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/lp/springer-journals/toxicity-after-radiochemotherapy-for-glioblastoma-using-temozolomide-a-lwcBD601Uq
- Publisher
- Springer Journals
- Copyright
- Copyright © 2011 by Niewald et al; licensee BioMed Central Ltd.
- Subject
- Medicine & Public Health; Oncology; Radiotherapy
- eISSN
- 1748-717X
- DOI
- 10.1186/1748-717X-6-141
- pmid
- 22017800
- Publisher site
- See Article on Publisher Site
Abstract
Purpose: Retrospective evaluation of toxicity and results after radiochemotherapy for glioblastoma. Methods: 46 patients with histopathologically proven glioblastoma received simultaneous radiochemotherapy (RCT). The mean age at the beginning of therapy was 59 years, the mean Karnofsky performance index 80%. 44 patients had been operated on before radiotherapy, two had not. A total dose of 60 Gy was applied in daily single fractions of 2.0 Gy within six weeks, 75 mg/m /day Temozolomide were given orally during the whole radiotherapy period. Results: A local progression could be diagnosed in 34/46 patients (70%). The median survival time amounted to 13.6 months resulting in one-year and two-year survival probabilities of 48% and 8%, respectively. Radiotherapy could be applied completely in 89% of the patients. Chemotherapy could be completed according to schedule only in 56.5%, the main reason being blood toxicity (50% of the interruptions). Most of those patients suffered from leucopenia and/or thrombopenia grade III and IV CTC (Common toxicity criteria). Further reasons were an unfavourable general health status or a rise of liver enzymes. The mean duration of thrombopenia and leucopenia amounted to 64 and 20 days. In two patients, blood cell counts remained abnormal until death. In two patients we noticed a rise of liver enzymes. In one of these in the healing phase of hepatitis a rise of ASAT and ALAT CTC grade IV was diagnosed. These values normalized after termination of temozolomide medication. One patient died of pneumonia during therapy. Conclusion: Our survival data were well within the range taken from the literature. However, we noticed a considerable frequency and intensity of side effects to bone marrow and liver. These lead to the recommendations that regular examinations of blood cell count and liver enzymes should be performed during therapy and temozolomide should not be applied or application should be terminated according to the criteria given by the manufacturer. Keywords: Glioblastoma, Radiotherapy, Chemotherapy, Toxicity, Bone marrow Background or liver irritation [1]. They reported a rate of neutrope- Since the randomized trial published by Stupp et al. [1] nia and thrombopenia grade III and IV CTC 2.0 (Com- in 2005 simultaneous radiochemotherapy applying a mon toxicity criteria) of 7%. Other author groups have total dose of60Gy in30fractions of 2Gyeachwithin published case reports with prolonged pancytopenia and six weeks and temozolomide in a dosage of 75 mg/m / isolated thrombopenia [2-4]. Additionally, single cases of day is regarded to be the gold standard in the treatment liver damage by temozolomide have been reported [5]. During the review of our data we had the impression of glioblastoma. However, Stupp et al. [1] observed con- siderable side-effects such as fatigue, bone marrow sup- that a noticeably higher proportion of our patients suf- pression, opportunistic infections, cerebral hemorrhage, fered from prolonged leucopenia and thrombopenia than mentioned in the literature. This led us to a more detailed analysis of our data concerning toxicity of * Correspondence: marcus.niewald@uks.eu simultaneous radiochemotherapy for glioblastoma. Department of Radiotherapy and Radiation Oncology, Saarland University Hospital, Kirrberger Straße, D-66421 Homburg, Germany Full list of author information is available at the end of the article © 2011 Niewald et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Niewald et al. Radiation Oncology 2011, 6:141 Page 2 of 7 http://www.ro-journal.com/content/6/1/141 interval between histology and start of radiotherapy Methods amounted to 27 days. From July 2000 to December 2009 a total of 46 The patient’s head was fixed by an individual mask, patients underwent simultaneous radiochemotherapy CT- and MRI-scans (often MPRage and T2 series) were for glioblastoma. Follow-up data were taken into performedand fusedinthe 3D-planning system. The account until December 2009. The patient characteris- planning target volume (PTV) was delineated afterwards, tics are summarized in Table 1. The mean time it consisted of the tumour (bed) with a safety margin of 1.5 - 2 cm in all directions respecting anatomical bar- Table 1 Patient