The Cold Knife and The Hot Rays
The key to successful treatment of cancer is to diagnose it at a stage when the cancer can be removed entirely from the body. We have at our disposal two methods by which such removal can be accomplished : by surgery, or by X-rays. These are not alternative techniques for all forms of cancer. Some forms of cancer are “radio-resistant,” or not responsive to doses of X-ray that can be given safely to the patient, whereas other forms are sensitive to X-rays and are called radiocurable or radiosensitive.
Among the radio-resistant cancers, which must be treated by surgery, are the cancers of the gastrointestinal tract and the associated organs, including the stomach, small and large intestines, gallbladder, pancreas and liver. Surgical resection is also the primary curative approach to brain tumors, cancers of the breast, kidney, testis and ovary, and bone and muscle.
Very radio-sensitive cancers, such as those arising from the lymph nodes and blood-forming tissues, which include leukemia, Hodgkin’s disease and lymphosarcoma, are usually best treated by X-rays. For cancers of the mouth and the face, the uterine cervix and the urinary bladder, either surgery or X-rays may be selected as the primary treatment.
There are, of course, many modifications of techniques used by surgeons and by radiotherapists. The ideal management of most patients with cancer is by a smooth working team of a surgeon, radiotherapist, pathologist and internist, with consultations between the specialists not only at the initial decisions regarding treatment, but as the case progresses. In medicine, responsibility over a patient is not safely divided between doctors, and at any’ given time the primary control over a patient must remain in the hands of one of the clinicians.
Inadequate surgery or radiotherapy, which at the initial course of treatment does not include the total extent of the cancer, is not only doomed to failure but may well spread cancer cells and speedup the fatal course of the patient. That is why even the ancients, whose experience with cancer was usually limited to cancer of the breast, followed the principle of Hippocrates, “primum non nocere,” meaning, “first do not harm.”
Surgical resections of internal cancers became possible following the discoveries of two great boons to mankind, anesthesia and asepsis, during the 19th century. The German surgeon, Theodore Billroth, remains a giant of the early era, especially for his operations on the stomach and intestines. During the 20th century, with further improvements of surgical techniques, and the introduction of blood transfusions and antibiotics, all portions of the human body became surgically approachable. American surgeons had an important role in the developments, with Harvey Cushing’s operations on the brain, and Evans Graham’s removal of the lung for cancer.
During the past 2 decades, increasingly extensive operations for cancer have been perfected, and cancers of the cervix, head and neck that were previously considered beyond operation are now accepted for surgery. The use of heart lung pumps, artificial kidneys, and the replacement of bones and blood vessels are forerunners of transplantation of whole organs, and further surgical miracles. At the same time, we are observing the reexploration of more conservative resections of cancers of the breast, thyroid and other sites, with indications that these more limited procedures may have a definite place in the treatment of cancer also. The question is not whether radical or more limited surgery is superior, because both have their place. The question is, what procedures are best under what circumstances and in what patients.
Reference to radiation here includes other forms of ionizing radiation as well as those that emanate from X-ray vacuum tubes. The monumental discovery of Wilhelm Roentgen, in 1895, of the penetrating new electromagnetic rays, led to their use in diagnostic procedures almost at once. Within a few years X-rays were shown to have a destructive effect on normal tissues, and by 1910 these effects were shown to lead to the development of cancers. Several clinicians also observed that exposure of skin cancers to X-rays made them disappear, as earlier workers had seen with radium. A systematic study of the place of ionizing radiation in the treatment of cancer became possible. C. Regaud of France was among the influential pioneers who worked out the source, the sequence of doses, and the filtration and distance factors that allowed quantitation of the radiation factors. Higher speeds, deeper penetration, sharper delineation and greater sparing of surrounding tissues have been achieved with the introduction of multimillion volt and radioactive cobalt sources.
The basic principle in the curative use of radiation for cancer is also to encompass the total tumor mass and its extensions within the field of radiation at doses that will destroy the cancer but allow the normal tissues to survive or to recover. It is obvious that the limitation of this method is similar to that of surgical resection : the cancer is curable only if it is destroyed entirely by being within the field of radiation at levels lethal to the cancer.
But the deadly character of cancer lies in its ability to spread and to seed its cells in distant organs of the body. These metastases often exist as microscopic colonies when the patient is undergoing treatment for a cancer that clinically is presumed to be still localized. For these patients, the application of methods of treatment that do not include the whole body will not be successful. Chemical bullets that would selectively hunt out and destroy cancer cells, or in some way provide the body with the ability to render such cells harmless, is the only answer to this problem.
Chemotherapy, a term and concept introduced by Paul Ehrlich of Germany in his successful attack on syphilis, has been the dream and, until now, the awakening to disappointment, of the cancer research workers. A major national investment, the National Cancer Chemotherapy Program, has been organized. Through these and previous efforts, there have been introduced into clinical practice a number of drugs that are useful in the management of certain types of advanced cancer. We shall return later to the experimental aspects of the exciting, promising field of cancer chemotherapy. The facts as to the place of chemotherapy in the treatment of human cancer today, however, can lead only to a conservative, very tentative conclusion.
There is only one cancer, acute leukemia of children, where chemotherapy is the primary and the only treatment. Remissions that may last for many months are obtained with the use of chemicals known as antimetabolites (Methotrexate and 6-mercaptopurine), and cortisone. All children eventually have the disease return in an active, fatal form. For chronic forms of leukemia, a number of chemicals are clinically useful, and can be combined with X-ray treatments or used alone. The effects here are those of improving the condition of the patient, and no cures or significant prolongation of life have been achieved.
For the more common cancers that are clinically presumed to be localized, the use of chemotherapy alone can only be condemned. Even experimentally, the only justified place of chemical agents thus far available for patients with cancer that can be treated by surgery or radiation is as additives to the surgery or radiation. For cancers that are widely spread, a number of chemicals may be of definite value. The oldest is included under chemotherapy only by tradition, since it is known that the effects are due to the changes in the hormone secretions. We mean by this to include the removal of ovaries or of the testes, or of the adrenals and the pituitary gland as a species of internal chemotherapy. These procedures do produce improvements and temporary regressions of a proportion of advanced cancers of the breast and of the prostate. The effects can be reproduced by giving patients large doses of male or female sex hormones.
The beneficial results of the removal of ovaries in younger women with advanced breast cancer were reported by the British surgeon, G. Beatson, in 1896. The effects of removing testes in men with advanced cancer of the prostate were discovered by Charles Huggins in 1936. Of the original 20 such patients, 4 were alive and without clinical evidence of disease 5 years later.
Another definitely useful chemical treatment in cancer was introduced by Roy Hertz and his group at the National Cancer Institute, who showed that Methotrexate, the antimetabolite first used for acute leukemia in children, also produced striking regression of disseminated choriocarcinoma. This is a cancer that arises in the products of conception, usually in young women, and is noted for its rapid, fatal course. In women treated with Methotrexate when distant metastases are present, more than half are alive and clinically well 5 years later.
The victories of chemotherapy over the more common forms of cancer still lie in the future. But there have been enough real effects already established to empower us to maintain high optimism that this is the practical approach to the clinical problem of cancer. However, at this stage our optimism must be carefully held in check. It is tragic to hear that a patient has decided not to undergo surgery or radiation because a chemotherapeutic discovery may be just around the corner. No one can tell when such a discovery might take place, and it would take years to establish that the initial promising responses were indeed valid or lasting. By that time, the immediate problem of the patient with cancer now would be only of historical interest.