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p. 1999

Micrometastases are present in most solid tumors at the time of

diagnosis. Neoadjuvant therapy was designed to treat micrometastatic

disease before surgery, in hopes of increasing survival. Although it is not

clear whether neoadjuvant therapy increases survival, residual viable

tumor serves as a marker of response to chemotherapy, and

neoadjuvant therapy may reduce tumor size to allow more surgical

options in the patient.

Case 95-3 (Question 1)

When monitoring therapy in children, one has to remember the agerelated differences in measured parameters and large differences in

size. Blood pressures are lower and heart rates and respirations are

higher in younger children. Intake and output need to be considered in

relationship to the patient’s size.

Case 95-1 (Question 3)

It is important to adjust creatinine clearance measurements or estimates

to adult size (i.e., per 1.73 m

2

) to correctly adjust drug doses for renal

function in children.

Case 95-1 (Question 4)

Infants have larger body surface area–weight ratios than older children.

Further, organ function changes rapidly during the first year of life.

Therefore, chemotherapy dosing guidelines in protocols generally

specify how to calculate doses for smaller children and infants (i.e.,

converting to mg/kg dosing from mg/m

2

, or halving doses).

Case 95-2 (Question 2)

Leucovorin, when used with methotrexate, reduces methotrexate-related

toxicities to rapidly proliferating cells. In treating children with high-dose

methotrexate and leucovorin rescue, serum methotrexate concentrations

are measured so that leucovorin will be discontinued at the correct time.

Renal dysfunction, fluid accumulation in the patient, or drug interactions

can slow methotrexate excretion and require prolonged leucovorin

rescue.

Case 95-3 (Questions 3, 4)

Rhabdomyosarcoma is a soft tissue tumor of skeletal muscle origin, and

it is the most common soft tissue sarcoma of childhood, occurring in 3%

of all children with cancer. The two most common histologic types in

children are embryonal and alveolar. Using the combination of

vincristine, dactinomycin, and cyclophosphamide with local control of

surgery or radiation, it is associated with an approximate 75% failurefree survival for patients with non-metastatic disease.

Case 95-4 (Question 1)

Acute lymphoblastic leukemia (ALL) involves replacement of normal

bone marrow elements because of abnormalities in cellular proliferation.

Signs and symptoms relate to the deficiency in normal bone marrow

elements.

Case 95-5 (Question 1)

Important prognostic variables in ALL are based on clinical and

laboratory findings, including age and white blood cells at diagnosis, sex,

race, immunologic classification, cytogenetics, and early treatment

response/minimal residual disease.

Case 95-5 (Question 1)

The treatment of ALL is divided into phases, including remission

induction therapy, central nervous system (CNS) preventive therapy,

consolidation/intensification phases, and maintenance therapy. All

phases are different, each using multiple agents, schedules, and toxicity.

Case 95-5 (Questions 3, 5, 6,

10–12)

p. 2000

p. 2001

Induction treatment is a combination of systemic and intrathecal

chemotherapy that is administered to induce a complete remission.

Given disease-induced morbidity and treatment-related complications,

this early phase of therapy can be associated with considerable

complications.

Case 95-5 (Questions 2, 3)

Central nervous system preventive therapy is a key component of ALL

treatment. Contemporary treatment/preventive regimens are composed

of intrathecal administration of antimetabolite chemotherapy. Central

nervous system radiation is reserved for specialsituations.

Case 95-5 (Questions 4, 5, 7,

8)

The post-induction phase consists of intensified chemotherapy

treatments that are tailored to the specific type of leukemia and the

patient’s response to prior induction therapy.

Case 95-5 (Question 9),

Case 95-6 (Question 4)

Maintenance therapy is the longest phase of ALL treatment and consists

mainly of oral antimetabolite therapy that is less myelosuppressive than

therapies given during the consolidation/intensification phase. Because

of its prolonged length and low disease-related morbidity, this phase is

associated with the highest rates of noncompliance.

Case 95-5 (Questions 10–12)

Patients with relapsed ALL will often achieve a second remission of

their disease but have a high likelihood of further relapses. Various

approaches including intensified chemotherapy or stem cell

transplantation have been used in the treatment of relapse.

