Drs. Veronesi & Fisher on Scientific Evidence & Paradigm Shifts

ST. GALLEN, Switzerland—Two pioneers in modern breast cancer treatment give slightly different viewpoints on how the field has changed over the past decades.

In his opening address here at the 8th International Conference on Primary Therapy of Early Breast Cancer, Umberto Veronesi, MD, Scientific Director of the European Institute of Oncology in Milan, said the most dramatic paradigm shift has been an increasing appreciation of maintaining a breast cancer patient's quality of life, as opposed to trying only for a cure.

The following speaker, Bernard Fisher, MD, Distinguished Service Professor at the University of Pittsburgh, chose to emphasize the importance of evidence-based medicine in the changing world of cancer care. He noted that all the important recent changes in medicine, whether shifts in paradigms or not, have been based on scientific evidence. And he says there have been no more than three true paradigm shifts in the modern era of this specialty.

The two experts did not speak at cross purposes but rather from different perspectives.

“The main shift is the progressive awareness of quality of life, which is changing the traditional approach based on maximum tolerated treatment,” Dr. Veronesi said.

“Breast irradiation and breast cancer surgery used to be brutal, but this new trend has led to limited surgery instead of mutilating operations, more targeted radiation therapy instead of radiation to the entire breast, and less aggressive chemotherapy instead of the high-dose approach.”

Commenting on the move away from radical mastectomy in favor of surgeries that allow a woman to keep her breast, Dr. Veronesi said it is based on the finding that local recurrence does not influence prognosis.

“Prognosis is linked to the presence or absence of distant occult metastasis—that is the really important prognostic factor, and it is due to the intrinsic property of the cancer cell to metastasize or not to metastasize,” he said.

Dr. Veronesi hoped that this shift toward treatments that respect quality of life will motivate more women to participate in early detection programs. This, in turn, he said, will reinforce this and other new paradigms.

As examples he cited the use of genetic studies to identify women at high risk, hormonal modulators to reduce breast cancer incidence, imaging to detect very early tumors and greatly enhance the chance of cure, choosing systemic therapies based on the patient's likelihood of responding to them, and use of drugs targeting mutated genes in the cancer cell.

Sentinel lymph-node mapping has become recognized as an important innovation, he said, and not only because it can obviate axillary dissection. It also appears to improve event-free survival, Dr. Veronesi said, “because axillary tissue contains immunological properties which should be left intact.”

Internal Mammary Node Mapping

A still controversial innovation he cited is internal mammary node mapping.

“This is a very conservative procedure, it can be accessed through the same incision as an inner quadrantectomy,” Dr. Veronesi said.

But it can also mean a stage migration for women when it is combined with the results of a sentinel node biopsy. “Patients with a negative axilla but positive internal mammary nodes have a much different prognosis than when both are negative,” he said.

And the paradigm shift toward highly focused radiation fields such as partial breast irradiation and intra-operative radiation is allowing women to choose breast conservation even if they cannot afford to return to the treatment center for follow-up breast-irradiation sessions.

“We discovered that after conserving surgery, all the true recurrences occur in the same quadrant where the tumor was located, and tumors occurring on other quadrants are new tumors,” said Dr. Veronesi, who trained as a radiation oncologist as well as a surgeon.

“So there is no logical reason to radiate all the breast; we have to concentrate where the risk for local recurrence is much higher.”

ELIOT

There are many approaches to partial breast irradiation. One that Dr. Veronesi is involved in developing is electron intraoperative therapy (ELIOT). He said an Italian trial is showing that at three years, patients who had quadrantectomy plus ELIOT have the same outcomes as those who had quadrantectomy plus external-beam radiation.

“We are confident that these researches will give us totally new ideas, new hypotheses, new concepts,” Dr. Veronesi concluded. “But all these changes, which go in the direction of a better quality of life and less aggressive treatment, are also more precise, more rational approaches that are reducing mortality.”

Careful with Paradigms

Dr. Fisher, as could be expected, did not use the phrase “paradigm shift” in his speech. He has often commented that its overuse is one of his pet peeves.

In his presentation he did applaud many of the same advances in technology and treatment that Dr. Veronesi listed, although Dr. Fisher emphasized that these important changes have all been scientifically based, with origins in science and clinical trials rather than in opinion, conjecture, or anecdotalism.

Asked after his speech which of these changes could be described as true paradigm shifts, Dr. Fisher said there really have been only two that apply to breast cancer treatment, or possibly three.

One was the shift away from the Halstedian paradigm of radical breast surgery. That change involved testing of lesser surgical procedures ultimately leading to the common use of breast conservation today.

The other true paradigm shift is related to the use of systemic therapy to treat breast cancer, he said, starting with chemotherapy but now including systemic endocrine and biological therapies.

Arguably, Dr. Fisher said, a third true paradigm shift might have been Halsted's radical breast-surgery innovation itself.

“Halsted's contributions were based on generating scientific hypotheses and testing them in clinical trials,” Dr. Fisher said, “just as all the other important innovations have been.”

But most of the recognized advances were not new paradigms, he insisted. Instead they were refinements that made the new paradigms practicable. The progression from quadrantectomy to lumpectomy, from whole-breast radiation to external regional radiation and brachytherapy, and from systemic chemotherapy to endocrine therapies, are each a refinement of a new paradigm.

In the interview after his presentation, Dr. Fisher said medicine has always had an interest in maintaining a good quality of life for the patient, but that in each era this might have meant something different. The Halsted's radical mastectomy was devised with the goal of improving the quality of a woman's life, as it might be compared with the woman having no surgery for breast cancer at all.

“My own philosophy about breast cancer is to keep a patient free of disease until she dies of something else, which she inevitably will,” Dr. Fisher said, pointing out that this principle does not include the word “cure.”