical Center, and Dr. Barken of the Prostate Cancer Research and Educational Foundation (PC-REF) in San Diego, California, is planning on facilitating clinical trials with noscapine in prostate cancer.

My Take

Potentially useful against CLL leukemia/lymphoma/myeloma, prostate cancer, non-small cell lung cancer, glioma (administered alone or in combination with chemo and/or radiation to enhance cytotoxicity), hormone resistant breast cancer, or perhaps co-administered with taxanes.

Distinct advantages include i) oral bioavailability, ii) encouraging experimental data, iii) low toxicity, iv) low cost, and v) synergistic potential with other modalities and drugs.

The future lies with more affirmative clinical trials and the development of more potent derivatives such as 9-bromonoscapine (Mol Cancer Ther. 2006 Sep;5(9):2366-77) and to develop other analogs of Noscapine with higher tubulin binding activity  and/or affect tubulin polymerization differently, or able to arrest cell cycle progression at lower concentrations.

Clarithromycin for lung cancer

Advanced comments welcome … In the process of reasearch and writing up, thank you for your patience !

Artesunate and Antimalarials for Cancer

Advanced comments welcome … In the process of reasearch and writing up, thank you for your patience !

Gamma-Delta Immunotherapy

A Preamble

γδ T cells or “gammadelta” T cells are unique to primates and represent a minority white cell in our blood (0.5-5%); yet they play an essential role in sensing ‘danger’ by invading pathogens as they expand dramatically in many acute infections and may be a key fighter in cancer as well.  I want to discuss very exciting findings of how to harness these cells as an anticancer strategy but why does it belong in this blog?

Technically, gammadelta therapy is an immune therapy and is not “off-label” per se, because since these are a patient’s own cells, there is no issue of FDA approval or non-approval, and thus no issue of being on or off-label !   But, the key here are the drugs used to expand gammadelta T cells to use them to fight cancer are approved for other uses and these agents can be used off-label to direct the expansion of gammadelta T cells, hence the mention of this treatment here.

I am not easily excited, having been “in the business” if you will for decades and having seen so many mediocre agents and methods come and go in our “war against cancer” where true advance has been been disappointingly few.  But this time we may be on to something truly special.  The title of a recent review article by N Caccamo of Italy “Amiophosphonate-activated gammadelta T cells in immunotherapy of cancer: Doubt no more” ( Expert Opin Biol Ther 2008 Jul; 8:7, pp. 875-883) sums up the excitement.

Some Background

The background is not necesarily an easy one to understand if you do not have a science or medical background.  There are surprisingly few general introductory books on the topic, but the dated (1992) paperback “The Transformed Cell” by Steven Rosenberg is still a good primer for those who are interested but not necessarily want to earn college credit on the subject. And if you are not much interested at all in how this method works and all the immunology mumbo jumbo, but just want to know the practicalities of the treatment, you may as well skip to the last 2 sections to avoid a headful (and a headache!).

I have also put in BOLD some key concepts here in  order to highlight the key concepts for non-scientist or patients to help understand all this.

We as mammals have two innate immune defense systems:  an adaptive immune system unique to vertebrates in which lymphocytes participate with recognition of peptide antigens and which can be defined by memory of the target; and a more ancient innate immunity which is cell based (macrophages, monocytes, NK cells, NKT cells, dendritic cells) and which has no memory once demobilized.  The gammadelta cells can be thought of as unconventional T cells at the interface between and linking the two immune systems, and contribute to the elimiation of infections or cancers by direct and indirect killing as well as modulation and stimulation of other immune cells (eg macrophages and NK cells) and the secretion of cytokines, notably interferon gamma and TNF-alpha.

Gammadelta T cells were known since the time when I was graduating medical school, in the mid to late ’80s (See Lanier et al. The gamma T cell antigen receptor. J Clin Immunol 1987;7(6):429-40 and Pardoll et al., The unfolding story of T cell receptor gamma, FASEB J, 1987; 1(2):103-9.) and it became known  that gammadelta T cells can kill tumor cells.  However, over the years, these cells received much less attention than Natural Killer (NK) cells, NKT lymphocytes and the much more populous alphabeta T cells in regards to applications in cancer immunotherapy.

