DEXAMETHASONE REDUCES IMMUNOTHERAPY EFFICACY IN GLIOBLAASTOMA

  Dexamethasone given to combat cerebral edema in patients with glioblastoma may negatively affect immunotherapy, according to work in mice and clinical data.

"There are many biologic, endogenous factors contributing to immunosuppression and immune evasion in glioblastoma," said Dr. David A. Reardon of Harvard Medical School, in Boston.

"Our work highlights a critical exogenous and iatrogenic factor - the use of dexamethasone for the treatment of symptomatic cerebral edema - that represents an additional and significant potential hurdle for immunotherapy among patients afflicted with these devastating tumors," he told Reuters Health by email.

In a statement, Dr. Reardon noted that cerebral edema is a common, potentially life-threatening complication in glioblastoma patients. Corticosteroid treatment can help suppress the inflammation in the brain, he added.

Dr. Reardon and colleagues first studied the effects of dexamethasone administered with programmed cell death protein 1 (PD-1) blockade to syngeneic murine glioblastoma models.

Dexamethasone reduced survival in both immunocompetent and immunosuppressed animals in a dose-dependent manner, they report in Clinical Cancer Research. This was true of addition of dexamethasone to anti-PD-1 therapy alone or to anti-PD-1 therapy along with radiotherapy, a standard treatment for patients with glioblastoma.

In particular, say the researchers, "Dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone."

The team then went on to examine data from 181 patients with glioblastoma treated with either anti-PD-1 or anti-PD-L1 therapy who were followed for a median of 22 months after diagnosis. Most had had recurrent disease and about 35% were receiving dexamethasone at baseline.

Use of dexamethasone at any dose was associated with reduced overall survival and was the strongest identified negative risk factor. Even after multivariable adjustment, compared with no dexamethasone, dosage of less than 2 mg was associated with a significantly higher risk of death (hazard ratio, 2.16). For a higher dosage, the corresponding hazard ratio was 1.97.

"Our results suggest that we should try to avoid dexamethasone among patients with glioblastoma who are treated with immunotherapy, and if corticosteroids are clinically required, we should use these drugs judiciously," Dr. Reardon said in the stratement. "Further, our results highlight that other strategies for the treatment of cerebral edema that do not have such a broad anti-inflammatory effect critically need to be investigated."

SOURCE: https://bit.ly/2VoVK03 Clinical Cancer Research, online November 25, 2020.

Reuters Health Information © 2020 

LEPTOMENINGEAL METASTASES MAY RESPOND TO IMMUNOTHERAPY

 

Immunotherapy with pembrolizumab holds promise for improving the generally dismal outlook in patients with leptomeningeal metastases, a phase 2 trial suggests.

Results from the trial were reported at the Society for Immunotherapy of Cancer's 35th Anniversary Annual Meeting.

"Unfortunately, when patients present with leptomeningeal disease, they usually have a poor prognosis. Their median survival is measured at 6-24 weeks," commented lead study author Jarushka Naidoo, MBBCh, an adjunct assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, and a consultant medical oncologist at Beaumont Hospital in Dublin.

"While there may be some standard approaches for how we treat leptomeningeal disease, there are no universal standard therapies that are efficacious across solid tumor types," Naidoo added.

With this in mind, Naidoo and colleagues tested systemic pembrolizumab in a trial of patients with leptomeningeal metastases from solid tumors.

The trial closed early because of poor accrual, after enrolling 13 patients: 5 with breast carcinoma, 3 with high-grade glioma, 3 with non–small cell lung cancer, 1 with squamous cell carcinoma of the skin, and 1 with head and neck squamous carcinoma. Nine patients (69%) had received at least two prior lines of systemic therapy.

Response, Safety, and Biomarkers

Overall, five patients (38%) had a central nervous system response, as ascertained from radiologic response on MRI, cytologic response in cerebrospinal fluid (CSF), and/or clinical response in neurologic symptoms, Naidoo reported.

Two patients had a complete CNS response: a patient with squamous cell carcinoma of the skin, who was still alive at 3 years, and a patient with non–small cell lung cancer, who survived 9 months but succumbed to metastases elsewhere.

For the entire cohort, median CNS progression-free survival was 2.9 months, and median overall survival was 4.9 months.

"This is consistent with published prospective studies of systemic agents for leptomeningeal disease," Naidoo pointed out. "Notably, even though numbers are small, we do see the tail-on-the-curve phenomenon in both of these survival curves, which is consistent with immune checkpoint blockade prospective studies."

The rate of grade 3 or higher treatment-related adverse events was 15.4%, and there were no grade 3 or higher immune-related adverse events.

The number of patients was too small for formal correlational testing, but both patients who achieved a complete response developed immune-related adverse events.

The trial's biomarker analyses showed that an aneuploidy assay using CSF tumor-derived DNA performed well at detecting leptomeningeal metastases, with sensitivity of 84.6%, compared with just 53.8% for CSF cytopathology (the current preferred method).

A multiplex assay of CSF cytokines identified similar baseline profiles for patients who went on to have responses and showed similar changes in profile (notably a reduction in proinflammatory cytokines) for the two patients who had complete responses.

Given the trial's 38% CNS response rate, pembrolizumab "needs to be studied in larger populations of patients to confirm this result, but it could be used as a potential treatment option for patients with leptomeningeal disease from solid tumors," Naidoo concluded. "Reassuringly, pembrolizumab was well tolerated, and this is extremely important in a patient population that is traditionally quite frail and in which other standard therapies that are used, such as high-dose methotrexate or intrathecal chemotherapy, are associated with far higher rates of toxicity."

An Unmet Need

"Leptomeningeal metastasis is a strong unmet need, although its occurrence is fortunately quite rare," commented Kim Margolin, MD, a clinical professor and medical oncologist at City of Hope National Medical Center in Duarte, Calif., who was not involved in this study.

The trial is noteworthy for showing activity of programmed death–1 (PD-1) blockade given only systemically and not with additional intrathecal therapy (as has been done in a concurrent study at MD Anderson Cancer Center) and for providing insight into various biomarkers, Margolin said in an interview.

