Pediatr Blood Cancer 2004;43:148–151

BRIEF REPORTSuccessful Treatment of Progressive Stage 4s Hepatic

Neuroblastoma in a Neonate With Intra-ArterialChemoembolization

Michael Weintraub, MD,1* Allan I. Bloom, MD,2 Eitan Gross, MD,3 Shoshana Revel-Vilk, MD,1

Sarit Shahroor, MD,4 Benjamin Z. Koplewitz, MD,2 and Arnold I. Freeman, MD1

INTRODUCTION

Neuroblastoma (NB) is the most common extra-cranialsolid tumor of childhood. It has a highly variable clinicalpresentation, from localized disease, usually in youngerinfants, that has an excellent prognosis, to widely dis-seminated disease in older children with a dismal outcomedespite multi-modality therapy [1]. Stage 4s NB is aunique clinical and biological entity [2]. It occurs ininfants less than 1 year of age, with metastatic diseaseconfined to liver, skin, or bone marrow (but limited to lessthan 10% of nucleated marrow cells). Despite metastaticspread, stage 4s NB has a favorable outcome, with 85–92%of patients becoming long-term survivors, sometimeswith minimal or even no therapy [1,6,8].

Stage 4s NB in neonates up to 2 months of age is anexception to this excellent outcome [1]. Neonates withstage 4s NB and massive liver infiltration may have astormy course, characterized by relentless enlargement ofthe liver that causes extreme abdominal distention, re-sulting in upward displacement of the diaphragm andrespiratory compromise, leading to death from cardior-espiratory failure. These infants may also developprogressive liver failure and disseminated intravascularcoagulation (DIC) secondary to diffuse liver infiltration bytumor [3]. Although there are no exact figures, the mor-tality among neonates with this form of 4s NB appears tobe high despite aggressive therapy, which includeschemotherapy, surgery, and radiation.

We present a case of a neonate with the classicpresentation of hepatic 4s NBwith respiratory and hepatic

failure, who had a rapid and sustained response to directchemoembolization of the hepatic artery.

CASE DESCRIPTION

A 3-week-old girl infant presented to her pediatricianwith a distended abdomen.On physical examination, therewas amass in the right abdomen. Therewas no respiratorydistress. She was referred for further evaluation. An ultra-sound and CT showed a mass in the right adrenal gland,and a diffusely enlarged liver.

Urinary catecholamines were elevated-norepinephrine107 mg/mM creatinine (upper limit of normal 21), andepinephrine-6.11 mg/mM creatinine (upper limit ofnormal-3). Serum LDH was 1,579 U (normal range300–620 U). A bone scan showed no metastatic deposits.Bone marrow aspirate and biopsy showed involvement

Stage 4s neuroblastoma (NB) is a uniqueentity seen in infants less than 1 year of age, withmetastatic disease confined to liver, skin, or bonemarrow. Despite metastatic spread, stage 4s NBhas a favorable outcome. An exception to this isseen in neonates who present with progressiveenlargement of the liver with secondary respira-tory compromise and liver failure. We describe a4-week-old neonate who presented with 4s NB,

with a rapidly enlarging liver, resulting inrespiratory and hepatic failure, who had a rapid,sustained, and ongoing response to chemoembo-lization of the hepatic artery. This approach isfeasible at this age, and may be effective inimproving the outcome in this group of patients.Pediatr Blood Cancer 2004;43:148–151.� 2004 Wiley-Liss, Inc.

Key words: chemoembolization; hepatic neuroblastoma; neonatal neuroblastoma;neuroblastoma

——————1Department of Pediatric Hematology-Oncology, Hadassah University

Hospital, Jerusalem, Israel

2Department of Radiology, Hadassah University Hospital, Jerusalem,

Israel

3Department of Pediatric Surgery, Hadassah University Hospital,

Jerusalem, Israel

4Department of Pediatric Intensive Care, Hadassah University

Hospital, Jerusalem, Israel

*Correspondence to: Michael Weintraub, Pediatric Hematology-

Oncology, Hadassah University Hospital, Ein Kerem, Jerusalem,

Israel 91120. E-mail: michaelw@hadassah.org.il

Received 12 January 2003; Accepted 13 April 2004

� 2004 Wiley-Liss, Inc.DOI 10.1002/pbc.20080

with clumps of tumor cells, but less than 10% of marrownucleated cells. An open biopsy of the adrenal mass andliver showed NB, unfavorable histology, without N-Mycamplification. The liver was completely replaced by NBcells with effacement of normal liver architecture.

The patient deteriorated rapidly and, on the fifth dayfrom admission, progressive enlargement of the liver andabdominal girth caused increasing respiratory compro-mise. Shewas placed onmechanical ventilation. Inviewofthe respiratory deterioration, chemotherapy was begunwith intravenous carboplatinum (500 mg/M2) and etopo-side (100mg/M2). After 24 hr, therewas a further increasein the size of the liver, and decreased urine output. Therewas evidence of decreasing hepatic synthetic functionwith an albumin level of 16 g/L (normal 35–50 g/L), aprothrombin time of 49% (normal 60–100%) and anInternational normalized ratio (INR) of 1.76. It wasconsidered that unless a more radical approach was taken,the patient would succumb. It was decided to attemptdirect hepatic arterial chemoembolization (HACE). Afterobtaining institutional (IRB) approval, and after a de-tailed discussion with the parents, informed consent wasobtained.