The use of killer cells against cancer has been a focus of research for nearly two decades. Since the original descriptions of in vitro lymphocyte-mediated cytotoxicity against cancer, there have been numerous quasi-sucessful attempts to exploit these for therapeutic use in the clinic.  I say “quasi-successful” because there are no mind blowing successes, regretfully.  Most modern research have focused on the role of either natural killer (NK) cells or cytotoxic CD8 + alphabeta T cells , and little attention has been paid to the role of gammadelta T cells due to a lack of understanding of how they work, as well as the practical problem of obtaining enough of them for bedside use.  Our clearer understanding of these cells and their role in infections, cancer and autoimmunity is only surfacing recently (The first world conference on gammadelta T cells only got under way in 2004).

Gammadelta cells share with alphabeta T cells certain functions such as cytokine production and potent cytotoxic (cell killing) activity but gammadelta cells recognize different sets of antigens, usually in a non-MHC-restricted fashion, and cancers are highly susceptible to gammadelta T-cell mediated lysis which led to the proposal that gammadelta T cells can be used for cancer immunotherapy (See Kabelitz D, Potential of human gammadelta T lymphocytes as immunotherapy for cancer, Int J Cancer 2004 Dec 10;112(5):727-32). Unlike conventional T lymphocytes which recognize peptide antigens,  this “alternative” T cell’s ability to recognize tumor cell ligands not seen by conventional alphabeta T cells is one property that makes them intriguing. The other unique property is the way they recognize antigens circumvents to ability to of cancer cells to eventually elide detection.

In Vitro Work

It has long been known that these cells can kill cancers.

Gammadelta T cells are able to kill myeloma (Kunzmann et al. Blood, 2000; 96(2): 384-392, also Clin Exp Immunol, 2006;144(3):528-33) and lymphoma cells (Fisch et al. Europ J Immunol 1997;27:3368-3379)

Human Vgamma9Vdelta2+ gammadelta-T cells found able innately to recognize and kill certain human prostate tumor cell lines (DU-145 and PC-3 but not LNCaP) (Liu et al. J Urol, 2005;173(5):1552-6).

Gammadelta-T cells are able to innately recognize and kill human breast cancer cells in a gammadelta-TCR-dependent manner (Guo BL et al. Breast Cancer Res Treat 2005; 93(2):169-75.).

Freshly prepared gammadelta T cells consisting mainly of Vdelta2 gammadelta T cells showed increased cytotoxicity against bisphosphonate-treated pancreatic carcinoma cells (J Immunother 2007; 30(4):370-7)

In summary, most epithelial tumours (including melanomas, pancreatic adenocarcinomas, squamous cell carcinomas of the head and neck, and lung carcinoma – See Scan J Immunol, 2007;66(2-3):320-8) were susceptible to allogeneic gammadelta T-cell lysis and in the case of an established ovarian carcinoma, to autologous gammadelta T-cell killing

Animal Studies

Early on. Hayday found that mice lacking gammadelta cells were highly vulnerable to skin cancer when exposed to carcinogens.

A ‘St Jude’s regimen” utilizing human gammadelta T-cells from leukapheresis and adoptive transfer of the cells with an anti-GD2 antibody and the cytokine Fc-IL7 demonstrated enhance survival in a mouse model of human disseminated neuroblastoma (Clin Cancer Res 2005;11(23):8486-8491.

In models of mice bearing localized and disseminated prostate cancer treated i.v. with gammadelta T cells developed measurably less disease and superior survival compared with untreated mice (Liu Z, J Immunol, 2008;180(9):6044-53).

Intravesical administration of gammadelta T cells with zoledronic acid demonstrated antitumor activity against bladder cancer cells in the orthotopic murine model and resulted in prolonged survival (Yuasa T et al. Cancer Immunol Immunother 2009;58(4):493-5020

Stimulating and Expanding Gammadelta T Cells is Key.

