Saturday, January 14, 2017

Case Study The Evolving Goal of Cure and Inflammatory Breast Cancer - Martha


The Texas Challenge


Case Study The Evolving Goal of Cure and Inflammatory Breast Cancer - Martha
Martha, age 26, was an attractive and busy mother of three preschool children. Her husband Michael, a successful banker, was active in community and church affairs. While not directly involved in politics, they did live in Austin and, as alumni of the University of Texas, kept current in knowing what was significant in their great state of Texas. In April 1974, that would have included the cognizance that if a person had to deal with the dreaded diagnosis of cancer, there was no greater institution than MDA for diagnosis, staging, and treatment of cancer in Texas, the United States, and, indeed, the world. At the time, MDA was one of two comprehensive cancer centers in the United States and it was part of the University of Texas. One could with confidence receive state-of-the-art care for any of the multiple expressions of cancer.

Unfortunately, in April 1974, Martha found a mass in her left breast. The following morning, Michael canceled his meetings, bundled their three children off to his in-laws, and took Martha to a general surgeon, Dr. Parker, who had insisted he see her immediately when Michael phoned. Dr. Parker confirmed the presence of a 4-cm mass in the upper outer quadrant of Martha’s left breast and palpated enlarged lymph nodes in her left axilla. Within 72 h, a mammogram and ultrasound confirmed
the physical examination, and a core needle biopsy was scheduled. The biopsy was read as a poorly differentiated ductal adenocarcinoma of the breast. Dr. Parker recommended that Martha undergo a modified radical mastectomy as her initial therapy.

Martha and Michael had a host of questions. They asked for details about the surgery. Were there complications to be expected? Was this the only surgical approach that would be considered? What were the chances this therapeutic approach would result in a cure? Here the surgeon paused, and in a careful and measured tone responded, “The answer to that question will depend on your stage of cancer. Your stage, to a great degree, will be determined by the number of axillary lymph nodes found
to contain metastatic cancer. Currently, I consider you to have stage II breast cancer. I would prefer to reserve further discussion of this question until I have more details.”

In 1974, it was uncommon for a physician to enter into a lengthy and detailed discussion of the probable outcome of the treatment of a serious illness, especially when it was considered to be negative. This information was transmitted to the patient gradually by contacts and discussions with her physician, other physicians, nurses, other patients, periodicals, and newspapers. Dr. Parker was pressed for time. He had worked Martha into his busy schedule as a favor to an associate and felt further discourse was unnecessary. His impression of the situation was that Martha had multiple nodes involved with metastatic cancer and a poor prognosis. Before Parker could leave, however, Michael had one additional question: Would Parker refer Martha to MDA for a second opinion?

This is the most delicate question a patient can ask a physician. It contains the implication that there may be another, more knowledgeable and experienced doctor who might better serve the patient, resulting in the transfer of care to the consultant with the location of this care at a different site. The concern about loss of cancer patients to MDA by physicians in the Houston area was such that the average distance from MDA to its patients was 150 miles. Fortunately, Dr. Parker had no ego problems and, in fact, looked forward to the recommendation he would receive. He phoned his good friend, Dr. Richard Martin, Chief of Surgery at MDA, and asked him to see Martha as soon as possible. Upon her arrival at the MDA registration office, Martha was met by Doris, a VIP patient care representative, whose job was to smooth any potential rough spots before they became an issue. After discussion with Dr. Parker, Dr. Martin scheduled a bone scan and an isotope liver scan in order to complete her preoperative staging prior to her initial visit with him.

In 1974, the standard approach in treating patients with advanced primary breast cancer was to perform a modified radical mastectomy which removed the cancer, the breast, and the axillary lymph nodes draining the involved breast. When nodes were involved, radiation therapy was begun about 3 weeks after surgery to allow the surgical wound to heal. At this time, there was a great deal of clinical research being conducted to establish the place for chemotherapy in the treatment spectrum of patients
with advanced primary breast cancer. Clinically, Martha was stage IIB and would be a candidate for chemotherapy after completing radiation therapy. The issue was going to be what type of chemotherapy. However, the direction that Martha’s postoperative therapy was going to take was
suddenly dictated by events. As Doris took her to radiology for the radioisotope injection prior to the bone scan, Martha had a grand mal seizure. Dr. Martin was notified, and he asked Dr. Blumenschein,
recently appointed Head of the Medical Breast Service, to assume her management.

