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Clinical Significance of Intensive Surgery With IntraoperativeRadiation for Advanced Neuroblastoma:

Does It Really Make Sense?By Tatsuo Kuroda, Morihiro Saeki, Toshiro Honna, Hidekazu Masaki, and Yukiko Tsunematsu

Tokyo, Japan

urpose: The aim of this study was to evaluate the signifi-ance of intensive surgery combined with intraoperativeadiation therapy (IORT) in advanced neuroblastoma.

ethods: Clinical features and outcome were reviewed in 33dvanced neuroblastoma patients (24 with INSS stage 4, 9ith stage 3), who had surgery (total excision 29, subtotalxcision 4) with IORT (10 to 15 Gy) against the primary tumorite.

esults: Three patients (8.8%) had relapse at the primary site,ll of which arose from the unirradiated area after stem cellransplantation. Among 29 patients with total excision, dis-ase-free survival was obtained in 15 (51.7%) for an averagef 6.9 years, which included 5 survivors of 9 patients (55.9%)ith amplified N-myc. In contrast, none of 4 patients with

mmediately after the surgery, had postoperative chemotherapy.

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ournal of Pediatric Surgery, Vol 38, No 12 (December), 2003: pp 1735-173

howed significantly longer survival rates in the patientsith total resection compared with those with macroscopic

emnants.

onclusions: The intensive surgery with IORT dramaticallyncreased the local eradication and improved the outcomeven in advanced neuroblastoma with N-myc amplification.owever, long-term survival was not obtained in patientsith unresectable residual disease. These results may indi-

ate the key role of surgical eradication in advancedeuroblastoma.Pediatr Surg 38:1735-1738. © 2003 Elsevier Inc. All rights

eserved.

NDEX WORDS: Neuroblastoma, intraoperative radiation

HE CLINICAL significance of intensive surgicaltherapy as a means to control the local lesion has

een controversial in the treatment of advanced neuro-lastoma to date. Renal vascular problems and otherajor complications were reported after extensive surgi-

al resection of neuroblastoma.1,2 In addition, neuro-lastoma cells in the peripheral blood were recentlyetected, suggesting that the tumor cells may be spreadhrough the systemic circulation in advanced disease.3-6

owever, the efficacy of intraoperative irradiationherapy (IORT) has been reported in advanced neuro-lastoma.7-10 To evaluate the clinical significance ofxtensive surgery with IORT in advanced neuroblas-oma, our 17-year experience of IORT was reviewed inhe current study.

MATERIALS AND METHODS

Thirty-three neuroblastoma patients with advanced stages (24 withtage 4, 9 with stage 3 [International Neuroblastoma Staging System]),ho had tumor resection with IORT (10 to 15 Gy, 12 MeV of electroneam) against the primary tumor site in our department between 1985nd 2001, were involved in the current study. The age of the patients atnitial diagnosis ranged from 7 months to 10.3 years (average 3.2ears), and included 16 boys and 17 girls. The primary tumor origi-ated from the adrenal gland in 28, retroperitoneal space in 4, andultiple sites in 1. All patients received chemotherapy with a combi-

ation of vincristine, cyclophosphamide, THP-Adriamycin, cisplatin,nd etoposide according to the protocol proposed by the Japanesetudy Group11 preceding the tumor resection, and all but 2, who died

wenty-one of 33 patients had stem cell transplantation (SCT)ostoperatively.The clinical features and the outcomes were analyzed retrospectively

n relation to the surgical eradication, the macroscopic residual, themplification of N-myc oncogene, and the minimal residual diseaseMRD) detected by polymerase chain reaction as previously de-cribed.12 The Kaplan-Meier analysis was done, and the differenceetween the survival curves was statistically tested by Logranknalysis.

RESULTS

urgical Eradication and Disease-Free Survival

In the current series, 29 patients had total tumoresection with intensive lymph node dissection, whereas

had histologically confirmed macroscopic residual aturgery. The macroscopic residual was highly suspectedut not confirmed in 1 patient. Among the former 29atients, disease-free survival was obtained in 1551.7%) for an average of 6.8 years after completing the

From the Departments of Surgery, Radiology, and Pediatric Oncol-gy, National Center for Child Health and Development, Tokyo, Japan.Presented at the 36th Annual Meeting of the Pacific Association of

ediatric Surgeons, Sydney, Australia, May 12-16, 2003.Address reprint requests to Tatsuo Kuroda, MD, Department of

urgery, National Center for Child Health and Development, 2-10-1kura, Setagaya-ku, Tokyo 157-8535, Japan.© 2003 Elsevier Inc. All rights reserved.0022-3468/03/3812-0009$30.00/0

acroscopic residual survived. The Kaplan-Meier analysis

herapy, surgical eradication.

