THEORIES ON THE NATURAL HISTORY OF BREAST CANCER

Date: Fri, 15 Nov 1996 22:40:34 -0800 (PST)
From: jbonine <jbonine@OREGON.UOREGON.EDU>
To: Breast Cancer Discussion List <BREAST-CANCER@morgan.ucs.mun.ca>
Cc: JBONINE <JBONINE@OREGON.UOREGON.EDU>
Subject: Theory: Post-Mastectomy Radiotherapy

Dear B-C List Colleagues,

My previous message posted a Summary of where I am going to go now in writing about radiotherapy after mastectomy. This message describes the theories that breast cancer oncologists think about, and how new ones are evolving to account for exciting new data on a survival benefit for some persons for radiotherapy after even a mastectomy. Later ones will deal with those new data, and whether some oncologists are unaware of those data.

John

THEORIES ON THE NATURAL HISTORY OF BREAST CANCER

For 60 years, starting in 1894 (or perhaps earlier), breast cancer was seen in medical literature to be a disease that arose in one location (the breast) and, if left untreated, spread through the lymphatic system first to nearby lymph nodes and subsequently to other organs in the body. This theory of "contiguous" development of metastases was articulated by Dr. W.S. Halsted, inventor of the Halsted radical mastectomy. It has thus become known as the Halsted theory, Halsted hypothesis, Halsted paradigm, Halsted model, or "halstedian view." In 1954 and 1967 an alternative theory was formulated and, after studies were done, was put forth in rather definitive terms in a 1980 lecture by Dr. Bernard Fisher. He stated "that breast cancer is a systemic disease . . . and that variations in effective local regional treatment are unlikely to affect survival substantially."

Following the therapeutic implications of this "systemic theory," the systemic disease has been attacked in recent years by chemotherapy and hormone therapy to the whole body. Under a pure version of this theory, the only purpose of so-called "local or regional control" (breast surgery and local or regional radiotherapy) is to prevent a local tumor from getting out of hand and causing harm in that location, not to prevent future metastases to other parts of the body. That is, under this theory any distant metastases of any significant have already occurred at the time that a breast tumor is found by touch (palpation) or in a mammogram. <snip>

I think that the average citizen instinctively holds a basically Halstedian theory in her mind. One commonly hears the notion that "getting the tumor out" is the most important step. Chemotherapy is seen as a kind of "mopping up operation" in case any metastases had occurred earlier from the breast to other parts of the body (the contiguous route for development of tumors). I know that I was quite surprised when I learned that my friend's oncologist recommended delaying surgery while doing chemotherapy, something that seemed contrary to the goal of getting rid of the "main problem" first. Subsequently, I came to understand that to do surgery first can actually be viewed as delaying chemotherapy, and why one might want to do the chemotherapy first.

Doctors trained in the past 15-20 years are more likely to have been trained under the "systemic theory," in which distant metastases of some size are considered to be probable in the case of any breast cancer that has been detected (other than DCIS, ductal carcinoma in situ). Such doctors may instinctively discount the new studies showing a *survival* advantage in some women from having radiotherapy after a mastectomy (though they seem to have little problem with studies showing survival advantages from radiotherapy that follows lumpectomies).

Or perhaps some of those who accept the evidence that radiation after lumpectomy improves survival statistics, but do not conceive of getting survival advantages from radiation after mastectomy, hold a basically Halstedian viewpoint, but cannot imagine what tumor burden might be left after a mastectomy with clean margins.

At any rate, what are we to make of the facts that (a) controlling regional disease with radiation after mastectomy helps some women survive longer (meaning that the site from which "secondary dissemination" could have occurred got eradicated by the radiotherapy -- a neo-Halstedian fact, perhaps you could call it) and (b) controlling distant disease with chemotherapy and/or tamoxifen helps some women survive longer (meaning that the disease had already disseminated or was systemic in the first place -- a systemic-theory-supporting fact)? One answer could be to construct a theory or hypothesis that accounts for both kinds of therapy successes.

Dr. Samuel Hellman of the University of Chicago did just this in a 1994 lecture, and labeled it a "spectrum theory."

In the 1994 Karnofsky Memorial Lecture, Dr. Hellman reviewed the history of theories of breast cancer development ("natural history") from 1894 to present, and then proceeded to state the case for what he calls the "spectrum theory." My discussion of the Halsted and systemic theories, above, is based in part on his lecture.

One of the reasons that he felt called upon to formulate a new theory was that the studies showing a survival benefit from radiation therapy after mastectomies could not be adequately explained by the reigning systemic theory that has the attention of most oncologists -- yet he believes that the studies, regardless of any limitations they may have, are providing important information that should not be ignored. Since data that contradicts a reigning theory can sometimes be disregarded, he thought it important to describe why it is the current theory (the "conventional wisdom") that should yield, not the data.

In his lecture, "Natural History of Small Breast Cancers," J. of Clinical Oncology, 12:2229 (1994) (but do not think that this involves only small cancers), Dr. Hellman wrote, in part:

"[Under the Halsted model, the] underlying premise is that breast cancer is an orderly disease that progresses in a contiguous fashion from primary site, by direct extension, through the lymphatics to the lymph nodes, and then to distant metastatic sites. It implies that effective treatment must recognize this orderly, contiguous disease spread. . . . . [It] was not until recently that an alternative hypothesis was accepted. That hypothesis suggests that breast cancer is a systemic disease and implies that small tumors are just an early manifestation of such systemic disease, which, if it is to metastasize, has already metastasized. This was first suggested [in 1954 and 1967 and then in 1980 by] Karnofsky lecturer, Bernard Fisher [who said the things I quoted earlier in this message]."

