ADVANCES IN ONCOLOGY:

MAJOR STRATEGIES IN COMBATING CANCER

 By: Stanley H. Kornhauser, Ph.D.
(Editor’s Note: The information that follows is not meant to be all-inclusive or in any way all-embracing, nor could it be given the large number of oncological diseases and their potential treatments What is offered, instead, is a series of  “bird’s-eye views” or “significant snapshots” that hopefully will give the reader an honest feel for what may be coming in the millennium--treatment by potential treatment, cure by hopeful cure.)

Though no “magic bullet”, “all-encompassing technology” or reliable, “across-the-board cure for cancer” is currently at hand, cancer is gradually succumbing to a slow but steady dose of strategies for its containment and elimination. In today’s army of anticancer researchers and specialists, surgeons, medical oncologists, radiation oncologists and molecular biologists are diligently working to develop new and improved surgical, radiation, chemotherapy, immunological and gene therapies for curing or controlling tumor growth.  As a result their efforts, amazing strides are being made in cancer diagnosis and treatment. Statistics are finally beginning to show that we are winning the war against cancer. For the first time, the overall cancer mortality rate has dropped. Between 1991 and 1995, there was a 3 per cent decrease in cancer mortality. This is a dramatic reversal of 6.5 percent rise in cancer mortality that occurred in the twenty years between 1970 and 1990. Experts now believe that there could be as much as a 20 to 25 percent reduction in the overall cancer morality rate in the next twenty years if this trend continues.

 What are some of the reasons for this prediction? Perhaps more for cancer than for any other disease group the promise of molecular medicine should be mentioned first. Why, because it offers the greatest hope for unraveling the complexities of cancer and for identifying novel therapeutic targets and compounds. Molecular medicine implies gene therapy, immunotherapy, DNA vaccines, anti-sense and gene based diagnostics. Molecular medicine is about understanding genetic variation, dissecting biochemical pathways and linking changes in gene and protein expression to disease. Cancer comprises many different diseases caused by the accumulation of deleterious genetic changes in a cell and influenced by a variety of genetic and environmental factors. Molecular medicine introduces the ability to target cancer that depends on its molecular characteristics, rather than simply its location in the body or its histologic or clinical presentation. Types of cancer that would be likely targets for this genetic therapy include chronic myelogenous leukemia, caused when chromosomes inside a cell break and rejoin abnormally, creating a new enzyme that eventually leads to cancer. By blocking or removing that single mutation, its possible to eliminate the disease. Scientists have now begun looking at drugs that are absolutely specific for that one enzyme. Molecular medicine also promises to give doctors new tools for early diagnosis. At present, patients go through a process called “staging” in which doctors assess how aggressive the cancer is by noting measures such as tumor size, location, metastases to lymph nodes, and tumor type. But soon this will be completely different. The potential key to this puzzle is to molecularly characterize every individual tumor, looking at the spectrum of gene mutations. That should give us clues to which are going to be lethal or simple.

 Important progress is being made in diagnostic tests for cancer. Blood tests called cancer markers have been developed that are very specific for certain cancers, such as PSA test for prostate cancer and CA-125 for ovarian cancer. The role of these tests is still being defined There are actually dozens of such markers some of them so sensitive, that they can detect recurrence of melanomas and other cancers before a lump appears and before they can be detected by clinical examination or x-ray. New blood tests are also on the horizon for measuring minute amounts of cancer cells in the blood, giving doctors a tool for determining very quickly how successful a therapy has been in eradicating the disease.
With the recent advent and continuing improvement of imaging techniques such as magnetic resonance imaging (MRI), computerized axial tomography (CAT), positron emission tomography (PET) and ultrasound, distinguishing cancer tissue from non-cancerous tissue, assessing a tumor’s size, location and shape has become more precise, so less damage is done to nearby tissue during treatment. In brain cancer, for example, leading medical centers already are teaming the imaging technology with powerful computers to guide surgeons doing ultra-delicate surgery. The aim is to remove tumor tissue without seriously damaging the brain’s neuronal circuitry. Similar technology also is being used to help pinpoint radiation on organ-based tumors. ` In 3-D conformal radiation therapy, for instance, many cross- sectional scans of tumor-bearing prostate are combined to create an exact 3-D image, which gets fed into a computerized rotating accelerator. The accelerator’s radiation beam is then shaped to precisely match the prostate dimensions, minimizing radiation damage of surrounding tissue. When the source of the radiation is placed within your body, it is called brachytherapy. There are two types of insertions, low dose and high dose. Both types uses placement of the radiation source close to the tumor, radioactive elements such as cesium, iridium, iodine, gold, phosphorous and palladium have been used for this procedure. Today, most centers use high dose insertions. After the patient is sedated. The applications are inserted using a remote controlled machine under a physician’s guidance. Sources of intense activity are placed in specific locations for a few seconds each. This method may require several insertions over several weeks. The main advantage is that there are no associated risks, such as the complication of blood clots in the lungs from prolonged bed rest. High dose rate brachytherapy is widely used for treatment of cancers of the cervix, endometrium, prostate, lung, esophagus, head and neck.

