Feature

Risk-adapted approach may help some children with medulloblastoma avoid radiation, chemotherapy

Giles W. Robinson

Molecular subtyping may help develop a risk-adapted approach for treating children with medulloblastoma.

Giles W. Robinson, MD, assistant member of the faculty in the division of neuro-oncology at St. Jude Children’s Research Hospital, and colleagues conducted a multicenter phase 2 trial that included 81 children with histologically confirmed medulloblastoma.

Researchers used clinical and histological criteria to stratify patients postoperatively into low-, intermediate- and high-risk groups.

All children underwent induction chemotherapy with methotrexate, vincristine, cisplatin and cyclophosphamide. Those in the high-risk group received five additional doses of vinblastine.

Following induction, low-risk patients underwent treatment with cyclophosphamide (1,500 mg/m2 on day 1), etoposide (100 mg/m2 on days 1 and 2) and carboplatin (area under the curve, 5 mg/mL per minute on day 2) for two 4-week cycles.

Intermediate-risk patients underwent focal radiation therapy to the tumor bed (54 Gy, with a clinical target volume of 5 mm over 6 weeks).

High-risk patients received IV topotecan (area under the curve, 120 ng-h/ML to 160 ng-h/mL on days 1-5) and cyclophosphamide (600 mg/m2 IV on days 1-5), followed by maintenance therapy with cyclophosphamide, topotecan and erlotinib (Tarceva, Genentech).

EFS served as the primary endpoint. Investigators also assessed patterns of methylation profiling associated with PFS.

Median follow-up was 5.5 years (interquartile range, 2.7-7.3).

The researchers suspended the trial for the low-risk group due to the low-risk EFS outcome.

Researchers reported 5-year EFS rates of 31.1% (95% CI, 19.3-43.3) in the entire cohort, 55.3% (95% CI, 33.3-77.3) in the low-risk cohort, 24.6% (95% CI, 3.6-45.6) in the intermediate-risk cohort (HR = 2.5; P = .016) and 16.7% (95% CI, 93.4-30) in the high-risk cohort (HR = 3.55, P = .0011).

Methylation subgroup analysis results showed a 5-year PFS rate of 51.1% (95% CI 34.6-67.6) in the sonic hedgehog (SHH) subgroup, compared with 8.3% (95% CI, 0-24) in group 3 and 13.3% (95% CI, 0-37.6%) in group 4.

Further analysis revealed two distinct methylation subtypes within the sonic hedgehog groups. Five-year PFS was 27.8% (95% CI, 9-46.6) in the iSHH-I group and 75.4% (95% CI, 55-95.8) in the iSHH-II group.

HemOnc Today spoke with Robinson about the treatment challenges in this patient population, the potential utility of risk stratification for these patients, and the directions future research must take.

 

Question: How did this study come about?

Answer: The basis of the study — launched in 2007 — was to avoid, defer or delay craniospinal irradiation (ie, whole brain and spine irradiation) for young children with brain tumors through risk-adapted alternative treatment options. Young children with medulloblastoma are highly susceptible to radiation toxicity, but they harbor tumors that are highly responsive to radiation therapy. Patients aged older than 3 years receive craniospinal irradiation, and their PFS and cure rates are much better. However, the probability of severe and debilitating neurocognitive side effects for very young children is so high that alternative therapy — even with inferior results — is selected. We struggle with this battle between survival at all cost and survival with less deficit. For this reason, in neuro-oncology, we call children aged younger than 3 years “infants,” because the therapy is different. We attempt to treat without craniospinal irradiation therapy, at least in the beginning.

In this study, we explored a risk-adapted approach based largely on tumor appearance — or histopathology — and extent of spread of disease, meaning metastatic vs. nonmetastatic. All patients with metastatic disease were treated as high risk, but those without metastatic disease were placed in low- or intermediate-risk groups. The rationale for this is that, within the group of infants, some have higher-risk medulloblastoma tumors than others. This differential response has been broadly observed along differences in pathology. Medulloblastoma of the desmoplastic-nodular variety and those with extensive nodularity seem to respond to chemotherapy better and more durably than medulloblastomas with classic or anaplastic histology. Therefore, patients with desmoplastic nodular tumors or medulloblastoma with extensive modularity received low-risk therapy, and patients with medulloblastoma with classic or anaplastic tumors had intermediate- or high-risk therapy. When this study was being developed, there were three major approaches to these infants: myeloablative chemotherapy; systemic and intraventricular methotrexate as a substitute for radiation; or focally treating tumors with radiation therapy and chemotherapy. We incorporated those three approaches into a single clinical trial and modified them somewhat in order to ask some questions. For example, we treated high-risk patients with metastatic disease with intensive chemotherapy but we didn’t use myeloablative doses of chemotherapy because it can be toxic. We also chose to do systemic methotrexate instead of both systemic and intraventricular methotrexate to avoid brain toxicity. Intermediate-risk patients received focal radiation therapy.