Case 95-6 (Questions 1–3)

Non-Hodgkin lymphoma accounts for 10% of childhood cancers. It has

a cure rate of more than 80%. It often presents as a mass in the

mediastinum or as pleural effusions. Masses may be large; therefore,

adjunctive therapies to prevent tumor lysis syndrome and nephropathy

are necessary.

Case 95-7 (Question 1)

PEDIATRIC MALIGNANCIES

In the United States, cancer is the leading cause of disease-related death for children

between 1 and 14 years of age.

1 However, 5-year survival rates for children

diagnosed with many common cancers have improved to greater than 80% because of

the advent of chemotherapy. Approximately 10,270 new malignancies are expected to

occur in children in the year 2017. Acute leukemias are the most common

malignancies of childhood (Table 95-1), and the solid tumors discussed in this

chapter represent 2.5% to 7.0% of all childhood malignancies.

1 Many common

pediatric solid tumors are uncommon in adults. Likewise, many tumors common in

adults occur infrequently in children. In general, sarcomas and embryonal tumors are

common in children, whereas carcinomas predominate in adults.

Small Round Cell Malignancies

Several pediatric malignancies present similarly to one another as small round cells,

making morphologic diagnosis by traditional light microscopy difficult. The less

typical forms of these diseases, such as peripheral primitive neuroectodermal tumors,

extraosseous Ewing sarcoma, extranodal lymphoma, rhabdomyosarcoma, metastatic

neuroblastoma, and some bone sarcomas, are even more challenging.

2 Therefore,

newer techniques aimed at detecting tumor-specific antigens or chromosomal

aberrations have been developed. This information may prove useful in identifying

prognostic subgroups and tumor types in children and adults with cancer. For

example, identification of the t(11;22) chromosomal translocation in both peripheral

primitive neuroectodermal tumors and Ewing sarcomas has resulted in the

classification of both into the Ewing sarcoma family of tumors.

Genetics

Table 95-1

Relative Incidence of Malignancies in Children 0 to 14 Years of Age

1

Malignancy Relative Incidence (%)

Acute lymphoblastic leukemia 26

Central nervous system 21

Neuroblastoma 7

Non-Hodgkin lymphoma 6

Wilms tumor 5

Acute myeloid leukemia 5

Hodgkin lymphoma 4

Rhabdomyosarcoma 3

Retinoblastoma 3

Osteosarcoma 2.5

Ewing sarcoma 1.5

Other histologic types 20

Similar to adult cancers, the association of many pediatric cancers with chromosomal

aberrations or genetic defects is well confirmed. Examples include the association of

Wilms tumor with congenital malformations, acute leukemias with Down syndrome,

and the association of some pediatric cancers with loss of the p53 or retinoblastoma

tumor suppressor genes.

2–4

Carcinogens

The role of carcinogens in pediatric cancer is probably less prominent than in adults

because of the long latency periods

p. 2001

p. 2002

required. Carcinogens, however, are implicated in the etiology of some childhood

cancers.

5 Postnatal exposure to ionizing radiation is associated with increased risks

for acute leukemias, chronic myelogenous leukemia, and solid tumors such as brain,

thyroid, bone, and other sarcomas. Treatment of pediatric malignancies with

alkylators or topoisomerase II inhibitors such as etoposide or doxorubicin is

associated with an increased risk of acute leukemias. Treatment of childhood acute

lymphoblastic leukemia (ALL), especially in those younger than 5 years of age who

received radiation, results in an increased risk of central nervous system (CNS)

neoplasms, leukemia, lymphoma, and other neoplasms later in life. The only welldocumented prenatal carcinogen is diethylstilbestrol, which is associated with an

increased risk of vaginal or cervical cancer in offspring.

6

Patient Age

Patient age can be a factor in pediatric cancer prognoses and their treatments.

Neuroblastoma is the most common malignancy in infants; however, an infant’s

prognosis is typically better than a child’s, which is attributed to the biology of the

disease in this age group.

7

In contrast, infants with ALL tend to have a worse

prognosis than children. The biology and location of rhabdomyosarcomas are often

different in younger versus older children, with younger children having better

overall survival.

8

Age may also be associated with treatment-related toxicity. Children may have

higher susceptibility to radiation-related toxicity than adults. Normal organ

development may be disrupted; the skeletal system and, in children younger than 4

years of age, the brain are particularly susceptible.

