Neuroblastoma Treatment (PDQ®)–Health Professional Version
Treatment of INSS Stage 4S and INRG Stage MS Neuroblastoma
International Neuroblastoma Staging System (INSS) stage 4S patients are younger than 12 months and have an INSS stage 1 or stage 2 primary tumor, whereas International Neuroblastoma Risk Group (INRG) stage MS patients are younger than 18 months with any stage of primary tumor. Both staging systems have the same definition of limited pattern of metastases.
Many patients with stage 4S neuroblastoma do not require therapy. However, tumors with unfavorable biology or patients who are symptomatic because of evolving hepatomegaly and organ compromise are at increased risk of death and are treated with low-dose to moderate-dose chemotherapy. Eight percent to 10% of these patients will have MYCNamplification and are treated with high-risk protocols.[1]
The previously used Children's Oncology Group (COG) neuroblastoma 4S group assignment criteria are described in Table 15.
Table 16 shows the INRG classification for stage 4S neuroblastoma used in ongoing COG studies.
Treatment Options for Stage 4S/MS Neuroblastoma
There is no standard approach to the treatment of stage 4S neuroblastoma.
Treatment options for stage 4S neuroblastoma include the following:
- Observation with supportive care (for asymptomatic patients with favorable tumor biology).
- Chemotherapy (for symptomatic patients, very young infants, or patients with unfavorable biology).
- Radiation therapy (rarely for patients with symptoms related to hepatomegaly from metastatic disease).
Resection of primary tumor is not associated with improved outcome.[3-5] Rarely, infants with massive hepatic 4S neuroblastoma develop cirrhosis from the chemotherapy and/or radiation therapy that is used to control the disease and may benefit from orthotopic liver transplant.[6]
Observation with supportive care
Observation with supportive care is used to treat asymptomatic patients with favorable tumor biology.
Chemotherapy
Chemotherapy is used to treat symptomatic patients, very young infants (diagnosed before age 2 months), or patients with unfavorable biology. Patients with evidence of rapid tumor growth in the first several weeks of life require immediate intervention with chemotherapy to avoid potentially irreversible abdominal compartment syndrome and hepatic and/or renal failure.[7]
Infants diagnosed with INSS stage 4S neuroblastoma, particularly those with hepatomegaly or those younger than 3 months, have the potential for rapid clinical deterioration and may benefit from early initiation of therapy.[7] It has been difficult to identify infants with stage 4S disease who will benefit from chemotherapy.
A scoring system to measure signs and symptoms of deterioration or compromise was developed to better assess this group of stage 4S patients.[8] This scoring system has been evaluated retrospectively, was predictive of the clinical course, and has been applied prospectively to guide the management of patients with INSS stage 4S disease.[8,9] The scoring system has been modified on the basis of the ANBL0531 results in the youngest infants discussed above to guide chemotherapeutic intervention for 4S in infants.[7]
Various chemotherapy regimens (cyclophosphamide alone, carboplatin/etoposide, cyclophosphamide/doxorubicin/vincristine) have been used to treat symptomatic patients. The approach is to administer the chemotherapy only as long as symptoms persist in order to avoid toxicity, which contributes to poorer survival. Additionally, lower doses of chemotherapy are often recommended for very young or low-weight infants, along with granulocyte colony-stimulating factors after each cycle of chemotherapy.
Evidence (chemotherapy for symptomatic patients, very young infants, or patients with unfavorable biology):
- The COG ANBL0531 (NCT00499616) trial prospectively studied a subset of 4S patients who had MYCN-nonamplified tumors with impaired or impending organ dysfunction or unfavorable biology (unfavorable histology and/or diploid DNA index). Forty-nine patients were enrolled, 41 of whom were symptomatic and 28 of whom had unfavorable biology. Patients were assigned to receive two, four, or eight cycles of chemotherapy on the basis of the tumor biology, age of the patient, and symptoms.[7][Level of evidence: 3iiiA]
- The 3-year overall survival (OS) was 81.4%. Eight of the nine deaths occurred in patients younger than 2 months at diagnosis. Five deaths were related to acute complications of rapidly progressing hepatomegaly (i.e., abdominal compartment syndrome, renal failure, respiratory failure, coagulopathy, and infection). Patients younger than 40 days at diagnosis had more than 13 times the risk of dying compared with patients older than 47 days. The study was amended after the five deaths to mandate immediate chemotherapy for patients with 4S disease younger than 2 months at diagnosis with evolving hepatomegaly. No deaths related to complications of hepatomegaly occurred in the subsequent infants enrolled, including 18 infants who were younger than 2 months.
- This study confirmed the inferior outcome of patients with unfavorable biology compared with symptomatic patients with favorable biology. Both of the patients with late death died as a result of metastatic disease and had unfavorable biology.
- Resection of the primary tumor was not mandated in this study, with only 16 patients having a greater than 50% resection of the primary tumor. Symptomatic patients without a biopsy were eligible for enrollment in the trial to encourage rapid treatment and avoid risky procedures. The trial allowed, and thus studied, patients with symptomatic 4S disease to avoid biopsy and thus, biological characterization until the patient's condition improved and biopsy was considered safe.
- Eighty stage 4S patients were enrolled on the COG-P9641 trial.[12]
- Overall, the 5-year event-free survival (EFS) was 77%, and the OS was 91%.
