The year since this book's first publication has proved to be something of a watershed in cancer research—characterized by as much hype as hope. The tamoxifen prevention trials claimed that the drug prevented 45 percent of breast cancer cases in high-risk women, but no one was sure for how long, or at what cost. Nobel laureate James Watson, discoverer of the structure of DNA, allegedly predicted a cure for cancer within two years—then told the media he'd never made that claim. One biotechnology company's stocks soared, then plummeted, as overblown reports about new drugs were swiftly punctured. Media ran headlines that took anxious cancer patients on a roller coaster ride from desperation to breathless expectancy and back to despair, as they discovered that the "magic bullet" anti-angiogenesis drugs touted by media and eager biotech companies had yet to be tested on humans, or even synthesized in quantities sufficient for human testing.

"Everybody is waiting for the cure," said Donald Coffey, a physician treating prostate cancer patients at Johns Hopkins. "All sorts of overhype and craziness are going on." ¹

But the truth behind the hype is that a revolution of sorts does seem to be unfolding in laboratories and clinics around the world. Scientists are working on a cellular level, manipulating genes and molecules, learning how to turn on and off the chemical switches that directly or indirectly control cell growth and proliferation. Details of how cancer cells divide and grow uncontrollably are at last being deciphered. "We have learned as much about cancer cells and advanced as far in the last 10 years as we have in computers," Coffey said. "We just can't believe the progress—it's exploding on us."

"When President Nixon declared war on cancer back in 1970, there was a lot of excitement and a lot of money available, but the science and technology were very primitive. It was like being given a book to read without an alphabet," said researcher Dennis Slamon, of the Revlon/UCLA Women's Cancer Research Program, from whose laboratory the new breast cancer drug Herceptin has emerged. "But once molecular biology and biotechnology came on line, once we were able to sequence genes, clone genes, and understand their function, we finally had an alphabet." The old cancer treatment paradigm of throwing in a "hand grenade," hoping that you kill more bad cells than good, is at last becoming outdated, Slamon believes, to be replaced by what he terms "the great hope and promise of molecular biology." ²

"The black box that was the cancer cell has been opened," agrees Bert Vogelstein, a genetics expert at Johns Hopkins. "As researchers, we feel a tremendous amount of hope, probably for the first time in the history of cancer treatment." ³

Others are less enthusiastic. British researcher Ian Tannock wrote in a recent Lancet supplement:

At cancer meetings, excitement surrounds the sessions on molecular oncology, and its application in biological and genetically based therapy. Sessions on surgery, radiation therapy, and chemotherapy are quiet by comparison….Patients and their support groups want to hear about gene therapy and immune-mediated biological therapy. There is disbelief when I try to convey gently the sad truth that in 1998 the impact of gene-based therapy is zero and of biological treatment is minimal. For the next few years, cancer management outside the context of a clinical trial will continue to be based almost entirely on surgery, radiation therapy, and systemic treatment with chemotherapy or hormones. ⁴

Lane points out that a quarter of a century has passed since specific genetic changes in human oncogenes were first identified, marking the beginnings of the molecular biological approach to the study of cancer. What will the next twenty-five years bring?

Twenty-five years from now we will be able to determine accurately, before treatment, the probability of a suitable therapeutic or palliative response in the individual tumour in the individual patient. In twenty-five years' time we will have developed a new generation of cheap and effective treatments for cancer that are not toxic to normal cellular components and that accurately target either the specific genetic defects in the tumour being treated or target the specific physiological state of the tumour and its interaction with the surrounding stroma.

Even ten years feels like a lifetime to someone with metastatic breast cancer—as it may well be. There are no promises here. It remains to be seen if the new treatments now being tested will be of benefit to you, even if you are able to gain access to them through clinical trials or through the expanded access programs for compassionate use that many drug companies have instituted. But some of them are already here, today, and more will be by the time you read this. So it makes good sense to inform yourself, and to hang on for the emotional ride that new hopes—and some inevitable new disappointments—are bound to provide. Let's take a look at some of the more promising developments on the immediate horizon.

Improvements in conventional treatments

Many of the newer therapies, such as the monoclonal antibody Herceptin, awaiting final approval by the FDA as of this writing, have been shown in clinical trials to work far better in conjunction with chemotherapy than alone.

Improvements and refinements are constantly being made in chemotherapy drugs, alone and in new combinations, and in the ways in which chemotherapy drugs are administered, making them less harmful to the rest of the body.

One example is the efficacy of dexrazoxane (Zinecard) in preventing or reducing the incidence and severity of the potentially damaging affects of Adriamycin on the heart. Liposomal anthracyclines have been developed to enclose toxic drugs in an "envelope" of protective lipids (fats) and thus protect other parts of the body. Anthracyclines in clinical trials, including liposomal daunorubicin, liposomal anamycin, and liposomal doxorubicin (to be approved and marketed under the names Doxil and Evacet), are demonstrating much lower toxicity profiles than those found with conventional formulations. Clinical trials have shown that liposomal doxorubicin reduces the cardiotoxity sometimes associated with conventional doxorubicin (Adriamycin), as well as reducing nausea and vomiting, mouth sores, fever and infection.

