Symposium on Pediatric Oncology
Supportive Care for the Child with Cancer J. van Eys, M.D., Ph.D.*
Enormous strides have been made in the successful treatment of children with malignant diseases. The acceptance of multimodal therapy, the emphasis on multidrug chemotherapy, and the introduction of adjuvant chemotherapy all have resulted in markedly improved life expectancy and a very significant increase in cures in solid tumors and leukemia alike. It must be remembered, however, that results have been in no small measure the consequence of our ability to support the patient through the multitude of complications from the malignancy as well as from iatrogenic causes. This improved outlook for the child with cancer now demands a different attitude in the approach toward these patients. In the early days of cancer treatment and especially chemotherapy, there was a search for effective agents in childhood cancer. Once these agents were found, the measure of success was no longer life prolongation, but rather indefinite remissions. Now that such indefinite remissions have become a reality, and now that we are talking about continuous, unmaintained remissions, we have to consider what our definition of cure should be. It is clear that a cure cannot be solely defined on the basis of eradication of physical evidence of the disease. Our current modes of therapy are continued over periods of years through significant periods of the child's growth and' development. Unless after such years of therapy the child has developed and grown commensurate with his expectations, and unless the physical cost of therapy is kept to a minimum, a truly cured child has not resulted. In addition, it must be remembered that a child has no independent existence in society. Therefore the impact oflife threatening illness on the family stability must continually be acknowledged and family pathology must be dealt with as much as the pathology in the child itself. All these considerations make it obvious that the concept of team approach to a child with cancer must involve a very large number of professionals. This article summarizes some of the areas requiring ·Professor and Chainnan, Department of Pediatrics, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas
Pediatric Clinics of North America-Vol. 23, No. I, February 1976
special attention. It is, of course, impossible to cover in detail any of these aspects considering the very wide scope of concerns that will be touched upon. Nor will it be possible to give an exhaustive literature survey of all the areas mentioned. Many of the comments are drawn from the experiences ofthe M. D. Anderson Hospital and Tumor Institute, Department of Pediatrics, Houston, Texas.
PHYSIOLOGICAL SUPPORT Necessary Supportive Facilities There is little doubt that the margin of safety of chemotherapy in children is very small. Especially in childhood leukemia it has been well established that the optimal outcome demands treatment to tolerance. The same experience is beginning to be amassed in the therapy of solid tumors. For instance, adriamycin and high dose methotrexate are quite effective in the treatment of soft tissue sarcomas and osteogenic sarcoma. Both drugs have a very significant toxicity, with resulting iatrogenic diseases which can be themselves life threatening. To avoid iatrogenic death or to anticipate major complications from the disease proper, it is absolutely essential that such treatment be executed in an institution where there are sufficient support facilities for rapid diagnosis. This includes a clinical chemical laboratory that is willing and able to do emergency determinations for a large variety of serum constituents that are ordinarily not determined on a standard basis. Examples that are most obvious are uric acid, which needs to be determined rapidly in patients with hematological malignancies during induction of remissions; calcium, which often is low during attacks of pancreatitis secondary to asparaginase therapy, or during rapid tumor lysis such as is seen in Burkitt's lymphoma; phosphorus, which recently has been found to be significantly elevated during massive tumor lysis; and serum copper, which has shown to be an invaluable measure of relapse in Hodgkin's disease. The laboratory should be able to do rapid and reliable hematological evaluations; interpretation of bone marrow aspirations and biopsies by hematologists that are attuned to the significant differences in the bone marrow of the young as compared with that seen in older people; and a coagulation laboratory that can distinguish rapidly between the depletion of coagulation factors from vitamin K deficiency and liver failure and that of diffuse disseminated intervascular coagulation. Rapid bacteriological determinations are absolutely essential, including those for opportunistic organisms which need to be identified accurately. A blood bank must be available to supply all the blood fractions that are frequently needed, and that must be used separately on specific indication to avoid unnecessary sensitization which might compromise later transfusions. Ideally, the laboratory should be able to handle tissue typing to optimize transfusion therapy. Karyotyping is a needed laboratory test to distinguish between the various forms ofleukemia. The frequent endocrinological defects that
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are seen after cranial irradiation, and the complications of hormone therapy all require the collaboration of a knowledgeable endocrinologist and backup by an appropriate endocrinological laboratory. Sophisticated radiological diagnostic facilities are of course essential including contrast studies, nuclear medicine, sonography, and digital axial tomography. While only a few selected institutions in the United States could claim to be optimal in all these facilities, it is absolutely essential that a critical mass of expertise in laboratory facilities and physician expertise be available to support the children through the often remarkably narrow range between therapeutic demands and therapeutic complications.