"I cannot take a stand on author conclusions other than to agree it warrants further evaluation in carefully selected patients, and it would be great to compare something like peripheral PD-1 blockade alone versus in combination with intrathecal therapy versus a combination such as CTLA4 blockade plus PD-1 blockade such as our group and others have shown to have increased activity in CNS metastases over PD-1 block alone," Margolin said.

"The drugs in this class are already approved, so there is no reason not to try them," she noted.

However, patients with leptomeningeal metastases of melanoma, for example, are likely to have already received anti-PD-1 immunotherapy.

"So the settings in which off-the-shelf PD-1 blockade would be useful are extremely limited," she concluded.

The current trial was funded by Merck, the National Institutes of Health, the Lung Cancer Foundation of America, the International Association for the Study of Lung Cancer, and Johns Hopkins University Seed Grants. Naidoo disclosed relationships with AstraZeneca, Merck, Bristol Myers Squibb, and Roche/Genentech. Margolin disclosed no relevant conflicts of interest.

SOURCE: Naidoo J et al. SITC 2020, Abstract 788.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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Cite this: Immunotherapy Could Fill Unmet Nee

SRS FOR MULTIPLE BRAIN METASTASES

Stereotactic radiosurgery (SRS) should replace whole-brain radiotherapy (WBRT) as the new standard of care for patients with four or more brain metastases, say researchers who report results from a randomized trial conducted in patients with four to 15 brain metastases

"SRS was associated with reduced risk of neurocognitive deterioration compared to WBRT, as demonstrated by a constellation of neurocognitive tests, individually or by composite scores," said lead author Jing Li, MD, PhD, associate professor of radiation oncology and codirector of the Brain Metastasis Clinic at the University of Texas MD Anderson Cancer Center, Houston.

She was speaking at the American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting, which was held online this year because of the COVID pandemic.

"The results from this phase 3 randomized trial strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival," said Li.

SRS is already the standard of care for patients with one to three brain metastases. Two previous phase 3 randomized trials showed that SRS was better at preserving cognitive function without compromising overall survival in comparison to WBRT.

However, there has been some controversy over the use of SRS for patients with multiple brain metastases, commented study discussant Sue S. Yom, MD, PhD, a professor in the Departments of Radiation Oncology and Otolaryngology–Head and Neck Surgery, University of California, San Francisco.

This study has shown "in a practice-changing manner that giving SRS can improve the quality of life of patients with metastatic disease," she said.

Up to 30% of cancer patients develop brain metastases. Historically, these have been associated with poor overall survival, in the range of 1 to 4 months.

Reduces Cognitive Decline

The new trial involved 72 patients with four to 15 untreated, nonmelanoma brain metastases (up to 20 lesions were allowed at the time of treatment); the median number of brain metastases was eight. Most (83%) of the trial participants were White, nearly half were aged 60 years or older, and 58% were women.

Patients were randomly assigned to receive either SRS (15–24 Gy per Radiation Therapy Oncology Group protocol 9005) or WBRT (30 Gy in 10 fractions). On the basis of previous research, 62% of patients in the WBRT arm were also given memantine, a dementia drug that can help preserve cognitive function.

All participants completed neurocognitive testing, including testing of learning, memory, attention span, executive function, verbal fluency, processing speed, and motor dexterity, at enrollment and longitudinally.

The primary endpoints were Hopkins Verbal Learning Test – Revised Total Recall (HVLT-R TR) score and local control at 4 months. Secondary endpoints included overall survival, distant brain failure, toxicity, and time to initiation of systemic therapy.

In the primary endpoint analysis, at 4 months, the HVLT-R TR standardized z-score increased by +0.21 (standard error [SE], 0.27) for patients who received SRS, but it declined by –0.74 (SE, 0.36) for WBRT-treated patients (P = .041). On the basis of Clinical Trial Battery Composite score, neurocognitive function of patients in the SRS arm improved on average +0.23 (SE, 0.14) but declined an average –0.73 (SE, 0.35) in the WBRT arm (P = .008).

Li pointed out that there was also a "clinically meaningful and statistically significant benefit" with SRS at 1 month (P = .033) and 6 months (P = .012).

A total of 69 patients (35 for SRS and 34 for WBRT) were evaluable for overall survival, which was similar between the groups (SRS median, 7.8 months; WBRT median, 8.9 months; P = .59). Treatment with SRS resulted in better local control rates (95% at 4 months with SRS and 86.7% with WBRT; P = .09), but the median time to distant brain failure was shorter (10.5 months for WBRT and 6.3 months for SRS; P = .37).

In her discussion of the study, Yom noted that overall survival time was similar in the two arms and that numerically, it may have even been a little longer in the SRS group. "While it is true that they had more relapses in untreated portions of the brain, they lived as long or longer than those who received WBRT and had better cognitive function," she noted

Yom also noted that of particular importance was the finding that SRS was associated with shorter interruptions of systemic therapy (time to systemic therapy: SRS, 1.7 weeks; WBRT, 4.1 weeks; P = .001). Patients with metastatic disease usually have cancer in locations other than the brain. They may be receiving some type of systemic therapy, which is interrupted with WBRT, Li commented.

Toxicities of grade 3 or higher were observed in four patients in the WBRT arm and two in the SRS arm. Radiographic evidence of radiation necrosis, a side effect associated with SRS, was observed in 17% patients in the SRS arm of the trial (4% of all treated lesions).

The trial was halted early owing to the publication of another phase 3 trial (NRG Oncology CC 001), which provided level 1 evidence for replacing standard WBRT with hippocampal-avoidance WBRT. Despite the early trial termination, Li concluded that these results "strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival."

Li has received research funding from BMS and Medtronic and honorarium from Novocure and Monteris.

American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting: Abstract 41, presented October 26, 2020.

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TEMOZOLOMIDE BENEFITS GLIOBLASTOMA PATIENTS

A comparison of U.S. and European treatment patterns for glioblastomas provides further evidence that adding systemic chemotherapy with temozolomide to radiotherapy offers a significant survival benefit over radiotherapy alone, and wider uptake of chemoradiation in Europe would extend the benefit to more patients.

