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Combined modality treatment of newly diagnosed glioblastoma multiforme in a regional neurosurgical centre
Journal of Clinical Neuroscience 16 (2009) 1174–1179
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Combined modality treatment of newly diagnosed glioblastoma multiforme in a regional neurosurgical centre Andrew J. Gauden a,*, Andrew Hunn b, Albert Erasmus b, Pauline Waites b, Arvind Dubey b, Stanislaw J. Gauden c a
Department of Neurosurgery, Royal Hobart Hospital, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia Department of Neurosurgery, Royal Hobart Hospital, Hobart, Tasmania, Australia c WP Holman Clinic, Launceston, Tasmania, Australia b
a r t i c l e
i n f o
Article history: Received 9 September 2008 Accepted 14 December 2008
Keywords: Glioblastoma Glioma Radiotherapy Resection Temozolomide Surgery
a b s t r a c t The ‘‘local experience” of the Stupp protocol was examined in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM) with particular emphasis given to the extent of surgical resection and its effect on survival. Thirty-one patients with newly diagnosed GBM who underwent combined modality treatment according to the Stupp protocol were assessed retrospectively. Variables assessed were the extent of surgery, size and site of the tumour, age and performance status. Primary end points were overall survival (OS) and progression-free survival (PFS). Median OS was 33 months for macroscopic tumour resection (9 patients; 29%), 15 months for debulking (15; 48%) and 9 months for biopsy (7; 22%). Macroscopic tumour resection resulted in significantly improved OS and PFS compared to the two less radical surgical options (p < 0.001). Patients with GBM undergoing maximal resection of the tumour followed by adjuvant radiotherapy and chemotherapy have an improved survival compared to patients undergoing either subtotal resection or biopsy alone. This statistically significant survival benefit was achieved in a regional neurosurgical centre with minimal additional toxicity. Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
1. Introduction Glioblastoma multiforme (GBM) is the most common and most malignant brain tumour in adults.1 It constitutes at least 80% of malignant astrocytomas with a reported incidence of 3–4 per 100,000 population per year.2 Despite much research into the treatment of GBM, these patients continue to have a poor outcome with a median survival of between 9 months and 14.6 months and a steady deterioration in the quality of life.3–5 More recent research has identified improved survival with surgical treatment followed by external beam radiotherapy and administration of temozolomide. However, the extent of surgery required to maximize this outcome remains unclear.6 Current protocols suggest that standard treatment of patients with a GBM should include maximal neurosurgical resection balanced against the preservation of neurological function.7–11 Although maximal surgical resection may improve survival, it is not always possible due to the infiltrative nature of the tumour or its location within eloquent areas and therefore debulking of the tumour or even biopsy alone may be the only available surgical * Corresponding author. Tel.: +61 3 6222 8562; fax: +61 3 6231 1979. E-mail address: [email protected] (A.J. Gauden).
options.12 Despite these recommendations, the effect of the extent of tumour resection on survival remains uncertain.13–16 Because of the infiltrative nature of the tumour, further postoperative treatment is required to prevent or delay tumour recurrence. Postoperative radiotherapy with concomitant administration of temozolomide chemotherapy followed by additional temozolomide significantly benefits survival and extends the median survival time to about 15 months.6,17,18 Despite the poor prognosis of this condition, the survival of patients with GBM varies considerably. Research has revealed several factors that influence the prognosis of an individual, including the patient’s age and the patient’s performance status on presentation.7,19–23 Patients that present with acute onset of disabling symptoms such as stroke-like presentations or seizures demonstrate an improved survival when compared to those patients with more subtle symptoms that gradually evolve over time.16 To the best of our knowledge, there is no study that assesses the influence of the extent of surgery when combined with adjuvant concomitant radiotherapy and temozolomide. In the present analysis we retrospectively evaluate the survival outcomes of 31 patients with primary GBM treated with a combined modality protocol characterized by initial surgery followed by adjuvant radiotherapy and temozolomide (Stupp protocol) and demonstrate
0967-5868/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2008.12.008
A.J. Gauden et al. / Journal of Clinical Neuroscience 16 (2009) 1174–1179 Table 1 Patient characteristics of 31 patients with histologically confirmed glioblastoma multiforme treated with surgery and postoperative radiotherapy with concomitant temozolomide chemotherapy Characteristic
n (%)
Age (years) Median Range P 70 <70
62 43–74 2 (6) 29 (94)
Sex Female Male
12 (39) 19 (61)
Karnofsky performance score P70 <70
28 (90) 3 (10)
Eastern Cooperative Oncology Group (ECOG) scale ECOG0 ECOG1
17 (55) 14 (45)
Extent of surgery Biopsy Complete resection Debulking/partial resection
7 (23) 9 (29) 15 (48)
EORTC RPA classification III IV V
3 (10) 28 (90) 0 (0)
Time from diagnosis to radiotherapy (days) Median Range
40 2–144
Corticosteroid therapy Yes No
31 (100) 0 (0)
Antiseizure medication Yes No
28 (90) 3 (10)
EORTC = European Organisation for RPA = recursive partitioning analysis.
