PEDIATRIC CANCER IN PERSPECTIVE: CURE IS NOT ENOUGH

GIULIO DANGIO, J. MD*

0NSIDERABI.E PESSIMISM H4S SPRUNG U P RE-

garding the prognosis for children with renal embryoma, and while it is still true that the mortality is high . . . , a review indicates that about 25% o patients can be permaf nently cured . . .a These words were not written in the 19th century by Wilms, but rather a scant three decades or so ago by Ladd and Gross reporting the best results obtainable u p to that time. They were exhorting their colleagues to make the attempt to cure and not to be defeated by the very diagnosis. In those same days, other texts that might have been consulted regarding the outlook for patients with the various malignant disease of infancy and childhood would have yielded a litany of hopeless, invariably lethal, and the like. This, then, was the outlook for children with cancer in the early, mid, and late 1940s. Even this was better than a few years before, when the parents of these children all too commonly were told that nothing could be done, and the child was dismissed to die at home. T h e early steps on the upward road were predictably along surgical lines; pioneering surgeons developed techniques to make successful cancer surgery possible in these small patients. More hopeful notes began to appear in the literature. T h e addition of radiation therapy to the armamentarium helped the situation, and better local control was achieved. Survival figures began to creep up; it was recognized, however, that distant meta5tases were the major problem, and several
Presented a t the American Cancer Societys National Confcience o n Childhood Cancer, Dallas, T X , May IF18, 1974. Supported in part by U.S.P.H.S. Grants No. R10CAI1722 and No. Ey-232860. * Chairman, Department of Radiation Therapy, Memorial Sloan-Kettering Cancer Center; Professor of Radiology, Cornell University Medical College, New York, NY. Addrcas for reprints: Giulio J. DAngio, MD, Chairman, Department of Radiation Therapy, 1275 York Avenue, New York, NY 10021. The cooperation of the many institutions enrolled in the National Wilms Tumor Study, and of the Study Committee, is gratefully acknowledged. Received for publication June 25, 1974.

maneuvers were devised in the attempt to lessen the likelihood of metastatic spread. It was reasoned that manipulation of the tumor during surgery promoted the dissemination of disease. This led to attempts to diminish this propensity by using preoperative radiation, notably for osteogenic sarcoma and for Wilms tumor. Coleys toxins came into being; several chemicals and drugs, including vitamin B12, were used in attempts to control the disease. Leukemia continued the implacable killer. And then came the advent of chemotherapy. T h e turning point for pediatric oncology was the discovery by Farber and his colleagues in 1948 that antifolic medication could produce hematologic remission in children with acute leukernia.5 T h e cancer world was electrified by the news. A simple medication had been found that could destroy malignant cells selectively wherever they lurked in the body. If this could be clone for leukemia, why not for the metastatic foci arising from solid tumors? There was a ferment of activity in the development of effective antineoplastic chemotherapeutic agents, and in the definition of their potential clinical usefulness. At first skeptical, and then wary of the toxic effect5 of these potent substances, surgeons and radiation therapists soon saw that their colleagues in pediatric oncology could provide valuable support in the palliation of children with advanced diseane. They began to work more and more closely with chemotherapists, introducing antineoplastic agents earlier and earlier in the course of treatment, and defining methods and techniques for the interdisciplinary care of these children. T h e role of the surgeon continued to be the removal o the bulk of f the tumor that was difficult for either the I adiation therapint o r the chemotherapist to destroy. T h e radiation therapist, it became clear, could eradicate residual nests of cells left behind by the surgeon, despite attempts at total removal. T h e chemotherapist, i t was found, could d o what neither of the others could accomplish; namely, destroy foci of neoplastic cell\ remote from the primary site,