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doi:10.1016/j.jpedsurg.2003.08.043

17358

treatment, 10 died of the disease, 2 died of complica-tions, and 2 are alive with tumor at present. During thelast 10 years, disease-free survival was obtained in 11 of20 patients (55.0%) with total resection and IORT. Incontrast, all 3 patients with confirmed macroscopic re-sidual died an average of 0.6 years after the treatment. Apatient with suspected macroscopic residual survived for8 years and 9 months and died of metastatic disease.

Two patients had minor maldevelopment of the irra-diated vertebra; however, no other major complication ofIORT has been identified in the current series so far.

Tumor Relapse at the Primary Site

No tumor relapse was seen in the radiated field ofIORT in our series including 3 patients with confirmedmacroscopic residual. Three patients (8.8%) had tumorrelapse around the primary site. The tumor relapsedbehind the kidney, which was masked by a lead plateduring IORT to preserve renal function in 1 case, andrelapse occurred outside the radiated area in the 2 othercases. All 3 patients with local relapse had total tumorresection followed by SCT precedingly.

N-myc Oncogene Amplification and the ClinicalOutcome

The amplification of N-myc oncogene was measuredin 19 patients who had total resection and IORT and wasamplified in 9. Among those with N-myc amplification,disease-free survival was obtained in 5 (55.9%) for anaverage of 3.7 years (2 years to 6.75 years), 3 died of thedisease, and 1 died of adenoviral pneumonia withoutevidence of tumor relapse.

Minimal Residual Tumor and the Clinical Outcome

Minimal residual disease (MRD) was examined atsurgery in 10 patients who had total resection and IORT;4 had positive MRD in bone marrow, whereas 6 had nodetectable MRD. Disease-free survival was obtained in 2of 4 patients (50.0%) with positive MRD and in 4 of 6patients (66.7%) with negative MRD after SCT.

Kaplan-Meier Analysis

The patients with total resection and IORT showedsignificantly longer survival compared with those withconfirmed macroscopic residual and IORT in theKaplan-Meier analysis (P � 0.01). In contrast, no statis-tically significant difference was found in the Kaplan-Meier survival curves of the patients with total resectionand IORT between SCT and conventional chemotherapy,the amplified and unamplified N-myc oncogene, andpositive and negative marrow MRD at surgery (Fig 1).

DISCUSSION

In advanced neuroblastoma, circulating tumor cellswere detected recently in the peripheral blood by severalmethods, suggesting that advanced disease is no longerlocalized.3-6,13 Therefore, the role of extensive surgerywith a higher incidence of major complications was notsupported in some reports.10,14,15 However, the impor-tance of intensive local treatment for advanced neuro-blastoma was emphasized in other studies.16-19 Totalsurgical resection with IORT is considered to be the mostintensive surgical therapy to control the local malignantlesion, because the electron beam of IORT is estimatedto reach to the depth of 1 cm into the tissue and eliminatethe viable tumor cells. Although several investigatorsreported the efficacy of IORT in advanced neuroblasto-ma,7-10 the basic question remains unanswered; doesIORT provide adequate local eradication for the unre-sected macroscopic residual, or should total resectionwith IORT be required?

The current results show the dramatic increase of localeradication provided by IORT, because no local relapsewas seen from the radiated field in the series. All localrelapses in the current series arose from the unradiatedarea after total resection, suggesting that the macroscopictotal resection may not guarantee the adequate localclearance. In addition, even the patients with macro-scopic residual developed no relapse from the radiatedlesion. The current results, therefore, seem to indicatethat IORT may be able to control the local unresectabletumor in neuroblastoma and that less radical surgicaldissection may be adequate if IORT is added. Kaneko etal10 suggested that the extensive surgery with high risk ofvascular complications might be avoidable with supple-mental IORT in advanced neuroblastoma. However,even though IORT controlled successfully the primarylesion, no long-term survival was obtained in all 3patients with confirmed macroscopic residual in ourseries. None of the 3 patients had tumor relapse at theirradiated area but all uniformly died of the tumor.Macroscopic residual may result in spread or dissemina-tion of the viable tumor cells before the tumor tissue isdestroyed by IORT.