characteristics riers which prevent tumour extension like the scull or the falx cerebri. Furthermore, critical structures like Item Mean value/No. of % patients brainstem, optic chiasm, optic nerves, lenses and the Gender inner ear were contoured, the tolerance doses of those organs were taken into account (dose-volume histo- Male 26 57 gram). A 3D conformal multiple-field technique apply- Female 20 43 ing 6 MV photons of a linear accelerator was used. A total dose of 60 Gy was applied in single fractions of 2.0 Mean age 58.6 [33.2-73] years Gy once a day and five times a week using 6 MV photons of a linear accelerator. Mean Karnofsky performance index 81% [60-100%] Chemotherapy was applied simultaneously in all patients. They received 75 mg/m Temozolomide daily Localization during the whole duration of radiotherapy. In order to frontal 10 22 treat nausea and vomiting early, the patients were trea- temporal 26 56 ted in an inpatient setting for the first few days of ther- apy. Laboratory tests (blood cell count, liver enzymes) parietal 5 11 were performed once or twice a week, chemotherapy occipital 3 7 was interrupted or even terminated in patients showing basal ganglia 1 2 white blood cell counts below 3000/μland/orplatelet multifocal 1 2 counts below 100.000/μl. Trimethoprim/Sulfamethoxa- zole were regularly given as a prophylaxis against pneu- Mean diameter of tumour 4.3 [1.5-8.0] cm monia caused by Pneumozystis carinii infection. The first follow-up examination was performed 6-8 Size of edema weeks after the end of radiotherapy, after that twice a none 5 11 year, consisting of clinical examination and MRT/CT scans. Side-effects were graded according to the CTC < 1 cm 6 13 3.0 system [6]. Further examinations were performed in > 1 cm 15 33 the Department for Neurosurgery. The diagnosis of a half hemisphere 18 39 progression was performed according to the RECIST total hemisphere 2 4 (response evaluation criteria in solid tumours) criteria. In order to improve the completeness of data concern- Pre-treatment ing survival, local tumour result, and side effects, struc- complete resection 27 59 tured questionnaires were sent to the patients’ local subtotal resection 5 11 doctors and the local authorities. partial resection 12 26 All data were entered into a medical databank biopsy 2 4 (MEDLOG, Fa.Parox, Münster, Germany) and evaluated statistically. Survival curves were computed using the Kaplan-Meier estimate, we tried to find out significantly Corticoid intake (beginning of therapy) independent prognostic factors using the Cox regression hazard model. None 0 0 All patients had given their written informed consent < 5 mg/day 1 2 before radiochemotherapy. An approval by the local < 10 mg/day 14 30 ethics committee was not necessary due to the retro- < 20 mg/day 21 46 spective nature of this evaluation. The research carried < 30 mg/day 2 4 out here is in compliance with the declaration of > 30 mg/day 8 18 Helsinki. Niewald et al. Radiation Oncology 2011, 6:141 Page 3 of 7 http://www.ro-journal.com/content/6/1/141 one step (compare Table 1), in a further 21% the dose Results remained constant, and in the remaining 16% the dose Median overall survival amounted to 13.6 months, with had to be increased. one/two year survival rates of 48 and 8%, respectively. Chemotherapy could be applied completely in 26 Thedataare depicted in Figure 1. Localtumourpro- (56.5%) patients. Two of these patients had a short (< 7 gression was seen in 32 patients (82%) resulting in a 6/ days) interruption of medication, one due to a subcuta- 12 months local control probability of 59.4 and 30%, neous liquor cushion which had to be treated surgically, respectively. In multivariate analysis, the total dose (p = the other due to an episode of seizures. The mean dura- 0.0035) and the age (p = 0.0445) were found to be sig- tion of continuous temozolomide intake was 35 (6-49) nificant prognostic factors whereas pre-treatment, dose days. On the other hand, chemotherapy could not be of cortisone, change of thedoseofcortisoneduring given completely in 20 patients (43%), due to a dete- therapy, latency between surgery and radiotherapy, and rioration of blood cell count, worsening of general Karnofsky performance status were not. The results can health status and liver damage. One patient died of also be illustrated in terms of median survival: the med- pneumonia during a phase of bone marrow aplasia hav- ian survival of older patients amounted to 0.88 years (n ing received a radiotherapy dose of 38 Gy. = 23; > = 59 years) whereas the survival of younger The blood cell counts before and after radioche- patients was 1.07 years (n = 23, < 59 years). Patients motherapy