Ten Challenges in the Management of Neuroblastoma
Ten Challenges in the Management of Neuroblastoma
As the EFS and OS for low- and intermediate-risk neuroblastoma have increased, the focus has been on reducing treatment intensity with the aim of minimizing the treatment burden, toxicity and long-term effects.
Infants with neuroblastoma without MYCN gene amplification generally have good outcomes. Those with unresectable disease and no MYCN amplification have had OS rates of 95–100% in the past with chemotherapy; however, there have been concerns over the long-term toxicity of such treatment. The INES 99.1 study evaluated the efficacy of low-dose chemotherapy in infants with nonmetastatic and unresectable neuroblastoma without MYCN amplification with the aim of reducing total chemotherapy doses and avoiding anthracyclines without affecting outcomes for these infants. Low-dose chemotherapy without anthracyclines was effective in 62% of infants with unresectable non-MYCN-amplified tumors. This did not compromise on OS (5-year OS: 99%) and may improve late toxicities for this group.
With regards to infants with disseminated neuroblastoma without MYCN amplification, most have a good outcome and De Bernardi et al. reported on two European trials focusing on reducing treatment intensity for this group. In trial 99.2, infants with either stage 4S disease or with stage 4 disease with a primary tumor crossing the midline or positive skeletal scintigraphy and no symptoms were observed. In trial 99.3, infants with overt metastases to the skeleton and/or lung and/or CNS were treated with a minimum of four chemotherapy courses. Both trials had OS rates of greater than 95%.
Treatment for high-risk neuroblastoma has become increasingly intensified with the aim of improving outcomes. This has come at a cost of increased toxicity, both acute and late. Below, neutropenia is referred to as an example of early toxicity and ototoxicity related to platinum drugs is discussed as an example, from among many more such as cardiotoxicity related to anthracyclines, of recent efforts to reduce late toxicities.
Febrile Neutropenia Rates of febrile neutropenia are high with dose-intense induction chemotherapy regimes. Within the SIOPEN high-risk neuroblastoma trial, patients were randomly assigned to receive primary prophylactic granulocyte colony-stimulating factor (G-CSF) or not during Rapid COJEC induction chemotherapy in order to examine whether its use would affect the incidence of febrile neutropenia. The study found significantly fewer febrile neutropenia episodes, days with fever, hospital days and antibiotic days in those patients receiving primary prophylactic G-CSF. They also found severe weight loss was reduced significantly in the G-CSF group. Protocol compliance was better in the G-CSF cohort, demonstrated by the shorter time to completion of induction chemotherapy. The use of primary prophylactic G-CSF did not adversely affect response rates or success of PBSC harvest.
Ototoxicity Induction regimes for high-risk neuroblastoma include potentially ototoxic platinum-based agents such cisplatin or carboplatin. These agents are known to cause high-frequency hearing loss that is nonreversible. The young age of most neuroblastoma patients makes them particularly susceptible and the long-term consequences on speech development and learning are especially important.
The estimated frequency of platinum-induced high-frequency hearing loss in patients with neuroblastoma depends to some extent on the grading system used. Kushner et al. reported on a large cohort of neuroblastoma patients treated with a high-dose cisplatin-containing induction regime and carboplatin-containing myeloablative therapy as per the Memorial Sloan-Kettering Cancer Center N7 regimen and the COG A3973 study. They found Brock grade 3 or 4 hearing loss in the speech range in 25% of patients tested after induction with two cycles of high-dose cisplatin/etoposide (cumulative dose of cisplatin: 400 mg/m); Brock grade 3 or 4 toxicity in 54% of patients tested after induction with three cycles of high-dose cisplatin/etoposide (cumulative dose of cisplatin: 600 mg/m) and 50% of patients who had hearing tested after induction containing two cycles of high-dose cisplatin and etoposide, followed by carboplatin-containing myeloablative therapy. They also found patients less than 5 years of age at diagnosis to be more severely affected.
Many studies have examined the risk factors for high-frequency hearing loss in pediatric patients treated with cisplatin. Li et al. recently confirmed that age at treatment (younger than 5 years) and the cumulative dose of cisplatin are the most important factors predicting for moderate to severe high-frequency hearing loss.
The role of chemoprotective agents such as amifostine in pediatric patients treated with cisplatin-based chemotherapy is uncertain. Three studies in pediatric patients receiving cisplatin for germ cell tumors, hepatoblastoma and medulloblastoma showed no improvement in ototoxicity with the use of amifostine. However, a recent study of amifostine in medulloblastoma patients treated with cisplatin showed a reduction in ototoxicity in the group given a higher dose of amifostine. The ultimate dose and scheduling of amifostine, as well as its own side effects, need to be further considered.
The COG is currently running a randomized Phase III study of another thiol, which has shown more potential to reduce ototoxicity in vitro, sodium thiosulfate for the prevention of cisplatin-induced otototoxicity in children. This study includes children receiving cisplatin for newly diagnosed malignancies, including neuroblastoma. A similar study is running internationally in a different disease group.
