Japanese Journal of Clinical Oncology Advance Access published online on July 30, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn068
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© The Author (2008). Published by Oxford University Press. All rights reserved
Patterns of Local Recurrence After Intraoperative Radiotherapy for Advanced Neuroblastoma
1 Department of Radiology, Tokyo Metropolitan Kiyose Children’s Hospital, Tokyo
2 Department of Radiology, Keio University, Tokyo
3 Department of Surgery, Tokyo Metropolitan Kiyose Children’s Hospital, Tokyo
4 Department of Internal Medicine, Tokyo Metropolitan Kiyose Children’s Hospital, Tokyo, Japan
For reprints and all correspondence: Etsuo Kunieda, Department of Radiology, Keio University Shinjuku, Tokyo 160-8582, Japan. E-mail: kunieda-mi{at}umin.ac.jp
Received May 23, 2008; accepted July 7, 2008
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Abstract |
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Objective: The purpose of this study was to retrospectively evaluate local recurrence patterns after intraoperative radiation therapy (IORT) combined with total or subtotal resection and intensive chemotherapy for advanced neuroblastoma.
Methods: The outcomes of 27 patients (14 boys and 13 girls) with advanced-stage neuroblastoma who received IORT as part of multimodality therapy between November 1988 and December 2006 were reviewed in order to evaluate the impact of IORT. Of particular interest was the local recurrence patterns observed.
Results: Six patients relapsed in the abdominal area: three out of six relapsed adjacent to the radiation fields. Other three relapsed in the field of electron ports. Among them, one relapsed in paraspinal lymph nodes, which are behind the irradiated volume but out of the reach of the electron beam, while another relapsed in the lymph nodes of the mesocolon, which had been displaced outside the irradiation field at the time of IORT. The last case relapsed beside the vertebral column near the left ureter, which had been shielded by a lead plate. These three ‘in-field’ recurrences would have been irradiated if external opposite two-beam radiations had been performed, instead of electron beams.
Conclusions: In spite of a complete tumor control in the treated volume, some ‘marginal’ recurrences were observed. Further investigation—for example, a combination of IORT and external-beam radiotherapy—should be considered to achieve higher local control and decrease complication rates.
Key Words: local recurrence • intraoperative radiotherapy • neuroblastoma
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODRESULTDISCUSSIONReferences |
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Neuroblastoma is the most common extracranial solid tumor in childhood. Although substantial improvement in outcome among certain well-defined subsets of patients has been observed during the past few decades, the outcome for children with a high-risk clinical phenotype has improved modestly, with long-term survival still <40% (1–3). The most frequent sites of occurrence are the adrenal gland and retroperitoneal region (4). In most studies, local failure represents the dominant form of disease relapse (4,5). Therapy aimed at achieving local control in patients with high-risk neuroblastoma has evolved significantly during the past decade. For Stage 2 or higher stage patients with MYCN oncogene amplification, or patients with regional lymph node metastases, postoperative radiotherapy is widely performed. In Stages 3 and 4 neuroblastoma, radiotherapy is commonly applied to sites of bulky disease as an adjuvant to surgery and chemotherapy with or without bone-marrow transplantation (6,7).
External-beam radiotherapy (EBRT) has been shown to improve response rates and event-free survival in children with regional lymph node metastases (8,9). The currently recommended radiation fields encompass the primary tumor volume and regional positive lymph nodes after induction chemotherapy, but before surgery (10).
Intraoperative radiation therapy (IORT) is a technique that allows higher effective doses of irradiation to be applied while critical structures are directly visualized, and dose-limiting structures are surgically displaced or shielded at the time of resection. Use of electron beams with the proper acceleration energy can deliver a high-radiation dose to the residual tumor and areas at high-risk for microscopic disease, while reducing the risk of late toxicity to structures outside of the target volume, such as the spinal cord or bony structures (11–18). Although many childhood malignancies are fairly radiosensitive, EBRT tends to be avoided, if it is possible, due to the high-risk of late effects in these young patients (19–21).
In neuroblastoma, radiotherapy occupies an important role in the comprehensive treatment strategy. IORT has been applied, either singly or in combination with EBRT (11–16,22). However, as far as we know, detailed analyses of local recurrence patterns have not yet been sufficiently performed. The purpose of the current study was to retrospectively evaluate the local recurrence patterns of neuroblastoma treated with IORT.
