It is the most common extracranial tumor during
childhood, representing 7% of all childhood cancers. The median age at diagnosis
is 19 months; 36% occur in children younger than 1 year of age and 89% before 5
14 Of neuroblastomas, 65% are abdominal (half of these adrenal) and
14 The majority of children older than 1 year of age at diagnosis
have metastatic disease at diagnosis. Lower-risk patients, which mostly includes
infants with stage 1, 2, or 4S, may have spontaneous remissions or at least a 75% to
greater than 90% 5-year event-free survival.
Intermediate-risk patients have a 50%
to 75% event-free survival, and high-risk patients a 19% to 42% 5-year event-free
16 With evolving therapies for high-risk patients (see below), survival may
be improved over these numbers.
Neural tumors related to neuroblastoma can be ganglioneuroma (benign) or
ganglioneuroblastoma (mixed benign and malignant) or pure neuroblastoma. At
biopsy, multiple specimens may be required to fully assess the malignant potential of
the tumor. As with other cancers, neuroblastoma results from the loss of cell-growth
control because of oncogene activation, tumor suppressor gene inactivation, and
related malignant processes. The association of MYCN oncogene amplification with
aggressive, poor-prognosis disease was the first key genetic alteration to be
identified. Recently, reports suggest that patients whose tumor is characterized by
hyperdiploidy with increases in whole chromosome copy number to approximately
triploidy generally have excellent outcomes, whereas segmental alterations of
chromosomes resulting in diploidy or tetraploidy are associated with poor
17,18 The latter includes loss of 1p or loss of heterozygosity at 11q, both of
which are being studied in current COG protocols as risk factors that may require
more aggressive treatments for patients otherwise categorized as intermediate-risk.
The explanations for these correlations are not clear, but this new biology may lead
to better understanding of this disease and its treatment.
CLINICAL PRESENTATION, DIAGNOSIS, STAGING, AND OTHER
Patients with neuroblastoma often present with a fixed, hard, abdominal mass noted
on physical examination by the family or physician, and possibly other signs or
symptoms, depending on the location of the primary tumor and metastases.
For example, gastrointestinal (GI) fullness, discomfort, or dysfunction can occur.
Other less common but characteristic signs include proptosis with periorbital
ecchymoses, increased renin hypertension, secretory diarrhea with increased
vasoactive intestinal peptide, respiratory distress, nerve root compression,
opsomyoclonus, and unilateral ptosis.
14 The most common sites of metastases are the
bone marrow, bone, liver, and skin.
14 Because bone marrow can be involved (distant
metastases), it is necessary to do a bone marrow aspirate to rule out bone marrow
I metaiodobenzylguanidine (MIBG) test is an important diagnostic tool for
neuroblastoma because of its high uptake into the tumor tissue (including metastatic
sites). The catecholamine metabolites vanillylmandelic acid (VMA) and
homovanillic acid (HVA) are elevated in the urine of 90% of patients with
neuroblastoma and are also useful in diagnosis.
14 Because infants have a better
prognosis than older children with neuroblastoma, efforts have been made to screen
infants using urinary concentrations of VMA and HVA.
19 To date, these efforts have
resulted in the diagnosis of more infants with good-risk disease but have not reduced
the number of older children diagnosed with poor-risk disease. This is thought to
reflect two distinct types of biology: a relatively benign biology in infants and a
relatively malignant biology in patients older than 12 to 18 months old.
International Neuroblastoma Staging System (Abbreviated)
Stage 1 Local tumor with complete gross excision
Stage 2A Unilateral localized tumor with incomplete gross excision
Stage 2B Unilateral localized tumor, complete or incomplete excision, with ipsilateral non-adherent
Stage 3 Involves both sides of the midline
Stage 4 Distant lymph node or organ involvement
Stage 4S Infants younger than 1 year of age with localized primary tumor (stage 1 or 2) with
dissemination limited to liver, skin, or less than 10% of bone marrow
Source: National Cancer Institute PDQ® Neuroblastoma Treatment. Bethesda, Maryland: National Cancer
Institute. Date last modified 12/15/2014.