That conclusion comes from a study of registry data from both sides of the Atlantic. The study showed a doubling in 2-year survival rates for patients with glioblastomas treated with radiotherapy plus chemotherapy compared with radiotherapy alone, a practice change that was prompted by a phase 3 trial published in The New England Journal of Medicine in 2005.

"Using population data from cancer registries, we observed a huge increase in radiotherapy plus chemotherapy between 1999 and 2013 in Europe and the U.S.," said Francesco Giusti, PhD, of the European Commission Joint Research Center in Ispra, Italy.

"Data from 1999 to 2005 was already showing a clear survival advantage for patients treated with chemotherapy plus radiotherapy compared with radiotherapy alone," he added.

However, when Giusti and colleagues compared practice patterns from before and after the publication of the practice-changing trial, they found that about 10% more patients in the United States were receiving combined chemotherapy and radiation, a difference reflected in superior survival rates in the U.S., he said.

Giusti presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

He and his colleagues looked at data from cancer registries contributing to the European Cancer Information System and the U.S. National Cancer Institute's Surveillance Epidemiology and End Results data.

The data set included patients diagnosed from 1999 through 2013 with glioblastoma as a first tumor.

During that time, results from the aforementioned phase 3 trial were published. They showed that, at a median follow-up of 28 months, the median survival was 14.6 months for the 287 patients assigned to radiotherapy plus temozolomide, compared with 12.1 months for the 286 patients randomized to radiotherapy alone.

The unadjusted hazard ratio for death in the combination therapy group was 0.63 (P < .001). The 2-year survival rate was 26.5% for chemoradiation and 10.4% for radiation alone.

Adding temozolomide to radiotherapy in the trial also appeared to be safe. The incidence of grade 3 or 4 hematologic adverse events was 7%.

Registry Data Study

To see how practice patterns changed in the United States and Europe after publication of the trial, Giusti and colleagues used registry data to calculate the proportion of cases by treatment type and overall survival during 1999-2005 (pre-study) and 2009-2013 (post-study).

The data included 34,229 cases from 11 countries in Europe and 36,925 cases from the United States.

The percentage of patients receiving both chemotherapy and radiation increased steadily over the study period. For example, among 18- to 49-year-olds, the percentage receiving the combined modalities in Europe increased from 20% in 1999-2001 to 70% in 2010-2013. In the United States, 40% of the same age group received combination therapy in 1999-2001, and this percentage grew to 80% in 2010-2013.

Overall survival rates in the general population were similar to those seen in the clinical trial during 1999-2005, when 2-year overall survival rates for patients treated with radiation alone were 11% in Europe and 12% in the United States. For patients treated with combined therapy, the respective 2-year survival rates in Europe and the United States were 24% and 25%.

"In the period after the trial, we observed a increasing 2-year survival rate to 28% in Europe and 29% in the U.S. for patients with radiotherapy plus chemotherapy," Giusti said.

Real-World Results

Invited discussant Matthias Preusser, MD, of the Medical University of Vienna in Austria, said the study shows that "population-based investigations are very valuable and should be further developed so that we can see how treatment patterns vary between countries and what the regional variations are, and whether new treatment standards actually reach clinical practice, and also to see whether there's an effect on a population basis that is different from what is seen in controlled clinical trials."

Preusser said it's clear from the study that survival is increased with the addition of chemotherapy to radiotherapy, and more patients in the United States than in Europe received the combination during the study period.

Pointing to a treatment algorithm from the European Association of Neuro-oncology published in 2017, Preusser noted that radiotherapy alone may still be recommended for patients with unfavorable prognostic factors or patients 70 years and older with methylguanine-DNA methyltransferase promoter non-methylated tumors.

"It seems the differences in the age distribution between the U.S. and European populations that were analyzed could be one explanation why the radiochemotherapy combination was applied more often in the U.S. population," Preusser said.

No outside funding was used to support the study. Giusti and coauthors reported having no conflicts of interest. Preusser disclosed relationships with multiple companies, including Merck, which markets temozolomide under the name Temodar.

SOURCE: Giusti F et al. ESMO 2020. Abstract 365MO.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

Medscape Medical News © 2020 WebMD, LLC

IMMUNOTHERAPY IN PATIENTS WITH BRAIN METASTASES

 Immunotherapy is associated with improved overall survival in patients with brain metastases who have undergone definitive surgery of their primary tumor, according to a database study.

Radiation therapy and other local therapies for brain metastases are associated with neurotoxic effects; cytotoxic chemotherapy, for its part, has shown limited effectiveness due to inability to cross the blood-brain barrier.

Immunotherapy has been shown to control intracranial metastases in patients with melanoma, but whether immunotherapy is effective in other cancers remains uncertain, Dr. Chi Lin and colleagues from the University of Nebraska Medical Center, in Omaha, note in in JAMA Network Open.

The team used data from the National Cancer Database to evaluate whether the use of immunotherapy in patients with brain metastases who received surgery of the primary site is associated with improved overall survival.

The study included more than 3,100 patients diagnosed with non-small-cell lung cancer, melanoma, breast cancer, colorectal cancer, or kidney cancer. Of these, 6% received immunotherapy, 6% received chemotherapy plus immunotherapy, 8% received radiation therapy plus immunotherapy, 5 % received chemoradiation plus immunotherapy, 10% received chemotherapy alone, 25% received radiation therapy alone, and 45% received chemoradiation alone.

Median overall survival was 22.6 months among patients who received immunotherapy versus 15.1 months among those who did not (P<0.001).

Similarly, median overall survival was significantly longer in patients who received radiotherapy plus immunotherapy (20.5 months) than in those who received radiotherapy alone (10.1 months) and in patients who received chemoradiation plus immunotherapy (28.5 months) than in those who received chemoradiation only (20.2 months).

The addition of immunotherapy to chemotherapy was not associated with a survival benefit.

On multivariable analysis, immunotherapy was associated with a 38% reduction in the risk of dying versus no immunotherapy (P<0.001), and immunotherapy plus radiation therapy was associated with a 41% reduction versus radiation therapy alone (P=0.003).

