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).

Figure 488-2 Multidisciplinary care of children with cancer. The inner circle designates primary modalities, and the outer ring identifies supportive care elements to which all children with cancer have access.

Figure 488-3 The primary modalities of therapy used in the treatment of children with cancer. The relative sizes of the circles designate the approximate proportion of overall role in the management of pediatric cancers.

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.

Table 488-1 PROTEIN TYROSINE KINASE INHIBITORS AND MONOCLONAL ANTIBODIES

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

Discussing the Treatment Plan with the Patient and Family

The diagnostic and treatment plan must be carefully explained to parents and, if the child is old enough to understand, to the patient. An honest discussion of the facts is the best policy. Children should be given as much information as they can understand and would find useful or that they express a desire or wish to know. Effects of treatment, such as the possible need to amputate a limb, loss of hair during chemotherapy, and possible temporary or permanent functional impairment must be anticipated and fully discussed. The possibility and probability of death from cancer should be covered in an age-appropriate manner. It usually is necessary to repeat explanations several times before distraught family members fully understand. Throughout treatment, parents, patients, siblings, and medical staff will need help in expressing feelings of anxiety, depression, guilt, and anger. Experienced professionals, including pediatric social workers, child psychologists and psychiatrists, child life specialists, and schoolteachers with special expertise in managing students with cancer should be called on by the pediatrician, pediatric oncologist, and nurses to assist when needed.

Treatment

Chemotherapy

The most widely used modality in pediatric cancer therapy is chemotherapy (see Fig. 488-3). Therapy nearly always involves combinations of drugs, such as VAC (vincristine, dactinomycin [Actinomycin D], and cyclophosphamide) and CHOP (cyclophosphamide, doxorubicin [Adriamycin], vincristine [Oncovin], and prednisone). Historically, sequential single-drug therapy rarely resulted in complete responses, and partial responses usually were infrequent and transient and grew progressively shorter in duration with each drug used. Combination chemotherapy became the standard when combinations of drugs with different mechanisms of action and nonoverlapping toxicities (e.g., POMP [mercaptopurine, vincristine (Oncovin), methotrexate, and prednisone], VAMP [vincristine, doxorubicin (Adriamycin), methotrexate, and prednisone], and MOPP [nitrogen mustard, vincristine (Oncovin), prednisone, and procarbazine] were first demonstrated to be effective in childhood leukemia. Most of the cytotoxic drugs for childhood cancer are selected from several classes of agents, including alkylating agents, antimetabolites, antibiotics, hormones, plant alkaloids, and topoisomerase inhibitors (Table 488-2). The increased metabolic and cell cycle activity of malignant cells makes them more susceptible to the cytotoxic effects of these types of agents (Fig. 488-4).

Table 488-2 COMMON CHEMOTHERAPEUTIC AGENTS USED IN CHILDREN

Figure 488-4 Site of action of the commonly used anticancer drugs. CMP, cytidine monophosphate; dCMP, deoxycytidine monophosphate; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; FH₂, dihydrofolate; FH₄, tetrahydrofolate.

(Redrawn from Balis FM, Holcenberg JS, Blaney SM: General principles of chemotherapy. In Pizzo PA, Poplack DG, editors: Principles and practice of pediatric oncology, ed 4, Philadelphia, 2002, Lippincott Williams & Wilkins, p 241.)

Because most antineoplastic agents are cell cycle dependent, their adverse effects usually are related to the proliferation kinetics of individual cell populations. Most susceptible are tissues or organs with high rates of cell turnover: bone marrow, oral and intestinal mucosa, epidermis, liver, and spermatogonia. The most common acute adverse effects are myelosuppression (with neutropenia and thrombocytopenia being the most problematic), immunosuppression, nausea and vomiting, hepatic dysfunction, upper and lower gastrointestinal mucositis, dermatitis, and alopecia. Fortunately, the tissues affected also recover relatively quickly, so that the acute adverse effects are nearly always reversible. Life-threatening effects of many chemotherapy agents include severe neutropenia with infection, fungemia or fungal pneumonia due to immunosuppression, and septicemia, not infrequently linked to indwelling intravascular devices (Table 488-3; Chapters 171 and 172). Cardiomyopathy caused by anthracyclines (e.g., doxorubicin and daunorubicin) and renal failure from platinum-containing agents also may be life threatening or disabling.