http://cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional. Accessed May 14,
A simplified description of the international staging system is shown in Table 95-
2. Twenty percent (20%) of infants (<1 year) and 59% of children have stage 4
disease at the time of diagnosis. A newer staging system has been designed by the
International Neuroblastoma Risk Group task force, but it is only used in the most
recent COG protocols. The new system has the designations L1, L2, M, and MS. M
and MS are the same as International Neuroblastoma Risk Group stages 4 and 4S. L1
and L2 are more localized disease and are differentiated by a list of “image-defined
A large number of prognostic factors have been identified and are discussed
14,19 Patients are currently stratified for treatment based on age, stage,
MYCN amplification, histology, and diploidy, or by the new staging system with
good or bad genomics and histology. COG guidelines divide low-risk and
intermediate-risk patients into four groups for the purpose of assigning treatments
Infants have better outcomes than older children for the same stage of
disease and low-stage infants have a significant incidence of spontaneous regression
or regression with minimal treatment.
In current US clinical trials, patients with low-risk disease are typically treated with
observation or surgery (groups 1 and 2, Table 95-3). Progression or recurrence may
be treated with surgery, unless disease is unresectable, in which case chemotherapy
is used. Two to four courses of chemotherapy may be used with initial surgery if
organ-threatening symptoms are present. Intermediate-risk disease is treated with
surgery and four to eight courses of chemotherapy (groups 3 and 4, Table 95-3, and
chemotherapy in Table 95-4) for favorable or unfavorable histology and ploidy.
Chemotherapy for patients with low-risk or intermediate-risk disease avoids
cisplatin to reduce nephrotoxicity and ototoxicity, limits the total doxorubicin dose to
avoid cardiac toxicity, limits the total etoposide dose to reduce the risk of secondary
acute myelogenous leukemia, and avoids ifosfamide to eliminate Fanconi renal
syndrome. Radiation therapy is used only for poor responders.
Example of Children’s Oncology Group Neuroblastoma Risk Groups and
Treatment for Low-Risk, Intermediate-Risk, and High-Risk Patients
Low-Risk; Surgery and Observation
Patients with stages 2A or 2B, >50% resected and MYCN not amplified
Infants with 4S with MYCN not amplified, favorable histology, and hyperdiploidy
Low-Risk, Group 2; Receive 2 Cycles of Chemotherapy with Surgery
Stage 2A/2B, <50% resected, or biopsy only and MYCN not amplified
one group if loss of heterozygosity at 1p or 11q
Stage 3, >1 year old, MYCN not amplified, favorable histology
Intermediate-Risk, Group 3; 4 Cycles of Chemotherapy with Surgerya
Infants with stage 3, MYCN not amplified, and diploidy or unfavorable histology
Stage 4, up to 18 months old, MYCN not amplified (good genomics)
Infants with stages 4S and MYCN not amplified, and either diploidy or unfavorable histology
Intermediate-Risk, Group 4; 8 Cycles of Chemotherapy with Surgery
Infants with stage 4S, unknown biology
Infants with stage 4, MYCN not amplified, with diploidy or unfavorable histology
Stage 3, up to 18 months old, MYCN not amplified and unfavorable histology
progenitor cell rescue, radiation to the primary site, and maintenance therapy.
of dinutuximab with GM-CSF on cycles 1, 3, 5 or interleukin-2 on cycles 2 and 4.
MYCN amplified and not included in previous groups.
chemotherapy regimens in low-risk and intermediate-risk patients.
aMYCN is an oncogene that is associated with more aggressive higher-risk neuroblastomas.
bGM-CSF is granulocyte-macrophage colony stimulating factor.
Neuroblastoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified 12/15/2014.
http://cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional. Accessed May 14,
Therapy for high-risk disease generally involves a first surgery for biopsy,
aggressive chemotherapy, second-look surgery for residual tumor resection, either
additional aggressive chemotherapy or high-dose chemotherapy with autologous
progenitor cell rescue, radiation to the tumor bed, and maintenance therapy (Table
16,19 High-dose chemotherapy with autologous progenitor cell rescue raised 5-
year, disease progression–free survival to 49% from historic values of 10% to 20%;
however, relapses can occur later with 7-year disease progression–free survival of
22,23 Survival can be improved (46% vs. 29% 5-year post-chemotherapy
mg/m2 given orally twice daily for 14 days of each 28-day cycle.
anti-GD2 monoclonal antibody, dinutuximab (ch14.18), along with interleukin-2 and
granulocyte-macrophage colony stimulating factor (GM-CSF), to the maintenance
regimen has been shown to further increase survival.