The addition of immunotherapy did not confer a survival advantage over chemotherapy or chemoradiation alone in the multivariable analysis.

Other factors associated with improved overall survival included younger age, treatment at an academic hospital, comorbidity score of 0, receiving chemotherapy, and having non-small-cell lung cancer (versus other cancers).

"The findings warrant future clinical trials investigating the association of chemotherapy, radiation therapy, and chemoradiation combined with immunotherapy with the survival of patients who receive definitive surgery of the primary tumor," the authors conclude.

Dr. Lin did not respond to a request for comments.

SOURCE: https://bit.ly/3hjjuLw JAMA Network Open, online September 9, 2020.

INTRAVENTRICULAR MTX FOR HOGH RISK MEDULLOBLASTOMA

Adding intraventricular methotrexate to systemic chemotherapy produced favorable survival outcomes in patients with desmoplastic medulloblastoma(DMB) and medulloblastoma with extensive nodularity (MBEN), according to research published in the Journal of Clinical Oncology.

Investigators conducted a prospective trial of 87 children diagnosed with nonmetastatic medulloblastoma before the age of 4 years who were treated from 2001-2011.

At 5 years after diagnosis, the 42 DMB/MBEN patients had a 93% progression-free survival (PFS) rate, a 100% overall survival (OS) rate, and a 93% craniospinal irradiation (CSI)–free survival rate.

"Our results suggest that ... poor outcomes of patients treated with systemic chemotherapy alone can be improved by the addition of intraventricular [methotrexate]," wrote Martin Mynarek, MD, of the University Medical Center Hamburg-Eppendorf (Germany), and colleagues.

However, it was a different story for the 45 patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (CLA), in which outcomes are historically worse. At 5 years, the PFS was 37%, the OS was 62%, and the CSI-free survival was 39% in these patients.

In 2006, the CMB and CLA patients started receiving local radiotherapy in addition to chemotherapy and intraventricular methotrexate, but the radiotherapy did not seem to help with their disease.

"Because data suggest no effects, or even adverse effects, of local radiotherapy, additional development of this approach does not seem justified," the investigators wrote.

"Interestingly, almost all patients with CMB/LCA had distant or combined relapses after local radiotherapy," they added. "One might speculate that local radiotherapy reduced disease burden of the primary tumor and subclinical metastasis in the posterior fossa, leading to a survival advantage of distant subclinical metastasis over local residues."

Treatment Details 

The 87 patients were enrolled in the BIS4 arm of the HIT 2000 trial (NCT00303810), which was designed to test six protocols and identify the optimal approach for treating young patients with medulloblastoma, supratentorial primitive neuroectodermal tumor, or ependymoma.

Patients started "HIT-SKK" chemotherapy within 2-4 weeks of surgery. They received three cycles of intravenous cyclophosphamide, vincristine, methotrexate (followed by leucovorin rescue after 42 hours), carboplatin, and etoposide, with concomitant intraventricular methotrexate, for a duration of 6 months (Neuro Oncol. 2011 Jun;13[6]:669-79).

Among patients who achieved a complete remission, treatment was ended after two additional cycles of chemotherapy. For other patients, secondary surgery, radiotherapy, and consolidation chemotherapy were recommended.

Starting in 2006, DMB and MBEN patients without complete remissions, as well as those with CMB or LCA, received 54 Gy of focal radiotherapy to the tumor bed after the first three treatment cycles

SHH-I vs. SHH-II DMB/MBEN 

DNA methylation profiling was available for 50 of the 87 patients in this analysis, 28 of whom had infantile sonic hedgehog (SHH)–activated DMB/MBEN. Data from these 28 patients – and 71 patients in a validation cohort – revealed no significant difference in 5-year PFS or OS based on methylation subtype.

The 5-year PFS was 73% in SHH-I patients and 83% in SHH-II patients (P = .25). The 5-year OS was 88% and 97%, respectively (P = .099).

"This suggests that the higher risk of relapse in the less favorable [SHH-I subtype] can be abrogated by the addition of intraventricular [methotrexate] to systemic chemotherapy," the investigators wrote.

The results suggest SHH-I patients "markedly benefit" from the addition of intraventricular chemotherapy, according to the authors of a related editorial, Giles Robinson, MD, and Amar Gajjar, MD, of St. Jude Children's Research Hospital in Memphis, Tenn.

"However, cross-trial comparison of PFS among the SHH-II subtype does not suggest that SHH-II patients derive the same benefit," the editorialists wrote.

These data divide SHH medulloblastoma into SHH-I, which benefits from chemotherapy with intraventricular methotrexate, and SHH-II, which can be cured without intraventricular methotrexate, high-dose chemotherapy, or focal radiotherapy, according to the editorialists.

This new information might prompt investigation of a risk-adapted approach. SHH-II patients would receive a reduced-intensity regimen with systemic chemotherapy only, and SHH-I patients would receive systemic chemotherapy combined with intraventricular methotrexate. This could avoid exposing young children to "more intensive therapy than necessary," according to the editorialists.

Non-WNT/Non-SHH Disease 

Patients with non-WNT/non-SHH medulloblastoma (CMB or LCA) were divided into molecularly defined subtypes group 3 (n = 14) and group 4 (n = 6). The patients in group 3 had lower survival rates than patients in group 4. The 5-year PFS rate was 36% and 83%, respectively (P < .001 ). The 5-year OS rate was 49% and 100%, respectively (P < .001).

"This represents the third recent publication to describe a poor PFS for group 3, and it signals a desperate need for better therapy," the editorialists wrote. As for the "encouraging" survival rate for group 4 patients, there were only six subjects, which makes this finding "worthy of follow-up but not actionable."

Even so, the investigators noted that "although poor survival has been reported for non-SHH CMB/LCA in almost every series of patients treated with CSI-sparing approaches, again, use of intraventricular [methotrexate] might be associated with slightly higher PFS, compared with conventional chemotherapy alone."

As expected, IQ was significantly lower in patients who received CSI salvage. The mean IQ was 74 in patients who received CSI and 90 in patients who did not (P = .012). Neurocognitive outcomes were poor in general among CMB/LCA survivors, "which was closely related to use of radiotherapy," according to the investigators.