Just knowing gammadelta T cells can kill cancer cells is not enough.  We and cancer patients all have these cells, but how to harness them to fight cancer in us or our patients? The limitations up until late ’90s has been the difficulties associated with identifying, harvesting, and expanding the cells. Thus the  key is in growing or expanding these cells either in the laboratory and externally applying the cells to the patient ( so-called adpotive therapy) or to stimulate and expand the gammadelta cells in our bodies somehow.  Both have been looked into:

Gammadelta cells is known to be stimulated by a number of non-peptide phosphorylated antigens, including a number of mycobacterial and bacterial derived molecules as when one encounters when one catches one of these infections (eg TB, E.Coli), as reported since the early ’90s.  Reports of gammadelta stimulation and expansion by small phosphorylated metabolites, amino-bisphosphonates (risedronate>alendronat>pamidronate) and synthetic phosphoantigens (defined as small, phosphorus-containing antigenic molecules) followed, openning up the opportunity of clinically applying this as a practical cancer treatment (reviewed by Fourniee and Bonneville in Res Immunol, 1996;147(5):338-47).

Pioneering work by the Italian team Casetti et al. elegantly demonstrated that co-stimulation simply with interleukin 2 plus non-peptide antigens or amino -bisphosphonates induced up to 100-fold increases in the numbers of peripheral blood Vgamma9Vdelta2 T cells in animals and together with a German team led by Wilhelm M et al. (see below, this laid the ground work for subsequent clinical endeavours in this field (Casetti R et al. Drug-Induced Expansion and Differentiation of V9V2 T Cells In Vivo: The Role of Exogenous IL-2, J Immunol 2005;175(3):1593-8).

Exciting Human Observations and Clinical Data

In the past few years, clinical data has been pouring in fast and furious suggesting practicability and efficacy of this unique therapy.

In 2005, Bennouna et al. presented a phase I trial of 18 BrHPP (Phosphostim) and low dose IL-2 treated patients with solid tumors in a poster session at ASCO (JCO, 2005; 2005 ASCO Annual Meeting Proc 23(16S), Pt II of II:2536).

By 2007, Godder KT et al. from the US reported intriguing 5 year follow-up results showing three-fold overall survival advantage in acute leukemics with increased gammadelta cells following partially mismatched allogeneic stem cell transplantation, and postulated a graft versus leukemia effect (Bone Marrow Transplant 2007;39(12):751-7).

One of the earlier trials using gammadelta therapy was carried out by a German team from Wuerzberg utilizing low-dose interleukin 2 (IL-2) in combination with pamidronate in patients with relapsed/refractory low-grade non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). They observed significant in vivo activation/proliferation of gammadelta T cells in 5 out of 9 patients (55%) who had positive in vitro response to pamidronate / IL-2 stimulation and objective responses (PR) were achieved in 3 patients (33%) . And thus the team demonstrated for the first time that this therapy was feasible (Wilhelm M. et al, Gammadelta T cells for immune therapy of patients with lymphoid malignancies, Blood, 2003;102(1):200-6).

Very recently, a Japanese team from Tokyo attempted adoptive immunotherapy using in vitro-activated autologous gammadelta T cells against advanced renal cell cancer had found that it was well tolerated and induced anti-tumor effects (kobayashi H. et al, Cancer Immunol Immunother. 2007 Apr;56(4):469-76) . A French team using gammadelta T cells expanded in vivo with BrHPP (IPH1101, Phosphostim) and interleukin 2 (IL-2) at administered by infusion to metastatic renal cell cancer patients resulted in stable disease in 6 patients out of 10 (Bennouna J. et al. Cancer Immunol Immunother 2008;57(11):1599-609).

Almost simultaneously, the Italian team led by Dieli F of Palermo initiated a phase I clinical trial in metastatic hormone-refractory prostate cancer to examine the feasibility of using zoledronate in combination with low-dose interleukin 2 (IL-2) to stimulate gammadelta cells against the cancer and registered 3 partial remissions and five stable diseases out of nine patients (Dieli et al. Cancer Res.2007;67(15):7450-7) .

