The Texas Cancer Center

The Cancer Breakthrough You've Never Heard Of

Chapter One

Any cancer surgeon of a hundred years ago would have little difficulty working beside his modern day colleagues, because the surgeon's scalpel remains the basic tool of cancer treatment. Over 90 percent of those patients who are cured of cancer today are still cured by surgery - surgery alone. While modern medicine has benefitted greatly from this century's technological advances, the treatment of cancer has advanced due to changing ideas about the growth and spread of malignant disease. Technological marvels such as CAT scanners and laser beams have contributed little to the overall survival of patients with cancer. The greatest part of this improvement came about during the last twenty-five years, the fruit of much careful research.

The central controversy among cancer surgeons has always been: how much normal tissue must a surgeon remove to be confident he "got it all"? In my view, attitudes established 100 years ago have hindered progress toward more conservative treatment. There has been a tendency to favor tradition over innovation. Reviewing this story is important, because all cancer patients are participants in a debate that is far from resolved.

Because breast cancer is so common, most of our knowledge about cancer surgery has been learned from the study of this type of cancer. Physicians have had an opportunity to treat breast cancer in many different ways. The history presented here focuses almost entirely upon this disease. This history of other malignancies is covered in the appropriate section of Appendix I.

THE BEGINNING OF MODERN SURGERY

Surgery was practiced on the battlefield for centuries by barbers, who were often derided as little more than butchers. In the mid-1800's, a surgeon's skill was measured by his speed, naturally so since he performed amputations and cared for wounds without anesthesia or antibiotics. "Respectable" physicians refused to be associated with such a brutal craft. Sir James Simpson, a discoverer of anesthesia, said, "A man laid on the operating table in one of our surgical hospitals is exposed to more chances of death than was the English soldier on the field of Waterloo."(1)

Things began to change in the last quarter of the nineteenth century. Ether anesthesia was becoming available in many hospitals. Joseph Lister had discovered that postoperative infections could be prevented by eliminating bacteria from the field of surgery, and surgeons washed their hands and instruments with greater frequency. Antiseptics (not antibiotics) were introduced. Surgeons in Germany developed instruments and techniques, that improved the craft of surgery and helped control blood loss. Microscopes became widely available, and more pathologists could diagnosis cancer. These major advances set the stage for the beginning of modern cancer surgery as we know it.

Into this setting stepped William S. Halsted, today called the "Father of American surgery". Halsted entered Columbia University's College of Physicians and Surgeons in 1874, at the age of twenty-two. Four years later he had completed medical school, internship, and surgical training. He went on to study in the great clinics of Germany and Austria for two years, a practice that was very common at the time. There he learned more about careful surgical technique and the importance of laboratory investigation. He was also introduced to the students of Rudolf Virchow, the "Pope of German medicine". Virchow had discovered that all growth, tissue repair, wound healing, or even cancer formation, depend upon a process of continually dividing cells - "omnis cellula e cellula". (All cells come from cells.) Old ideas, such as the notion that "evil humors" caused illness, were quickly discarded. Pathologists began the analytic study of disease. Since most illnesses are caused by sick cells, Virchow helped to elevate medicine from witchcraft to science.

In 1880, Halsted returned to New York City, where he became a respected young surgeon. It is most important to realize that in Halsted's day, most patients with cancer waited until their disease was far advanced before seeking the advice of a physician. The results of last minute treatment were discouraging. As Halsted said, "Most of us have heard our teachers in surgery admit that they have never cured a case of cancer of the breast . . . . There are undoubtedly many surgeons in active practice who have never cured a cancer of the breast."(2)

At that time breast cancer was treated with either removal of the tumor or complete removal of the breast. Halsted expanded upon the techniques he had learned in Germany and began to develop the radical mastectomy, an operation, which removed the entire breast and much of the surrounding tissue.

THE THEORY BEHIND RADICAL SURGERY

To understand Halsted's surgical strategy, it is necessary to understand a popular theory of cancer spread. The word "cancer" is derived from the Greek word for crab, karkinoma. Indeed, the disease was considered analogous to a crab in its behavior: reaching out in many directions to destroy healthy tissue. Halsted and many others believed that cancer cells did not spread through the blood stream. All tumors, they said, spread by direct extension. Cancer spread to the liver and lungs directly through the layers of the body into these organs; cancer cells reached the brain by traveling up the lymphatic network in the neck. This theory of "centrifugal spread" became the foundation of surgical oncology. We now know that this theory was wrong. Cancer does spread to distant organs primarily through the blood stream. But Halsted's great reputation at the time meant acceptance of his ideas as holy writ.

This flawed perception of tumor spread supported aggressive surgical treatment. Surgeons believed that if the tumor could be surrounded and removed the patient could be cured. The "centrifugal spread" theory meant that cure was totally in the hands of their surgeon, who cut out the farthest tentacles of the tumor. Halsted's study of anatomy and physiology allowed him to design a breast cancer operation based upon accurate anatomical dissection. His radical mastectomy procedure removed the entire tumor, the entire breast, the underlying chest muscles, and the lymph glands in the axilla (the arm pit). His surgical technique was careful, gentle, meticulous, and lengthy, a superior replacement for the hasty, flamboyant style of his predecessors. The tumor was handled minimally and never cut in two. Lymph ducts between the tumor and the axillary lymph nodes were left intact. The surgeon removed the surgical specimen in one piece, to avoid spilling tumor cells into the operative field. Halsted summarized a common notion of the time:"The division of one lymphatic vessel and the liberation of one cell may be enough to start a new cancer."(3) Certainly, no one wanted that.

In July 1885, former president Ulysses S. Grant died of cancer of the tongue, caused by many years of smoking and drinking. The extensive newspaper coverage of this event greatly elevated the public discussion of this previously "shameful" disease".(4) In the Victorian era cancer was a private matter, seldom discussed. Grant's illness helped to bring cancer out in the open.