"It is important to recognize that these studies were not designed to define outcome on the basis of molecular subgroup or subtype and that the sample size in all these studies is small," Dr. Robinson and Dr. Gajjar wrote. "Thus, caution should be used when basing any treatment recommendation on these results, and it is our strong-held opinion that any treatment change be done on a well-planned and well-monitored clinical trial."

This research was supported by the German Childhood Cancer Foundation, Styrian Childhood Cancer Foundation, and other organizations. Dr. Mynarek and colleagues disclosed relationships with Medac, Novartis, Eli Lilly, Bayer, Roche, and numerous other companies. Dr. Robinson disclosed relationships with Eli Lilly, Genentech, and Novartis. Dr. Gajjar reported relationships with Genentech and Kazia Therapeutics.

SOURCE: Mynarek M et al. J Clin Oncol. 2020 Jun 20;38(18):2028-40.

This story originally appeared on MDedge.com.

ASCO 2020-TUMOR MARKERS FOR INTRACRANIAL GERM CELL TUMORS

Tumor markers can be used to detect relapse with a high degree of sensitivity in patients with central nervous system nongerminomatous germ cell tumors (CNS-NGGCTs), according to a pooled analysis of cooperative group trials.

The findings suggest a role for the routine use of tumor markers for surveillance in CNS-NGGCT patients, said Adriana Fonseca, MD, a pediatric neuro-oncology fellow at the Hospital for Sick Children in Toronto.

She presented these findings as part of the American Society of Clinical Oncology virtual scientific program.

This pooled analysis represents the largest prospective cohort to date of relapsed intracranial germ cell tumors, Dr. Fonseca said. The analysis included 483 patients enrolled in five prospective CNS-NGGCT trials between 1989 and 2016. There were 106 patients who relapsed after the end of therapy; the relapsed patients had a median age of 13 years (range, 1-30 years) at diagnosis and 82% were male.

Tumor Marker Utility

There were 86 patients with tumor marker assessments at diagnosis, and 83 had tumor marker elevations in serum, cerebrospinal fluid (CSF), or both.

The three patients without tumor marker elevations at diagnosis had mixed GCT, choriocarcinoma, and yolk sac tumor, which are usually associated with tumor marker elevation, so this will be investigated further, Dr. Fonseca said.

The sensitivity of tumor markers at diagnosis was 94% for serum, 83% for CSF, and 97% for either serum or CSF.

The median time to relapse was 15.5 months. Relapses were local in 45 patients (44%), distant in 32 (33%), and combined in 22 (21%). Three intracranial relapses were located outside of the radiation field and were classified as distant.

Only two patients presented with isolated tumor marker elevations as the sole evidence of relapse, and the elevations usually preceded the presence of macroscopic disease, Dr. Fonseca said.

At the time of relapse, 88% of patients (n = 73) had tumor marker elevations. The sensitivity of tumor markers was 82% in serum, 85% in CSF, and 88% in either.

To better understand if tumor markers can be used for surveillance, the researchers analyzed data from patients who had either serum or CSF tumor marker levels available at both diagnosis and relapse.

Of the 74 evaluable patients who had elevated tumor markers at diagnosis, 68 had elevated tumor markers at relapse as well. This means 92% of relapsed patients were detectable by tumor markers, Dr. Fonseca said.

"Only six patients had tumor marker–negative relapses, and interestingly, one patient who was tumor marker negative at diagnosis relapsed with tumor markers positive," she added.

Rationale and Next Steps

CNS-NGGCTs are rare and heterogeneous tumors that respond best when treated using multimodal approaches, including surgical resection, chemotherapy, and radiation, according to Dr. Fonseca. The 5-year event-free and overall survival rates range from 72%-84% and 82%-93% respectively.

"GCTs are unique as they express tumor markers, such as AFP and beta-HCG, which we know are sensitive and specific and used for diagnostic and monitoring purposes," Dr. Fonseca said.

Current surveillance strategies use a combination of brain and spine MRI and serum tumor markers with declining frequency over time.

"CSF tumor markers are not performed during follow-up, and they are usually obtained only at the time of relapse," Dr. Fonseca said. "But what is the best surveillance strategy? We have to remember that some of our patients require sedation to undergo MRI, and recurrent sedations in children have been recently associated with potential detrimental neurocognitive effects."

Similarly, the administration of gadolinium used for MRI has been associated with an increased risk of renal fibrosis and negative neurological outcomes.

"Additionally, nonspecific areas of enhancement are commonly encountered and can lead to unnecessary further investigations," Dr. Fonseca said, adding that this can contribute to patients' and parents' anxiety and to increased overall health care costs and resource utilization.

Recent Children's Oncology Group data showed that 98% of patients with extracranial germ cell tumors who relapsed were detectable by tumor markers alone, and this led to a change in surveillance guidelines for those patients. This raised the question as to whether a similar approach could be used in CNS-NCCGTs, Dr. Fonseca explained.

"We hypothesized that tumor markers alone may be sufficient for relapse detection in children and adolescents treated for CNS-NGGCT, and hence, the frequency and associated risk with serial MRIs could be safely avoided," she said.

Though this study was limited by missing data in some cases, the inclusion of trials from different eras, and the use of different detection techniques across trials, the findings confirm the sensitivity of tumor markers in this setting.

"Tumor markers represent a valuable surveillance strategy with the potential to reduce MRI frequency in these patients," Dr. Fonseca said. "Additionally, the higher proportion of tumor marker–negative relapses, compared to extracranial GCTs, suggests a different biological behavior. Further studies to investigate the biology of the primary versus relapsed samples in GCTs are currently needed."

Dr. Fonseca and colleagues are "currently undertaking some correlative outcomes analyses to try to understand if the elevation or nonelevation to tumor markers is correlated with survival. We also would like to elucidate the optimal MRI frequency required for surveillance," she said.

Dr. Fonseca reported having no disclosures, and the researchers disclosed no funding for the study.

SOURCE: Fonseca A et al. ASCO 2020, Abstract 2503.

