National Cancer Institute Stops Gene-based Clinical Trials – Part 1

In prior posts we have discussed the clinical potential of genomic profiling for the selection of chemotherapeutics. Although, genomic analyses offer many insights, we described the limitations of these platforms. A recent report in the national media gives further credence to our position.

On July 22 and 23, 2010, the National Cancer Institute suspended two lung cancer and one breast cancer clinical trial that used genomic profiling to select active treatments for patients. The technique applied was developed at Duke University and reported, to much fanfare, in Lancet Oncology in 2007. The rather stunning success reported in this and related articles by the investigators from Duke, lead to a widespread belief that gene profiles would select active therapies for patients.

The first chink in the armor of this argument came when scientific reviewers issued an “expression of concern” regarding the validity of the method. Further analyses revealed evidence that the technologies for the prediction of response in individual patients could not be reproduced. As the reviewers stated, “The scientific community should be able to replicate the results with the reported data available.” They continued, “Having tried, we can confidently state that this is not yet true.” The NCI convened a group of 31 scientists, who concluded, “It is absolutely premature to use these prediction models to influence the therapeutic options open to cancer patients.”

Next week we’ll explore what went wrong with these seemingly promising trials.

Where’s the Proof? Clinical Trials and Cancer Testing

Numerous trials have been conducted to assess the predictive validity of the Rational Therapeutics Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD®) and similar platforms. However, we (and other investigators) are sometimes dismissed for lack of data supporting the validity of our methods.  Despite the unwillingness of the cooperative groups to formally test laboratory-directed therapy against standard protocol treatments, we have compiled a compelling collection of both retrospective and prospective correlative analyses that strongly support the clinical utility of these methodologies.

Two of the trials that I’ve reported prospectively compared the results of the EVA-PCD platform with objective response, time to progression and survival. The findings in breast cancer confirmed a significant correlation between drug sensitivity and progression-free survival in the evaluation of cisplatin plus gemcitabine (Nagourney et al, JCO 2000).

A second study conducted in ovarian cancer established the correlation between sensitivity and objective response, time to progression and overall survival (Nagourney et al, Gyn Onc 2003). More recently, a laboratory-directed protocol in NSCLC provided an objective response rate of 62 percent, statistically significantly superior to standard outcomes (p=0.003), with a median progression-free survival of 9.5 months and median overall survival of 22.3 months.

We and other investigators in the field have made it abundantly clear that we are very willing to participate in well-conducted formal studies. Amongst the organizations that have been approached to conduct such studies — NSABP, GOG, ECOG and CCG — have all been unwilling to undertake confirmatory studies. The costs of prospective clinical trials (now in the range of millions of dollars) remain a substantial hurdle for investigators in this field. Nonetheless, a fair test of these methodologies should be conducted.

Is There a Cure for Cancer?

Despite decades of headlines proclaiming the “cure for cancer,” no magic bullet has been found for this disease. This, in part, reflects the reality that cancer is not one disease, but many. Most cancers arise as a result of chronic exposures, resulting in mutations accumulated over a lifetime of cigarette smoking, high-fat diet, excessive sun exposure and alcohol consumption.

However, some cancers (particularly those found in children) occur spontaneously. These childhood malignancies are sometimes associated with a single genetic abnormality that gives rise to closely related clones of cells, often carrying the identical causative mutation. In these instances, an effective therapy can eradicate the tumor. Thus, childhood cancers are often more curable than cancers that occur in adults. For the average adult cancer, numerous abnormalities contribute to the ultimate carcinogenesis. When therapies are applied, they eliminate some – but not all – of the transformed cells. This results in the common experience of clinical improvement followed by subsequent recurrence.

In most adults, each patient’s cancer arises in a unique individual and from a unique combination of causative factors. It is unlikely that any one treatment can address all of the different cancer types that arise in this complex interaction between “seed and soil.” So, when we address the question “Is cancer curable?” the response is a resounding “maybe.”

Patients presenting with their own unique disease need therapy that specifically addresses their cancer biology. The newest classes of drugs that more selectively target changes in cancer cells, may be our best hope. Laboratory platforms that enable us to match patients to treatments (such as the EVA-PCD® platform offered at Rational Therapeutics) offer us a unique opportunity to provide the most effective, least toxic combinations with the hope of cures for the largest number of patients today and in the future.

New Book Highlights Customized Cancer Treatments

In his latest book Customized Cancer Treatment, Ralph W. Moss, PhD, discusses laboratory tests that can save cancer patients’ lives. Dr. Moss, who previously penned Cancer Therapy, Herbs Against Cancer, Questioning Chemotherapy and The Cancer Industry, takes another look at what’s working (and what isn’t) with today’s treatments.

One of my patients who had the opportunity to read the book says, “I just read Customized Cancer Treatment and found it breathtaking. This book should be required reading for everyone.” Before deciding what treatment is best for you, know your options.

Customized Cancer Treatment will be available in late November. However, if you’d like an advance copy, you can contact my office at 562.989.6455 for more information.

Methylphenidate and Cancer Fatigue

One of the most common symptoms that cancer patients experience is fatigue. Fatigue is also a common side effect of cancer chemotherapy. In one of our studies of breast cancer patients, 36 percent experienced fatigue as the principle side effect of the chemotherapy combination. Furthermore, the emotional stress associated with a cancer diagnosis can result in varying degrees of depression, also characterized by fatigue.

Studies conducted in recent years have established that cancer patients often benefit from the use of antidepressants. These can improve energy and counteract insomnia, while addressing the emotional challenges that many patients confront. While there are numerous forms of antidepressants, most function by enhancing the effects of neurotransmitters within the brain. The modern selective serotonin re-uptake inhibitors (SSRIs) are widely used in cancer patients.

Older classes of antidepressants work as direct CNS stimulants. The amphetamines and related methylphenidate are CNS stimulants. Studies conducted in the last decade establish that methylphenidate can be safely administered to cancer patients to counteract fatigue and depression. Indeed, methylphenidate is one of the most rapidly acting antidepressants and has been used in the psychiatric literature for many years. When used appropriately the drug is well tolerated. Interestingly, it does not result in weight loss, despite its CNS stimulant effects.

While these drugs can be important adjuncts to cancer therapy, they can also be extremely toxic with such serious side effects as: paranoia, anxiety, insomnia, weight loss, hypertension, cardiac stimulation and convulsions. It is therefore extremely important that these classes of drugs be administered judiciously under the direct supervision of a trained oncologist or psychiatrist.