Chapter 447. Neonatal Oncology

Tumors are a rare but important cause of mortality and morbidity in the newborn. The types of tumors that occur at this age are substantially different from those that occur in older children. Neonatal tumors include a wide spectrum of benign and malignant tumors, some of which have unique biologic characteristics and clinical presentations. Tumor behavior is not always predictable and apparently benign tumors may have a malignant potential, whereas others, malignant by histologic criteria, behave in a benign fashion in the neonate.1

The incidence of neonatal tumors varies from 17 to 121 per million live births.2-4 An apparent increase in the incidence of neonatal cancer may be due, at least in part, to the prenatal detection by ultrasound of tumors, such as neuroblastoma, that may never present clinically. Newborn cancer makes up about 2% of malignancies in children.1 Tumors presenting after birth tend to be detected early, 50% on the first day of life and many others within the first 7 days.5,6 Fifteen to 20% are associated with congenital anomalies and syndromes.1

Neonatal tumors differ in distribution from those found in older children. Table 447-1 shows the distribution of newborn tumors from a large published series.7 Overall, teratoma is the most common neoplasm, whereas neuroblastoma is the most common malignancy in newborns and infants in Western countries,8,9 followed by leukemia, sarcoma, and brain tumors. By comparison, acute leukemia is the most common cancer in newborns in a report from Asia.9

Neonatal Germ Cell Tumors

Germ cell tumors consist of a heterogeneous group of histologically benign and malignant tumors which arise from primordial germ cells. All subtypes can be seen in the neonate, although mature (benign) teratoma is the most common with a reported incidence of 1 in 35,000 live births.10

Mature (benign) teratoma is the most common germ cell tumor in the newborn, comprising 37% to 52% of congenital tumors.11 Malignant elements, usually endodermal sinus tumor (EST) are found in approximately 10% of teratomas in children under age 4 months,12 but neither the degree of histologic immaturity nor the presence of malignant elements has correlated with recurrence or progression to malignancy.11 After age 4 months the malignancy rate of teratomas rises, reaching almost 100% at age 3 years.12 Mature teratomas are usually extragonadal and midline, consistent with embryonic patterns of germ cell migration.13 The most common anatomic site of teratomas is sacrococcygeal, where these tumors may be primarily extrapelvic (type 1), extra- and intrapelvic (type 2), or entirely intrapelvic (type 3). Other common areas are intracranial, orbital, nasopharyngeal, neck, and anterior mediastinum.12 Extrapelvic sacrococcygeal teratomas may be very large, resulting in intrauterine rupture, bleeding, fetal death, or dystocia. Mortality is high, particularly if diagnosed before 30 weeks’ gestation.11Caesarian section should be done as soon as lung maturity is deemed adequate. In-utero tumor debulking has been done in high-risk fetuses who cannot be safely delivered.14 Postnatal therapy consists of complete resection whenever possible.

The survival for fetal and neonatal teratoma has been reported to be 53% and 85%, respectively, in a recent review.12 EST is the most common malignant germ cell tumor of fetus and newborn. Alpha feto-protein (AFP) levels are normally very high in newborn and young infants up to levels of 150,000 ng/ml or more and even higher in premature babies. AFP is cleared from the circulation with a half-life of 5 to 7 days, reaching adult levels by about 9 months of age.15 Thus, only rising levels are clinically useful in the early postnatal period. The range of normal serum AFP values in term babies and in premature babies is shown in Tables 447-2 and 447-3. Mature neonatal teratoma may recur locally as mature or immature teratoma or, despite apparent complete resection, as pure EST up to 36 months later.11,12,16 In a series from the Children’s Cancer Group, 9 of 80 (11%) apparently completely resected mature neonatal teratomas recurred locally, 2 as mature teratoma at age 6 months postresection and 7 as pure EST between ages 6 and 34 months.16 Malignant recurrence was seen in a nasopharyngeal, mediastinal, and cervical teratoma in addition to sacrococcygeal sites in another series, suggesting that all mature teratomas in the newborn may contain cells with a malignant potential.17 At the time of recurrence, patients may present with metastatic disease and with extradural spinal cord compression.18 The response to chemotherapy and survival of EST is excellent, even for those with metastases at the time of recurrence.19 All newborns with mature teratoma at any site should be carefully followed with AFP measurements at 3 monthly intervals until 36 months of age.

