Principles of Adjuvant Therapy in Childhood Cancer

History of Pediatric Oncology

The first demonstration that chemotherapy could be effective therapy for childhood malignancies occurred in 1948 when Farber and Diamond reported temporary remissions in children with acute lymphoblastic leukemia (ALL) when the folic acid antagonist aminopterin was given. Several years later, another folic acid antagonist, methotrexate, produced cures for choriocarcinoma. As additional chemotherapeutic agents were developed, these were combined in multidrug regimens that demonstrated significantly improved response rates and response duration compared with single agents. This was first demonstrated in children with ALL and confirmed in those with Wilms tumor.

The treatment of Wilms tumor also served as a model for the successful use of multimodality therapy. The adjuvant use of vincristine, dactinomycin, and regional radiation therapy after surgical excision produced substantial improvements in cure rates. Similar approaches were adopted for the treatment of rhabdomyosarcoma, Ewing sarcoma, lymphoma, and other solid tumors. Subsequently, the efficacy of chemotherapy in improving survival in patients with nonmetastatic osteosarcoma after operative therapy was demonstrated in a randomized cooperative group trial in which patients who received adjuvant chemotherapy had a 66% disease-free survival, as compared with a 17% disease-free survival in the patients who received surgical intervention alone. This use of adjuvant chemotherapy to control micrometastases has now become standard practice for most solid tumors in children.

Many advances in pediatric oncology have occurred since these early discoveries. Most of them are attributable to the continued collaboration of pediatric oncologists, surgeons, and radiation oncologists within cooperative groups. The Children’s Cancer Group was first funded in 1955, and ultimately four specific cooperative groups addressing children’s malignancies were created. In 2000 the four groups were merged to create the Children’s Oncology Group (COG), which now serves to coordinate large cooperative studies across institutions in the United States and some international sites. This chapter will focus primarily on the nonsurgical modalities that have contributed to the long-standing continuous improvement in outcomes for pediatric patients with malignant disease.

Chemotherapy regimens have evolved within the framework of the comprehensive multimodal approach to treatment. With the development of improved supportive care measures, dose-intensive chemotherapy programs have been successful in improving outcome for patients with Burkitt lymphoma, neuroblastoma, and other advanced-stage solid tumors. Further improvements in outcome and reductions in morbidity have been achieved by altering the schedule of chemotherapy administration, either by alternating effective groups of chemotherapeutic agents to overcome or prevent resistance or by administering agents by continuous infusion rather than bolus. More recently, noncytotoxic biologic therapies have been developed specifically to target biologic pathways. These agents include signal transduction inhibitors, various tissue growth factor receptor inhibitors, antiangiogenesis agents, tumor-targeted antibody therapies, and adoptive immunotherapy techniques. The dramatic improvement in DNA sequencing techniques has brought the concept of personalized medicine closer to reality as individual tumors now can be analyzed for specific mutations that help predict responders and nonresponders to specific agents. Improvements in radiation therapy have included the use of intraoperative radiation therapy, radiosurgery techniques, and proton beam therapy. All of these advances have led to dramatic improvements in survival and quality of life for children with solid tumors.

Epidemiology and Survival Statistics for Childhood Cancer

When compared with the adult incidence rates of cancer, the incidence of cancer in children is very small. However, whereas childhood cancer accounts for only 2% of all reported cancer cases, it accounts for 10% of all deaths among children and is the second leading cause of death after trauma in children aged 1–14 years.

The incidence of pediatric tumors has been relatively flat in the recent past, yet death rates have steadily declined. The death rate for cancers in children under 19 years was 6.5 per 100,000 population in 1970 but fell to 2.2 in 2014, an overall reduction of 66% (68% in children and 60% in adolescents). The 5-year relative survival rate for all cancers combined improved from 58% during the mid-1970s to 83% during 2006–2012 for children and from 68–84% for adolescents ( Table 63.1 ).

The incidence rates for specific cancers vary by age, gender, and race. Overall, the annual incidence rate for all types of childhood cancer is 16.2 per 100,000 children younger than age 15 years and 17.8 for those under 19 years. There is a bimodal distribution of pediatric tumors with a peak incidence before the age of 2 years and a second peak in adolescents and young adults. Before the age of 2 years, central nervous system (CNS) malignancies, neuroblastoma, acute myeloid leukemia (AML), Wilms tumor, and retinoblastoma account for the majority of diagnoses. Between ages 2 and 4 years, ALL is the most common childhood cancer. After age 9 years, the incidence of Hodgkin lymphoma, osteosarcoma, and Ewing sarcoma begins to increase sharply.

