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ORIGINAL ARTICLES

Prognostic factors including neoadjuvant chemotherapy in Mexican children with neuroblastoma Alberto Olaya-Vargas, Roberto Rivera-Luna, Rocío Cárdenas-Cardós, Araceli Castellanos Toledo, Óscar Alberto Pérez González, Julieta Robles Castro and Carlos Calderón Elvir Department of Oncology. Instituto Nacional de Pediatría. Secretaría de Salud. Mexico City. Mexico.

Introduction. There are several prognostic factors in children with neuroblastoma that have been outlined in the international literature. Material and methods. A retrospective study was carried out analysing the medical records of patients with the pathological diagnosis of neuroblastoma seen at the Department of Oncology from the Instituto Nacional de Pediatría (Mexico) between January 1984 to January 1997. A total of 32 clinical prognostic factors were assess in our population. Results. Fifty five patients whose age ranged from 1 to 168 months old, mean of 35 months were included. Out of 32 prognostic factors only 6 including sex (p= 0.0039), metastatic disease to bone (p= 0.003), bone marrow involvement (p= 0.0027), staging system (p= 0.000015), surgical treatment (p 0,0022) and neoadjuvant chemotherapy (p.005) were the most significant. Conclusions. It was concluded that besides the prognostic factors outlined, neoadjuvant chemotherapy is of utmost importance. It decreases tumor volume and allows surgery to be more successful, therefore believing that this variable represents a specific prognostic factor in cases of advanced neuroblastoma. Key words: neuroblastoma, prognostic factors, neoadjuvant chemotherapy. Olaya-Vargas A, Rivera-Luna R, Cárdenas-Cardós R, Castellanos Toledo A, Pérez González OA, Robles Castro J, Calderón Elvir C. Prognostic factors including neoadjuvant chemotherapy in mexican children with neuroblastoma. Clin Transl Oncol. 2005;7(1):12-7.

Factores pronósticos incluyendo quimioterapia neoadyuvante en niños mexicanos con neuroblastoma Introducción. Existen diferentes factores pronósticos en los niños con neuroblastoma, estos factores tienen diferente peso específico de acuerdo a la literatura internacional. Material y métodos. Se realizó un estudio retrospectivo, analizando los expedientes clínicos de los pacientes con el diagnóstico de neuroblastoma, tratados en el Instituto Nacional de Pediatría (México) de enero de 1984 a enero de 1997. Se analizaron un total de 32 factores pronósticos clínicos dentro de nuestra población. Resultados. Se incluyeron un total de 55 pacientes, con un rango de edad de 1 a 68 meses, con una media de 36 meses de edad. De los 32 factores pronósticos evaluados, únicamente 6 fueron significativos, los cuales incluyeron el sexo (p= 0,0039), enfermedad metastásica a hueso (p= 0,003), infiltración a médula ósea (p= 0,0027), estadificación (p= 0,000015), tratamiento quirúrgico (p= 0,0022) y el uso de quimioterapia neoadyuvante (p= 0,005). Conclusiones. En análisis de los resultados de los diferentes factores pronósticos nos permiten concluir que la quimioterapia neoadyuvante realiza un papel importante al permitir la disminución del volumen tumoral, lo que permite que la resección quirúrgica pueda ser completa. El resto de las variables que fueron significativas están asociadas directamente con la presencia de neuroblastoma en estadio avanzado. Palabras clave: neuroblastoma, factores pronósticos, quimioterapia neoadyuvante.

INTRODUCTION

Correspondence: Dr. Alberto Olaya-Vargas. Department of Oncology. Instituto Nacional de Pediatría SS. Insurgentes Sur 3700-C. 04530 México D.F. México. Received 19 February 2004; Revised 6 May 2004; Accepted 18 June 2004.

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Neural crest tumors include neuroblastoma (NB), ganglioneuroblastoma and ganglioneuroma. The neuroblastoma is one of the most common extracraneal solid tumors in children comprising 8% to 10% of all

Clin Transl Oncol. 2005;7(1):12-7

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OLAYA-VARGAS A, RIVERA-LUNA R, CÁRDENAS-CARDÓS R, ET AL. PROGNOSTIC FACTORS INCLUDING NEOADJUVANT CHEMOTHERAPY IN MEXICAN CHILDREN WITH NEUROBLASTOMA

childhood cancer-related illnesses1-3. However in Mexico it appears to be not a common tumor4,5. To date, the presence of partial deletion of the short arm of chromosome 1 (1p) and N-myc protooncogene appear to be very strong prognostic factors6-9. However, the finnancial cost and technical inability to routinely conduct cytogenetic and molecular studies on these patients in underdeveloped countries makes it imperative to use other prognostic factors including clinical, laboratory, radiologic, pathologic and treatment factors. The purpose of the current work is to assess these factors associated with NB in mexican children and compare them with those reported in the literature.

