|Year : 2021 | Volume
| Issue : 1 | Page : 15-18
Acute toxicity of temozolomide for the treatment of anaplastic astrocytoma: A case report
Yunni Diansari1, Norman Djamaluddin2, Ashita Hulwah1
1 Department of Neurology, Mohammad Hoesin Hospital, Universitas Sriwijaya, Palembang, Indonesia
2 Department of Internal Medicine, Hematolo Oncology Division, Mohammad Hoesin Hospital, Universitas Sriwijaya, Palembang, Indonesia
|Date of Submission||14-Jan-2021|
|Date of Decision||19-Feb-2021|
|Date of Acceptance||01-Mar-2021|
|Date of Web Publication||30-Mar-2021|
Dr. Yunni Diansari
Department of Neurology, Mohammad Hoesin Hospital, Universitas Sriwijaya, Jl Dr Moh Ali KM 3.5, Palembang 30662
Source of Support: None, Conflict of Interest: None
Temozolomide is an orally administered chemotherapeutic drug that has become a standard treatment for malignant gliomas. Severe toxicity of temozolomide is rare, especially shortly after administration. We report a 37-year-old male patient diagnosed with anaplastic astrocytoma following tumor resection. He was treated postoperatively with cranial radiation and adjuvant temozolomide 150 mg/m2 for six planned cycles. However, 3 days after finishing the first cycle of temozolomide, the patient's condition deteriorated. Laboratory results showed thrombocytopenia and lymphopenia, and chest X-ray revealed an infiltrate in the right segment of the lung, suggesting pneumonia. These conditions were thought to be caused by temozolomide. Although temozolomide is generally well tolerated by glioma patients, several adverse effects have been reported. In addition, malignancy, corticosteroids, and chemotherapy are known to increase the risk of immunosuppression. Close monitoring of patients treated with temozolomide is warranted, especially brain tumor patients, due to the risk of myelosuppression and severe infection. The work was approved by the Health Research Ethics Committee of DR Mohammad Hoesin Hospital (No. 130/kepkrsmh/2020) on December 15, 2020.
Keywords: Acute toxicity, case report, malignant glioma, temozolomide
|How to cite this article:|
Diansari Y, Djamaluddin N, Hulwah A. Acute toxicity of temozolomide for the treatment of anaplastic astrocytoma: A case report. Glioma 2021;4:15-8
|How to cite this URL:|
Diansari Y, Djamaluddin N, Hulwah A. Acute toxicity of temozolomide for the treatment of anaplastic astrocytoma: A case report. Glioma [serial online] 2021 [cited 2023 Feb 5];4:15-8. Available from: http://www.jglioma.com/text.asp?2021/4/1/15/312463
| Introduction|| |
Malignant gliomas are the most common type of primary central nervous system tumors, with an incidence of 5–8/100,000 per head of population. Multimodal treatment is the standard of care including maximal safe resection followed by partial brain irradiation combined with temozolomide. Although temozolomide has been proven to be generally well tolerated by glioma patients, several toxicities have been reported, including hematologic toxicity, myelosuppression, and severe infection.,,,,,, The timing of the toxicities vary, but adverse effects developing over a short period are rare. This case report describes a 37-year-old male diagnosed with anaplastic astrocytoma who developed acute toxicity after the first cycle of temozolomide.
| Case Report|| |
A 37-year-old male was transferred to our hospital with a 3-month history of progressively worsening headache and blurry vision in both eyes. Neurologic examination was remarkable for decreased visual acuity of 1/300 in both eyes, bilateral papilledema, and weakness in his left extremities. There was no history of fever, head trauma, or previous malignancy. The patient had been diagnosed at a previous hospital with a suspected cerebral abscess based on computed tomography [Figure 1]. Laboratory workup and chest X-ray showed no abnormalities. We also excluded human immunodeficiency virus infection. The patient was treated with broad-spectrum antibiotics (ceftriaxone and metronidazole) and a craniotomy was performed to drain the abscess 3 days later. However, a cystic mass suggesting a tumor was detected during surgery. The histopathology results were consistent with anaplastic astrocytoma, which was supported by positive immunostaining of tumor tissue for glial fibrillary acidic protein and vimentin. Head magnetic resonance imaging 3 days postcraniotomy showed a residual mass [Figure 2].
