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Hyperfractionated Low-Dose Radiotherapy for High-Risk Neuroblastoma After Intensive Chemotherapy and Surgery

From the Departments of Epidemiology and Biostatistics, Pediatrics, and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Brian H. Kushner, MD, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: kushnerb{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To assess prognostic factors for local control in high-risk neuroblastoma patients treated with hyperfractionated 21-Gy total dose to consolidate remission achieved by dose-intensive chemotherapy and surgery.

PATIENTS AND METHODS: Patients with high-risk neuroblastoma in first remission received local radiotherapy (RT) totaling 21 Gy in twice-daily 1.5-Gy fractions. RT to the primary site followed dose-intensive chemotherapy and tumor resection; the target field encompassed the extent of tumor at diagnosis, plus 3-cm margins and regional lymph nodes. RT to distant sites followed radiologic evidence of response. Local failure was correlated with clinical factors (including other consolidative treatments) and biologic findings.

RESULTS: Of 99 consecutively irradiated patients followed for a median of 21.1 months from RT, 10 relapsed in or at margins of RT fields at 1 to 27 months (median, 14 months). At 36 months after RT, the probability of primary-site failure was 10.1% ± 5.3%. No primary-site relapses occurred among the 23 patients whose tumors were excised at diagnosis, but there were three such relapses among the seven patients who were irradiated with evidence of residual disease in the primary site. Four of 18 patients with MYCN-amplified disease and serum lactate dehydrogenase greater than 1,500 U/L had local failures (23.4% ± 10.7% risk at 18 months). Acute radiotoxicities were insignificant, but three of 35 patients followed for 36 months had short stature from decreased growth of irradiated vertebra.

CONCLUSION: Hyperfractionated 21-Gy RT is well tolerated and, together with dose-intensive chemotherapy and surgery, may help in local control of high-risk neuroblastoma. Extending the RT field to definitively encompass regional nodal groups may improve results. Visible residual disease may warrant higher RT dosing. Patients with biologically unfavorable disease may be at increased risk for local failure. RT to the primary site may not be necessary when tumors are excised at diagnosis.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THROUGH THE 1980s, survival rates of children with stage 4 neuroblastoma were less than 20%.¹ Chemotherapy dose intensification has improved response rates,^2-4 and myeloablative regimens,⁵ cis-retinoic acid,⁶ and monoclonal antibody-mediated immunotherapy⁷ may have decreased relapse rates. Nevertheless, local and systemic recurrences remain formidable obstacles to cure.^8-17

Chemotherapy alone cannot be relied on to eradicate all malignant cells within the bulky tumors typical of high-risk neuroblastoma. Hence, surgery plays a critical role in achieving local control,^18,19 and radiotherapy (RT) is commonly used as well.^20,21 Retrospective studies from the 1980s of RT for neuroblastoma included little^22,23 or no²⁴ data on stage 4 disease; their findings may no longer be relevant in view of accumulating evidence that the large majority of nonmetastatic neuroblastomas are curable without cytotoxic therapy of any sort.^25-27 A more recent, prospective study²⁸ showed an advantage for RT in locoregional neuroblastoma, an entity that might include high-risk cases, but that study did not correlate results with critical adverse biologic prognostic factors such as MYCN amplification²⁹ or serum lactate dehydrogenase (LDH) greater than 1,500 U/L.³⁰ Intraoperative RT has been used in high-risk neuroblastoma, but with uncertain benefit.^31,32 Local RT is often,^8,11-15 but not always,^9,16,17 used before myeloablative consolidation, especially to sites with residual disease.

We have used hyperfractionated RT totaling 21 Gy as part of a consistent strategy for preventing local failure in patients with high-risk neuroblastoma. Aside from a report of our preliminary findings (47 patients),³³ no report to date focuses on a protocol-based radiotherapeutic approach for local control of high-risk neuroblastoma. We now present an analysis of an extensive experience (99 patients), carried out with the aim of gaining insights into how to improve results.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Beginning in 1986,³⁴ a standard RT protocol was used in patients with high-risk neuroblastoma treated at Memorial Sloan-Kettering Cancer Center. High-risk neuroblastoma was defined as stage 4 disease, unresectable stage 3 disease with MYCN amplification diagnosed after the first year of life, or MYCN-amplified stage 4 disease in infants.³⁵ The aim was to consolidate regressions of the primary tumor and measurable metastatic deposits. The RT was delivered using 6-MV photon beams with customized blocking and computed-tomographic planning; electron beams of various energies also were used when appropriate for superficial targets. The total dose was 21 Gy, given in 1.5-Gy fractions, two fractions per day (4 to 6 hours apart), on 7 consecutive weekdays. The primary site was irradiated after resection of tumor and after the completion of all chemotherapy; the target field encompassed the extent of tumor at diagnosis and included 3-cm margins and regional lymph nodes, if possible. Distant sites were irradiated (usually in conjunction with the primary site) after there was radiographic evidence of response at the site in question. Consent for RT was obtained in accordance with institutional review board guidelines.

