Concomitant and adjuvant temozolomide of newly diagnosed glioblastoma in elderly patients

Clinical Neurology and Neurosurgery 115 (2013) 2142–2146

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Concomitant and adjuvant temozolomide of newly diagnosed glioblastoma in elderly patients Timo Behm a , Antonia Horowski a , Simon Schneider b , Hans Christoph Bock a , Dorothee Mielke a , Veit Rohde a , Florian Stockhammer a,∗ a b

Department of Neurosurgery, Universitätsmedizin Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany Department of Medical Statistics, Universitätsmedizin Göttingen, Humboldtallee 32, 37073 Göttingen, Germany

a r t i c l e

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Article history: Received 22 May 2013 Received in revised form 8 July 2013 Accepted 4 August 2013 Available online 12 August 2013 Keywords: Glioblastoma Elderly Radiochemotherapy Matched pairs

a b s t r a c t Objective: The effect of concomitant and adjuvant temozolomide in glioblastoma patients above the age of 65 years lacks evidence. However, after combined treatment became standard at our center all patients were considered for combined therapy. We retrospectively analyzed the effect of temozolomide focused on elderly patients. Methods: 293 patients with newly diagnosed glioblastoma treated single-centered between 1998 and 2010, by radiation alone or concomitant and adjuvant radiochemotherapy, were included. Treatment groups were analyzed by multi- and univariate analysis. Matched pairs for age, by a 5-year-caliper, extent of resection and general state was generated for all patients and elderly subgroups. Results: 103 patients received radiation only and 190 combined treatment. Multivariate and matched pair analysis revealed a benefit due to combined temozolomide (HR 1.895 and 1.752, respectively). For patients older than 65 years median survival was 3.6 (95% CI 3.2–4.7) and 8.7 months (6.3–11.8) for radiotherapy only and combined treatment (HR 3.097, p < 0.0001, n = 90). Over the age of 70 and 75 years median survival was 3.2 (2.3–4.2) vs. 7.5 (5.1–10.9, HR 4.453, p < 0.0001, n = 62) and 3.2 (1.4–3.9) vs. 9.2 months (4.7–13.5; HR 9.037, p < 0.0001, n = 24), respectively. In 8/56 (14%) patients over the age of 70 years temozolomide was terminated due to toxicity. Conclusion: Retrospective matched pair analysis gives class 2b evidence for prolonged survival due to concomitant and adjuvant temozolomide in elderly glioblastoma patients. Until prospective data for combined radiochemotherapy in elderly patients will be available concomitant and adjuvant temozolomide therapy should not be withheld. © 2013 Elsevier B.V. All rights reserved.

1. Introduction In adult patients glioblastoma is the most frequent malignant primary brain tumor. Due to infiltrative growth this tumor has a dismal prognosis despite advances in tumor resection. Radiotherapy has retained a primary standard therapy. The EORTC trial 26981/22981 introducing a combined concomitant and adjuvant administration of temozolomide provided class 1 evidence for survival benefit [1,2]. However, due the conviction elderly patients could not be referred to such intensive treatment, patients older than 70 were excluded from the trial. Likewise, resent prospective trials for elderly glioblastoma patients sought for treatment less intense and toxic without offering a combined treatment arm [3,4].

∗ Corresponding author. Tel.: +49 551 39 22804; fax: +49 3212 1149855. E-mail addresses: fl[email protected], fl[email protected] (F. Stockhammer). 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.08.002

In this retrospective study we hypothesis that also elderly patients benefit from combined treatment. A major drawback in retrospective analyses is the selection bias whether patients received additional chemotherapy or not. General condition and age both influence the treatment decision and are independent prognostic factors themselves [5,6]. We implemented two statistical strategies to overcome this restriction: First, a multivariate model identifies any independent prognostic factor. However, due to the required large sample size to maintain power subgroup analysis could not performed in the elderly subgroups. Second, by creating matched pairs. Any patient of the combined treatment group will be assigned to a chaperone with the same category (Karnofsky performance score (KPS) and extent of resection) and matching for age using a caliper. In this retrospective study we investigated all patients with newly diagnosed glioblastoma either receiving combined temozolomide treatment or not to compare these two analytic strategies. We then focused on subgroups of elderly patients performing matched pair analysis, only.

