Once the black sheep of cancer treatments, chemotherapy has become the leading weapon for increasing the number of patients who can be cured of cancer. At the same time, researchers are reducing the debilitating side effects that chemotherapy patients have typically had to endure. 

"When chemotherapy was developed in the 1950's,cancer statistics were pretty much static," observed Dr. Bruce Chabner, head of the National Cancer Institute's Division of Cancer Treatment. "Surgery had gone as far as it could go in curing local disease, and the radiation therapy of the 1960's and 1970's only improved the cure of local and regional disease. Unfortunately at the time of diagnosis, about half of cancer patients already have spread of their disease beyond their original site, and the only therapy that has made inroads against these cancers is chemotherapy." Now an additional 50,000 patients with cancer who cannot be cured by surgery or radiation are being saved each year by drug treatments. Five years ago, chemotherapy cured just a few thousand patients annually. The future promise of chemotherapy is very bright. Recent discoveries of ways to improve the effectiveness of drugs and overcome resistance to them, as well as better understanding of how cancer cells spread to other parts of the body, are beginning to produce new treatment tactics that should further increase drug cures and extend chemotherapy to common cancers not currently vulnerable to its effect. 

"The prognosis for patients with disseminated malignancy has improved considerably," Dr. Chabner said. Especially notable is the increase in long-term disease-free survival time for patients with testicular cancer from 10% in 1973 to 70% in 1983. Supposedly today the cure rate approaches 100%. Similarly, the response rate for patients with ovarian cancer has risen from 30% in 1973 to 90% today. Further improvements in the efficacy of chemotherapy are expected to be attained with the refinement of high-dose chemotherapy, regional chemotherapy, bone marrow transplantation, the use of colony-forming assays to predict response, the use of combinations of noncross-resistant drugs, and the development of analogs of currently used agents. 

The new chemotherapy approaches are increasing the damage done to cancer cells and diminishing effects on normal tissue. Chemotherapists are also better able to control the occasional side effects of nausea and vomiting. Currently, one patient in four who receive chemotherapy is cured! 

The importance of drugs is universally acknowledged now that cancer specialists realize that the disease is often systemic, or bodywide, not confined to one site or tissue. In such cases, only treatments like drugs that can reach the nooks and crannies of the body wherever cancer cells may be hiding can be successful. 

Cancer cells lose their ability to control their own growth. Normal cells know when to stop growing. If half of your liver is removed in an operation, for example, your liver will grow back. Once local repair is complete, growth stops. 

Something happens to cancer cells so that they lose their ability to respond to the body's signal to stop growing. They become wild, erratic cells that keep multiplying. 

By themselves, cancer cells are not usually destructive, but they keep proliferating in the body so that they eventually crowd out the normal tissue of organs. That's what kills the patient. If the cancer is in the lungs, for example, the eventual replacement of healthy tissues by malignant cells interferes with breathing. 

Many of the new drugs and biological agents now being tested are aimed at controlling the growth of cancer cells rather than destroying them. In a sense, we want to give cancer cells the correct signal to stop growing and behave like normal cells. 

The drugs fall into four main categories: 

Alkylating agents. The genetic material, or DNA, of a cell is made up of molecules, called bases, that must be duplicated and precisely paired when the cell divides. Alkylating agents interfere with the orderly pairing process and prevent successful division. Some of the prominent drugs in this family: Cytoxan and L-PAM. 

Antimetabolites. These compounds chemically resemble vitamins or other nutrients and are therefore absorbed by the cell. But once inside, they disrupt the cell's metabolic machinery. Such agents include methotrexate,5-FU and 6-mercaptopurine (6-MP). 5-FU, for example, resembles uracil, a substance the cell needs to make DNA. It is not, however, a proper substitute and effectively blocks DNA synthesis. 

Antibiotics. Some of these were discovered in research for new drugs to fight infections. They disrupt the synthesis of RNA, a substance the cell needs to make essential proteins. Two leading antibiotics in cancer therapy: bleomycin and Adriamycin. 

Steroids. It isn't precisely known how these hormones, which include prednisone and estrogen, work against cancer. They are believed to prevent the production of proteins or other key enzymes. 

Some of the anti-cancer drugs don't fall into general categories. Vinblastine and vincristine, derived from the periwinkle plant, prevent the cell from doubling. The drug L-Alparaginase is an enzyme that destroys asparagine, an amino acid that some cancer cells can't make for themselves and must draw from the bloodstream. Normal cells, which synthesize the asparagine they need, are apparently unaffected by the drug. 

Among the new developments are these:  

• The growing use of drugs to treat possible hidden cancer immediately after the obvious tumor has been removed by surgery or destroyed by radiation. This approach is called adjuvant chemotherapy. The drugs are believed to kill off the seeds of spreading cancer, or metastasis.
• The realization that chemotherapists have been "too timid" and that more intensive drug regimens given for shorter periods of time are likely to result in a greater number of lasting remissions, which are considered tantamount to cure. Dr. Chabner said, "We get the best results when patients are given full doses of the drugs as fast as possible immediately after surgery or radiation." Traditionally, when toxic effects of drugs got too severe, therapists reduced or stopped treatment. Now they know more about how to help patients survive the treatment, both physically and emotionally.
• The use of drug treatments to shrink tumors before they are treated with surgery or radiation, a technique that converts some inoperable cancers into ones that can now be removed or destroyed. At the same time, this technique can improve the cosmetic effects of cancer treatment, permitting less radical surgery or less extensive radiation. Tumors are often most responsive to chemotherapy when first discovered, before they are treated with surgery or radiation.
• The development of analogues of established drugs that retain their cancer fighting properties but have fewer toxic effects.
• The linking of toxic chemicals to immunological weapons like monoclonal antibodies that are capable of recognizing and attacking specific cells. This technique allows the linked chemotherapy agents to attack just the cancer cells and not normal cells.
• The administration of drugs to a limited area of the body, such as the bladder, colon or abdominal cavity, to destroy cancerous tissue with minimal damage to normal tissue. This technique, called regional perfusion, can improve the drug response, reduce the risk of recurrence and minimize the side effects in some patients.
• The discovery of new drugs that can overcome the resistance cancer cells often develop to established drugs. Drug resistance has been the major roadblock to the successful use of chemotherapy in patients with widespread metastatic disease.
• Of the 10,000 new compounds that are now tested annually, approximately 8 are brought to clinical trials each year. From 1971 through 1985, 25 of the 91 compounds that reached clinical trials have shown significant antitumor activity.
• Out of 1,000 laboratory-engineered chemical relatives of cis-platinum, the most potent of the recently developed chemotherapy agents, 2 have been found to retain their potency but have less severe side effects. 

Cyto-differentiators: A new class of nontoxic drugs that render malignant cancer cells benign instead of killing them. In recent years, researchers discovered that normal cells, when very young, are much like cancer cells. They divide and spread rapidly and are undifferentiated, that is, without specific functions like skin or blood cells. If the young cell is disrupted, perhaps by a carcinogen, as it is growing toward the more mature, differentiated stage, it can become stuck in its immature phase, proliferating randomly and eventually forming a tumor. 

Gene Therapy