Neuroblastoma in the Fetus and Newborn

Neuroblastoma (NB) is the most common malignancy in the neonate and infant. Forty percent of neuroblastomas present in the first year of life and 60% by age 2. There is a clear association between age, site, and extent of NB. Infants less than 1 year of age most commonly have localized disease arising equally from thoracic and abdominal sites; older children tend to have disseminated disease from an adrenal primary.20 Ninety percent of neonatal NB presents with stage 1 or 4S disease with a good survival,1 but the outlook may vary depending on tumor biology. Stage 4S NB is unique to the neonatal/infancy periods and is characterized by widely disseminated disease, often without an identifiable primary tumor, which usually regresses spontaneously. (For a description of neuroblastoma biology, see Chapter 457, “Neuroblastoma.”)

From a clinical point of view, the combination of biologic features with clinical features such as stage and age has proven to be useful in allocating patients to three risk groups, low, intermediate, and high, with a 10-year probability of survival of 95%, 80%, and 30%, respectively. Although most infants have low-risk disease, those with stage 3, 4, and 4S neuroblastoma (NB) with MYCN amplified tumors have a significantly worse survival rate than infants with stage 4 disease without MYCN amplification, demonstrating that biology is more important than age or stage.21

Spontaneous regression is frequent in infants. Substantial increases in the annual incidence rates of infant neuroblastoma was seen in Japan22 and Canada23 when mass screening programs were implemented, suggesting that many or most of the tumors detected by screening would have undergone spontaneous regression and might never have presented clinically. This suggests that such tumors are able to respond to apoptotic mechanisms that prevent survival of aberrant cells during development.1 The routine use of fetal ultrasonography has also resulted in increasing detection of an abdominal mass. Neuroblastoma (NB) is the second most common abdominal mass detected by prenatal ultrasound, once renal lesions are excluded. Differential diagnosis of a suprarenal mass in the newborn includes adrenal hemorrhage, other adrenal tumors, and subdiaphragmatic extrapulmonary lung sequestration. Most tumors detected prenatally or by screening are of favorable stage and have favorable biology.24 NB therapy depends on age, stage, and tumor biologic characteristics. A current study is investigating whether perinatal localized tumors can safely be managed with observation alone.20 By contrast, newborns with stage III, IV, and IVS disease with poor prognostic biological features have a very poor survival even with intensive chemotherapy and autologous stem cell transplantation.

Stage IVS neuroblastoma in the neonate is potentially life-threatening. Two separate studies have confirmed the increased risk, with only about 43% of neonatal patients with stage IVS NB surviving.8,25 The cause of death is often massive and rapidly progressive liver enlargement resulting in respiratory compromise, vena cava obstruction, and/or gastrointestinal compression. A scoring system to help in therapeutic decision making for such patients has been published.26 Any sign of respiratory distress or inferior vena cava (IVC) compression requires emergency therapy. Prompt referral to an oncology service is necessary. Therapy includes chemotherapy with or without radiation therapy, both of which may be life saving. Radiation is given at a dose of 200 to 600 cGy using tangential fields and thereby sparing kidney, gonad, and vertebral body, with minimal likelihood of significant long-term sequelae.27 This therapy is necessary to deal with immediate mechanical complications and does not necessarily have to be continued after resolution of the immediate problem. Therapy should include precautions against tumor lysis syndrome, which may occur in young infants with stage IVS NB.

Congenital Leukemia

Congenital leukemia most commonly refers to leukemia diagnosed within the first month of life, is most commonly of myeloid origin, with acute monocytic and myelomonocytic leukemia being most prevalent.28 Epidemiologic studies show that high birth weight increases the risk for congenital leukemia and other childhood malignancies such as Wilms tumor (WT), neuroblastoma (NB), and astrocytomas, possibly related to effects of increased cell turnover and high levels of insulin growth factor,29 Low birth weight and prematurity are associated with an increased risk of development of WT but not leukemia.