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2. Materials and methods Patients had to fulfill the following criteria to be eligible for analysis: newly diagnosed histologically confirmed glioblastoma from 1998 to 2010 in our institution, no previous chemotherapy or radiation of the head, at least 18 years of age and indication for adjuvant treatment. Conclusive data had to be available concerning the extent of resection, KPS, subsequent radiation and chemotherapy and hematological toxicity during therapy. The endpoint was date of death or last follow-up within the last 6 months prior to analysis. The latter patients were censored for survival analysis. 2.1. Statistical analysis and pair matching Both treatment groups were analyzed by multivariate log-rank test (Statistica, Statsoft, Tulsa, OK). For comparison of statistical analysis matched pairs were generated from the same cohort on a semi-automated manner. The tool is written in virtual basic and an add-in based custom made for Excel (Microsoft). Matches can be found to each individual of the index cohort screening the reference cohort. In this process exact category matching was performed for KPS and extent of resection, such as gross total, partial or biopsy modeled after the EORTC 26981/22981 [1]. Extent of resection was assigned to “partial resection” when tumor remnants were left or postoperative MRI within 72 h, if performed, revealed remaining contrast enhancement. All other debulking surgeries were assigned to “gross total” resection. For the patient’s age caliper matching was performed [7]. Thereby, the tool optimizes the caliper to the smallest possible with a minimum loss of matches by cross-checking all possible matches. The maximum caliper for age was set to 5 years, allowing further optimization by the tool. For analysis of the elderly subgroups patients were filtered for age older than 65, 70 and 75 years. The pair matching of the age filtered subgroups proceeded the same way matching for KPS, resection state and age. Survival analysis of the matched pairs was done by log-rank test (Prism 5 for Mac, GraphPad Software, La Jolla, CA, USA). 3. Results 372 patients with newly diagnosed glioblastoma were treated from 1998 to 2010 and screened for this study. 44 patients were excluded due to adjuvant treatment modalities other than radiotherapy only or combined radiochemotherapy according to the EORTC 26981/22981: ACNU (29), PCV (3), temozolomide + bevacizumab (2), alternative temozolomide schedule (1), concomitant TMZ omitted (19). 19 patients were lost to follow up and in 16 patients some treatment details were missing. 293 patients were eligible for this analysis. 103 patients received radiation only and 190 combined treatment with a median age of 67.7 years (range 30.3–84.8) and 62.4 years (range 22.4–82.4), a median KPS before surgery of 60% (range 30–90%) and 70% (range 30–100%) and with a proportion of biopsy-only being exactly 12.6% in both groups, respectively. For detailed patient characteristics see Table 1.

Fig. 1. Ages of the matched pairs. Goodness of fit R2 = 0.8956.

depicted in Fig. 1. KPS and extent of resection matched by category with a median of 70% (range 50–90) and 9.8% of both groups, respectively. Median survival of the matched groups was 4.9 (95% CI 4.3–7.2) months for radiotherapy only and 11.6 (8.7–13.5) for combined treatment (HR 1.752, 95% CI 1.285–2.427, p = 0.0007, Fig. 2). 3.2. Elderly subgroups 139 patients were older than 65 years. Of these 80 patients had combined treatment and 59 RT only. According to the matching restrictions 90 patients (45 in each group) were paired. Median survival was 3.6 (95% CI 3.2–4.7) for RT only and 8.7 months (6.3–11.8) for combined treatment (HR 3.097, 95% CI: 1.920–4.993, p < 0.0001). 91 patients were older than 70 years, of which 62 were included in matched pairs. Median survival was 3.2 (95% CI 2.3–4.2) and 7.5 months (5.1–10.9; HR 4.453, 95% CI: 2.423–8.184, p < 0.0001). 39 patients were older than 75 years, of which 24 were included in matched pairs, Median survival was 3.2 (95% CI 1.4–3.9) vs. 9.2 months (4.7–13.5; HR 9.037, 95% CI: 3.037–26.89, p < 0.0001, Fig. 3). In the subgroup of patients over the age of 70 years receiving concomitant and adjuvant temozolomide (n = 56) termination of temozolomide was caused by toxicity in 8 (14%) patients. All of these (n = 8) experienced a prolonged low platelet count of less than 100 nl–1 . Persisting leukopenia of less than 3000 ␮l–1 was only seen in one patient, without signs of infection. In the remaining 47 patients tumor progression, decline of general condi-

