The New Treatment Paradigm in Cancer Research

Dr J S Macdonald MDDr. John S. Macdonald
Senior Consultant for The Oncology Consortia of CRITERIUM, INC.

In the past, typical anti-cancer systemic therapies that worked, albeit poorly, did so by killing cancer cells only slightly better than they killed normal cells. There were relatively few of these drugs and they were given to patients with all kinds of cancers. This toxic therapy could be depended upon to make patients sick all the time while rarely making cancers significantly improve.? To effectively develop these new treatments, clinical investigators must not only be excellent physicians but also be first rate molecular and cellular biologists.

CHEMOTHERAPEUTIC AGENTS KILL MORE CELLS THAN THEY SHOULD
The classic chemotherapeutic agents are relatively non specific toxins that function by killing or at least seriously injuring cells. These agents cause significant toxicity to patients because all or most of the cells in the body are injured by these drugs. A successful chemotherapeutic agent kills cancer cells a little better than it kills normal cells.

CHEMOTHERAPY MAKING A CANCER COMPLETELY DISAPPEAR IS RARE
One of the real negative aspects of chemotherapy is that all patients receiving a drug experience toxicity which may be life threatening, but only a minority of patients with cancer will actually have treatment make the tumor regress. Having chemotherapy make a cancer completely disappear with treatment with the therapy producing a CR or complete response, is rare. The final phase III trials required to show that a new treatment is equal to or superior to a standard therapy, require hundreds of patients most of whom will be made sick by the therapy but not get any anti-tumor benefit.

CLASSIC CHEMOTHERAPY PRODUCES UNWANTED ADDITIONAL EFFECTS
Finally since classic chemotherapy agents are toxins they may produce late effects such as second cancers and major organ (bone marrow, kidney, liver, lung, etc.) damage in patients who receive treatment and or cured of their original cancers. So the bottom line with classic chemo is that these are agents that are always toxic, rarely curative, require hundreds of patients on clinical trials to demonstrate efficacy and may result in serious late effects.

Recently this paradigm of toxic relatively ineffective cancer therapies is changing. Because of increased knowledge of molecular biology and molecular genetics, more specific targeted therapies that are less toxic to normal cells are being developed. Some dramatic improvements in survival have been reported with such treatments.

IN TARGETED THERAPIES, ONLY CANCER CELLS ARE DAMAGED
AND NORMAL CELLS ARE SPARED

The key factors that make targeted cancer therapies and immunotherapy different from and in theory superior to chemotherapy are that these treatments dependent upon specific anti-tumor effects. In other words in the ideal situation only? the cancer cells are injured or killed with a targeted approach or an immunotherapy approach. Thus if a target exists only in tumor cells or is over expressed in tumor cells, then a targeted therapy only affects the cancer cell and does minimal if any damage to normal cells. Ideally the result is tumor death and no normal cell toxicity. Likewise with immunotherapy, the only cells damaged would be the cells (tumor cells) carrying the antigen or marker that the immune system recognizes. Again the result is that cancer cells are damaged and normal cells are spared.

TARGETED THERAPIES ARE MORE EFFICIENT AND LESS TOXIC
The factor to keep in mind is that the clinical development of more targeted therapies should clearly be much more efficient than development of chemotherapy. Only patients with the specific target are entered in clinical trials so the likelihood of benefit is increased. Targeted or immunotherapeutic treatments may be active against the tumor at dose levels that are minimally toxic. Thus small targeted relatively non toxic trials may be used in development of newer approaches to cancer treatment.

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