This study included patients who were more than 3 months from the start of RT, more than 12 months from diagnosis, and in first complete, first very good partial, or first partial remission (by international criteria³⁵). Progressive disease was defined as a new lesion or a greater than 25% increase in an existent lesion.³⁵

Induction included dose-intensive use of cyclophosphamide-doxorubicin-vincristine and cisplatin-etoposide in the context of the N4, N5, N6, or N7 protocols.^3,36-38 The N6 and N7 protocols used identical chemotherapy regimens, and these built on the earlier N4 and N5 regimens. The cumulative doxorubicin dosages were 150 mg/m² in N4, 180 mg/m² in N5, and 225 to 300 mg/m² in N6 and N7 regimens.

In addition to 21-Gy local RT, consolidation of remission consisted of: (1) myeloablative therapy that included melphalan (180 mg/m²) or thiotepa (900 mg/m²), but no total-body irradiation³⁴; (2) immunotherapy with the anti-G_D2 monoclonal antibody 3F8⁷; and/or (3) 3F8 immunotherapy plus targeted RT using 20 mCi/kg of ¹³¹I-labeled 3F8.³⁸

Long-term follow-up included special attention to height (seated and standing), endocrine status, cardiac function, kidney function, vision (eg, cataracts), neurodevelopment, and secondary tumors or malignancies.

RT port films and dosimetry records were compared with diagnostic images to determine the relationship between local failure and the treatment field. Local failure was correlated with: (1) clinical findings at diagnosis—namely, extension of disease into nodal groups contiguous with, but beyond, the anatomic compartment (pelvis, abdomen, thorax, and neck) that contained the primary tumor ("extracompartmental nodes"); (2) clinical findings at the start of RT—namely, the absence or presence of residual disease in the primary site immediately before the start of irradiation; (3) induction chemotherapy and consolidative treatments; and (4) adverse biologic prognostic markers—namely, MYCN amplification (> 10 copies), serum LDH greater than 1,500 U/L, and serum ferritin greater than 142 ng/mL. Shimada histopathology was not deemed useful for analysis in this study, because it was unfavorable in 96% of assessable cases.

The probability (± SE) of local failure was estimated using the cumulative incidence function calculated from the start of RT.³⁹ Event-free survival was estimated with the Kaplan-Meier method (relapses and treatment-related myelodysplasia/leukemia were counted as events; there were no toxic deaths).⁴⁰

	RESULTS

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Patient Characteristics
Of 99 consecutively irradiated patients (57% male) in first remission, 97 (98%) had stage 4 disease, two (2%) had unresectable stage 3 disease with MYCN amplification, and 89 (90%) had tumor in the abdomen. Patients were 1.1 to 24.2 years old (median, 3.9 years) when irradiated and were a median of 9.1 months from diagnosis; the median follow-up from diagnosis was 30.2 months.

Forty-five patients (45%) relapsed, including 35 who had no failures in radiation fields but relapsed first in bone marrow alone (n = 11), bone alone (n = 5), bone marrow and bone (n = 6), brain (n = 8), or other sites (n = 5). Ten patients relapsed within or at margins of radiation fields (Table 1): four (patient nos. 1 through 4) relapsed in the primary site alone; four (patient nos. 5 through 8) relapsed in the primary site and elsewhere; one (patient no. 9) relapsed in the primary site and in an irradiated distant site (as well as in bone marrow); and one (patient no. 10) relapsed in an irradiated distant site (and in bone marrow) but not in the primary site. These nine primary-site relapses and two relapses within irradiated distant sites were found in the 10 patients at 7 to 34 months from diagnosis (median, 21.5 months), and at 1 to 27 months after RT (median, 14 months).

View larger version (17K): [in this window] [in a new window]   Fig 1. Graph of the probability (—— ) ± SE (– – – –) of local failure in the primary site for the entire cohort of 99 patients.