as well as the minimal values during radio- having been treated completely showed a median survi- therapy are summarized in Table 2. As stated above, val of 1.05 years (n = 41) whereas patients with an the side effects were classified according to the CTC incomplete treatment only survived 0.81 years in median 3.0 system, resulting in the distributions depicted in (differences not significant using Mantel-Haensel-test). Figures2and 3.Insummary,toxicitygrade threeCTC The planned total dose of 60 Gy could be applied to to platelet count was diagnosed in two patients (4%) 41 (89%) patients. In the remaining five, therapy had to and grade 4 in six patients (13%), in total, six males be terminated prematurely after reaching doses of 38 Gy and 2 females, whereas toxicity grade 4 CTC to white (1 pat.), 40 Gy (1 pat.), 56 Gy (2 pats.) and 58 Gy (1 blood cell count was found in seven patients (15%, pat.) due to a deterioration of general health status. four males and three females) as the most unfavour- The dose of corticosteroids (all patients were applied able values during therapy. However, at the end of dexamethasone) needed by the patients was evaluated radiotherapy there were still three patients (7%) with after radiochemotherapy and compared to the doses grade 3 and five patients (11%) with grade 4 toxicity to taken before. The dexamethasone dosage was chosen the platelet count whereas only 4 patients (9%) were regularly according to the patient’s complaints and the diagnosed to have toxicity to the leucocyte count grade general health status. Due to an often very fast dete- 4 CTC. The duration of these side effects is summar- rioration of the patients’ status CT- and MRI examina- ized in Table 3. tions were not performed always. Thus, we cannot Nine patients (20%) were applied erythrocyte transfu- exclude that in some patients a local tumor progression sions due to symptomatic anemia (2-6 units), in six of may have lead to termination of therapy. In 63% of the those patients further thrombocyte transfusions were patients corticoid intake could be reduced by at least Figure 1 Overall survival (Kaplan-Meier estimate, survival curve solid, borders of 95% interval dashed). Niewald et al. Radiation Oncology 2011, 6:141 Page 4 of 7 http://www.ro-journal.com/content/6/1/141 Table 2 Mean blood values Before therapy Nadir (minimal values during therapy) After therapy Hemoglobine [g/dl] 13.3 [10.4-16.7] 12.0 [7.1-15.3] 12.9 [7.1-15.3] Leucocytes [1000/μl] 10.6 [2.2-20.5] 5.3 [0.1-11.0] 6.2 [0.2-14] Thrombocytes [1000/μl] 227 [103-390] 141 [4-291] 166 [14-419] given (2-10 units). Seven patients received Filgastrim for same radiotherapy plus a chemotherapy of 75 mg/m / leucopenia for on average 10 days [2-20 days]. day temozolomide given simultaneously. The latter Frequencyand gradeoftoxicitytotheliver aresum- patients also received adjuvant chemotherapy with six marized in Table 4. In one patient, GOT, GPT and g- courses of temozolomide (150-200 mg/m ). The combi- GT values were elevated extremely up to values of 3172 nation therapy clearly improved survival (median survi- U/l, 9020 U/l and 782 U/l, respectively. These values val 14.6 vs. 12.1 months, one-year survival rate 61.1% vs. recovered at least in part after the end of chemotherapy. 50.6%); since that time radiochemotherapy is regarded This patient was in the recovery phase of a hepatitis B to be the gold standard in the treatment of glioblastoma. infection, which was not known at the beginning of A second randomized trial with fewer patients was pub- therapy. Chemotherapy was terminated due to liver toxi- lished by Athanassiou in 2005 [11]. The authors stated a city in two patients. median survival time of 8.9 months (radiotherapy) com- Two (4%) of the patients had adjuvant chemotherapy pared to 13.6 months (radiochemotherapy) resulting in using temozolomide after radiochemotherapy. This a one-year survival probability of 15.7% vs. 56.3%. results from the fact that adjuvant chemotherapy was In our collective, radiochemotherapy was terminated not applied routinely in the department at that time the prematurely in 43% of the patients. This value seems patients were treated (partially before Stupp had pub- high compared to those reported in the two randomized lished his trial [1]). Three patients (7%) underwent trials mentioned above: Stupp et al. [1] cite an early dis- further surgery due to local relapse. continuation of Temozolomide application in 13% of the patients, the main reason was side effects. Hematotoxi- Discussion city grade 3 and 4 were noticed in 7% of the patients, In the treatment of glioblastoma the effect of the combi- mainly neutropenia and thrombopenia. nation