Clinically, 50% of neonates with congenital leukemia present with cutaneous infiltration, a rare finding in older children.28 Hepatosplenomegaly, petechiae, and ecchymoses are common, and hyperleukocytosis, respiratory distress, and meningeal involvement occur more frequently in this age group. Approximately 10% of newborns with Down syndrome (DS) present with circulating blasts resulting from transient myeloproliferative disease (TMD). The blasts are clonal in origin and indistinguishable from those of acute megakaryoblastic leukemia (AMKL). Organ infiltration is commonly observed, particularly of the liver, spleen, heart, and skin. The blasts usually disappear spontaneously within the first 3 months of life, but 20% to 25% of these children with DS and TMD go on to develop true AMKL.30 TMD may occur in children without clinical DS but with extreme levels of mosaicism on genetic testing. Conversion to true leukemia appears to be much less frequent in these patients.Occasional cases of TMD and subsequent AML have been reported in non-DS newborns.9 The blasts of TMD and AMKL in DS are associated with somatic mutations in the gene, GATA1, which encodes a myeloid transcription factor, and an increased sensitivity to chemotherapeutic agents, such as cytarabine.31,32GATA1 mutations have been found in the Guthrie blood spot in infants who subsequently developed AMKL, suggesting that mutations may occur early in hematopoietic development, may be used as a specific marker for diagnosis of TMD in DS neonates, and may serve as a marker for increased risk of DS-related AMKL.33 Most patients with DS and TMD only require observation, but about 15% present with life-threatening complications including liver and cardiac failure, hyperviscosity syndrome due to hyperleukocytosis, or respiratory impairment. These newborns usually require chemotherapy; low-dose cytarabine is commonly used.30

Congenital acute lymphoblastic leukemia (ALL) is less frequent than myeloid leukemia, but is biologically different and has a significantly poorer prognosis than ALL in older children. Neonatal ALL is usually B-lineage. Rearrangements of the MLL gene on 11q23 are observed in at least 80% of cases and are associated with very poor prognosis. Most MLL rearrangements in the newborn and young infant are due to a translocation of chromosomes 4 and 11, t(4 11)(q21;q23), and less commonly due to other translocations such as t(9;11)(p22;q23) and t(11;19)(q23;p12). Analysis of MLL gene rearrangements in identical leukemic twins suggests that the rearrangement occurs prenatally and that leukemic cells are already present in the peripheral blood at birth.34 A large study of more than 200 infants showed no difference in outcome according to the specific translocation, in contrast to outcomes observed in MLL-rearranged ALL in older children.35 As in neonatal AML, there is an increased frequency of poor prognostic features, such as hyperleukocytosis and central nervous system (CNS) disease, whereas good prognostic features such as hyperdiploidy and favorable cytogenetics are not usually found.36 Identical 11q23 abnormalities have been observed in secondary leukemia following treatment with epipodophyllotoxins that inhibit the DNA topoisomerase II enzyme, resulting in the hypothesis that maternal diet in pregnancy may contain foods with substances that have a similar activity and that this may be important in the pathogenesis of these infant leukemias.37

Many different chemotherapy regimens have been tried in neonatal ALL, but induction failure rate is high and toxic mortality is frequent. At present there is no evidence that myeloablative therapy with hematopoietic stem cell transplant (HSCT) improves the outcome in MLL-rearranged infant ALL, although this has not been properly evaluated in the newborn patient. A Japanese study of 9 newborns with MLL-rearranged leukemia showed that 2 of 5 who underwent stem cell transplant survived compared, to 0 of 4 treated with chemotherapy alone; both survivors were given total body irradiation (TBI) despite their young age.38 Total body irradiation, shown to improve survival when used in conditioning regimens for HSCT in older children with ALL, is usually not considered an optimal approach in the neonate because of adverse growth and cognitive sequelae. If cases of transient leukemia are excluded, the prognosis is extremely poor for most infants with congenital B-lineage or biphenotypic leukemia. By contrast, infants with AML have comparable outcomes to those seen in older children, if treated with the same intensive regimens.39

Skin Nodules in Neonatal Oncology

One of the intriguing differences between cancers in the neonate and infant compared to what appears to be the same malignancy in older children, is the tendency of the newborn to present with skin nodules. The differential diagnosis of a newborn with multiple skin nodules, often termed a “blueberry muffin” appearance, includes congenital infections such as toxoplasmosis, rubella, cytomegalovirus, and other herpes viruses (TORCHES), as well as several malignancies such as congenital leukemia, lymphoma, and neuroblastoma. About half the infants with congenital leukemia will have skin nodules at presentation, and they may also be seen in newborns with Down syndrome and transient myeloproliferative disease (TMD). Skin nodules have also been described as a rare manifestation in other malignancies such as rhabdomyosarcoma and adrenocortical carcinoma. In the fetus, the skin functions as a transient hematopoietic organ and may revert back to this function in the neonate and young infant if there is a demand to increase blood cell production. In that capacity, the skin may provide a microenvironment more permissive for malignant cell growth.40