- The 5-year EFS was 63% and OS was 84% for the 41 patients with asymptomatic stage 4S neuroblastoma treated with surgery or biopsy alone; the EFS was 95% and OS was 97% for the 39 patients treated with surgery and chemotherapy (EFS P = .0016; OS P = .1302).Previously, chemotherapy toxicity was thought to be responsible for the poorer survival of patients with stage 4S disease; however, the use of chemotherapy on the COG-P9641 trial was restricted to specific clinical situations with a recommended number of cycles.
- Also, on the COG-P9641 trial, asymptomatic infants with biologically favorable (MYCN-nonamplified) INSS stage 4S disease did not receive chemotherapy until the development of progressive disease or clinical symptoms.[12]
- Infants who became symptomatic had disease-related organ failure and infectious complications resulting in an inferior OS compared with those who received immediate chemotherapy (four to eight cycles of therapy). The 3-year OS for infants who did not receive chemotherapy was 84% versus 97% for infants who received chemotherapy (P = .1321).
- On the COG-ANBL0531 trial, the 2-year OS rate for INSS stage 4S patients was 81%, which is lower than that reported in other cooperative trials such as COG-P9641.[7] Many patients enrolled on the ANBL0531 study were more ill than patients entered on previous trials, in part because tumor biopsy was not required in symptomatic infants. Previous trials mainly included asymptomatic patients and most had favorable biology. Treatment on ANBL0531 was allocated on the basis of symptoms, age, and tumor biology.
- A prospective study was performed in 125 infants with stage 4S MYCN-nonamplified tumors or INSS stage 3 primary tumors and/or positive bone scintigraphy not associated with changes in the cortical bone documented on plain radiographs and/or computed tomography.[9] A pretreatment symptom score was used to determine initial treatment; observation was recommended for infants with low symptom scores (n = 86) and chemotherapy was recommended for infants with high symptom scores (n = 37).The chemotherapy for patients with high symptom scores included two to four 3-day courses of carboplatin and etoposide; if symptoms persisted or progressive disease developed, up to four 5-day courses of cyclophosphamide, doxorubicin, and vincristine were administered. One-half of the patients underwent complete or partial resection of the primary tumor.
- There was no difference in the 2-year EFS and OS between asymptomatic and symptomatic patients (EFS, 87% vs. 88%; OS, 98% vs. 97%), although many of the investigators preferred to give chemotherapy in the presence of a low symptom score.
- For infants with low symptom scores, there was no difference in the outcome between the initially untreated infants (n = 56; OS, 93%) and treated infants (n = 30; OS, 86%).
- The OS was 90% for infants presenting with high symptom scores.
- There was no significant difference in 2-year OS between patients with unresectable primary tumors and patients with resectable primary tumors (97% vs. 100%) and between patients with negative and positive skeletal scintigraphy without radiologic abnormalities (100% vs. 97%).
Radiation therapy (for patients with symptoms related to hepatomegaly from metastatic disease)
In rare cases of marked hepatomegaly in symptomatic MS (4S) infants with neuroblastoma who were unresponsive to chemotherapy, very low-dose radiation therapy has been used. In a series of 41 symptomatic infants with MS disease, radiation therapy was administered to five infants, three of whom died.[7]
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
- ANBL1232 (NCT02176967) (Response and Biology-Based Risk Factor–Guided Therapy in Treating Younger Patients With Non–High-Risk Neuroblastoma):
- For all newly diagnosed INRG MS patients younger than 18 months, the following occurs:
- Patients younger than 3 months with existing or evolving hepatomegaly or who are symptomatic are entered in the trial, and chemotherapy begins immediately. Full staging must be completed within 1 month; a tumor biopsy is not performed until the patient is stable.
- Patients aged 3 to 12 months who are symptomatic are entered in the trial, and chemotherapy begins immediately. Tumor biopsy is performed after the patient is stable.
- Patients aged 12 to 18 months who are symptomatic have a tumor biopsy before starting chemotherapy.
- Patients aged 3 to 18 months who are asymptomatic and patients younger than 3 months who are asymptomatic and have no evolving hepatomegaly have a tumor biopsy followed by close observation initially, to continue for 3 years.Patients with INRG MS tumors that have unfavorable histology or unfavorable genomic features with or without symptoms are treated according to a response-based algorithm to determine length of treatment. For INRG MS patients under observation without chemotherapy, an objective scoring system is used to monitor them for clinical changes and initiate therapy. For patients with complete resolution of symptoms and at least a 50% reduction in primary tumor volume (partial response), chemotherapy is discontinued, and observation continues for 3 years after completion of therapy. If the disease progresses, the patient leaves this study.