of standard radiotherapy with simultaneous che- Athanassiou et al. [11] found a myelosuppression in motherapy using temozolomide has been examined for 8.7% of their patients. Leucopenia grade 3 and 4 were at least 15 years. The first phase II trials were published noticed in 3.5% and thrombopenia grade 3 and 4 in in 1993 and 1996 [7,8]. Brock et al. [9] recommended a 5.2%. One patient with severe myelotoxicity died of sep- dosage of 75 mg/m /day which is still regarded to be sis. Unfortunately, the authors did not state in how the standard. Very favourable survival data after radio- many patients treatment could be applied completely or chemotherapy were found by Stupp et al. in 2002 [10] how long the duration of side effects was. (2-year-survival rate 31%). In the randomized trial pub- Furthermore, we have found several papers showing lished by the same author group in 2005 [1] the results retrospective toxicity data in the literature, see Table 5. In summary, the authors stated a rate of leucocyte toxi- of radiotherapy alone applying a total dose of 60 Gy in 30 fractions within six weeks were compared with the city grades 3 and 4 CTC in the range 3% to 15% and a Figure 3 CTC-Classification of hematologic toxicity (end of Figure 2 CTC-Classification of hematologic toxicity (maximum). therapy). Niewald et al. Radiation Oncology 2011, 6:141 Page 5 of 7 http://www.ro-journal.com/content/6/1/141 Table 3 Duration of side effects (days) Some interesting case reports were also found. Nagane et al. [3], Jalali et al. [2] and Singhal et al. [4] report a 3° CTC 4° CTC total of 4 cases with long-lasting myelosuppression after Thrombocytes (n = 6) 64 [26-125] 24 [14-38] temozolomide (one patient has died of sepsis). Leucocytes (n = 7) 20 [5-28] 13 [2-22] Liver toxicity is currently under debate. While New- Hemoglobine (n = 1) 4 0 lands et al. [21] could not find a liver metabolism of temozolomide, liver affections were reported in litera- ture [5,22,23]. In one case, temozolomide was applied Table 4 Liver toxicity at the beginning and end of together with valproic acid, in the two other cases a therapy and maximum values viral hepatitis was reactivated. We have seen two 3° CTC 4°CTC patients with liver toxicity which led to interruption of Start Maximum End Start Maximum End chemotherapy, reactivation of hepatitis could be proven g-GT 1 3 4 0 0 0 in one. GOT 0 1 0 0 1 0 Due to the low number of events prognostic factors GPT 0 4 3 0 1 0 could not be computed in our collective. Data taken from the literature show that female patients may have a higher risk of hematologic toxicity than males [24]. frequency of thombocyte toxicity grades 3 and 4 CTC in Armstrong et al. [25] state after having analyzed an the range 0 - 15% of their patients [12-20]. These results ample collective of 680 patients that in males a body have been analyzed in detail, the known prognostic fac- surface > 2 m , missing medication with steroids, and tors (elderly patients, unfavourable Karnofsky perfor- bowel medication may enhance the risk of high-grade mance index, the percentage of patients having been toxicity, while in females a creatinine level > 1 mg/dl, a operated on) did not influence markedly the rate of side platelet count below 270000/mm , missing medication effects. Table 5 Literature data Authors Number of Toxicity 3/4° Toxicity 3/4° Remarks I Remarks II patients leucocytes thrombocytes Randomized trials Athanassiou et al. 130 3.5% 5.2% 1 pat. died of sepsis 2005 [11] Stupp et al., 2005 573 4% 3% Severe infections in 3% [1] Retrospective analyses Armstrong 2008 203 Clinically significant lymphopenia Abstract [12] in 45% of women and 6% of men Combs et al. 2005 53 2% 0 No severe late effects temozolomide 50 mg/m [26] Combs et al. 2008 160 Hematologic toxicity Premature discontinuation Comparison temozolomide 50 vs. 75 mg/m [14] 5% (50 mg/m ) vs. 14% (75 mg/ 6.5% vs. 14% m ) Fiorica et al. 2010 42 0 5% [15] Gerber 2007 [16] 52 Neutro-penia 15% Mean duration 332 days 10% required platelet transfusions, 67% In 18% [1-389 days] discontinued radiochemo-therapy Gerstein et al. 51 Hematologic toxicity Premature discontinuation 2009 [17] 14% in 41% Jeon 2009 [27] 79 Hematologic toxicity 1 pat. with severe lung 7.5% infection Kimple 2010 [19] 32 3% 0 Minniti et al. 2008 32 3% 3% Pneumonia in 3% [20] Our data 46 15% 17% 43% discontinued treatment Niewald et al. Radiation Oncology 2011, 6:141 Page 6 of 7 http://www.ro-journal.com/content/6/1/141 Neurosurgery, Saarland University Hospital, Kirrberger Straße, D-66421 of gastroesophageal reflux disease and application of Homburg, Germany. analgesics are independent prognostic factors. Our data do not allow to