Histiocytic disorders may also cause skin nodules in a neonate. Congenital self-healing reticulocytosis (Hashimoto-Pritzker disease) is a form of skin histiocytosis presenting in the neonate. This condition presents with a few scattered papules to multiple papules or vesicles in the skin because of infiltration with Langerhans-type histiocytes that contain Birbeck granules upon examination by electron microscopy. The lesions may increase in number after birth, but will involute spontaneously within a few months. Distinction from the skin manifestations of infection, leukemia, and neuroblastoma is made on the basis of skin biopsy, but distinction from the skin-only form of Langerhans cell histiocytosis (LCH), can be considerably more difficult as the cells are identical on immunohistochemistry. Because 50% of skin-only LCH progresses to involve other organs within a few weeks to months and may be life threatening, all newborns and infants with skin-only LCH should be followed carefully clinically, but without radiologic investigations.41

Newborn Brain Tumors

Brain tumors in the newborn comprise 5% to 12% of neonatal tumors.42,43Association with Li-Fraumeni syndrome was reported in 2 of 9 newborns in a Danish series. Other associations reported included a history of previous fetal deaths, maternal irradiation, maternal ingestion of anticonvulsants, and antiemetics, as well as infections during pregnancy such as toxoplasmosis (glioma) and chicken pox (medulloblastoma).44 About half are detected prenatally. Postnatal clinical features include hydrocephalus, enlarged head circumference, and asymmetric skull growth. Associated congenital anomalies are common.45 Most frequent histologic diagnoses are intracranial teratoma, low- or high-grade astrocytoma, medulloblastoma, and primitive neuroectodermal tumor (PNET). The majority are supratentorial tumors. Benign brain tumors are common in the neonatal period and include choroid plexus papillomas (10–20% of infant brain tumors), craniopharyngioma, and hemangioma. Intracranial teratoma is the most common brain tumor in neonates and may present with massive tumor, extension into orbit or neck, hydrocephalus, or as an incidental finding in a stillborn fetus. Intracranial teratoma has the worst survival of all perinatal teratoma, with 11% survival in a recent review.45 Therapy of brain tumors includes surgical resection and chemotherapy. The poor prognosis is usually the result of the high surgical risk and the avoidance of radiation therapy at this vulnerable age.

Retinoblastoma

Retinoblastoma (RB) is the most common intraocular tumor of childhood. It presents in infants and young children and may be present in the newborn. All RB tumors show loss of function of the tumor suppressor gene, RB1. RB1 mutations occur in 60% of patients as somatic mutations, (mutations found only in tumor cells) and in 40% as germ-line (inherited) mutations. Patients with germ-line mutations in RB1 are at a very high risk (90%) of a second mutation and bilateral RB. Ninety-three percent of the RB1 mutations can be identified in reference laboratories allowing molecular based genetic counseling and screening.46 Of 46 neonates with RB in one study, 42 had bilateral (familial) RB, 20 at presentation, and 22 with asynchronous contralateral tumors developing later. Thus, most RBs diagnosed in the neonatal period are the result of inherited mutations in the RB1 gene.47

Early diagnosis is essential for survival and prevention of blindness. Early stage RB is treatable with cryo- or laser therapy. Later diagnosis may result in the need for enucleation sometimes with intensive chemotherapy and radiation therapy. All infants less than 2 months of age should undergo screening with a red pupil reflex test to detect significant ocular abnormalities and RB.46,48 Half the newborns with familial RB1 mutations were found to have paramacular or macular tumors when delivered at 36 weeks gestation.46Patients with a positive family history who undergo early screening have been shown to have tumors diagnosed at a younger age and with less extensive disease and have a better ocular surviva.48 The best chance for preservation of vision in patients with familial RB is making the diagnosis prenatally, to prevent development of large tumors.46 Familial RB is associated with a high incidence of second malignancy, particularly if radiation therapy is given as part of the therapy,49 but spontaneously developing tumors arising outside of the radiation field are also well described.