Research
and
Treatment
of
Cancer,
that this treatment protocol is possible in a moderately sized regional centre. 2. Patients and methods Between 2004 and 2008, 31 patients with a diagnosis of primary GBM were treated by the neurosurgical unit at the Royal Hobart Hospital and were subsequently treated with a standardized radiotherapy/chemotherapy protocol. The protocol used included maximal resection of the tumour followed by postoperative radiotherapy with sensitizing temozolomide chemotherapy, followed by a 6 month course of higher dose temozolomide. All patients with newly diagnosed and histologically confirmed GBM presenting to our facility who had a good performance status with minimal neurological deficit were considered suitable for this combined modality protocol and were included in the study. The patients’ initial symptoms on presentation were recorded and their baseline performance status measured by the Karnofsky performance scale, the Eastern Cooperative Oncology Group (World Health Organization) scale, and the adapted Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classification systems.1,24,25 Tumour size and location were also recorded from the MRI conducted at the time of diagnosis. Baseline characteristics of the patients are summarised in Table 1. Median age at diagnosis was 62 years (range, 43–74 years). Twelve patients of the cohort were female (39%) and 19 were male (61%). The extent of initial surgical treatment was guided by the location and size of the tumour and whether it was considered resect-
1175
able by the treating neurosurgeon. The extent of macroscopic resection was defined by the intraoperative assessment of the surgeon and this was confirmed using postoperative MRI with contrast after surgery. Total macroscopic resection of the tumour was achieved in 9 patients (29%), partial resection or debulking of the tumour in 15 patients (48%), and biopsy alone in 7 patients (22%). Patients undergoing biopsy of the tumour had a resection volume of <10% of the original tumour volume. Of the patients who had the tumour debulked, the volume resected ranged from 10% to 50% in 8 patients, while the remaining 7 patients had >50% of the tumour resected. Total macroscopic clearance, according to intraoperative findings and a subsequent postoperative cranial MRI scan, was achieved in all patients judged to have total excision of the tumour. The volume and location of the tumour in each of the excision treatment groups is shown in Table 2. Postoperative histopathologic evaluation confirmed a primary GBM in all patients. All patients received postoperative external beam radiotherapy based on three-dimensional conformal planning techniques. A median dose of 55.8 Gy, according to the International Commission on Radiation Units and Measurements dose prescription protocols 50 and 62, was applied in a median number of 31 fractions. Sensitizing temozolomide was administered concomitantly at a dose of 75 mg/m2 of body surface area, 5 days per week from the first to the last day of radiotherapy. One month after completion of the radiotherapy component of treatment, all patients commenced adjuvant temozolomide chemotherapy at 200 mg/m2 for 5 consecutive days each month for 6 months. After completion of chemoradiotherapy the patients were followed-up over the course of their adjuvant temozolomide and further MRI with contrast was ordered at 1 month post chemoradiotherapy and 3 monthly after that to assess the extent of the disease and evidence of any recurrence. The range of follow-up was 3 months to 38 months with a median follow-up of 12 months. Outcomes assessed included overall survival, progression-free survival and the adverse effects experienced during the treatment. Overall survival was defined as the survival time from the primary diagnosis obtained with imaging modalities such as CT scans and MRI. Progression-free survival was defined as the time from surgical treatment to tumour progression defined by MRI. Follow-up was recorded from the initial treatment to the last visit or patient contact. Overall survival and progression-free survival were compared for each surgical subgroup using the Kaplan-Meier method. Adverse effects were recorded for each patient and whether these effects resulted in cessation of treatment was noted. The effect of prognostic factors on outcome was assessed using the univariate Cox proportional regression model. Further subgroup analysis was made using multivariate analysis of the variables of age, gender, size and site of tumour, performance status of the patient, extent of resection, presence of symptoms on diagnosis, and the use of steroids and anticonvulsants. Statistical calculation was performed using the Statistical Package for the Social Sciences version 15 for Windows (SPSS; Chicago, IL, USA).
3. Results 3.1. Overall survival Fig. 1 summarises the overall survival for the study group. The median overall survival was 17 months (range, 3–36 months). The actuarial overall survival was calculated as 48% at 1 year and 16% at 2 years. Nine patients (29%) were still alive at the end of the follow-up period. Two of these patients (6%) had no MRI evi-
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A.J. Gauden et al. / Journal of Clinical Neuroscience 16 (2009) 1174–1179
Table 2 Extent of surgical tumour resection of 31 patients with histologically confirmed glioblastoma multiforme by tumour volume and location Extent of surgical intervention (n)
Volume (cm3) (SE)
Left/right (n/n)
Pareital (n)
Frontal (n)
Temporal (n)
Occipital (n)
Basal ganglia (n)
Biopsy alone (7) Debulking (subtotal resection) (15) Total macroscopic resection (9)
30.90 (6.58) 68.89 (11.67) 56.26 (17.49)
2/5 3/12 4/5
4 6 6
1 3 0
0 5 2
0 1 1
1 0 0
SE = standard error.
survival (p < 0.048). Other presentation factors such as performance status assessed with other measurement scales and tumour size and location did not influence the overall survival. 3.2. Progression-free survival
Fig. 1. A Kaplan-Meier survival curve showing overall survival for the entire study group.
dence of residual disease post treatment and at the end of followup. Surgical tumour resection (macroscopic excision or tumour debulking) improved overall survival (19 months [standard error, SE] 1.99) compared to overall survival with biopsy of the tumour alone (9 months [SE 1.79]) (p < 0.014) (Table 3). The extent of neurosurgical intervention affected patients’ overall survival (p < 0.001; Fig. 2). Patients in whom the tumour had been totally excised survived for a median of 33 months (SE 0.83), a significant improvement over debulking (15 months (SE 5.12) and biopsy alone (9 months [SE 1.79]). Patients who presented with a seizure, independent to the extent of surgery, survived longer (median overall survival of 32 months [SE 9.80]) compared to those presenting without seizure (10 months [SE 2.94]) (p < 0.025). This effect was also independent of tumour size, location and performance status of the patients. A statistically significant association was detected between the Karnofsky score of the patients on presentation and their overall
Table 3 Median overall survival and extent of resection of 31 patients with histologically confirmed glioblastoma multiforme Extent of surgical intervention (n)
Median overall survival in months (SE)
p value*
Total macroscopic resection (9) Combined macroscopic resection + debulking (24) Debulking (subtotal resection) (15) Biopsy alone (7)
33 (0.83) 19 (1.99)
p < 0.001 p < 0.014
15 (5.12) 9 (1.79)
NS N/A
NS = not significant, N/A = not applicable, SE = standard error. * p values were calculated from a comparison of treatment group to biopsy alone.
