NEWS ARTICLES about Senator John McCain’s diagnosis of glioblastoma accurately describe glioblastoma as aggressive and having a poor prognosis. But as Walter J. Curran, Jr, MD, pointed out in one of those reports, “substantial improvements in surgical approaches” have enabled more patients to undergo complete resections, and immunotherapeutic agents have shown “initial promising results.”1 In addition, improvements in imaging have resulted in better definition of tumor volumes for radiation planning and “are helpful in follow-up assessment,” Dr. Curran told The ASCO Post.
A radiation oncologist, Dr. Curran is Executive Director of Winship Cancer Institute at Emory University in Atlanta and a member of the ASCO Board of Directors. He is also a group chairman and principal investigator for NRG Oncology, a nonprofit research group that brings together the research areas of the Radiation Therapy Oncology Group, the National Surgical Adjuvant Breast and Bowel Project, and the Gynecologic Oncology Group.
“BOTH ON imaging and in the OR, it is tough to know where a tumor begins and ends. There is infiltration of tumor into what looks like normal tissue on just visual inspection, as well as on magnetic resonance imaging (MRI),” Dr. Curran explained. An oral formulation of aminolevulinic acid hydrochloride (ALA; Gleolan), was approved by the U.S. Food and Drug Administration (FDA) “as an optical imaging agent indicated in patients with gliomas (suspected World Health Organization grades III or IV on preoperative imaging), as an adjunct for the visualization of malignant tissue during surgery.”2 When swallowed by patients prior to surgery and used with a surgical operating microscope adapted for fluorescence, the agent allows for better visualization, according to studies cited by the FDA in its approval.
“That’s the first FDA approval relevant to surgical management of patients with glioblastoma in years,” Dr. Curran stated. “There is always some evolutionary change in the surgical tools, but this was a result of prospective research. It was, I think, an important step forward.”
ONE OF THE TRIALS cited by the FDA was a multicenter study involving 415 patients with a preoperative diagnosis of high-grade glioma by MRI. Among patients with high-grade glioma randomized to ALA, the completeness of resection (based on a central blinded read of early postsurgical MRI) was 64% vs 38% in the control arm, for a difference of 26% (95% confidence interval [CI] = 16%–36%), according to the FDA.
“The safety of ALA is supported by 5 clinical trials that included 527 patients with glioma,” the FDA announcement continued. “ALA is associated with such risks as phototoxic reactions, hypersensitivity reactions, and interpretation errors (false-negatives and false-positives). An increase in the extent of resection might increase the risk of serious neurologic deficits in the short term.”
A previously published literature review of 22 surgical series using 5–aminolevulinic acid (5-ALA) for brain neoplasm resections and involving 1,163 patients found “5-ALA sensitivity was highest in high-grade gliomas (85%),” and 5-ALA specificity was also high in high-grade gliomas (82%). “The resection of tumors for which 5-ALA has high sensitivity and specificity, such as high-grade gliomas, may lead to an increase in the extent of resection compared to operations using only standard white light,” the authors concluded.3
MR Spectroscopy Approaches
CONTINUED IMPROVEMENTS in MRI and magnetic resonance (MR) spectroscopy have resulted in better “defining tumor margins for the purpose of radiation planning,” Dr. Curran noted. “Information is starting to be more effectively displayed anatomically on MRI, and we have been able to get data on the distribution, for example, of alanine and lactate, two metabolites that are more commonly seen in and around tumors,” he explained.
After a course of surgery, radiation, and chemotherapy for patients with malignant glioma, it is sometimes confusing on MRI as to whether you are looking at a treatment effect or recurrent tumor, and MR spectroscopy can be very helpful in that setting.— Walter J. Curran, Jr, MD
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“Our group at Emory, as well as groups elsewhere, have used MR spectroscopy to study how to better define radiation treatment volumes for glioblastoma patients,” Dr. Curran said. “We have a number of cases where the volume we treat with MR spectroscopy vs what we would have done without it are very different. We would have missed tumor-bearing areas, which did not enhance in typical contrast-enhancing MRI but were highly suspicious for tumor on MR spectroscopy and turned out to be confirmed as tumor-bearing areas.”