NIVOLUMAB VS. BEVACIZUMAB FOR GLIOBLASTOMA

As reported in JAMA Oncology by David A. Reardon, MD, and colleagues, the phase III CheckMate 143 trial showed no difference in overall survival among adult patients with a first recurrence of glioblastoma treated with nivolumab vs bevacizumab following standard radiation and temozolomide therapy.

David A. Reardon, MD

Study Details

In the open-label trial, 369 patients from sites in 12 countries were randomly assigned between September 2014 and May 2015 to receive nivolumab at 3 mg/kg (n = 184) or bevacizumab at 10 mg/kg (n = 185) every 2 weeks until disease progression or unacceptable toxicity. The MGMT promoter was methylated in 43 patients (23.4%) in the nivolumab group and 42 patients (22.7%) in the bevacizumab group and unmethylated in 59 (32.1%) vs 67 (36.2%), with status unknown in the remaining patients. A total of 73 patients (39.7%) vs 79 patients (42.7%) were using corticosteroids at baseline. The primary endpoint was overall survival in the intent-to-treat population.  

Overall Survival

Median follow-up was 9.5 months at data cutoff (January 2017). Median overall survival was 9.8 months (95% confidence interval [CI] = 8.2–11.8 months) in the nivolumab group vs 10.0 months (95% CI = 9.0–11.8 months) in the bevacizumab group (hazard ratio [HR] = 1.04, 95% CI = 0.83–1.30, P = .76), with 12-month overall survival rates of 42% vs 42%.

In exploratory hypothesis-generating subgroup analyses, multivariate analysis indicated that no baseline corticosteroid use vs baseline use (HR = 0.59, 95% CI = 0.36–0.95) and methylated vs unmethylated MGMT promoter status (HR = 0.47, 95% CI = 0.29–0.78) were associated with longer overall survival in the nivolumab group. Methylated MGMT promoter status (HR = 0.54, 95% CI = 0.32–0.89) was also associated with longer survival in the bevacizumab group. Among 31 patients treated with nivolumab vs 22 patients treated with bevacizumab with methylated MGMT promoter status and no baseline corticosteroid use, median overall survival was 17.0 vs 10.1 months (HR = 0.58, 95% CI = 0.30–1.11). Among patients with corticosteroid use at baseline, overall survival was poorer with nivolumab treatment (HR = 1.41, 95% CI = 1.01–1.97). 

Median progression-free survival was 1.5 months vs 3.5 months (HR = 1.97, P < .001). Objective response rates in patients evaluable for response were 7.8% vs 23.1%, with median response durations of 11.1 vs 5.3 months.

Adverse Events

Treatment-related grade 3 or 4 adverse events occurred in 18.1% of patients in the nivolumab group, with the most common being fatigue (3.3%), vs 15.2% of the bevacizumab group, with the most common being hypertension (7.9%). Neurologic treatment-related adverse events of any grade occurred in 13.7% (grade 3 or 4 in 4.4%) vs 9.7% (grade 3 or 4 in 1.2%). The most common immune-mediated adverse events were diarrhea (14.8% vs 7.9%), increased alanine aminotransferase (8.2% vs 5.5%), and rash (9.3% vs 4.2%). No treatment-related deaths were observed.

The investigators concluded, “To our knowledge, the CheckMate 143 randomized clinical trial is the first phase III study investigating the use of a [programmed cell death protein 1] inhibitor in patients with recurrent glioblastoma. The study did not meet the primary endpoint of overall survival. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types. Patients with methylated MGMT promoter glioblastoma and no baseline corticosteroid use may potentially derive benefit from treatment with immune checkpoint inhibition.”

Dr. Reardon, of Dana-Farber/Harvard Cancer Center, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by Bristol-Myers Squibb. For full disclosures of the study authors, visit jamanetwork.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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WBRT AVOIDING HIPPOCAMPUS

A better way of using radiation in patients with brain metastases is now established with the publication of data from a phase 3 trial.

The trial compared whole-brain radiotherapy (WBRT) plus memantine with and without hippocampal avoidance (HA), and showed that sparing the hippocampus resulted in less deterioration of executive function, learning, and memory, as well as less fatigue.

The study was published online February 14 in the Journal of Clinical Oncology.

"This study is practice-changing," commented Joseph P. Weiner, MD, a radiation oncologist at Rutgers Cancer Institute of New Jersey, New Brunswick, who wrote an accompanying editorial.

"As radiation oncologists, brain metastases are one of the most common things we treat. So the implications of this study are very wide," he told Medscape Medical News.  

"We knew from an earlier phase 2 study that sparing the hippocampus was beneficial, but because that evidence was from a phase 2 study, insurance companies would deny coverage," he commented. "They would say get phase 3 data and then they'll approve coverage. This was going on for years, and it was terrible. As a healthcare provider, I was so frustrated, knowing that I could do better for my patients but was not allowed to," he said.

  No insurance company is going to argue with these results.    Dr Joseph Weiner

"So when this paper came out, I was really excited that we finally have these data. These results confirm what we knew from the phase 2 trial, that adding hippocampal avoidance to WBRT plus memantine does benefit patients. Now that we have phase 3 data from a randomized trial, no insurance company is going to argue with these results," he said.

HA Technique "Takes Some Learning" 

The multicenter phase 3 NRG CC001 trial compared WBRT with hippocampal avoidance (HA-WBRT) plus memantine (the investigational group) or WBRT plus memantine.

"Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist that blocks pathologic excessive stimulation of NMDA receptors and has been shown to be beneficial in dementia and neuroprotective in preclinical models of brain irradiation. It is now a standard of care for patients receiving WBRT," explained lead author Paul D. Brown, MD, Mayo Clinic, Rochester, Minnesota.

Mastering the HA technique takes some learning and may send radiation oncologists back to their anatomy textbooks, Brown said.

