Overview of Cancer Treatment Trials

Knowing the Enemy

In an era gripped by the promise of cytotoxic chemotherapy, a few dissenting voices was heard. Indiscriminate chemotherapy could not be the only strategy to attack cancer. To attack a cancer cell, one needed to begin by identifying its unique biological behavior, and vulnerabilities.

Hormone Therapy for Prostate Cancer

Charles Huggins, a urological surgeon at the University of Chicago, was a specialist in diseases of the bladder, kidney, genitals, and prostate. The prostate is a small walnut shaped gland wrapped around the outlet of the urinary tract in men. Cancer of the prostate represents one-third of cancer incidence in men, six times that of leukemia and lymphoma. In the late 1920s, by performing surgical castration on dogs, Huggins found that the hormone testosterone kept both the normal and cancer cells in the prostate alive.

Rather than performing a surgical castration on his patients, Huggins injected a female hormone into their bodies to inhibit testosterone function. He called the method “chemical castration.” As with surgical castration, Huggins found that patients responded to the therapy, with minimal side effects. But many of the patients who responded to the therapy eventually relapsed.

Beatson’s Riddle

In the late 1890s, a Scottish surgeon named George Beatson had learned that the removal of the ovaries from cows changed the quality of their udders and altered their capacity to lactate. Intrigued by the inexplicable link between ovaries and breasts, Beatson surgically removed the ovaries of three women with breast cancer. To his astonishment, the breast tumors of his three patients shrank dramatically after the surgery. But when surgeons in London tried to apply the method to a larger group of women, only about two-thirds of the breast cancer patients responded.

Solving the Riddle

In the mid-1960s, Elwood Jensen, a young chemist in Chicago, working with Huggins, came close to solving Beatson’s riddle. He found out that estrogen, the principal hormone secreted by the ovaries, worked by binding to a receptor in a target cell. He discovered that breast cancer cases could be divided into two types, depending on whether it’s estrogen sensitive or insensitive, “ER-positive” and “ER-negative” tumors. ER-positive tumors, possessing the receptor, would respond to Beatson’s surgery. ER-negative tumors not possessing the receptor, would be unresponsive.

The simplest way to prove this theory was to launch an experiment. But the surgical procedure had fallen out of fashion. An alternative was to use a drug to inhibit estrogen function. But Jensen had no such drug.

Tamoxifen Trial

Tamoxifen was an anti-estrogen compound developed by the hormone biologist Arther Walpole in the early 1960s. In the summer of 1969, Moya Cole, a Manchester oncologist specializing in breast cancer, launched a clinical trial at Christie Hospital in Manchester. Forty-six women with breast cancer were treated with tamoxifen. The response was almost immediate in ten patients. The tumors in the breast and the lung metastases shrank. But like Huggins’s prostate cancer patients, many of the patients who responded to the therapy eventually relapsed.

Halsted’s Ashes

Moya Cole’s tamoxifen trial in 1969 was designed to treat women with late stage metastatic breast cancer. But Cole wondered about an alternative strategy. What if women with early stage tumors were treated with tamoxifen?

Bonadonna’s Adjuvant Chemotherapy Trial

A similar idea occurred to a 33-year-old oncologist named Paul Carbone at the NCI ten years ago. Inspired by Min Chiu Li, Carbone had launched a small trial in 1963 and found out that adding chemotherapy after surgery reduced the rate of relapse from breast cancer. Carbone and his team called this treatment “adjuvant chemotherapy.” It would remove microscopic deposits of malignant cells left behind after surgery, completing the cancer-cleansing task that the surgery had set out to do.

In 1972, an Italian oncologist name Gianni Bonadonna proposed to the NCI a large randomized trial to study adjuvant chemotherapy for early stage breast cancer.

In the summer of 1973, Bonadonna began his trial by randomizing nearly four hundred women – half to treatment with CMF (a toxic three-drug cocktail) and half to no treatment.

Bonadonna presented his results in the winter of 1975. About half of the women in the no treatment group had elapsed while only one-third of the group receiving the adjuvant chemotherapy had relapsed. So adjuvant chemotherapy had prevented cancer relapses in about one in every six patients.

The Fisher Adjuvant Tamoxifen Trial

What if the adjuvant therapy was done with hormonal therapy instead of chemotherapy?

In January 1977, Bernie Fisher recruited 1,891 women with early stage ER-positive breast cancer. He treated half with adjuvant tamoxifen and the other half with no tamoxifen. By 1981, he found out that adjuvant therapy with tamoxifen reduced cancer relapse rates by one-half. In 1985, Fisher reported that the effect of tamoxifen treatment was even more dramatic. Among the 500 women older than fifty assigned to each group, adjuvant tamoxifen had prevented fifty-five relapses and deaths.

Lessons Learned

By the 1980s, the old paradigms of treatment had evolved into new paradigms. Halsted’s radical approach to attack cancer cells was reborn as adjuvant therapy. Ehrlich’s “magic bullet” was reincarnated as hormonal therapy.

Although neither of these alternatives offer definitive cures, these trials had confirmed two important principles of cancer biology and cancer therapy:

1. These trials etched the message that cancer was heterogeneous. Cancers came in variety of forms, each with unique biological behaviors. The heterogeneity was genetic: some responded to hormonal treatments, other not. And the heterogeneity was anatomic: some cancers were local, while others spread to distant organs.
2. Understanding that heterogeneity was of deep consequence. It was essential to “know” the cancer as intimately as possible before rushing to treat it. For instance, tamoxifen treatment only applies to ER-positive breast cancers.

Palliative Care

Palliative care is the branch of medicine that focuses on symptom relief and comfort, founded by Cecily Saunders, an English nurse, physician and social worker. She created a hospice in London in 1967 to care specifically for the terminally ill and dying.

Counting Cancer

In November 1985, a Harvard biologist named John Cairns measured the progress in the War on Cancer by revitalizing old records that had existed since World War II. He went through the cancer registry, and state-by-state statistics on cancer-related deaths to get a portrait of cancer over time. He used the cancer registry to estimate the number of lives saved by the therapeutic advances since 1950 and divide these therapeutic advances into various categories.

His findings were: (1)Less than 5 percent of patients diagnosed with cancer in America; and (2) Less than 10% of patients who would die of cancer, had enjoyed the advances in cancer therapy and screening.

Cairn’s analysis was widely influential, but it needed some measure of the comparative trends in cancer mortality over the years. John Bailar and Elaine Smith from Harvard provided such an analysis in the New England Journal of Medicine in May 1986.

Bailar-Smith Analysis

In the analysis, Bailar-Smith did not use survival-rate analysis because survival-rate analysis can be sensitive to biases such as cancer screenings. They used overall mortality instead. To compare samples over time, they normalized the population to the same standard.

According to Bailar-Smith: Cancer-related deaths had increased by 8.7 percent from 1962 to 1985. The increase reflected many factors, but mainly because of the increase in lung cancer caused by the increase in smoking rates in the United States. Bailar-Smith noted that the 35 years of intense efforts to improve the treatment of cancer must be judged a qualified failure.

As Cairns had already pointed out, prevention was the only intervention known to reduce the aggregate mortality for a disease. Bailar argued that prevention, as a strategy, had been neglected by the NCI in its pursuit of cures. Treatment strategies received 80 percent of the money while prevention research received about 20 percent. A similar bias existed in private research institutions. Bailar-Smith noted, “A shift in research emphasis, from research on treatment to research on prevention, seems necessary if substantial progress against cancer is to be forthcoming”