3.1. All patients Multivariate analysis of all ages confirms age over 65 years (p < 0.0001) and KPS <70% (p = 0.01) as negative prognostic factors. Combined temozolomide treatment appears as independent positive prognostic factor (HR 1.895, p < 0.0001, median survival 4.8 (95% CI 4.2–5.8) vs. 13.5 (11.8–15.3) months). Matched pairs of all ages revealed 81 patients in each group with a median age of 67.0 (range 41.2–84.8) vs. 66.9 years (range 41.3–81.7). The maximum caliper was 4.999 years. The paired ages reveal a R2 of 0.8956

Fig. 2. Survival analysis of pairs matched for age, KPS and extent of resection (n = 162). Median survival of patients treated by combined radiochemotherapy (RT/TMZ) was 11.56 months compared to 4.93 months with radiation only (RT). HR = HR 1.752, 95% CI 1.285–2.427, p = 0.0007.

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Table 1 Patients characteristics depicting the equal distribution of age, Karnofsky performance status (KPS) and extent of resection in the matched pair cohort. All patients

>65 years

>65 years, matched pairs

RT only

Combined

All

RT only

Combined

All

RT only

Combined

All

All

103

190

293

59

80

139

45

45

90

Death (%) Median survivor follow up [month]

103 (100) –

176 (93) 21.0

279 (95) 21.0

59 (100) –

76 (95) 15.7

135 (97) 15.7

45 (100) –

42 (93) 15.0

87 (97) 15.0

Sex Male (%) Female (%)

55 (53) 48 (46)

116 (61) 74 (39)

171 (58) 122 (42) p = 0.2165

29 (49) 30 (51)

46 (58) 34 (42)

75 (54) 64 (46) p = 0.3902

23 (51) 22 (49)

24 (53) 21 (47)

47 (52) 43 (47) p = 1.0000

Age Median (years) Range

67.7 30.3–84.8

62.4 22.4–82.4

64.4 22.4–84.8 p = 0.0007

72.4 65.8–84.8

71.6 65.1–82.4

72.3 65.1–84.8 p = 0.1618

71.9 65.8–84.8

70.9 65.4–81.7

71.8 65.4–84.8 p = 0.5697

Pre-OP KPS Median Range

60 30–90

70 30–100

70 30–100 p < 0.0001

60 30–90

70 50–100

70 30–100 p = 0.0008

70 50–90

70 50–90

70 50–90 p = 1.000

Extent of resection Gross total (%) Partial (%) Biopsy (%)

73 (71) 17 (17) 13 (13)

133 (70) 33 (17) 24 (13)

206 (70) 50 (17) 37 (13) p = 0.9819

43 (73) 8 (14) 8 (14)

56 (70) 11 (14) 13 (16)

99 (71) 19 (14) 21 (15) p = 0.9034

35 (78) 5 (11) 5 (11)

35 (78) 5 (11) 5 (11)

70 (78) 10 (11) 10 (11) p = 1.0000

tion or completion of the sixth cycle were reasons for temozolomide termination. 4. Discussion Any cut off age to consider patients as “elderly” lacks any rational. The age of 70 years is not related to any biological tumor behavior [8]. However, this age was set as upper inclusion criterion for the EORTC 26981/22981 by Stupp et al. [1], causing the dilemma of missing data for older patients.