In 1892, Halsted started a thirty year tenure as Professor of Surgery and Surgeon-in-Chief to the newly opened Johns Hopkins Hospital and Medical School in Baltimore. Two years later, Halsted wrote about the first fifty patients he had treated with his new operation -- the radical mastectomy. Many of these patients had come to him with tumors the size of hens' egg, others, the size of an orange. All the patients had axillary lymph nodes filled with cancer. In spite of this, Halsted's results were astonishingly good for his time. He reported that only three patients had developed local recurrences among the fifty he had treated. This was considered an overwhelming achievement. Halsted's radical mastectomy for breast cancer soon gained wide acceptance in the United States and Europe. For the first time an American surgical procedure had been adopted abroad. This further contributed to the status of Halsted's procedure and to the pride of American surgeons.

Halsted also introduced laboratory study into medical research and training. His own laboratory research included the use of cocaine as a local anesthetic. Halsted and a small group of physicians became addicted to the drug, which destroyed the lives of all except Halsted. For the last 28 years of his life he struggled with cocaine and morphine addiction. This information was kept secret during Halsted's life and not fully revealed until 1969. Then the records of Sir William Osler, his physician and friend, were opened.(5) But Halsted's death in 1922, was not drug related. Ironically, he died following surgery for a gall stone -- a disease he could treat with surgery. It is difficult to overestimate Halsted's influence on the surgical treatment of cancer and the training of surgeons. The radical mastectomy became the "Gold Standard" against which all breast cancer treatment would be measured. His detailed surgical training program became a model for all surgical training in the United States.

Together, 17 surgical residents and 55 assistant residents finished Halsted's program, and 42 became teachers of surgery in similar programs across the United States and Canada.5 From these programs, 166 chief residents in surgery graduated, all disciples of Halsted's ideas about cancer and surgical training. Many surgeons today are proud to trace their own academic lineage directly back to Halsted. Surgeon Sherwin Nuland in his book Doctors - The Biography of Medicine said, "Even after almost thirty years of being a surgeon, my own occasional flutterings of self-doubt in the operating room can always be stilled by reminding myself that my professor was Gustaf Lindskog, whose professor was Samuel Harvey, whose professor was Harvey Cushing, whose professor was William Halsted . . . the quiverings are gone in the wink of an eye."(6)

The training of surgeons was different from that of other specialists. The 8-year program that Halsted developed was a great important over the old apprentice system. Surgeons-in-training spent many hours in the operating room learning from those, who were two or three years older. Surgeons learned to make decisions quickly in the operating room. They teased their colleagues in internal medicine for spending endless hours discussing the diagnosis and treatment of patients with exotic diseases. A surgeon was expected to be decisive. The training program was shaped like a pyramid with dozens of medical students at the bottom and one or two chief residents at the top. The structure has been compared to that of the military, and surgeons-in-training were expected to follow orders. At each medical school the real person in charge was the chairman of the department of surgery. He appointed residents and hired surgeons to the faculty who shared his views about surgery. It is not surprising that ideas about radical surgery became accepted very quickly.

THE GROWTH OF RADICAL SURGERY

The philosophy and techniques of radical surgery for breast cancer were soon applied to other types of malignancies. Ernst Wertheim of Vienna, Austria, popularized the radical hysterectomy for carcinoma of the cervix. Hugh Young performed the first radical prostatectomy for prostate cancer at Johns Hopkins in 1904. Halsted assisted him during this operation.

In 1908, Sampson Handley proposed that malignant melanoma should be removed with a 2-inch margin of normal skin, measured in all directions around the cancer. Surprisingly, this recommendation was based upon a single autopsy of a single patient who died of melanoma, which had spread throughout her body. Handley's recommendation continues to be widely quoted in the modern surgical literature, although surgeons admit that a single autopsy is not sufficient evidence to support his conclusions. Handley was also a proponent of the theory of centrifugal spread, which was gaining support.

Ernest Miles proposed a radical procedure for cancer of the rectum; it removed the entire rectum and surrounding tissue, resulting in a permanent colostomy. George Crile, Sr. developed a radical neck dissection for tumors of the head and neck, a procedure that removed the tumor along with the muscles, jugular vein, and lymph nodes of the affected side of the neck. Head and neck surgeons developed the "commando" operation, which removed part of the jaw bone. (Its popularity has been attributed to its name, derived from the commandos of World War I.(7)) Some surgeons even removed the pelvis and both legs -- the entire lower half of the body -- in an operation called a hemicorpectomy.

In the 1910's cancer caused 4.4 percent of the deaths in the United States making it the eighth leading cause of death behind tuberculosis, heart disease, diarrhea, violence, pneumonia, kidney failure and apoplexy (now known as stoke).3 By and large, the medical profession was making some progress. Sociologist Lawrence Henderson put this period into perspective. He said,"Sometime between 1910 and 1912 in this country, a random patient, with a random disease, consulting a doctor chosen at random, had, for the first time in the history of mankind, a better than a fifty-fifty chance of profiting from that encounter." (8) In 1913, the American Society for the Control of Cancer, which later became the American Cancer Society, was formed to distribute information about cancer and to compile statistics.

By the 1920's, surgeons were beginning to win their fight against cancer. This was primarily because patients started seeking medical attention earlier with smaller tumors. Some were actually cured of their disease. Radical surgery was saving some lives. Cancer, unmentionable during the Victorian era, was gaining public attention as a curable disease.

Now comes a paradox. At the time of radical surgery's apparent triumph, the premise behind it evaporated. The famous pathologist James Ewing, of Memorial Hospital in New York, published evidence that cancer cells did indeed spread to distant sites by circulating in the blood stream, not by growing tentacles out into adjacent organs. Surgeons decided that tumor cells broke off from the primary tumor and progressed in an orderly fashion to the lymph nodes and then into the blood stream. Lymph nodes were considered a partial barrier to the spread of tumor cells.