Of the four patients who relapsed in the primary site alone, only patient no. 1 had an irradiated distant site (it remained relapse-free). Patient no. 2 relapsed at the superolateral margin of the treatment portal. At diagnosis, this patient had a retroperitoneal tumor with extension into posterior mediastinal nodes; relapse developed in supraclavicular nodes, while the retroperitoneum and the posterior mediastinum remained disease-free. Patient no. 3, who presented at diagnosis with a massive thoracoabdominal tumor, had the longest post-RT duration of remission before local failure (27 months). Patient no. 4 had evidence of disease in the primary site by MIBG (although not by computed tomography) when irradiated and was the sole patient with an isolated local relapse who also had MYCN amplification, serum LDH greater than 1,500 U/L, and serum ferritin greater than 142 ng/mL.

Relapses in the primary and in distant sites occurred within 8 months of RT in four of five patients with those clinical findings. Patient no. 5 had evidence of residual disease in the primary site when irradiated. Patient no. 6 had a primary tumor in the posterior mediastinum; a nodal relapse occurred in the adjacent supraclavicular area (similar to patient no. 2). Patient no. 7, who received emergency RT (not the consolidative RT that is the subject of this report) to block possible progression of an orbital metastasis after the second chemotherapy cycle, developed progressive disease at the margin of the radiation field. Patient no. 8 was in complete remission when irradiated but relapsed early, as did patients nos. 6 and 7. These three patients had MYCN amplification and serum LDH greater than 1,500 U/L; their clinical courses were consistent with inherently unfavorable or aggressive tumor biology. Patient no. 9 had residual disease in the primary site when irradiated and developed progressive disease not only in the primary site but also in an irradiated distant site (see below).

Local Control: Irradiated Distant Sites
Measurable distant metastatic deposits were irradiated in accordance with the protocol in 27 patients (one patient had two distant sites irradiated): skull, n = 10; orbit(s), n = 8; combined orbit(s) and skull, n = 5; mandible, n = 2; leg, n = 2; and liver, n = 1. Nine patients in this group had MYCN amplification. With a median follow-up of 20.3 months, two of the 27 patients relapsed in an irradiated distant site; the failure rate was 7.7 ± 7.9% at 36 months. Both relapses were in skull bones and both occurred relatively soon after RT (at 4 and 8 months, respectively). Patient no. 9, who also relapsed in the primary site, had a massive tumor burden at diagnosis; for a year, he had been evaluated repeatedly for child abuse because of bumps and ecchymoses on his head, which ultimately were understood to be caused by metastatic neuroblastoma. Patient no. 10 had MYCN-amplified disease and a serum LDH (1,423 U/L) that approached the 1,500 U/L level associated with poor outcome.

Toxicity
The RT was well tolerated. For very young patients, who required twice-daily general anesthesia, propofol was used and clear liquids were allowed until 2 hours before each treatment. Weight loss or dehydration did not complicate the short course of treatment. There were no unexpected acute side effects. Gastrointestinal symptoms were minimal to absent. Slight, clinically insignificant erythema developed with superficial RT using electrons. The most common side effect was a decrease in platelet counts after RT to the primary site. Nine of 11 patients who received RT to the neck developed asymptomatic hypothyroidism that was detected in routine screening tests performed within 1 year of treatment; this condition was readily managed with hormone supplements.

An emerging problem is poor growth: three of 35 patients followed for at least 36 months have short stature from decreased growth of vertebral bodies. Otherwise, late effects within radiation fields have been rare thus far. Scoliosis developed in a patient who had spinal surgery for a thoracic tumor (the vertebral bodies were irradiated symmetrically). Congestive heart failure complicated relapse and sepsis in one patient. Herpes zoster occurred three times in the cranial radiation field of one patient. Mild neurodevelopmental delay emerged in a patient who received RT to an extensive cranial field; a causative role is uncertain since the RT was administered so as to spare underlying brain. The only abnormal mass was a nontoxic multinodular goiter (7.5 years after RT). Secondary leukemia/myelodysplasia developed in six patients, but a contributory role for local RT is uncertain.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Rates of local failure in large series of high-risk neuroblastoma patients in first remission approximate 20% to 30%.^8-10,12-17 A common practice is to avoid local irradiation when a site has no evidence of disease, but otherwise to give 10 Gy to 24 Gy of standard fractionation local RT before myeloablative consolidation with total-body irradiation. In contrast, we used hyperfractionated 21 Gy in all high-risk neuroblastoma patients to consolidate disease regressions achieved by dose-intensive induction chemotherapy and surgery. This strategy reliably produced local control in the primary site and in distant sites deemed to be at particular risk for relapse.