Newborn Kidney Tumors

Nearly two-thirds of abdominal masses in the newborn arise from the kidneys. The majority of these masses are non-neoplastic, such as hydronephrosis, multicystic, dysplastic, and polycystic kidneys50 Neonatal renal tumors are uncommon and represent less than 10% of neonatal tumors (eTable 447.1). Benign congenital mesoblastic nephroma (CMN) comprises 78% of neonatal kidney tumors. Three histologic subtypes of CMN have been defined, the classic type comprising 24% of cases, the cellular type 66% of cases, and a mixed type with both classic and cellular histology 10% of cases. Molecular characterization of CMN demonstrates a characteristic translocation, t(12;15), in the cellular subtype of CMN.51 Wilms tumor is much less common in this age group and accounted for only 4 of 27 newborn renal tumors in a National Wilms Tumor Study Group (NWTSG) study of newborn renal tumors.52 An association of WT with congenital anomalies includes sporadic aniridia, hemihypertrophy, Beckwith-Wiedemann syndrome, and other overgrowth syndromes. Neonatal renal tumors usually present as asymptomatic abdominal masses detected by prenatal ultrasound or physical examination. Neonatal hypertension, hypercalcemia, maternal polyhydramnios, and hydrops fetalis may occur. Polyhydramnios is more common in CMN, which is also significantly associated with preterm labor and prematurity, observed in 46% of newborns with prenatally diagnosed renal tumors.53 Review of prenatal ultrasound features showed no characteristics that distinguish CMN and WT.51 CMN is treated by surgical removal and patients have an overall excellent chance of survival. However, the cellular form of CMN has been described to rupture, leading to peritoneal contamination during surgery. For such patients, rigorous follow-up is indicated and adjuvant chemotherapy may be required.

Neonatal WT is treated with primary excision followed by chemotherapy at 50% of usual doses recommended for older children, because of an increased risk of toxic deaths in very young infants. Reduction of chemotherapy doses to 50% by the NWTSG resulted in 4-year survival rates for the 256 babies with stages I, II, and III WT of 96%, 95%, and 90%, respectively.54 Subsequently, the NWTS showed that children less than 24 months of age with small (less than 500 gm), stage I favorable histology WT had an 86.5% disease-free survival rate with resection alone.55 A review of prenatally detected renal tumors confirmed an excellent prognosis, but many perinatal complications were seen and close monitoring of all prenatal renal tumors is mandatory.53 Neonates with nephrogenic rests in the contralateral normal kidney should have prolonged monitoring with ultrasonography at 3 monthly intervals to monitor for development of asynchronous tumors in the remaining kidney.

Liver Tumors

Liver tumors in the neonate comprise approximately 5% of tumors in the perinatal period.56 The most common primary tumor is hemangioendothelioma (HE), followed by mesenchymal hamartoma, and hepatoblastoma (HB). Secondary tumors include metastatic neuroblastoma, renal tumors, and others such as endodermal sinus tumor (EST) and choriocarcinoma.1 In Isaacs’s review, 162 (83.5%) newborn liver tumors were benign, of which 117 were hemangioma/hemangioendotheliomas (HE) and 45 mesenchymal hamartomas, whereas 32 (16.5%) tumors were malignant.56

Liver tumors may be detected prenatally and may be associated with anemia, hydramnios, or hydrops fetalis. Postnatal abdominal distention, abdominal mass, and respiratory compromise may also be seen. Radiologic investigations do not always reliably distinguish benign from malignant tumors.57 HE may proliferate rapidly after birth followed by slow involution over several years. Five percent of unifocal and 49% of multifocal HE has associated cutaneous hemangiomas. Congestive cardiac failure and consumptive coagulopathy (Kasabach-Merritt syndrome) require urgent therapy, often with surgical resection, corticosteroids, low-dose vincristine, or interferon-α.56 However, interferon therapy has been associated with a significant risk of spastic paraplegia in young babies.

HB is the most common primary malignant liver tumor. Alpha feto-protein (AFP) is usually increased in HB but the high levels found normally in newborns can complicate the interpretation of this test in this age group (Tables 447-2 and 447-3). Therapy of HB consists of surgery and adjuvant chemotherapy; liver transplantation may be required for HB not amenable to surgical resection.58

The most common presentation of mesenchymal hamartoma is with a multicystic or cystic and solid abdominal mass detected ultrasonographically or clinically. The treatment is surgical removal. Death may occur because of the rapid enlargement of a cystic mass causing respiratory distress and compression of intra-abdominal blood vessels. Arteriovenous shunting within the tumor may occasionally result in heart failure.56

