Every Cancer Patient’s Outcome is Important

Clinical oncologists can be divided into different camps. There are those who see patient outcomes as a means-to-an-end. Each clinical response provides a data point and when those data points reach critical mass they become reportable. These are the trialists. They see the world through a utilitarian lens. They use aggregate data, through sufficient patient accrual, to achieve significance. This, they hope, will lead practice-changing observations. Trialists populate academic centers and an ever-expanding number of “mega medical groups” that are now gobbling up private oncology practices. They apply metrics to gauge success, as their focus has moved away from individual patient needs toward the achievement of a “greater good” for the population as a whole. Statistical significance is the currency of their realm and clinical protocols their preferred tool.

In the other camp reside physicians, that dwindling cadre of doctors whose principal focus is the good response of each individual patient. They are the practitioners who eke out a living in an environment of diminishing returns. Having relinquished both autonomy and income over recent years, their one remaining reward is the benefit they can bring to each patient. With neither the desire nor ability to publish their results, individual patient survival becomes their paramount goal. Their job is to alleviate suffering, provide comfort and sponsor the health of their clients. Patients preparing to meet with a cancer specialist should consider carefully who is treating them – and why.

I was reminded of this when a 48-year-old gentleman recently requested an opinion. He had presented to an emergency room with a month-long history of sharp abdominal pain. The CT scan revealed extensive intra-abdominal disease, which upon endoscopic biopsy, proved to be of gastric (stomach) origin. He was immediately referred to an accomplished university-based clinical investigator for consultation.

Metastatic gastric cancer is a very difficult disease to treat. One bright spot has been the discovery that 20 percent of patients carry an epidermal growth factor receptor (HER-2) mutation that enables them to receive Herceptin-based therapy. As luck would have it, this patient did not carry the HER-2 mutation. The university investigator explained that there were limited treatment options. In light of his metastatic presentation, the doctor felt that aggressive, multi-agent chemotherapy might only engender toxicity. The patient was offered either single agent 5-FU for palliation or the opportunity to participate in a clinical trial. The patient considered his options and chose to seek an opinion with me.

20 percent response rateI reviewed the patient’s status and explained that while the opinion of the university investigator was valid it might underestimate the patient’s individual chance of response. I explained that gastric cancer statistics, like all medical statistics, are population based. That is, a 20 percent response rate does not mean that every patient gets 20 percent better, but instead, that 20 out of every 100 respond while 80 do not. Our job was to find out which group he belonged to.

The patient decided to undergo a biopsy and submitted tissue to Rational Therapeutics for EVA-PCD® analysis. The results were strikingly favorable with several drug combinations revealing both activity and synergy. After careful comparison, I recommended the combination of a Cisplatin, Taxotere and 5-FU (DCF), a regimen originally developed at the MD Anderson almost 10 years earlier.

On March 12th, the patient began treatment on an every-other-week schedule. As he did not circulate tumor markers like CEA or CA 19-9, there was no easy measure of his response so I elected to repeat the PET/CT after just two cycles. Much to my delight, the patient had achieved a complete remission with resolution of all measurable disease, including the bulky abdominal masses, numerous lymph nodes and the stomach. As I described the remarkable PET/CT results, the patient’s wife began to weep. Her husband, the father of their two young children, wasn’t dying after all. He was no longer a grim cancer statistic. With mother’s day approaching, this was the first good news that they had received in six months. At once, the patient began to discuss business trips, travel plans and family outings. He breathed a slow sigh of relief as he realized that, once again, he had a life.

Good outcomes, even in the worst diseases, occur in all oncology practices. Every doctor can regale you with the story of a patient who responded beautifully and went on to survive years beyond everyone’s expectations. The reason we remember these stories is because they occur so infrequently. Complete remissions in metastatic gastric cancer are vanishingly rare. That is the reason that the university investigator offered single agent 5-FU. It’s easy, nontoxic, well tolerated, but it also cures no one. The rationale is well established: Why poison patient’s you cannot cure? Playing the averages, this strategy is a winner. Yet, on an individual patient basis it may, in fact, be a very big loser.

What are we to do with the “non-average” patient? What about the outliers? Should we not, at least, try to find them? We do it with stocks, racehorses, Indy-drivers, real-estate investments and every underdog sports team in every league. It’s the outliers after all that we call winners.

Cancer patients are not clinical trial subjects. They are unique individuals with their own very unique biology. Every patient is an experiment in real time, an “N of 1.” We must respect the dignity of each individual and we are duty-bound to apply every tool at our disposal to assist him or her in the pursuit of his or her own very personal best outcome – providing truly personalized cancer treatment. This patient did not have a 20 percent response. Instead, he was one of the fortunate few who responded very well. And for him that response was 100 percent.

Gastric Cancer: A Call for Patient Selection

Gastric cancer is the fourth most common cancer worldwide with more than 930,000 diagnoses and 800,000 deaths attributed to this disease each year. Although relatively uncommon in the U.S., constituting only 2 percent of new cancers, in countries like Korea it makes up 20 percent of all new malignancies.