Taking the major prognostic covariates and the small subgroup of elderly patients into account, we performed matched pairs analysis followed by univariate analysis. Compared to multivariate analysis the hazard ratio was comparable (1.752 vs. 1.895, respectively). Than we performed matched pair analysis on patients over the age of 65, 70 and 75 years, presenting sustained survival advantage in the elderly patients receiving additional concomitant and adjuvant temozolomide. The doubt for an effect of concomitant and adjuvant temozolomide in elderly patients was raised, when recursive partitioning

Fig. 3. Survival analysis of pairs matched for age, KPS and extent of resection. Subgroup analysis. (a) age > 65 years (n = 90), (b) age > 70 years (n = 62) and (c) age > 75 years (n = 24). Survival advantage for combined radiochemotherapy (RT/TMZ) sustained (Hazard ratios of 3.097, 4.453 and HR 9.037, respectively).

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analysis (RPA) of the EORTC 26981/22981 was performed. Age older than 50 years qualify for group IV or V, showing a non-significant benefit from combined treatment for the latter group. Disregarding fact that no resection had been performed and a poor performance status being also a criterion for group V, it was presumed that older age tend to be a predictive factor for combined treatment being less effective [9]. However, a later long-term follow-up subgroup analysis of the same study cohort reports a survival benefit of the patients older than 60 years treated by combined therapy [2]. These data are inline with our retrospective data revealing a benefit from combined radiochemotherapy disregarding age as a restricting factor. In line to our results are prospective data of patients with ages between 60 and 75 years reporting a prolonged median survival of 16.3 months when treated by radiochemotherapy compared to 11.2 months with radiation only [10]. The scope of this study was the safety of fluorescence-guided resection, therefore, none of the patients had biopsies only. Further, patients in altered general condition were excluded. This selection might explain the superior survival data compared to the corresponding group in the present analysis. Vast retrospective data come from 13,932 patients with glioblastoma compare the era before and after introduction of radiotherapy combined with temozolomide [11]. However, there were no records about the chemotherapy truly administered, so the treatment was assumed according to the era the treatment took place. In line with our data patients of 70–79 years had a significant survival benefit when treated in the temozolomide era, but patients older than 80 years did not benefit. Other retrospective smaller series report a benefit of combined treatment compared to radiotherapy only in elderly patients. However, these studies restricted inclusion criteria to good general state, excluded patients who only received biopsies and allowed a selection bias by omitting multivariate or matched pair analysis [6,12]. Acknowledging the extent of resection as prognostic factor, we matched patients according their resection state. However, as a limitation of this study, postoperative MRI within 72 h, featuring today’s standard after glioma resection, has only been performed in the latter patients. Instead, intraoperative resection control consisting of 5-ALA fluorescence guides resection [13] and 3D ultrasound [14] has been frequently used in our institution. In our study, multivariate analysis confirms the prognostic disbenefit from partial versus gross total resection (HR 0.559, 95% CI: 0.416–0.753, p = 0.0001) in line with previous data [15]. Prospective controlled data dealing solely with elderly patients are published recently, randomizing radiotherapy alone versus dose-dense temozolomide as single first line treatment (NOA-08 trial) [3]. For the entire study cohort temozolomide treatment appeared as not inferior. A benefit was shown for the subgroup of patients with methylated MGMT promoter receiving temozolomide, which, due to available MGMT data in only 56% of the patients, consisted of just 42 patients. In our study a MGMT promoter methylation analysis was, especially in the patients treated before 2007, not performed routinely. Nevertheless, concerning the actual treatment recommendation in elderly patients the NOA-08 raises further questions: first, NOA-08 has had no arm offering combined radiochemotherapy, which is actually the standard therapy in the non-elderly. Therefore, even in patients with methylated MGMT promoter receiving temozolomide, omitting concomitant radiotherapy could result in undertreatment. Second, MGMT data are mostly missing in patients who received stereotactic biopsy, which is comparatively frequent in elderly patients. Third, in our retrospective data combined treatment revealed a clear benefit without stratification for MGMT status. This suggests a high effect of combined treatment, which could be even stronger when restricted to patients with methylated MGMT promoter, suggesting a better effect of combined treatment compared to temozolomide only.