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thus aborting the development of lethal metastases. It is indubitable that development of the team approach has been responsible for many of the advances made. T h e first neoplasm to fall before this combined attack was the Wilms tumor; the concept has been expanded to include the entire spectrum of malignant neoplastic processes. T h e rediation therapist today is intimately involved with the care of the child with acute leukemia, once the domain of the cheniotherapist. T h e surgeon is an important member of the team caring for Hodgkins disease patients, once in the practically exclusive pur\,iew of the radiation therapist. T h e chemotherapist has achieved a position of importance in the management of osteogenic sarcoma, a disease which only surgery had had any hope of controlling. Diseases became better understood. T h e definition of so-called sanctuary areas, where chemotherapeutic agents do not penetrate effectively, led to programs wherein routine suppressive irradiation was given to children having a high risk of involvement of these zones. Treatment of the brain and spinal cord of children with leukemia i s a notable example. As more and more effective chemotherapeutic agents became available, it was logical to test them singly, and, when found to be useful, to mix them in various combinations in an attempt to achieve even greater tumor cell kill. Many ingenious multiple agent regimens came into use, employing combinations of drugs with differing toxicities so as best to spare normal tissues. A most successful technique was developed for establishing rapidly and with accuracy the relative merits of two or more treatment regimens; that is, the cooperative clinical trial, in which many institutions band together to pool patients for study purposes. Many important clinical advances can be credited to these <groupsof cooperating institutions. Outside this mechanism, there are some centers with specialized staffs and large enough patient loads which can run specifically designed, relatively small investigations, sometimes called pilot studies, to permit first estimates of the usefulness of a particular treatment or method. There are still other institutions, adequately staffed with expert specialists-and those prerequisites are important-which are not enrolled in cooperative groups and which do not have large enough patient populations to run definitive intra-

mural investigations. These institutions perform a valuable service by entering patients into clinical trials through alternate methods that sometimes are available to them. One mechanism that exists in the National Wilms Tumor Study, for example, is the so-called Independent Group. Institutions of the kind described enter their patients into the Study. They enjoy the benefits of carefully designed tieatment protocols that define workup, treatment, and followup period. T h e treatment results with nonmetastatic Wilms tumor patients obtained by the Independent Group have been compared with those obtained by one of the larger clinical trial groups. Diseasefree interval and survival rates by actuarial analysis show that equally good results are obtained by both groups (Figs. 1 and 2 ) . This demonstrates what can be accomplished by expert teams working in well-staffed institutions following carefully designed, relatively straightforward treatment protocols. Everyone benefits from approaches of this kind. Pediatric cancer is too rare a disease for individual practitioners to develop expertise and thus provide the patient with the best method of treatment. At the same time, the disease being infrequent, each patient becomes a valuable resource for the study of better treatment methods. T h e relentless, aggressive attack against childhood cancer has led to a crescendo of success; medicine can take justifiable pride in the progress made. Median survival times for children with acute leukemia now exceed 5 years. T h e survival of children in the most successful arms of the National Wilms Tumor Study are now well above S6%, and in certain of the early stages of that disease are approaching 100yo. What a difference from the one in four of Ladd and Gross! Some of us have lived through the change, and have reason to expect that, within our medical lifetimes, Wilms tumor will be cured in virtually every child suffering from the disease. Rliabdomyosarcoma, Ewings tumor, osteogenic sarcoma-the despair of physicians a few years ago-are falling before the combined attack; day by day, it seems the list becomes even longer. Those concerned with the malignant diseases of childhood are not satisfied with these results, however. As the number of survivors increases, and the length of their survival also increases, concern is being expressed because of the late consequences of successful treat-

