Principles of Treatment

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Chapter 488 Principles of Treatment

Treatment of children with cancer is one of the most complex endeavors in pediatrics. It begins with an absolute requirement for the correct diagnosis (including subtype), proceeds through accurate and thorough staging of the extent of disease and determination of prognostic subgroup, provides appropriate multidisciplinary and usually multimodal therapy, and requires assiduous evaluation of the possibilities of recurrent disease and of adverse late effects of the disease and the therapies rendered. Throughout treatment, every child with cancer should have the benefit of the expertise of specialized teams of providers of pediatric cancer care, including pediatric oncologists, pathologists, radiologists, surgeons, radiotherapists, nurses, and support staff, including nutritionists, social workers, psychologists, pharmacists, other medical specialists, and teachers trained to work with seriously ill children.

The best chance for cure of cancer is during the initial course of treatment; the cure rates for patients with recurrent disease are much lower than those for patients with primary disease. All patients with cancer should be referred to an appropriate specialized center as soon as possible when the diagnosis of cancer is suspected. All such centers in North America are identified on the Children’s Oncology Group website ( and on the National Cancer Institute cancer trials website ( The remarkable increases in cure rates for childhood malignancies since the 1980s would not have occurred without the collective participation of patients and their physicians in clinical research programs at these centers. In the USA, the National Cancer Institute’s Clinical Trials Cooperative Groups Program has been associated with a >80% reduction in the incidence of mortality due to cancer among children <15 yr of age despite an overall increase in cancer incidence during this interval (Fig. 488-1). This remarkable achievement represents the effects of an effective multimodal, multi-institutional, multidisciplinary collaboration.

The most current information on treatment of all types of childhood cancer is available in the PDQ (Physician Data Query) on the National Cancer Institute website (

Diagnosis and Staging

Accurate diagnosis and staging of the extent of disease is imperative, especially for childhood cancers that have high cure rates, because the nature of therapy depends strongly on the type of cancer. In addition, prognostic subgroups based on the stage of disease have been established for most cancers that occur in children. Accordingly, children with a better prognosis are treated with less intensive therapy, including lower doses of chemotherapy or radiation therapy, a shorter duration of treatment, or elimination of at least 1 treatment modality (radiation therapy, chemotherapy, surgery). Accurate staging thus reduces the risk of excessive acute adverse effects and long-term complications of therapy in patients whose prognosis indicates that less therapy is required for cure. Overtreatment of patients with a more favorable prognosis is a definite risk if the patient is not referred to a cancer treatment center for management of adverse effects of such treatment. Conversely, undertreatment also is a clear risk if the diagnosis and stage are not correct, resulting in a compromise of an otherwise high potential for cure.

Diagnostic imaging is a critical phase of evaluation in most children with solid tumors (i.e., cancers other than leukemia). MRI, CT, ultrasonography, scintigraphy (nuclear medicine scans), positron emission tomography (PET), and spectroscopy, as appropriate, all serve a clear purpose in the evaluation of children with cancer, not only before treatment to determine the extent of disease and the appropriate therapy but also during follow-up to determine whether the therapy was effective. In addition, response to treatment as determined by imaging techniques is being increasingly used to guide changes in the therapy.

Expertise in pathology and laboratory medicine provides critical diagnostic support and guides therapy in most children with cancer. Relatively noninvasive methods of obtaining tumor tissue (such as fine needle aspiration and percutaneous image-guided biopsies) can be performed in pediatric centers with appropriate expertise in diagnostic imaging, interventional radiology, cytology, and anesthesia support. Sentinel node mapping is increasingly being applied in the staging of children’s cancers. Determining the adequacy of surgery by evaluating frozen sections of the surgical margins for tumor cells is essential in many tumor operations.

A Multimodal, Multidisciplinary Approach

Many pediatric subspecialties are involved in the evaluation, treatment, and management of children with cancer, including provision of primary therapy and supportive care services (Fig. 488-2). More than 2 of the primary modalities are often used together, with chemotherapy being the most widely used, followed, in order of use, by surgery, radiation therapy, and biologic agent therapy (Fig. 488-3).