MATERIAL AND METHOD The medical records of patients with the histopathological diagnosis of NB registered at the Oncology Department of the Instituto Nacional de Pediatría between January 1984 and January 1997 were analysed. Patients under treatment, without histopathological diagnoses or with incomplete files were excluded from the study. The analysis included placing each patient in the three staging systems (tables 1, 2, 3) and conducting a comparative analysis. A total of 32 selected variables were analysed as clinical prognostic factors based on the international literature and on our experience5,8,10-13 (table 4).

For the statistical analysis, an SPSS version 10 program was used to estimate the descriptive, as well as the X2 distribution analysis with a statistical significance of p < 0.05. The significance variables was evaluate with multivariety analysis. All variables were compared to the disease-free survival rate in search of a statistically significant correlation with Cox test. RESULTS A total of 55 patients, between 1 and 168 months old (average of 35.6 months) were included. There were 18 cases (32.7%) under a year old and 37 over a year old (67.4%). Of the total number of patients, 33 (60%) were males and 22 (40%) females with a 1.5:1 ratio. All patients had at least one symptom at diagnosis, while 63.7% had symptoms at least 2 months before diagnosed with the disease (mean 4.78 months). The most frequent symptoms reported were: palpable mass (70%), fever (50%), pain (30%), radicular compresion (27%), superior vena cava syndrome (11 %), untreatable diarrea (7%), seizures, Horner's syndrome and skin lesions in one patient, respectively (2%). No case had documented hypertension, hematuria or hemihypertrophy. With respect to their location, tumors were more frequently found in the retroperitoneum (36.4%), followed by the adrenal glands (30.9%), intramedullarly (3.6%), mediastinum (5.5%), and other sites (5.5%). It is noteworthy that 18.2% of the cases were in unknown sites. With respect to the behavior

TABLE 1. Evans (CCSG) staging sytem in 55 patients with neuroblastoma Stage

Number of patients (%)

Stage I Stage II

1 (2) 2 (4)

Stage III

7 (13)

Stage IV

40 (72)

Stage IVS

5 (9)

Description Tumor confine to the structure of origin Tumor extending in continuity beyond the structure of origin but not crossing the midline, regional ipsilateral lymph nodes may be involved Tumor extendity in continuity beyond the midline; regional Iymph nodes possibly involved bilaterally Remote disease involving the skeleton, bone marrow, soft tissue and distant lymph node groups As defined in stage I or II, except for the presence of remote disease confined to the liver, skin on bone marrow (without bone metastasis)

TABLE 2. Pediatric Oncology Group (POG) staging system in 55 patients with neuroblastoma Stage


Stage A

1 (2)

Stage B Stage C

2 (4) 7 (13)

Stage D

40 (72)

Stage D-S 29

5 (9)

Description Complete gross resection of primary tumor, microscopic residual disease positive or negative, nodes adhered to primary tumor may be positive, other intracavitary nodes negative Grossly unresected primary tumor, nodes and nodules the same as in stage A Complete or incomplete resection of primary tumor; intracavitary nodes not adhered to primary tumor histologically positive; liver as in stage A Dissemination of disease beyond intracavitary nodes (i.e., extracavitary nodes, liver, skin, bone marrow, bone, etc.) Infants less than 1 year old with stage IV-S disease


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TABLE 3. International Neuroblastoam Staging System (INSS) in 55 patients with neuroblastoma Stage


Stage 1

1 (2)

Stage 2A

1 (2)

Stage 2B

1 (2)

Stage 3

6 (11)

Stage 4

41 (74)

Stage 4-S

5 (9)

Description Localized tumor confined to the area of origin, complete gross excision, with or without microscopic residual disease, identifiable nodes ipsilateral and contralateral negative microscopically Unilateral tumor with incomplete gross excision; identifiable ipsilateral and contralateral lymph nodes negative microscopically Unilateral tumor with complete or not gross excision; positive ipsilateral regional lymph node, identifiable contralateral Iymph nodes negative microscopically Tumor infiltrataing across the midline with or without regional Iymph node involvement; or unilateral tumor with contralateral regional Iymph node involvement; or midline tumor with bilateral Iymph node involvement Disemination of tumor to distant Iymph nodes, bone, bone marrow, liver or other organs (except as defined in stage 4S) Localized primary tumor as defined for stage 1 or 2 with dissemination limited to liver, skin or bone marrow

TABLE 4. Comparative analysis of prognostic factors analysed in patients with neuroblastoma Variables

