Why Do Cancer Surgeons Cure More Patients Than Medical Oncologists?

Surgery remains the most curative form of cancer treatment. While the reasons for this are many, the most obvious being earlier stage of disease and the better performance status of the patients, there are other factors at work. Surgeons tend to be rugged individualists, prepared to make life and death decisions at a moment’s notice. The surgeon who enters the pelvis expecting an ovarian cyst only to find disseminated ovarian cancer must be prepared to conduct a total hysterectomy and bilateral ovary removal if he/she is to save the patient’s life. It is these types of aggressive interventions that have that revolutionized the treatment of advanced ovarian cancer.

What of the medical oncologists who, with the exception of leukemia and some lymphomas, confront diseases that are difficult to eradicate and for which treatments can be toxic? Trained as incrementalists, they do not expect cures so much as palliation. Their role is not to make hard decisions, but instead to rely upon precedence. Educated in the school of small advances, these physicians are not rewarded for individual successes but they are harshly criticized for any departures from community standards.

Deprived of the opportunity to make bold decisions, medical oncologists follow opinion leaders who instruct them to accrue to standardized protocols. As meaningful advances are few and far between, enormous numbers of patients must be accrued to provide sample sizes with any hope of achieving statistical significance. Among the most disturbing examples of this approach was a trial reported in patients with inoperable pancreatic cancer. The study compared single agent gemcitabine to gemcitabine plus erlotinib. The trial achieved an improvement in survival that led the FDA to approve the two-drug combination. Yet, the actual improvement in median survival was a mere 10 days. The authors beamed, “To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine.” (Moore, MJ et al J Clin Oncol, 2007). To the average observer however, a clinical trial that required 569 patients to improve median survival from 5.91 months to 6.24 months (10 days) would hardly seem cause for celebration.

Medical oncologists have become so accustomed to these marginal advances that they are unmoved to depart from standard protocols lest they be accused of breeching guidelines. This might be acceptable if chemotherapy provided meaningful benefits, but the extremely modest advantages provided by even the best clinical trials scream for medical oncologists to think, well, more like surgeons.

While community oncologists think it heresy to step around a National Comprehensive Cancer Network (NCCN) guideline, investigators at the best institutions, the opinion leaders, have begun to question the merit of blind protocol accrual and come to recognize that many critical questions cannot be easily answered through the current trial process. Questions such as the role of liver resection for colon cancer patients with disease spread to the liver or the role of additional chemotherapy after that liver surgery, simply may not lend themselves to randomized trials. In a review of the topic by one of the leading investigators in the field, Dr. Nancy Kemeny from Memorial Sloan-Kettering in New York examined this dilemma, “The management plan for each patient should be decided by a multidisciplinary team, it may not be possible or ethically defensible to perform large randomized adjuvant trials comparing chemotherapy with surgery alone or comparing modern chemotherapy with older regimens. It may be reasonable to extrapolate from adjuvant trials and meta-analyses showing predominantly disease-free survival benefit. Each decision on postoperative chemotherapy should be viewed in context of prior treatment, surgical preference and individual patient characteristics.”

How refreshing. Finally a clinical investigator has recognized that patients must be managed on an “individual basis” regardless of what the clinical trial data does or does not support.

The concept of personalized medicine flies in the face of contemporary guideline driven treatment. Individualized care is on a collision course with the NCCN. It is time for medical oncologists to reclaim the high ground in doing what is right for patients, using resources that enable them to make smart decisions and to eschew standardized care. In cancer, the dictum “one size fits all” is more accurately “one size fits none.”

Nut Consumption, Pancreatic Cancer and Woody Allen

In the 1973 Woody Allen movie ”Sleeper,” Miles Monroe (played by Allen), is the nerdy owner of the Happy Carrot health food store who undergoes cryostasis (deep freeze) only to be awakened 200 years later. He finds himself in a place where all that he had come to know has disappeared. Two physicians observing him from a distance comment on his unusual dietary request: wheat germ, organic honey and tiger’s milk. Puzzled, one physician asks why he would want such odd foods. The second physician explains that 200 years earlier, low fat foods were considered healthy. “What, no deep fat, no steak, no cream pies, or hot fudge?” she asks incredulously. “No”, he explains, “those were thought to be unhealthy…. precisely the opposite of what we now know to be true.”

