Abstract
Aim: Due to their high rate of neo-angiogenesis, malignant gliomas may qualify for treatment with anti-angiogenic substances. We report on a series of patients with malignant glioma not eligible for standard postoperative combined radiochemotherapy due to decreased health status. Patients and Methods: A total of nine patients with malignant glioma, postoperatively presenting with a Karnofsky performance score (KPS) below 70, were treated with standalone metronomic low-dose chemotherapy with temozolomide and celecoxib (cyclo-oxygenase-2 inhibitor). Overall survival was defined as the primary end-point and the functional status (KPS) and time to progression as secondary end-points of our analysis. Results: The median KPS after surgery was 60. Treatment achieved a decrease in tumor and edema volume and, more importantly, preserved the functional status defined as the ability to care for self (KPS 70%) until disease progression. No notable side-effects were recorded. Conclusion: In patients with decreased general condition (KPS <70), not eligible for standard treatment, anti-angiogenic therapy offers a reasonable alternative approach. Our results indicate prolonged survival and preserved quality of life in comparison to best supportive care.
Malignant gliomas account for most cases of primary brain tumors (1). In the case of glioblastoma (GBM), standard treatment consists of microsurgical resection and postoperative radiochemotherapy, followed by adjuvant cyclic administration of temozolomide (2). For anaplastic glioma, administration of procarbacine, lomustine and vincristine has again recently been popularized (3). Despite these treatment options, prognosis of GBM remains dismal, with a median survival of 14.6 months (2). Additionally, external-beam radiotherapy and temozolomide are associated with toxicity rates of up to 14.4% (common toxicity criteria grade 4) (4, 5). Thus, the benefit of standard care has been questioned in patients presenting with a poor condition after surgical resection or in elderly patients, as benefit has only been proven in patients presenting with a Karnofsky Perfomance Status (KPS) >70 and age below 65 (or 70) years (6). Functional outcome and quality of life in patients with poor health status or old age remain unclear, as they are generally excluded from most clinical trials.
Due to the increased incidence of glioblastoma in the elderly, more than half of all patients are older than 65 years (7). Treatment of these patients with best supportive care results in overall survival (OS) of only 3-6 months (8). Thus, recent efforts have focused on optimal therapeutic strategies for patients older than 70 years. Comorbidities and raised incidence of side-effects lead to individual decision whether the ‘standard treatment’ (2) is likely to be tolerated or not. Fractionated radiotherapy (RT) alone positively influences OS in the elderly (9, 10). The NOA-08 trial also reported similar effects of standalone one-week-on/one-week-off temozolomide therapy without RT (11). In particular, the sub-group of patients with methylated O6-Methylguanin-DNA-Methyltransferase (MGMT) seems to benefit from temozolomide, so that chemotherapy should be used preferentially over external-beam RT, as described in the Nordic phase III trial (12).
Example of a patient treated with dual anti-angiogenic therapy with low-dose temozolomide and celecoxib. Magnetic resonance imaging scans preoperatively (a), the day after surgical resection (b), and at follow-up at 3 months (c) and 6 months (d) after resection.
Both investigations showed the benefit in terms of OS in elderly patients, but chemotherapy-related adverse effects of grade 3 or more (according to WHO system) ranged from 14% in the Nordic study (8.77% grade 3-4 for leucopenia and 5.2% grade 3-5 infections) to grade 3-4 of 28% in the NOA-08 study. Particularly in patients in a poor general state after surgery, adverse events should be minimized, which questions a standard-dose temozolomide treatment.
In vitro results of Tuettenberg et al. found temozolomide to inhibit tumor endothelial cell proliferation already at 1/10 of the concentration required to achieve inhibition of tumor cell proliferation (13). Cyclo-oxygenase-2 (COX2) inhibitors provide anti-angiogenic potency by down-regulation of angiogenic growth factor and vascular endothelial growth factor, which results in blocking of endothelial cell proliferation and induction of endothelial cell apoptosis (14-16). In particular, highly vascularized tumors such as malignant gliomas may benefit from this mechanism (Figure 1). A clinical analysis of metronomic continuous administration of low-dose temozolomide (20 mg twice daily) and a COX2 inhibitor (200 mg daily) showed excellent results and no significant toxicities when given as primary adjuvant treatment (13) and as second-line treatment in cases of recurrence (17). However, an increased rate of distant recurrences was recorded (18), whereas recurrences usually occur in the vicinity of the resection cavity (19, 20). After a mean time of 10.4 (±0.9) months, more than half of patients (62.5%) developed a distant recurrence, defined as occurring at more than 3 cm away from the primary site. Notably, in 40% of these patients, local control within the original location was still good (18).