The patient was transported to the interventionalradiology suite. The Seldinger technique was used tocannulate the left common femoral artery. A selectiveceliac and superiormesenteric arteriogramwas performedusing a modified 4-French Rim catheter (Cook, Inc.,Bloomington, IN). This demonstrated conventional visc-eral anatomy but with distortion of the hepatic artery dueto marked hepatomegaly (Fig. 1). Using a two to threeFrench coaxial catheter the right hepatic artery wasselected. After cannulation, a solution containing 10mg ofcis-platinum and 7 mg of doxorubicin was slowly injectedover 30 min [14]. Following injection of chemotherapy,embolizationwas achieved using polyvinyl alcohol (PVA)

particles 155–250 microns diameter (Cook, Inc.) untilcessation of flow in the vessel was observed (Fig. 2). Theinfant tolerated the procedure well.

Within 12 hr of the procedure, the size of the liverstabilized and then began to decrease. The abdominal girthdecreased from a maximum of 52 cm on the day of theprocedure to 42 cm, 2 weeks after the procedure. Therewas a transient increase in serum aspartate aminotransfer-ase (AST) from a baseline level of 67 U to a peak of 392 U(normal range 2–60U) 3 days following the procedure anda gradual decline to pre-treatment levels after 18 days.Serum bilirubin decreased from 85 mM/L (normal range2.5–17 mM/L) to 15 mM/L after 28 days. The effect of thechemotherapy (both IV and IA) on hematological para-meters was significant with a white blood cell nadir after7 days of 0.34� 109/L with an absolute neutrophil count(ANC) of 27, and a nadir platelet count of 16,000� 109/Lafter 5 days. TheANC recovered to above 500 after 18 daysand the platelet count to above 100,000 after 21 days. Theinfant was weaned from the ventilator 7 days after theprocedure, resumed oral feedings, and was dischargedfrom the hospital 3 weeks after the procedure. Repeatultrasound and CT, 3 weeks following the procedure,showed a 50% reduction in the size of the liverwith severalhypodense lesions felt to represent areas of necrosis. Inlight of the favorable and rapid response, and based on theassumption that the disease could continue to regressspontaneously, no additional therapy was given.

Over the next 3 months, the liver size returned tonormal. An MIBG scan performed 8 weeks after theprocedure showed a solitary small area of uptake in theposterior aspect of the right lobe of the liver with noadditional foci. An ultrasound of the abdomen at that timerevealed multiple calcifications in the rim of the right

Fig. 1. A digital subtraction arteriogram of the celiac artery. The right

hepatic artery is indicated (arrow).

Fig. 2. A digital subtraction arteriogram after right hepatic artery

chemoembolization. The vessel is attenuated (arrow) and there is no

flow seen in the intra-hepatic branches following occlusion with

polyvinyl alcohol (PVA) particles.

Chemoembolization for Hepatic Neuroblastoma 149

hepatic lobe. There was mild hypomagnesemia, whichrequiredoral supplementationand resolvedafter 2months.The patient is now10months from the procedure, and at 11months of age is completely asymptomatic, gainingweight and attaining normal developmental milestones.Her hematologic and biochemical parameters are withinnormal limits. The most recent CTand MIBG scans showno liver abnormality. Follow-up echocardiography andaudiograms are normal.

DISCUSSION

Stage IV-S NB is a unique cancer, which generallyregresses spontaneously despite initial metastatic spread.Most infants with stage IV-S NB do well with minimal oreven no therapy [1,2,6,8]. The biological basis for thisunusual behavior is unknown.

Despite the overall excellent prognosis of infants withstage IV-S NB, there is a small but distinct subset ofpatients who do poorly [4–6,9]. These are young infants,mostly under 2 months of age, who present with massiveliver involvement. These patients often have a rapidlyprogressive enlargement of the liver that often does notrespond to chemotherapy or to radiation. They developprogressive cardiorespiratory embarrassment secondaryto upward displacement of the diaphragm by the enlargingliver, with ultimate respiratory death. The huge liver mayresult in an increase in intra-abdominal pressure causingan obstructive uropathy with resultant renal failure [3]. Athird important cause of death in these infants is liverfailure with DIC, secondary to replacement of liver tissueby NB. The mortality rate in this subset of patients has notbeen accurately delineated, but appears to be very high.The Italian NB group reported on the outcome of patientswith 4s NB. Most deaths in the younger infants were theresult of progressive liver enlargement. Attempts at thera-peutic intervention were unsuccessful in most of theseinfants, including heroic measures such as temporarysurgical externalization of the liver or placement of silasticpatches [7]. The Children’s Cancer Group reported on theexcellent outcome of 80 patients with stage 4s NB. Overhalf of the patients did not require specific therapy. Only 6of 80 infants died. Five of these deaths were in infantsyounger than 2months of age at diagnosis and were due tocomplications of extensive liver involvement [8]. Thegroup at theChildren’sHospital of Philadelphia developeda scoring system to guide the need for therapeutic inter-vention in infants with hepatic stage 4s NB. Infants wereassigned scores based on the presence of organ compro-mise secondary to liver enlargement. All of the six patientswho had a score greater than 2, died of disease [9]. It isimportant to stress that infants with massive hepatic NBusually die from mechanical causes secondary to theenlarged liver or from DIC and not because of metastaticspread. It has thus been assumed that if the liver enlarge-