I was reminded of this scene by a paper published in the British Journal of Cancer (BJC). Based on observations from 75,680 women in the Nurses’ Health Study, investigators showed that the regular consumption of nuts was inversely associated with the risk of pancreatic cancer. Indeed, those who consumed one ounce of almonds, Brazil nuts, cashews, hazelnuts, macadamias, pecans, pine nuts, pistachios or walnuts, three times per week had a 35 percent reduction in the risk of pancreatic cancer (P = 0.007). This was found to be independent of age, height, obesity, smoking, diabetes, or other dietary factors. Although the study was funded by the International Tree Nut Council Nutrition Research and Education Foundation, they had no participation in the design or analysis of the data.

The consumption??????????????????????????????????????????????????????????????????????????? of nuts has previously been shown to be highly beneficial. In a Spanish study of 7,000 people, ages 55 to 90, those who ate three servings per week had a 55 percent reduction in death from cardiovascular disease and a 40 percent reduction in death from cancer. Clearly, the association between nut consumption and health is both strong and broad based, as it extends from cardiovascular disease to cancer.

The majority of the calories in nuts come from lipids (fats) including monounsaturated and polyunsaturated fats like oleic acid, found in olive oil, linoleic, gamma-linolenic and alpha-linolenic acids as well as the saturated fats, stearic and palmitic acids. Of the nuts commonly consumed the highest lipid content is in macadamia nut, followed by peanuts, pecans, cashews, walnuts, pine nuts, hazel nuts, pistachios, almonds and chestnuts. The protein content of nuts favors peanuts and pine nuts. A number of micronutrients are also found in nuts including flavonoids, stilbenes, proanthocyanidins, calcium, iron, B6 and magnesium.

The BJC study stands in strong contradistinction to the oft-repeated admonition that nuts should be avoided, as voiced for many years by health experts and dieticians. The fat avoidance craze of recent decades held that foods containing lipids were to be eschewed. Health conscious individuals were encouraged to eat grains and carbohydrates.

Today we recognize the important benefits of lipids and find that higher fat and high protein diets are gaining traction over the older food pyramid. We now find that high carbohydrate intake may in part be responsible for many contemporary maladies suggesting that the agrarian revolution of 10,000 years ago that made high calorie/low fiber grains readily available may ultimately prove to have been more a curse than a blessing.

An expert is one whose “faculty for judging or deciding rightly, justly, or wisely” is recognized and granted sway over society. But who judges the experts? The current BJC study suggests that in many fields of science and medicine the experts can be wrong. How many people denied themselves the pleasure and, we now come to learn, the health benefits of nuts based upon expert recommendations?

In our contemporary diagnosis and management of cancer, might the experts be leading us astray in other areas? Perhaps we should all ponder that point as we nibble on a few Macadamia nuts.

Cancer Patients: Cure the Curable, Treat the Treatable and Avoid Futile Care

During my interview with Jeff Michaels on the March 28, 5:00 P.M. Fox News, we explored the themes of my current book, Outliving Cancer. One of the points that most interested my interviewer was the appropriate use of our laboratory platform for the selection of therapy. He asked, “Are there some patients for whom there is no cure?” I responded by explaining what it is, that our laboratory test is designed to do: “Cure the curable, treat the treatable, and avoid futile care.” Jeff Michaels stopped me and asked that I might repeat what I had just said. It seemed that my succinct description resonated.

However simple this distillation of our work may seem, I realized it was actually rather profound. After all, we are confronting an escalating crisis in medicine. How do we meet the needs of a growing population of cancer patients with shrinking resources? How do we allocate treatments to those most likely to respond and finally, how do we avoid the misadventures of toxic and ineffective therapies for those destined to fail chemotherapeutic intervention? On every level, laboratory models can assist us. For those patients with early stage breast cancer, ovarian cancer, small cell lung cancer, non-Hodgkin lymphoma and many leukemias, the expectation of a cure is well within our reach. These patients must receive the very best treatments from the start.

The larger population of patients we confront are those with diseases like gastric, colon, non-small cell lung, recurrent breast, recurrent ovarian or sarcoma for whom cures are less likely and effective therapies must be tolerable so that they can provide benefit without undue toxicity. These are the patients for whom cancer can become a “chronic disease.”

Finally, we must all confront patients for whom treatments offer little likelihood of benefit, yet significant risks of toxicity. These heavily pretreated patients, or those who present with refractory malignancies like pancreatic, kidney cancer or melanoma – represent a special subset. Here the role of the physician is to decide that almost Shakespearean question, “To treat or not to treat.”