Fig. 3 demonstrates the progression-free survival for the study group. Median progression-free survival was 11 months (range, 1–31 months, SE 2.90), with a progression-free survival rate of 55% at 6 months and 32% at 12 months for all patients. Similar to overall survival, surgical treatment that achieved complete macroscopic resection or debulking demonstrated an improved progression-free survival against biopsy alone with progression-free survival calculated as 14 months (SE 3.17) and 5 months (SE 0.60) respectively (p < 0.045). The extent of neurosurgical resection demonstrated differences in progression-free survival (p < 0.007). Total macroscopic excision of the GBM was recorded as having a median progression-free survival of 28 months (SE 9.92). This was significantly better than median progression-free survivals of 7 months (SE 1.67) for debulking and 5 months (SE 0.6) for biopsy alone (Fig. 4, Table 4). Further analysis revealed an association between the presence of seizure as a presenting symptom and an improved progression-free survival. Patients who presenting with a seizure had a median progression-free survival of 28 months (SE 6.98), longer (p < 0.015) than for those who presented with no seizure (median progression-free survival, 7 months [SE 3.39]). Similar to overall survival, this effect was independent of tumour size, location and performance status of the patients. Other variables did not demonstrate any statistically significant association with progression-free survival. 3.3. Toxicity of treatment Radiotherapy was tolerated well in all patients with no significant RTOG grade 2 or higher acute toxicity reported. All patients completed the course without interruption. Temozolomide chemotherapy was generally well tolerated by most patients. Four patients (13%) experienced side effects from the chemotherapy. Two patients had their regime ceased because of myelosupression related to temozolomide (6%), other patients continued with the regime with a modified dose. One patient developed a petechial rash (3%) and one patient developed neutropaenia (3%).
4. Discussion The median overall survival of the patients in this study was 17 months, which compares favourably with other research.1,6 Stupp et al., in a large trial of 573 patients, reported an overall survival of 14.6 months in the combined modality arm.6 The survival data that were obtained in this study demonstrated a statistically significant improvement in survival among patients treated with more radical surgical resection of the tumour as well as those who presented with acute onset of seizures. The effect of the extent of resection is highly contentious, although from a cytokinetic viewpoint the reduction of tumour
A.J. Gauden et al. / Journal of Clinical Neuroscience 16 (2009) 1174–1179
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Fig. 2. Kaplan-Meier survival curves showing the relationship between the extent of neurosurgical resection of glioblastoma multiforme and overall survival (p < 0.001).
Fig. 3. A Kaplan-Meier survival curve showing progression-free survival for the entire study group.
burden would theoretically be beneficial.26 A recent review suggests that although more extensive excision is associated with longer life expectancy in general, there are limitations in data quality.27 This is partially due to selection biases that exist not only in deciding whether to perform a biopsy or to proceed to attempting resection, but also for treating with a subtotal resection or a gross macroscopic resection.28 Other influences that affect these treatment decisions and excision probability include the location of, and the anatomy of, the tumour. There are also significant policy differences between institutions in terms of aggressiveness of treatment. Some studies have failed to demonstrate a benefit with more extensive surgical resection versus biopsy of the tumour alone.15,19,29–31 More recent studies have suggested that more
Fig. 4. Kaplan-Meier survival curves showing the relationship between the extent of neurosurgical resection of glioblastoma multiforme and progression-free survival (p < 0.007).
extensive resection does lengthen overall survival.7,16,20,21,32–35 Few reports attempt to differentiate between total and partial resection in surgical management of the tumour. One such report by Simpson et al. was conducted on the data obtained by three prospective trials and suggested that those patients undergoing total or partial resection had a significantly longer median survival than those undergoing biopsy alone (11.3 and 10.4 versus 6.6 months). However, the difference between total and partial resection was not statistically significant.33 A review conducted from 20 studies comprising 5691 patients found that only 4 reports found that
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A.J. Gauden et al. / Journal of Clinical Neuroscience 16 (2009) 1174–1179
Table 4 Median progression-free survival and extent of resection of 31 patients with histologically confirmed glioblastoma multiforme Extent of surgical intervention (n)
Median progression-free survival in months (SE)
p value*
Total macroscopic resection (9) Combined macroscopic resection + debulking (24) Debulking (subtotal resection) (15) Biopsy alone (7)
28 (9.92) 14 (3.17)
p < 0.007 p < 0.045
7 (1.67) 5 (0.60)
NS N/A
NS = not significant, N/A = not applicable, SE = standard error. * p values were calculated comparing treatment group to biopsy alone.