Importance of Pathology of Childhood Tumors in Selecting Chemotherapy

Unlike adult malignancies, which are primarily carcinomas, fewer than 10% of solid tumors of childhood are epithelial malignancies. Although the spectrum of malignancies in childhood is more limited than in adults, the exact diagnosis is often more difficult because of the prevalence of small round blue cell tumors in childhood. These very primitive or embryonal malignancies often lack morphologically distinguishing characteristics. As a result, Ewing sarcoma, neuroblastoma, lymphoma, small cell osteosarcoma, and primitive neuroectodermal tumors may appear quite similar by light microscopy. An error in diagnosis of Ewing sarcoma in a patient who actually has a lymphoma of bone would lead to vastly different therapy and a poor outcome.

The exact diagnosis in pediatric cancer patients is crucial because chemotherapy for childhood malignancies is carefully tailored to each specific tumor type. This has become even more important over the past two decades as pediatric oncologists have continued to define the prognostic subgroups for many tumors that help dictate the best therapy and the dose intensity of the therapy required for cure. Whereas the survival rate for patients with stages 1–3 Wilms tumor with favorable histology is more than 90%, with standard therapy consisting of surgery, vincristine and actinomycin, with or without doxorubicin and radiation, a diagnosis of Wilms tumor with diffuse anaplasia carries a far worse prognosis and requires more intensive therapy for cure.

The initial step in the accurate diagnosis of a tumor is the availability of adequate material with which to make the diagnosis. Therefore, it is crucial that during the initial surgical procedure, whether it is a biopsy or resection, an adequate quantity and quality of tissue is obtained. The amount of tissue required for diagnostic purposes should be discussed with the surgeon, pathologist, and pediatric oncologist before the procedure to ensure the proper handling of the specimen (e.g., the need for fresh tissue, frozen samples, and fixed specimens for histologic and biologic diagnostic use). Whereas light microscopy remains the primary tool of pathologists, they can now rely also on immunohistology, electron microscopy, DNA content of tumor, cytogenetic abnormalities, and specific tumor gene expression to establish a diagnosis.

Tumor Biology: Understanding Childhood Cancer and Treatment Principles

Cancer is a genetic event. Genetic alterations within a single cell that result in the activation of an oncogene or the loss of a tumor suppressor gene can lead to the accumulation of cells lacking the ability to respond to growth-regulating signals and the subsequent development of cancer. The advent of more sophisticated tumor sequencing techniques now allows for identification of very specific genetic alterations that result in focal defects in the cellular physiology of the tumor tissue. Understanding the specific characteristics of an individual tumor provides information that helps dictate treatment regimens and patient-specific toxicities. As this capability continues to evolve, tumors will be treated based on genetic analysis of a specific patient’s tumor rather than by generalized protocols for a generic tumor type.

Cancer Cytogenetics

The association of a consistent chromosomal aberration with a specific cancer was first made in 1960 with the discovery of the minute “Philadelphia chromosome” (9;22)(q34;q11) in chronic myeloid leukemia (CML). With the discovery of chromosomal banding techniques in the 1970s, cancer cytogeneticists were first able to identify sub-chromosomal deletions, inversions, and translocations occurring in cancer cells. Study of these aberrant regions led to the identification of oncogenes and tumor suppressor genes, a process that is continuing today.

The presence of consistent cytogenetic abnormalities associated with a specific childhood leukemia or solid tumor helps in both cancer diagnosis and assignment of prognosis. Specific cytogenetic aberrations have been identified in rhabdomyosarcoma, Ewing sarcoma, synovial sarcoma, germ cell tumors, medulloblastomas, neuroblastomas, retinoblastomas, and Wilms tumors. Chromosomal aberrations can help predict prognosis. The finding of a chromosome 1q deletion, the presence of double minute chromatin bodies, or the presence of homogeneous staining regions in neuroblastoma confers a poor prognosis. The treatment of Wilms tumor is based on risk stratification determined by multiple tumor characteristics that impact prognosis. The finding that a copy number gain of 1q in favorable-histology Wilms tumor is associated with a worse prognosis allows one to potentially tailor therapy to be more aggressive for this subset of patients.

