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Resection May Offer Better Survival for Low-Grade Gliomas

Samson, Kurt

doi: 10.1097/01.NT.0000425880.20208.26
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Investigators compared low-grade glioma survival at two hospitals, one that favored early resection as the front-line treatment and the other with a more conservative “watchful waiting” approach after biopsy. During a mean follow-up period of seven years, 32 percent of patients who underwent resection died compared with 52 percent in the watch-and-wait group. Overall survival was significantly better with early surgical resection (p=.01).

Early surgical resection of diffuse low-grade gliomas provided significantly better survival rates than the “watchful waiting” track favored by many cancer centers, a study at two Norwegian university hospitals has found.

Researchers from the Medical Imaging Laboratory and the National Center of Competence in Ultrasound and Image-Guided Surgery of St. Olavs University Hospital in Trondheim, Norway, compared low-grade glioma (LGG) survival at two hospitals, one that favored early resection as the front-line treatment and the other with a more conservative “watchful waiting” approach after biopsy.

During a mean follow-up period of seven years, 32 percent of patients who underwent resection died compared with 52 percent in the watch-and-wait group. Overall survival was significantly better with early surgical resection (p=.01).

The findings were reported Nov. 14, 2012, in the Journal of the American Medical Association, but were released online Oct. 25 to coincide with the study's presentation at the European Association of Neurosurgical Societies annual meeting in Bratislava, Slovakia.

Low-grade gliomas include astrocytomas, oligodendrogliomas, and oligoastrocytomas. They are typically not seen as curable with surgery due to diffuse brain infiltration, but the impact of surgical resection has been unclear. The only data available before now has been from uncontrolled surgical series, the researchers noted, citing a 2005 study in the Lancet.

“Due to lack of better evidence, management of suspected LGGs has remained one of the major controversies in neuro-oncology, and treatment strategies often differ considerably between neurosurgical centers,” said lead author Asgeir S. Jakola, MD, a neurosurgeon at St. Olavs.

He noted that this is the first controlled study directly comparing survival between the two treatment options.

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In the new study, patients were seen at one of the two hospitals between1998 and 2009, and all underwent a blinded histopathological review to ensure uniform classification of low-grade glioma (LGG). The study ended in April 2011, with a median follow-up of seven years. The hospitals are exclusive providers of brain cancer treatment in two adjacent regions in Norway.

A total of 153 patients were included, 66 from the center favoring biopsy and watchful waiting, and 87 from other center. Initial biopsy was performed in 71 percent of patients at the first hospital, and in 12 percent at the hospital favoring early resection.

One-year survival was 89 percent at either center, but survival increased with time, the team found. Estimated survival times for the watchful waiting approach versus resection were, respectively: 70 percent versus 80 percent for three-years; 60 percent versus 74 percent for five years, and 44 percent versus 68 percent for seven years. The estimated absolute survival difference of 14 percent at five years increased to 24 percent at seven years.

There were no significant differences in surgical complications between the two hospitals (9 percent versus 8 percent) or acquired deficits (18 percent versus 21 percent); deficits were characterized as “worsened neurological function of any magnitude in the 30-day postoperative period.” Malignant transformation was more common, however, when biopsy alone was the initial management (56 percent versus 37 percent).

The authors also cautioned against interpreting outcomes other than survival due to nonstandardized follow-up and different neurological testing among patients.

The data on surgical morbidity were less robust due to the retrospective nature of the study, “but the findings indicate that an aggressive approach is feasible,” Dr. Jakola told Neurology Today.

“This study significantly strengthens the case-series evidence decision-making was based on,” he said. “We hope that the findings will lead to a more homogenous management of these patients.”

Indolent — or slow-growing — gliomas “should not be an excuse” for not performing surgery because individual LGG behavior is extremely difficult to reliably predict, he said. He recommended that all patients be thoroughly evaluated to consider if resection is an option.

Whether or not a glioma is a candidate for resection is subjective and based on the experience of each surgeon or center, he added. “There should be a low threshold for seeking a second opinion with centers used to a more active approach. This is important for patients since the survival difference is substantial. Clinical judgment in individual patients is necessary and risks and benefits should be discussed with the patients.”

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The National Comprehensive Cancer Center practice guidelines in oncology support maximal safe resection as a feasible first line of treatment for LGG, noted James M. Markert, MD, James Garber Galbraith endowed chair and director of neurosurgery at the University of Alabama at Birmingham.

In an accompanying editorial, he wrote that the majority of studies support the approach.“Over the past 25 years, increasing numbers of studies support the concept of maximizing the extent of resection in patients with glioma while maintaining neurologic function; however, no Class I evidence exists for this approach,” he wrote.

That the new study showed such a potential difference in survival “provides important data to help inform the complex question of whether to attempt aggressive LGG resection,” Dr. Markert noted.

Nonetheless, the study had some limitations: the outcome assessment was determined retrospectively and was therefore subject to reporting bias and crossover. However, because of the difficulty inherent in performing a randomized controlled study in such patients, “this is not a surprising limitation,” he said.

Additional follow-up of the patients would be valuable, with more definitive measurement of survival and more rigorous assessment of complications, neurological deterioration, and malignant degeneration, he said.

Mitchel S. Berger, MD, the Kathleen M. Plant distinguished professor and chairman of neurological surgery University of California, San Francisco (UCSF), told Neurology Today that the findings are in alignment with current practices at most major cancer centers in the United States.

“We have been seeing this for many years, so the findings are not surprising,” said Dr. Berger, director of UCSF's Brain Tumor Research Center.

A number of retrospective studies have found similar survival benefits with early resection, including a 2008 paper published in the Journal of Clinical Oncology by Dr. Berger and colleagues that showed the extent of resection in more than 200 patients who underwent initial resection for hemispheric LGGs.

Median preoperative and postoperative tumor volumes and extent of resection were 36.6 cm, 3.7 cm, and 88 percent, respectively, with greater resection margins associated with better outcomes, including survival.

“We showed exactly the same thing in our study,” he said.

Dr. Berger noted, however,that it would be difficult to conduct a randomized prospective trial like the Norwegian study in the US.“We could never do a study like this,” he said, “because no patient would allow themselves to be randomized into the watch-and-wait group.”

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• Jakola AS, Myrmel KS, Kloster R, et al. Comparison of a strategy favoring early surgical resection vs. a strategy favoring watchful waiting in low-grade gliomas. JAMA 2012;308:1881–1888.
• Markert JM. The role of early resection vs biopsy in the management of low-grade gliomas. JAMA 2012:308:1919.
• Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurg 2008;62:753–764.
• Cavaliere R, Lopes MBS, Schiff D. Low-grade gliomas: an update on pathology and therapy. Lancet Neurol 2005;4:760–770.
• Smith JS, Chang EF, Berger MS, et al. Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol 2008;26:1338–1345.
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