The fall of the centrifugal spread theory in the 1920's did not dampen the enthusiasm of American and European surgeons for radical surgery, and it's important to realize why this occurred. As patients lived longer, more of them returned with recurrent disease in the area of the surgical scar. This was called local recurrence, and it was often the first evidence of failure. Most patients with local recurrence were soon found to have cancer in distant organs -- distant metastases. Local recurrence became the equivalent of a death sentence, since few patients lived more than an additional two years.(9),(10),(11) Surgeons mistakenly criticized themselves, believing that they were responsible for the recurrence, the spread of disease, and ultimately the death of the patient. Why? Because they had failed to remove enough tissue, or because tumor cells had spilled into the wound. Cushman Haagensen, the famous breast surgeon from Columbia-Presbyterian Hospital in New York, said,". . . the surgeon certainly is accountable . . . for local recurrence in the field of operation. . . ."(12)

Most surgeons witnessed this pattern of recurrence repeatedly in their practices and suffered great anguish. Time after time, surgeons returned to the operating room ever more determined to perform surgery that would eliminate every cancer cell. Surgeons continuously reiterated the importance of radical surgery to their colleagues and the surgical residents they trained. Another paradox was emerging: surgeons were seeing smaller and smaller tumors, yet performing more radical operations -- removing more tissue.

EARLY CHALLENGES TO RADICAL SURGERY

In the first decades of the twentieth century, few doctors questioned the doctrine of radical surgery. Rudolf Matas of Tulane was one of the few. Ironically, Matas and Halsted were close friends - a relationship that endured in spite of this professional disagreement. In the United States no one else dared to confront Halsted's radical mastectomy until more than a generation after his death in 1922. Instead, early challenges to Halsted came from abroad.

Working in Paris, Marie and Pierre Curie introduced radium into the treatment of cancer in 1898. By the 1920's this treatment was widely accepted. In 1922, Geoffrey Keynes, an English surgeon (the brother of economist John Maynard Keynes), began using local excision and radiation therapy to treat breast cancer. He treated many patients with stage I breast cancer (There was no evidence of tumor cells in the lymph nodes). Over 70 percent of his patients survived five years, a respectable figure for the times. As the sole practitioner of local excision and radiation he was criticized, and his results were unfairly compared to the best results of his colleagues. Eventually he reverted to total removal of the breast, because 8 percent of his patients developed local recurrence. But this rate of recurrence was actually no higher than that following radical surgery, and even today would be considered a good result. In his autobiography, The Gates of Memory, Keynes wrote, "A built-in dogma of thirty years standing dies hard, and I was regarded with grave disapproval and shaking of heads by the older surgeons of my own hospital."(13)

During this period, Duncan Fitzwilliams, working at St. Mary's Hospital in England, treated 93 patients with early breast cancer using excision alone. He claimed to have results equivalent to radical surgery. He said,"Those who have been brought up in the atmosphere of the radical operation with no experience of anything less extensive must remember that they are repeating dogma and not speaking from formed judgement. Medicine is never advanced by such action."(14)

In 1937, the Congress established the National Cancer Institute to conduct cancer research. Cancer replaced tuberculosis as America's most dread disease. By the 1940's cancer had become the second leading cause of death behind heart attacks and stroke.

As World War II approached, more physicians investigated radiation therapy. Sakari Mustakallio of the University Central Hospital in Helsinki, Finland, began treating patients with tumor excision and low dose radiation therapy.(15) So did Vera Peters at the Princess Margaret Hospital, Toronto, Ontario, using a higher dose of radiation.(16) Both obtained survival results comparable to the radical mastectomy. Robert McWhirter, a radiotherapist in Scotland, began removing the entire breast, an operation called a simple mastectomy. After surgery he administered radiation to the lymph glands in the arm pit. All those investigators achieved excellent survival results, although the low radiation doses used in Finland led to higher rates of local recurrence. In 1943, Frank Adair reported that 63 patients treated at Memorial Sloan-Kettering Hospital in New York with conservative surgery had survived as long as those treated with radical surgery. Nevertheless, Adair concluded,"But it would be disastrous if we were to take a step backward"(17)

EVIDENCE AGAINST RADICAL SURGERY INCREASES

After World War II the American Society for the Control of Cancer changed its name to the American Cancer Society and focused on fund raising. During the 1950's, a new generation of surgeons and radiation therapists began to challenge Halsted's ideas and practice breast-sparing treatment of breast cancer. It came about in this way.

In England, Reginald Murley, a young surgeon, and radiotherapist I.G. Williams tracked down the records of patients who had been treated by Keynes twenty to thirty years earlier.(18) Murley supported radical surgery and expected to find that Keynes' conservative treatment had failed. He was surprised to find solid evidence that patients treated with simple excision and radiation therapy survived as long as those treated at the same hospital by radical surgery. This discovery led surgeons and radiotherapists in several hospitals throughout England to begin offering breast-sparing treatment.(19),(20),(21) One study reported a high local recurrence rate if radiation was not used.(22),(23) What is more important, they began to challenge the notion that local recurrence was the cause of distant metastases. Williams and Murley said,"It is, however, possible that local recurrence per se is an infrequent source of distant metastases and that the appearance of the latter has been determined quite independent of the former."

In 1954, Keynes wrote about his experience in the 1920's and 1930's challenging the radical mastectomy: "Orthodoxy in surgery is like orthodoxy in other departments of the mind -- it starts as a tentative belief in some particular course of action, but later begins to almost challenge a comparison with religion. It comes to be held as a passionate belief in the absolute rightness of that particular view. A dissentient view is regarded as a criminal subversion of the truth, and the holder is sometimes exposed to slander and abuse . . . In speaking today of the unorthodox view of carcinoma of the breast, I do not mean to suggest the orthodoxy has been manifested in its more violent forms. None of us has been burnt at the stake, but feelings have run pretty high."(24)

In the United States, Murley told George Crile, Jr. (son of the surgeon who developed the radical neck dissection) of the Cleveland Clinic, about the excellent results achieved by Keynes prior to World War II. Crile, like Murley, was a young surgeon who supported radical surgery. But, he was intrigued by Murley's evidence. He persuaded his colleagues at the Cleveland Clinic to allow him to try this more conservative approach. Crile thus became the first American surgeon to practice conservative surgery for breast cancer. Most of his patients were treated with a partial mastectomy alone, i.e., excision of the tumor plus a wide margin of healthy tissue. Radiation therapy was only used on those few patients with more advanced tumors. Although his results were always comparable with those achieved through radical surgery, Crile was nevertheless criticized as an extremist.