Among the causes are Helicobacter pylori infection, diets rich in smoked food, a high intake of nitrates and nitrites and cigarette smoking. A rare but aggressive form of the disease is associated with a gene mutation known as CDH1. The high frequency of metastatic disease at the time of initial diagnosis often precludes surgery, leaving systemic chemotherapy as the principal treatment option.

Annals of Oncology coverA recent report in The Annals of Oncology (No improvement in median survival for patients with metastatic gastric cancer despite increased use of chemotherapy: Bernards N. et al, Annals of Oncology. November, 2013) describes a retrospective analysis by Dutch investigators who examined the use of chemotherapy in patients with inoperable gastric cancer.

In total, 4,797 cases were examined from 1990 to 2011. Over this time, the proportion of patients presenting with metastatic disease increased from 24 percent in 1990 to 44 percent in 2011. At the same time, palliative chemotherapy use increased from 5 percent to 36 percent. Younger patients and those of higher socioeconomic status had the largest increase in chemotherapy use, while older patients, those with linitis plastica and those with multiple metastases had lower chemotherapy use. Despite the significant increase in the use of chemotherapy, the median survival for patients was unchanged at 15 weeks in 1990 and 17 weeks in 2011 (P = 0.1).

Over this period, early treatment regimens like 5-fluorouracil (5FU) and FAM were largely replaced by combinations like Docetaxel/Cisplatin/5-FU (DCF), Cisplatin/Irinotecan, Epirubicin/Oxaliplatin/Capecitabine (EOX) and Carboplatin/Taxol. While response rates and palliative benefits have continued to improve, this has not translated into improved overall survival. This reflects a dilemma that has confronted medical oncologists for decades.

For many years, clinical trialists have held that one cannot assess the benefit of a treatment by comparing responders to non-responders. That is, time to progression and survival must compare all patients on a given treatment arm to those on the control arm. Their rationale was that “one must treat all patients to obtain the benefit seen in some.”  Put differently you cannot “cherry pick” your winners and losers. It was said that this proscription was needed to avoid selection bias. But as any medical or nonmedical person would recognize, people who respond to treatment do better than those who do not. Lacking the ability to identify responders upfront, these trialists have insisted upon a one-size-fits-all approach to the detriment of clinical therapeutics and drug development.

With the dawn of the molecular era we see chinks in the armor of these trial designs as investigators now question why everyone should receive a treatment if only a small percentage will benefit. In gastric cancer, HER2 over-expression, found in 20-25 percent of patients, is now routinely used to identify patients who will respond to trastuzumab. But what of the other 75-80 percent of patients who do not carry HER2 and for whom there are no widely used determinants of clinical response? Do the results of Bernard article suggest that these patients should not receive therapy?

The Bernard article offers an interesting insight into what may be the future of medical oncology. As cancer therapy is increasingly scrutinized, not only for response or palliation but also for overall survival, patients may soon be denied treatments unless the results of the therapy rise to this, the highest level of evidence, for the entire population of treated patients.

Would it not be preferable to use laboratory analyses, like the EVA-PCD®, to select among treatment candidates before subjecting all patients to the risk and expense of toxic chemotherapy? In this regard, the author’s comments are poignant: “Identification of the subgroup of patients which benefit from palliative chemotherapy is of the utmost importance to avoid unnecessary treatment.” As a laboratory investigator engaged in the field of drug selection science (functional profiling), I couldn’t agree more.

HER2 Two

I met a charming patient in my office this week. A gentleman with advanced gastric cancer. Upon further examination of his cancer, the adenocarcinoma cells were found to be strongly positive for human epidermal growth factor receptor 2 (HER2).

Many of my readers are familiar with this surface receptor, a member of the epidermal growth factor family. It’s discovery, and the subsequent development of treatments directed toward this target, are well described in the literature. While most people are familiar with this protein in breast cancer, it is only in the last several years that we have recognized the importance of HER2 expression in diseases like gastric and esophageal cancer.

Discussing the implications with the patient and his sons, I realized that this attractive therapeutic target might not be available for use due to the patient’s underlying heart disease. One of the toxicities of HER2-targeted therapies is congestive heart failure. As I pondered the dilemma, I was reminded of one of my patients from 16 years earlier.

At that time, a strapping 69-year-old woman arrived in my office with a large, high-grade breast cancer and 13 positive lymph nodes. She was also HER2 positive. The problem was that in 1997, the drug trastuzumab was not widely available and never (not ever), used in the adjuvant setting. With that as a backdrop, I treated the patient based on laboratory analysis using the best combinations I could identify. Now, 16 years later, still free of disease, she represents a rare success for someone afflicted with such aggressive (and yes, HER2-positive) disease.

The reason this former patient came to mind was that her excellent success 16 years earlier had not required the use of HER2-directed therapy. Ingrid Ottesen had done very well using assay-directed therapy chemotherapy without the addition of trastuzumab.  All we needed for Ingrid was the best use of available drugs. Despite the possible contraindication for trastuzumab in this gentleman’s case, we can still hope for a good outcome if we use the available drugs that best meet his need. After all, it worked perfectly for Ingrid.

You can read about Ingrid in Chapter 14 in Outliving Cancer, to be released later this month.FINAL book cover-lo res