Radiation therapy is also being made more effective by utilizing new techniques that are built on important advances made in the fields of biology, physics and engineering. These techniques include hyperthermia, clinical modifiers, high linear energy transfer radiation (LET) and hyperfractionation. In hyperthermia, using heat in combination with radiotherapy and chemotherapy has been demonstrated to increase the response rate for some tumors. Clinical modifiers that modify radiation sensitivity are being used to decrease damage to normal tissues.  One such clinical modifier or “radioprotector” acts through the use of a hyperbaric oxygen chamber. Patients placed in such a chamber breathe air with a higher than normal concentration of oxygen thus decreasing any damage to normal tissues. High linear energy transfer radiation is radiation with accelerators that use heavy particles or subatomic particles  (e.g., protons, helium ions and neutrons) rather than electrons, x-rays or gamma rays. Two features make this radiation more effective. First, it can kill poorly oxygenated cells better than standard radiation can. Second, tumor cells are less able to repair sublethal damage from high (LET) radiation. The last technique mentioned, hyperfractionation, in which patients are given radiation treatment twice daily rather than the conventional once daily also has been gaining considerable interest in the oncological community. By using multiple smaller doses of radiation, a higher overall dose can be delivered. The treatments are usually given at least six hours apart to allow for tissue repair. Preliminary data suggests an improvement in the control of head and neck tumors without significant difference in acute toxicity. 

With greater understanding of the nature of cancer and of how chemicals interact, chemotherapy now has become also a standard therapy. While surgery and radiation therapy are used to treat localized tumors, chemotherapy treats the whole body. Doctors recommend chemotherapy for several reasons. The goal might be: to cure a specific cancer; to control tumor growth when a cure isn’t possible; to relieve symptoms such as pain; to shrink tumors before surgery or radiation therapy or to destroy microscopic metastases after tumors are removed surgically. Several exciting innovative uses of chemotherapy that hold even more promise for curing or controlling cancer are now available. These include new chemotherapy medications,, novel approaches to targeting drugs more specifically  at the cancer cells (like attaching drugs to monoclonal antibodies or packaging them inside liposomes) to produce fewer side effects, drugs to reduce  side effects like colony-stimulating factors and chemoprotective agents (such as dexrazoxane and amifostine), hematopoietic stem cell transplantation, agents that overcome multidrug resistance, and evaluating resistance of cells to drugs before undertaking an empiric selection of drug combinations.

Since surgery is used in the diagnostic, treatment and post treatment phases of cancer management, oncologists often suggest surgery in a variety of circumstances. Each of the many types of surgery having its own goal. In general, there are eight reasons why surgery might be recommended. They are: to prevent or lower the risk of developing cancer; to diagnose or stage the disease; to remove the primary tumor; to remove other tumors; to relieve symptoms; to reconstruct or rehabilitate; to support chemotherapy and radiation therapy and to treat complications. Surgery’s role in cancer treatment has expanded considerably over the past few years. Better understanding of the natural history of many tumors, safer anesthetic techniques and improved preoperative and postoperative care have led to better immediate and long term survival rates. The technique of lymphatic mapping or sentinel lymph node mapping (SLN) in which surgeons use dyes and radioactive tracers to help them be more selective in removing nodes is one of the more promising techniques in use today.  SLN mapping appears to permit better identification of micrometastases than standard methods making it a better tool for identifying patients who might benefit from adjuvant chemotherapy. Other advances in cancer control and care that are somewhat related to surgical procedures are endoscopic and photodynamic laser therapy, hyperthermia and hyperthermic perfusion therapy, cryosurgery and radiofrequency surgery. In endoscopic laser therapy a light beam is passed through a flexible tube which is aimed precisely into the target tissue. In photodynamic laser therapy a chemical is injected into the malignant tissue making it more sensitive to light. After the tumor is sensitized, the laser is directed at the tissue making it more selective in its cell-destroying action. Hyperthermia—the word means elevated temperature and refers to the use of heat in the treatment of cancer. This technique makes cells more sensitive to radiation by preventing them from repairing radiation damage. It also seems to improve the effect of some of the drugs used in chemotherapy, such as bleomycin, cisplatin and the nitrosoureas. Several methods may soon be available to help predict a tumor’s response to hyperthermia based on small samples of the cancerous cells. It may also soon be possible to improve results by manipulating the flow of blood to the tumor by manipulating its sensitivity to heat. Hyperthermic perfusion therapy is just a way to deliver chemotherapy drugs to tumors in parts of the body that can be isolated from the circulatory system. The arms and legs are most frequently isolated, however, isolation of the liver and lung are currently in development.