|Figure 1: Preoperative head computed tomography scan showing hypodense lesion with clear edge measuring 4.9 cm × 2.7 cm × 3.8 cm in the right parietooccipital region, with perifocal edema with ring enhancement (red arrow) after contrast administration|
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|Figure 2: Axial T1-weighted head magnetic resonance imaging postcraniotomy and tumor removal showing residual mass (white arrow) with hemorrhagic component (red arrow) in right parietooccipital region|
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Cranial radiation at a dose of 60 Gy in 30 fractions was initiated 6 weeks later, without concurrent temozolomide. The patient continued to receive various doses of dexamethasone during the radiotherapy and follow-up periods, with no antibiotic prophylaxis. About 1 month after finishing cranial radiation, the patient started chemotherapy with six cycles of oral temozolomide, 150 mg/m2 for 5 days every 4 weeks. Before temozolomide administration, the patient was afebrile and hemodynamically stable. Chest X-ray [Figure 3]A and abdominal ultrasound showed no abnormalities. Laboratory tests, including blood cell count, liver function, kidney function, and coagulation parameters, were all within normal ranges, except for a slight decrease in lymphocyte count [Table 1]. The patient tolerated chemotherapy well and continued to take low-dose dexamethasone.
|Table 1: Blood counts before and after first cycle of temozolomide administration|
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Three days after finishing the first cycle of temozolomide, the patient presented to the emergency department of our hospital with deteriorating consciousness accompanied by fever and shortness of breath. He was somnolent, with blood pressure 70/palpation, pulse 90 beats/min, respiratory rate 30 times/min, and body temperature 38°C. Auscultation of the lungs revealed inspiratory crackles in both lung bases without wheezing. His heart rate was regular, without evidence of gallop or murmur. His extremities showed no evidence of cyanosis or clubbing, except for petechiae on the skin surface. A complete blood count workup revealed dramatic changes in his hematologic profile compared with the previous examination [Table 1]. Chest X-ray showed an infiltration in the right lung segment suggesting pneumonia [Figure 3]B. The patient received oxygen inhalation and norepinephrine as vasopressor. We also initiated broad-spectrum antibiotics (ceftriaxone 2 g/day and azitromycine 500 mg/day) while waiting for blood culture and sputum analysis results. Thrombopheresis was performed for thrombocytopenia. The patient's oxygenation and vital signs continued to deteriorate, and he died of respiratory failure 15 h after treatment.
|Figure 3: Chest X-ray films. Chest X-rays (A) prior to temozolomide initiation showing no abnormality, and (B) 3 days after first cycle of temozolomide showing infiltrating lesion in (red arrow) right lung|
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The patient signed the informed consent before treatment, and the study was approved by the Health Research Ethics Committee of DR Mohammad Hoesin Hospital (No. 130/kepkrsmh/2020) on December 15, 2020.
| Discussion|| |
Temozolomide has improved survival among patients with malignant glioma. Although temozolomide is associated with several toxicities, most are Grade 1 or 2 and are tolerable. Gastrointestinal side effects, such as nausea and vomiting, are particularly common, but other toxicities have also been reported.,,,,,,
Bae et al. found that hematologic toxicities including thrombocytopenia (13.7%) and anemia (11%) were common, while nonhematologic toxicities, including nausea (44.3%), vomiting (37%), and anorexia (14.3%), were the three most common toxicities. No patients developed fatal Pneumocystis jiroveci pneumonitis (PJP), and there was no mortality due to temozolomide. Kesari et al. reported leukopenia (47.7%) and neutropenia (34.1%) as the most common toxicities, while Panet-Raymond et al. found that fatigue (48%) and anemia (38.0%) were the most common side effects of temozolomide.
PJP pneumonia is a rare temozolomide toxicity. The first case of temozolomide-associated pneumonia was reported by Maldonado et al. in an 88-year-old male patient with glioblastoma multiforme after two cycles of adjuvant temozolomide. This patient completed tumor resection followed by radiochemotherapy with concurrent temozolomide 75 mg/m2 for 6 weeks. Neuwelt et al. found an incidence of PJP of only 0.4% during temozolomide cycles without PJP prophylaxis.