ment could be arrested, even temporarily, then the diseasewould ultimately regress as in other cases of stage IV-SNB.Unfortunately, achieving this temporary growth arresthas been elusive.

We present an alternative therapeutic approach to 4shepatic NB with intra-arterial injection of chemotherapyand embolization of the hepatic artery. A 3-week-old girlinfant presented with the classic picture of rapidly pro-gressive hepatic NB, apparently unresponsive to chemo-therapy, and was in respiratory, renal, and hepatic failure aweek following admission. According to the gradingsystem suggested by the Philadelphia group, she had ascore of 4, placing her at near certainty for furtherprogression and death. She had an excellent response toa single hepatic artery chemoembolization using cis-platinum, doxorubicin, and PVA, which resulted in a rapiddecrease in the size of the liver, and, within 2 months, anear-complete response with minimal toxicity.

Intra-arterial chemotherapy (IAC) is a form of regionalchemotherapy and is based on the premise that higherdoses of drugs would be delivered to the tumor bed [10].IAC has been utilized in several clinical circumstances. Inextremity osteosarcoma, IAC with cis-platinum has beenshown to improve rates of local control, but has had noimpact on event-free survival [11]. Intra-HACE has beenutilized in colon carcinoma metastatic to liver whereimproved local response rates have been seen with noimpact on survival [12]. Chemoembolization combinesthe cytotoxic effect of the chemotherapeutic agent to-gether with an ischemic insult produced by arterialocclusion. Hepatic malignancies such as hepatocellularcarcinoma (HCC) and hepatic metastases from coloncarcinoma receive their blood supply primarily from thehepatic artery. This is in contrast to normal liver tissue,which receives its blood supply mainly from the portalvein.

Intra-arterial hepatic chemoembolization has beenshown to be safe and effective in pediatric tumors.Malogolowokin et al. used hepatic chemoembolization(HACE) with cisplatinum and doxorubicin in 11 childrenwith primary liver tumors. All patients responded, and infive of them the response allowed surgical resection [13].Gerber et al. used IAC with doxorubicin and cisplatinumin a group of children with advanced hepatic tumors.Multiple cycles were administered with minimal toxicity.Five of eleven patientswere rendered eligible for orthopticliver transplantation (OLT) following this treatment [14].

Initially there was concern whether this procedure wassafe and feasible in our patient who was only 4 weeks old.Our experience in this one patient suggests that theprocedure is well tolerated and feasible even at this youngage. Furthermore, in our case, a single course of chemo-embolization arrested tumor growth, followed by involu-tion of the liver to normal. In both series reporting onthe use of hepatic chemoembolization in children with

150 Weintraub et al.

primary liver tumors, multiple cycles were administeredwith no significant toxicity [13,14]. Moreover, in thereport by Malogolowokin et al., plasma levels ofcisplatinum and doxorubicin were undetectable followingHACE in all the pediatric patients sampled, suggestingsignificant first pass metabolism of the drugs in the liver,and accounting perhaps for the minimal systemic toxicity.Our patient had no apparent short-term toxicity except fora transient myelosuppression and hypomagnesemia.

Our patient was initially treated with 1 day of intra-venous chemotherapy with etoposide and carboplatinum,but with clear evidence of further disease progression(with a further increase in abdominal girth and the onset ofoliguria). This was followed within 24 hr by intra-arterialchemoembolization with doxorubicin and cisplatinum.Clearly, it is not possible to determine absolutely which ofthese was critical. Prior reports indicate that intravenouschemotherapy and radiation are often not effective inneonates with progressive hepatic 4s NB with organcompromise. In one report, 10 of 11 patients who receivedintravenous chemotherapy or radiation, died of diseaseprogression [7].

Embolization has been utilized to prevent rapid wash-out of the chemotherapy from the liver. However,embolization alone, or surgical tying of the hepatic arteryhas also been employed for many years in adult HCC andcolon cancer metastatic to liver with response rates ofapproximately 25–30%, as evidenced by tumor shrinkagein the liver. Determining which of these two entities, thatis, IAC with cisplatinum and doxorubicin versus chemo-embolization is more important would require a studytreating these neonates with one or the other. This wouldbe a difficult task given the rarity of neonatal NB withmassive liver involvement.

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