- For all newly diagnosed INRG MS patients younger than 18 months, the following occurs:
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
- Canete A, Gerrard M, Rubie H, et al.: Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European Neuroblastoma Experience. J Clin Oncol 27 (7): 1014-9, 2009. [PUBMED Abstract]
- Pinto NR, Applebaum MA, Volchenboum SL, et al.: Advances in Risk Classification and Treatment Strategies for Neuroblastoma. J Clin Oncol 33 (27): 3008-17, 2015. [PUBMED Abstract]
- Guglielmi M, De Bernardi B, Rizzo A, et al.: Resection of primary tumor at diagnosis in stage IV-S neuroblastoma: does it affect the clinical course? J Clin Oncol 14 (5): 1537-44, 1996. [PUBMED Abstract]
- Katzenstein HM, Bowman LC, Brodeur GM, et al.: Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric oncology group experience--a pediatric oncology group study. J Clin Oncol 16 (6): 2007-17, 1998. [PUBMED Abstract]
- Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol 18 (3): 477-86, 2000. [PUBMED Abstract]
- Steele M, Jones NL, Ng V, et al.: Successful liver transplantation in an infant with stage 4S(M) neuroblastoma. Pediatr Blood Cancer 60 (3): 515-7, 2013. [PUBMED Abstract]
- Twist CJ, Naranjo A, Schmidt ML, et al.: Defining Risk Factors for Chemotherapeutic Intervention in Infants With Stage 4S Neuroblastoma: A Report From Children's Oncology Group Study ANBL0531. J Clin Oncol : JCO1800419, 2018. [PUBMED Abstract]
- Hsu LL, Evans AE, D'Angio GJ: Hepatomegaly in neuroblastoma stage 4s: criteria for treatment of the vulnerable neonate. Med Pediatr Oncol 27 (6): 521-8, 1996. [PUBMED Abstract]
- De Bernardi B, Gerrard M, Boni L, et al.: Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol 27 (7): 1034-40, 2009. [PUBMED Abstract]
- Keene DJ, Minford J, Craigie RJ, et al.: Laparostomy closure in stage 4S neuroblastoma. J Pediatr Surg 46 (1): e1-4, 2011. [PUBMED Abstract]
- Harper L, Perel Y, Lavrand F, et al.: Surgical management of neuroblastoma-related hepatomegaly: do material and method really count? Pediatr Hematol Oncol 25 (4): 313-7, 2008. [PUBMED Abstract]
- Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012. [PUBMED Abstract]
Treatment of Recurrent Neuroblastoma
Tumor growth resulting from maturation should be differentiated from tumor progression by performing a biopsy and reviewing histology. Patients may have persistent maturing disease with metaiodobenzylguanidine (MIBG) uptake that does not affect outcome, particularly patients with low-risk and intermediate-risk disease.[1] An analysis of 23 paired MIBG and positron emission tomography (PET) scans in 14 patients with refractory or recurrent high-risk neuroblastoma treated with iodine I 131-MIBG (131I-MIBG) found that the MIBG scan was more sensitive than fluorine F 18-fludeoxyglucose (18F-FDG) PET for detecting metastatic bone lesions, although there was a trend for 18F-FDG PET to be more sensitive for soft tissue lesions.[2]
Subclonal ALK mutations or other MAPK pathway lesions may be present at diagnosis, with subsequent clonal expansion at relapse. Consequently, serial sampling of progressive tumors may lead to the identification of potentially actionable mutations.[3,4] Modern comprehensive molecular analysis comparing primary and relapsed neuroblastoma from the same patients revealed extensive clonal enrichment and several newly discovered mutations, with many tumors showing new or clonal-enriched mutations in the RAS-MAPK pathway. This was true for patients with both high-risk and low-risk tumors at diagnosis.[5,6] (Refer to the Genomic and Biologic Features of Neuroblastoma section of this summary for more information).
If neuroblastoma recurs in a child originally diagnosed with high-risk disease, the prognosis is usually poor despite additional intensive therapy.[7-10] However, it is often possible to gain many additional months of life for these patients with alternative chemotherapy regimens.[11,12] Clinical trials are appropriate for these patients and may be offered. Information about ongoing clinical trials is available from the NCI website.
Prognostic Factors for Recurrent Neuroblastoma
The International Neuroblastoma Risk Group Project performed a survival-tree analysis of clinical and biological characteristics (defined at diagnosis) associated with survival after relapse in 2,266 patients with neuroblastoma entered on large clinical trials in well-established clinical trials groups around the world.[7] The survival-tree analysis revealed the following:
- Overall survival (OS) in the entire relapsed population was 20%.
- Among patients with all stages of disease at diagnosis, MYCN amplification predicted a poorer prognosis, measured as 5-year OS.
- Among patients diagnosed with International Neuroblastoma Staging System (INSS) stage 4 without amplification, age older than 18 months and high lactate dehydrogenase (LDH) level predicted poor prognosis.
- Among patients with MYCN amplification, those diagnosed with stage 1 and stage 2 have a better prognosis than do those diagnosed with stage 3 and stage 4.
- Among patients with MYCN-nonamplified tumors who are not stage 4, patients with hyperdiploidy had a better prognosis than did patients with diploidy in those younger than 18 months, while among those older than 18 months, patients with differentiating tumors fared much better than did patients with undifferentiated and poorly differentiated tumors.
Significant prognostic factors determined at diagnosis for postrelapse survival include the following:[7]
- Age.
- INSS stage.
- MYCN status.
- Time from diagnosis to first relapse.
- LDH level, ploidy, and histologic grade of tumor differentiation (to a lesser extent).
The Children’s Oncology Group (COG) experience with recurrence in patients with low-risk and intermediate-risk neuroblastoma showed that most patients can be salvaged. The COG reported a 3-year event free survival (EFS) of 88% and an OS of 96% in intermediate-risk patients and a 5-year EFS of 89% and OS of 97% in low-risk patients.[13,14] Moreover, in most patients originally diagnosed with low-risk or intermediate-risk disease, local recurrence or recurrence in the 4S pattern may be treated successfully with observation alone, surgery alone, or with moderate-dose chemotherapy, without myeloablative therapy and stem cell transplant.