He said in his book, Cancer and Common Sense,"Those responsible for telling the public about cancer have chosen to use the weapon of fear. They have created a new disease, cancer phobia, a contagious disease that spreads from mouth to ear."(25) In 1955, a summary of the book filled six pages of Life magazine, despite many efforts by the proponents of radical surgery to stop its publication. Life's editor, Ralph Graves, told Crile that he had "a most revealing glimpse of medical politics."(26)

THE EXPANSION OF RADICAL SURGERY

The gulf between the advocates of radical surgery and supporters of conservative surgery kept widening. Supporters of radical surgery developed elaborate mechanical techniques to reduce local recurrence. They excised so much tissue that skin grafts were often required to cover the surgical defect. The remaining skin was shaved very thin, to remove any possible tumor cell close to the surface of the skin. Surgical wounds were sometimes irrigated with a toxic solution to kill tumor cells, that might have spilled into the wound. It was thought that cancer could spread prior to and during surgery, and surgeons handled tumors as if they were land mines. Residents in training were told not to touch the patient's breast to avoid shedding tumor cells into the blood. (Never mind that the patient may have been sleeping on her breast tumor for months.)

Rituals developed around the operation. Radical surgery specified the location of the biopsy incision (within the area of a mastectomy incision), the interval between diagnostic biopsy and surgery (only minutes), the location of the mastectomy incision (low, if possible), and so on. Surgeons were trained to remove the biopsy incision as a part of the radical operation. Surgeons who failed to follow these procedures were subject to severe disciplinary measures. Many surgeons changed gowns, gloves and instruments after the biopsy and again before closing the skin. The goal of surgery was to remove every cancer cell and to be certain that no malignant cell returned to the surgical incision. Surgeons focused completely upon the details of the operation. They believed that the precise execution of this intricate procedure was the patient's only chance for cure. This was, and in many cases still is, a reasonable conclusion. Surgeons were trying to maximize the only effective weapon against cancer. This commentary should not be interpreted as criticism of these heroic efforts.

The proponents of radical surgery moved ahead with more aggressive procedures. In the late 1940's surgeons in Europe began performing an extended radical mastectomy. Besides removing the entire breast, the chest muscles, and the axillary lymph nodes, this procedure also excised lymph nodes located beneath the breast bone. Dr. Jerome Urban at Memorial Sloan-Kettering Hospital became a leading advocate of this procedure. Some patients whose cancers were located near the breast bone appeared to benefit from this procedure, but it never gained wide acceptance and was eventually abandoned. Leading surgeons at Columbia University and the Mayo Clinic pressed for even more extensive surgery. They divided the collar bone and removed the first rib to remove additional tissue! Fortunately, this procedure also was quickly abandoned. Even following radical surgery, radiation therapy was occasionally administered to eradicate residual tumor cells. While some of these procedures reduced local recurrence, unfortunately, none consistently improved patient survival. Radiation therapy was used primarily for advanced cancer.

The surgeon was very much in charge of the patient's care. He performed surgery hoping for a cure. If the patient developed local recurrence, he knew that cure was no longer possible. He could send the patient for radiation therapy, which could kill the tumor on the chest wall. This prevented the cancer from causing an offensive wound on the chest. A third form of treatment, chemotherapy, became popular in the 1950's. This was drug treatment which attempted to kill cancer cells throughout the body. Surgeons also referred their patients for this additional treatment.

By the late 1950's, major cancer centers, beginning with the Mayo Clinic in Rochester, Minnesota, began to plan treatment early in the course of disease. Patients with advanced or complicated malignancies would be seen by a surgeon, radiation therapist, and oncologist simultaneously. This approach is called multidisciplinary treatment. These committees would plan the most effective treatment strategy. For example, chemotherapy or radiation treatment might be given prior to surgery to shrink the tumor. Thus, patients were no longer moved from one doctor to another as each exhausted his ability to control the patient's illness. This new approach improved the care of cancer and has been widely praised throughout the medical community.

Naturally, there has been some competition among specialists. Each specialist wants to maximize his own role. Multidisciplinary treatment tends to avoid these conflicts by treating each patient with several types of treatment. If most patients are treated with most forms of treatment, then the treating physicians are arguing among themselves. This is one of the drawbacks of the multidisciplinary approach: too much treatment.

BREAST-SPARING TREATMENT GAINS MOMENTUM

During the 1960's, perhaps because radiation therapy had been pioneered in Paris by the Curies, enthusiasm for breast-sparing surgery arose in France.(27),(28),(29),(30),(31),(32),(33),(34) The leading French radiotherapist, F. Baclesse, reviewed his experience with 100 patients treated with local excision and radiation from 1937 - 1953. He concluded that his results were every bit as good as those of radical surgery. After that, physicians in Paris, Marseille, Creteil, and Villejuif began reporting excellent survival statistics following treatment that spared the breast.

But many patients were treated with inadequate tumor excision or no tumor excision at all. All too often they developed a local recurrence, and the breast was then totally removed. Under this circumstance, the operation was called a salvage mastectomy. The French then made a surprising observation. Investigators at the Curie Foundation concluded, "It appears that local recurrences following lumpectomy and radiotherapy or radical radiotherapy alone do not alter the prognosis."(35) Patients treated with a salvage mastectomy did surprisingly well, and over half lived another five years. This was far better than the one- or two-year survival rate seen among patients who developed recurrence following radical surgery.

In 1964, the first scientific study of breast-sparing surgery was begun at the Guy's Hospital in London. The study compared tumor excision plus low dose radiation therapy to radical mastectomy. This trial initially concluded that the overall survival rate of patients treated with a partial mastectomy was equal to that following radical mastectomy. Unfortunately, many patients had disease, which had spread to the axillary lymph nodes. The low dose of radiation was not effective in killing this disease. Many of these patients developed extensive local recurrences and died because of this flaw in the study. The poor results among these patients were widely publicized by critics of conservative surgery, and the conservative movement was set back.