HOWEVER, "A third hypothesis considers breast cancer to be a heterogeneous disease that can be thought of as a spectrum of proclivities extending from a disease that remains local throughout its course to one that is systemic when first detectable."

Now, friends and colleagues, listen to what he says next:

"This hypothesis suggests that metastases are a function of tumor growth and progression. Lymph node involvement is of prognostic importance not only because it indicates a more malignant tumor biology, but also because persistent disease in the lymph nodes can be the source of distant disease." [Most italics here and throughout these pages are added by John Bonine, with no further notation of the fact.]

Note the implications of that quotation: tumor-containing lymph nodes (and perhaps other sites) might be a SECOND source from which cancer can spread to the rest of the body.

"Persistent disease, locally or regionally, may give rise to distant metastases and, therefore, in contrast to the systemic therapy [that is, the chemotherapy or tamoxifen], locoregional therapy is important."

In other words, better surgical removal of residual tumors may be important. He labels his new theory a "third, or spectrum, theory" and says in some instances inadequate treatment of potential local or regional tumors may lead to additional metastasis occurring.

Radiotherapy may be important, even after "local" control has been done through a lumpectomy or even a mastectomy, so that "regional" problem is addressed, to prevent it from becoming the source of a later systemic problem through additional metastases.

Dr. Hellman expresses it this way:

"The first general question useful in distinguishing among the the three hypotheses is at what time in the natural history of breast cancer do distant metastases occur? The systemic disease hypothesis suggests that these occur before clinical detection and argues that local eradication of disease makes little or no difference."

Run that last sentence by your eyes again. Doctors are generally stating these days that breast cancer is "a systemic disease" by the time that we can detect its existence in any person's body. Systemic diseases are attacked systemically -- through chemotherapy or anti-estrogen therapy (or ovarian ablation, as recently noted), and under the systemic theory, "local eradication of disease makes little or no difference."

But Dr. Hellman of the University of Chicago thinks that breast cancer is not always ONLY a systemic disease by the time it is discovered, but instead can be a disease in which, some of the time, the continued presence of local tumors can lead to additional metastases in the future and thus we must in some instances try to go after even those whose presence we cannot detect.

He says that persons with small breast cancers might be of two types -- a group of that has "indolent and clinically unimportant cancers," and a "second group" of persons who have "a localized cancer that, if left to grow, will become disseminated and result in the patient's death." Unfortunately, when patients are seen with small breast cancers detected only by mammography (and this would ipso facto mean also those who have small cancers that cannot be detected at all) "we cannot tell whether the tumor detected is one of these indolent and clinically unimportant cancers or not."

But Dr. Hellman says that the evidence suggests that there are at least some patients who have small cancers that, if left untreated, will eventually metastasize -- but that if treated by radiation therapy may not, producing greater survival.

"The randomized trial performed in Stockholm of adjuvant radiation following mastectomy bears directly on this point. The study is important since the treatment would be acceptable by today's standards" (among other things). Note this:

"This study shows the expected reduction in locoregional recurrences, but is also shows an accompanying decrease in distant metastases and deaths due to breast cancer." Read that sentence again.

A group of researchers looked at all randomized trials of mastectomy with or without radiotherapy, and concluded, earlier in 1994: "'The reduction of breast cancer deaths suggests that radiation therapy may have a value beyond the clearly established improvements obtainable for local control.'" (Dr. Hellman cites Cuzick, et al., "Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy," J. Clin. Oncol. 12:447-453 (1994).)

Dr. Hellman says that there are tumors "that are destined to remain localized," others "that metastasize as a function of size," others "that possibly disseminate from persistent lymph node disease," and finally some that "have occultly disseminated by the time of diagnosis, since locoregional treatment is not universally effective in preventing metastases." This last group benefits from systemic therapy, such as chemotherapy. The first group needs little concern. The second, and possibly third, group is where regional and local radiotherapy can make a difference -- even after mastectomy. The problem is knowing what kind of tumor one is seeing, and in part one cannot know which are which.

He suggests that if a tumor is quite small (less than or equal to 2 cm in size) it may be sufficient to use local and regional treatment (surgery and radiation), even with "some axillary node involvement," because even if there has been some metastasis to distant sites in the body, the body may be able to deal with a small number of cells (or they not be very malignant). ""When tumors are larger, the likelihood for metastasis increases. . . ."

In conclusion, Dr. Hellman wrote:

"Both the Halsted and the systemic hypotheses are too restricting. The hypothesis most consistent with the data is that breast cancer is best thought of as a spectrum of disease with increasing proclivity for metastasis as a function of tumor size, but for anytumor size there is a proportion of patients with distant metastasis." (My emphasis.)

Colleagues, I will have much more to write about this, for I am trying to read and understand all the major scientific journals articles on the use of radiation therapy after mastectomy for some persons. This first posting can stand as an attempt to demonstrate why radiation therapy after a mastectomy might(theoretically) help prevent distant metastases and promote long-term survival.

My later postings will survey the literature of the past two years saying that radiation therapy for some post-mastectomy patients HAS INDEED proved to lead to more survival for some women. I'll also summarize the results of my survey soon. And I'll quote from the views of some other prominent researchers, such as Dr. Abram Recht of Harvard University Medical School.

John

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