We present a cohort of patients with malignant glioma not eligible for combined radiochemotherapy by decision of the Interdisciplinary Tumor Board and were assigned to receive dual anti-angiogenic chemotherapy with continuous low-dose temozolomide in combination with the COX2 inhibitor celecoxib. Analysis was focused on OS, functional status and safety.
Patients and Methods
Between September 2011 and January 2013, nine patients were retrospectively included in this investigation. All patients had histopathologically-proven malignant glioma (GBM or anaplastic glioma). Those patients not fulfilling the criteria to receive radiochemotherapy due to poor general condition (defined as KPS <70) were assigned to receive low-dose temozolomide and celecoxib based on individual approval by the Interdisciplinary Neurooncological Board. Patients with a history of myocardial ischemia or thromboembolic events were not considered appropriate candidates.
Treatment protocol. Treatment was started within 3 to 4 weeks of surgery and a baseline magnetic resonance imaging (MRI) examination was conducted prior to treatment. Patients received 20 mg temozolomide twice daily in combination with 200 mg celecoxib once a day. The therapy was continued until clinical or radiological progression using McDonald's criteria (21).
Patient follow-up. Standard follow-up was scheduled every three months and included contrast-enhanced MRI, and physical and neurological examination. Additionally, laboratory testing was conducted weekly for the first month after the initiation of chemotherapy and biweekly thereafter.
Parameters. Time to progression was defined when tumor progression was present using the McDonald's criteria (21). Toxicity was quantified according to the common toxicity criteria classification (22). The general condition of the patients during follow-up was assessed using the KPS (23). Furthermore, a volumetric assessment of both the visible tumor (defined as contrast enhancing areas on T1-weighted MRI) and the perifocal edema (hyperintense areas in T2-weighted MRI) were acquired to quantify treatment response according to McDonald's criteria (21).
Results
Between August 2011 and May 2013, nine patients (male:female=2:7) were included in this retrospective investigation (one anaplastic astrocytoma WHO grade III, eight glioblastoma). The patients were aged between 53 and 85 years (mean=69 years) and presented postoperatively with a median KPS of 60. Functional status, determined using the KPS was preserved until disease progression in all patients. Four patients had started standard radiochemotherapy after resection but had to discontinue because of severe adverse events and were subsequently assigned after 6.2 (range=4-10) weeks to receive low-dose temozolomide in combination with celecoxib.
Overall survival (a) and time to progression (b) of patients treated with dual anti-angiogenic therapy with low-dose temozolomide and celecoxib. Values are given as mean for all nine patients with upper and lower limits.
Extent of resection. In seven patients, a gross total resection was achieved, whereas a sub-total resection or biopsy was performed in one patient each.
Time to progression and overall survival. Chemotherapy with low-dose temozolomide and celecoxib was started on average 16 days after confirmed diagnosis. OS was 9 months (range=5-19 months) and the mean time to progression 7 months (range=2-19 months) (Figure 2).
Tumor (a) and edema (b) volume as indicator of treatment effect. During dual anti-angiogenic therapy, tumor and edema volume were stable until disease progression.
There was no obvious difference in outcome between patients treated first with combined radiochemotherapy and those started on dual anti-angiogenic treatment right away [OS: primary low-dose vs. secondary low-dose=10.2 (4-19) vs. 11.75 (8-17) months; time to progression: primary low-dose vs. secondary low-dose=8.8 (2-19) vs. 9 (6-12) months].
Tumor volume and edema remained minimal during dual anti-angiogenic chemotherapy in all patients. This indicates the efficacy of treatment until disease progression after approximately 9 months (Figure 3), when therapy was discontinued.
