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Kaisorn Chaichana, Scott Parker, Alessandro Olivi, and Alfredo Quiñones-Hinojosa

Object

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults. Although the average survival is ~ 12 months, individual survival is heterogeneous. The ability to predict short- and long-term survivors is limited. Therefore, the aims of this study were to ascertain preoperative risk factors associated with survival, develop a preoperative prognostic grading system, and evaluate the utility of this grading system in predicting survival for patients undergoing resection of a primary intracranial GBM.

Methods

Cases involving adult patients who underwent surgery for an intracranial primary (de novo) GBM between 1997 and 2007 at The Johns Hopkins Hospital, an academic tertiary-care institution, were retrospectively reviewed. Multivariate proportional hazards regression analysis was used to identify preoperative factors associated with survival, after controlling for extent of resection and adjuvant therapies. The identified associations with survival were then used to develop a grading system based on preoperative variables. Survival as a function of time was plotted using the Kaplan-Meier method, and survival rates were compared using Log-rank analysis. Associations with p < 0.05 were considered statistically significant.

Results

Of the 393 patients in this study, 310 (79%) had died as of most recent follow-up (median time from surgery to death 11.9 months). The preoperative factors, independent of extent of resection and adjuvant therapies (carmustine wafers, temozolomide, and radiation), found to be negatively associated with survival were: age > 60 years (p < 0.0001), Karnofsky performance status score ≤ 80 (p < 0.0001), motor deficit (p = 0.02), language deficit (p = 0.001), and periventricular tumor location (p = 0.04). Patients possessing 0–1, 2, 3, and 4–5 of these variables were assigned a preoperative grade of 1, 2, 3, and 4, respectively. Patients with a preoperative grade of 1, 2, 3, and 4 had a median survival of 16.6, 10.2, 6.8, and 6.1 months, respectively.

Conclusions

The present study found that older age, poor performance status, motor deficit, language deficit, and periventricular tumor location independently predicted poorer survival in patients undergoing GBM resection. A grading system based on these factors was able to identify 4 distinct groups of patients with different survival rates. This grading system, based only on preoperative variables, may provide patients and physicians with prognostic information that may guide medical and surgical therapy before any intervention is pursued.

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Kaisorn L. Chaichana, Scott L. Parker, Alessandro Olivi, and Alfredo Quiñones-Hinojosa

Object

Seizures are a common presenting symptom and cause of morbidity for patients with malignant astrocytomas. The authors set out to determine preoperative seizure characteristics, effects of surgery on seizure control, and factors associated with prolonged seizure control in patients with malignant astrocytomas.

Methods

Cases involving adult patients who underwent primary resection of a hemispheric anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) at the Johns Hopkins Medical Institutions between 1996 and 2006 were retrospectively reviewed. Multivariate logistical regression analysis was used to identify associations with pre-operative seizures, and multivariate proportional hazards regression analyses were used to identify associations with prolonged seizure control following resection.

Results

Of the 648 patients (505 with GBM, 143 with AA) in this series, 153 (24%) presented with seizures. The factors more commonly associated with preoperative seizures were AA pathology (p = 0.03), temporal lobe involvement (p = 0.04), and cortical location (p = 0.04), while the factors less commonly associated with preoperative seizures were greater age (p = 0.03) and larger tumor size (p ≤ 0.001). Among those patients with a history of seizures, outcome 12 months after surgery was Engel Class I (seizure free) in 77%, Class II (rare seizures) in 12%, Class III (meaningful improvement) in 6%, and Class IV (no improvement) in 5%. Postoperative seizures were rare in patients without a history of preoperative seizures. The factor positively associated with prolonged seizure control was increased Karnofsky Performance Scale score (p = 0.002), while the factors negatively associated with seizure control were preoperative uncontrolled seizures (p = 0.03) and parietal lobe involvement (p = 0.005). Seizure recurrence in patients with postoperative seizure control was independently associated with tumor recurrence (p = 0.006).