 

Q: How did you arrive at those modifications to dosing or treatment?

A: Intraventricular methotrexate seems to have a degree of success in desmoplastic nodular patients, but with neurotoxicity that has led to the omission or delay of some doses. The thought was that maybe some of those patients didn’t actually require intraventricular doses. Focal radiation used after chemotherapy is designed to deploy and reap the benefit of radiation, but only to the tumor, avoiding radiation to the whole brain and spine. Logically, this could only benefit children whose tumors had not spread outside of a focal area, so this was aimed at patients with nonmetastatic disease. Then there was the all-chemotherapy approach given to the high-risk patients. This involved systemic methotrexate and a consolidation regimen that was intensive but not myeloablative.

 

Q: Can you explain the risk - stratification approaches you used in this study?

A: This was designated by histology and by clinical risk criteria. Patients who were desmoplastic nodular but not metastatic went into the low-risk category. Patients with nonmetastatic and classic or anaplastic disease were in the intermediate group. Any patients with metastatic disease went into the high-risk group. For the intermediate-risk group, we also enrolled nonmetastatic 3- to 6-year-olds to see if we could bend that age group beyond 3 to see how they responded.

However, it is important to recognize that this stratification approach was designed before we knew about the molecular makeup of medulloblastoma. More recently medulloblastoma has been analyzed from a molecular standpoint and has been found to be made up of essentially four different distinct biological diseases.

 

Q: How will those changes in stratification impact your approach?

A: It makes it much more refined. The four groups are wingless (WNT), sonic hedgehog, group 3 and group 4 and there is some rough correlation between subgroup and histology but it is not as accurate as molecular subgrouping. Therefore, a principal component of our study was to take the trial — which was written in 2006-2007 — and put it into the context of the new understanding of molecular subgroups of medulloblastoma. To do this, we collected what we call a molecular cohort and gathered as many young childhood medulloblastoma samples as we could. We looked molecularly at all 190 samples from patients aged younger than 6 years. We found there was a complete absence of the WNT subgroup among those aged younger than 6 years, and there were very few group 4 cases. We really saw that two of the four subgroups were dominant in this young population: the sonic hedgehog and the group 3 subgroups.

 

Q: Can you talk about your results?

A: We looked at results in two ways. One was the original way, using the old classification. Here we found that low-risk patients did better than intermediate- and high-risk patients. However, the molecular analysis showed that PFS was subgroup driven. We found that low-risk patients were all sonic hedgehog, and that sonic hedgehog patients who fell into the intermediate- or high-risk categories had equivalent survival to low-risk patients. This meant that it was the sonic hedgehog patients who were benefitting from the therapy that we gave them rather than the group 3 and group 4 patients who were doing poorly. The bottom line is that the response to therapy was much more molecularly derived than by our original risk stratification.

 

Q: This sounds like a lot to parse out.

A: It is, but its progress.

 

Q: How do you take this information into account for future studies?

A: Essentially, what we discovered is that sonic hedgehog patients had a sizable benefit from radiation-sparing therapy, but group 3 and group 4 did not. If we’re going to employ radiation-sparing therapy, we should do it in the sonic hedgehog group, but not in groups 3 or 4.

 

Q: What should be done for those in group 3 and group 4?

A: This will require much larger analyses of all available treatment approaches.

 

Q: What do you consider the major takeaways of your findings?

A: A key finding is that PFS for the sonic hedgehog group was about 50%, which is not great. But using a technique called DNA methylation profiling, we could split these patients into two groups: sonic hedgehog 1 and sonic hedgehog 2. Patients in the sonic hedgehog 2 group outperformed the sonic hedgehog 1 patients. So, although this study doesn’t move the needle forward in improving curative care for pediatric medulloblastoma patients, it did allow us to determine which patients could do well on reduced-intensity therapy going forward. In the big picture, we have identified a group of young childhood medulloblastomas, called sonic hedgehog 2, that can be potentially cured without radiation and highly toxic chemotherapy. We have also identified a second group of young childhood medulloblastoma, sonic hedgehog 1, that likely need more intensive treatment regimens but which hopefully could still be spared radiation therapy. Finally, we have identified a group of young childhood medulloblastomas — group 3 and a small number of those in group 4 — who desperately need better therapy. Our work is cut out for us, but there are better outcomes on the horizon. – by Rob Volansky

 

Reference:

Robinson GW, et al. Lancet Oncol. 2018;doi:10.1016/S1470-2045(18)30204-3.

For more information:

Giles W. Robinson, MD, can be reached at St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105; email: giles.robinson@stjude.org.