"The hippocampus is not a structure that we learn about as radiation oncologists. We do learn about it in medical school but then we don't hear much about it in the rest of our oncology training, so all of the radiation oncologists in this trial had to relearn their anatomy to be able to locate the hippocampus on imaging. My coauthor, Vinai Gondi, MD, [Northwestern Medicine Cancer Center, Warrenville, Illinois], has created an atlas that helps the radiation oncologist walk through the anatomy of the brain and make sure they can contour it correctly," he saidHA-WBRT will become the standard of care for patients with brain metastases, provided the tumors are not in or near the hippocampus, Brown told Medscape Medical News.

The fact that HA-WBRT did not worsen the patient's condition is also encouraging, Weiner added.

"Any time we are de-escalating our treatment, as we do here with sparing the hippocampus, we need to make sure we are not causing our patients some unintended problem," he said.

"And this paper shows that we're not. Although we are not prolonging their overall survival, we are maintaining the quality of their remaining time. I think we're going to see a lot more of this being done around the country and around the world to the betterment of patients' outcomes," Weiner said.

  This study has opened the door for this to become primetime treatment.   Dr Joseph Weiner

"This study validates what we thought was the right thing to do," he continued. "I have already been able to treat two patients using hippocampal avoidance. So this study has opened the door for this to become primetime treatment. It really is a practice-changing paper. And it has wide implications. It's not like some little niche tumor, this is one of the most common things we as radiation oncologists do," he said.

Study Details 

The trial was conducted in 518 patients with brain metastases outside a 5-mm margin around the hippocampus. All patients were over 18 years of age, had a Karnofsky performance score of 70 or greater, and a pathologically proven diagnosis of solid tumor malignancy.

Before being randomized, each patient underwent a baseline evaluation that included a history and physical examination, neurologic examination, performance status, thin-slice MRI, and a battery of cognitive tests. They also reported their quality of life and symptom burden.

These evaluations were repeated at month 2, 4, 6, and 12.

The primary endpoint was time to cognitive function failure.

Baseline characteristics were similar between the two groups. Median age was 61.5 years (range, 20-91 years), and most patients (57.7%) had primary lung cancer.

Median follow-up was 7.9 months (range, 0-15.6 months).

Cognitive failure risk was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine.

After adjusting for variables including age, prior radiosurgery, and prior surgical resection, the adjusted hazard ratio was 0.74 (95% CI, 0.58 - 0.95; P = .02).

At 2 months, there was no difference in cognitive deterioration rates between the groups.

However, at 4 months, patients in the HA-WBRT plus memantine group had less deterioration in executive function, as measured by the Trail Making Test Part B (TMT-B) compared with patients who received WBRT plus memantine (23.3% vs 40.4%; P = .01).

They also had less deterioration in learning (11.5% vs 24.7%; P = .049) and memory (16.4% vs 33.3%; P = .02) at 6 months, as measured by the Hopkins Verbal Learning Test – Revised (HVLT-R).

Patients in the HA-WBRT plus memantine group also had less fatigue (P = .04), less difficulty remembering things (P = .01),  less difficulty speaking (P = .049) and using imputed data, less interference of neurologic symptoms in daily activities (P = .008), and fewer cognitive symptoms (P = .01).

There were no differences in overall survival, intracranial progression-free survival, or toxicity.

The study was funded by the National Cancer Institute. Weiner and Brown have reported no relevant financial relationships.

J Clin Oncol. Published online February 14, 2020. Abstract, Editorial

BREAKTHROUGH IN BRAIN SURGEY

Patients are often kept awake during brain surgery but asking them to play the violin at the same time is a novel approach taken by a London hospital.

The patient was 53-year-old Dagmar Turner who plays in the Isle of Wight Symphony Orchestra.

The surgery team at King’s College Hospital had to remove a large grade 2 (slow growing) glioma. This had been diagnosed after she had a seizure during a performance and it had grown further requiring surgery.

The tumour was in the right frontal lobe of her brain, close to the area controlling left hand fine movements on the violin strings and fingerboard.

During her consultation, she learned that her neurosurgeon, Professor Keyoumars Ashkan, also held a music degree and is an accomplished pianist.

Understanding her fear of losing her musical skills during the operation, Prof Ashkan and the surgical team planned the surgery in stages. She was under general anaesthetic for the craniotomy then brought round for tumour removal, while she played her instrument.

The hospital carries out around 400 similar procedures a year but this was the first involving a violin.

In a news release, Prof Ashkan said: "We knew how important the violin is to Dagmar so it was vital that we preserved function in the delicate areas of her brain that allowed her to play. We managed to remove over 90% of the tumour, including all the areas suspicious of aggressive activity, while retaining full function in her left hand."

Dagmar Turner praised the King's team: "The violin is my passion; I’ve been playing since I was 10 years old. The thought of losing my ability to play was heart-breaking but, being a musician himself, Prof Ashkan understood my concerns. He and the team at King's went out of their way to plan the operation – from mapping my brain to planning the position I needed to be in to play. Thanks to them I’m hoping to be back with my orchestra very soon."

EVEROLIMUS-OCTREOTIDE FOR RECURRENT MENINGIOMA

According to the results from the small phase II CEVOREM trial, a targeted combination of the mTOR inhibitor everolimus and the somatostatin agonist octreotide showed antitumor activity in patients with recurrent meningioma not amenable to any type of surgery or radiotherapy. These findings were published in Clinical Cancer Research by Graillon et al.Aggressive meningiomas that progress after surgery and radiotherapy represent an unmet medical need. The current 6-month progression-free survival rate is estimated to be between 11% and 15% in untreated recurrent meningiomas, and treatment is considered of interest if the 6-month progression-free survival exceeds 35%.

Study Methodology

CEVOREM is an open-label, prospective, multicenter, single-arm phase II study that was conducted at two centers in France. The researchers investigated the effectiveness of everolimus and octreotide in 20 adults with meningiomas as defined by the World Health Organization. Two patients had grade 1 tumors, 10 had grade 2 tumors, and 8 had grade 3 tumors. In addition, four patients harbored an NF2 germline mutation. All patients received 10 mg of oral everolimus daily and 30 mg of octreotide administered monthly by intramuscular injection.

The primary endpoint of the study was the 6-month progression-free survival rate. Secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety.