Although the OS after recurrence in children presenting with high-risk neuroblastoma is generally extremely poor, patients with high-risk neuroblastoma at first relapse after complete remission or minimal residual disease (MRD) in whom relapse was a single site of soft tissue mass (a few children also had bone marrow or bone disease at relapse) had a 5-year OS of 35% in one single-institution study. All patients underwent surgical resection of the soft tissue disease. MYCN amplification and multifocal soft tissue disease were associated with a worse postprogression survival.[15]
Recurrent Neuroblastoma in Patients Initially Classified as Low Risk
Locoregional recurrence
Treatment options for locoregional recurrent neuroblastoma initially classified as low risk include the following:
- Surgery followed by observation or chemotherapy.
- Chemotherapy that may be followed by surgery.
Local or regional recurrent cancer is resected if possible.
Patients with favorable biology and regional recurrence more than 3 months after completion of planned treatment are observed if resection of the recurrence is total or near total (≥90% resection). Those with favorable biology and a less-than-near-total resection are treated with chemotherapy.[13,14]
Infants younger than 1 year at the time of locoregional recurrence whose tumors have any unfavorable biologic properties are observed if resection is total or near total. If the resection is less than near total, these same infants are treated with chemotherapy. Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide, or cyclophosphamide and topotecan. The cumulative dose of each agent is kept low to minimize long-term effects from the chemotherapy regimen as used in previous COG trials (COG-P9641 and COG-A3961).[13,14]
Older children with local recurrence with either unfavorable International Neuroblastoma Pathology Classification at diagnosis or MYCN gene amplification have a poor prognosis and may be treated with surgery, aggressive combination chemotherapy, or they may be offered entry into a clinical trial.
Evidence (surgery followed by observation or chemotherapy):
- A COG study of low-risk patients with stages 1, 2A, 2B, and 4S neuroblastoma enrolled 915 patients, 800 of whom were asymptomatic and treated with surgery alone followed by observation. The other patients received chemotherapy with or without surgery.[14]
- About 10% of patients developed progressive or recurrent tumor. Most recurrences were treated on study with surgery alone or moderate chemotherapy with or without surgery, and most patients were salvaged, as demonstrated by the EFS (89%) and OS (97%) rates at 5 years.
Metastatic recurrence or disease refractory to standard treatment
Treatment options for metastatic recurrent neuroblastoma initially classified as low risk include the following:
- Observation.
- Chemotherapy.
- Surgery followed by chemotherapy.
- High-risk therapy.
Metastatic recurrent or progressive neuroblastoma in an infant initially categorized as low risk and younger than 1 year at recurrence may be treated according to tumor biology, as defined in the previous COG trials (COG-P9641 and COG-A3961):
- If the biology is completely favorable, metastasis is in a 4S pattern, and the recurrence or progression is within 3 months of diagnosis, the patient is observed systematically.
- If the metastatic progression or recurrence occurs more than 3 months after diagnosis or not in a 4S pattern, then the primary tumor is resected, if possible, and chemotherapy is given.Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize long-term effects from the chemotherapy regimen, as used in previous COG trials (COG-P9641 and COG-A3961).
Any child initially categorized as low risk who is older than 1 year at the time of metastatic recurrent or progressive disease and whose recurrence is not in the stage 4S pattern usually has a poor prognosis and is treated as follows:
- High-risk therapy.
Patients with metastatic recurrent neuroblastoma are treated like patients with newly diagnosed high-risk neuroblastoma. (Refer to the Treatment Options for High-Risk Neuroblastoma section of this summary for more information.)
Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk
The treatment options for locoregional and metastatic recurrence in patients with intermediate-risk neuroblastoma are derived from the results of the COG-A3961 trial. Among 479 patients with intermediate-risk neuroblastoma treated on the COG-A3961 clinical trial, 42 patients developed disease progression. The rate was 10% of those with favorable biology and 17% of those with unfavorable biology. Thirty patients had locoregional recurrence, 11 patients had metastatic recurrence, and 1 patient had both types of recurrent disease. Six of the 42 patients died of disease, while 36 patients responded to therapy. Thus, most patients with intermediate-risk neuroblastoma and disease progression may be salvaged.[13]
Locoregional recurrence
Treatment options for locoregional recurrent neuroblastoma initially classified as intermediate risk include the following:
- Surgery (complete resection).
- Surgery (incomplete resection) followed by chemotherapy.
- Radiation therapy. Radiation therapy is considered only for patients with disease progression after chemotherapy and second-look surgery.[13]
The current standard of care is based on the experience from the COG intermediate-risk treatment plan (COG-A3961). Locoregional recurrence of neuroblastoma with favorable biology that occurs more than 3 months after completion of chemotherapy may be treated surgically. If resection is less than near total, then additional chemotherapy may be given. Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize long-term effects from the chemotherapy regimen, as used in a previous COG trial (COG-A3961).[13]
Metastatic recurrence
Treatment options for metastatic recurrent neuroblastoma initially classified as intermediate risk include the following:
- High-risk therapy.
Patients with metastatic recurrent neuroblastoma are treated like patients with newly diagnosed high-risk neuroblastoma. (Refer to the Treatment Options for High-Risk Neuroblastoma section of this summary for more information.)