Disclosure: Robinson reports no relevant financial disclosures.

Giles W. Robinson

Molecular subtyping may help develop a risk-adapted approach for treating children with medulloblastoma.

Giles W. Robinson, MD, assistant member of the faculty in the division of neuro-oncology at St. Jude Children’s Research Hospital, and colleagues conducted a multicenter phase 2 trial that included 81 children with histologically confirmed medulloblastoma.

Researchers used clinical and histological criteria to stratify patients postoperatively into low-, intermediate- and high-risk groups.

All children underwent induction chemotherapy with methotrexate, vincristine, cisplatin and cyclophosphamide. Those in the high-risk group received five additional doses of vinblastine.

Following induction, low-risk patients underwent treatment with cyclophosphamide (1,500 mg/m2 on day 1), etoposide (100 mg/m2 on days 1 and 2) and carboplatin (area under the curve, 5 mg/mL per minute on day 2) for two 4-week cycles.

Intermediate-risk patients underwent focal radiation therapy to the tumor bed (54 Gy, with a clinical target volume of 5 mm over 6 weeks).

High-risk patients received IV topotecan (area under the curve, 120 ng-h/ML to 160 ng-h/mL on days 1-5) and cyclophosphamide (600 mg/m2 IV on days 1-5), followed by maintenance therapy with cyclophosphamide, topotecan and erlotinib (Tarceva, Genentech).

EFS served as the primary endpoint. Investigators also assessed patterns of methylation profiling associated with PFS.

Median follow-up was 5.5 years (interquartile range, 2.7-7.3).

The researchers suspended the trial for the low-risk group due to the low-risk EFS outcome.

Researchers reported 5-year EFS rates of 31.1% (95% CI, 19.3-43.3) in the entire cohort, 55.3% (95% CI, 33.3-77.3) in the low-risk cohort, 24.6% (95% CI, 3.6-45.6) in the intermediate-risk cohort (HR = 2.5; P = .016) and 16.7% (95% CI, 93.4-30) in the high-risk cohort (HR = 3.55, P = .0011).

Methylation subgroup analysis results showed a 5-year PFS rate of 51.1% (95% CI 34.6-67.6) in the sonic hedgehog (SHH) subgroup, compared with 8.3% (95% CI, 0-24) in group 3 and 13.3% (95% CI, 0-37.6%) in group 4.

Further analysis revealed two distinct methylation subtypes within the sonic hedgehog groups. Five-year PFS was 27.8% (95% CI, 9-46.6) in the iSHH-I group and 75.4% (95% CI, 55-95.8) in the iSHH-II group.

HemOnc Today spoke with Robinson about the treatment challenges in this patient population, the potential utility of risk stratification for these patients, and the directions future research must take.

 

Question: How did this study come about?

Answer: The basis of the study — launched in 2007 — was to avoid, defer or delay craniospinal irradiation (ie, whole brain and spine irradiation) for young children with brain tumors through risk-adapted alternative treatment options. Young children with medulloblastoma are highly susceptible to radiation toxicity, but they harbor tumors that are highly responsive to radiation therapy. Patients aged older than 3 years receive craniospinal irradiation, and their PFS and cure rates are much better. However, the probability of severe and debilitating neurocognitive side effects for very young children is so high that alternative therapy — even with inferior results — is selected. We struggle with this battle between survival at all cost and survival with less deficit. For this reason, in neuro-oncology, we call children aged younger than 3 years “infants,” because the therapy is different. We attempt to treat without craniospinal irradiation therapy, at least in the beginning.

In this study, we explored a risk-adapted approach based largely on tumor appearance — or histopathology — and extent of spread of disease, meaning metastatic vs. nonmetastatic. All patients with metastatic disease were treated as high risk, but those without metastatic disease were placed in low- or intermediate-risk groups. The rationale for this is that, within the group of infants, some have higher-risk medulloblastoma tumors than others. This differential response has been broadly observed along differences in pathology. Medulloblastoma of the desmoplastic-nodular variety and those with extensive nodularity seem to respond to chemotherapy better and more durably than medulloblastomas with classic or anaplastic histology. Therefore, patients with desmoplastic nodular tumors or medulloblastoma with extensive modularity received low-risk therapy, and patients with medulloblastoma with classic or anaplastic tumors had intermediate- or high-risk therapy. When this study was being developed, there were three major approaches to these infants: myeloablative chemotherapy; systemic and intraventricular methotrexate as a substitute for radiation; or focally treating tumors with radiation therapy and chemotherapy. We incorporated those three approaches into a single clinical trial and modified them somewhat in order to ask some questions. For example, we treated high-risk patients with metastatic disease with intensive chemotherapy but we didn’t use myeloablative doses of chemotherapy because it can be toxic. We also chose to do systemic methotrexate instead of both systemic and intraventricular methotrexate to avoid brain toxicity. Intermediate-risk patients received focal radiation therapy.