In the midst of this rancorous debate, George Crile, Jr. returned to the battle. In 1965, he published his experience with local excision, maintaining strongly, as before, that conservative treatment was safe and effective. At Harvard, Oliver Cope was also practicing breast-sparing surgery with favorable results. In 1967, he presented his experience to a meeting of the New England Surgical Society, but the society refused to publish his report in its journal.

The excellent results of conservative treatment were subtly beginning to influence some advocates of radical surgery, who began reducing the scope of their procedures. Radical mastectomy left the patient only a thin layer of skin to cover the rib cage, giving the chest appearance of a washboard. As early as 1963, the American surgeon Hugh Auchincloss had suggested that most patients could be treated with a modified radical mastectomy. This operation did not remove the large pectoral muscle overlying the ribs of the chest wall. The modified procedure eliminated the washboard appearance because of the presence of a muscle between the skin and the ribs. The patient still lost the entire breast and the lymph nodes under the arm. Earlier studies in Europe had shown that the modified procedure did not compromise patient survival, and many English surgeons had already adopted this procedure. The modified procedure was gaining acceptance in the United States. Patients seeking conservative surgery were frequently told by their surgeons, "I do the modified procedure." These surgeons believed that they were modernizing the treatment of breast cancer. Even Halsted reported in 1894 that he had done seven incomplete operations "due to the small size or recent appearance of the tumor."(36)

By the 1970's, the treatment of breast cancer was clearly one of the most argued subjects in medicine. In 1972, an editorial in the prestigious British Medical Journal said, "there is more controversy about the management of breast cancer than almost any other topic in tumor therapy, and more so now than ever before."(37) In 1970, John Stehlin of St. Joseph Hospital in Houston began to treat patients with partial mastectomy and radiation therapy. He, too, was severely criticized by his colleagues. In 1979, he published his experience with 79 patients, providing additional evidence that conservative surgery was as effective as more radical treatment. Those following the medical uproar were not surprised when he began his paper by saying, "The treatment of no other form of cancer has evoked such a degree of controversy and emotionalism as has that of carcinoma of the breast."(38) Samuel Hellman, an oncologist from the University of Chicago, has compared the persecution of those surgeons who opposed radical surgery to that of the so-called heretics in the Spanish Inquisition.(39) I would only add that the dogma of radical surgery has applied to most cancers -- not just cancer of the breast. Normally sedate medical meetings erupted in fierce debate. While some surgeons mentioned lumpectomy to their patients as an option, most of them continued to practice mastectomy.

THE TIDE BEGINS TO TURN

By 1975, over 150,000 American women were developing breast cancer annually. Crile had treated 291 patients with surgery, which saved the breast, but most American women were still treated with mastectomy. Over twenty medical centers in Finland, Canada, England, France, Italy, and the United States were treating patients with breast-conserving surgery and radiation. Over sixty articles on breast-sparing surgery had been published in prominent medical journals in the U.S. and abroad, and they all carried a single message:Breast-conserving surgery works. It is just as effective as radical surgery in the treatment of breast cancer. Except for Keynes, the first modern physician to practice breast-sparing surgery, no surgeon, no radiation therapist, and no institution, has ever returned to total removal of the breast after starting to use breast-sparing therapy.

Nevertheless, American patients with breast cancer had a difficult time learning about alternative forms of treatment, much less finding a surgeon who advocated breast-sparing treatment. The vast majority of surgeons, intellectual descendants of William Halsted and his doctrine, were steadfastly committed to mastectomy. They pointed to the poor results of partial mastectomy in the past. They seldom mentioned that this procedure had not been seriously used since the nineteenth century, when it was used for the treatment of large tumors. Advocates of radical surgery said they were waiting for additional results from scientific trials of breast-sparing surgery. But in 1975, the American lumpectomy study had not yet begun.

In fairness, there were problems associated with some reports favorable to conservative surgery. In some studies many patients returned with local recurrence, in others the conservative treatment was restricted only to patients with early disease. Thus the good results might have been due to patient selection and not to treatment. Still, the preponderance of circumstantial evidence suggested that partial mastectomy was a safe and effective procedure for patients with early breast cancer.

In 1973, Umberto Veronesi of Milan, Italy, began a scientific study comparing partial mastectomy plus radiation with radical mastectomy. Veronesi removed one-fourth of the breast and called the operation a quadrantectomy. This was the first such study since the Guy's Hospital Trial. By 1980, 701 patients had been studied. Veronesi showed statistically that survival and local recurrence results were equal for both forms of treatment.

A CONCERTED EFFORT BEGINS

Bernard Fisher of the University of Pittsburgh had begun to question some of Halsted's principles back in 1957, when he organized the multiinstitutional National Surgical Adjuvant Breast Project (NSABP) to study various aspects of breast cancer treatment. Through a series of trials, this group has done far more than improve the surgical, radiation, and chemotherapeutic treatment of breast cancer.(40) Working in the laboratory and in clinical trials, Fisher and the NSABP reversed many of Halsted's hypotheses.

Halsted had concluded that tumor cells spread by direct extension and in an orderly manner to neighboring lymph nodes. The NSABP concluded that tumor cells do not progress in an orderly pattern, and that they break away from the tumor and travel to lymph nodes in clusters. Halsted believed that lymph nodes where barriers to the passage of tumor cells. The NSABP concluded that lymph nodes are not effective barriers to tumor spread. Halsted believed that positive lymph nodes could themselves become the cause of additional tumor spread. The NSABP concluded that positive lymph nodes are an indicator of a poor prognosis and not its cause. If cancer cells are living within a patient's lymph nodes, her immune resistance is probably weak. Halsted believed that the tumor grew and spread on its own, independent of the patient. The NSABP concluded that a complex interaction between the tumor and the patient affects all aspects of the cancer. Halsted believed that the blood stream was unimportant in the spread of tumor cells. The NSABP concluded that the blood stream is very important in the spread of tumor cells. Halsted believed that cancer cells remained localized to the tumor for a long time. The NSABP concluded that tumor cells begin to circulate early; they called breast cancer a systemic disease. Halsted believed that the type of surgical treatment was very important in a patient's outcome. The NSABP concluded that local treatment had little affect on survival.