Study Results

The researchers found that the overall 6-month progression-free survival was 55% (95% confidence interval [CI] = 31.3%–73.5%), and overall 6- and 12-month survival rates were 90% (95% CI = 65.6%–97.4%) and 75% (95% CI = 50.0%–88.7%), respectively. A major decrease (> 50%) was observed in the growth rate at 3 months in 78% of the tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (P < .0002) and 0.48%/3 months at 6 months after treatment (P < .0003).

“The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas,” concluded the study authors.

Translational Relevance

“The combination of everolimus and octreotide yielded a meaningful, prolonged tumor stabilization in many patients,” said lead author of the study, Thomas Graillon, MD, PhD, Assistant Professor of Neurosurgery at La Timone Hospital in Marseille, France, in a statement. “Our results indicate that this combination treatment could be considered as a viable treatment option for aggressive meningiomas and studied further in a randomized trial.”

Disclosure: For full disclosures of the study authors, visit clincancerres.aacrjournals.org.

BETTER RESULTS WITH BRAIN PROTON RT

A new study shows that children with medulloblastoma who were treated with radiotherapy had better intellectual outcomes when the radiation was delivered as proton beam therapy compared to traditional photon radiotherapy.

Proton beam radiotherapy remains controversial, mainly because it is more expensive than traditional radiotherapy and there is little evidence to show that the extra cost is worth it.

The main advantage claimed for proton therapy is a reduction in adverse effects. This has been particularly emphasized for children with brain cancer.

"Our findings show a clear cognitive advantage with proton radiotherapy, even in the context of craniospinal irradiation," said study author Lisa S. Kahalley, PhD, associate professor and director of research, Baylor College of Medicine and Texas Childrens Hospital, Houston.

"In the absence of a randomized clinical trial, it would be difficult to discount our findings, given the methodological strengths of our study, when making treatment decisions for patients who could feasibly receive protons instead of photons," she said.

The results were published in the Journal of Clinical Oncology.

"This supports what has been suspected, specifically, that decreased integral dose to the brain in developing brains has measurable benefit," said Sameer R. Keole, MD, a radiation oncologist at the Mayo Clinic, Phoenix, Arizona, who was approached for comment.

These are some of the best data he has seen, and they validate the benefit of proton therapy in pediatric brain tumors, Keole told Medscape Medical News.

"This is the closest we are going to get to a randomized clinical trial," he said, adding that the "likelihood of having one in this cohort is zero, and I don't think it would be ethical."

If not for the controversy regarding cost, "we wouldn't be having this discussion. We would be making greater use of proton therapy," Keole commented.

"The initial investment is intimidating," he said, "but we sometimes forget that it can cost about $30–$40 million to set up any state-of-the-art radiation center."

Study Details

The biggest claim for proton beam therapy is that it limits adverse effects in comparison with traditional radiotherapy. This has particularly been emphasized as a big advantage when treating the developing brains of children with cranial tumors.

Proton beam therapy decreases the amount of radiation that reaches healthy brain tissue beyond the boost margins, the authors explain.

"With less irradiation of healthy cerebellar tissue, cognitive outcomes improve, likely due to reduced white matter damage allowing for preserved or more recoverable cerebrocerebellar connections," study author Don Mabbott, PhD, professor of psychology at the University of Toronto and a member of the Pediatric Brain Tumor Program at the Hospital for Sick Children, Toronto, Canada, told Medscape Medical NewsFor their study, Mabbott and colleagues compared children with medulloblastoma who underwent either craniospinal proton radiotherapy (n = 37) or photon radiotherapy (n = 42) between 2007 and 2018. The same treatment protocols were followed for both groups of patients.

The two cohorts came from the Hospital for Sick Children, Toronto, Canada, and Texas Children's Hospital in Houston. Patients at the Hospital for Sick Children all received standard radiotherapy, because Canada did not have a proton center at the time of the study. Children treated at Texas Children's Hospital received proton therapy, which has been standard of care since 2007 at the the MD Anderson Proton Therapy Center.

Baseline clinical and demographic variables were similar in both groups, but boost dose (P < .001) and boost margin (P = .001) were significantly higher in the cohort that received photon radiotherapy.

The results show that children who were treated with proton radiotherapy had significantly better scores for global intelligence quotient (IQ), perceptual reasoning, and working memory (P < .05). Conversely, patients who received traditional photon therapy showed significant declines in global IQ, working memory, and processing speed (P < .05).

Overall, the proton therapy group demonstrated stable scores for all outcomes except processing speed, which declined significantly over time (P = .003).

Patients treated with proton therapy had stable global IQ and working memory (global IQ mean, 0.3 [SE, 0.5]; P = .100; working memory mean, 0.1 [SE, 0.7]; P = .891). By contrast, the patients in the photon radiotherapy group experienced a decline of global IQ (mean, –0.9 [SE, 0.4]; P = .009) and working memory (mean, –2.2 [SE, 0.6]; P = .001).

A nonsignificant decline in verbal reasoning (–0.4; P = .141) and a significant decline in processing speed (–0.9; P = .003) were observed for both groups.

"This is the first longitudinal study that compared changes in intelligence indices over time between pediatric patients with medulloblastoma treated with proton beam therapy as compared to a matched cohort treated with standard radiotherapy," Kahalley told Medscape Medica News.

"This study is powerful because both MD Anderson and Toronto Sick Kids are considered centers of excellence for pediatric brain tumor care," commented Keole.

Although there were some differences between the cohorts, presumably due to practice differences, they were small, he noted. "Overall, these are remarkably well-balanced cohorts, and it is notable that the starting measure scores are equivalent between the two cohorts. This eliminated the argument of selection bias and is a distinguishing feature."

Keole also noted that the American Society of Radiation Oncology (ASTRO) has supported insurance coverage for proton beam therapy for pediatric patients since 2014, when the ASTRO model policy was first issued. "This model policy was updated in 2017 and represents ASTRO's current position with respect to insurance coverage for proton therapy," Keole said. "The 2017 model policy update continues to list pediatric tumors as a level I indication."

The study was supported by the National Institutes of Health and the Canadian Institute of Health Research. Mabbott, Kahalley, and Keole have disclosed no relevant financial relationships.