This is a particularly delicate circumstance as it forces the doctor, the patient and the family to confront the most difficult question of all, “Am I dying?” The answer is “maybe.” Without seeming flip, every patient no matter what diagnosis, has some chance of response to therapy. If we examine the performance characteristic of our laboratory analyses, they consistently double response rates. With this group however a doubling of response rate may still provide a rather low likelihood of meaningful benefit. If the laboratory finds drug resistance in this group, it is a near certainty that the patient will not respond.

However distressing this data may be, it may be comforting to know that the patient has left no stone unturned. For those patients where a treatment appears active, despite their diagnosis or treatment history, then the discussion surrounding tolerance, toxicity and realistic likelihood of benefit can be undertaken intelligently. This is the embodiment of rational therapeutics.

Outliving Cancer: Surviving Even the Deadliest Forms of Cancer

FINAL book cover-lo resMy book of the same title (Outliving Cancer, Basic Health 2013) is an exploration of cancer biology through the lens of individual patients.

The conceptual framework within which my laboratory operates, reflects the basic premise that cancer doesn’t grow too much it dies too little. Thus, effective cancer therapy (regardless of contemporary wisdom) provides benefit only when the drugs induce cell death. While the forms of cell death may vary from necrotic, to apoptotic, autophagic and others, it is, in the end, the death of the cell that heralds a successful outcome.

We, along with a small group of collaborators, have pioneered the concept of individualized cancer care using each patient’s tumor as the study model. Fresh biopsies exposed to chemotherapies and signal transduction inhibitors, live or die depending upon their relative sensitivity to the drugs in question.

The simple elegance of our platform has provided immense insight into cancer biology, insights we describe in the book, which may ultimately lead to a greater understanding of all human diseases.

Having successfully applied this approach in many diseases, we have published findings in leukemia, breast, ovarian, and most recently, in lung cancers. We are now very excited by observations in one of the most difficult cancers – pancreatic. Ongoing work in this disease will be the subject of upcoming clinical trials.

One patient with pancreatic cancer comes to mind. Steve Lockwood presented to medical attention in the Spring of 2010 with weight loss, abdominal pain, and unrelenting low back pain. He was seen by a local medical oncologist after a CT scan revealed a large mass in the pancreas, extensive liver metastases and disease throughout the abdomen. He then sought the opinion of UCLA and the City of Hope.  Neither institution could offer any solutions. Luckily his wife, a nurse, had heard about our work and brought him to Rational Therapeutics.

His tumor markers were doubling every week. He couldn’t eat and required daily intravenous hydration, as well as high dose narcotics to get through each day. He was deteriorating so rapidly that I had concerns that he might be too ill for me to help. We decided to conduct an open liver biopsy. As his tumor markers, CA19.9, climbed into the multiple thousands, we found a three-drug combination to be the most active for his tumor.

Within a week, the pain began to subside. After two weeks, it was demonstrably better. By the time we began treatment cycle two, he had begun to gain weight and came off pain medications entirely.

Two cycles later, his tumor markers were normal and his PET CT remarkably improved. An additional cycle later, his PET CT was normal.

While there are many difficult cancers, metastatic pancreatic cancer figures among the worst. The fact that we could find a treatment was cause for celebration. The fact that Steven now remains in remission, after three years, is nothing short of a miracle. As I have written before, there are two kinds of cancer patients: those we can treat and those we can’t. Steve Lockwood turned out to be one of those patients we could.

Like Niebuhr’s Serenity prayer, oncologists need the serenity to accept the cancers they cannot treat, the courage to treat those that they can, and the wisdom to know the difference. It is our use of laboratory assays to select treatments that provides us with that particular form of wisdom.

Assessing the Benefit-Risk Ratio of Nitrates

Many readers may have come across a recent report linking the consumption of processed meats (sausage, bacon cold cuts, etc.) to the incidence of pancreatic cancer. Intriguingly, the higher risk seemed to only apply to men and not women. The explanation for this remains obscure, but may reflect other dietary habits more common to men or other factors, such as increased alcohol consumption or smoking. But this is only a speculation.

The presumptive mechanism of cancer causation seems to revolve around the presence of nitrates in these cured meats. Nitrates are added to meats as preservatives. Preservatives function to inhibit bacterial growth responsible for food spoilage. Nitrates under the acid conditions in the stomach, are converted to nitrites. And it is these nitrites, primarily in the form of nitrosamines, which may be the culprits.

When we exam these findings several issues must be considered. First, however nefarious the consuming public may think the meat packing industry, I for one am fully convinced that these companies do not add nitrates to cause cancer. Quite the contrary. The most dangerous organisms found in foodstuffs, through spoilage and lethal food toxins, are the anaerobic organisms. The most frightening of all is clostridium botulinum, which produces the fatal condition known as botulism. Nitrates converted to nitrites are potent inhibitors of clostridia.