24 Typical conditioning regimens
preceding autologous progenitor cell rescue include carboplatin and etoposide with
either cyclophosphamide or melphalan, or thiotepa and cyclophosphamide.
CLINICAL PRESENTATION AND DIAGNOSIS
limits. Her laboratory test results also include the following:
Hemoglobin (Hgb), 5.1 g/dL (normal, 11–14 g/dL)
Lactate dehydrogenase (LDH), 424 units/L
Urine HVA, 570 mg/g creatinine (normal, <26 mg/g)
Urine VMA, 31 mg/g creatinine (normal, <11 mg/g)
Biopsies of the abdominal mass and bone marrow are positive for neuroblastoma cells that are MYCN
Typical Cycles of Chemotherapy Used in Children’s Oncology Group Low-Risk
and Intermediate-Risk Neuroblastoma
2 Carboplatin, cyclophosphamide, doxorubicin
4 Carboplatin, doxorubicin, etoposide
6 Carboplatin, cyclophosphamide, doxorubicin
8 Cyclophosphamide, doxorubicin
Table 95-3 for common chemotherapy guidelines for neuroblastoma patients.
Neuroblastoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified 12/15/2014.
http://cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional. Accessed May 14,
Virtually all of H.K.’s findings are consistent with neuroblastoma. The low
hemoglobin and albumin and high LDH, however, are not specific for this cancer. In
addition to the biopsy, the elevated urine VMA and HVA are most helpful in
confirming the diagnosis of neuroblastoma. In H.K., biopsies of the bone marrow,
lymph nodes, and primary tumor were necessary to demonstrate the presence or
absence of neuroblastoma at more than one site for staging purposes.
CASE 95-1, QUESTION 2: What stage of disease does H.K. have? What treatment willshe receive?
H.K.’s abdominal disease with distant bone marrow involvement indicates stage 4
(or M) disease. Considering her age and disease stage, H.K. has a high risk of dying
from her disease. Her MYCN also was amplified. Therefore, she is started on
chemotherapy consisting of vincristine, doxorubicin, and cyclophosphamide for
cycles 1, 2, 4, and 6, and cisplatin and etoposide for cycles 3 and 5.
CASE 95-1, QUESTION 3: H.K. is 81.5 cm tall, weighs 11.65 kg, and has a body surface area of 0.5 m
For her third chemotherapy cycle, consisting of cisplatin 50 mg/m
/day on days 1 through 4 and etoposide 200
Monitoring Vital Signs for Etoposide
Although prevention and monitoring of toxicities from chemotherapy agents in
children follow the same basic rules as in adults, there are some differences. When
monitoring vital signs for hypotensive reactions to etoposide, normal blood pressure
will be lower (hypotension is defined as a systolic blood pressure under 74 mm Hg
for a 2-year-old girl) and the pulse higher (mean, 119 beats/minute for a 2-year-old)
It is important to have baseline vital signs so that hypotension or
tachycardia will be recognized.
Monitoring Hydration for Cisplatin
In adults receiving cisplatin, hydration is often standardized with 1 to 2 L of
intravenous (IV) fluids given before the drug, 1 to 2 L with the drug, and then
continuous hydration for at least 24 hours after the dose.
volumes should be calculated based on the child’s size. To decrease the risk of
cisplatin nephrotoxicity, most pediatric protocols recommend IV fluids at twice
maintenance rates to maintain urine outputs of at least 2 to 3 mL/kg/hour. The COG
calculates maintenance fluids as 1,500 mL/m2
/24 hours, so H.K. should receive
3,000 mL/0.5 m2 = 1,500 mL during 24 hours (62.5 mL/hour). H.K.’s measured urine
output is 4 mL/kg/hour, which should be adequate to prevent nephrotoxicity. Weight
should also be monitored throughout cisplatin administration to assure fluid balance.
Acute weight gain may require diuretics to prevent overhydration, and weight loss
may indicate dehydration with impending reduction of urine output that could lead to
acute nephrotoxicity. Increased IV fluids would help prevent the latter.
Adjustment of Creatinine Clearance to Adult Size
CASE 95-1, QUESTION 4: H.K.’s measured creatinine clearance (CrCl) is 39 mL/minute. Should her
cisplatin be withheld or the dose adjusted because of low creatinine clearance?