In addition, MR spectroscopy enables the ability to look at the anatomy prior to and after care for a better comparative assessment, Dr. Curran continued. “After a course of surgery, radiation, and chemotherapy for patients with malignant glioma, it is sometimes confusing on MRI as to whether you are looking at a treatment effect or recurrent tumor, and MR spectroscopy can be very helpful in that setting.”
Standard and Evolving Treatment
STANDARD TREATMENT of glioblastoma is surgery to remove as much of the tumor as possible while preserving function, followed by radiation and chemotherapy, usually with temozolomide, “given in a daily schedule during radiation and then every 4 weeks for 6 to 12 months after radiation,” Dr. Curran said.
The National Cancer Institute (NCI) Physician Data Query (PDQ) statement for health professionals on adult central nervous system tumors treatment (updated January 31, 2017) reports that a biodegradable carmustine wafer (Gliadel) has been developed for localized chemotherapy. “The concept of delivering high doses of chemotherapy while avoiding systemic toxicity is attractive because malignant glioma–related deaths are nearly always the result of an inability to control intracranial disease rather than the result of distant metastases,” the PDQ statement noted.4
Two randomized, placebo-controlled trials “have shown an overall survival advantage associated with the carmustine wafers vs radiation therapy alone,” 58.1 vs 39.9 weeks in one study, and 13.8 months vs 11.6 months in the other, according to the PDQ statement. The upper age limit for patients in both studies was 65 years old.
A trial being conducted by Cancer Research UK is looking at the safety and efficacy of 5-ALA and carmustine wafers as part of the treatment of patients with glioblastoma. Patients will drink 5-ALA a few hours before surgery to remove the tumor, and those with confirmed high-grade glioblastoma that is mostly removed during surgery will have carmustine wafers implanted. Following recovery from surgery, patients will receive up to 6 weeks of radiotherapy and also take temozolomide tablets. Results are not yet available, but the Cancer Research UK website reports that the trial is no longer recruiting patients.5
Dr. Curran said that currently, the wafers “are rarely used” but “might be used at the time a reoperation is done, if a tumor recurs after chemoradiation and the initial surgical procedure.”
The angiogenesis inhibitor bevacizumab (Avastin) has been approved by the FDA for the treatment of recurrent glioblastomas. “The option that many people with recurrent disease choose is to participate in a clinical trial,” Dr. Curran stated. An important distinction, he stressed, is whether the patient actually has recurrent disease or has not had a complete surgical resection and has residual disease. If the latter, “at some point, there is a high risk that it could start regrowing. That is where the imaging is really important,” Dr. Curran stressed.
Electric Field Device
TUMOR-TREATING FIELDS therapy using a portable, patient-operated device (marketed as Optune) is based on the generation of mild electrical currents to selectively disrupt mitosis in cancer cells. The device was approved by the FDA first to treat patients with glioblastoma that has recurred or progressed after chemotherapy but more recently as adjuvant therapy for patients with newly diagnosed glioblastoma.
“When using [the device], a health-care professional places electrodes on the surface of the patient’s scalp to deliver low-intensity, alternating electrical fields…. The unique shape and special characteristics of rapidly dividing tumor cells make them susceptible to damage when exposed to tumor-treating fields, which could halt tumor growth,” according to the FDA announcement of the expanded indication for the device.6 Approval of the expanded indication was based on a clinical trial in 695 patients with newly diagnosed glioblastoma multiforme. The average progression-free survival was 7 months among those who received temozolomide and used the device vs 4 months for those taking temozolomide alone. Overall survival rates were 19.4 vs 16.6 months.
TWO IMMUNOTHERAPIES were cited by Dr. Curran as having “initial promising results”—pembrolizumab (Keytruda) and nivolumab (Opdivo). “There are a number of active trials with these agents,” he noted. “Let’s hope some of them turn out to be positive.” Both agents are programmed cell death protein 1 (PD-1) inhibitors, so “knowing whether the tumor overexpresses PD-1 is helpful,” he added.