In the grand scheme of things, it is highly likely, in fact certain, that many, many more people have been saved from nitrites in food than would ever die from pancreatic cancer. These risk-benefit ratios are the subjects that keep epidemiologists up at night.

Nitrates in food are not the only possible man-made exposures that we encounter on a daily basis. Take for example chlorinated water. The “chlorine” in water is, for all intents and purposes, bleach. That’s right every time you drink tap water you are being exposed to tiny quantities of bleach. It is probably unnecessary for me to explain to the average reader, the risks and hazards of common household bleach, which is a solution of hypochlorite. And, however toxic that bottle under your sink may seem, remember that is only a 5 percent solution.

Another example is fluoride. While the benefits of fluoridation of water are numerous, including bone density and improved hardness of the enamel of teeth, demonstrably reducing tooth decay, fluorine itself is not, at least theoretically, free of risk. We know that sodium fluoride is an inhibitor of phosphodiesterase, an enzyme responsible for regulating cyclic AMP and cyclic GMP levels in the cell. These protein kinase A signals events may be tonically affected by changing levels of fluoride in the cell, to what end it is hard to say.

Like chlorination or fluoridation of water, nitrates in food represent risks that we as a society have accepted, based upon what we deem as acceptable benefit-risk ratios.

It is possible, that the increased incidence of food-borne illness and enteric infections, increased dental caries associated with the elimination of all these risks, may far exceed the hazards associated with these exposures.

The human species evolved over millennia in an environment exploding with free radical activity, fortunately we have developed defenses, superoxide dismutase, glutathione, peroxidase, catalase, etc., that counteract the toxic effects of these chemical compounds. Whether the man-made exposure substantively changed the balance will be a topic of discussion for years to come.

The Bad News is, You’re Going to Survive

There is a common tendency on the part of cancer patients, upon receiving their diagnosis, is to act as if their life is over and that there is nothing they do to affect it.

Given the dismal outcome for many solid tumor patients, the tendency to give up is understandable. What often happens is the patient starts bingeing, eating and drinking too much, gaining weight, and foregoing all the lifestyle changes they had worked so hard to incorporate before the diagnosis. They’ll stop exercising and continue to smoke, figuring it has no impact.

But, what if you’re not dying? What if your first anniversary passes and you’re still well? How about your second, or third?

This has been the experience of several of my patients, who jokingly now admit that they’ve never been in worse physical condition, largely due to “letting themselves go” after the diagnosis. In response, we suggest that patients maintain a normal lifestyle even in the face of the most difficult diagnoses. Appropriate nutrition, physical activity and emotional well-being all contribute to good outcomes.

Like our pancreatic cancer patient,who I need to put on a diet, many patients over indulge. In a way, this is a new wrinkle in the old adage, “If I knew I was going to live this long, I would’ve taken better care of myself.”

When it’s Time to Put Your Pancreatic Cancer Patients on a Diet

Last week, I had a discussion with a friend and colleague regarding our work and its application to cancers of almost every stripe. During our chat, I received a call from the infusion center requesting the clarification of an order. I responded to the nurse’s inquiry and returned to our conversation. Apropos, my guest inquired whether I ‘d had much success in pancreatic cancers. I smiled and explained that the call I had just received was regarding a patient with that exact diagnosis who is now approaching the one-year anniversary of our first meeting in June 2010.

At 59 years of age, the patient found himself diagnosed with pancreatic carcinoma that had virtually overtaken his liver. Visits to his oncologist and subsequent second opinions at UCLA and City of Hope offered few options. He returned to my care and we conducted a biopsy to examine his drug response profile. The patient could hardly have been more ill. Uncontrollable pain, abdominal distention, a liver that extended almost to his pelvic brim and tumor markers in the thousands that were doubling ever one to two weeks. We certainly had our work cut out for us.

I remember starting his treatment and leaving town for a week to attend the American Society of Clinical Oncology meeting in Chicago. After my departure, I was informed that his CA 19.9 (on his first cycle of therapy) had continued upward, cresting at 6,000 (normal is 0 — 30). I was greatly disappointed by the news. Pancreatic cancer is hard to treat, but I had felt confident that this patient would respond. And then, his pain diminished and he started winding off the industrial doses of narcotics that he had once required. His appetite and exercise tolerance both improved as well. The tumor markers began falling precipitously. And, over the coming month, that giant liver returned to normal.