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PATIENTS AND METHOD |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODRESULTDISCUSSIONReferences |
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Patients
The records of 27 advanced-stage neuroblastoma patients (14 boys and 13 girls), who received IORT at Tokyo Metropolitan Kiyose Children's Hospital as part of their multimodality therapy between November 1988 and December 2006, were reviewed (Table 1). Biological features such as MYCN amplifications (23) DNA diploidy or Shimada classification (24,25) of the specimen were investigated from the medical records of the patients. Serial CT and/or MRI images at the time of the local recurrence were carefully reviewed by a radiologist and a radiation oncologist.
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Patient ages ranged from 2 days to 13-year old (median age: 3 years). Disease stage was classified according to the International Neuroblastoma Staging System (INSS) (26,27). Six patients were Stage 3, while 18 were Stage 4. Two were Stage 2 cases with high-risk biological features, such as MYCN amplification or bulky residual tumor after the resection. During the period of the study, all patients who required radiation to the site of the intra-abdominal or retroperitoneal primary disease were treated with IORT.
Surgery and Irradiation
Patients first underwent a partial resection for the purpose of tumor volume reduction and/or biopsy. After several courses of chemotherapy, complete resection of the residual tumor was attempted (a ‘second look’ operation strategy). At the time of the second operation, IORT by electron beam was scheduled.
The IORT was accomplished by transporting the patient from the operating room to the radiotherapy suite subsequent to tumor resection. Either single or multiple Lucite guide-cones of rectangular shape were placed in order to form a field for localized irradiation under sterile conditions. By placing the cones directly on the target volume after surgical exposure, a precise treatment volume was directed and visual confirmation of the exclusion of adjacent organs was achieved. Inclusion of bowels and ureters into the cone was avoided to preclude those from irradiation. Shielding of the normal tissue was accomplished by physical exclusion from the radiation field, or with lead sheet coverings when necessary. After the cone was placed in the operation field, photographs of the IORT port were taken in order to record the range of the irradiation.
The irradiation fields were planned to include the tumor bed and the involved lymph nodes remaining after the intensive chemotherapy preceding the tumor resection. We intended to use as few ports as possible and carefully placed the multiple ports on the target volume so that the adjacent ports were placed very closely together but did not overlap. At the time of the resection, the surgeons and a radiation oncologist assessed the clinical target volume to include the range of the primary tumor and lymph node involvement. In addition, scar tissues found at surgery were included in the target volume even when viable cells were not found with pathological surveys.
Chemotherapy
The patients received chemotherapy with a combination of vincristine, cyclophosphamide, THP–Adriamycin, cisplatin and etoposide according to the protocol proposed by the Japanese Study Group (28,29). Prior to tumor resection, patients first received several cyclic courses of intensive induction chemotherapy. All but two, who died immediately after surgery, had postoperative chemotherapy. Eleven out of the 27 patients had bone-marrow transplantation preceded by myeloablative chemotherapy.
After the course of therapy was completed, all patents were periodically examined at intervals of 1–3 months. The majority of the patients was subsequently monitored by physicians from our institution, but a few were seen by community pediatricians in hospitals or clinics closer to the patients’ homes. In the case of the latter, physical and radiological examinations were carried out with a similar schedule to that of our institution. CT or MRI as well as 123I-MIBG scintigraphy were performed every 3 months in order to survey the patient for either local recurrence or distant metastases.
Statistical Analysis
Follow-up was determined from the date of the IORT, rather than date of diagnosis, as well as Kaplan–Meier time-to-event estimates of the local recurrence. The subgroups were compared using the log-rank statistics.
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RESULT |
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Total resections of the tumors were accomplished in all but three cases. Electron-beam energy was 6 MeV (4 MeV for one patient who was 6-month old at the time of IORT) and doses of 8, 10, 12 and 15 Gy were used for 1, 10, 14 and 2 patients, respectively. The selection policy for the beam energy was to use 6 MeV in order to include the clinical target volume (shallower than 1.5 cm depth) in the high-dose volume, except for the cases with shallow spinal cord. Before 2001, doses of 12 Gy or higher were employed, but subsequently we changed the protocol for doses of 10 Gy or lower. The prescribed doses were defined at the peak dose of the depth profile for the electron beam. Fifteen patients were irradiated with a single electron beam, whereas the other 12 patients needed more than two adjacent ports (five two-port, five three-port and two four-port fields) to produce an appropriate conformed field. The field sizes ranged from 25 to 105 cm2 (summations for multiple ports: median 50).
No additional ERBT to intra-abdominal or retroperitoneal primary sites was scheduled at the time of surgical resection. However, seven patients received EBRT in extra-abdominal regions, outside of the treated area of IORT, in order to treat metastatic lesions identified prior to resection. One patient received total body irradiation followed by bone-marrow transplantation.