Conclusions

The identification and consideration of factors associated with prolonged seizure control may help guide treatment strategies aimed at improving the quality of life for patients with malignant astrocytomas.

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Kaisorn L. Chaichana, Matthew J. McGirt, John Laterra, Alessandro Olivi, and Alfredo Quiñones-Hinojosa

Object

Unlike their malignant counterparts, low-grade gliomas are associated with prolonged survival. However, these tumors have a propensity to progress after resection and ultimately undergo malignant degeneration. The factors associated with recurrence and malignant degeneration remain relatively unknown. The authors set out to determine factors that were independently associated with recurrence and malignant degeneration in patients who underwent resection of a hemispheric low-grade glioma.

Methods

Adult patients who underwent craniotomy and resection of a hemispheric low-grade glioma (WHO Grade II) at the Johns Hopkins Medical Institution's academic tertiary-care institution between 1996 and 2006 were retrospectively reviewed. Multivariate proportional hazards regression analyses were used to identify associations with tumor recurrence and malignant degeneration.

Results

Of the 191 consecutive patients with low-grade gliomas in this series (89 fibrillary astrocytomas, 89 oligodendrogliomas, and 13 mixed gliomas), 83 (43%) and 44 (23%) experienced tumor recurrence and malignant degeneration at last follow-up, respectively. The 5-year progression-free and malignancy-free survival rates were 44 and 74%, respectively. Independent predictors of recurrence were duration of longest lasting symptom (relative risk [RR] 0.978, 95% CI 0.954–0.996, p = 0.01), tumor size (RR 1.328, 95% CI 1.109–1.602, p = 0.002), and preoperative contrast enhancement (RR 2.558, 95% CI 1.241–5.021, p = 0.01). Independent factors associated with malignant degeneration were fibrillary astrocytoma pathology (RR 1.800, 95% CI 1.008–4.928, p = 0.04), tumor size (RR 1.086, 95% CI 1.044–1.358, p = 0.04), and gross-total resection (RR 0.526, 95% CI 0.221–1.007, p = 0.05).

Conclusions

The identification and consideration of factors associated with recurrence and malignant progression may help guide treatment strategies aimed at delaying recurrence and preventing malignant degeneration for patients with hemispheric low-grade gliomas.

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Kaisorn L. Chaichana, Khan K. Chaichana, Alessandro Olivi, Jon D. Weingart, Richard Bennett, Henry Brem, and Alfredo Quiñones-Hinojosa

Object

As the population ages, the incidence of glioblastoma multiforme (GBM) among older patients (age > 65 years) will increase. Older patients, unlike their younger counterparts, are not often offered aggressive surgery because of their age, comorbidities, and potential inability to tolerate surgery. The goal of this study was to identify preoperative factors associated with decreased survival for older patients who underwent resection of a GBM. The identification of these factors may provide insight into which patients would benefit most from aggressive surgery.

Methods

All patients older than 65 years who underwent nonbiopsy resection of an intracranial GBM at a single institution between 1997 and 2007 were retrospectively reviewed. Factors associated with overall survival were assessed using multivariate proportional hazards regression analysis after controlling for peri- and postoperative factors known to be associated with outcome (extent of resection, carmustine wafer implantation, temozolomide chemotherapy, and radiation therapy). Variables with p < 0.05 were considered statistically significant.

Results

A total of 129 patients with an average age of 73 ± 5 years met the inclusion/exclusion criteria. At last follow-up, all 129 patients had died, with a median survival of 7.9 months. The preoperative factors that were independently associated with decreased survival were Karnofsky Performance Scale (KPS) score less than 80 (p = 0.001), chronic obstructive pulmonary disease (p = 0.01), motor deficit (p = 0.01), language deficit (p = 0.005), cognitive deficit (p = 0.02), and tumor size larger than 4 cm (p = 0.002). Patients with 0–1 (Group 1), 2–3 (Group 2), and 4–6 (Group 3) of these factors had statistically different survival times, where the median survival was 9.2, 5.5, and 4.4 months, respectively. In log-rank analysis, the median survival for Group 1 was significantly longer than that for Group 2 (p = 0.004) and Group 3 (p < 0.0001), while Group 2 had longer survival than Group 3 (p = 0.02).