Cisplatin is either not administered or administered at a reduced dosage when the
creatinine clearance is less than 50 to 60 mL/minute/1.73 m2
creatinine clearance of 39 mL/minute appears to be low, it is relative to the patient’s
size (i.e., 39 mL/minute/0.5 m2
). Guidelines for dosing drugs cleared by glomerular
filtration are based on creatinine clearance for normal adult body size, 1.73 m2
Therefore, it is important to correct H.K.’s creatinine clearance to adult body size.
Multiplying by 1.73/0.5, her creatinine clearance is 135 mL/minute/1.73 m2
not a reason to withhold cisplatin. One precaution is that the accuracy of serum
creatinine and creatinine clearance in assessing renal function during cisplatin
therapy in children has been questioned.
Partial Response and Hematopoietic Progenitor Cell Rescue
CASE 95-1, QUESTION 5: H.K. obtains a partial response to the aforementioned initial chemotherapy
What further treatment has the most potential benefit for H.K.?
The best chance for prolonged disease-free survival for H.K. is dose-intensive
chemotherapy combined with autologous peripheral blood progenitor cell rescue.
The regimen she is receiving was designed to be followed by high-dose
chemotherapy and stem cell rescue. The 2- to 3-year disease-free survival is better
with high-dose chemotherapy followed by autologous progenitor cell
14,16,19,22,23 The plan for H.K. is to proceed to high-dose chemotherapy
(carboplatin, etoposide, and melphalan) with an autologous progenitor cell rescue. If
a complete response is achieved, she would then receive radiation to the bed of the
primary tumor, followed by 6 monthly cycles of isotretinoin (cis-retinoic acid) and 5
cycles of dinutuximab with granulocyte-macrophage colony
stimulating factor (GM-CSF cycles 1, 3, 5) and interleukin-2 (cycles 2, 4). All
three of these treatments, dose-intensive chemotherapy with progenitor cell rescue,
isotretinoin, and the dinutuximab regimen, have been shown to independently
Further Treatments Based on Disease Biology
With rapid advances in neuroblastoma biology being made, future alternatives may
include more biologic treatments. One agent in clinical trials is
compound that delivers radiation directly to catecholamine-secreting cells such as
neuroblastoma. Studies have used
I-MIBG as part of the conditioning regimen
before progenitor cell rescue in patients with neuroblastoma.
anaplastic lymphoma kinase receptor tyrosine kinase inhibitor, has entered phase I–II
clinical trials in pediatric patients and shows some promise for a small percentage of
DESCRIPTION, EPIDEMIOLOGY, AND PATHOPHYSIOLOGY
Wilms tumor, also known as nephroblastoma, is a kidney tumor composed of various
kidney cell types at different stages of maturation.
childhood cancers are Wilms tumor, making it the most common intra-abdominal
1 The peak incidence occurs at 3 to 4 years of age.
Wilms tumor has an excellent prognosis. Four-year relapse free survival is greater
than 50% for all categories of Wilms tumor except stage IV with diffuse anaplasia.
For low-stage patients, 4-year relapse-free survival is generally greater than 86%.
Histology is the most important indicator of likely outcomes with diffuse anaplasia
being distinctly worse than either focal anaplasia or favorable histology.
The relationship of genetic factors to Wilms tumor is demonstrated by the
approximately 1.5% of patients with Wilms tumor who have family members with the
disease and the approximately 10% who have aniridia, hemihypertrophy, or
32,33 Chromosomal aberrations at 11p13 and 11p15, known
respectively as WT1 and WT2, and WTX on the X chromosome, are associated with
nonfamilial Wilms tumor. Genes at these sites are involved with normal development
of the urinary tract and other tissues involved in the anomalies. It is thought that the
relationship between congenital anomalies and Wilms tumor may relate to
methylation and inactivation of a set of neighboring genes involved with the two
32 The familial syndrome is related to FWT1 (17q12-21) and
FWT2 (19q13.4), which have been identified more recently and about which less is
33 Loss of heterozygosity (LOH) at 1p and 16q correlates with increased risk
of recurrence in stage III or IV disease with favorable histology. Treatment
guidelines suggest increased chemotherapy for patients with these findings (Table
Patients with Wilms tumor frequently present with an asymptomatic abdominal mass,
although malaise and pain may be reported.
32 Hematuria and high renin hypertension
each occur in approximately 25% of patients. Metastases, when present at diagnosis,
most commonly involve the lungs (80%) or liver (15%).