The best news was the PET/CT that confirmed his dramatic response. The better news still, the subsequent PET/CT that revealed virtually complete resolution of all measurable disease. Oh, and yes, the normalization of the tumor markers.

I turned to my guest and said, “Yes, we can even fix pancreatic cancer in some patients. Would you like to meet one?” We walked together to the infusion center and I introduced the patient to my friend. As the patient sat receiving the final hydration of his, now maintenance, therapy, I realized how much weight he had gained. In fact, I said only half jokingly, “I’m going to have to put you on a diet.”

Now, there’s a change, a pancreatic cancer patient a year after diagnosis for whom my principle current concern is his weight gain. Weight Watchers anyone?

A Pancreatic Cancer Patient – Seven Years Later

More than seven years ago, I was asked to see a patient in consultation. This vigorous 54-year-old gentleman had already undergone a Whipple procedure for the treatment of a pancreatic carcinoma. His skilled-surgeon had resected most of the tumor, but could not clear the margins. With each successive attempt, he identified additional tumor. Unable to achieve a complete surgical resection, the patient was closed, recovered and visited me for a discussion of therapeutic options.

We identified a two-drug combination to be used in conjunction with external beam radiation, a regimen that few — if any — investigators would have suggested. Adjusting the doses to achieve a tolerable schedule, he completed the entire course of therapy with acceptable toxicities. Contrary to his surgeon’s expectations, the patient achieved a complete and durable remission. He returned to his active lifestyle, remarried and became an advocate for the aggressive management of pancreatic cancer.

Now, seven and a half years later with a rising CA 19.9, he is identified to have a focus of uptake on PET CT in the body of the pancreas. A surgical exploration to remove the tumor provided adequate tissue for an EVA-PCD analysis. The patient was once again tested against the standard therapies used in this setting. Among the drugs we examined are the EGFR inhibitors, the taxanes, the combination of EGFR inhibitor + gemcitabine and the platinum + 5FU combination. Each one of these would be a reasonable choice. Indeed, FOLFOX, Tarceva + gemcitabine, the GTX regimen and — most recently — Taxol-gemcitabine based combinations, would all be favored choices for medical oncologists in the U.S. today. Yet, this patient was sensitive only to cisplatin + gemcitabine and none of the others.

Following publications from a group in Scottsdale, Arizona, many oncologists are utilizing Taxol + gemcitabine. There are proponents for Tarceva + gemcitabine, and those who prefer FOLFOX. At least for this patient, none of them would’ve been right. Interestingly, after more than seven years later the patient’s profile reflects the same combination that was used initially. It is interesting to ponder, based on this finding, whether this is a new primary or a sanctuary-site recurrence with so long a disease-free interval to remain sensitive to the platinum-based combination. We now hope to provide him seven and a half more excellent years… at the very least.

What Can We Offer Patients With Pancreatic Cancer?

Recently, I received a call from a previous patient for whom I was not the treating oncologist.  Originally, she had heard about our work on a radio interview and asked her physician in Ohio to send a sample to our laboratory. The results of her assay concluded that a three-drug combination (cisplatin plus Taxol plus gemcitabine) — not commonly used in a pancreatic cancer — was her best option.

Unbeknownst to me, after beginning therapy, the patient had a prompt and dramatic response. When the patient recently contacted me, I cursorily examined the chart prior to our discussion and noted the date of June 24. At first, I thought the patient was showing evidence of progression barely two months after our analysis. Recognizing that no test is perfect and that even our best recommendations may not work, I contacted the patient to discuss her case. It was only then that I realized that indeed the assay data was from 14 months ago and that her response had been excellent for more than a year.

After congratulating the patient on her good outcome and discussing modifications in her therapy (predicated on some x-ray findings of early progression) I asked what her physician’s reaction to the good result had been. The response was muted. Indeed, the physician, having witnessed a rather remarkably good response, only commented that she knew the patient wouldn’t be cured. Recognizing that metastatic pancreatic cancer has an objective response rate measured in single digits and a median overall survival of 4-6 months, I was disappointed to realize that a patient who was well 14 months after diagnosis didn’t seem to impress the treating oncologist.

We are now engaged in reviewing the patient’s diagnostic studies to determine if the EVA-PCD findings will provide information to further guide therapy. While I was very realistic with the patient — explaining that there is no certainty that further benefit can be obtained — there are, in fact, a number of drugs that could hold benefit for the patient. These including: erlotinib, irinotecan and a number of novel combinations. We will be interested to see if further good results can be obtained and are gratified by the patient’s good outcome to date.