Radiotherapy In addition to the toxicities of systemic chemotherapy, local treatments such as surgery and radiotherapy can also have adverse effects.
External beam radiotherapy to the primary tumor site postsurgery improves local control in neuroblastoma and may have an impact on OS for these patients. There is a dose-dependent risk of late effects on normal tissues such as the liver and kidneys, which may lie adjacent to the target volume and incidentally be included in the high-dose irradiated volume. There have been many developments in the planning and delivery of radiotherapy in recent years, including the use of intensity modulated radiotherapy, which has the potential to improve the conformity of dose distributions, potentially enabling dose escalation to tumors and reduction of toxicity to organs at risk. The use of these techniques within pediatric oncology has been controversial, owing to the potential increase in secondary malignancies because of the increased low dose to nontarget tissues. Proton beam radiotherapy is only just beginning to be used in neuroblastoma.
Survivorship In relation to late toxicity, the largest collection of outcome data on long-term survivors of neuroblastoma has been published by the Childhood Cancer Survivor Study (CCSS). This examined over 900 5-year neuroblastoma survivors treated between 1970 and 1986 and compared their incidence of secondary neoplasms, chronic health conditions and selected sociodemographic outcomes with a cohort of over 3000 siblings of CCSS participants. The incidence of secondary cancers was 3.5% at 20 years and 7% at 30 years after diagnosis. There was an increased incidence of chronic health conditions, most commonly involving neurological, sensory, endocrine and musculoskeletal systems. Neuroblastoma survivors were less likely to have ever been employed or be married and had a lower income.
With regard to high-risk patients alone, a retrospective single-center study reviewed 16 survivors of stage 4 neuroblastoma treated between 1984 and 2009. Renal changes were observed in 62.5%, endocrine disturbances in 56.3% and sensorineural hearing loss in 37.5%. Other observed late effects included hepatobiliary changes, musculoskeletal problems, pulmonary abnormalities, dental changes and neurological changes. Secondary neoplasms were determined in three patients.
The term 'cancer survivorship' has gained international recognition and is a focus for research. In 2007, the National Cancer Survivorship Initiative (NCSI) was formed in the UK, originating from the Cancer Reform Strategy. The aims of the initiative are to improve the provision of care and support for children and young people surviving cancer, and to improve the overall support to parents and carers. Some of the strategies involve developing individualized survivorship treatment plans and risk-stratifying patients at risk of long-term complications from their cancer treatment.
The high incidence of secondary late effects following treatment for neuroblastoma emphasizes the importance of careful medical and psychosocial long-term follow-up of these patients.
Challenge 8
Minimizing Treatment-related Morbidity
As the EFS and OS for low- and intermediate-risk neuroblastoma have increased, the focus has been on reducing treatment intensity with the aim of minimizing the treatment burden, toxicity and long-term effects.
Infants with neuroblastoma without MYCN gene amplification generally have good outcomes. Those with unresectable disease and no MYCN amplification have had OS rates of 95–100% in the past with chemotherapy; however, there have been concerns over the long-term toxicity of such treatment. The INES 99.1 study evaluated the efficacy of low-dose chemotherapy in infants with nonmetastatic and unresectable neuroblastoma without MYCN amplification with the aim of reducing total chemotherapy doses and avoiding anthracyclines without affecting outcomes for these infants. Low-dose chemotherapy without anthracyclines was effective in 62% of infants with unresectable non-MYCN-amplified tumors. This did not compromise on OS (5-year OS: 99%) and may improve late toxicities for this group.
With regards to infants with disseminated neuroblastoma without MYCN amplification, most have a good outcome and De Bernardi et al. reported on two European trials focusing on reducing treatment intensity for this group. In trial 99.2, infants with either stage 4S disease or with stage 4 disease with a primary tumor crossing the midline or positive skeletal scintigraphy and no symptoms were observed. In trial 99.3, infants with overt metastases to the skeleton and/or lung and/or CNS were treated with a minimum of four chemotherapy courses. Both trials had OS rates of greater than 95%.
Treatment for high-risk neuroblastoma has become increasingly intensified with the aim of improving outcomes. This has come at a cost of increased toxicity, both acute and late. Below, neutropenia is referred to as an example of early toxicity and ototoxicity related to platinum drugs is discussed as an example, from among many more such as cardiotoxicity related to anthracyclines, of recent efforts to reduce late toxicities.
Febrile Neutropenia Rates of febrile neutropenia are high with dose-intense induction chemotherapy regimes. Within the SIOPEN high-risk neuroblastoma trial, patients were randomly assigned to receive primary prophylactic granulocyte colony-stimulating factor (G-CSF) or not during Rapid COJEC induction chemotherapy in order to examine whether its use would affect the incidence of febrile neutropenia. The study found significantly fewer febrile neutropenia episodes, days with fever, hospital days and antibiotic days in those patients receiving primary prophylactic G-CSF. They also found severe weight loss was reduced significantly in the G-CSF group. Protocol compliance was better in the G-CSF cohort, demonstrated by the shorter time to completion of induction chemotherapy. The use of primary prophylactic G-CSF did not adversely affect response rates or success of PBSC harvest.