At the moment, there is at least one active phase I trial “Immunotherapy of Hepatocellular Carcinoma With Gamma Delta T Cells” which involves the direct intrahepatic injection of gammadelta cells going on in Rennes, France under the direction of Dr. Jean-Luc Raoul.

My Take

Although we have known about gammadelta cells, but the ability to use fairly straightforward medicines such as the amino-bisphosphonates and interleukin-2 off-label to dramatically expand these cells in a patient without serious side-effects opens the way to a practical immunotherapy.  The fact that there is laboratory data showing efficacy against leukemia/myeloma and also human experience which is positive for some solid tumor (prostate and kidney) cancer types gives hope that this treatment can be broadly deployed against an array of cancers, both hematologic and solid tumors.  The fact that this therapy calls for a protocol that is much more simple (30 minute treatment every month) than the parenteral Vitamin C protocol with much more science behind it than IPT (Insulin Potentiation Therapy) and other alternative cancer regimens makes this a very attractive options for patients seeking an alternative to conventional chemotherapy or radiotherapy.  Although NK cells are much more popularly known but there is no practical way to expand NK cells in the patient but this gammadelta therapy is eminently praticable.  My colleague Dr. Thomas Nesselhut at the Institut of Tumortherapie in Duderstadt, Germany is starting to apply this as a part of the Dendritic Cell therapy protocol that we have been collaborating on for the past 5 years and it appears quite promising.  We are currently gearing up to offer this as a viable alternative therapy while working out some of the legal and logistics hurdles to deployment.  All very exciting indeed.  Your comments welcome !

Future Directions

-> Clinical trials covering other cancers beyond prostate, kidney and myeloma. and NHL.

-> Development of more potent gammadelta stimulants or expansion protocols.

-> Exploring naturally-derived gammadelta agonists for dietary preventative therapeutic regimens.

-> Exploring the preventative possibilities of gammadelta therapy

Amino Bisphosphonates as Anti-Cancers

The use of bisphosphonates (eg Aredia, Zometa, Clodronate) for cancer is not new and is not considered off-label, so why this blog? Well, these agents are only applied narrowly and used palliatively in most cases, ie only in certain cancers (notably myeloma, breast, prostate and more recently lung cancers) and only when there is bone metastases.  I have recently discussed the potential for adjuvant use of Clodronate in breast cancer, but I will share here some of the very exciting recent discoveries with newer generation bisphosphonates [so-caled amino bisphosphonates or nitrogen containing bisphosphonates "NBPs", namely Aredia (pamidronate disodium) Zometa (zoledronic acid) Fosamax (alendronate) Actonel (risedronate) and Boniva (ibandronate)] as direct anti-cancers, ie the off-label potential to apply the newer generation NBPs in a combinatorial manner in the treatment of cancers.  So, where as it was originally and previously thought that bisphosphonates are useful in bone metastases because of the ability of these agents to inhibit bone resorption, newer understanding leads us to knowledge that such agents are really direct anti-cancers as well.  Without elaborating on the complex biochemical and molecular pathways (See diagram below, e.g. NBPs are thought to inhibit farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway,  in turn inhibiting the prenylation of small G-proteins such as Ras, Rap1, Rho and Rab, reduces the signals they mediate, and thereby prevents the growth, adhesion/spreading, and invasion of cancer cells) which have been extenstively reviewed, suffice it to say that NBPs cause direct cell cycle disruption and induce cancer cell death (so-called apoptosis), and this direct apoptotic effect of NBPs such as Zometa has now been reported in breast, prostate, myeloma, leukemia, colon cancers. Moreover, NBPs also independently inhibit cancer cell invasiveness, and exert anti-angiogenic effects as well via a variety of potential mechanisms.