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It was assumed that older patients reveal enhanced toxicity when treated with alcylating agents. In a series of 19 glioblastoma patients older than 65 years severe myelosupression was seen in 15% [16]. The total toxicity rate was reported with 42% including inappropriate ADH secretion and fatigue, which is not necessarily related to temozolomide administration. Likewise in our study, 14% of the elderly patients had to terminate temozolomide due to myelosuppression. This is similar to 12% of the patients after concomitant therapy in the EORTC trial [1]. A series of 43 patients older than 65 years receiving concomitant temozolomide reports termination of temozolomide due to myelosuppression in only 1 patient (2%). 3 further patients stopped temozolomide due to pneumonia or rash, resulting in a toxicity rate of 9% [17]. No patient had to stop temozolomide due to toxicity in a prospective trial omitting radiation and applying temozolomide only on days 1–5 in a 28 days cycle [18]. Patients included had an age of older than 70 years, had a mostly poor performance and no tumor resection. These data report a comparable toxicity as known in patients younger than 65 years [1,19]. Besides survival and toxicity the patients quality of life and selfdependence must be kept in mind. As a limitation of this study, these data could not be provided retrospectively. In the EORTC 26981/22981 the rate of patients reporting a fatigue was increased from 26% to 33% when radiotherapy was combined with temozolomide [1]. In elderly patients radiotherapy implies the risk of cognitive decline. Compared to temozolomide treatment, patients suffered from communication deficit [3] and a potential decline of cognitive, physical and role functioning [4]. One the other hand, tumor progression is the major cause for decline in quality of life [20], thus offering the most effective treatment might provide quality of life maintenance as well. To our opinion, elderly patients must be closely watched, and considered sparing from intense treatment, e.g. completing radiation, in therapy related deterioration. In our retrospective series the patients received a conventional radiotherapy with 30 fractions of 1.8–2 Gy. Alternatively, abbreviated protocols had been introduced to meet the needs of patients with expected shortened survival. Due to hypofractionation the radiation was completed within two, three or four weeks applying 30, 45 or 50 Gy, respectively. Hypofractionation revealed equal survival compared to the conventional 60 Gy in six weeks [4,21,22]. In the Nordic elderly trial temozolomide with 200 mg/m2 was administered as a third arm performing superior to conventional but equal to hypofractionated radiotherapy [20]. Likewise NOA-08 the scope of the Nordic elderly trial was to kept treatment intensity less aggressive considering of the poorer prognosis in elderly patients. Thus, until recurrence neither concomitant nor sequential treatment was offered. In fact, the treatment was mostly discontinued due to tumor progression rather than toxicity. Again, one might assume, that a more intense e.g. combined treatment could result in a better tumor control with acceptable toxicity, as proposed in our retrospective analysis. Accordingly, a prospective trial by Muni et al. reports a survival advantage in poor performing, either elderly or dependent patients, by only adding adjuvant temozolomide to hypofractionated radiation [23]. Currently the EORTC 26062/22061 addresses the issue of combined hypofractionated treatment enrolling elderly patients only. Preliminary data applying this protocol exist from a series of 31 patients, of which 16 were older than 70 years. Tolerance was good with unexpected low toxicity [24]. However, efficiency data of concomitant temozolomide in abbreviated radiotherapy do not exist and might prove equal to only adjuvant therapy as retrospective data suggests [25]. Perhaps lowered total concomitant temozolomide dose due to the abbreviated radiotherapy hampers additional efficiency. Other than for hypofractionated radiotherapy, there is no trial planned addressing elderly patients receiving the current standard treatment protocol.

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5. Conclusion According to the presented data, the concomitant and adjuvant temozolomide should be considered for glioblastoma patients irrespective of the age.

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