the extent of surgical resection is related to improved survival.19 Despite the contention concerning the use of extensive surgery there is a general trend favouring maximal resection of the tumour over biopsy alone.15,19 However, there have been no recent prospective randomized trials that have compared the different levels of surgical resection against survival rates. Our analysis demonstrated a significant benefit of surgical resection of the tumour over biopsy alone with a median overall survival of 19 months for patients undergoing surgical treatment compared to 9 months for those with biopsy alone. A similar effect was noted in progression-free survival of these patients. Both overall survival and progression-free survival was increased in patients undergoing radical excision of the tumour compared to patients who had a subtotal resection or tumour debulking. Patients undergoing radical excision had a median overall survival of 33 months compared to 15 months for patients who underwent partial excision or tumour debulking. These findings demonstrate a significant improvement in both overall survival and progression-free survival of patients with GBM undergoing aggressive surgical therapy and adjuvant chemoradiotherapy. Furthermore, these results suggest that there is an additional improvement in survival and quality of survival for those patients undergoing radical excision of the tumour. Based on these findings we support the view that more radical surgical treatment of GBM does improve survival of the patient, although possibly only if followed by combination adjuvant therapy. However, more research with larger scale prospective trials are needed to further confirm this finding. The performance status of the patient at diagnosis of the tumour is widely accepted to affect the survival of the patient and in addition to age is considered an important prognostic indicator.7,19–23,36,37 The most widely published of these, the Karnofsky scale, has been demonstrated to affect the prognostic outcomes of the patients in a study of 832 patients with GBM.23 In our analysis, the Karnofsky score of the patients was significantly associated with improved overall survival. This measure has been associated with survival in other research.1 Because this retrospective analysis was mainly concerned with patients of better performance status, it is unclear as to whether this finding is significant. This is particularly important as treatment regimens should be directed to the patient’s individual situation with specific consideration given to variables such as their performance status. Other authors have postulated that patients with GBM who present with an acute onset of symptoms such as a new onset seizure or with symptoms that are particularly disabling may demonstrate a trend to an improved survival.13,16,38 This is possibly because those with more subtle symptoms may have a longer time before a diagnosis can be made. In our patient cohort, 8 patients (26%) presented with an acute onset of seizures. This proportion is relatively consistent with other reports of seizure incidence which suggest that about 17% of patients with GBM present with these symptoms.16,39,40 A significant increase in both overall survival and progression-free survival was noted in
the patients presenting with seizures when compared to those with more subtle symptoms. This appeared to be independent of any other variable such as location or size of the tumour. This finding suggests that a history of seizure in the presentation is a positive prognostic indicator and may identify an area for further research. This study is retrospective, so it is recognized that this may affect the validity of the findings as well as generate difficulties in ascertaining the degree of surgical clearance and related comments about the management of the tumour. This difficulty has been noted in other published research.16 However, the patients in this series were all treated by the same neurosurgical centre using agreed standard protocols. This would have minimized the descriptive error in using terms such as ‘‘debulking” and ‘‘resection”. It can therefore be assumed that the description of the extent of resection may be useful in determining the patient’s outcome. Although progression-free survival was used as an alternative outcome variable, there are difficulties in objectively assessing tumour response with serial imaging.16 Acknowledging these difficulties, both measurements of overall survival and progressionfree survival were used as survival outcomes. In any future research, a more standardized objective approach to assessing tumour response should be considered. 5. Conclusion This study suggests that treatment of GBM with the Stupp protocol is possible in a moderately sized regional centre. Furthermore it suggests that patients with GBM who undergo radical excision of the tumour followed by adjuvant radiotherapy and temozolomide chemotherapy have an improved survival compared to patients undergoing either subtotal excision or biopsy alone. This statistically significant survival benefit was achieved with minimal additional toxicity. The findings of our study suggest that patients who present with acute-onset symptoms, such as seizure, have a better outcome in terms of survival than patients with more chronic subtle presentations. As outlined in other research, patients with better performance status on diagnosis will have improved outcomes. These findings outline the importance of a good assessment of a patient’s performance status and other prognostic indicators in outlining plans of treatment and further research. Our findings advocate more extensive resection of the tumour to improve survival outcomes. Further research should be conducted to investigate this finding because this study is retrospective and is based on a small sample size. 6. Financial disclosure No financial support was received in conjunction with the generation of this submission.
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A.J. Gauden et al. / Journal of Clinical Neuroscience 16 (2009) 1174–1179 8. Black P. Brain tumors (first of two parts). N Engl J Med 1991;38:1374. 9. Berger M. Malignant astrocytomas. Surgical aspects. Semin Oncol 1994;21:172. 10. Vuorinen V, Hinkka S, Farkkila M. Debulking or biopsy of malignant glioma in elderly people–a randomised study. Acta Neurochir (Wien) 2003;145:5–10. 11. Hess KR. Extent of resection as a prognostic variable in the treatment of gliomas. J Neurooncol 1999;42:227–31. 12. Combs SE, Wagner J, Bischof M, et al. Postoperative treatment of primary glioblastoma multiforme with radiation and concomitant temozolomide in elderly patients. Int J Radiat Oncol Biol Phys 2008;70:987–92. 13. Algan O, Nelson D, DInapoli R, et al. High-grade gliomas. In: Gunderson L, Tepper J, editors. Clinical Radiation Oncology. Pennsylvania: Churchill Livingstone; 2001. p. 355–77. 14. Pollack L, Gur R, Walach N, et al. Clinical determinants of long-term survival in patients with glioblastoma multiforme. Tumori 1997;83:613–7. 15. Kreth F, Warnke P, Scheremet R, et al. Surgical resection and radiation therapy versus biopsy and radiation therapy in the treatment of glioblastoma multiforme. J Neurosurg 1993;78:762–6. 16. Yuile P, Dent O, Cook R, et al. Survival of glioblastoma patients related to presenting symptoms, brain site and treatment variables. J Clin Neurosci 2006;13:747–51. 17. Coombs S, Gutwein S, Schulz-Ertner D, et al. Temozolomide combined with irradiation as post-operative treatment of primary glioblastoma multiforme. Phase I/II study. Strahlenther Onkol 2005;181:372–7. 18. Patwardhan R, Shorter C, Willis B, et al. Survival trends in elderly patients with glioblastoma multiforme: Resective surgery, radiation, and chemotherapy. Surg Neurol 2004;62:207–13. 19. Quigley M, Maroon J. The relationship between survival and the extent of the resection in patients with supratentorial malignant gliomas. Neurosurgery 1991;29:385. 20. Devaux B, O’Fallon J, Kelly P. Resection, biopsy, and survival in malignant glial neoplasma. A retrospective study of clinical parameters, therapy, and outcome. J Neurosurg 1993;78:767. 21. Laws E, Parney I, Huang W, et al. Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. J Neurosurg 2003;99:467. 22. Green S, Byar D, Walker M, et al. Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. Cancer Treat Rep 1983;67:121. 23. Lamborn K, Chang S, Prados M. Prognostic factors for survival of patients with glioblastoma: recursive partitioning analysis. Neuro-oncol 2004;6:227. 24. Karnofsky D, Burchenal J. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C, editor. Evaluation of Chemotherapeutic Agents. Columbia University Press; 1949. p. 196.