The NSABP successfully challenged many of the ideas about breast cancer that had dominated the twentieth century. The Halstedian model was replaced by an alternative view of tumor spread. No individual, no institution has contributed more to our understanding of cancer than Bernard Fisher and the NSABP. (There are still many questions remain unanswered. These will be discussed more thoroughly in Chapters 2 and 3.)

In one very important study (Trial B-04), the NSABP focused attention on the treatment of axillary lymph nodes. Surgeons treated over 1,000 women with breast cancer. None of the women had enlarged lymph nodes in the arm pit. The lymph nodes were said to be clinically negative, i.e., there was no evidence of cancer on clinical (physical) examination. Surgeons know that physical examination of these nodes is unreliable; 30 percent to 40 percent of patients with no palpable nodes are found to have microscopic tumor spread by the pathologist (pathologically positive) after the nodes have been removed.

In this study, all patients had a mastectomy, but the axilla was treated in three different ways: the nodes were surgically removed. (40% of patients had positive nodes.), the nodes were irradiated, or the nodes were not treated and only observed. About 18 percent of the patients in the last group developed lymph nodes enlarged with cancer and required an operation to remove them. (It needs to be explained why only 18 percent of patients developed enlarged lymph nodes and not the full 40 percent found to have positive nodes in the group treated with surgery. Part of the differences was due to the methods of detection. Physical examination only was used to find positive nodes in the first group. Microscopic examination was used to find positive nodes in the second group. But, it seems likely that some patients with microscopic disease in their nodes were able to destroy those tumor cells before the nodes became clinically involved.)

The overall survival rates in all three groups were identical. In other words, there was no survival advantage to eliminating those cancer cells by either surgery or radiation therapy, and nodisadvantage to leaving tumor cells alone and simply observing the patient. The NSABP concluded that the surgeons could prudently leave cancer cells behind in a patient's lymph nodes without hurting her chances for survival, an idea contrary to all previous notions about cancer surgery.

The innocence, or nonthreatening nature, of recurrence in the lymph nodes had first been reported by George Crile in 1960. He believed that intact regional nodes offered a degree of immune protection.(41) He stated, "the survival rate of the patients treated with delayed treatment of the axilla [arm pit] was similar to that of the patients treated by radical mastectomy."(42) This was a remarkable observation for its time. It was contrary to all established principles and practice of cancer surgery. Nowhere in the annals of surgery had anyone said that a surgeon could safely and prudently leave cancer cells behind inside the patient.

This observation by Crile and its verification by the NSABP never attracted much attention among surgeons. They continued to remove lymph nodes to learn how far the disease had spread. Patients with positive lymph nodes were often treated with chemotherapy, while those with negative nodes were not. Thus, lymph node removal was performed to find out whether or not to administer chemotherapy. It was not performed to remove cancer. For some, this distinction was unimportant. The biological mystery was largely ignored.

A confounding issue now entered the discussion --multicentricity, or the observation that many patients with breast cancer had small areas throughout the breast that resembled early cancer. Surgeons argued that it was foolhardy to leave behind breast tissue, that might become malignant. No surgeon wanted to say, "I think we got it all," or "We got most of the cancer." Proponents of radical surgery argued that radiation therapy was a poor treatment for malignant tissue that could be surgically eliminated. It soon became clear that patients did not develop recurrent cancer nearly as often as the pathologists found these "multicentric" changes. But, even today, radiation therapy is used to kill these cells.

EVIDENCE FOR CONSERVATIVE SURGERY GROWS

By the 1970's, the pioneers in breast-sparing surgery had concluded that local recurrence was not an ominous event. Sakari Mustakallio reviewed his 30 years of experience in Helsinki and concluded, "Thus, provided they are treated, regional metastases by no means impair the patient's prognosis . . ."(43) Vera Peters in Toronto considered her 30 years of practice and observed,". . . surgery alone is followed by a significantly higher recurrence rate, but an effect on survival could not be demonstrated."(44) J.M. Spitalier of Marseille, France concluded, "Late recurrences were all operable and did not appear to be associated with decreased survival."(45) These surprising observations could be confirmed only with a scientifically sound study.

In 1976, the NSABP began its much-awaited lumpectomy trial and in 1985, it published the first results.(46) Lumpectomy was the removal of the tumor along with a very narrow margin of normal tissue. All patients had their axillary (arm pit) lymph nodes removed. This trial compared three different forms of treatment to the breast: modified radical mastectomy, lumpectomy alone, or lumpectomy plus postoperative radiation therapy. Pathologists were asked to verify that the edges of the removed tissue were free of tumor cells. However, everyone acknowledged that some microscopic tumor might have already spread into surrounding breast tissue, far from the eye of the pathologist.

The results were as follows. Patients treated with a modified radical mastectomy developed local recurrence about 8 percent of the time,.patients treated with lumpectomy alone developed local recurrence 43 percent of the time, and patients treated with lumpectomy plus radiation therapy developed local recurrence 12 percent.(47)

Those who developed local recurrence were treated with a second operation, either salvage mastectomy or another lumpectomy. According to traditional surgical beliefs, patients who developed local recurrence should have fared poorly. But, the survival results were surprising. Patients initially treated by lumpectomy alone survived every bit just as long as those treated with aggressive treatment (mastectomy or lumpectomy plus radiation therapy). The 43-percent recurrence rate among lumpectomy patients did not decrease overall survival. These results confirmed and extended earlier findings from Sweden, Canada and France.