Cryosurgery is an important method of treatment that treats cancers by freezing and thawing. Although the technology is still evolving, this technique holds promise in the treatment of prostate, breast, lung and brain tumors. In radio frequency surgery heat is generated by using high-frequency electric current that passes from an electrode probe into the tissues.

This heat has been found very effective in killing tissues. As tissue temperatures rise above 113 degrees F, protein is permanently damaged and cell membranes fuse. The process is rapid, requiring only minutes. This technique holds promise for primary and metastatic liver tumors.

Clearly, after reviewing the above information one can say without qualification that we are entering a new phase in the war against cancer. In coming years, doctors will be better able to combine therapeutic agents in increasingly effective ways. They will become more sophisticated in combining modality therapy, using surgery + radiation+ chemotherapy with better results in such cases as lung, esophageal and rectal cancers. They will become more knowledgeable about the nature and conditions that lead to cancer, such as premalignant polyps and lesions, and they will have the appropriate technology to deal with it.

We are also in the midst of a revolution in our ability to image parts of the body, painlessly and in fine detail. We now understand the intricate workings of the human genome—ultimately responsible for controlling all biological processes in health and disease. By the year 2003 the entire DNA sequence of the human genome will be determined. Powerful computer networks will allow detailed comparisons of genetic structure for identifying new risk factors. Gene chips will detect minute code changes of considerable relevance. Novel screening technologies will allow us to detect just a few cancer cells in a patient. Robotically guided destructive processes will target abnormal cells in patients long before any cancer-related symptoms develop. Even now the literature reports that Japanese scientists have developed a robot smaller than a grain of rice that can travel through veins to hunt down a tumor and then destroy it.

The robots, which are based on cylindrical magnets, resemble small screws and are capable of burrowing through 2 centimeters in just 20 seconds.

These magnets will be small enough to be introduced into the blood stream by a hypodermic needle and then steered around the body magnetically. Robots such as these could be used to deliver drugs to tumors by burrowing into them and unleashing a hot metal spike to destroy them. And all this is likely by the first quarter of this century. There is more. There is anti-sense therapy, an approach at the genetic level that blocks the process by which cancer-causing proteins are produced. There is genetic therapy, previously mentioned above, which attempts to fix damaged DNA. There are cancer vaccines, agents that stimulate the body own immune system. There are the anti-angiogenesis agents. They work by blocking the growth of new blood vessels to the tumor. Another weapon in the cancer arsenal are the anti-metastatic factors. They prevent cancer cells from entering the bloodstream by dissolving tissue and boring holes through capillary walls.

Tumors do more than pick up growth factors that circulate in the bloodstream; they also make them by switching on “oncogenes”. Many cancers, for example, have been found to contain mutations in the RAS oncogene, and companies are racing to develop drugs that inhibit its growth-promoting activity. These agents are called Anti-oncogenic factors.

A very modern and sophisticated way to use antibodies is to produce them in the laboratory as monoclonal antibodies. Their importance in cancer treatment lies in the fact that like guided missiles, these biological constructs home in on specific proteins displayed on the surface of the cancer cells. By locking strategic sites, monoclonals can interfere with a tumor’s ability to absorb growth factors from the blood stream. They can also carry radioactive and chemical toxins that directly destroy malignant tissue.

While all these advances are beginning to fulfill our long-held dreams of cancer control and cure, the delivery system has changed in equally significant ways. Despite the widespread impact of  “managed care” on health care in general, cancer is still likely to be cared for by cancer specialists, often with a medical oncologist as the “quarterback”. However, as we look forward to perfecting these advances our effort should focus on the best way to integrate modern cancer care with the managed care health industry. Questions that still need to be answered for the future are:  Which patients need oncologists? What specialists do patients need to consult with regarding their condition? How long should they be treated? Who should follow the patient? Which tests and treatments are appropriate and necessary and which are not required? How can differences of opinion about treatment be resolved? What is the role of clinical trials and investigational therapy in cancer management, particularly with reference to payment and reimbursement? How are people, society and healthcare systems going to deal with these tremendous technological advances for cancer?

As a result of these advances even full –blown cancer no longer can be looked upon as hopeless.

If doctors can figure out ways of stopping a primary tumor from spreading, or of preventing small malignancies from growing large, they may yet work wonders. Cancer patients would still have a serious chronic disease but one that can be controlled—like diabetes, hypertension and athersclerosis—for 10 years, 20 years, even longer. In the future, a diagnosis of cancer will still invoke dread. But if our cancer researchers and clinicians are on the right track with all these new advances, and we believe they are, it will seem less and less like an automatic death sentence.

About the author:

Dr. Stanley H. Kornhauser is president of the National Institute of Electromedical Information and Director of planning and biomedical technology for the American Academy of Anti-Aging Medicine. He also serves as program manager for the Cancer Center at NYHQ located in Flushing. The Center is recognized as one of the largest regional resources in oncology and offers a comprehensive and integrated program of diagnostic, treatment, rehabilitation and support services, world class physicians and advanced technologies. For further information contact: (718) 670-1756.