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25. Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649–55. 26. Hoshino T. A commentary on the biology and growth kinetics of low-grade and high-grade gliomas. J Neurosurg 1984;61:895–900. 27. Nader S, Mitchel B. Glioma extent of resection and its impact on patient outcome. Neurosurgery 2008;62:753–66. 28. Vives K, Piepmeier J. Complications and expected outcome of glioma surgery. J Neuro-Oncol 1999;42:289–302. 29. Coffey R, Lunsford L, Taylor F. Survival after stereotactic biopsy of malignant gliomas. Neurosurgery 1988;22:465. 30. Duncan C, Goodman G, Ludgate C, et al. The treatment of adult supratentorial high grade astrocytomas. J Neurooncol 1992;13:63. 31. Sandberg-Wollheim M, Malmstrom P, Stromblad L-G, et al. A randomized study of chemotherapy with procarbazine, vincristine, and lomustine with and without radiation therapy for astrocytoma grades 3 and/or 4. Cancer 1991;68:22–9. 32. Wood J, Green S, Shapiro W. The prognostic importance of tumor size in malignant gliomas: A computed tomographic scan study by the Brain Tumor Cooperative Group. J Clin Oncol 1988;6:338. 33. Simpson J, Horton J, Scott C, et al. Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: results of three consecutive Radiation Therapy Oncology Group (RTOG) clinical trials. Int J Radiat Oncol Biol Phys 1993;26:239. 34. LaCroix M, Abi-Said D, Fourney D, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 2001;95:190. 35. Bucci M, Maity A, Janss A, et al. Near complete surgical resection predicts a favorable outcome in pediatric patients with nonbrainstem, malignant gliomas: results from a single center in the magnetic resonance imaging era. Cancer 2004;101:817. 36. Nakagawa K, Aoki Y, Fujimaki T, et al. High-dose conformal radiotherapy influenced the pattern of failure but did not improve survival in glioblastoma multiforme. Int J Radiat Oncol Biol Phys 1998;40:1141–9. 37. Shinoda J, Sakai N, Murase S, et al. Selection of eligible patients with glioblastoma multiforme for gross total resection. J Neuro-Oncol 2001;52:161–71. 38. Ozbek N, Cakir S, Gursel B, et al. Prognostic significance of seizure in patients with glioblastoma multiforme. Neurol India 2004;52:76–8. 39. Frankel S, German S. Glioblastoma multiforme. Review of 219 cases with regard to natural history, pathology, diagnostic methods and treatment. J Neurosurg 1958;15:489–503. 40. Roth J, Elvidge A. Glioblastoma multiforme: A clinical survey. J Neurosurg 1959;17:236–50.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Combined modality treatment of newly diagnosed glioblastoma multiforme in a regional neurosurgical centre Andrew J. Gauden a,*, Andrew Hunn b, Albert Erasmus b, Pauline Waites b, Arvind Dubey b, Stanislaw J. Gauden c a
Department of Neurosurgery, Royal Hobart Hospital, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia Department of Neurosurgery, Royal Hobart Hospital, Hobart, Tasmania, Australia c WP Holman Clinic, Launceston, Tasmania, Australia b
a r t i c l e
i n f o
Article history: Received 9 September 2008 Accepted 14 December 2008
Keywords: Glioblastoma Glioma Radiotherapy Resection Temozolomide Surgery
a b s t r a c t The ‘‘local experience” of the Stupp protocol was examined in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM) with particular emphasis given to the extent of surgical resection and its effect on survival. Thirty-one patients with newly diagnosed GBM who underwent combined modality treatment according to the Stupp protocol were assessed retrospectively. Variables assessed were the extent of surgery, size and site of the tumour, age and performance status. Primary end points were overall survival (OS) and progression-free survival (PFS). Median OS was 33 months for macroscopic tumour resection (9 patients; 29%), 15 months for debulking (15; 48%) and 9 months for biopsy (7; 22%). Macroscopic tumour resection resulted in significantly improved OS and PFS compared to the two less radical surgical options (p < 0.001). Patients with GBM undergoing maximal resection of the tumour followed by adjuvant radiotherapy and chemotherapy have an improved survival compared to patients undergoing either subtotal resection or biopsy alone. This statistically significant survival benefit was achieved in a regional neurosurgical centre with minimal additional toxicity. Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
1. Introduction Glioblastoma multiforme (GBM) is the most common and most malignant brain tumour in adults.1 It constitutes at least 80% of malignant astrocytomas with a reported incidence of 3–4 per 100,000 population per year.2 Despite much research into the treatment of GBM, these patients continue to have a poor outcome with a median survival of between 9 months and 14.6 months and a steady deterioration in the quality of life.3–5 More recent research has identified improved survival with surgical treatment followed by external beam radiotherapy and administration of temozolomide. However, the extent of surgery required to maximize this outcome remains unclear.6 Current protocols suggest that standard treatment of patients with a GBM should include maximal neurosurgical resection balanced against the preservation of neurological function.7–11 Although maximal surgical resection may improve survival, it is not always possible due to the infiltrative nature of the tumour or its location within eloquent areas and therefore debulking of the tumour or even biopsy alone may be the only available surgical * Corresponding author. Tel.: +61 3 6222 8562; fax: +61 3 6231 1979. E-mail address: [email protected] (A.J. Gauden).