Chemotherapy, surgery, and RT each contribute to local control of high-risk neuroblastoma. Greater chemotherapy dose intensity correlates with an increased rate of complete resection, which in turn correlates with improved survival.^18,19 A randomized trial would be needed to quantify the benefit conferred specifically by local irradiation. Evidence consistent with an advantage to the use of primary-site irradiation comes from a comparison of local control rates among groups of patients with identical primary site disease status at the time of consolidation therapy. Only one previous study of a large number of patients in first remission provides data on disease status of the primary site, the use of local RT, and outcome.¹² In that study, performed by the Childrens Cancer Group (CCG), 99 patients underwent myeloablative consolidation that included 10 Gy of total-body irradiation; patients with no evidence of disease in the primary site did not receive local irradiation and had a local relapse rate of 31% at 36 months, while patients with residual primary-site disease received 10 Gy (for abdominal disease) or 20 Gy of local RT and had a local relapse rate of 26% at 36 months. By comparison, in our 92 patients who, when irradiated, had no evidence of disease in the primary site, the local relapse rate was 7.2% at 36 months, and three of seven with residual disease in the primary site had local failure.

Despite the confounding factor of differences in induction and post-RT treatment, the contrast in results between the CCG study and ours supports the use of low-dose local RT for eradication of minimal residual neuroblastoma in previous sites of bulk disease. Further support for this approach comes from the high success rate (only two failures among our 27 patients) of 21-Gy hyperfractionated RT for consolidating chemotherapy-induced regressions of measurable distant metastatic deposits. Limited data from previous studies also support the use of local RT in high-risk neuroblastoma.^8,14

Despite the small number of events, an analysis of our experience identifies possible risk factors for local failure. Evidence of residual disease in the primary site at the time of RT is one risk factor, and the presence of extracompartmental nodal extension at diagnosis may be another. Further improvements in local control in the primary site may therefore result from higher RT dosing for visible residual disease and from extending the radiation field to definitively encompass regional lymph node groups. In addition, data from this study and from our previous surgical study¹⁹ support the advantage of increased dose intensity for induction chemotherapy (Table 2).

Patients with both MYCN-amplified tumors and serum LDH greater than 1,500 U/L at diagnosis also seem to have an increased risk of local failure. These biologic markers may reflect inherently unfavorable or aggressive tumor biology. However, other factors may account for the prominence of these markers in our analysis, which, because of the small number of events, precluded use of multivariate methodology. Thus, of the four patients with these adverse findings who had local failure, one (patient no. 4) had evidence of residual disease in the primary site when irradiated, and two (patient nos. 6 and 7) relapsed at margins of radiation fields.

In the 1980s, local RT became an integral component of our treatment program for high-risk neuroblastoma because several findings suggested that this modality could exert clinically important antitumor effects: (1) palliative RT in low doses often produced responses or symptomatic relief²³; (2) progression-free survival improved with conventional or myeloablative regimens that were supplemented with local RT^41-43; and (3) in vitro studies showed a moderate to high radiosensitivity of neuroblastoma cell lines.^44,45

We chose 21 Gy based on reports that described antineuroblastoma effects with doses ranging from less than 16 Gy to 35 Gy.^23,42 We decided on twice-daily administration of 1.5 Gy because laboratory studies showed low repair capacity of neuroblastoma cell lines^44,45 and optimal cytotoxicity with twice-daily fractions of 1.2 Gy to 1.5 Gy delivered 6 hours apart.⁴⁵ Also, by maintaining a relatively low fraction size, late complications in healthy tisues might be minimized (alpha/beta model).⁴⁶ We reserved RT to the primary site until after tumor resection and completion of induction chemotherapy to avoid myelosuppression or other toxicities, as well as scheduling conflicts, that might interfere with chemotherapy dose intensity. This timing also allowed use of RT against minimal residual disease, which thereby avoided the hypoxic conditions (conducive to radioresistance) that prevail within bulky lesions. For the same reason, we reserved use of RT to distant lesions until we had radiographic evidence of response.