(courtesy Caraglia M, et al. Endocrine-Related Cancer (2006) 13 p.14, Fig 2)

Now, back to the clinic.  With all the direct anti-cancer effects of the NBPs, we should then see some survival advantages of patients treated with Zometa or Aredia, but how come that hasn’t been widely reported and only noted in a subset of Zometa treated myeloma patients?  It seems like the problem is with the pharmacokinetics of the drugs themselves.  It turns out that not only are the half-lives of the drugs are very short in the blood ( no more than an hour or two), the maximum concentration achieved is also up to 100 fold less than what was demonstrated to cause cancer apoptosis (self-destruction) in the test tube experiments, although concentrations are adequate for anti-invasive effects.  These drugs tend to concentrate in the bones though, which explains why they are effective for controlling cancer metastatic to the bone.   However, all is not loss: it turns out that it is possible to manipulate the drugs to bring out its anticancer effects via pharmacological manipulations such as encapsulating the NBPs in liposomes and exploiting the NBP’s synergisms with other agents.

NBPs have been reported to be synergistic with various cytotoxic agents, cox-2 inhibitors, imatinib, bortezomib, rapamycin, ATRA (retinoic acid), thalidomide, histone deacetylase inhibitors (HDACs), and interferon beta on growth ihibition.

Perhaps most exciting is the recent finding that NBPs have immunomodulating properties, specifically by stimulating and expanding cytotoxic gammadelta T lymphocytes (See separate blog on this topic). There are very exciting recent reports of NBPs combined use with low dose Interleukin 2 (IL-2) to induce gammadelta T cells as immuotherapy against a variety of cancers.

My Take

NBPs are already in common use, and are quite non-toxic.  I think its use as a direct anticancer can be broadened to more cancer types as primary treatment used in a combinatorial manner if the latest research on gammadelta cell therapy (See my blog on this) is confirmed and its combined use with other potentially synergistic agents should be actively explored.  Based on principles of molecular action, I suspect that MMP inhibitors such as the tetracyclines and HMG Co-A reuctase inhitors (so-called “statins”, see separate blog on statins for cancer) should be synergistic with NBPs as well.  Baulch-Brown from Australia already demonstrated Zometa synergism with Lescol (Fluvastatin) against myeloma in vitro ( Leuk Res. 2007 Mar;31(3):341-52), and similar results were obtained with Zocor by a German group (Anticancer Drugs. 2006 Jul;17(6):621-9).  As to the choice of NBP, current research seems to point to Zometa as being more powerful but it has to be administered parenterally.  Ibandronate (Boniva) is worth exploring for application because it can be given orally and has a better safety profile although less data is available but maybe I will explore this in a separate blog soon!

Adjuvant Clodronate for Breast Cancer

Clodronate is a first generation bisphosphonate (a.k.a. clodronic acid, marketed under the Brand names of Bonefos, Clasteon, Difosfonal, Loron, Mebonat and Ossiten in Europe & the U.K., Canada, and elsewhere, not yet commercially available in the US, where the FDA deems it “approvable” as of 2005 ) that shares with its more famous cousin Fosamax the ability to inhibit bone resorption and is thus used for treating osteoporosis to increase bone mass and reduce fractures. Because of the propensity of these agents to adsorb mineral and inhibit bone resorption, they have also been applied to treat cancer metastases to the bone, as well as to lower cancer associated hypercalcemia since the 1980’s.  So why is it appearing in my blog as an “off-label” treatment for cancer? Well, it can be used in cancer as other bisphosphonates, but usually in a palliative sense to control bone metastases and/or hypercalcemia associated with cancer, but not as a standalone treatment for the cancer itself.  However, there is compelling data for Clodronate’s use as an adjuvant agent, especially in breast cancer.