options.12 Despite these recommendations, the effect of the extent of tumour resection on survival remains uncertain.13–16 Because of the infiltrative nature of the tumour, further postoperative treatment is required to prevent or delay tumour recurrence. Postoperative radiotherapy with concomitant administration of temozolomide chemotherapy followed by additional temozolomide significantly benefits survival and extends the median survival time to about 15 months.6,17,18 Despite the poor prognosis of this condition, the survival of patients with GBM varies considerably. Research has revealed several factors that influence the prognosis of an individual, including the patient’s age and the patient’s performance status on presentation.7,19–23 Patients that present with acute onset of disabling symptoms such as stroke-like presentations or seizures demonstrate an improved survival when compared to those patients with more subtle symptoms that gradually evolve over time.16 To the best of our knowledge, there is no study that assesses the influence of the extent of surgery when combined with adjuvant concomitant radiotherapy and temozolomide. In the present analysis we retrospectively evaluate the survival outcomes of 31 patients with primary GBM treated with a combined modality protocol characterized by initial surgery followed by adjuvant radiotherapy and temozolomide (Stupp protocol) and demonstrate
0967-5868/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2008.12.008
A.J. Gauden et al. / Journal of Clinical Neuroscience 16 (2009) 1174–1179 Table 1 Patient characteristics of 31 patients with histologically confirmed glioblastoma multiforme treated with surgery and postoperative radiotherapy with concomitant temozolomide chemotherapy Characteristic
n (%)
Age (years) Median Range P 70 <70
62 43–74 2 (6) 29 (94)
Sex Female Male
12 (39) 19 (61)
Karnofsky performance score P70 <70
28 (90) 3 (10)
Eastern Cooperative Oncology Group (ECOG) scale ECOG0 ECOG1
17 (55) 14 (45)
Extent of surgery Biopsy Complete resection Debulking/partial resection
7 (23) 9 (29) 15 (48)
EORTC RPA classification III IV V
3 (10) 28 (90) 0 (0)
Time from diagnosis to radiotherapy (days) Median Range
40 2–144
Corticosteroid therapy Yes No
31 (100) 0 (0)
Antiseizure medication Yes No
28 (90) 3 (10)
EORTC = European Organisation for RPA = recursive partitioning analysis.
Research
and
Treatment
of
Cancer,
that this treatment protocol is possible in a moderately sized regional centre. 2. Patients and methods Between 2004 and 2008, 31 patients with a diagnosis of primary GBM were treated by the neurosurgical unit at the Royal Hobart Hospital and were subsequently treated with a standardized radiotherapy/chemotherapy protocol. The protocol used included maximal resection of the tumour followed by postoperative radiotherapy with sensitizing temozolomide chemotherapy, followed by a 6 month course of higher dose temozolomide. All patients with newly diagnosed and histologically confirmed GBM presenting to our facility who had a good performance status with minimal neurological deficit were considered suitable for this combined modality protocol and were included in the study. The patients’ initial symptoms on presentation were recorded and their baseline performance status measured by the Karnofsky performance scale, the Eastern Cooperative Oncology Group (World Health Organization) scale, and the adapted Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classification systems.1,24,25 Tumour size and location were also recorded from the MRI conducted at the time of diagnosis. Baseline characteristics of the patients are summarised in Table 1. Median age at diagnosis was 62 years (range, 43–74 years). Twelve patients of the cohort were female (39%) and 19 were male (61%). The extent of initial surgical treatment was guided by the location and size of the tumour and whether it was considered resect-
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able by the treating neurosurgeon. The extent of macroscopic resection was defined by the intraoperative assessment of the surgeon and this was confirmed using postoperative MRI with contrast after surgery. Total macroscopic resection of the tumour was achieved in 9 patients (29%), partial resection or debulking of the tumour in 15 patients (48%), and biopsy alone in 7 patients (22%). Patients undergoing biopsy of the tumour had a resection volume of <10% of the original tumour volume. Of the patients who had the tumour debulked, the volume resected ranged from 10% to 50% in 8 patients, while the remaining 7 patients had >50% of the tumour resected. Total macroscopic clearance, according to intraoperative findings and a subsequent postoperative cranial MRI scan, was achieved in all patients judged to have total excision of the tumour. The volume and location of the tumour in each of the excision treatment groups is shown in Table 2. Postoperative histopathologic evaluation confirmed a primary GBM in all patients. All patients received postoperative external beam radiotherapy based on three-dimensional conformal planning techniques. A median dose of 55.8 Gy, according to the International Commission on Radiation Units and Measurements dose prescription protocols 50 and 62, was applied in a median number of 31 fractions. Sensitizing temozolomide was administered concomitantly at a dose of 75 mg/m2 of body surface area, 5 days per week from the first to the last day of radiotherapy. One month after completion of the radiotherapy component of treatment, all patients commenced adjuvant temozolomide chemotherapy at 200 mg/m2 for 5 consecutive days each month for 6 months. After completion of chemoradiotherapy the patients were followed-up over the course of their adjuvant temozolomide and further MRI with contrast was ordered at 1 month post chemoradiotherapy and 3 monthly after that to assess the extent of the disease and evidence of any recurrence. The range of follow-up was 3 months to 38 months with a median follow-up of 12 months. Outcomes assessed included overall survival, progression-free survival and the adverse effects experienced during the treatment. Overall survival was defined as the survival time from the primary diagnosis obtained with imaging modalities such as CT scans and MRI. Progression-free survival was defined as the time from surgical treatment to tumour progression defined by MRI. Follow-up was recorded from the initial treatment to the last visit or patient contact. Overall survival and progression-free survival were compared for each surgical subgroup using the Kaplan-Meier method. Adverse effects were recorded for each patient and whether these effects resulted in cessation of treatment was noted. The effect of prognostic factors on outcome was assessed using the univariate Cox proportional regression model. Further subgroup analysis was made using multivariate analysis of the variables of age, gender, size and site of tumour, performance status of the patient, extent of resection, presence of symptoms on diagnosis, and the use of steroids and anticonvulsants. Statistical calculation was performed using the Statistical Package for the Social Sciences version 15 for Windows (SPSS; Chicago, IL, USA).