Age at diagnosis Sex Symptoms at diagnosis Duration of symptoms prior to diagnosis Palpable tumor Fever Arterial hypertension Horner syndrome Superior vena cava compression syndrome Hemihypertrophy Pain at tumor site Protracted diarrhea Seizures Skin tumor infiltration Spinal tumor compression syndrome Number of symptoms (>2) Primary tumor site Hemoglobin at diagnosis Total leucocyte count at diagnosis Tye of surgery (biopsy versus tumor resection) Pathologic diagnosis (undifferentiated versus differentiated) Number of metastasis (one versus multiple) Liver metastasis Lung metastasis Spinal metastasis Bone marrow metastasis Metastatic subcutaneous nodes Metastatic central nervous system disease Bone metastasis Lymph node metastasis Evans staging system INSS staging system

Correlation ANOVA p 0.085 0.0039 0.72 0.31 0.94 0.53 0.66 0.64 0.31 0.91 0.11 0.72 0.64 0.64 0.82 0.25 0.96 0.72 0.31 0.0022 0.14 0.000047 0.67 0.91 0.50 0.0027 0.12 0.51 0.003 0.57 0.000015 0.00024

of the NBs, only 7.4% were sole tumors, while 82.6% were metastatics tumors at diagnosis. Of these, 55% had one metastasis and 45% multiple metastases. The mean number of metastasis at diagnosis was 2 (SD 0.87), to bone (60%), bone marrow (29%), liver (25%),

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subcutaneous tissue (16%), lungs (11%), spinal cord (5%) and CNS (3%). Based on Evans classification, 2% of the cases were stage I, 4% stage II, 13% stage III, 72% stage IV and only 9% stage IVs. According to the INSS classification system, 2% were stage I, 2% stage 2a, 2% stage 2b, 11% stage 3, 74% stage 4 and 4s 9%. All patients were given standard treatment using chemotherapy based on Evan’s staging system following St. Judes 94 protocol, except those stage I and II under 365 days, where control of the primary tumor was done surgically. Stage III and IV cases were given radiotherapy directed to the primary tumor when control was not achieved during the first phase of treatment or second stage surgery if the tumor was resecable after the first phase of treatment with chemotherapy. Eighteen patients (31%) achieved total tumor resection; in 60% the lesion was biopsied and 5% was submitted to a partial resection of the primary tumor. A statistical correlation was carried out using the Cox test beetween each of the tested variables and the final outcome of the disease in order to establish the predictive value. It was found that for sex, type of surgery, presence and number of metastasis, as well bone and bone marrow involvement, Evans or INSS staging were statistically significant (p < 0.005). 1) Sex: it was seen that all female patients died (22 patients) in contrast to male patients of which 23 died and 10 were disease-free after two years with a p =0.0039. 2) Type of surgery: it was found that of those patients with favorable evolutions, 70% had been submitted to complete resection of their primary tumor, in comparison to 12% of the patients with a fatal evolution (p=0.0022), while 88% of the patients with fatal evolution had partial tumor resection or biopsy of the tumor. 3) Number of metastases at diagnosis: there was a statistically significant relation (p=0.000047) between the total number of metastases and the final evolution. In those patients with a favorable evolution, the


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%

Overall survival 1.0

100

Cum survival

0.8

BM metastasis Negative Positive

0.6

60

0.4

40

0.2

20

0.0 0

10

20 30 Months after diagnosis

40

50

p < 0.00001 Stage I Stage II Stage III Stage IV Stage IVS

80

0 0

5

10

15 Months

20

25

Fig. 1. Overall survival in patients with bone marrow (BM) metastasis.

Fig. 2. Overall survival in patients with neuroblastoma for stage.

mean number of metastases was 0.4, and for patients with a fatal evolution it was 2.3. 4) Metastases to bone and bone marrow: when analyzed separately and compared with the final evolution, they were statistically significant as factors of bad prognosis with a p=0.0027 and 0.003, respectively (fig. 1). 5) Staging: staging was statistically significant with a p=0.000015 for the Evans classification and p=0.00024 for the INSS classification without any statistical differences between either. The other 25 variables analysed were of no prognostic value, although they were carefully analysed according to age. Based on each patient’s age, two groups were comrised: those under 12 months old and those 13 months and older. Eighteen patients were under 12 months of age, of which 5 (28%) had a favorable evolution and 13 (72%) a fatal evolution. No statistical differences were found in comparison to the group of patients over 12 months old, of which 5 (13%) had a favorable evolution and 32 (87%) a fatal evolution. Overall survival was 36%. The current survival curve after 2 years was 100% for stage I patients, 100% for stage II, 0% for stage IV, 42% for stage III and 11% for stage IV. A statistically significant difference was shown (p < 0.02) between stage I survival compared with stage II and IV; the difference was even greater (p