Recurrent Neuroblastoma in Patients Initially Classified as High Risk
Any recurrence in patients initially classified as high risk signifies a very poor prognosis.[7] Clinical trials may be considered. Palliative care should also be considered as part of the patient's treatment plan.
An analysis of several trials included 383 patients with neuroblastoma whose tumor recurred or progressed on COG modern-era early-phase trials. The 1-year progression-free survival (PFS) rate was 21%, and the 4-year PFS rate was 6%, while the OS rates were 57% at 1 year and 20% at 4 years. Less than 10% of patients experienced no subsequent recurrence or progression. MYCN amplification predicted worse PFS and OS rates.[16] Although the OS after recurrence in children presenting with high-risk neuroblastoma is generally extremely poor, patients with high-risk neuroblastoma at first relapse after complete remission or MRD in whom relapse was a single site of soft tissue mass (a few children also had bone marrow or bone disease at relapse) had a 5-year OS of 35% in one single-institution study.[15]
Treatment options for recurrent or refractory neuroblastoma in patients initially classified as high risk include the following:
- Chemotherapy combined with immunotherapy.
- Temozolomide, irinotecan, and dinutuximab.[17]
- 131I-MIBG. 131I-MIBG alone, in combination with other therapy, or followed by stem cell rescue.
- ALK inhibitors. Crizotinib, or other ALK inhibitors, for patients with ALK mutations.[18]
- Chemotherapy.
- Topotecan in combination with cyclophosphamide or etoposide.[19]
- Temozolomide with irinotecan.
Chemotherapy combined with immunotherapy produces the best response rate and response duration of treatments for high-risk patients with disease progression.
Evidence (chemotherapy combined with immunotherapy):
- In the ANBL1221 (NCT01767194) trial, patients in first relapse or progression were randomly assigned to receive either temozolomide/irinotecan/dinutuximab or temozolomide/irinotecan/temsirolimus.[17]
- Of the 17 patients treated with the combination that included dinutuximab, 9 patients (53%) had an objective response, compared with 1 of 18 patients treated with the regimen that contained temsirolimus.
Evidence (131I-MIBG):
- For children with recurrent or refractory neuroblastoma, 131I-MIBG is an effective palliative agent and may be considered alone or in combination with chemotherapy (with stem cell rescue) in a clinical research trial.[20-25]; [26,27][Level of evidence: 3iiiA]
- A North American retrospective study of more than 200 patients treated with 131I-MIBG therapy compared children who had recurrence or progression of disease with children who had stable or persistent disease since diagnosis.[28]
- The rate of immediate progression after 131I-MIBG therapy was lower and OS at 2 years was better (65% vs. 39%) in patients with stable, persistent disease.
- Tandem consolidation using 131I-MIBG, vincristine, and irinotecan with autologous stem cell transplant (SCT) followed by busulfan/melphalan with autologous SCT was retrospectively reported in eight patients and resulted in three complete responses, two partial responses, and one minor response.[27]
- Single autologous SCT with escalating dose 131I-MIBG and carboplatin/etoposide/melphalan was studied in additional patients.[29]
- After induction chemotherapy, 27 refractory patients and 15 progressing patients were treated, resulting in four responses. Eight patients with partial response to induction were treated, resulting in three responses.
- The 12% incidence of sinusoidal obstructive syndrome was dose limiting.
Evidence (chemotherapy):
- The combination of irinotecan and temozolomide had a 15% response rate in one study.[30][Level of evidence: 2A]
- A retrospective study reported on 74 patients who received 92 cycles of ifosfamide, carboplatin, and etoposide; it included 37 patients who received peripheral blood stem cell rescue after responding to this drug combination.[31]
- Disease regressions (major and minor responses) were achieved in 14 of 17 patients (82%) with a new relapse, 13 of 26 patients (50%) with refractory neuroblastoma, and 12 of 34 patients (35%) who were treated for progressive disease during chemotherapy (P = .005).
- Grade 3 toxicities were rare.
- Topotecan in combination with cyclophosphamide or etoposide has been used in patients with recurrent disease who did not receive topotecan initially.[32,33]; [19][Level of evidence: 1A]
- High-dose carboplatin, irinotecan, and/or temozolomide has been used in relapsed patients resistant or refractory to regimens containing topotecan.[33]
Allogeneic transplant has a historically low success rate in recurrent or progressive neuroblastoma. In a retrospective registry study, allogeneic SCT after a previous autologous SCT appeared to offer no benefit. Disease recurrence remains the most common cause of treatment failure.[34]
Clinical trials of novel therapeutic approaches, such as a vaccine designed to induce host antiganglioside antibodies that can replicate the antineoplastic activities of intravenously administered monoclonal antibodies, are currently under investigation. Patients also receive a beta-glucan treatment, which has a broad range of immunostimulatory effects and synergizes with anti-GD2/GD3 monoclonal antibodies. In a phase I study of 15 children with high-risk neuroblastoma, the therapy was tolerated without any dose-limiting toxicity.[35] Long-term PFS has been reported in patients who achieve a second or later complete or very good partial remission followed by consolidation with anti-GD2 immunotherapy and isotretinoin with or without maintenance therapy. This includes patients who had previously received anti-GD2 immunotherapy and isotretinoin.[36]
Recurrent Neuroblastoma in the Central Nervous System
Central nervous system (CNS) involvement, although rare at initial presentation, may occur in 5% to 10% of patients with recurrent neuroblastoma. Because upfront treatment for newly diagnosed patients does not adequately treat the CNS, the CNS has emerged as a sanctuary site leading to relapse.[37,38] CNS relapses are almost always fatal, with a median time to death of 6 months.