3. Results 3.1. Overall survival Fig. 1 summarises the overall survival for the study group. The median overall survival was 17 months (range, 3–36 months). The actuarial overall survival was calculated as 48% at 1 year and 16% at 2 years. Nine patients (29%) were still alive at the end of the follow-up period. Two of these patients (6%) had no MRI evi-
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Table 2 Extent of surgical tumour resection of 31 patients with histologically confirmed glioblastoma multiforme by tumour volume and location Extent of surgical intervention (n)
Volume (cm3) (SE)
Left/right (n/n)
Pareital (n)
Frontal (n)
Temporal (n)
Occipital (n)
Basal ganglia (n)
Biopsy alone (7) Debulking (subtotal resection) (15) Total macroscopic resection (9)
30.90 (6.58) 68.89 (11.67) 56.26 (17.49)
2/5 3/12 4/5
4 6 6
1 3 0
0 5 2
0 1 1
1 0 0
SE = standard error.
survival (p < 0.048). Other presentation factors such as performance status assessed with other measurement scales and tumour size and location did not influence the overall survival. 3.2. Progression-free survival
Fig. 1. A Kaplan-Meier survival curve showing overall survival for the entire study group.
dence of residual disease post treatment and at the end of followup. Surgical tumour resection (macroscopic excision or tumour debulking) improved overall survival (19 months [standard error, SE] 1.99) compared to overall survival with biopsy of the tumour alone (9 months [SE 1.79]) (p < 0.014) (Table 3). The extent of neurosurgical intervention affected patients’ overall survival (p < 0.001; Fig. 2). Patients in whom the tumour had been totally excised survived for a median of 33 months (SE 0.83), a significant improvement over debulking (15 months (SE 5.12) and biopsy alone (9 months [SE 1.79]). Patients who presented with a seizure, independent to the extent of surgery, survived longer (median overall survival of 32 months [SE 9.80]) compared to those presenting without seizure (10 months [SE 2.94]) (p < 0.025). This effect was also independent of tumour size, location and performance status of the patients. A statistically significant association was detected between the Karnofsky score of the patients on presentation and their overall
Table 3 Median overall survival and extent of resection of 31 patients with histologically confirmed glioblastoma multiforme Extent of surgical intervention (n)
Median overall survival in months (SE)
p value*
Total macroscopic resection (9) Combined macroscopic resection + debulking (24) Debulking (subtotal resection) (15) Biopsy alone (7)
33 (0.83) 19 (1.99)
p < 0.001 p < 0.014
15 (5.12) 9 (1.79)
NS N/A
NS = not significant, N/A = not applicable, SE = standard error. * p values were calculated from a comparison of treatment group to biopsy alone.
Fig. 3 demonstrates the progression-free survival for the study group. Median progression-free survival was 11 months (range, 1–31 months, SE 2.90), with a progression-free survival rate of 55% at 6 months and 32% at 12 months for all patients. Similar to overall survival, surgical treatment that achieved complete macroscopic resection or debulking demonstrated an improved progression-free survival against biopsy alone with progression-free survival calculated as 14 months (SE 3.17) and 5 months (SE 0.60) respectively (p < 0.045). The extent of neurosurgical resection demonstrated differences in progression-free survival (p < 0.007). Total macroscopic excision of the GBM was recorded as having a median progression-free survival of 28 months (SE 9.92). This was significantly better than median progression-free survivals of 7 months (SE 1.67) for debulking and 5 months (SE 0.6) for biopsy alone (Fig. 4, Table 4). Further analysis revealed an association between the presence of seizure as a presenting symptom and an improved progression-free survival. Patients who presenting with a seizure had a median progression-free survival of 28 months (SE 6.98), longer (p < 0.015) than for those who presented with no seizure (median progression-free survival, 7 months [SE 3.39]). Similar to overall survival, this effect was independent of tumour size, location and performance status of the patients. Other variables did not demonstrate any statistically significant association with progression-free survival. 3.3. Toxicity of treatment Radiotherapy was tolerated well in all patients with no significant RTOG grade 2 or higher acute toxicity reported. All patients completed the course without interruption. Temozolomide chemotherapy was generally well tolerated by most patients. Four patients (13%) experienced side effects from the chemotherapy. Two patients had their regime ceased because of myelosupression related to temozolomide (6%), other patients continued with the regime with a modified dose. One patient developed a petechial rash (3%) and one patient developed neutropaenia (3%).
4. Discussion The median overall survival of the patients in this study was 17 months, which compares favourably with other research.1,6 Stupp et al., in a large trial of 573 patients, reported an overall survival of 14.6 months in the combined modality arm.6 The survival data that were obtained in this study demonstrated a statistically significant improvement in survival among patients treated with more radical surgical resection of the tumour as well as those who presented with acute onset of seizures. The effect of the extent of resection is highly contentious, although from a cytokinetic viewpoint the reduction of tumour
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Fig. 2. Kaplan-Meier survival curves showing the relationship between the extent of neurosurgical resection of glioblastoma multiforme and overall survival (p < 0.001).