In a pioneering double-blind controlled study of Clodronate in treating breast cancer metastatic to the bone, Canadian researchers Paterson et al. (1993) noted reduced bone-related morbidity in treated patients and recommended that Clodronate be further investigated for potentially reducing bone metastasis as an adjuvant treatment for those who are at risk.  Not long thereafter, Diel et al. (1998) from the University of Heidelberg published a landmark trial in the New England Journal of Medicine on the subject and found in the 302 patient randomized trial that adjuvant clodronate at 1600 mg a day reduced not only bone metastases in breast cancer, but reduced other organ metastasis as well as the risk of death.  Subsequent, a Finnish study published in 2001 unexpectedly showed a decrease in survival in clodronate treated breast cancer patients, thus confounding the topic.  With accumulating evidence in favor, the FDA issued an approvability letter in 2005 for the use of clodronate as an adjuvant treatment in breast cancer. Finally in 2006, a larger randomized double-blinded placebo controlled multi-center study of over one thousand patients over 5 years confirmed reduced skeletal metastasis as well as possibly favorable survival in breast cancer patients (esp those with Stage II or III disease rather than Stage I) receiving clodronate as adjuvant over the initial 2 years.

There are quite a few discussions and review of the use of clodronate for breast cancer online and there is no doubt remaining controversy based on the earlier Finnish trial and a more recent meta-analysis which found no attributable benefit to the drug.  Furthermore, the drug is not commercially available in the US and not FDA approved despite its approvability, and these all hinder more wide-scaled use of the drug.  Lately, there has also been increasing concern for the risk of osteonecrosis of the jaw as a complication of long-term bisphosphonate use, but unlike other bisphosphonates, the risk of ONJ with clodronate is extremely low at 0 – 0.5% (rare cases reported only) after taking it for 2 years (see Mayo Clin Proc 2007; 82:516-522), and this should not be a major deterrent in those considering its use.

My Take

Given some of the favorable trial results above and the very safe and relatively inexpensive (under $200 per month from Canada) nature of the drug, in addition to its benefit in reducing bone loss in breast cancer patients simultaneously receiving anti-estrogen therapy, I think Clodronate ought to be seriously considered as adjuvant treatment for Stage II and III breast patients, and I have been recommending it for the past 5 years.  It is not available in the US, but can be obtained from Canada, Mexico, Europe and Asia. Newer generation bisphosphonates may have more potent anti-cancer potential (See my more recent blog on gammadelta cell therapy as well as amino bisphosphonates if interested) and may in the future replace Clodronate for this use, so I eagerly await further trials in the area of using bisphonates as adjuvant therapy for breast cancer.

Tetracyclines for cancer

PPAR agonists for cancer

Naltrexone for Cancer

Naltrexone is an opioid receptor antagonist approved and used for management of alcohol and opioid dependency.  Low dose naltrexone or LDN (at 1/10th of the dose used for drug rehab) however has been proposed as an off-label therapy for a broad range of immune disorders such as HIV, MS, autoimmune thyroiditis, and colitis, and is one of the more popular off-label treatments for cancer thanks to some promising trials, low toxicity, relative low cost and much internet publicity such as found on the Low Dose Naltrexone Homepage and a Low Dose Naltrexone Forum.  But what is the connection between cancer and opioids? And most importantly, does it work?

Opiates and Cancer

First some background on opioids and cancer.  Firstly, there is the difference of endogenous opiates (eg endorphins and enkephalins) vs. exogenous opiates (drugs).  The effects of opioids on cell growth is complex and is believed to be mediated through opioid and non-opioid receptor signalling (See Chen YL et al. The Other side of the Opioid Story: Modulation of Cell Growth and Survival Signalling, Curr Med Chem 2008:15(8):772-8), thus opioids directly modulate cell growth and endogenous opiates can directly suppress cancer growth.  On the other hand, exogenous opiates can suppress the immune system, which is not ideal for treating cancer. It has been known for some time from animal studies that opioids interfere with the immune system ( Sacerdote P, Opioids and the Immune System, Palliat Med 2006;20 Suppl 1:s9-15), and that opioid pain killers such as morphine can decrease and depress immunity.  In animal studies for example, morphine causes worsening of cancer, although the effect is different amongst different opioids, with buprenorphine (“Bupe”) perhaps the least immunosuppressive.