give clear reasons for the Authors’ contributions MN supervised data acquisition and evaluation and wrote the manuscript. discrepancies between our results and those taken from CB collected the data and performed a part of the evaluation. This paper is the literature. We only can assume that one reason may a short version of Dr. CB’s thesis. JF was responsible for radiotherapy of the be the retrospective evaluation of an unselected patient patients and reviewed the manuscript. NL was responsible for the physical part of radiotherapy. collective performed here with a wide variety of ages, RK was responsible for surgery of the patients and reviewed the manuscript. Karnofsky performance statuses and tumour extensions CR supervised radiotherapy of the patients and reviewed the manuscript. All as well as co-morbidity. Otherwise, it may be possible authors have read and approved the final manuscript. that under the impression of the first long-lasting hae- Competing interests matological side effects medication was interrupted even The authors declare that they have no competing interests. earlier than recommended by the manufacturer which Received: 26 July 2011 Accepted: 21 October 2011 may have lead to a virtual higher proportion of unfa- Published: 21 October 2011 vourable results. To ouropiniontheonlystrategytolimit this toxicity References is to strictly follow the rules given by the manufacturer 1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al: Radiotherapy plus and to interrupt or to terminate the medication at the concomitant and adjuvant temozolomide for glioblastoma. The New time points recommended. To our experience it would England journal of medicine 2005, 352:987-996. not have been possible to identify those patients with an 2. Jalali R, Singh P, Menon H, Gujral S: Unexpected case of aplastic anemia in a patient with glioblastoma multiforme treated with Temozolomide. J unfavourable result before radiotherapy, thus alteration Neurooncol 2007, 85:105-107. of the fractionation protocol, reduction of the dose of 3. Nagane M, Nozue K, Shimizu S, Waha A, Miyazaki H, Kurita H, Homori M, temozolomide prematurely or even not to apply temozo- Fujioka Y, Shiokawa Y: Prolonged and severe thrombocytopenia with pancytopenia induced by radiation-combined temozolomide therapy in lomide concomitantly to radiotherapy do not appear to a patient with newly diagnosed glioblastoma–analysis of O6- be reasonable possibilities. methylguanine-DNA methyltransferase status. J Neurooncol 2009, 92:227-232. 4. Singhal N, Selva-Nayagam S, Brown MP: Prolonged and severe Conclusions myelosuppression in two patients after low-dose temozolomide Our values fit well to those taken from the retrospective treatment-case study and review of literature. J Neurooncol 2007, analyses. However, the results in the randomized trials 85:229-230. 5. Chheda MG, Drappatz J, Greenberger NJ, Kesari S, Weiss SE, Gigas DC, are far more favourable which may be a result of patient Doherty LM, Wen PY: Hepatitis B reactivation during glioblastoma selection. Unfortunately, the known prognostic factors treatment with temozolomide: a cautionary note. Neurology 2007, could not be tested in our collective. 68:955-956. 6. Common Toxicity Criteria. 2006 [http://www.eortc.be/services/doc/ctc/ Bearing in mind the limited power of a retrospective ctcaev3.pdf]. evaluation we would like to conclude that simultaneous 7. Newlands ES, O’Reilly SM, Glaser MG, Bower M, Evans H, Brock C, radiochemotherapy for glioblastoma yields reasonable Brampton MH, Colquhoun I, Lewis P, Rice-Edwards JM, et al: The Charing Cross Hospital experience with temozolomide in patients with gliomas. local control and survival rates. However, a certain risk Eur J Cancer 1996, 32A:2236-2241. of toxicity to the bone marrow must be taken into 8. 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Combs SE, Gutwein S, Schulz-Ertner D, van Kampen M, Thilmann C, Edler L, Wannenmacher MM, Debus J: Temozolomide combined with irradiation as postoperative treatment of primary glioblastoma multiforme. Phase I/ II study. Strahlentherapie und Onkologie 2005, 181:372-377. 27. Jeon HJ, Kong DS, Park KB, Lee JI, Park K, Kim JH, Kim ST, Lim DH, Kim WS, Nam D-H: Clinical outcome of concomitant chemoradiotherapy followed by adjuvant temozolomide therapy for glioblastaomas: single-center experience. Clinical Neurology And Neurosurgery 2009, 111:679-682. doi:10.1186/1748-717X-6-141 Cite this article as: Niewald et al.: Toxicity after radiochemotherapy for glioblastoma using temozolomide - a retrospective evaluation. 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Radiation Oncology – Springer Journals
Published: Oct 21, 2011