Blood Component Therapy In the past the major reasons for death in hematological malignancies of childhood were infection and hemorrhage. The type of infection seen and the treatment of such infections have been dealt with elsewhere in this symposium. Infections still remain a major cause of morbidity and death. The development of adequate blood banking procedures, and the ability to do sophisticated component replacement therapy have been among the major breakthroughs in the management of children with malignancies. There is little difference whether deficiencies of blood components are iatrogenic or disease induced. However, when blood component deficiency is due to disease, be it myelophthisis or liver malfunction, replacement therapy is only necessary during attempts at bringing the malignancy under control. This is the reason for the observation that much of blood component therapy does not occur during the initial stages of a disease such as leukemia but is rather more apt to occur during the late stage of disease. 7 Nevertheless, it is the ability to provide prompt and specific blood component therapy that has allowed more vigorous chemotherapy, and as many feel, greater therapeutic success. At present, an up-to-date blood bank can readily make available whole blood, packed red cells, frozen red cells, leukocyte poor red cells, rare blood types, platelet concentrates (which are HLA type specific), fresh frozen plasma, cryoprecipitate and factor VIII concentrates, vitamin K-dependent coagulation factor concentrates, albumin, gamma globulin preparations (both pooled and hyperimmune for specific diseases), and often, granulocytes. It is very rare that a whole blood transfusion is indicated-even during hemorrhage packed cells with saline or fresh frozen plasma often suffice and are even preferable. It must be remembered that there is no such thing as a truly compatible transfusion. Each transfusion carries with it the danger that a subsequent transfusion will not be as effective. For children with malignancies this is a very real danger since they are very likely to require further transfusions. In addition, the use of whole blood sensitizes against all components, which is unacceptable when only red cells and intravascular volume are demanded by the clinical situation. As bone marrow transplantation becomes more and more a feasible mode of therapy for selected patients, it must also be remembered that even a
single transfusion from future donor to a potential recipient endangers the future marrow graft. One must add to these new risks the old dangers of mismatch, contamination, hyperkalemia, allergic and anaphylactic reactions, and volume overload. Infections remain a problem; we still encounter hepatitis, both of the hepatitis B variety and from other viral agents. Other transmitted infections include lues, cytomegalovirus, and others. It is clear that transfusions remain an area where cost versus need requires careful balance. Just because blood components are freely available does not mean that they should be used injudiciously. In spite of all these warnings, there is no doubt that much of the success of modern chemotherapy was made possible by blood component therapy. Again, the scope of this article precludes detailed discussion of the various blood component usages. However, a short discussion of newer insights and reemphasis of specific principles for the major blood components is appropriate.
Platelets Because bleeding and infection were the primary causes of death in pediatric malignancies, especially leukemia, the use of platelet concentrates was the first breakthrough in component therapy. The clinical study of Gaydos et al. 2 showed that the likelihood of hemorrhage is proportionate to the platelet count and that the lower the platelet count the more likely the hemorrhage is severe when it occurs. Everything being equal, hemorrhage does not occur above a platelet count of 100,000 and severe hemorrhage above a platelet count of20,000. Therefore most centers that deal with leukemia therapy use platelets prophylactically in patients with a platelet count of less than 20,000. Platelets can be obtained by removal of platelets from routinely drawn blood bank blood, or by platelet phoresis of single donors. The latter is preferable to avoid sensitization to platelet antigens. Sometimes relatives are preferred donors for successful platelet transfusions after platelets from random donors cease to be effective. However, with this success there is now a tendency to overuse platelets, or to treat a laboratory result rather than a patient. Any platelet transfusion endangers the success of later transfusions. Therefore one should interpret the result ofthe platelet count in light of the total patient: Is the patient actually bleeding? Are the platelets still circulating young or old (large or small)? A patient who is going into remission of his acute lymphocytic leukemia rarely bleeds even at low platelet counts whereas a patient who has a severely suppressed marrow may still have greater than 10,000 platelets circulating but all are over four days old. Therefore there is the almost universal experience that newly diagnosed children with leukemia do not have bleeding episodes as often as children with end stage disease. Is the patient receiving drugs that interfere with platelet function? Hopefully, every pediatrician knows about aspirin, but other drugs do likewise: robitussin, phenergan, and many more. In the setting of children with cancer, the effect of carbenicillin 1 is especially disturbing. Is thrombocytopenia truly a lack of production or is there a consumptive coagulopathy? In that case platelets should be used judiciously and the