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membered that there are relatively few longterm survivors after chemotherapeutic management living today, and that detailed, protracted studies of this patient population are essential. Damage to vital organs is bad enough as it is; in addition, injury to the parenchyma may set the stage for the development of second malignant neoplasms. Certainly, no comfort can be taken from the vinyl chloride story. This compound, known to be hepatotoxic not only in laboratory ' 2 4 6 0 {C Ih 1 6 1 8 20 22 24 26 A m animals b u t in humans, has now been def, a initely associated with the eventual appearFIG. 1. The National Wilms' Tumor Study. Actuarial curves showing percentage of patients living diseaseance of angiosarcoma of that organ in man. free vs. months on study. T h e results obtained by one We therefore habe a chilling chain of events of the national cooperative study groups are shown by to contemplate: chemically-induced organ curve A, and those by the Independent Group by curve I. damage and, eventually, cancer of that same organ. ment given to the child and a d ~ l e s c e n t . ~ It is clear that the child cured of cancer Every treatment has its undesirable side ef- must be followed for life, not so much befects, some minor, some major. Those asso- cause late recurrence of disease is feared as to ciated with surgery usually are immediate, permit early detection of the delayed consepredictable, and well-known. T h e effects of quences of radio- and chemotherapy. Careradiation, however, often are more subtle, and ful studies of these late effects must be conmay be long delayed. Years may pass before ducted; there are several under way. T h e there become apparent the full effects o dis- understanding of treatment effects is difficult f turbed growth and development, o r the im- at best, and is made doubly so because of the pairment of function of organs and structures interaction of radiation therapy and chemoincluding the gonad. Oncogenesis and damage therapy, the one tending to enhance the local to the genetic apparatus are even more spec- effects of the other. These are not always tral accompaniments. Many if not all of these predictable. Results of one aspect of an insame effects can be predicted for patients sur- vestigation specifically designed to detect the viving after receiving intensive chemotherapy. late consequences of chemotherapy given to Some are carcinogens in laboratory animals. children can be cited as an example. LongThey all are toxins, affecting most the rapidly term Wilms' tumor survivors were chosen for dividing cells such as the bone marrow and in- the study, with neuroblastoma and rhabdotestinal epithelium. Some have greater or myosarcoma patients as controls. Actinomycin lesser specificity for other organs such as the D is commonly used for the treatment of liver, kidney, or lung. This damage can, at Wilms' tumor. It is a known radiation entimes, be crippling or even lethal as patients hancer. It might be expected that the delare followed over the years. I t must be re- eterious effects of radiation therapy would be accentuated by the concomitant use of actinomycin D. Included among the expected deleterious effects was oncogenesis, both radiation therapy and actinomycin D being carcinogens i n animals. I n a portion of this study recently reported, 583 patients with the index diseases were collected from three cooperating institutions, and the frequency of second malignant neoplasms in irradiated sites was tallied.8 It was found that patients receiving antifolic medications as well as radiation had a five-fold increase in the risk i 4 Q Q i c i +*-+-2-c of developing a second malignant neoplasm. Actinomycin D seemed t o decrease that risk, FIG.2. Same as Fig. I , but showing survival data. also by a factor of five. These results, although
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preliminary, antl requiring additional information for substantiation, are a total surprise antl indicate the amount and kind of work that must be done before we are in a position to evaluate with accuracy the risk of treatments given. Thus, while the emphasis properly is on improving survival rates, there is a parallel effort to refine treatment, reducing it to the minimum necessary to achieve cure. Investigators are engaged in a variety of approaches to achieve this end. First, there are attempts to understand the lethal potential of these diseases once they have developed. Identifying the important variables for each tumor type so as to be able to estimate prognosis is an obvious technique that has come into full use only relatively recently. Age, stage, site of origin, histologic type and grade-all of these are of importance in assessing the risks of local recurrence and distant dissemination. Systems of therapy must be based on such assessments. T h e correct answer, for example, to the question, How should neuroblastoma be treated? must include a definition of the age of the chilcl, the stage, and possibly the site of origin of the tumor.4 Some of these patients require more aggressive therapy than others; i t would be wrong to deliver toxic treatments of any kind, or to embark on extetisive and potentially risky surgery, in children who would derive no clear benefit from the therapeutic maneuver. T h e understandable tendency to add more treatments to existing regimens in attempts to obtain better suppression of both local and remote disease must be viewed in the light of what is becoming known regarding the late effects of treatment. Indiscriminate concatination of therapies, however laudable the intent, is not to be encouraged. More treatment is not necessarily better treatment. There should be a careful assessment of whether more therapy is, in fact, needed for the particular disease entity under consideration. It has already been said that a thorough knowledge of pediatric neoplasia is necessary before the relative risks of adding a treatment vs. withholding that treatment can be weighed accurately. Additionally, a sound rationale should always be in hand before introducing new or even standard methods into existing programs. It goes without saying that adequate numbers of patients must be available to assess the efficacy of change. T h e concept that a little treatment is good, and that a lot