Treatment options for recurrent neuroblastoma in the CNS include the following:
- Surgery and radiation therapy.
- Novel therapeutic approaches.
Current treatment approaches generally include eradicating bulky and microscopic residual disease in the CNS and minimal residual systemic disease that may herald further relapses. Neurosurgical interventions serve to decrease edema, control hemorrhage, and remove bulky tumor before starting therapy.
Compartmental radioimmunotherapy using intrathecal radioiodinated monoclonal antibodies has been tested in patients with recurrent metastatic CNS neuroblastoma after surgery, craniospinal radiation therapy, and chemotherapy.[12]
Treatment Options Under Clinical Evaluation for Recurrent or Refractory Neuroblastoma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
- APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
- ADVL1312 (NCT02095132) (A Phase I/II Study of AZD1775 [MK-1775] in Combination With Oral Irinotecan in Children, Adolescents, and Young Adults With Relapsed or Refractory Solid Tumors): Wee1 is a tyrosine kinase that is activated in response to DNA damage and plays a role in chemoresistance and tolerance of oncogene-induced cellular stress. The Wee1 inhibitor AZD1775 (MK-1775) was developed to overcome this checkpoint and render cells more sensitive to chemotherapy, and it may be more effective in tumors with high levels of the MYC or MYCN oncogene.
- ADVL1621 (NCT02332668) (A Phase I/II Study of Pembrolizumab [MK-3475] in Children With Advanced Melanoma or a PD-L1–Positive Advanced, Relapsed or Refractory Solid Tumor or Lymphoma): Part 1 of this study will find the maximum tolerated dose, confirm the dose, and find the recommended phase II dose for pembrolizumab therapy. Part 2 of the study will further evaluate the safety and efficacy at the pediatric phase II recommended dose.
- ENCIT-01 (NCT02311621) (A Phase I Feasibility and Safety Study of Cellular Immunotherapy for Recurrent/Refractory Neuroblastoma Using Autologous T-cells Lentivirally Transduced to Express CD171-Specific Chimeric Antigen Receptors [CAR]):Patients with recurrent or refractory neuroblastoma are resistant to conventional chemotherapy. For this reason, the investigators are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a CAR. The CAR enables the T cell to recognize and kill the neuroblastoma cell through the recognition of CD171, a protein expressed on the surface of the neuroblastoma cell. This is a phase I study designed to determine the maximum tolerated dose of the CAR T cells.
- NANT2015-02 (NCT03107988) (Phase I Study of Lorlatinib [PF-06463922], an Oral Small Molecule Inhibitor of ALK/ROS1, for Patients With ALK-Driven Relapsed or Refractory Neuroblastoma): This is a pediatric dose-finding study of a third-generation ALK inhibitor. Lorlatinib is sensitive to some ALK mutations to which crizotinib is resistant. An expansion study to include more children is also being planned.
- N2011-01 (NCT02035137) (Randomized Phase II Pick-the-Winner Study of 131I-MIBG, 131I-MIBG With Vincristine and Irinotecan, or 131I-MIBG With Vorinostat for Resistant/Relapsed Neuroblastoma): This study will compare three treatment regimens containing MIBG, including their effects on tumor response and associated side effects, to determine whether one therapy is better than the other for people diagnosed with relapsed or persistent neuroblastoma.
- NANT2017-01 (NCT03332667) (MIBG With Dinutuximab): In this pediatric phase I trial, 131I-MIBG will be administered in combination with dinutuximab (a chimeric 14.18 monoclonal antibody) to neuroblastoma patients with refractory or relapsed disease. This study will utilize a traditional phase I dose escalation 3+3 design to determine a recommended phase II pediatric dose. An expansion cohort of an additional six patients may then be enrolled.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
- Marachelian A, Shimada H, Sano H, et al.: The significance of serial histopathology in a residual mass for outcome of intermediate risk stage 3 neuroblastoma. Pediatr Blood Cancer 58 (5): 675-81, 2012. [PUBMED Abstract]
- Taggart DR, Han MM, Quach A, et al.: Comparison of iodine-123 metaiodobenzylguanidine (MIBG) scan and [18F]fluorodeoxyglucose positron emission tomography to evaluate response after iodine-131 MIBG therapy for relapsed neuroblastoma. J Clin Oncol 27 (32): 5343-9, 2009. [PUBMED Abstract]
- Schleiermacher G, Javanmardi N, Bernard V, et al.: Emergence of new ALK mutations at relapse of neuroblastoma. J Clin Oncol 32 (25): 2727-34, 2014. [PUBMED Abstract]
- Padovan-Merhar OM, Raman P, Ostrovnaya I, et al.: Enrichment of Targetable Mutations in the Relapsed Neuroblastoma Genome. PLoS Genet 12 (12): e1006501, 2016. [PUBMED Abstract]
- Eleveld TF, Oldridge DA, Bernard V, et al.: Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet 47 (8): 864-71, 2015. [PUBMED Abstract]
- Schramm A, Köster J, Assenov Y, et al.: Mutational dynamics between primary and relapse neuroblastomas. Nat Genet 47 (8): 872-7, 2015. [PUBMED Abstract]
- London WB, Castel V, Monclair T, et al.: Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group project. J Clin Oncol 29 (24): 3286-92, 2011. [PUBMED Abstract]
