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  • Dr. Robert A. Nagourney, MD

In Medical Oncology Logic Prevails (Finally)

Breast cancer remains a challenging public health issue, with 231,000 new diagnoses and 40,290 deaths in the US in 2015. Chemotherapy is widely used in breast cancer, both before (neo-adjuvant) and after (adjuvant) surgery.

Today numerous guidelines (NCCN, etc.) and nomograms exist for the calculation of risks and benefits for different interventions. Modern management has led to improved disease-free and overall survival. Purveyors of “evidence based medicine” point to these successes in support of protocol therapies, yet many of these improvements actually reflect earlier detection and the broad use of Tamoxifen over chemotherapy benefits.

One dilemma facing medical oncologists surrounds the use of preoperative (neo-adjuvant) chemotherapy. Patients with large or node positive disease at diagnosis often receive chemotherapy before surgery. Although there are proponents and opponents of this approach, it has been shown that patients who achieve complete remission at the time of surgery (disappearance of all cancer) have a favorable prognosis. With contemporary Adriamycin or Taxane-based therapy 25% or more of patients can be rendered disease-free at the time of surgery.

But what of those patients who have residual disease after aggressive chemotherapy, the ones who do not achieve a complete remission? Until now, the “evidence” did not offer much guidance. It has long been academic dogma that these patients should go on to complete their radiation and/or hormonal therapy but not receive additional chemotherapy. The clinical community has generally followed these guidelines and denied patients additional chemotherapy despite their potential risk of recurrence.

To many clinicians this has seemed at odds with medical logic. After all, if a surgeon finds residual disease at the time of potentially curative surgery they will generally continue operating until they “clear the margins”. If an infected abscess is identified, it is surgically drained and the drains are left in place until there is complete resolution. Yet if chemotherapy fails to provide a complete remission, we are instructed, lo commanded, not to pursue other treatments based upon the “evidence”.

Into this arena arrives a Japanese trial reported at the San Antonio Breast Cancer Symposium. Dr. Masakazu Toi and colleagues from Kyoto University randomized 910 patients, all HER2 (-), to receive post-operative chemotherapy following neo-adjuvant Anthracycline or Taxane-based regimens. Patients also received hormone therapy if they were ER (+). In total 455 patients were assigned to oral Capecitabine for 8 cycles.

Despite years of heated argument, these investigators proved what should have been obvious all along, that the use of post-operative adjuvant chemotherapy in patients with residual disease following neo-adjuvant therapy provides real benefit. At 2 years, the risk of disease recurrence was reduced by 31%.

So what has changed? The investigators used logic. They reasoned that patients who had residual disease were at high risk. They reasoned that these patients could still benefit. The reasoned that current neo-adjuvant chemotherapy no longer includes drugs like 5-FU. They may have also understood that antimetabolites like 5 FU can capture “repair-efficient” tumor cells. We had shown the same to be true in our original Cisplatin/Gemcitabine studies some years earlier.

The lessons here are much larger than breast cancer. They go beyond this trial. They call into question the tenets of “evidence based medicine”. What occurred is emblematic of how evidence based medicine can be misused.

It had never been shown that patients who received additional therapy did worse. Instead no one had taken the time to show that they did better. In this game, the default position is abject nihilism. If you cannot prove that the earth is round then it must be flat. No room for discussion.

We have long recommended that patients with residual disease after neo-adjuvant therapy submit tissue for analysis. This is precisely because these residual tumors are different in their biology from the founder {{cta('8abe8785-a4a0-40ee-b960-71ebb51d4a37','justifyright')}} clones. The application of non-cross resistant therapies has the very real capacity to eradicate resistant clones through intelligent drug selection.

The choice of Capecitabine, however, may not be perfect for every patient. Is it not possible that some patients should receive a Platin, Gemcitabine, Vinorelbine or one of the growing numbers of signal transduction inhibitors available for later stage disease?

We applaud Dr. Toi for addressing this critical question and testing this important hypothesis. We enjoin medical oncologists to apply logic when the “evidence” fails to meet their need. Evidence based medicine is not a straightjacket to restrict the use of logic. It is a guideline for the use of available evidence where it exists.

Where it does not exist then the best evidence and logic should be applied, not denied.

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