“There is work being done with a number of vaccines, but they are mostly institutional studies, including the one at Duke,” Dr. Curran reported. Earlier this year, Duke Cancer Institute researchers published the results of a phase I study in 11 patients with glioblastoma who received dose-intensified temozolomide along with an investigational dendritic cell vaccine that selectively targets a cytomegalovirus protein (pp65).7 The study showed the combination to be well tolerated, while resulting in “unexpectedly significant survival increases,” according to the Duke researchers.”8 Although the study was not designed to assess efficacy, 4 of the 11 patients survived for more than 5 years.
“One of the dendritic cell vaccines that is furthest along in testing for glioblastoma is DCVax-L,” according to the NCI. “In a small phase I/II trial testing DCVax-L in patients with operable glioblastoma, the median survival was approximately 31 months.”9 A phase III trial with progression-free survival as the primary endpoint is underway.
“ALTHOUGH CURRENT therapies cannot offer a cure for glioblastoma, we do have long-term survivors,” Dr. Curran pointed out. Someone alive 5 or 6 years after treatment would be considered a long-term survivor, “but there are 10-year or longer survivors of glioblastoma.” Long-term survivors “tend to be younger patients, and they tend to be people who had what was described as a complete surgical resection.”
Although current therapies cannot offer a cure for glioblastoma, we do have long-term survivors.— Walter J. Curran, Jr, MD
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In addition, “we now know there are molecular features associated with longer survival,” Dr. Curran said. For example, someone with an isocitrate dehydrogenase (IDH) mutation has a better chance of long-term survival than someone without it.
“IDH mutations have a definite effect on prognosis and may be predictive of response to radiation and/or alkylating chemotherapy,” according to a 2013 article in Current Neurology and Neuroscience Reports, but the “ability to target gliomas with IDH mutations remains limited.”10 The authors called for more investigation “to determine optimal therapeutic strategies to target the IDH-mutated subsets of gliomas.”
A 2016 article in Annals of Oncology reported, “Inhibition of mutant IDH shows promise as a treatment approach in hematologic malignancies, with further development ongoing in solid tumors and glioma.”11 ■
DISCLOSURE: Dr. Curran reported no conflicts of interest.
2. U.S. Food and Drug Administration: Aminolevulinic acid hydrochloride, known as ALA HCl (Gleolan, NX Development Corp) as an optical imaging agent indicated in patients with gliomas. Available at www.fda.gov/drugs/informationondrugs/approveddrugs/ucm562645.htm. Accessed August 18, 2017.
3. Ferraro N, Barbarite E, Albert TR, et al: The role of 5-aminolevulinic acid in brain tumor surgery: A systematic review. Neurosurg Rev 39:545-555, 2016.
4. National Cancer Institute: Adult central nervous system tumors treatment (PDQ®)-health professional version. Available at www.cancer.gov/types/ brain/hp/adult-brain-treatment-pdq. Accessed August 18, 2017.
5. Cancer Research UK: A trial looking at 5-ALA and Gliadel wafers as part of treatment for glioblastoma (GALA-5). Available at www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-5ala-and-gliadel-wafers-as-part-of-treatment-for-glioblastoma-gala5. Accessed August 18, 2017.
6. U.S. Food and Drug Administration: FDA approves expanded indication for medical device to treat a form of brain cancer. Available at www.fda.gov/newsevents/newsroom/pressannouncements/ucm465744.htm. Accessed August 18, 2017.
7. Batich KA, Reap EA, Archer GE, et al: Long-term survival in glioblastoma with cytomegalovirus pp65-targeted vaccination. Clin Cancer Res 23:1898- 1909, 2017.
8. Khanna S: Immunotherapy for glioblastoma well tolerated: Survival gains observed. Available at dukecancerinstitute.org/news/immunotherapy-glioblastoma-well-tolerated-survival-gains-observed%C2%A0%C2%A0. Accessed August 18, 2017.
9. National Cancer Institute: With immunotherapy, glimmers of progress against glioblastoma. Available at www.cancer.gov/types/brain/research/immunotherapy-glioblastoma. Accessed August 18, 2017.
10. Cohen A, Holmen S, Colman H: IDH1 and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep 13:345, 2013.
11. Dang L, Yen K, Attar EC: IDH mutations in cancer and progress toward development of targeted therapies. Ann Oncol 27:599-608, 2016.
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