After conservative treatment, promptly treated recurrent cancer in the breast or neighboring lymph nodes can be removed with little, in any, risk to patient survival. This remarkable observation was the antithesis of 100 years of surgical belief and practice. It suggested two important questions. One, does this observation apply to other malignancies? Two, why does local recurrence following limited surgery appear to behave in such an innocent, or nonthreatening, fashion?

RESEARCH RAISES QUESTION

No cancer has been studied as thoroughly as breast cancer. For other malignancies, there has been much less experience with conservative surgery. It is uncertain whether the general lessons learned from breast cancer can be applied to other malignancies. But, as you will see in the last half of this book, there is increasing evidence that many cancers seem to behave like breast cancer. That is, local recurrence following limited surgery is not an ominous event.

Soft tissue sarcomas are tumors that arise from muscle, fat or other body tissue. Before 1960, these cancers were often treated with amputation. Since then, surgeons have treated sarcomas with wide excision and postoperative radiation therapy. After reviewing the experience of many institutions, it is clear that radiation reduces local recurrence, but does not enhance overall survival. Murray Brennan of Memorial Sloan-Kettering Cancer Center conducted a scientific trial comparing patients using wide excision with or without radiation therapy. Brennan concluded, "[A] decrease in local recurrence is not accompanied by an improvement in the long-term survival rate." (48)

The same results have been found in the treatment of malignant melanoma. The World Health Organization (WHO) Collaborating Centres for Evaluation and Treatment of Melanoma collected 593 cases.(49) Patients treated with narrow margins of excision had an increased rate of local recurrence, but their overall survival was not decreased. The WHO trial showed no correlation between the width of excision and eventual mortality. (Studies of other kinds of cancer are summarized in appendix I.)

The innocent behavior of local recurrence is still a mystery -- a mystery that has been largely ignored. Explanations have been suggested, but none has received general acceptance. Some surgeons believe that a few microscopic cancer cells left behind at surgery may spread and ultimately prove fatal. Others believe that the those few cells may grow into a detectable tumor, but that the recurrence can be removed without jeopardy to the patient's life. This distinction is very important for patients who wish to preserve their bodily form and function. Every stroke of the surgeon's knife is dependent upon his perception of local recurrence.

I believe that the dilemma of local recurrence has a logical explanation. Just as small primary cancers are usually harmless, small recurrent cancers may be just are as harmless. I will present my explanation in Chapter 4. Some knowledge of the interaction between a cancer and the patient is helpful to understand this dilemma. This interaction is discussed next in Chapters 2 and 3.

As the new century begins radical surgery is being modified and conservative surgery is finding greater acceptance. Many leaders in the field of surgical oncology believe that additional trials of conservative surgery are necessary before traditional treatment is altered. The eradication of every possible cancer cell is still the primary objective. Fear of local recurrence continues to be the basis of cancer treatment.

In 1992, George Crile, Jr., America's pioneer in partial mastectomy and conservative surgery for cancer, died of lung cancer. He had devoted his professional life to protecting women from disfiguring surgery. At the time of his death his surgical principles had been verified, but he had received little recognition or praise for his accomplishments. In his autobiography, The Way it Was -- Sex, Surgery, Treasure and Travel, 1907 - 1987, Crile said:

"In retrospect most of what I said has been proved to be correct. However, to my knowledge none of my critics has ever retracted their statements. Nor was I ever elected to any office in the American Cancer Society, the American Medical Association, any other self-respecting medical organization."

Over a period of 30 years he became immune to the criticism of his fellow surgeons. He received no significant award or recognition for his pioneering work in breast cancer, because the leaders in American surgery were still defending their outmoded surgical principles.

References

1. Robinson JO. The history of surgical oncology. In McKenna RJ, Murphy GP, eds. Fundamentals of Surgical Oncology. New York: Macmillan Pub Co, 1986, p.60.

2. Halsted W.S. The results of operations for the cure of cancer of the breast performed at Johns Hopkins Hospital from June 1889 to January 1894. Annals of Surgery 1894; 20:497-555.

3. Halsted W.S. The results of operations for the cure of cancer of the breast performed at Johns Hopkins Hospital from June 1889 to January 1894." Annals of Surgery 1894; 20:510.

4. Paterson JT. The Dread Disease: Cancer and Modern American Culture. Harvard Press: Cambridge. Massachusetts, 1987.

5. Haagensen C.D. Diseases of the Breast. Philadelphia: W.B. Sanders Co., 1986, p. 870.

6. Nuland S.B. Doctors: The Biography of Medicine. New York: Vintage Books, 1988, p. 406.

7. Crile, Jr., George. What Women Should Know about the Breast Cancer Controversy. Pocket Books, New York. 1974.

8. Patterson J.T. The Dread Disease: Cancer and Modern American Culture. Cambridge: Harvard University Press, 1987.

9. Recht A, Hayes D: Local recurrence. In Harris JR, Henderson IC, Hellman S, Kinne D (eds): Breast Diseases. Philadelphia: Lippincott, 1987, 508-524.

10. Carter RL: Significance of local recurrence. In Stoll BA (ed): "Secondary Spread of Breast Cancer." Chicago: Year Book Medical Publishers, 1977, 31-44.

11. Shimkin MB, Lucia EL, Low-Beer BVA, Bell HG: Recurrent cancer of the breast. Cancer 7:29-46, 1954.

12. Haagensen C.D. Carcinoma of the breast. New York: American Cancer Society, 1950.

13. Keynes, Geoffrey. The Gates of Memory. Clarendon Press: Oxford, 1981, p. 216.

14. Fitzwilliams DCL. A plea for more local operation in really early breast carcinoma. BMJ 1940; 2:405-408.

15. Mustakallio S. Conservative treatment of breast carcinoma -- review of 25 years follow up. Clin Radiol 1972; 23:110-6

16. Peters MV. Cutting the "Gordian knot" in early breast cancer. Ann R Coll Phys Surg Can 1975; 8:186-92.

17. Adair F.E. The role of surgery and irradiation in cancer of the breast. Journal of the American Medical Association (JAMA) 1943; 121:553-559.