- Pole JG, Casper J, Elfenbein G, et al.: High-dose chemoradiotherapy supported by marrow infusions for advanced neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (1): 152-8, 1991. [PUBMED Abstract]
- Castel V, Cañete A, Melero C, et al.: Results of the cooperative protocol (N-III-95) for metastatic relapses and refractory neuroblastoma. Med Pediatr Oncol 35 (6): 724-6, 2000. [PUBMED Abstract]
- Lau L, Tai D, Weitzman S, et al.: Factors influencing survival in children with recurrent neuroblastoma. J Pediatr Hematol Oncol 26 (4): 227-32, 2004. [PUBMED Abstract]
- Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001. [PUBMED Abstract]
- Kramer K, Kushner BH, Modak S, et al.: Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. J Neurooncol 97 (3): 409-18, 2010. [PUBMED Abstract]
- Baker DL, Schmidt ML, Cohn SL, et al.: Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med 363 (14): 1313-23, 2010. [PUBMED Abstract]
- Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012. [PUBMED Abstract]
- Murphy JM, Lim II, Farber BA, et al.: Salvage rates after progression of high-risk neuroblastoma with a soft tissue mass. J Pediatr Surg 51 (2): 285-8, 2016. [PUBMED Abstract]
- London WB, Bagatell R, Weigel BJ, et al.: Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials. Cancer 123 (24): 4914-4923, 2017. [PUBMED Abstract]
- Mody R, Naranjo A, Van Ryn C, et al.: Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Lancet Oncol 18 (7): 946-957, 2017. [PUBMED Abstract]
- Mossé YP, Lim MS, Voss SD, et al.: Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study. Lancet Oncol 14 (6): 472-80, 2013. [PUBMED Abstract]
- London WB, Frantz CN, Campbell LA, et al.: Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children's Oncology Group study. J Clin Oncol 28 (24): 3808-15, 2010. [PUBMED Abstract]
- DuBois SG, Groshen S, Park JR, et al.: Phase I Study of Vorinostat as a Radiation Sensitizer with 131I-Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma. Clin Cancer Res 21 (12): 2715-21, 2015. [PUBMED Abstract]
- Polishchuk AL, Dubois SG, Haas-Kogan D, et al.: Response, survival, and toxicity after iodine-131-metaiodobenzylguanidine therapy for neuroblastoma in preadolescents, adolescents, and adults. Cancer 117 (18): 4286-93, 2011. [PUBMED Abstract]
- Matthay KK, Yanik G, Messina J, et al.: Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol 25 (9): 1054-60, 2007. [PUBMED Abstract]
- Matthay KK, Tan JC, Villablanca JG, et al.: Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to Neuroblastoma Therapy Consortium Study. J Clin Oncol 24 (3): 500-6, 2006. [PUBMED Abstract]
- Matthay KK, Quach A, Huberty J, et al.: Iodine-131--metaiodobenzylguanidine double infusion with autologous stem-cell rescue for neuroblastoma: a new approaches to neuroblastoma therapy phase I study. J Clin Oncol 27 (7): 1020-5, 2009. [PUBMED Abstract]
- DuBois SG, Chesler L, Groshen S, et al.: Phase I study of vincristine, irinotecan, and ¹³¹I-metaiodobenzylguanidine for patients with relapsed or refractory neuroblastoma: a new approaches to neuroblastoma therapy trial. Clin Cancer Res 18 (9): 2679-86, 2012. [PUBMED Abstract]
- Johnson K, McGlynn B, Saggio J, et al.: Safety and efficacy of tandem 131I-metaiodobenzylguanidine infusions in relapsed/refractory neuroblastoma. Pediatr Blood Cancer 57 (7): 1124-9, 2011. [PUBMED Abstract]
- French S, DuBois SG, Horn B, et al.: 131I-MIBG followed by consolidation with busulfan, melphalan and autologous stem cell transplantation for refractory neuroblastoma. Pediatr Blood Cancer 60 (5): 879-84, 2013. [PUBMED Abstract]
- Zhou MJ, Doral MY, DuBois SG, et al.: Different outcomes for relapsed versus refractory neuroblastoma after therapy with (131)I-metaiodobenzylguanidine ((131)I-MIBG). Eur J Cancer 51 (16): 2465-72, 2015. [PUBMED Abstract]
- Yanik GA, Villablanca JG, Maris JM, et al.: 131I-metaiodobenzylguanidine with intensive chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma. A new approaches to neuroblastoma therapy (NANT) phase II study. Biol Blood Marrow Transplant 21 (4): 673-81, 2015. [PUBMED Abstract]
- Bagatell R, London WB, Wagner LM, et al.: Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children's Oncology Group study. J Clin Oncol 29 (2): 208-13, 2011. [PUBMED Abstract]
- Kushner BH, Modak S, Kramer K, et al.: Ifosfamide, carboplatin, and etoposide for neuroblastoma: a high-dose salvage regimen and review of the literature. Cancer 119 (3): 665-71, 2013. [PUBMED Abstract]
- Simon T, Längler A, Harnischmacher U, et al.: Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial. J Cancer Res Clin Oncol 133 (9): 653-61, 2007. [PUBMED Abstract]
- Kushner BH, Kramer K, Modak S, et al.: Differential impact of high-dose cyclophosphamide, topotecan, and vincristine in clinical subsets of patients with chemoresistant neuroblastoma. Cancer 116 (12): 3054-60, 2010. [PUBMED Abstract]
- Hale GA, Arora M, Ahn KW, et al.: Allogeneic hematopoietic cell transplantation for neuroblastoma: the CIBMTR experience. Bone Marrow Transplant 48 (8): 1056-64, 2013. [PUBMED Abstract]
- Kushner BH, Cheung IY, Modak S, et al.: Phase I trial of a bivalent gangliosides vaccine in combination with β-glucan for high-risk neuroblastoma in second or later remission. Clin Cancer Res 20 (5): 1375-82, 2014. [PUBMED Abstract]
- Kushner BH, Ostrovnaya I, Cheung IY, et al.: Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-GD2 immunotherapy and isotretinoin: a prospective Phase II study. Oncoimmunology 4 (7): e1016704, 2015. [PUBMED Abstract]