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underlying cause combated. Is the bleeding truly due to thrombocytopenia or is there a component of coagulation factor deficiency, or worse, a bleeding wound or other mechanical bleeding site? After all, external bleeding from thrombocytopenia is never spontaneous; there is always a mechanical break in the integrity of mucous membranes or skin. Often such a bleeding site is not amenable to specific treatment, such as periodontal bleeding, but surprisingly often, local measures are necessary and even sufficient. Finally, an infiltrated spleen or portal hypertension can cause significant thrombocytopenia due to hypersplenism without significant bleeding, and without significant rise in platelet count after transfusion. There are, therefore, times when a platelet transfusion is not indicated in spite of very low platelet count whereas conversely bleeding can be the result of inadequate platelet function in spite of a near adequate count. Red Cell Therapy Anemia is a very frequent condition among children with malignancies. What was said for platelets must be reemphasized for red cells, but even more strongly. The indication for red cell transfusion is not the presence of a low hemoglobin and certainly not the presence of a hemoglobin ofless than 10 gm per cent, as many physicians hold. Rather, the indications are hypovolemia, inadequate oxygen carrying capacity, and a threat of uncontrollable blood loss resulting in the above conditions. The latter may be a patient resistant to platelet therapy who is thrombocytopenic and has a hemoglobin of less than 7 gm per cent. Furthermore, children with cancer are nevertheless children and one must never forget other causes of anemia, such as iron deficiency (we do draw large volumes of blood in our diagnostic zeal), drug-related hemolytic anemias (such as those secondary to glucose-6-phosphate dehydrogenase deficiency), or immune related anemias caused by disease or past transfusions. Granulocytes The use of granulocytes is still somewhat controversial. There is now no technical obstacle to generating adequate numbers of white cells by leukophoresis from single donors. 6 There is likewise little doubt that these cells are functional in vivo. 8 However, whether such transfusions influence the outcome of the infection in children with malignancies is unknown. In our experience at the M. D. Anderson Hospital, the increase in peripheral blood count after granulocyte transfusions that is achievable is far greater than in adults, probably because of the use of adult donors for little children. The clinical impression is that such transfusions are beneficial, or at least palliative. Coagulation Factors Bleeding because of coagulation factor deficiencies is often not considered. Yet in children with cancer there are many situations in which deficiencies of clotting factors are the primary cause of morbidity.
One sees consumption coagulopathy wherein primarily factors V, VIII, and fibrinogen are depleted. There is liver failure with all coagulation factors deficient whereas asparaginase therapy can give severe hypofibrinoginemia. Prolonged antibiotic therapy can produce vitamin K deficiency and this can be aggravated by malabsorption. The use of coagulation factor concentrates can be life saving and deserves equal attention to platelet therapy. Environmental Support The armamentarium of modern medicine allows a wide variety of drugs, biologicals, and surgical interventions in our combat of disease. In many instances iatrogenic disease is a recognized and rarely completely avoidable consequence of our intervention. Just as comprehensive care requires teamwork and coordination among the personnel of all participating disciplines, so do we need coordination among the environmental demands imposed on our care by all the specialized therapeutic attempts. The extreme is the life island or laminar air flow rooms. For children the psychological demands from such isolation are severe and the results are not necessarily sufficiently better through the use of life islands than the use of more conventional hospital settings. However, at a less extreme level what would be routine in more simple diseases might have profound consequences for the immune suppressed patient. Attention to the care of intravenous fluid lines and meticulous avoidance of entering parenteral alimentation lines are absolutely essential to minimize bacterial and fungal sepsis. Blood drawing through venipunctures must be done carefully, but at the same time it must be remembered that finger or heel sticks are more traumatic and far more often constitute portals of entry for infections. Whenever hospitalization is necessary, the child with a malignancy needs an environment where the special problems that are encountered are expected, acknowledged, and preferentially avoided. There are still too many burns from inadvertently extravasated chemotherapeutic agents, and too many calcium solutions form accretions subcutaneously with severe inflammation. The personnel must be attuned to the need for prompt and vigorous response to signs of bleeding, infection, and shock, yet they must be equally aware of the fact that derangements in homeostasis and laboratory parameters that would alarm a pediatrician if encountered in a normal child, can be quite acceptable in the child on chemotherapy. All this is to point out that the care of the child with cancer, at least as yet, is best executed in a milieu where the staff has experience. And not just the doctor, but also (ifnot primarily) the paramedical personnel who, after all, care for the patient minute by minute. Nutritional Support The interactions between nutrition and cancer are very complex. However, there are signs that cachexia is beginning to become a significant cause of mortality now that bleeding and infection are more readily controllable. Nutrition of the child with cancer places special
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demands on the physician. There are the anorexia and dysphagia of malignancy itself; there are the nausea and vomiting from chemotherapy and radiotherapy; malabsorption occurs from abdominal radiotherapy; protein-losing enteropathy is common; and specific nutrient deficiencies are not infrequently encountered. There are very few controlled studies of nutritional rehabilitation in cancer, and the few that exist are in adult patients. However, if the lessons of kwashiorkor and marasmus apply to children with malignancies, then we can assume that there will be a point beyond which the patient is irretrievable in spite of all attempts at nutritional rehabilitation. There is good evidence that nutritional debilitation per se results in immune suppression. Thus greater attention to nutritional rehabilitation with early parenteral alimentation is now becoming more widely practiced. In some successful chemotherapy protocols, such as that used at the M. D. Anderson Hospital (e.g., vinblastine sulfate (Velban) and bleomycin for embryonal carcinoma), early parenteral alimentation is required to successfully complete the regimen.