In contrast, with total resection and IORT, disease-freesurvival was obtained in 51.7% of the overall patients.Especially during the last 10 years, disease-free survivalwas obtained in 55.9% of the patients with amplifiedN-myc oncogene, which is more optimistic when com-pared with the results from the nationwide study ofneuroblastoma.20 The results suggest the importance ofsurgical eradication in advanced neuroblastoma and,therefore, that aggressive surgery with IORT should bejustified, even though some researchers have pointed outthe high incidence of complications after extensive sur-

1736 KURODA ET AL

gery and recommended less radical surgery for advancedneuroblastoma.1,2,10,14,15 This finding is supported also bythe results of Kaplan-Meier analysis. In the currentseries, statistically significant differences in the survivalcurves were shown only between the patients with totalsurgical resection and those with macroscopic residual,whereas known prognostic factors such as the amplifi-cation of N-myc oncogene did not significantly alter thesurvival rate. Surgical eradication must be an importantand predictive clinical prognostic factor in advancedneuroblastoma.

The volume of the residual tumor may affect theoutcome. Interestingly, minimal residual tumor, whichwas detectable only by polymerase chain reaction (PCR),showed different clinical features from the macroscopicresidual. Long disease-free survival was obtained in66.7% of cases of negative MRD, and also in 50% ofcases of positive marrow MRD at surgery. Survival rate

by the Kaplan-Meier analysis was not significantly dif-ferent according to the MRD. The minimal residualtumor may be curable by modern chemotherapy includ-ing SCT or total body irradiation.

No major complications, other than mild maldevelop-ment of hemivertebra, was identified in our series, sug-gesting that IORT can be performed safely. However,review of the cases with local relapse suggested thatIORT did not cover an adequate area, and high-risklesions could be left unirradiated. Furthermore, the radi-ation dose may be decreased at the edge of the field byrespiratory movement. These risks may limit the efficacyof IORT in the practical setting.

The current results suggest a key role of surgicalresection and local clearance in advanced neuroblastoma.IORT is considered a strong supplemental therapy toincrease local eradication and to improve the clinicaloutcome in advanced neuroblastoma.

REFERENCES

1. Day DL, Johnson RT, Odrezin GT, et al: Renal atrophy orinfarction in children with neuroblastoma. Radiology 180:493-495,1991

2. Canete A, Jovani C, Lopez A, et al: Surgical treatment forneuroblastoma: Complications during 15 years experience. J PediatrSurg 33:1526-1530, 1998

Fig 1. Kaplan-Meier survival curves. (A) Total resection versus confirmed macroscopic residual. (B) Stem cell transplantation versus

conventional chemotherapy. (C) Amplified versus unamplified N-myc oncogene. (D) Positive versus negative MRD at surgery. The patients with

total resection and IORT showed significantly longer survival compared with those with confirmed macroscopic residual and IORT (P < .01; A).

However, no statistically significant difference of survival curve was found in the patients with total resection and IORT between stem cell

transplantation and conventional chemotherapy (B), amplified and unamplified N-myc oncogene (C), and positive and negative MRD at surgery

(D) in Kaplan-Meier analysis. NS, not significant. MRD, minimal residual disease.

1737INTRAOPERATIVE RADIATION FOR NEUROBLASTOMA

3. Burchill SA, Bradbury FM, Smith B, et al: Neuroblastoma celldetection by reverse transcriptase-polymerase chain reaction (RT-PCR)for tyrosine hydroxylase mRNA. Int J Cancer 57:671-675, 1994

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16. Matthay KK, Atkinson JB, Stram DO, et al: Pattern of relapseafter autologous purged bone marrow transplantation for neuroblas-toma: A Children’s Cancer Study Group pilot study. J Clin Oncol11:2226-2233, 1993

17. La Quaglia MP, Kushner BH, Heller GA: Stage 4 neuroblastomadiagnosed at more than 1 year of age: Gross total resection and clinicaloutcome. J Pediatr Surg 29:1162-1166, 1992

18. Tsuchida Y, Yokoyama J, Kaneko M, et al: Therapeutic signif-icance of surgery in advanced neuroblastoma: A report from the studygroup of Japan. J Pediatr Surg 27:616-622, 1992

19. Castel V, Tovar JA, Costa E, et al: The role of surgery in stageIV neuroblastoma. J Pediatr Surg 37:1574-1578, 2002

20. Kaneko M, Tsuchida Y, Uchino J, et al: Treatment results ofadvanced neuroblastoma with first Japanese study group protocol.Study Group of Japan for Treatment of Advanced Neuroblastoma.J Pediatr Hematol Oncol 21:190-197, 1999

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