Background 1: Zagon

Now back to Naltrexone, an opioid antagonist.  There is no doubt that Dr. Ian Zagon at Penn State is a major pioneer researcher in endogenous opiates and the major bench-side explorer of “off-label” applications of LDN.  In his own words about the journey of discovery of opioid effects on cancer, he said : “When we discovered the effects of opioid antagonists such as naltrexone and naloxone in 1979, this was purely happenstance. Around 1975, we were interested in the effects of opiates… on children who were born to mothers that were addicted. The scientific literature revealed that these babies and children had neurological difficulties and were lower in body weight. We (myself and Dr. Patricia McLaughlin) developed a model to look at this in animals. Along the way, I was doing another project on neuroblastoma, a childhood tumor. When I found that these exogenous opioids altered growth of these developing animals… This started in 1977-1978. We then progressed to injecting cells into mice and creating cancers, and examined whether these exogenous opioids would repress growth of these cancers. In fact, they did…” (as quoted on the LDN forum).

It turns out from Zagon’s research, that the central actor may be one “OGF” or opioid growth factor, or otherwise known technically as [Met5]-enkephalin.  Zagon proposed that OGF is an inhibitory peptide whose action is modulated via an OGF receptor and which modulates cancer cell proliferation and migration, and angiogenesis. Zagon has demonstrated that OGF inhibits pancreatic (BxPC-3), colon (HT-29), renal cell (Caki-2), neuroblastoma, and head and neck (CAL-27) cell lines (Int J Oncol, 2000 Nov;17(5):1053-61). Moreover, OGF also suppressed pancreas cancer in animals (Cancer Lett 1997 Jan 30;112(2):167-75) , and synergistically enhanced the efficacy of chemotherapy against pancreas cancer (Cancer Chemother Pharmacol 2005 Nov;56(5):510-20) and enhanced survival in squamous cell head and neck cancer as well(Cancer Chemother Pharmacol 2005 Jul;56(1):97-104).  Based on such observations, Zagon & McLaughlin filed a patent in 1997 claiming that the administration of an opiate antagonist such as Naltrexone “at an amount sufficient to effect the intermittent blockade of the zeta receptor present in the cancer (and surrounding tissues) thereby producing a subsequent period of elevated endogenous enkephalin levels or receptor numbers to inhibit, arrest and even prevent tumor growth” (US Patent 6136780)

Background 2. Bihari

Almost working in parallel as Zagon, but from the clinical side and not in the laboratory, there is one Dr. Bernard Bihari, who is an addiction specialist who used Naltrexone and claims to have discovered the immunomodulatory benefits of Naltrexone in 1985.   The story goes that Dr. Bihari began noticing in the 1980s that some of his addict patients with immune deficiency (subsequently discovered to be HIV/AIDS) had symptomatic improvement on lower doses of Naltrexone, so he conjectured that Naltrexone somehow upregulated their immune system (See AIDS Patient Care 1995 Feb;9(1):3).  Along this line of thinking and based on some reports that lymphoma responded to endorphin treatment in animals, he had treated a recurrent lymphoma patient with low dose naltrexone and the lymphoma got better.  He subsequently also treated a woman named CP with advanced melanoma and the cancer responded. Then from 1999 onwards, Dr. Bihari investigated the effects of LDN in private patients, using a low dose of 3mg given at night and theorizing that the treatment induced an increase in endorphins, especially metenkephalin, in the pre-dawn hours.  The endorphins would in turn directly suppress cancer growth and upregulate the immune system.  This theory coincided with Zagon’s animal work on how OGF may inhibit cancer and is consistent with the actions of naltrexone.  Unfortunately, there has not been any organized clinical trial or even published case series on this, except for what has been presented in the Low Dose Naltrexone website, that “as of March 2004 … medication by Dr. Bihari in some 450 patients with cancer, almost all of whom had failed to respond to standard treatments, suggests that more than 60% of patients with cancer may significantly benefit from LDN. Of the 354 patients with whom Dr. Bihari had regular follow-up, 86 have shown objective signs of significant tumor shrinkage, at least a 75% reduction. 125 patients have stabilized and/or are moving toward remission” Apparently,  of patients treated, “88 LDN-only group includes five breast cancer patients, one patient who had widespread metastatic renal cell carcinoma, three with Hodgkin’s disease and six with non-Hodgkin’s lymphoma. Reportedly, other cases, some on LDN for as long as four years, included a score of patients with non-small cell lung cancer, as well as patients with ovarian cancer, uterine cancer, pancreatic cancer (treated early), untreated prostate cancer, colon cancer, malignant melanoma, throat cancer, primary liver cancer, chronic lymphocytic leukemia, multiple myeloma and some others” according to another website.  Again reportedly, in June 2002 an oncologist and an oncology physician’s assistant from the National Cancer Institute reviewed some 30 charts of cancer patients at Dr. Bihari’s office, and about half were chosen as appearing to have responded to LDN without question.  Supposedly, copies of these records were sent to the NCI for further data collection on its part for consideration for NCI’s Best Case Series. Four cases of prostate cancers responding to LDN was reported as well in a patent “Method of Treating Cancer of the Prostate” Bihari filed in 2000. But again, regretfully, none of any of these cases ended up being published in the medical literature, and they circulate as quasi-anecdotal mentions online.