7 Prepubertal girls may have a

decreased risk of fertility problems from chemotherapy and, conversely, children

appear to have a greater risk for anthracycline cardiovascular toxicity than adults.

9,10

Treatment of adolescents and young adults has become an interesting issue in

recent years.

11 Because of various referral practices, several of the malignancies that

are most common in this age group (acute leukemias, lymphomas, sarcomas) are

treated by both adult and pediatric oncologists. Historically, this has divided the

available patient data for this population; thus, minimal new treatment-related

information is published. Outcomes for adolescent and young adult patients have not

improved as much in the last 30 years as for either younger or older patients. This

age group has generally had better results when treated on pediatric protocols; the

reasons are not clear, although suggestions have been made that pediatric protocols

are more aggressive, pediatric oncologists are less likely to reduce doses for

toxicity, biology is at higher risk, and fewer data are available on how to determine

appropriate dosages in adolescents and young adults. This dilemma has led to the

Children’s Oncology Group (COG) (described in the next paragraph) and adult

cooperative groups joining together on investigational protocols to pool data

collected from this population so that more meaningful conclusions might be drawn.

Multi-Institutional Research Groups

With the exception of a few pediatric oncology centers, most treatment centers do not

have sufficient numbers of patients with specific diagnoses to scientifically establish

the efficacy of therapeutic regimens within a reasonable time frame. Thus, most

pediatric centers join the COG, the largest pediatric multi-institutional research

group in the United States, Canada, Australia, and New Zealand. Through this

mechanism, clinical trials often can be finished in 3 to 4 years, allowing for more

rapid progress in the treatment of pediatric cancers. The majority of pediatric

hematology and oncology patients in the United States are either treated on a COG

protocol or treated based on the standard treatment arm of a current protocol. There

are also trials available through smaller consortia that specialize in early phase

clinical trials or pilot studies. Unlike the more common adult cancers, few alternative

chemotherapy regimens are available for pediatric malignancies. With the number of

childhood cancer survivors increasing, research is focusing on reducing the longterm risks and complications of treatment modalities. It is important to determine

which patients are at greatest risk from their cancer and to stratify treatments

according to prognoses. Ideally, the minimal treatment needed to produce cure would

be given when the prognoses are good. On the other extreme, maximal treatment

would be given when the prognoses are poor, and potential benefits outweigh the

treatment-associated risks. Progress is already being made in this direction, and the

future holds promise, especially with rapid gains in our understanding of the biology

of cancers.

Late Effects

Late effects can be described as toxicities or complications that either persist or

occur after therapy is finished. Most of the early data on late effects are from adult

Hodgkin lymphoma patients or from children with cancer. Both groups receive

aggressive therapy and often live for years or decades after treatment. Examples of

late effects include joint or bone problems, heart failure, second malignancies,

strokes, and cognitive dysfunction.

12 A group of pediatric institutions have been

collecting data on thousands of pediatric cancer survivors and a sample of their

siblings, comparing the health problems of the two groups. This study is known as the

Childhood Cancer Survivor Study. In 2006, Oeffinger reported data from the study

showing that more than 60% of the survivors had at least one chronic medical

problem, and 27% had a severe or life-threatening health problem.

12 The overall

relative risk of a health problem compared to siblings was 3.3-fold, with specific

risks as high as 54-fold for joint replacements and 15-fold for heart failure. This type

of knowledge has reemphasized the need for clinicians to limit therapies for low-risk

patients and thus reduce late effects and enhance quality of life for survivors. A

website hosted by St. Jude Children’s Research Hospital contains a listing of all

published studies from the Childhood Cancer Survivor Study

(www.stjude.org/ccss). A CureSearch and Children’s Oncology Group–sponsored

website (www.survivorshipguidelines.org) contains an extensive set of guidelines

for the screening and management of childhood cancer survivors. An important

recommendation relating to care of cancer survivors is to ensure that they have a

record of their treatments that they can keep and provide to their health care

providers for the remainder of their lives.

13 This will enable the health care

providers to use publications and guidelines that might help the survivor’s care.

PEDIATRIC SOLID TUMORS

Neuroblastoma

DESCRIPTION, INCIDENCE, AND EPIDEMIOLOGY

Neuroblastoma is a tumor which develops from immature cells originating from the

sympathetic nervous system.

14