- Kramer K, Kushner B, Heller G, et al.: Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-kettering Cancer Center Experience and A Literature Review. Cancer 91 (8): 1510-9, 2001. [PUBMED Abstract]
- Matthay KK, Brisse H, Couanet D, et al.: Central nervous system metastases in neuroblastoma: radiologic, clinical, and biologic features in 23 patients. Cancer 98 (1): 155-65, 2003. [PUBMED Abstract]
Changes to this Summary (06/04/2019)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added text to state that about 5% of children with Beckwith-Wiedemann syndrome have the molecular etiology of mutations causing decreased activity of CDKN1C. Also added text about the results of a review of all large studies of genetically subtyped Beckwith-Wiedemann syndrome (cited Mussa et al. as reference 29).
Added text to state that in a study that compared the genomic data of primary diagnostic neuroblastomas originating in the adrenal gland with that of neuroblastomas originating in the thoracic sympathetic ganglia, 16% of thoracic tumors harbored ALK mutations (cited Oldridge et al. as reference 52).
The Opsoclonus/myoclonus syndrome subsection was extensively revised.
Added text to state that adolescents and adults rarely develop neuroblastoma, accounting for less than 5% of all cases. When neuroblastoma occurs in this age range, it shows a more indolent clinical course than does neuroblastoma in younger patients, and it shows de novo chemotherapy resistance.
Added text to state that in adolescents, approximately 40% of the tumors will have loss-of-function mutations in ATRX, compared with less than 20% in younger children and 0% in infants younger than 1 year.
Added Adults as a new subsection in the Prognostic Factors subsection.
Added text about the results of a study that compared the genomic and epigenomic data of primary diagnostic neuroblastomas originating in the adrenal gland with that of neuroblastomas originating in the thoracic sympathetic ganglia.
Added text to state that the clinical trials did not include postinduction-phase assessments of Curie or International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) scores after transplant and immunotherapy, and cutoffs and outcomes associated with those assessments may differ from the preinduction and postinduction scores.
Added text to describe the Children's Oncology Group (COG) image-defined risk factors, which use an anatomic localization approach.
Added text to state that the L2 tumors that underwent primary resection may have been selected for less-risky resectability in the European multicenter study LNESG1.
Revised Table 5 to include radiation therapy as a treatment option for patients with stage 4S/MS neuroblastoma and recurrent neuroblastoma.
The Radiation Therapy subsection was extensively revised.
Added text to state that some patients with presumed neuroblastoma have been observed without biopsy; this strategy is being studied further by the COG in the ANBL1232 trial.
The Radiation therapy subsection was extensively revised.
Revised text to state that for children with high-risk neuroblastoma, the 5-year overall survival with current treatments is about 50% for patients diagnosed between 2005 and 2010.
Revised text to state that the postconsolidation phase consists of radiation therapy to the site of the primary tumor and residual metastatic sites, immunotherapy, and retinoid therapy.
The Postconsolidation phase subsection was extensively revised.
Added text to state that the classification for the ANBL1531 trial is based on the International Neuroblastoma Risk Group staging system.
Added text to state that boost radiation was discontinued in the ANBL1531 trial because no clear benefit over historical controls was apparent.
Added text to state that boost radiation was discontinued in the ANBL17P1 trial because no clear benefit over historical controls was apparent.
Added radiation therapy as a treatment option for stage 4S neuroblastoma.
Added Radiation therapy (for symptomatic patients related to hepatomegaly from metastatic disease) as a new subsection.
Added radiation therapy as a treatment option for locoregional recurrent neuroblastoma initially classified as intermediate risk. Also added text to state that radiation therapy is considered only for patients with disease progression after chemotherapy and second-look surgery.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of neuroblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Neuroblastoma Treatment are:
- Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)
- Andrea A. Hayes-Jordan, MD, FACS, FAAP (University of North Carolina - Chapel Hill School of Medicine)
- Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Nita Louise Seibel, MD (National Cancer Institute)
- Stephen J. Shochat, MD (St. Jude Children's Research Hospital)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Neuroblastoma Treatment. Bethesda, MD: National Cancer Institute. Updated . Available at: https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq. Accessed . [PMID: 26389190]
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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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