DIAGNOSIS, STAGING, AND OVERVIEW OF TREATMENT
Diagnosis of Wilms tumor is based on biopsy and computed tomography (CT) of
chest and abdomen to rule out metastatic disease. Treatment in the United States is
based mostly on disease stage after surgical resection or debulking and favorable
histology versus focal or diffuse anaplasia. Surgical resection is the primary
treatment, followed by adjuvant chemotherapy (Table 95-5). A simplified
description of the staging is as follows: stage I is limited to the kidney and can be
completely removed surgically; stage II is extended beyond the kidney but can be
completely excised; stage III is characterized by residual tumor confined to the
abdomen; stage IV is distant metastases; and stage V is bilateral disease.
Metastases are present in only 15% of patients at diagnosis, and even these patients
have relatively good prognoses. Notably, in Europe the majority of treatments use
neoadjuvant chemotherapy before surgery. The benefits and risks of each method
have been discussed elsewhere.
34 COG studies suggest surgery followed by adjuvant
chemotherapy except in stage V (bilateral disease), where neoadjuvant chemotherapy
is used in an attempt to preserve kidney function. Current protocols use newer
regimens and also examine the possibility of surgery without chemotherapy for some
Wilms Tumor Treatment Regimens by Stage and Histology
Stage I, Any Histology, and Stage II, Favorable Histology
Stage III or IV, Favorable Histology; Stages II, III, or IV Focal Anaplasia
Stages II through IV, Diffuse Anaplasia
(computed tomography) shows metastases, unless there is complete resolution after chemotherapy.
dactinomycin, doxorubicin, plus outpatient cyclophosphamide and etoposide.
MD: National Cancer Institute. Date last modified August 15, 2014.
http://cancer.gov/cancertopics/pdq/treatment/wilms/HealthProfessional. Accessed May 14, 2015
CLINICAL PRESENTATION AND TREATMENT
106/69). His laboratory results include the following:
Hgb, 7.9 g/dL (normal, 11.5–13.5)
Erythrocyte sedimentation rate, 139 mm/hour (normal, <10)
B.N. has a history of hypospadias and left hydronephrosis. Scans show a right kidney mass extending
B.N. has stage IV disease with favorable histology and the cells are negative for loss
of heterozygosity at 1p and 16q. The expected treatment for him is 24 weeks of
vincristine, dactinomycin, and doxorubicin, assuming findings at surgery are
consistent with pretreatment scans. He will receive abdominal radiation; he would
also receive pulmonary radiation unless the lung metastases completely disappear
with chemotherapy. The series of five National Wilms Tumor studies have sought to
progressively minimize toxicities from radiation and chemotherapy while maintaining
the excellent cure rate. The fourth National Wilms Tumor Study Group (NWTS-4)
study demonstrated that intermittent, higher doses of dactinomycin allowed higher
dose intensity with less myelosuppression than lower doses given daily for 5 days.
Using greater dose intensity and dose density, 6 months of therapy was shown to be
as effective as 15 months of therapy given the traditional way.
visits were made and estimated costs were reduced by 50%.
evaluated surgery followed by 18 to 24 weeks of chemotherapy. Chemotherapy was
determined by the stage and histology findings (Table 95-5). Abdominal radiation
therapy was added to chemotherapy for stage II disease with unfavorable histology
(focal or diffuse anaplasia) or stages III or IV with any histology; pulmonary
radiation was added for stage IV disease if the chest radiograph was positive for
metastases. The latter part of the guideline has now changed to depend on whether or
not the pulmonary nodules clear with chemotherapy or not. For patients with stage V,
or those with inoperable tumors, surgery could be delayed until neoadjuvant
chemotherapy reduces the tumor size.
Dosing Chemotherapy in Infants and Young Children
CASE 95-2, QUESTION 2: Are there any special precautions for dosing chemotherapy in B.N.?
The NWTS-2 study noted an excessive number of toxic deaths in infants with good
prognosis, and this resulted in a dosing change.
37 After chemotherapy doses were
decreased by 50%, severe hematologic toxicity, toxic deaths, and pulmonary and
hepatic complications were reduced.
Importantly, no decrease in therapeutic effect
was noted. Reduction of chemotherapy doses in infants is a consideration for other
39–41 Reasons for increased toxicity in infants may include
altered pharmacokinetics or organ sensitivity as well as the larger body surface
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