Is There a Role for Maintenance Therapies in Medical Oncology?

There is a long tradition of maintenance therapy in pediatric oncology. Children with acute lymphoblastic leukemia uniformly receive three stages of therapy: induction, consolidation, and finally maintenance. The maintenance stage consists of weekly, or even daily therapies.

The historical experiences of relapse in this population lead investigators to consistently expose these patients to drugs for a period of years. Despite the apparent success of this approach in childhood cancers, long-term maintenance therapy did not gain popularity in adult oncology. Why?

There are probably several reasons. One reason is that childhood leukemia is among the most chemo-responsive diseases in medicine. As such, there are many active drugs available for treatment and many non-cross-resistant maintenance schedules that can be employed.

A second reason is the relative tolerability of drugs like oral thioguanine or mercaptopurine that are used in chronic maintenance therapy. By contrast adult tumors rarely achieve complete remissions. The number of active drugs has historically been very limited and the tolerance of long-term treatments characteristically poor.

Despite this, there is an appealing rational for maintenance therapy. Once we recognized and incorporated the tenents of apoptosis and programmed cell death into cancer management, we were forced to reconsider many of the principles of older treatment protocols.

Conceptually, maintenance allows for a cytotoxic exposure when the cell enters a “chemosensitive” period in its life cycle.  Cancer cells that are “out surviving” their normal counterparts often do so in a quiescent stage (G0 Gx). In order to capture these cells, drugs must be present in the body when these cells awaken from their dormancy. As we have now achieved increasingly durable remissions in diseases like breast cancer, small cell lung and ovarian, we are confronting patients in long-term complete remission. When you add to this newfound population the availability of comparably mild agents, like the low dose Gemcitabine/Cisplatin doublet, we now have at our disposal active drugs that can be safely continued for long periods of time.

Using laboratory selection to identify first line (induction), second line (consolidation) and finally third line (maintenance) schedules, we can now offer our patients well-tolerated combinations that offer the hope of more durable remissions.

The GOG 178, in which continued taxol dosing provided more durable remission in ovarian cancer, provided the first inklings of this. Unfortunately, taxol is toxic. And the more durable remissions came at an increasingly high price: neuropathy, myelosuppression, alopecia, fatigue and malaise, which greatly limited the utility of this approach. Yet it does not limit its theoretical attractiveness as we continue to develop targeted agents with more selective activity and modified toxicity profiles. We anticipate maintenance therapies will become more widespread.

Based upon our experiences to date, we are successfully using this approach with our patients who achieve good clinical remissions.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

11 Responses to Is There a Role for Maintenance Therapies in Medical Oncology?

  1. Rich66 says:

    I would think metronomic oral chemos and hormonals would be good partners for post induction. Of course, a cell test post induction might give better identification of most active/least toxic regimens for consolidation and maintenance.

    • Metronomic therapy, the low dose continual exposure to drugs, in part intended to target the tumor vaculature and microenvironment, might be an interesting adjunct to more toxic, induction regimens. Trials using cytoxan plus avastin, for example, have been conducted, using this concept in ovarian cancer. I would agree that some form of “mild” post treatment low dose therapy is most appealing. The exact right drug or drug combination to achieve this goal has remained elusive, but it is a great concept to pursue.

      • Linda S. says:

        Hi Dr. Nagourney —
        If you don’t mind one more question? There have been some interesting reports on some commonplace drugs that seem to have potential roles in fighting ovarian cancer, perhaps usable in a maintenance mode: low dose naltrexone (from UPENN study), beta blockers (from MD Anderson), copper-chelating agents typically used in Wilson’s disease, cox inhibitors like Celebrex…. is there any way to study this potentiality in assays, either singly or in combination?

        thanks as always,

        Linda

  2. Elaine L. says:

    Dr. N, what is your position on using hormonal therapy for women whose ovarian cancer tumor tests ER+. We on the Ovarian Cancer National Alliance have found that there is no uniformity among oncologists on this issue. My oncologist says that it has not been proven to help in OC as it has in BC.

    • As you are aware the ovary produces estrogen (E2) during reproductive years. The breast and uterine endometrium among other organs are the targets of this important steroid, While the ovary is less estrogen dependent, being driven by the pituitary LH and FSH, ER(+) status in ovarian tissue is common. The term “driver” is increasingly used to describe mutations that “drive” cancers, as opposed to “also ran” mutations, that may be epi-phenomena. Arguably some ovarian cancers might be driven by their ER(+) status and we know that some physicians use Tamoxifen in the later stages of this disease. What would be of interest would be a measure of down stream signaling assocaited with the ER(+) patients to better define those most likley to respond to E2 inhibition. Our EVA-PCD platform usually does not give strong cell-death signals for Tamoxifen esposure in most tumors. To date, the data in OC has been much less impressive than that in BC. Nonetheless, there may be a subset of patients who would benefit. We should re-double our efforts to identify candidates for this or related simple approaches to adjuvant therapy.

  3. Barbara Frese says:

    Maintenance therapies make sense to me and glad to hear your opinion about it.

  4. Linda S says:

    Dr. N — do you have an opinion on vaccines for cancer?

    Linda S.

    • Vaccines are an immensely appealing approach to cancer therapy. Unfortunately, to date, they have not provided very high response rates. The concept being to “wake up” the immune systme by exposing it to cell extracts as antigens. Melanoma and Lymphoma have been favored targets to date. By adding adjuvants like Keyhole Limpet hemocyanin (KLH) or GM-CSF it had been hoped to further excite the immune response. While the results have been modest, the recent success with the related Dendritic cell therapy sipuleucel-T (Provenge) has provided survival advatage in prostate. It is a very important and worthwhile field and will some day provide a useful tool in this fight.

  5. Dr. Nagourney

    Although the EVA-PCD (functional profiling) platform usually does not give strong cell-death signals for tamoxifen exposure in most tumors, sometimes agents can “chemosensitize” tumor cells. There is a chemosensitizing effect of tamoxifen.

    A functional profiling assay is conducted on human tumor samples utilizing native microspheroids (fresh, live cells) replete with vascular, stromal and inflammatory cells to analyze cellular responses in the context of the tumor microenvironment.

    This snapshot of cellular response recapitulates patient response to cytotoxic compounds, signal transduction inhibitors, and growth factor agonists/antagonists in real time.

    Tamoxifen acts as an antagonist in breast and conversely an agonist in uterus. Agonist (potentiating) effects at high doses.

    Tamoxifen at concentrations of 2.5 micromolar or greater significantly inhibits the P-glycoprotein (gatekeeper in the blood-brain barrier) multidrug resistant membrane pump, as well as inhibiting protein kinase C (preventing the increase in vascular resistance).

    The functional profiling platform is still very versatile.

  6. kathryn s. helmrich says:

    Thank you for including me on your email list. I really know very little about this, fortunately,… but find it interesting….and also…. reassuring, that some Doctors out there are still in the business of searching for better understanding … and more effective treatment.I think the above entry is quite interesting.
    I am just about like a lay person… as I am a nurse, who has never worked in oncology… but I do have a some what related question :

    While a a medications nurse in a nursing home.. I encountered use of tamoxifen . I was surprised that it was not discontinued, but administered it per order. I have to admit that I did not wear gloves.. I know that I had heard that a person should… but I was busy.

    I later developed some kind of problem which has been diagnosed as MS. Could this intermittent contact with tamoxifen cause enough of the decrease in strength of the blood brain barrier.. to allow other unwanted stuff to get in?

    Like a virus.. or something that would cause an “over-kill” sort of immune response ?

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