The current patient showed tumor progression after radiotherapy, with deterioration of neurologic function and enlarged tumor mass. Temozolomide was initiated as standard therapy for malignant glioma after tumor resection and complete radiotherapy. Unfortunately, the patient's condition deteriorated 3 days after completing the first cycle of temozolomide, with severe infection caused by pneumonia, and blood counts showing thrombocytopenia and lymphopenia, all thought to be caused by temozolomide.
As noted above, most adverse effects of temozolomide are mild, and life-threatening hematologic toxicity, myelosuppression, and severe infection are rare. The current patient developed hematologic toxicity, despite having a normal hematologic profile before temozolomide administration. He also developed severe infection due to pneumonia, although the etiology of the pneumonia (PJP or other bacteria) was unclear because bronchoscopy was not performed due to severe respiratory failure.
PJP infection is a common cause of pneumonia in patients with immunosuppression caused by underlying malignancy. Temozolomide increases the risk of PJP and is notably the only drug that warns of a risk of PJP on the package insert. One pathogenic mechanism of temozolomide-induced PJP involves lymphopenia, especially decreased numbers of CD4 T-cells., A definitive diagnosis of PJP is based on the detection of organisms in respiratory samples such as sputum, bronchoalveolar lavage fluid, or lung tissue; however, it is difficult to obtain respiratory samples in patients with severe respiratory failure.,,
Most patients with malignant gliomas receive corticosteroids, radiation, and chemotherapy, each of which is toxic to lymphocytes, and their combined use can thus result in substantial immunosuppression and opportunistic infections. The current patient was thought to be immunocompromised due to treatment with corticosteroids and temozolomide. He also had marked lymphopenia, which is associated with an increased risk of opportunistic infections, including PJP, and he did not receive PJP prophylaxis during temozolomide treatment.
The current report highlighted the rare occurrence of temozolomide toxicity after a very short period of administration, compared with other reports. Comez et al. reported a case of profound pancytopenia caused by aplastic anemia after the third cycle of temozolomide in a patient receiving concomitant anticonvulsants and previously treated with concurrent radiotherapy and temozolomide. Lam et al. also reported aplastic anemia in a 21-year-old female patient with anaplastic astrocytoma with MGMT promoter methylation, who was treated with concurrent chemoradiotherapy and diagnosed with aplastic anemia about 3 months after the first dose of temozolomide (75 mg/m2/day concurrent with radiation). Gorospe Sarasúa et al. reported on a 69-year-old patient who developed fever with progressive respiratory failure caused by PJP after 4 weeks of temozolomide therapy. Hayashi et al. reported three cases of fatal pneumonia suspected to be caused by PJP based on serological diagnosis (marked elevation of serum KL-6 and β-D-glucan levels). All three patients were treated with temozolomide after surgery for malignant glioma, and the pneumonia developed 40 days to 3.5 months after temozolomide therapy.
In conclusion, it is important to be aware of the potentially life-threatening toxicity of chemotherapeutic agents including temozolomide. The inclusion of corticosteroids in the chemotherapy regimen has been consistently reported to result in immunosuppression, thus increasing the risks of hematologic toxicity and fatal pneumonia. Patients should thus be monitored carefully throughout treatment.
Financial support and sponsorship
Institutional review board statement
The study was approved by the Health Research Ethics Committee of DR Mohammad Hoesin Hospital (No. 130/kepkrsmh/2020) on December 15, 2020.
Declaration of patient consent
The authors certify that they have obtained the appropriate patient consent form. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Avgeropoulos NG, Batchelor TT. New treatment strategies for malignant gliomas. Oncol 1999;4:209-24.
Bae SH, Park MJ, Lee MM, Kim TM, Lee SH, Cho SY, et al
. Toxicity profile of temozolomide in the treatment of 300 malignant glioma patients in Korea. J Korean Med Sci 2014;29:980-4.
Niewald M, Berdel C, Fleckenstein J, Licht N, Ketter R, Rübe C. Toxicity after radiochemotherapy for glioblastoma using temozolomide – A retrospective evaluation. Radiat Oncol 2011;6:141.
Maldonado F, Limper AH, Lim KG, Aubrey MC. Temozolomide-associated organizing pneumonitis. Mayo Clin Proc 2007;82:771-3.