How might Naltrexone work in cancer?

In summary, based mainly on Zagon’s work, naltrexone at low dose administered nocturnally could bne postulated to work via 1) a stimulation of endogenous opiates as well as the number and density of opiate receptors on tumor cell membranes making them more responsive to the inhibitory effects of circulating opiates, which in turn suppresses tumor growth directly, 2) an enhancement of cellular immunity as a result of effects of higher levels of endogenous opiates, and 3) metabolites such as methylnaltrexone which exert antiangiogenic effects.

What does the medical literature say?

Bihari had published nothing on LDN and cancer in the medical literature.

Zagon had reported on using naltrexone in a mouse neuroblastoma model showing inhibition of growth and prolonged survival in those mice that develop tumors and protected some mice from developing tumors altogether (Brain Res 1989 Feb 20;480(1-2):16-28).  At a similar dose of 0.1mg/kg, his team was also able to retard implanted human colon cancer in mice (Cancer Lett 1996 Mar 29;101(2):159-64), apparently via an stimulation of metenkephalins, which is in line of his research hypothesis.

Clinically, only two single case reports of 1) a long surviving metastatic pancreas cancer treated with LDN and alpha-lipoic acid (Integr Cancer Ther 2006; 5(1):83-9), and 2) a B-cell lymphoma with clinical reversal using only LDN Integr Cancer Ther 2007; 6(3):293-296) can be found in the medical literature that I can find.

Along these lines, an OGF plus gemcitabine for pancreas cancer trial is on the way (starting this month!) at Penn State, but while there are several trials on LDN for Crohn’s and MS and other conditions on the way, there is nothing on the horizon testing LDN for cancer per se.

My Take

I have been prescribing off-label Naltrexone to my cancer patients for many years.  I remember being asked by organizers from Drs. Bihari’s camp to present at the 1st Annual LDN Conference in 2005 but declined to attend because I had no clear cut cases to report  (Then they asked me to report on the tolerability of the treatment, which is not meaningful, and I didn’t go).  Indeed, over the years, I have not seen any definitive responses that I can attribute to LDN with certainty.  I wish to give some credence to the cases of response found online, but such are anecdotes that cannot strictly be considered admissible evidence in clinical science, only suggestive leads for further investigations. There are inherent limitations for testing LDN of course: not every patient is a candidate (eg if on narcotics for cancer pain) for LDN and most who take it are on at least a few other treatment modalities making a judgement of LDN efficacy difficult.  Then also, the drug itself is cheap and generic and thus there is no industry interest in funding formal trials.  However, I still prescribe LDN to this day since the theoretical background is not unsound, the side-effects are minimal, and the substance is readily available and at such a reasonably low cost that I usually do not mind the addition of LDN to a patient’s treatment, especially if requested and especially in cases of pancreas or colon ca, melanoma, SCCHN where there has been studies or prostate cancer where there has been a patent filed.  Personally, I think LDN may perhaps have greater promise in other conditions such as Crohn’s and MS rather than cancer, and OGF may be a more direct opioid treatment option for cancer in the future.

Your comments welcome.