PSYCHOLOGICAL SUPPORT As important as physiological support and therapy of unavoidable iatrogenic disease are by themselves, they are insufficient to allow a claim of total cure. At present it is very popular to discuss the dying child. Usually such discussions are introduced with a statement to the effect that dying is not popular and is being denied. There is no doubt that our ability to support the dying child is often very poor, both for personal reasons and for want of knowledge of guiding data. But it must also be remembered that in childhood cancer, cure is almost the norm-not in each and every disease-but there is no childhood cancer that is a priori hopeless; even leukemia may not be invariably fatal. Therefore to approach each child with cancer as a child who will die is committing psychological euthanasia. Rather each child should be approached as a person who might die but also who might live.lO If we do not support the whole person we may find a biologically cured child who has not developed mentally, and who has not learned the experiences a normal child needs to learn to be competitive with his peers. A full psychological support system is necessary to generate truly cured children, if we define cure as a child with normal functions. This does not mean that a child with cancer, whether cured or not yet cured, will ever be totally the same as a peer without cancer. That is neither possible, nor indeed desirable; children with cancer cannot ignore nor should they have ignored a large part of their formative being. But if we want to approach a true cure, the effects of cancer should be as minimal as possible, and the children should be at ease with their existence as it is. To develop a psychological support system there has to be primarily a specific attitude. Such an attitude should pervade the entire staff and all members need to be secure in their roles. This is fairly easily accomplished in relatively small pediatric oncology services where an esprit de corps generates mutual respect and consequently cooperative support. When
logistics demand separate roles of adults in contact with the patients, such psychological support is often delegated to mental health teams or pastoral counseling services. Such groups are necessary but not suffi.cient. Pastoral counseling is a service based on a specific viewpoint that would be diluted if the pastors were asked to supply general moral support. The mental health team is more necessary to support the staff, if the staff does its work well. Lack of perception of the need for a mental health team clearly demonstrates lack of empathy with patients' needs.
Specific Mental Health Problems in Oncology There are specific problems that need to be addressed, the first being delayed development. Even when cure is a reasonable possibility, parents do not always dare to hope. The result is that the child receives concessions made in the mistaken idea that they contribute to the child's mental comfort. The classic occurrence of school phobias in children with malignancies is but one example of the consequences of such an attitude. 5 Clearly this requires constant support of the parents. Discussion groups among parents are essential to hear alternative solutions to common problems. The children should be challenged according to their ability. They should be sent to school and schooling should be provided in the hospital and clinic. Attempts at normalizing the child's life through parties and other diversions should never be allowed to have as the aim the idea that the cancer does not exist, but rather that the cancer is acceptable. The second recurring problem is poor self-image. Much of our current treatment, be it surgery, radiotherapy, chemotherapy, or immunotherapy is physically disfiguring. It is often a devastating problem for children who already have an untested self-image to absorb these bodily changes. However, the children initially rarely deal with these problems in an unhealthy way. They strive desperately for mental normalcy. It is the task of all who care for these children to indeed accept them as they are and not as we would like them to be. Self-image has to be tested against peers; thus peer contact is essential, even to the point of having regular teenage group sessions. There is one major difference between the management of children with cancer and adults with cancer. Adults can be rehabilitated but children have rarely developed skills to the point where true rehabilitation is an issue. Children may have vocational aspirations that are unreasonable to a degree which constitutes denial. Realistic dealing with children needs to be continually emphasized. It is here that the mental health team is most necessary to support the staff members in their approach to the patients. This must be accomplished through continued contact with all involved.