The techniques available to analyze the genetic composition of tumors have dramatically changed over the past two decades. Newer laboratory methods allow for significantly more information about a specific tumor to be obtained faster and cheaper than in the past. This capability has led to a rapidly expanding array of genetic data on individual tumors that not only improves the understanding of the tumor type in general but also allows for specific therapeutic decisions to be made based on individual tumor gene alterations. A comprehensive review of progress in the understanding of the genetic underpinnings of oncologic disease is beyond the scope of this chapter, but recent reviews provide extensive insights into this important and rapidly changing field.

Chemotherapy Principles in Pediatric Oncology

The goal of cytotoxic chemotherapy treatment for childhood malignancy is to maximize tumor kill while maintaining acceptable side effects. Clinical trials have led to the development of standard combination chemotherapy regimens for most childhood cancers. Adjuvant therapy (after local control measures) has remained the mainstay of cancer therapy, but neoadjuvant chemotherapy (before definitive local control measures) has proved to be effective in patients with metastatic disease and to begin to control microscopic metastatic disease immediately in patients with localized tumors.

In the clinical development of promising anticancer agents, phase I clinical trials are designed as dose-escalation studies to determine the maximally tolerated dose of a new drug. Phase II studies explore the efficacy of a drug to establish the spectrum of activity of the agent. Phase III trials use a prospective randomized control design to compare established effective chemotherapy combinations to new treatment regimens.

Combination chemotherapy remains the mainstay of the medical treatment of childhood cancer. In the 1960s the benefit of combining several drugs together was demonstrated first for ALL. Complete remission by using single agents could be expected in only about half of the patients, whereas the combination of four or five drugs produced remission rates of more than 95%.

The principle of designing combination chemotherapy regimens by using non-cross-resistant agents with nonoverlapping toxicities has been successfully used for childhood solid tumor treatment for the past 25 years. The improvement in survival rates over this period for neuroblastoma, Ewing sarcoma, anaplastic Wilms tumor, and osteosarcoma can be directly linked to effective combination chemotherapy treatment.

Adjuvant and Neoadjuvant Chemotherapy

The use of adjuvant chemotherapy is supported by the finding that fewer than 20% of sarcoma and lymphoma patients with initially nonmetastatic solid tumors can be cured by resection or radiation therapy alone, or in combination. In the majority of these patients, recurrence is at a distant site, lending strong support to the hypothesis that micrometastatic disease exists at the time of presentation for the majority of patients with clinically nonmetastatic disease. In Wilms tumor, as many as 40% of patients can be cured with resection or radiation therapy alone. However, survival can be increased to 90% with the addition of adjuvant combination chemotherapy.

Because the goal of adjuvant chemotherapy is to prevent the appearance of metastatic disease, it is vital that chemotherapy begins as soon as possible after local control measures are completed. For this reason, most current chemotherapy regimens for childhood solid tumors recommend that chemotherapy is given within 2 weeks of initial surgical treatment. One approach to prevent delays in instituting chemotherapy in patients with nonmetastatic disease is to delay resection until after several courses of neoadjuvant chemotherapy can be administered following a biopsy of the tumor for diagnosis. Chemotherapy can begin as soon as the diagnosis is established at a time when the distant tumor burden is at its lowest. This approach has become standard in the treatment of Ewing sarcoma and osteosarcoma, and has the theoretical advantage of minimizing the development of chemotherapy resistance. Furthermore, delayed surgical intervention may allow a more complete or less morbid resection and pathologic assessment of tumor responsiveness to the chemotherapy agents on an individual patient basis.

Diagnostic biopsy followed by neoadjuvant chemotherapy and delayed resection of the primary tumor for complex neuroblastoma reduces the operative complication rate without compromising survival. Treating these tumors on the front end with chemotherapy reduces intraoperative blood loss and the need for nephrectomy. However, neoadjuvant chemotherapy is beneficial only for tumors for which a known highly effective combination chemotherapy program limits the risk of tumor progression at the primary site prior to surgery.

Chemotherapy Dose Intensity

To develop an effective combination chemotherapy program, it is important to select not only the correct combination of agents but also the correct dose of each agent. The trend for the past 10 years in pediatric oncology has been to increase chemotherapy dose intensity, with the goal of maximizing efficacy. In designing dose-intensive programs, the individual toxicities of the agents to be intensified must be considered. The best agents to use in high doses are those with limited organ toxicity and whose toxicity profile is mainly hematologic.