Fig. 3. A Kaplan-Meier survival curve showing progression-free survival for the entire study group.
burden would theoretically be beneficial.26 A recent review suggests that although more extensive excision is associated with longer life expectancy in general, there are limitations in data quality.27 This is partially due to selection biases that exist not only in deciding whether to perform a biopsy or to proceed to attempting resection, but also for treating with a subtotal resection or a gross macroscopic resection.28 Other influences that affect these treatment decisions and excision probability include the location of, and the anatomy of, the tumour. There are also significant policy differences between institutions in terms of aggressiveness of treatment. Some studies have failed to demonstrate a benefit with more extensive surgical resection versus biopsy of the tumour alone.15,19,29–31 More recent studies have suggested that more
Fig. 4. Kaplan-Meier survival curves showing the relationship between the extent of neurosurgical resection of glioblastoma multiforme and progression-free survival (p < 0.007).
extensive resection does lengthen overall survival.7,16,20,21,32–35 Few reports attempt to differentiate between total and partial resection in surgical management of the tumour. One such report by Simpson et al. was conducted on the data obtained by three prospective trials and suggested that those patients undergoing total or partial resection had a significantly longer median survival than those undergoing biopsy alone (11.3 and 10.4 versus 6.6 months). However, the difference between total and partial resection was not statistically significant.33 A review conducted from 20 studies comprising 5691 patients found that only 4 reports found that
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Table 4 Median progression-free survival and extent of resection of 31 patients with histologically confirmed glioblastoma multiforme Extent of surgical intervention (n)
Median progression-free survival in months (SE)
p value*
Total macroscopic resection (9) Combined macroscopic resection + debulking (24) Debulking (subtotal resection) (15) Biopsy alone (7)
28 (9.92) 14 (3.17)
p < 0.007 p < 0.045
7 (1.67) 5 (0.60)
NS N/A
NS = not significant, N/A = not applicable, SE = standard error. * p values were calculated comparing treatment group to biopsy alone.
the extent of surgical resection is related to improved survival.19 Despite the contention concerning the use of extensive surgery there is a general trend favouring maximal resection of the tumour over biopsy alone.15,19 However, there have been no recent prospective randomized trials that have compared the different levels of surgical resection against survival rates. Our analysis demonstrated a significant benefit of surgical resection of the tumour over biopsy alone with a median overall survival of 19 months for patients undergoing surgical treatment compared to 9 months for those with biopsy alone. A similar effect was noted in progression-free survival of these patients. Both overall survival and progression-free survival was increased in patients undergoing radical excision of the tumour compared to patients who had a subtotal resection or tumour debulking. Patients undergoing radical excision had a median overall survival of 33 months compared to 15 months for patients who underwent partial excision or tumour debulking. These findings demonstrate a significant improvement in both overall survival and progression-free survival of patients with GBM undergoing aggressive surgical therapy and adjuvant chemoradiotherapy. Furthermore, these results suggest that there is an additional improvement in survival and quality of survival for those patients undergoing radical excision of the tumour. Based on these findings we support the view that more radical surgical treatment of GBM does improve survival of the patient, although possibly only if followed by combination adjuvant therapy. However, more research with larger scale prospective trials are needed to further confirm this finding. The performance status of the patient at diagnosis of the tumour is widely accepted to affect the survival of the patient and in addition to age is considered an important prognostic indicator.7,19–23,36,37 The most widely published of these, the Karnofsky scale, has been demonstrated to affect the prognostic outcomes of the patients in a study of 832 patients with GBM.23 In our analysis, the Karnofsky score of the patients was significantly associated with improved overall survival. This measure has been associated with survival in other research.1 Because this retrospective analysis was mainly concerned with patients of better performance status, it is unclear as to whether this finding is significant. This is particularly important as treatment regimens should be directed to the patient’s individual situation with specific consideration given to variables such as their performance status. Other authors have postulated that patients with GBM who present with an acute onset of symptoms such as a new onset seizure or with symptoms that are particularly disabling may demonstrate a trend to an improved survival.13,16,38 This is possibly because those with more subtle symptoms may have a longer time before a diagnosis can be made. In our patient cohort, 8 patients (26%) presented with an acute onset of seizures. This proportion is relatively consistent with other reports of seizure incidence which suggest that about 17% of patients with GBM present with these symptoms.16,39,40 A significant increase in both overall survival and progression-free survival was noted in
the patients presenting with seizures when compared to those with more subtle symptoms. This appeared to be independent of any other variable such as location or size of the tumour. This finding suggests that a history of seizure in the presentation is a positive prognostic indicator and may identify an area for further research. This study is retrospective, so it is recognized that this may affect the validity of the findings as well as generate difficulties in ascertaining the degree of surgical clearance and related comments about the management of the tumour. This difficulty has been noted in other published research.16 However, the patients in this series were all treated by the same neurosurgical centre using agreed standard protocols. This would have minimized the descriptive error in using terms such as ‘‘debulking” and ‘‘resection”. It can therefore be assumed that the description of the extent of resection may be useful in determining the patient’s outcome. Although progression-free survival was used as an alternative outcome variable, there are difficulties in objectively assessing tumour response with serial imaging.16 Acknowledging these difficulties, both measurements of overall survival and progressionfree survival were used as survival outcomes. In any future research, a more standardized objective approach to assessing tumour response should be considered. 5. Conclusion This study suggests that treatment of GBM with the Stupp protocol is possible in a moderately sized regional centre. Furthermore it suggests that patients with GBM who undergo radical excision of the tumour followed by adjuvant radiotherapy and temozolomide chemotherapy have an improved survival compared to patients undergoing either subtotal excision or biopsy alone. This statistically significant survival benefit was achieved with minimal additional toxicity. The findings of our study suggest that patients who present with acute-onset symptoms, such as seizure, have a better outcome in terms of survival than patients with more chronic subtle presentations. As outlined in other research, patients with better performance status on diagnosis will have improved outcomes. These findings outline the importance of a good assessment of a patient’s performance status and other prognostic indicators in outlining plans of treatment and further research. Our findings advocate more extensive resection of the tumour to improve survival outcomes. Further research should be conducted to investigate this finding because this study is retrospective and is based on a small sample size. 6. Financial disclosure No financial support was received in conjunction with the generation of this submission.
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