Chemo-embolization is a method of delivering chemotherapy drugs directly to liver metastases via infusion through implanted tubes. It can be used in selected, otherwise healthy patients who have encapsulated, hypervascular tumors. In trials, this technique has shown reduced toxicity with higher doses of chemotherapy and has produced results superior to systemic chemotherapy. Lisann Charland, with a tumor in her liver and minimal disease elsewhere, had this treatment done at Stanford over three years ago as of this writing, and continues to be stable.

A new process called photo-dynamic therapy (PDT), involving the administration of drugs which can kill tumors when activated by light without hurting healthy surrounding tissue, is currently in clinical trials to treat surface skin lesions in breast cancer. PDT destroys cancerous cells by using fixed-frequency laser light to activate photosensitizing drugs which accumulate more readily and persist longer in cancer cells than in other body cells. Injected by vein, and timed precisely, these photosensitizing drugs work by releasing quantities of an active form of oxygen which destroys the cancer.

In early 1998, the FDA approved Xeloda (capecitabine), a new oral fluoropyrimidine carbamate, and the first oral tumor-activated anticancer drug that has an effect mainly at the site of the tumor rather than in normal tissues. In tumors, Xeloda becomes fluoururicil (5F-U), a known effective chemotherapy agent. In Phase II clinical trials, Xeloda was able to reduce tumors by at least half in a quarter of heavily pre-treated patients. This oral drug is likely to replace the 5F-U continuous administration pumps late stage patients have been using, with better tolerance, fewer side effects and more convenience.

Among the newer chemotherapy agents in clinical trials are the anthrapyrazoles, similar to anthracyclines like doxorubicin, of which losoxantrone is the most promising, as well as teloxantrone, piroxantrone and CI-958. Other thymidylate synthase inhibitors being tested besides capecitabine (see Xeloda, above) are Raltritrexed, Uracil/tegafur, SI and others. A number of antifolates, of which edatrexate appears to be the most promising, are under investigation. New vinca alkaloids, similar to vinorelbine, are under evaluation, as is at least one new taxane, similar to paclitaxel and docetaxel. A new drug called miltefosine (a hexadecylphosphocholine) has been approved in Europe and is under current use as a topical agent for local recurrences of breast cancer. Analogues of camptothecin such as irinotecan (CPT-11), topotecan and 9-AC are being studied.

A number of aromatase inhibitors are being tested similar to Arimidex (anastrozole) which is already widely in use, among them Femara (letrozole) approved for advanced breast cancer in 1997, and vorozole, which has been submitted for FDA approval. Other hormonal treatments under investigation include mifepristone, onaprisone, toremifene, droloxifene and other antiestrogens and antiprogestins. The role of the newly approved estrogen antagonist raloxifene (Evista) in advanced cancer is under investigation.

Drugs that work to strengthen bone loss can act as palliative agents for patients dealing with bone metastases. Among these are bisphosphonates, pamidronate (Aredia), clodronate and Strontium-89.

Vitally important to patients undergoing treatment are the drugs Zofran, Kytril, and a new drug called Anzamet, which have been so effective in preventing or greatly decreasing treatment-induced nausea and vomiting. The widespread use of these drugs has made effective chemotherapy treatment possible for many patients previously unable to tolerate its debilitating effects, and has dramatically improved quality of life for almost all people receiving chemotherapy.

Refinements are not only being made to specific chemotherapy drugs and regimens, but to the theoretical models and hypotheses that support their use, emphasizing a need for new strategies. In an article entitled, "Evolving Concepts in the Systemic Drug Therapy of Breast Cancer," Dr. Larry Norton, a breast cancer oncologist and researcher from Memorial Sloane-Kettering Cancer Center in New York City, admits that, "It is possible that further understanding of the natural history of tumors will enable better treatments to be developed." In advanced cancer, "dose intensity" strategies like high-dose chemotherapy have shown clear limitations, even when apparent complete responses are achieved, thus "throwing doubt on the assertion…that optimal cytotoxic therapy can kill all tumor cells." Other approaches are sorely needed, Norton believes:

This will require a better understanding of the molecular biology of breast cancer and the ability to predict and assess the sensitivity of individual patient's tumors to individual therapies….Furthering our understanding of the biology and behavior of tumor cells may lead to significant improvements in the long-term prognosis for patients with early and advanced breast cancer. ⁷

Notes

1. Robert S. Boyd, “Sharpening the Attack on Cancer,” The Philadelphia Enquirer, May 9, 1998.
   
2. Craig Horowitz, “The Cancer Killer,” New York Magazine, Vol. 31, No. 20, p. 68, May 25, 1998.
   
3. Claudia Wallis, “Molecular Revolution,” Time, Vol. 151, No. 19, May 18, 1998.
   
4. Ian F. Tannock, “Conventional Cancer Therapy: Promise Broken or Promise Delayed?” Lancet, 351 (suppl II), pp. 9-16, 1998.
   
5. David Lane, “The Promise of Molecular Biology,” Lancet, (suppl II), pp. 17-20, 1998.
   
6. Shannon Brownlee and Nancy Shute, “Killing Cancer,” U.S. News, May 18, 1998.
   
7. Larry Norton, “Evolving Concepts in the Systemic Drug Therapy of Breast Cancer,” Seminars in Oncology, Vol. 24, No. 4 (Suppl 10), August, 1997.