The leukemias that occur in childhood usually are managed with chemotherapy alone, with a small proportion of patients receiving cranial or craniospinal radiation therapy to prevent or treat overt central nervous system (CNS) leukemia. Children with non-Hodgkin lymphoma also are treated with chemotherapy alone, with the exception of radiation therapy for CNS involvement. Localized therapy with surgery or irradiation, or both, is an important component of treatment of most solid tumors, including Hodgkin lymphoma, but systemic multiagent chemotherapy usually is necessary because tumor dissemination generally is present even if it is undetectable. Chemotherapy alone usually is not adequate to eradicate gross residual tumors. Hence, it is not unusual for children with malignant tumors to require treatment with all three modalities (see Fig. 488-3). Unfortunately, most treatments that are effective in children with cancer have a narrow therapeutic index (a low ratio of efficacy to toxicity). The acute and chronic adverse effects of these treatments can be minimized but not entirely avoided.

Over the past 15 yr, biologic agent therapy has become an important modality in a few childhood cancers (see Fig. 488-3). This type of treatment generally refers to immunotherapy, biologic response modifiers, or endogenously occurring molecules that have therapeutic effects in supraphysiologic doses. Examples are retinoic acid therapy in acute promyelocytic leukemia, monoclonal antibody therapy for neuroblastoma and certain non-Hodgkin lymphomas, imatinib mesylate for chronic myelogenous and Philadelphia chromosome–positive leukemias, and radioactive metaiodobenzylguanidine therapy for neuroblastoma.

Chemotherapy is used more widely in children than in adults because children better tolerate the acute adverse effects and the malignant diseases that occur in childhood are more responsive to chemotherapy than are malignant diseases of adults. Radiation therapy is used sparingly in children because they are more vulnerable than adults to its late adverse effects.

Whenever possible, treatment is given on an outpatient basis. Children should remain living at home and in school as much as possible throughout treatment. Increasingly, pediatric cancer therapies are being administered to ambulatory patients, with the advent of such innovations as programmable infusion pumps, oral chemotherapeutic regimens, early discharge from hospital with intensive outpatient supportive care, and home health care services. Some patients miss a considerable amount of school in the 1st yr after diagnosis due to the intensity of therapy or its adverse effects and to the ensuing complications of the disease or therapy. Tutoring should be encouraged so that children do not fall behind in their schooling; counseling should be provided as appropriate. In-hospital school services should be provided for patients who must spend much of their time as inpatients receiving therapy for disease or for managing adverse effects.

Development of selective, highly effective therapy for cancer in both children and adults had been hindered by a lack of understanding of the molecular mechanisms that underlie malignant transformation. De novo or acquired resistance to chemotherapy and radiation therapy remains an obstacle to cure. Ongoing discoveries of molecular and cellular mechanisms that explain the cancer process have led to increasingly specific antineoplastic therapies, generally referred to as molecularly targeted therapies. Their most prominent feature is a relative lack of normal tissue toxicity, such that the additional therapeutic benefit occurs with minimum additional toxicity. Many of the new biologic agent therapies, such as imatinib and rituximab, fall into this category (Table 488-1). Complementary and alternative remedies are increasingly being provided by parents to their children with cancer, with or without knowledge of the medical professionals entrusted with the child’s care (Chapter 59). Many of these have not been evaluated by rigorous testing and most are ineffective; some are toxic or interfere with the metabolism of other drugs. Although dramatic advances in the discipline have reduced the empiricism of therapy for cancer, much remains to be discovered.


Imatinib BCR-ABL CML
Philadelphia chromosome positive ALL
PDGFRα Hypereosinophilic syndrome
Systemic mastocytosis
cKIT Systemic mastocytosis
Gastrointestinal stromal tumor
Dasatinib BCR-ABL CML
Philadelphia chromosome-positive ALL
Nilotinib BCR-ABL CML
Philadelphia chromosome-positive ALL
Gefitinib EGFR Non–small cell lung cancer
Erlotinib EGFR Non–small cell lung cancer
Trastuzumab ERBB2/HER-2 Breast cancer
Cetuximab EGFR Non–small cell lung cancer
Squamous cell cancer of head/neck
Bevacizumab VEGFR-1, -2 Non–small cell lung cancer
Breast cancer
Renal cell carcinoma
Colorectal cancer

ALL, acute lymphoblastic leukemia; CML, chronic myelogenous leukemia; CMML, chronic mono myelogenous leukemia.

Discussing the Treatment Plan with the Patient and Family

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