Table 488-3 INFECTIOUS COMPLICATIONS OF MALIGNANCY

Least susceptible to chemotherapy and radiation therapy are cells that do not replicate or that replicate slowly, such as neurons, muscle cells, connective tissue, and bone. However, children are not exempt from toxicities of these tissues, probably because they are still undergoing proliferation, albeit at a slower pace than other tissues, during growth and growth spurts.

Physically, children can endure the acute adverse effects of chemotherapy better than adults can in many ways. The maximum tolerated dosage in children, when expressed on the basis of body surface area or body weight, commonly is greater than that in adults. A comparison of anticancer drugs tested in phase I trials in both adult and pediatric patients showed that the maximum tolerated dosage in children was greater than that in adults for 70% of the agents, equal to that in adults for 15% of the agents, and less than the adult dose for only 15% of the agents. For all the drugs that were compared, the mean pediatric maximum tolerated dosage was greater than the adult mean.

Evolving treatment approaches that have not reached general clinical application in children are specific tumor-directed therapies such as tumor antigen–specific monoclonal antibodies, tumor vaccines, antisense DNA and RNA transcripts, and antiangiogenic agents.

Acute Toxic Effects and Supportive Care

Adverse treatment effects that occur early in therapy can result in oncologic emergencies. These include metabolic disorders, bone marrow suppression, and compression by tumors on vital structures (Table 488-4). In tumor lysis syndrome (TLS), uric acid, phosphates, and potassium are released in the circulation in large quantities from death of tumor cells. Hyperuricemia can lead to impairment of renal function, which further exacerbates the metabolic abnormalities. TLS can occur before therapy in patients with large tumor burden (e.g., Burkitt lymphoma, lymphoblastic lymphoma, and high white blood cell count leukemia) but is usually seen within 12-48 hours of initiating chemotherapy. TLS is infrequently reported in other tumors (Hodgkin lymphoma, neuroblastoma, hepatoblastoma). Before therapy is initiated, the serum levels of uric acid, electrolytes, calcium, phosphorus, and creatinine should be measured and adequate hydration ensured. Allopurinol (a xanthine oxidase inhibitor) should be started to prevent further accumulation of uric acid. In patients with established TLS with high uric acid levels or those at high risk for TLS, rasburicase (an enzyme that degrades uric acid) should be given instead of allopurinol. Symptomatic hyperkalemia and hyperphosphatemia with subsequent hypocalcemia can develop in the setting of inadequate renal function.

Virtually all chemotherapy regimens can produce myelosuppression, as can malignancies that invade and replace bone marrow. Anemia can be corrected by transfusions of packed erythrocytes, and thrombocytopenia can be corrected by platelet infusions. Patients receiving immunosuppressive therapy should receive irradiated blood products to prevent graft versus host disease and leukoreduced blood products to prevent transfusion-associated reactions and infections. Neutropenia (neutrophil counts <500/mm³) poses a risk of life-threatening infection. Febrile neutroopenic patients should be hospitalized and treated with empiric broad-spectrum intravenous antimicrobial therapy pending the results of appropriate cultures of blood, urine, or any obvious sites of infection (Chapter 171). Treatment is continued until fever resolves and the neutrophil count rises. If fever persists for >3-5 days while the patient is receiving broad-spectrum antibiotics, the possibility of fungal infection must be considered. Fungal infections caused by Candida and Aspergillus are common in immunosuppressed patients. Opportunistic organisms such as Pneumocystis jiroveci can produce fatal pneumonia. Prophylactic treatment with trimethoprim-sulfamethoxazole is given when severe or prolonged immunosuppression is anticipated.

Viruses of low pathogenicity can produce serious disease in the setting of immunosuppression caused by malignancy or its treatment. Patients should not be given live virus vaccines. Children who are receiving chemotherapy and who are exposed to chickenpox should receive varicella-zoster immunoglobulin (VZIG) or, if VZIG is not available, oral acyclovir should be considered. If clinical disease develops, the child should be hospitalized and treated with intravenous acyclovir.

Adequate pain management is critical. The World Health Organization (WHO) guidelines are particularly useful in the management of pain associated with cancer and cancer therapy (Chapter 71).