more is a lot better clearly does not pertain to the treatment of malignant diseases in children, with all their vagaries, and the potential deleterious consequences of the therapies employed. This aspect of clinical research in pediatric oncology, then, focuses on the definition of minimum necessary treatment given with the least noxious agents or modalities that will achieve the desired result. Some of the clinical trials of national scope concerned with pediatric cancer have embraced this concept. T h e question being asked in groups of patients with high cure rates is not whether more treatment will give an even better result, but whether less treatment will give an equally good survival rate, the benefits being less morbidity and better quality of life.zx T h e search for always greater therapeutic specificity goes on. There is hope, for example, that the manipulation of tumor-host interactions will make it possible to develop tumor-cell-specific therapy, whereby the neoplastic intruder is destroyed, leaving the adjoining normal cell unscathed.1 It is natural for physicians to focus on treatment. A far better focus is prevention. The recent identification of environmental oncogenic factors, some of them prenatal, some of them found even in the household, and their elimination are obvious and totally effective ways of curing cancer, before it develops. T h e tumors that are associated with the immunodeficiency diseases are more difficult. T h e efforts of those who strive to restore the immunocompetence of these children are watched with great interest, in the hope that, in so doing, the lymphomata that follow these conditions like shadows will be prevented from developing. Thorough study of the entities at the extremes of immunologic impairment, and their asociated malignant processes, will help u s understand whether similar mechanisms are involved in the development and unbridled growth of neoplasia in normals. Not dissimilar in ultimate aim are the important advances being made in defining familial patterns and clinical syndromes associated with a high risk of malignant disease. So-called genetic engineering might be successful in prevention, perhaps by the introduction of innocuous viruses designed to alter the genetic apparatus of patients in high risk
* T h e Intergroup Rhabdomyosarcoma Study, Harold M. Maurer, MD, Chairman, Medical College of Virginia, Richmond, V.4.

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groups.'* Finally, the attempt to identify oncogeiiic viruses in humans goes on. Tantalizing leads-the inclusion bodies visible in the rare digital fibroma of infancy and childhood,'" antl the Epstein-Barr virus associated with Burkitt's tumor and the nasopliaryngeal carcinoma"."-spur on the investigator i n this field, the goals being preventive or therapeutic vaccines. Pediatric cancer seen in perspective, then, puts us almost at the end of a long tunnel, looking back in one direction towards the Idackness of "no hope" and "no cure." Look-

ing forward, we see a wide antl open road with well-spaced way-stops en route to our final destination. Some of these way-stops surely are the development of ever more refined and precisely targeted methods of treatment, so that the increasing nunibers of successfully treated children of today do not become the chronically ill adults of tomorrow. T h e end of the road will be reached via prophylactic and preventive measures, when cancer, as a threat to the life and limb of children, will have been eliminated forever. Indeed, cure is not enough.

REFERENCES
1. Bernstein, I. D.: Immunologic defences against cancer. /. Pediatr. 83:906918, 1973. 2. D'Angio, G. J.: Management of children with IVilms' tumor. Cancer 30:1528-1533, 1972. 3. Epstein, M. A., Achong, B. G., and Barr, Y. M.: Virus paiticles in cultured lymphoblasts from Burkitt's lymphoma. L a w e t i:702-703, 1964. 4. Evans. A. E., D'i\ngio, G. J., and Randolph, J: A proposed staging for children with neuroblastomaChildrcn's Cancer Study Group A. Cancer 273374-378, 1971. 5 . Farber, S., Diamond, L. K . , Mercer, R. D., Sylvester, R. F., and Wolff, J. A.: Temporary remissions in acute leukemia in children prolonged by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N . Engl. J. M e d . 238:787-793, 1948. 6. Ladd, W. E., and Gross, R. E.: Abdominal Surgery of Infancy and Childhood. Philadelphia, 11'. B. Saunders, 1941.

7. Meadows, A , , and D'Angio, G . J.: Late effects of canccr treatment-methods and techniques for detection. Semzn. Oncol. 1:87-90, 1974. 8. Meadows, A., Jaffe, N., Newton, W., Evans, A,, Mikc, V., Harris, C., Miller, R., and D'Angio, G . J.: T h e influence of chemotherapy on second malignant neoplasms in irradiated children. Proc. A m . Assoc. Cancer Res. 15:175, 1974 (abstr.). 9. Old, L. J., Boyse. E. A., Oettgen, H . F., de Harven, E., Geering, G., Williamson, B., and Clifford, P.: Precipitating antibody in human serum to an antigen present in cultured Burkitt's lymphoma cells. Proc. Natl. Acad. Sci. USA 56:1699-1704, 1966. 10. Reye, R. D. K.: Recurring digital fibrous tumors of childhood. Arch. Pathol. 80:228-231, 1965. 11. Rogers, S., and Pfuderer, P.: Gene therapy-A potentially invaluable aid to medicine and mankind. Res. Comrnun. Chern. Pathol. Pharmacol. 2:587-600, 1971.