Neonates with cancer present many therapeutic challenges, including efficacy and toxicity of chemotherapy drugs. In general, neonatal tumors manifest the same sensitivity to chemotherapeutic agents as tumors in older children. However, virtually all pharmacokinetic aspects of drug absorption, distribution, metabolism, and elimination in the neonate are different from those of older patients.59,60 The paucity of data regarding optimal chemotherapy in the neonatal period has resulted in empiric recommendations for neonatal dosage regimens, based on extrapolation from experience with older children. This has translated to initial dosing that has been derived by scaling from pediatric or adult dosage and then titrating according to clinical response. A number of formulae have been proposed for scaling adult doses to infants and children, but simple body weight (BW) and body surface area (BSA) ratios are most often applied in the clinical setting. The BSA dose scaling method is perceived to be more accurate, as BSA correlates with the development of physiologic systems. Other data,61,62 however, suggest that weight-based dosing tends to give the best estimate of the body’s ability to eliminate a drug from plasma in subjects 12 months of age and younger.

Drug pharmacokinetic characteristics are classically composed of four major components—absorption, distribution, metabolism, and elimination—which occur somewhat simultaneously following administration. During the neonatal period, major physiologic changes occur, which affect all four pharmacokinetic steps. Ideally, pharmacokinetic studies should be undertaken for each chemotherapeutic agent given to neonates. This is based on the observation that many drugs have 3 to 9 times longer half-lives in neonates, whereas others may be metabolized more rapidly compared to adults. These differences, which disappear by 2 to 6 months of age, exceed the up to 3-fold factor commonly ascribed to interindividual pharmacokinetic variability.63

Absorption

Absorption via the gastrointestinal tract is a major determinant of the pharmacokinetics of oral drugs. The rate and magnitude of drug absorption from the gastrointestinal tract depend on gastric pH and emptying time, intestinal transit time, and gastrointestinal enzyme activity.59 Gastric emptying is slow (6–8 hours) in neonates, and consequently, the rate at which most orally administrated drugs are absorbed is slower in neonates and young infants, and the time to achieve maximal plasma concentrations (Tmax) and therapeutic effect may be longer. The slow gastric emptying in the neonate may increase tissue concentration of some chemotherapeutic agents, such as methotrexate, for which length of exposure increases efficacy and toxicity.13

Gastric pH is neutral at birth and falls to 1.5 to 3 within hours. Acid-labile drugs are more efficiently absorbed and have greater bioavailability in neonates and infants. Conversely, drugs that are weak acids may require larger oral doses.

The absorption of oral drugs is also affected by a decreased activity of gastrointestinal enzymes, such as pancreatic enzymes, which are low in infants younger than 4 months of age. In addition, irregular peristalsis results in highly variable absorption from the small intestine, whereas reduced bile acid metabolism results in prolonged clearance of chemotherapy agents and increased toxicity.

Distribution

Independent of the route of administration, once absorbed, the drug enters the bloodstream, and is distributed into various compartments of the body. Drug distribution varies significantly with age because of developmental changes in body composition, protein binding, hemodynamic factors (cardiac output, tissue perfusion), and membrane permeability. Significant differences in the volume of distribution (Vd) and protein binding capacity between neonates and older children are responsible for the difference in the ability to handle drugs.64-66

Drug distribution is influenced by age-dependent changes in body water and fat content. At birth, total body water approximates 75% and falls to about 60% at 1 year and the extracellular water compartment falls from about 40% of body weight in the neonate to about 20% in the adult. Water-soluble chemotherapy drugs have a larger volume of distribution in neonates than in older patients and achieve a lower concentration of water-soluble drugs at the receptor sites in neonates and infants compared to older patients. These drugs may be more accurately dosed using body surface area rather than weight, because clearance divided by body surface area is relatively constant in an individual over time.59,60 However, the use of body weight for determining drug dosage for infants younger than 1 year of age remains a common practice.67

The extent of plasma protein binding is another important factor since only the unbound fraction of a drug reaches the receptors to exert therapeutic effects. Albumin and a1-acid glycoprotein are the two major drug-binding proteins in plasma. Albumin has a higher binding affinity for acidic compounds and a1-acid glycoprotein for basic compounds. Protein binding is usually reversible, although covalent binding may occur occasionally, typically with alkylating agents. Because of the low concentration of plasma proteins in the neonate and the presence of competing serum compounds (such as bilirubin), differences in protein binding capacities of certain drugs (for example prednisone) commonly used in chemotherapy regimens suggest that dose modifications of these drugs may be important.