In our study, three patients had a subtotal resection, and none of them had local recurrences. However, two of them died shortly after surgery (2 and 69 days), and therefore, we were unable to analyze the impact of IORT on the subset of patients with subtotally resected tumors.
With Stage 3 or less, overall survival rate was 78 and 78% at 2 and 5 years, respectively, and with Stage 4, overall survival rate was 71 and 21% at 2 and 5 years, respectively (P = 0.05). With Stage 3 or less, local recurrence rate was 24 and 31% at 2 and 5 years, respectively, and with Stage 4, local recurrence rates were 33, 33 and 33% at 2, 5 and 10 years, respectively (Fig. 1: no statistical significance). The local recurrence rate for the patient treated with myeloablative chemotherapy followed by bone-marrow transplantation, and conventional chemotherapy protocol, is indicated in Fig. 2. Cases with myeloablative chemotherapy indicated higher local control but these had no statistical significance.
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Local recurrences in the area of the abdomen were observed in six patients (Table 2). Three relapsed adjacent to the irradiation fields. In contrast, three others relapsed above or behind the area of electron ports. Of these three, one patient relapsed in the paraspinal lymph nodes behind the irradiation field, which was beyond the reach of the electron beam (
2 cm). Another relapsed in the lymph nodes of the mesocolon, which had been moved outside the irradiation field at the time of IORT in order to prevent radiation damage of the transverse colon. The last case relapsed in the left aspect of the vertebral column. This portion had been shielded by a lead plate, to prevent radiation-induced damage to the left ureter.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODRESULTDISCUSSIONReferences |
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The efficacy of IORT has been reported in advanced neuroblastoma (11,13,14,22). Retrospective studies of patients who received IORT using different chemotherapy protocols report higher local control rates compared with those treated with conventional therapy protocols alone (14–18,22). Although the most effective intraoperative dose is not yet known, a single dose of IORT is usually restricted to 10–20 Gy, roughly equivalent to
25–50 Gy in standard fractionation protocols (30). Our retrospective study suggests that 10–12 Gy using adequate electron-beam energy is sufficient for the elimination of microscopic viable tumor cells, and this finding is consistent with prior studies (14–16). The complication rate of IORT is satisfactorily low (15,16). Kaneko et al. (22) have suggested that extensive surgery, with a correspondingly high risk of vascular complications, might be avoidable with supplemental IORT in advanced neuroblastoma cases. In spite of apparently excellent tumor control in the irradiated region, recurrences near the treated volume occurred in six patients of our cohort. Among these, three relapsed in the area of the port. However, this occurred beyond the range of the electron beam. There is a possibility that the subsequent EBRT after IORT might have prevented some of the recurrences. In particular, the radiation dose would have been delivered to the mesocolon, paraspinal lymph nodes and left ureter if EBRT had been carried out with parallel opposite beams for the same range of electron ports of the IORT.
The recommended radiation fields in EBRT encompass the primary tumor volume as well as regional positive lymph nodes remaining after induction chemotherapy, but before surgery (10). Advantages of EBRT compared with IORT include its widespread availability, because the radiation delivered is spread out among a wider area. Recently, lower doses tend to be used with EBRT in addition to the intensive myeloablative chemotherapy along with bone-marrow transplantations (31,32).
Although the control rate of advanced-stage neuroblastoma was improved through these multi-disciplinary treatments, in-field local control with EBRT might not be as high as that seen with IORT. In addition, late toxicities of EBRT, including growth retardation due to irradiation of growth plates of bones and insufficiency of other organs may result in significant treatment-related sequelae. Simon et al. (33) reported that higher doses of EBRT appeared effective in the treatment of residual tumors after surgery. However, despite a strictly confined beam, delivery of higher dose radiation may lead to higher rates of late adverse effects.
In contrast, potential disadvantages of IORT include the limited size of the irradiation field employed and the need for multiple ports to conform a single conjunctive irradiation field to encompass the clinical target volume. Although past reports suggest good local control, detailed analyses of local recurrence patterns have not yet been performed.
Based on our results, we would suggest that a combination of IORT and EBRT might improve local recurrence rates with decreased complication rates. Although the simple addition of EBRT and IORT doses may result in higher complication rates in areas in which the applied field overlaps, future studies seeking to determine the optimal combination doses in each approach, in order to maximize outcome with limited adverse effects, would be appropriate. We may consider the additional use of EBRT only for high-risk patients for local recurrence with IORT alone, or for cases in which IORT raises technical problems with regard to extirpating the entire neuroblastoma cells.
Conflict of interest statement
None declared.
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References |
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