18. Williams, I.G., Murley, R.S., and Curwen, M.P. Carcinoma of the female breast: conservative and radical surgery. Brit. Med. J. 1953, 2: 787-796.

19. Osborne M.P., Ormiston N., Harmer C.L., and others. Breast conservation in the treatment of early breast cancer. Cancer 1984, 53: 349-355.

20. Taylor, H., Baker, R., Fortt, R.W., and Hermon-Taylor, J. Sector mastectomy in selected cases of breast cancer. Brit. J. Surg. 1971, 58: 161-163.

21. Bulman, A.S., Zeitman, A., Phillips, R.H., and Ellis, H. Interim results of treatment of breast cancer with breast conservation for all patients. Surgery 1987, 101: 395-399.

22. Tagart REB. Partial mastectomy for breast cancer. Brit Med J, 2:1286, 1978.

23. Tagart R, Bratherton D, Hartley L, Sikora K. Partial mastectomy alone in early breast cancer. Brit Med J, 290:434, 1985

24. Keynes, G. Carcinoma of the breast, the unorthodox view. Proc Cardiff Med Soc 1954; 4.

25. Crile G Jr. Cancer and Common Sense. American Book-Stratford Press, Inc.:New York. 1955

26. Crile G. The Way it Was: Sex, Surgery, Treasure, and Travel, 1907-1987. Kent, Ohio: The Kent State University Press. 1992.

27. Calle, R., Vilcoq, J.R., Zafrani, B., and others. Local control and survival of breast cancer treated by limited surgery followed by irradiation. Int. J. Radiation Oncology Biol. Phys. 1986, 12: 873-878.

28. Sarrazin, D., Dewar, J.A., Arriagada, R., and others. Conservative management of breast cancer. Br. J. Surg. 1986, 73: 604-606.

29. Amalric, R., Santamaria, F., Robert, F., and others. Radiation therapy with or without primary limited surgery for operable breast cancer. Cancer 1982, 49: 30-34.

30. Spitalier, J.M., Brandone, H., Ayme, Y., and others. Traitements curatifs a esperance conservatrice des cancers du sein-generalites-resultats d'ensemble a 5 et 10 ans. Mediter. Med. 170 (Suppl): 3-7, 1978.

31. Kurtz, J.M., Spitalier, J.-M., Amalric, R. and others. Mammary recurrences in women younger than forty. Int. J. Radiation Oncology Biol. Phys. 1988; 16: 271-276.

32. Leung S, Otmezguine Y, Calitchi E, et al. Locoregional recurrences following radical external beam irradiation and interstitial implantation for operable breast cancer - a twenty-three year experience. Radiotherapy and Oncology 1986, 5: 1-10.

33. Verhaeghe, M., Laurent, J.C., Clay, A., and others. Mastectomie partielle avec curage pour les petits cancers du sein. Bull. Acad. Nat. Med. 1979, 163: 836-842.

34. Kurtz, J.M., Amalric, R., Delouche, G. and others. The second ten years: long-term risks of breast conservation in early breast cancer. Int. J. Radiation Oncology Biol. Phys. 1987, 13: 1327-1332.

35. Calle, R., Pilleron, J.P., Schlienger, P., and Vilcoq, J.R. Conservative management of operable breast cancer. Cancer 1978, 42: 2045-2053.

36. Halsted W.S. The results of operations for the cure of cancer of the breast performed at Johns Hopkins Hospital from June 1889 to January 1894. Annals of Surgery 1894; 20:497-555.

37. Editorial: Treatment of early carcinoma of breast. British Medical Journal 1972; 2:417-418.

38. Stehlin JS Jr, Evans RA, Gutierrez AA, et al. Treatment of carcinoma of the breast. Surgery Gynecology and Obstetrics 149:911-922, 1979.

39. Hellman S. Dogma and inquisition in medicine. Cancer 1993; 71:2430-3.

40. Fisher B, Redmond C, Fisher E.R. et al. "The contribution of recent NSABP clinical trials of primary breast cancer therapy to an understanding of tumor biology - an overview of findings." Cancer 46:1009-1025, 1980.

41. Crile G. Possible role of involved regional nodes in preventing metastasis from breast cancer. Cancer 1969, 24: 1283-1285.

42. Crile, G. Simplified treatment of cancer of the breast: early results of a clinical study. Ann. Surg. 1961, 153: 745-761.

43. Mustakallio S. Conservative treatment of breast carcinoma - review of 25 years follow up. Clin Radiol 1972; 23:110-6.

44. Peters, M.V. Radiation therapy in the management of breast cancer. In: Proceedings of the 6th national cancer conference. Lippincott, New York, Pp. 163-174, 1970.

45. Kurtz, J.M., Spitalier, J.M., and Amalric, R. Late breast recurrence after lumpectomy and irradiation. Int. J. Radiation Oncology Biol. Phys. 1983, 9: 1191-1194.

46. Fisher B., Anderson S., Fisher E.R., et al. "Significance of ipsilateral recurrence after lumpectomy." Lancet 338:327-331, 1991.

47. Fisher B, Wickerham DL, Deutsch M, Anderson S, Redmond C, Fisher ER. Breast tumor recurrence following lumpectomy with and without breast irradiation: an overview of recent NSABP findings. Sem Surg Oncol 1992; 8:153-160.

48. Brennan M.F., Casper E.S., Harrison L.B., et al. "The role of multimodality therapy in soft-tissue sarcoma." Annals of Surgery, 1991, 214: 328-338.

49. Cascinelli N., van der Esch E.P., Breslow A., Morabito A., Bufalino R. "Stage I malignant melanoma of the skin: the problem of resection margins." European Journal of Cancer 1980; 16: 1079-1085.v

Texas Cancer Center - 1011 Augusta Drive - Suite 210 - Houston, Texas 77057 Telephone (713) 975-6270 - FAX (713) 977-2716 - E-mail raevansmd@iapc.net Copyright - Texas Cancer Center 1999. All rights reserved. Page lasted modified June 1, 2000 unless noted.