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.”

Breast Cancer and Avastin, the Ongoing Saga

As many are now aware, in November of 2011, the United States FDA withdrew approval for bevacizumab (Avastin) for the treatment of breast cancer. Medicare and the National Comprehensive Cancer Network  (NCCN) are now re-examining their guidelines. In the interim, reimbursement for Avastin is a patchwork of approvals and denials across the country.

Into this mix comes an interesting concept apparently floated by Roche’s European affiliates. Described in a brief press release was the suggestion that Roche might be prepared to attach Avastin reimbursement to its efficacy. That is – Roche would only demand payment from patients and third party payers if the treated patient revealed objective evidence of response. This is an interesting idea!

The concept of conditional reimbursement is extremely intriguing. Contrary to contemporary reimbursement policy, the purveyors of therapy would only receive compensation if they could prove benefit, not mind you, benefit in the broad brush Phase III tiny statistically significant result (e.g. the FDA approval of erlotinib plus gemcitabine in pancreatic cancer for a median survival advantage of 10.6 days!), but instead very real benefit on a patient-by-patient basis.

We use erlotinib plus gemcitabine, as well as Avastin combinations, to great benefit for many of our patients and applaud the availability of these drugs and combinations. But we never, just give them. Were the federal government, major payers or HMOs to be prepared to reimburse novel therapies predicated on their efficacy, we might envisage a meaningful advance in cancer therapeutics.

Today, few small laboratories, start-up companies and early stage biotech firms have the resources to marshal multi-million dollar clinical trials to test new therapies. This may in part be why advances in cancer therapy are moving so slowly forward.  The barriers to entry are insurmountable, causing many good ideas to fall by the wayside for lack of the hundreds of millions of dollars required to achieve FDA approval and Medicare reimbursement. But what if on an individual basis, reimbursement policies reflected the most meaningful of all endpoints – individual patient response and survival. Even the largest pharmaceutical companies are now coming to realize that despite their clout they too are suffering under the guidelines forced upon drug developers in this era of ever increasing regulation.

This is a concept worth pursuing. Let’s see where it goes.

Is Rationed or Rational Medical Care In Our Future?

We are witness to a sea change in medicine. Doctors and nurses are being replaced by “healthcare providers;” medical judgment is being phased out in favor of therapeutic algorithms; and the considered selection of treatments is giving way to rigid therapy guidelines. All the while, the regulatory environment increasingly precludes the use of “off label” drugs. It is understandable why insurers, governmental entities and hospital chains might welcome these changes. After all, once therapies have been reduced to standardized formulae, one can predict costs, resource allocations and financial exposures to the twentieth decimal place. For many medical conditions, these approaches will provide adequate care for the majority of patients.

But, what of the outliers? What of those complicated disease entities like cancer, whose complexity and variability challenge even the best minds? How do we bang the round peg of cancer therapy into the square hole of formulaic care?

There are several answers. The first is the least attractive: In this scenario, predicated upon cancer’s incidence in an older population, at the end or beyond their productive (and reproductive) years, we simply don’t allocate resources. Most civilized modern societies haven’t the stomach for such draconian measures and will seek less blunt instruments.

The second is a middle of the road approach. In this scenario, standardized guidelines that provide the same treatment to every patient with a given diagnosis are developed. Every medical oncologist knows the drill: FOLFOX for every colon cancer, Cytoxan plus Docetaxel for every breast cancer and carboplatin plus paclitaxel for ovarian cancer. The treatments work adequately well, the schedules are well established, the toxicities are well known and no one is cured. The beauty of this approach is that the average patient has an average outcome with the average treatment. By encompassing these regimens into standardized algorithms, we may soon be able to eliminate physicians entirely — first, with nurse practitioners and physician’s assistants and, ultimately, with computers. What is perhaps most surprising about this scenario has been the willingness of the medical oncology community to embrace it, a sort of professional self-induced extinction. At the time of this writing, this is the predominant model and is becoming increasingly entrenched under the auspices of NCCN and related guidelines. The operative term being guidelines, in as much as these “guidelines” are rapidly becoming “dictates.”

The final approach, and the one I find most appealing, is that which utilizes the clinical, scientific, laboratory and technical acumen of the physician to the maximum. Combining diagnostic skill with scientific insight, the physician becomes the captain of the ship, who must assume control from the autopilot once the vessel has entered the tempest and use his/her experience and training to guide the patient to a soft landing. This requires the capacity to think and demands an up-to-date knowledge of many disciplines. The judicious application of laboratory-directed approaches can further enhance the skillset, introducing objective data that is then used to guide drug and treatment selections. Predicated upon an understanding of the patient’s tumor biology, cancer therapy becomes an intellectual exercise that draws upon literature, and a knowledge of pharmacology and physiology. Adding the wealth of newly developed signal inhibitors to the mix only enhances the odds of a good outcome.

This approach improves responses and eliminates futile care. It provides patients the opportunity to participate in their own management. Correctly delivered, it would make available to every patient any FDA-approved drug. While it would seem to some that this would open the floodgates of drug use, I would strenuously disagree. It would instead limit drug administration to those patients most likely to respond, a goal currently pursed by virtually every major institution, yet accomplished by none. While a handful of targeted approaches have come to fruition in the last few years — erlotinib for EGFR mutation, and sunitinib in kidney cancers — most of the molecular profiling being done today doesn’t aid in the selection of therapy but instead provides negative information (e.g. RAS in colon cancer, ERCC1 over expression in lung) enjoining the physician against the use of a given agent but then leaving the unfortunate patient to fend for themselves amidst a panoply of randomly chosen options.

This is the approach that I have chosen to adopt in my own care of cancer patients. Our rapidly growing successes in ovarian, breast, lung, melanoma, leukemias and other diseases could and should serve as a model for others.