There was no history of seizure in Martha’s past and her brain scan was unremarkable. She was admitted to the hospital for observation, a spinal tap, and an electroencephalogram (EEG). While no evidence for a brain metastasis could be found, it was assumed that was the cause of her seizure. Because there was no detectable brain lesion on which surgery or radiation therapy could focus, it was decided that chemotherapy might offer some benefit, if it crossed the blood brain barrier. However, for
purposes of tumor debulking and staging, she first needed to undergo a left modified radical mastectomy, to include an axillary dissection on the left. Technically, she would remain in stage IIB unless regional spread of cancer or under-measurement of tumor size was discovered at surgery
and/or measurable brain metastases appeared.

Understandably, Martha and Michael had been quite shaken by the rapid turn of events, but realized that the best course was to push on as aggressively as possible. They were informed that, because of the concern about her seizure, radiation therapy was not to follow surgery, as was usual. Rather, chemotherapy consisting of at least six courses of FAC would be started 2 weeks after her mastectomy.

The surgery and pathology examination established that Martha had a 4 cm tumor and 18 axillary lymph nodes involved with metastatic breast cancer. Her stage remained the same, IIB, but her prognosis grew worse as a result of the 18 positive lymph nodes. Without effective adjuvant chemotherapy,
Martha had less than a 50% chance of remaining disease free beyond 2 years from diagnosis and a 12% chance for survival after 10 years. This meant that at diagnosis she had a .88% probability of harboring lethal microscopic metastatic breast cancer. This gave Martha a prognosis approaching that of patients with stage IV breast cancer and raised a question about the clinical wisdom of treating her with anything less than the most aggressive drug program then available for patients with metastatic breast cancer.

Fortunately, Dr. Buzdar had initiated MDA’s adjuvant chemotherapy program for postmastectomy stage II patients with positive nodes and stage III breast cancer in January 1974. So in April, Martha began FAC 2 weeks after her mastectomy. At this same time, competing investigator teams around the world were beginning to address this issue with less aggressive combination chemotherapy programs, such as CMF (Dr. Bonadonna in Milan), L-PAM—5-FU (Dr. Bernard Fisher, NSABP, in Pittsburgh), and AC (Drs. Stephen E. Jones and Sydney E. Salmon in Arizona).

Toxicity was never a significant factor for Martha during her program of FAC administration. That is to say, toxicity never was severe enough to cause a lowering of a drug dose or a prolongation of a treatment interval (dose rate). She experienced nausea, occasional vomiting, mucositis, and 100% hair loss, but there were no EKG changes. One episode of temperature elevation also occurred during a time when her white blood cells were depleted and caused her to be hospitalized to receive IV antibiotic therapy. Martha’s experience was typical of most patients who received FAC in that adjustments and minor modifications in the toxicity protocols were able to solve most issues. Those that remained eventually fell to the magic of outpatient pump technology that permitted continuousinfusion Adriamycin administration, which minimized myocardial toxicity, and Neupogen (granulocyte colony stimulating factor), which bolstered production of white blood cells.

When the FAC protocol was initially designed, concerns about the persistence of a reduced but still viable microscopic tumor burden led to prolonged maintenance chemotherapy of patients who had completed 6 months of FAC induction chemotherapy. In the MDA FAC program, this consisted of CMF cycles that were given on a monthly schedule for 18 months after induction adjuvant therapy. The CMF regimen was given intramuscularly and by mouth, as a patient’s veins were thoroughly trashed after 6 months of FAC. The dose and schedule of each of the drugs was as follows: cyclophosphamide 500 mg/m2 orally in four divided doses on day 2 of each 28-day cycle, methotrexate 30 mg/m2 intramuscularly on days 1 and 8, and 5-FU 500 mg/m2 orally in 4 divided doses on days 1 and 8.

