Addition of isotretinoin benefits none

The addition of carboplatin as a radiosensitizer to intensify radiotherapy improved event-free survival (EFS) by 19% at 5 years, but only in children with high-risk group 3 medulloblastoma, according to a study from the Children’s Oncology Group. Results are published in JAMA Oncology and support the value of integrating clinical and molecular risk stratification in children with medulloblastoma.

Additionally, the researchers concluded that the addition of isotretinoin during maintenance chemotherapy did not improve survival in these children. That arm of the trial was halted early for futility.

“Medulloblastoma is the most common embryonal brain tumor and occurs mainly in children (median age, 8 years). With multimodal therapy, including neurosurgical resection, craniospinal radiation, and combination chemotherapy, most children may be cured. There are few curative options for therapy following relapse,” wrote Sarah E. S. Leary, MD, of the Cancer and Blood Disorders Center, Seattle Children’s, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, and fellow researchers.

“Clinical and histologic characteristics associated with an increased risk of relapse in medulloblastoma include metastatic disease, diffuse anaplasia, or incomplete surgical resection; these factors define high-risk medulloblastoma,” they added.

In previous preclinical and clinical trials, both carboplatin (in potentiating radiotherapy) and isotretinoin (as a differentiating agent) were shown to improve progression-free (PFS) and event-free survival (EFS), respectively.

In this four-arm, phase III, randomized clinical trial, Leary and colleagues enrolled 261 patients ages 3 to 21 years with newly diagnosed high-risk medulloblastoma for institutions that belong to the Children’s Oncology Group. The median age was 8.6 years, most were boys (70%), and most had metastatic disease (72%). In addition, 22% had diffuse anaplasia, and 5% had greater than 1.5-cm2 residual disease.

The researchers randomized the subjects into four separate treatment arms, to receive either 36-Gy craniospinal radiation therapy and vincristine (weekly) with/without carboplatin (daily), followed by six cycles of maintenance chemotherapy with cisplatin, cyclophosphamide, and vincristine with/without 12 cycles of isotretinoin both during and after maintenance.

EFS was the primary endpoint. 5-year EFS among all patients was 62.9% (95% CI: 55.6%-70.25), and overall survival was 73.4% (95% CI: 66.7%-80.1%). Patients who received carboplatin had a 5-year EFS of 66.4% (95% CI: 56.4%-76.4%), compared with 53.7% (95% CI: 35.3%-72.1%) for those without carboplatin (P=0.047).

Patients randomized to receive isotretinoin were given 80 mg/m2 twice daily 14 days for 28 days, for 12 cycles during and after maintenance therapy, which was comprised of six 28-day cycles of cisplatin (75 mg/m2) on day 1; cyclophosphamide (1,000 mg/m2) on days 2-3; and vincristine (1.5 mg/m2) on days 1 and 8. However, isotretinoin randomization was closed early due to futility when an interim analysis showed that adding it to maintenance therapy was unlikely to lead to a significant difference in EFS.

The primary biologic endpoint of the study was molecular subgroup classification according to DNA methylation array.

“Genomic studies have identified at least 4 distinct molecular subgroups of medulloblastoma that may improve diagnostic and prognostic specificity. The 2016 World Health Organization Classification of Tumors of the Central Nervous System defined an integrated diagnosis including WNT (WNT signaling pathway activated), SHH (SHH signaling pathway activated) with or without TP53 mutation, and non-WNT/non-SHH (provisionally designated group 3 and group 4) medulloblastoma,” explained Leary et al.

When patients were classified according to molecular subgroups, researchers found the following 5-year overall survival rates differed as follows:

  • WNT pathway activated: 100% (95% CI: 61.9%-85.5%).
  • SHH pathway activated: 53.6% (95% CI: 33.0%-74.2%).
  • Group 3: 73.7% (95% CI: 61.9%-85.5%).
  • Group 4: 76.9% (95% CI: 67.3%-86.5%).

Leary et al conducted a combined analysis of metastatic status and molecular subgroups, which demonstrated the following:

  • In 20 children with group 3 M0 stage disease, 5-year EFS was 95.0% (95% CI: 84.2%-100%) and OS was 100% (95% CI: 100%-100%) compared with children with metastatic disease, who had an EFS of 53.6% (95% CI: 37.9%-69.3%) and an OS of 64.9% (95% CI: 50.2%-79.6%) (P=0.002 for EFS; P=0.003 for OS).
  • In 19 children with M0 group 4 disease, 5-year EFS was 84.2% (95% CI: 66.0%-100%) and OS was 75.0% (95% CI: 63.8%-86.2%) (P=0.08 and 0.31, respectively).
  • In 59 children with metastatic group 3 disease, the effects of carboplatin were maintained, as shown by a 5-year EFS of 64.8% (95% CI: 43.8%-85.8%) and an OS of 77.4% (95% CI: 58.8%-96.0%), compared to results in children not treated with carboplatin: EFS, 40.3% (95% CI: 19.9%-60.7%) and OS, 51.2% (95% CI: 31.0%-71.4%) (P=0.045 for EFS; P=0.046 for OS).

MYC amplification and isochromosome 17 were associated with inferior survival in group 3 patients, while loss of chromosome 11 or gain of chromosome 17 were associated with superior survival in group 4 patients.

Children in the carboplatin arm experienced greater hematologic toxic effects, and during the first cycles of maintenance therapy had an increased risk of thrombocytopenia and febrile neutropenia. No differences were seen in rates of high-grade toxicity according to carboplatin randomization. Finally, researchers found no deleterious effects of carboplatin on neurocognitive outcomes.

“The outcomes of these studies reflect the complex biologic characteristics of these tumors and the difficulty in translating molecular phenotypes to the clinic. The study by Leary et al provides us with glimmers of hope for the survival of children with high-risk group 3 medulloblastoma and that the treatment paradigm for all patients with high-risk disease can be improved through incorporation of detailed molecular analyses. The trial also presents a window into the behavior of high-risk group 3 medulloblastoma with a nod to future treatment options for more treatment-responsive, favorable high-risk patients,” wrote Allison M. Martin, MD, and Sadhana Jackson, MD, in an accompanying editorial.

Study limitations include unstratified randomization according to molecular subgroup and the inability to assess the effects of incomplete resection on survival compared with other risk factors; potential inappropriate assignment of standard-risk patients to high-risk treatment without central radiologic review; discrepancies in pathologic diagnoses; and neurocognitive outcomes only being available for a small set of patients.

  1. Adding carboplatin to traditional high-risk therapy specifically benefited only children with group 3 medulloblastoma, including those with metastatic disease.

  2. The addition of isotretinoin during maintenance chemotherapy did not improve survival in these children.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This study was funded by the National Cancer Institute through the National Clinical Trials Network (NCTN), as well as through grants from the NCTN Operations Center, NCTN Statistics & Data Center, St Baldrick’s Foundation, Sontag Foundation, NIH 5R01CA114567, and The Brain Tumor Charity Clinical Biomarkers Award.

Leary and Jackson reported no disclosures.

Martin reported owning shares in Celgene that were sold in 2019.

Cat ID: 115

Topic ID: 78,115,730,115,129,130,138,192,925,480,482,96