Neuwelt AJ, Nguyen TM, Fu R, Bubalo J, Tyson RM, Lacy C, et al
. Incidence of Pneumocystis jirovecii
pneumonia after temozolomide for CNS malignancies without prophylaxis. CNS Oncol 2014;3:267-73.
Hanna KS, Mancini R, Burtelow M, Bridges B. Aplastic anemia in a patient with anaplastic oligodendroglioma postradiation: Case report and review of the literature. J Hematol Oncol Pharm 2018;8:34-9.
Yin JQ, Patel P, Thompson T. A case of temozolomide chemoradiotherapy induced Pneumocystis jirovecii
pneumonia in a non-HIV patient. Am J Respir Crit Care Med 2018;197:A5412.
Skorupan N, Ranjan S, Mehta S, Yankulina O, Nenortas N, Grossman S, et al
. Pneumocystis jirovecii
prophylaxis in patients treated for high-grade gliomas: A survey among neuro-oncologists. Neurooncol Pract 2019;6:321-6.
Ding Z, Ding M, Ning X, Pang J, Zhao C. Clinical safety study of temozolomide combined with radiotherapy after glioma resection. Biomed Res 2017;28:5987-91.
Yu A, Faiq N, Green S, Lai A, Green R, Hu J, et al
. Report of safety of pulse dosing of lapatinib with temozolomide and radiation therapy for newly-diagnosed glioblastoma in a pilot phase II study. J Neurooncol 2017;134:357-62.
Cosentini D, Badalamenti G, Grisanti S, Basile V, Rapa I, Cerri S, et al
. Activity and safety of temozolomide in advanced adrenocortical carcinoma patients. Eur J Endocrinol 2019;181:681-9.
Lam N, Cusano F, Bullock JE. Cancer case temozolomide for anaplastic astrocytoma: A case report of aplastic anemia, sustained treatment response and spontaneous marrow recovery case presentation. Am J Cancer Case Reports 2013;1:79-85.
Tafuto S, von Arx C, Capozzi M, Tatangelo F, Mura M, Modica R, et al
. Safety and activity of metronomic temozolomide in second-line treatment of advanced neuroendocrine neoplasms. J Clin Med 2019;8:1224.
McDuff SG, Dietrich J, Atkins KM, Oh KS, Loeffler JS, Shih HA. Radiation and chemotherapy for high-risk lower grade gliomas: Choosing between temozolomide and PCV. Cancer Med 2020;9:3-11.
Kesari S, Schiff D, Henson JW, Muzikansky A, Gigas DC, Doherty L, et al
. Phase II study of temozolomide, thalidomide, and celecoxib for newly diagnosed glioblastoma in adults. Neuro Oncol 2008;10:300-8.
Panet-Raymond V, Souhami L, Roberge D, Kavan P, Shakibnia L, Muanza T, et al
. Accelerated hypofractionated intensity-modulated radiotherapy with concurrent and adjuvant temozolomide for patients with glioblastoma multiforme: A safety and efficacy analysis. Int J Radiat Oncol Biol Phys 2009;73:473-8.
Grossman SA, Ye X, Lesser G, Sloan A, Carraway H, Desideri S, et al
. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res 2011;17:5473-80.
Takeuchi K, Yakushijin Y. Pneumocystis jirovecii
pneumonia prophylaxis for cancer patients during chemotherapy. Pathogens 2021;10:237.
Hayashi H, Saito Y, Kokuho N, Morimoto T, Kobayashi K, Tanaka T, et al
. Fatal pneumonia associated with temozolomide therapy in patients with malignant glioma. Jpn J Clin Oncol 2012;42:632-6.
Khan BA, Khan S, White B, Eranki A. Severe Pneumocystis jiroveci
pneumonia in a patient on temozolomide therapy: A case report and review of literature. Respir Med Case Rep 2017;22:179-82.
Comez G, Sevinc A, Sever ON, Babacan T, Sarı I, Camci C. An unusual case of aplastic anemia caused by temozolomide. Case Rep Med 2010;2010:975039.
Gorospe Sarasúa L, Ureña-Vacas A, Muñoz Del Toro JR. Pneumocystis jirovecii
pneumonia complicating the progress of a patient with glioblastoma multiforme receiving temozolomide. Arch Bronconeumol 2016;52:534-5.
[Figure 1], [Figure 2], [Figure 3]