There are also significant differences in central nervous system volumes between neonates and older children. Neonates have relatively larger cerebrospinal fluid (CSF) volumes, which do not correlate with body surface area. In addition, there is an increased ability of drugs such as methotrexate and cytosine arabinoside (ARA-C) to penetrate the newborn central nervous system (CNS), which reflects incomplete myelination. Both parameters should be taken into consideration when prescribing drugs for infants with a brain tumor or with metastatic CNS involvement.

Metabolism

Metabolism transforms lipophilic compounds to more hydrophilic metabolites, for excretion into bile or urine. After liver biotransformation, metabolites that may be either pharmacologically active or inactive can be eliminated by either renal or biliary excretion or both. Drug metabolism can be divided into two different types of reactions, phase I and phase II metabolism. Phase I metabolism generally results in either the introduction of a functional group into the parent compound (oxidation, reduction, methylation) or the exposure of new functional groups of the parent drug. Phase I metabolism processes reach maximal maturity at different ages. Phase II metabolism involves conjugation of functional groups of molecules with hydrophilic endogenous substrates. In neonates, Phase II processes are at a substantially lower rate than in adults (50–70%). For example, glucuronidation reaches its full maturity by 3 to 4 years of age. Delayed maturation of drug-metabolizing enzyme activity may account for lack of efficacy or increased toxicity of drugs in neonates.

Most phase I and phase II hepatic drug-metabolizing enzymes are of lower capacity at birth, including the major cytochrome P-450 (CYP) isoenzymes, responsible for biotransformation of a large number of pharmacologic agents.68 Tissue concentrations of certain CYP P-450 enzymes in the liver, kidneys, and intestines are important determinants of the rate of metabolism of these drugs. Maturation of CYP-450 isoenzymes occurs at different ages. Neonatal levels of CYP 3A4/3A5, the major drug-metabolizing CYP isoenzymes, are less than 30% of adults.69 Decreased metabolic rate activity can affect antineoplastic agents in two ways, by decreasing activation of drugs such as cyclophosphamide, which are prodrugs (bioreversible derivatives that undergo transformation in vivo to release the active drug), and by decreasing inactivation of drugs such as vincristine that rely on metabolic processes for inactivation. Cyclophosphamide, which is activated by CYP3A4 and CYP2D6, has lower transformation rates and biologic antineoplastic activity in the neonate, compared to older children.70 Drugs such as vincristine and daunorubicin, excreted via the biliary system, may have prolonged cytotoxic activity in this early age period.

The above-mentioned developmental pharmacology principles together with clinical observations of increased toxicity in infants, for example, in the Wilms tumor studies,71 have led to the recommendation that chemotherapy drug dosages be reduced by 50% on a weight basis in infants younger than 1 year of age for most drugs. This recommendation has been adopted for other solid-tumor treatments as well and is specifically relevant for the anthracyclines, vincristine and other vinca alkaloids, cisplatin, and actinomycin-D.72 However, reduction of chemotherapy doses is not usually recommended for neonatal acute myeloid leukemia (AML).

Elimination

The majority of drug elimination mechanisms are markedly reduced at birth.73,74 Two major pathways of kidney elimination of drugs and their metabolites are glomerular filtration and tubular secretion. At birth, both mechanisms are limited. The glomerular filtration rate (GFR) is approximately 40 ml/min/1.73m2 in full-term neonates, approximately 30% of the healthy adult value. The GFR increases rapidly during the first 3 weeks of life, and then rises steadily, reaching adult levels by 3 to 5 months of age.75,76 The clinical implications for GFR maturation become apparent when considering drugs that are primarily eliminated by glomerular filtration, such as methotrexate, cisplatin, and carboplatin. Similarly, tubular secretion is reduced in the neonate and achieves adult capacity at about 1 year of age. The ability of the newborn kidney to concentrate urine is also reduced, being around 600 to 700 mOsm/kg H2O for the newborn compared to1,000 mOsm/kg H2O for adults. Urinary pH is also lower in the newborn compared to the older child. Drugs that are more soluble in alkaline urine, such as methotrexate, are excreted at a slower rate.60,65,72 Hence, neonatal renal drug clearance is decreased due to reduced GFR and reduced active secretion.77 Therefore, chemotherapy drugs that are primarily eliminated by the kidneys should be individually tailored using age-appropriate dosages.

Based on the prevalence of specific cancer types, some drugs are more likely to be part of neonatal cancer protocols and will be discussed in greater detail.