Depending on the type of cancer therapy, patients can lose >10% of body weight. Patients sometimes reduce their food intake because of temporary, treatment-associated nausea, stomatitis, and vomiting. Appetite loss is not a cause for alarm. Malnutrition is a particular risk in patients receiving radiation therapy involving the abdomen or the head and neck, intensive chemotherapy, or total body irradiation and high-dose chemotherapy before marrow transplantation. If oral supplementation proves inadequate, such patients can require enteral tube feedings or parenteral hyperalimentation.

Late Adverse Effects

Injury to tissues with low repair potential often results in long-lasting or permanent deficit. These effects can be either from the tumor or its treatment. For example, a brain or spinal tumor can leave the child with a permanent paresis or autonomic dysfunction, anthracycline-induced cardiomyopathy usually produces refractory cardiac dysfunction, and the leukoencephalopathy caused by intrathecal methotrexate and by CNS radiation therapy often is only partially reversible. The potential types of late adverse effects depend on the child’s age at the time of treatment, the location(s) of the cancer, and the therapy administered. A good resource for the pediatrician, patient, and family who have to anticipate the possibilities is available at www.survivorshipguidelines.org.

Late adverse effects of therapy can cause substantial morbidity (Table 488-5). Successful surgical resection can result in loss of important functional structures. Irradiation can produce irreversible organ damage, with symptoms and functional limitations depending on the organ involved and the severity of the damage. Many problems related to radiation therapy do not become obvious until the patient is fully grown, such as asymmetry between irradiated and nonirradiated areas or extremities. Irradiation of fields that include endocrine organs can cause hypothyroidism, pituitary dysfunction, or infertility. In sufficient doses, cranial irradiation can produce neurologic dysfunction and spinal irradiation can produce growth retardation.

Chemotherapy also carries the risk of long-lasting organ damage. Of particular concern are leukoencephalopathy after high-dose methotrexate therapy; infertility in male patients treated with alkylating agents (e.g., cyclophosphamide); myocardial damage caused by anthracyclines; pulmonary fibrosis caused by bleomycin; renal dysfunction due to ifosfamide, nitrosourea, or platinum agents; and hearing loss from cisplatin. Development of these sequelae may be dose-related and usually is irreversible. Appropriate baseline and intermittent testing should be performed before these drugs are administered to ensure that there is no pre-existing damage to the organs likely to be affected and to permit monitoring of the adverse effects of treatment-induced changes.

Perhaps the most serious late adverse effect is the occurrence of second cancers in patients successfully cured of a first malignancy. The risk appears to be cumulative, increasing by about 0.5% per year, resulting in approximately a 12% incidence at 25 yr after treatment. Patients who have been treated for childhood cancer should be examined annually, with particular attention to possible late adverse effects of therapy, including second malignancies (Fig. 488-5).

Figure 488-5 Proposed risk-stratified shared care model for childhood cancer survivors. Solid line denotes primary responsibility for risk-based care; risk stratification based upon determination of the long-term follow-up staff. CA, cancer; DX, diagnosis; Onc, Oncologist; PCP, primary care provider; RX, therapy.

(Adapted from Oeffinger KC, McCabe MS. Models for delivering survivorship care, J Clin Oncol 24(32):5119, 2006; with permission from the American Society of Clinical Oncology.) (From Oeffinger KC, Nathan PC, Kremer LCM: Challenges after curative treatment for childhood cancer and long-term follow up of survivors, Pediatr Clin North Am 55:251–273, 2008.)

Palliative Care

At all stages of caring for children with cancer, principles of palliative care should be applied to relieve pain and suffering and to provide comfort (Chapter 40). Pain is a serious cause of suffering among patients with cancer. It may be the result of organ obstruction or compression or bone metastasis, or it may be neuropathic. Pain should be managed in a stepwise manner, as recommended by the WHO, in accordance with the principles of selecting the appropriate analgesic, prescribing the appropriate dosage, administering the drug by the appropriate route, and choosing an appropriate dosing schedule to prevent persistent pain and to relieve breakthrough pain (Chapter 71). In addition, the dosage should be titrated aggressively while attempts are made to prevent, anticipate, and manage side effects. Adjuvant drugs and sequential trials of analgesic drugs should be considered.

The goals in the care of dying patients are to avoid distress for the patient, family, and caregivers; to provide care consistent with the patient’s and family’s wishes; and to comply with and advocate for clinical, cultural, and ethical standards.