Conclusions

Older patients with an increasing number of these factors may not benefit as much from aggressive surgery as patients with fewer factors. This may provide insight into identifying which patients older than 65 years of age may benefit from aggressive surgery.

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Kaisorn L. Chaichana, Thomas Kosztowski, Ashwini Niranjan, Alessandro Olivi, Jon D. Weingart, John Laterra, Henry Brem, and Alfredo Quiñones-Hinojosa

Object

Patients harboring anaplastic astrocytomas (AAs) typically have a poor prognosis, with median survival times of approximately 3 years following resection. However, a significant variability in individual outcomes remains, with some patients surviving for a few months and others for several years. The ability to predict patient outcomes based on preoperative variables would help prognosticate survival and may also guide treatment strategies. The prognostic implications of a preoperative contrast-enhancing AA remain poorly understood.

Methods

The medical records of all patients who underwent a craniotomy for a hemispheric AA from 1996 to 2006 at a single institution were retrospectively reviewed. Multivariate proportional hazards regression analysis was used to identify independent associations with recurrence and survival. The Kaplan-Meier method and log-rank analysis were used to plot and compare outcomes for patients with and without preoperative contrast enhancement.

Results

One hundred sixty-five patients were available for analysis. The AAs were contrast enhancing in 102 patients (62%), and nonenhancing in 63 patients (38%). There were no significant differences in clinical and treatment-related variables between patients with and without contrast enhancement. After multivariate analysis, contrast enhancement was independently associated with decreased survival (p = 0.02) and increased recurrence (p = 0.04). The 5-year overall survival rates for patients with contrast-enhancing versus nonenhancing tumors were 31 and 38.5%, respectively. The 3-year rates of progression-free survival for patients with contrast-enhancing versus nonenhancing tumors were 32 and 56%, respectively. Interestingly, heterogeneously enhancing tumors appear to result in poorer outcomes as compared with other types of enhancement (such as ring enhancing, nodular, and others). Among patients with contrast-enhancing AAs, gross-total resection significantly delayed recurrence (p = 0.05) but did not significantly prolong survival (p = 0.52).

Conclusions

This study may provide insights into risk-stratifying patients with AAs, and most specifically those with AAs that enhance with contrast administration.

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Kaisorn L. Chaichana, Patricia Zadnik, Jon D. Weingart, Alessandro Olivi, Gary L. Gallia, Jaishri Blakeley, Michael Lim, Henry Brem, and Alfredo Quiñones-Hinojosa

Object

Glioblastoma is the most common and aggressive type of primary brain tumor in adults. These tumors recur regardless of intervention. This propensity to recur despite aggressive therapies has made many perceive that repeated resections have little utility. The goal of this study was to evaluate if patients who underwent repeat resections experienced improved survival as compared with patients with fewer numbers of resections, and whether the number of resections was an independent predictor of prolonged survival.

Methods

The records of adult patients who underwent surgery for an intracranial primary glioblastoma at an academic tertiary-care institution between 1997 and 2007 were retrospectively reviewed. Multivariate proportionalhazards regression analysis was used to identify an association between glioblastoma resection number and survival after controlling for factors known to be associated with survival, such as age, functional status, periventricular location, extent of resection, and adjuvant therapy. Survival as a function of time was plotted using the Kaplan-Meier method, and survival rates were compared using log-rank analysis.