 

Q: How did you arrive at those modifications to dosing or treatment?

A: Intraventricular methotrexate seems to have a degree of success in desmoplastic nodular patients, but with neurotoxicity that has led to the omission or delay of some doses. The thought was that maybe some of those patients didn’t actually require intraventricular doses. Focal radiation used after chemotherapy is designed to deploy and reap the benefit of radiation, but only to the tumor, avoiding radiation to the whole brain and spine. Logically, this could only benefit children whose tumors had not spread outside of a focal area, so this was aimed at patients with nonmetastatic disease. Then there was the all-chemotherapy approach given to the high-risk patients. This involved systemic methotrexate and a consolidation regimen that was intensive but not myeloablative.

 

Q: Can you explain the risk - stratification approaches you used in this study?

A: This was designated by histology and by clinical risk criteria. Patients who were desmoplastic nodular but not metastatic went into the low-risk category. Patients with nonmetastatic and classic or anaplastic disease were in the intermediate group. Any patients with metastatic disease went into the high-risk group. For the intermediate-risk group, we also enrolled nonmetastatic 3- to 6-year-olds to see if we could bend that age group beyond 3 to see how they responded.

However, it is important to recognize that this stratification approach was designed before we knew about the molecular makeup of medulloblastoma. More recently medulloblastoma has been analyzed from a molecular standpoint and has been found to be made up of essentially four different distinct biological diseases.

 

Q: How will those changes in stratification impact your approach?

A: It makes it much more refined. The four groups are wingless (WNT), sonic hedgehog, group 3 and group 4 and there is some rough correlation between subgroup and histology but it is not as accurate as molecular subgrouping. Therefore, a principal component of our study was to take the trial — which was written in 2006-2007 — and put it into the context of the new understanding of molecular subgroups of medulloblastoma. To do this, we collected what we call a molecular cohort and gathered as many young childhood medulloblastoma samples as we could. We looked molecularly at all 190 samples from patients aged younger than 6 years. We found there was a complete absence of the WNT subgroup among those aged younger than 6 years, and there were very few group 4 cases. We really saw that two of the four subgroups were dominant in this young population: the sonic hedgehog and the group 3 subgroups.

 

PAGE BREAK

Q: Can you talk about your results?

A: We looked at results in two ways. One was the original way, using the old classification. Here we found that low-risk patients did better than intermediate- and high-risk patients. However, the molecular analysis showed that PFS was subgroup driven. We found that low-risk patients were all sonic hedgehog, and that sonic hedgehog patients who fell into the intermediate- or high-risk categories had equivalent survival to low-risk patients. This meant that it was the sonic hedgehog patients who were benefitting from the therapy that we gave them rather than the group 3 and group 4 patients who were doing poorly. The bottom line is that the response to therapy was much more molecularly derived than by our original risk stratification.

 

Q: This sounds like a lot to parse out.

A: It is, but its progress.

 

Q: How do you take this information into account for future studies?

A: Essentially, what we discovered is that sonic hedgehog patients had a sizable benefit from radiation-sparing therapy, but group 3 and group 4 did not. If we’re going to employ radiation-sparing therapy, we should do it in the sonic hedgehog group, but not in groups 3 or 4.

 

Q: What should be done for those in group 3 and group 4?

A: This will require much larger analyses of all available treatment approaches.

 

Q: What do you consider the major takeaways of your findings?

A: A key finding is that PFS for the sonic hedgehog group was about 50%, which is not great. But using a technique called DNA methylation profiling, we could split these patients into two groups: sonic hedgehog 1 and sonic hedgehog 2. Patients in the sonic hedgehog 2 group outperformed the sonic hedgehog 1 patients. So, although this study doesn’t move the needle forward in improving curative care for pediatric medulloblastoma patients, it did allow us to determine which patients could do well on reduced-intensity therapy going forward. In the big picture, we have identified a group of young childhood medulloblastomas, called sonic hedgehog 2, that can be potentially cured without radiation and highly toxic chemotherapy. We have also identified a second group of young childhood medulloblastoma, sonic hedgehog 1, that likely need more intensive treatment regimens but which hopefully could still be spared radiation therapy. Finally, we have identified a group of young childhood medulloblastomas — group 3 and a small number of those in group 4 — who desperately need better therapy. Our work is cut out for us, but there are better outcomes on the horizon. – by Rob Volansky

 

Reference:

Robinson GW, et al. Lancet Oncol. 2018;doi:10.1016/S1470-2045(18)30204-3.

For more information:

Giles W. Robinson, MD, can be reached at St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105; email: giles.robinson@stjude.org.

Disclosure: Robinson reports no relevant financial disclosures.

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