To further complicate the situation, it was decided that patients should not be denied the possible benefits of immunotherapy, so BCG was added to the program (63108 viable units of the Connaught
strain given by scarification on days 9, 16, and 23 of each cycle). Immunotherapy was part of a rigid belief system and BCG was its trinity. Emotions ran high every time it was discussed. To his discredit,
Blumenschein supported its inclusion in the MDA adjuvant breast protocol.  However, he began to worry about his judgment when one of the proponents of BCG was heard to challenge an opponent by asking, “Would you deny your mother BCG?”

The scarifications, aptly named, were visible and permanent. In a notable episode, an attractive young breast cancer patient on the BCG protocol was taking a stroll on a Florida beach. It wasn’t very long
before she acquired an ardent male admirer. He became overly persistent in asking too many questions. She put an end to things when she answered his query as to the reason for the multiple scars on her upper arms, thighs, and shoulders. “Don’t be concerned,” she said, “it’s a new treatment for syphilis.”
Martha made it through the first 12 months without missing a beat, but her enthusiasm began to wane as she contemplated a second 12 months of CMF and BCG. Her oncologists also began to realize that
the CMF maintenance dose, schedule, and route of administration were inferior. Even the concept was inferior if the goal of the chemotherapy, indeed, was cure. With the BCG component, patients began to suffer from “scarification burn out.” Suffice it to say, all of the patients continued to receive full doses of FAC. The other elements of the program were given and received with less enthusiasm and diligence.

For a comparative evaluation of the FAC protocol, a group of stage II and III breast cancer patients with at least one involved axillary node, who were treated at MDA with surgery and/or radiation therapy with curative intent, were selected for close follow-up in a study that utilized historical controls. After examining the records of patients treated between January 1972 and December 1973, 152 patients were found who were similar enough to the FAC-treated patients to qualify for the historical control group. The only subset of patients that was not evenly matched between the groups was the group with .10 positive lymph nodes. Because 40% of the patients in the FAC-treated group had .10 positive nodes while only 25% of controls were so staged, the control group was expected to have a slight survival advantage. However, an initial analysis at 1-year postmastectomy showed that 94% of the FAC BCG patients remained relapse free whereas only 75% of the control patients had been disease free. At 2 years, the relapse-free outcomes were 93 and 55%, respectively. Thus, the study showed conclusively that the FAC adjuvant program benefited pre- and postmenopausal, stage II and III breast cancer patients. Although Martha had .10 positive nodes, she was indeed fortunate to have developed her breast cancer at a time when she could be placed in the FAC treatment group!

Irradiation is an effective killer of breast cancer cells and plays an important role in eliminating microscopic metastases from the chest wall and peripheral lymphatics on the side of the mastectomy. It is an established therapeutic modality for the adjuvant treatment of node-positive disease. However, there are some limitations in its use. The time required to deliver a therapeutic dose of ionizing irradiation is usually 5 6 weeks, which is delivered daily Monday through Friday. During this time, concomitant Adriamycin chemotherapy should be avoided and there should always be a 3-week interval between radiation and Adriamycin therapy. Because of the daily schedule required for radiation therapy, Martha chose to receive her radiation therapy in Austin. It began 4 weeks after her sixth and final course of FAC.

Martha had no further problem with seizures but she was fatigued and worn down from the 6 months of therapy. Fortunately, there was no sign of heart muscle damage even though she had received a total of 240 mg/m2 of Adriamycin, still given at that time by IV bolus. While she did begin the maintenance program after the radiation therapy and continued to receive CMF and BCG for the first 12 months period following diagnosis, mutual enthusiasm to continue beyond 15 months was lacking and her adjuvant therapy was discontinued. This seemed reasonable because it had been noted in other programs by this time that the results after 12 months of adjuvant treatment were no different than those achieved after 24 months. In fact, BCG as adjuvant and CMF as maintenance therapy have never been shown in a clinical trial to influence patient outcome.

Martha was seen by Blumenschein at 3-month intervals for the first 10 years after diagnosis, at which time she graduated to an annual visit. Currently, she continues to remain free of breast cancer 36 years following regional therapy with a modified radical mastectomy, radiation therapy, and systemic therapy with FAC induction followed by BCG and CMF maintenance.

This more than likely qualifies as a cure!

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