Cytosine Arabinoside

Cytosine arabinoside (ARA-C) is one of the most active antimetabolites utilized for treating leukemia.76 Infants tend to accumulate much higher plasma ARA-C concentrations, primarily because of reduced deamination capacity. Neonates also do not eliminate plasma ARA-C by conversion to ARA-U as effectively as older children, leading to higher plasma concentrations. Using standard doses, the plasma concentrations of ARA-C in infants are commonly in the range of 300 to 2500 micromolar.78,79 Pediatric patients with higher than 300 micromolar peak plasma ARA-C concentrations are more likely to develop CNS toxicity80 and therefore dose reduction in the neonate is recommended.

Cyclophosphamide

Cyclophosphamide is a prodrug that requires activation by CYP-450 3A4 and 2D6.59 The slower clearance of this drug in neonates is partially related to the lower production rate of the active metabolite resulting in decreased antineoplastic activity.70

Anthracyclines

Daunorubicin is an important component of many protocols for treatment of malignancy in neonates and infants. It is a cytostatic agent that has proven activity in leukemia and solid tumors. The utility of the drug is limited due to its cardiotoxicity. The cumulative dose is the major risk factor for development of congestive cardiomyopathy. Anthracyclines are metabolized mainly in the liver. Dose reduction is recommended in neonates based on the immaturity of the infant liver as well as the reported cases of toxic death.81These recommendations have led to reduction in the frequency of severe toxicity from anthracyclines in neonates.71

Cisplatin

Germ cell tumors, neuroblastoma, and hepatoblastoma are relatively common neoplasms in neonates. Cisplatin compounds are important components of therapy of these tumors. The platinum drugs are excreted via the kidneys. The tolerance and toxicity of cisplatin have been assessed in infants in whom doses were based on weight.81 Electrolyte disturbances were the most common immediate side effects. Despite glomerular filtration rate (GFR) of less than 80 ml/min/1.73m2 in about half of the infants, long-term toxicity (eg, high-frequency hearing loss) was not more frequent than in older children,81 Dosing on a per weight basis is recommended.

Methotrexate

High-dose regimens of the antimetabolite methotrexate as well as its intrathecal administration are widely used in treatment of acute leukemia/lymphoma and osteosarcoma. Methotrexate is eliminated by glomerular filtration and active tubular secretion via the organic anion tubular transporter. This elimination pathway is less developed in neonates and infants,60,65,72 and translates to a 25% lower administered dose, calculated based on body surface area (BSA) (mg/m2) to achieve similar serum concentrations in infants compared to older children. However, when given intrathecally, the relatively larger central nervous system (CNS) volume does not correlate well with BSA, and lower-than-expected methotrexate concentrations were observed in young infants.59 The generally accepted intrathecal methotrexate dose is 6 mg for patients less than 12 months of age.82

Vincristine

Vincristine is a vinca alkaloid, which is mainly cleared by liver metabolism. Severe hepatotoxicity has been attributed to decreased biliary excretion. In infants, neurotoxicity of vincristine is manifested by extreme hypotonia, poor cry, inability to feed, pain, and hyperesthesia. Fatal flaccid paralysis has been documented.67,71 Patients with BSA lower than 0.5 m2 tend to be at risk for severe neurotoxicity and hepatotoxicity.67 This has led to the recommendation that infants weighing less than 6 kg should receive vincristine dosing based on body weight.67

Etoposide (Vp16)

Etoposide clearance depends on hepatic metabolism. Cytochrome P-450 3A4 is the main isoenzyme responsible for the o-demethylation of etoposide to its catechol metabolite in humans.83 Etoposide dosage regimens based on BSA may be more appropriate for infants and result in less variation in both steady state concentrations and systemic exposure than dose calculations based on body weight.59

Rapid, age-related physiologic changes during the first year of life, affect the absorption, distribution, metabolism, and elimination of drugs. These longitudinal processes should be taken into consideration in chemotherapy dosing in newborns. The lack of direct research data and the resulting knowledge gap regarding optimal dosing of chemotherapy for neonates and infants have led to extrapolation of treatment regimes from dosages used in older children. The result is increased risk of toxicity in infants and inferior outcomes compared with older populations. In general, many neonatal and infant protocols suggest dose reduction of chemotherapy drugs by 50% of doses calculated on body surface area. For lower-weight infants of less than 6 to 10 kg, calculated doses are typically based on actual weight. Recent studies suggest that the simple weight-based model tends to give the best estimate of dose in infants.61,62 In general, dosing based on body weight in the first year of life tends to result in lower doses as compared to calculations based on body surface area (BSA) for this age group.