The Child Who Is Not Cured The emphasis on the child who might be cured is in no way meant to detract from the very real need to support family and child in time of impending death. So much has been written about death and dying that little more should be added at this time. Suffice it to say that the dying
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child has a right to do SO, as has the dying adult. We should not impose or transfer our mental difficulties with accepting the phenomenon of the dying child on to others. 9 It is rare that parents need to be treated because of their grief or that a child needs to be given psychotherapy because of inability to cope adequately with dying. Almost all attempts of caring adults to treat morbid grief in relatives are reflections of their own difficulties at assimilating the concept of the dying child. The above statements are oversimplifications but they must be emphasized. The mental health team is very necessary, but primarily to support the staff. Rarely is it necessary to treat the child through them except by their being available as empathizing fellow humans.
The Family of the Child with Cancer Not infrequently, the siblings are caught in the stresses of cancer in the family. If the child is accepted as the responsibility of the medical team, care is inadequate unless the whole family is supported. The whole family has to adapt to the fatally ill child. We tend to help the parents only and then often the mother primarily, because she usually carries the burden of care and interpretation of the medical findings to the rest of the family. On occasion the siblings become more understanding of disease and tolerant of their sick brother or sister. On other occasions, the parents devote so much time to their sick child that siblings almost have to act out to get the attention they deserve. At the M. D. Anderson Hospital, we actually invite brothers and sisters to come to the clinic and play in the volunteer play area so that they share in the sick child's experience. Further Responsibilities The child that we cure needs very careful follow-up, beyond the period at risk. This too has been dealt with in other articles in this symposium. But it must be stressed again that we cannot allow a child to go without special attention because of the real risk of late recurrence, second malignancies, and possibly defective reproductive performance. There are very few data on the mental, psychological, and social outcome of patients. 4 Such information must be acquired to generate a data base from which optimization of therapy can be devised. However, it must be obtained in such a way that there is no interference with the concept of cure.
SUMMARY A brief overview of topics in physiological and psychological care of the pediatric cancer patient has been given. To a large degree only a catalogue of support modalities could be listed. Many of our current achievements in disease suppression and eradication owe their successes to our ability to amass physiological support. Now, to achieve truly cured children, attention needs to be focused on the psychosocial development of child and family alike.
REFERENCES l. Brown, C. H., Natelson, E. A., Bradshaw, M. W., et al.: The hemostatic defect produced by
carbenicillin. New Engl. J. Med., 291 :265-270, 1974. 2. Gaydos, L. A., Freireich, E. J., and Mantel, N.: The quantitative relation between platelet count and hemorrhage in patients with acute leukemia. New Engl. J. Med., 260:905909, 1961. 3. Holland, J. F.: Who should treat acute leukemia. J.A.M.A., 209:1511-1513, 1969. 4. Holmes, H. A., and Holmes, F. F.: After ten years, what are the handicaps and life styles of children treated with cancer. Clin. Pediat., 14:819-823, 1975. 5. Lansky, S. B., Lowman, J. T., Vats, T., et al.: School phobia in children with malignant neoplasms. Am. J. Dis. Child., 129:42-46, 1975. 6. McCredie, K. B., Freireich, E. J., Hester, T. P., et al.: Increased granulocyte collection with the blood cell separator and the addition of etiocholanolone and by hydroxyethyl starch. Transfusion, 14:357-364, 1974. 7. Simone, J. V.: Use of fresh blood components during intensive combination chemotherapy of childhood leukemia. Cancer, 28:562-563, 1971. 8. Vallejos, C., McCredie, V. E., Bodey, G. P., et aI.: White blood cell transfusions for control of infections in neutropenic patients. Transfusion, 15 :28-33, 1975. 9. van Eys, J.: The dying child. Cancer Bull., 26:105-106, 1974. 10. van Eys, J.: Caring for the child who might die. In Barton, D. (ed.): Care for the Dying: A Textbook for the Health Care Professionals. Baltimore, Williams and Wilkins Co., in press. Department of Pediatrics M. D. Anderson Hospital and Tumor Institute Texas Medical Center 6723 Bertner Drive Houston, Texas 77030