Most chemotherapeutic agents have a sigmoidal dose-response curve with a steep linear phase followed by a plateau phase. The principle of chemotherapy dose intensity is to administer the maximal tolerated dose of the agent that falls within the linear phase of the dose-response curve in the shortest possible interval while maintaining tolerable toxicity. Dose intensity is defined as the amount of drug delivered per unit time, expressed as milligrams per square meter per week. Therefore, dose intensity can be increased by giving higher doses of a chemotherapeutic agent or giving the agent more frequently (or both).

It has been demonstrated in animal systems that a 2-fold increase in administered cyclophosphamide dose can lead to a 10-fold increase in tumor cell kill, whereas a decrease in dose intensity of as little as 20% in an osteosarcoma animal model can decrease the cure rate by 50%. Similar clinical observations have been made in childhood leukemia and osteosarcoma. A prospective clinical trial of high-risk ALL patients revealed that patients receiving less than 94% of the planned dose of chemotherapy during the intensive portion of therapy had a 5.5-fold increased risk of relapse. In osteosarcoma patients, those who received less than 80% of the proposed chemotherapy doses had a 3-fold increased risk of relapse.

The positive impact of increasing the dose intensity on improving the response rate and survival duration has been demonstrated for Burkitt lymphoma, osteosarcoma, Ewing sarcoma, testicular cancer, breast cancer, and advanced ovarian cancer. This finding has had a significant impact on the design of clinical trials for childhood solid tumors.

For many years, efforts have focused on identifying the most effective agents to intensify, followed by maximizing the supportive care to allow dose escalation. Increasing the dose intensity of active chemotherapy agents in pediatric clinical trials has been possible because of recent advances in supportive care to decrease or minimize the toxic effects on normal tissues that occur from higher dose chemotherapy. The use of cytokines to speed recovery of white blood cells and platelets (granulocyte colony-stimulating factor [G-CSF] and interleukin-11 [IL-11]), and the use of cardioprotectant agents to allow a higher cumulative dose of doxorubicin, are examples of the use of ancillary approaches to minimize toxicities in order to permit dose-intensive therapy for solid tumors.

Many pediatric studies have demonstrated that collection of peripheral blood progenitor cells (PBPCs) from children as small as 10 kg is feasible. The infusion of PBPCs has been effective in engrafting pediatric patients after myeloablative chemoradiotherapy. In myeloablative therapy, “supralethal” doses of chemotherapy are given, and hematopoietic recovery will occur only if a stem cell source (either PBPCs or bone marrow) is infused into the patient after completion of the myeloablative regimen. The feasibility of repetitive collection, storage, and infusion of PBPCs for use with multiple-cycle dose-intensive chemotherapy in newly diagnosed neuroblastoma patients has been demonstrated in a Children’s Cancer Group study.

Myeloablative chemotherapy regimens with or without total body irradiation as preparation for autologous stem cell transplant have been demonstrated to be an effective method of dose-intensive consolidation treatment after induction therapy in high-risk neuroblastoma. In a randomized COG trial, high-risk neuroblastoma patients who received an autologous bone marrow transplant had an improved 3-year event-free survival compared with patients who proceeded to consolidation chemotherapy alone. Given the success of increasing chemotherapy dose intensity by using a single myeloablative transplant in high-risk neuroblastoma, studies looking at two or even three consolidative stem cell transplants have demonstrated improved event-free survival. Current high-risk neuroblastoma patients are now treated with high-dose chemotherapy, radiation, and successive PBSC transplants, followed by immunotherapy.

Chemotherapeutic Agents

The rational design of combination chemotherapy programs requires an understanding of the mechanism of action, the site of metabolism, the rate of drug clearance, and the toxicity profile for each drug. Most chemotherapy agents work by interfering with DNA or RNA synthesis, transcription, or repair. Unfortunately, these agents are not selective for cancer cells. The same metabolic pathways are disrupted in normal cells, leading to the toxic effects observed with chemotherapy.

Chemotherapeutic agents can be divided into classes by their mechanism of action. The classes of agents include alkylating agents (cisplatin and its analogs), antimetabolites, topoisomerase inhibitors, antimicrotubule agents, differentiation agents, miscellaneous nonclassified agents, and biologic agents. Understanding the individual mechanisms of action helps in the design of drug combinations with additive or synergistic antitumor effects. The most common agents from each class, their mechanism of action, common side effects, and tumors in which they are active are listed in Table 63.2 .