Adverse events. No hematological or cardiac adverse events were noted. There was no indication of problems with infections, gastrointestinal adverse reactions, fatigue, nausea or vomiting. Leucopenia and low platelet count were not observed during therapy.
Karnofsky performance status. All patients presented with a KPS below 70 (mean of 60) after surgery except for one patient with a KPS of 80, who had to be switched to low-dose chemotherapy because of severe leukopenia after standard treatment. Thus, the standard Stupp regimen was not considered feasible. Notably, all patients maintained their KPS until progression (Figure 4).
Discussion
A small cohort of patients suffering from malignant glioma was treated with a dual anti-angiogenic therapeutic regimen. Patients not eligible for combined radiochemotherapy as recommended in the guidelines (24) were enrolled. Prolonged OS and time to progression were demonstrated in comparison to literature data on best supportive care, regardless of the importance of a poor performance status as a negative prognostic parameter (6). Our preliminary investigation offers the possibility of adjuvant chemotherapy for patients who are usually ineligible for any specific therapy at all. The OS was found to be 9 months, which indicates a significant increase compared to 3 months with best supportive care (8, 25).
There have been several efforts to establish guidelines for adjuvant chemotherapy in elderly patients in the past, as an increasing number of patients aged older than 70 years are being treated (7). Chemotherapy with standalone temozolomide therapy was well tolerated in older patients in the NOA-08 (11) and NORDIC (12) trials. Especially tumors with certain molecular attributes (e.g. MGMT-methylation) respond well to monotherapy with standard-dose temozolomide (one week on/one week off) and lead to OS comparable to the results of our study (9 months vs. 8.4 months) (11).
In most prospective randomized trials, patients classified as functionally dependent (defined as KPS <70) are excluded. In NOA-08, a KPS of >60 was required to be eligible for the trial. Therefore, there is a paucity of evidence for any treatment of such patients; most of them will be assigned to best supportive care as even highly experimental treatments require a functionally independent status. Both decisions are based on individual discussion in tumor boards.
Tuettenberg et al. reported the principle of dual anti-angiogenic therapy with ‘low-dose’ temozolomide and celecoxib in 2005 (13). They demonstrated inhibition of tumor endothelial cell proliferation at a much lower temozolomide dose (1/10th) in this combination compared to the dose needed to suppress tumor cell proliferation. The addition of a selective COX2 inhibitor clearly enhanced the antitumoral effect, whilst not leading to augmented rates of adverse events. The efficacy of this low-dose regimen was demonstrated in our patient cohort with volumetric data. The prompt reduction of contrast enhancement on MRI may be due to tightening of the blood–brain barrier via vascular endothelial growth factor-mediated pathways, seen also in patients with high-grade gliomas treated with bevacizumab. The finding that this dual anti-angiogenic chemotherapy seems to be more often associated with distant recurrences is not fully understood. These distant recurrences, however, are diagnosed after a mean period of 11 months (18), such that this should not be relevant to the overall prognosis.
Karnofsky performance score of all patients treated with dual anti-angiogenic therapy with low-dose temozolomide and celecoxib. The score reflects the good tolerability of patients to the dual anti-angiogenic therapy over time.
The low risk of adverse reactions with the dual anti-angiogenic low-dose regimen particularly supports its feasibility for patients in poor general condition. Whilst temozolomide has proven its advantages compared to nitrosourea-based chemotherapeutics in terms of hematoxicity and other side-effects (26-28), in our cohort, four patients did not tolerate standard doses of temozolomide. After assigning them to the low-dose schedule, no further adverse reaction was observed. The described therapeutic regimen, thus, seems well-tolerated even by patients presenting in poor general condition after surgical intervention.
Conclusion
Promising results with dual anti-angiogenic low-dose chemotherapy were observed in patients with malignant glioma who would usually not be offered any treatment other than best supportive care. The low risk of side-effects may make this a unique adjuvant therapeutic regimen for patients with glioblastoma and poor performance status.
Footnotes
Financial Disclosure
The Authors report no conflict of interest concerning the materials or methods used in this study or the findings specified here.
- Received April 5, 2015.
- Revision received April 28, 2015.
- Accepted May 1, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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