Results

Five hundred seventy-eight patients with primary glioblastoma met the inclusion/exclusion criteria. At last follow-up, 354, 168, 41, and 15 patients underwent 1, 2, 3, or 4 resections, respectively. The median survival for patients who underwent 1, 2, 3, and 4 resections was 6.8, 15.5, 22.4, and 26.6 months (p < 0.05), respectively. In multivariate analysis, patients who underwent only 1 resection experienced shortened survival (relative risk [RR] 3.400, 95% CI 2.423–4.774; p < 0.0001) as compared with patients who underwent 2 (RR 0.688, 95% CI 0.525–0.898; p = 0.0006), 3 (RR 0.614, 95% CI 0.388–0.929; p = 0.02), or 4 (RR 0.600, 95% CI 0.238–0.853; p = 0.01) resections. These results were verified in a case-control evaluation, controlling for age, neurological function, periventricular tumor location, extent of resection, and adjuvant therapy. Patients who underwent 1, 2, or 3 resections had a median survival of 4.5, 16.2, and 24.4 months, respectively (p < 0.05). Additionally, the risk of infections or iatrogenic deficits did not increase with repeated resections in this patient population (p > 0.05).

Conclusions

Patients with glioblastoma will inevitably experience tumor recurrence. The present study shows that patients with recurrent glioblastoma can have improved survival with repeated resections. The findings of this study, however, may be limited by an intrinsic bias associated with patient selection. The authors attempted to minimize these biases by using strict inclusion criteria, multivariate analyses, and case-control evaluation.

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Matthew J. McGirt, Khoi D. Than, Jon D. Weingart, Kaisorn L. Chaichana, Frank J. Attenello, Alessandro Olivi, John Laterra, Lawrence R. Kleinberg, Stuart A. Grossman, Henry Brem, and Alfredo Quiñones-Hinojosa

Object

Gliadel (BCNU) wafer and concomitant temozolomide (TMZ) therapy, when used individually as adjuvant therapies, extend survival from that achieved by resection and radiation therapy (XRT) for glioblastoma multiforme (GBM). It remains unstudied whether combining Gliadel and TMZ therapy is safe or further improves survival in patients with newly diagnosed GBM. The authors reviewed their initial experience utilizing combined Gliadel, TMZ, and radiation therapy for the treatment of GBM.

Methods

All cases involving patients undergoing primary resection of GBM with or without Gliadel wafer (3.85% BCNU) implantation and adjuvant XRT over a 10-year period (1997–2006) were retrospectively reviewed. Beginning in 2004, concomitant TMZ became the standard of care at the authors' institution and all patients with Gliadel implantation also received concomitant TMZ (Stupp protocol). Overall survival and treatment-related morbidity were assessed for all patients treated with Gliadel plus concomitant TMZ (XRT + Gliadel + TMZ). Age-matched (≤ 70 years) comparison of survival and morbidity was performed between the XRT + Gliadel + TMZ (post-2003) and XRT + Gliadel (pre-2004) cohorts.

Results

Thirty-three patients were treated with XRT + Gliadel + TMZ. The median survival in this group was 20.7 months, with a 2-year survival rate of 36%. Six-month morbidity included surgical site infection in 1 case (3%), perioperative seizures in 2 cases (6%), deep-vein thrombus in 1 (3%), pulmonary embolism in 3 (9%), and cerebral edema requiring admission for intravenous dexamethasone in 1 case (3%). Myelosuppression required premature termination of TMZ in 7 patients (21%) (thrombocytopenia in 5, neutropenia in 2 cases). In patients ≤ 70 years of age, XRT + Gliadel + TMZ (30 patients, post-2003) was independently associated with improved median survival (21.3 vs 12.4 months, p = 0.005) versus XRT + Gliadel (78 patients, pre-2004), with 2-year survival of 39 versus 18%, respectively. In these patients, XRT + Gliadel + TMZ was not associated with an increase in perioperative morbidity in comparison with XRT + Gliadel.

Conclusions

In this experience, concomitant TMZ therapy in addition to Gliadel wafer implantation was associated with a median survival of nearly 21 months without increased perioperative morbidity. Temozolomide can be safely administered to patients receiving Gliadel wafers after resection of GBM.