Ototoxicity Induction regimes for high-risk neuroblastoma include potentially ototoxic platinum-based agents such cisplatin or carboplatin. These agents are known to cause high-frequency hearing loss that is nonreversible. The young age of most neuroblastoma patients makes them particularly susceptible and the long-term consequences on speech development and learning are especially important.
The estimated frequency of platinum-induced high-frequency hearing loss in patients with neuroblastoma depends to some extent on the grading system used. Kushner et al. reported on a large cohort of neuroblastoma patients treated with a high-dose cisplatin-containing induction regime and carboplatin-containing myeloablative therapy as per the Memorial Sloan-Kettering Cancer Center N7 regimen and the COG A3973 study. They found Brock grade 3 or 4 hearing loss in the speech range in 25% of patients tested after induction with two cycles of high-dose cisplatin/etoposide (cumulative dose of cisplatin: 400 mg/m); Brock grade 3 or 4 toxicity in 54% of patients tested after induction with three cycles of high-dose cisplatin/etoposide (cumulative dose of cisplatin: 600 mg/m) and 50% of patients who had hearing tested after induction containing two cycles of high-dose cisplatin and etoposide, followed by carboplatin-containing myeloablative therapy. They also found patients less than 5 years of age at diagnosis to be more severely affected.
Many studies have examined the risk factors for high-frequency hearing loss in pediatric patients treated with cisplatin. Li et al. recently confirmed that age at treatment (younger than 5 years) and the cumulative dose of cisplatin are the most important factors predicting for moderate to severe high-frequency hearing loss.
The role of chemoprotective agents such as amifostine in pediatric patients treated with cisplatin-based chemotherapy is uncertain. Three studies in pediatric patients receiving cisplatin for germ cell tumors, hepatoblastoma and medulloblastoma showed no improvement in ototoxicity with the use of amifostine. However, a recent study of amifostine in medulloblastoma patients treated with cisplatin showed a reduction in ototoxicity in the group given a higher dose of amifostine. The ultimate dose and scheduling of amifostine, as well as its own side effects, need to be further considered.
The COG is currently running a randomized Phase III study of another thiol, which has shown more potential to reduce ototoxicity in vitro, sodium thiosulfate for the prevention of cisplatin-induced otototoxicity in children. This study includes children receiving cisplatin for newly diagnosed malignancies, including neuroblastoma. A similar study is running internationally in a different disease group.
Radiotherapy In addition to the toxicities of systemic chemotherapy, local treatments such as surgery and radiotherapy can also have adverse effects.
External beam radiotherapy to the primary tumor site postsurgery improves local control in neuroblastoma and may have an impact on OS for these patients. There is a dose-dependent risk of late effects on normal tissues such as the liver and kidneys, which may lie adjacent to the target volume and incidentally be included in the high-dose irradiated volume. There have been many developments in the planning and delivery of radiotherapy in recent years, including the use of intensity modulated radiotherapy, which has the potential to improve the conformity of dose distributions, potentially enabling dose escalation to tumors and reduction of toxicity to organs at risk. The use of these techniques within pediatric oncology has been controversial, owing to the potential increase in secondary malignancies because of the increased low dose to nontarget tissues. Proton beam radiotherapy is only just beginning to be used in neuroblastoma.
Survivorship In relation to late toxicity, the largest collection of outcome data on long-term survivors of neuroblastoma has been published by the Childhood Cancer Survivor Study (CCSS). This examined over 900 5-year neuroblastoma survivors treated between 1970 and 1986 and compared their incidence of secondary neoplasms, chronic health conditions and selected sociodemographic outcomes with a cohort of over 3000 siblings of CCSS participants. The incidence of secondary cancers was 3.5% at 20 years and 7% at 30 years after diagnosis. There was an increased incidence of chronic health conditions, most commonly involving neurological, sensory, endocrine and musculoskeletal systems. Neuroblastoma survivors were less likely to have ever been employed or be married and had a lower income.
With regard to high-risk patients alone, a retrospective single-center study reviewed 16 survivors of stage 4 neuroblastoma treated between 1984 and 2009. Renal changes were observed in 62.5%, endocrine disturbances in 56.3% and sensorineural hearing loss in 37.5%. Other observed late effects included hepatobiliary changes, musculoskeletal problems, pulmonary abnormalities, dental changes and neurological changes. Secondary neoplasms were determined in three patients.
The term 'cancer survivorship' has gained international recognition and is a focus for research. In 2007, the National Cancer Survivorship Initiative (NCSI) was formed in the UK, originating from the Cancer Reform Strategy. The aims of the initiative are to improve the provision of care and support for children and young people surviving cancer, and to improve the overall support to parents and carers. Some of the strategies involve developing individualized survivorship treatment plans and risk-stratifying patients at risk of long-term complications from their cancer treatment.
The high incidence of secondary late effects following treatment for neuroblastoma emphasizes the importance of careful medical and psychosocial long-term follow-up of these patients.
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