Clinical features characteristic of the patient population also influenced the choice of total dose and fractionation schedule. High-risk neuroblastoma patients present major challenges for local RT. First, most patients are 5 years old or younger, which complicates RT planning and implementation. Second, the primary tumors often are large and abut marrow-containing structures, such as the vertebral column or pelvic bones, and/or major organs such as the heart, kidneys, liver, and lungs. Third, extensive involvement of cranial bones and large metastatic deposits in or near the orbits occur in approximately 20% of cases. Fourth, chemotherapy for high-risk neuroblastoma includes radiation sensitizers (doxorubicin and thiotepa), nephrotoxic agents (platinum compounds and ifosfamide), and cardiotoxic agents (doxorubicin and cyclophosphamide).

The above-listed conditions—young age, large radiation field for the primary tumor, proximity of cranial/orbital radiation fields to brain and optic structures, and chemotherapy-related organ damage—raise concerns about radiotoxicity. Possible acute problems include myelosuppression, mucositis, diarrhea, and hemorrhagic cystitis; late-appearing problems might include short stature, abnormal facial/cranial bone formation, neurodevelopmental delay, cataracts, deterioration of critical organs (heart, kidney, liver, lungs, and endocrine glands), and secondary malignancies. However, a dose of 21 Gy entails modest effects on bone growth and formation,⁴⁷ and hyperfractionation minimizes injury to normal tissues. (The dose of 21 Gy compares favorably with the 40- to 60-Gy doses in use for other pediatric small round-cell tumors such as rhabdomyosarcoma and Ewing’s sarcoma⁴⁸). Additional measures to reduce radiotoxicity risks include careful shielding of adjacent vital structures, selective further decreases in radiation dose (eg, 15 Gy for kidney), and use of electrons to prevent unnecessarily deep penetration of radiation.

Our patients tolerated the RT well, and to date the treatment has not been associated with a high risk of late adverse effects. Nevertheless, the expectation of finding additional delayed radiotoxicities mandates efforts to modify treatment strategies. One possibility is to avoid primary-site irradiation in patients whose primary tumors are entirely excised at diagnosis. In CCG studies,¹² such patients have not routinely received consolidative local RT, yet they have a low rate of local recurrence. The absence of local failures in our 23 patients whose primary tumors were entirely excised at diagnosis is consistent with a very favorable outlook for local control in this group of patients. Our results, the CCG experience, and concern about late sequelae have led us to change our policy: we no longer treat the primary site in patients whose primary tumors are excised at diagnosis unless MYCN amplification is present. However, we continue to advocate surgical resection of the primary tumor at diagnosis only if the procedure would not jeopardize vital organs or entail a prolonged delay in initiation of chemotherapy.³

Targeted RT may eventually eliminate need for a local RT, and might reduce radiotoxicity risks by allowing more assured sparing of normal tissues. We have accumulated a sizable experience with ¹³¹I-3F8,³⁸ and treatment with ¹³¹I-MIBG is used with increasing frequency,^49,50 but longer follow-up is needed to assess efficacy and toxicity before either of these targeted therapies can routinely supplant established treatment modalities. Furthermore, laboratory studies suggest that targeted RT with ¹³¹I may not be effective against microscopic disease.^51,52

In patients with high-risk neuroblastoma, the main obstacle to cure is distant relapse, not local failure. The combined use of novel systemic treatments with recently confirmed efficacy, including cis-retinoic acid,⁶ anti-G_D2 monoclonal antibodies,⁷ and low-dose oral etoposide,⁵³ holds promise for improved control of bone marrow disease. Relapse in the brain emerged as a major problem in our patient population (eight patients)⁵⁴; high-dose use of active antineuroblastoma agents with good penetrance across the blood-brain barrier, such as thiotepa, carboplatin, and topotecan, may prevent relapse in the CNS and reinforce systemic remission. The aforementioned treatments also may help in local control, which, although of lesser concern than distant relapse, is essential for achieving continued improvement in the prognosis of patients with high-risk neuroblastoma.

	ACKNOWLEDGMENTS

 
Supported in part by grant nos. CA61017 and CA72868 from the National Cancer Institute, Bethesda, MD; the Robert Steel Foundation; the Katie’s Find A Cure Fund; and the Justin Zahn Fund, New York, NY.

We thank the following radiation oncologists for their expertise in treating many of the patients in this study: Smitha V. Gollamudi, MD; Karen Lindsley, MD; Lynda R. Mandell, MD, PhD; Thomas E. Merchant, DO, PhD; and Karen D. Schupak, MD.

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Submitted June 2, 2000; accepted March 5, 2001.

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