Somatostatin analogs in meningioma

Somatostatin analogs in meningioma

Meningiomas are associated with several sex hormones-related risk factors and demonstrate a predominance in females. These associations led to investigations of the role that hormones may have on meningioma growth and development. While it is now accepted that most meningiomas express progesterone and somatostatin receptors, the conclusion for other receptors has been less definitive.

Miyagishima et al. performed a review of what is known regarding the relationship between hormones and meningiomas in the published literature. Furthermore, they reviewed clinical trials related to hormonal agents in meningiomas using MEDLINE PubMedScopus, and the NIH clinical trials database.

They identified that all steroid-hormone trials lacked receptor identification or positive receptor status in the majority of patients. In contrast, four out of five studies involving somatostatin analogs used positive receptor status as part of the inclusion criteria.

Several clinical trials have recently been completed or are now underway using somatostatin analogs in combination with other therapies that appear promising, but a reevaluation of hormone-based monotherapy is warranted. Synthesizing this evidence, they clarified the remaining questions and present future directions for the study of the biological role and therapeutic potential of hormones in meningioma and discuss how the stratification of patients using features such as grade, receptor status, and somatic mutations, might be used for future trials to select patients most likely to benefit from specific therapies 1)


Jensen et al. performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. They applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. They included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked “very low.” Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistency in study designs is warranted to assess somatostatin analog therapy for well-defined meningioma subgroups 2).

Between January 1996 and December 2010, 13 patients harboring a progressive residual meningioma (as indicated by MR imaging criteria) following operative therapy were treated with a monthly injection of the SST analog octreotide (Sandostatin LAR [long-acting repeatable] 30 mg, Novartis). Eight of 13 patients had a meningioma of the skull base and were analyzed in the present study. Postoperative tumor enlargement was documented in all patients on MR images obtained before the initiation of SST therapy. All tumors were benign. No patient received radiation or chemotherapy before treatment with SST. The growth of residual tumor was monitored by MR imaging every 12 months.

Results: Three of the 8 patients had undergone surgical treatment once; 3, 2 times; and 2, 3 times. The mean time after the last meningioma operation (before starting SST treatment) and tumor enlargement as indicated by MR imaging criteria was 24 months. A total of 643 monthly cycles of Sandostatin LAR were administered. Five of the 8 patients were on SST continuously and stabilized disease was documented on MR images obtained in these patients during treatment (median 115 months, range 48-180 months). Three of the 8 patients interrupted treatment: after 60 months in 1 case because of tumor progression, after 36 months in 1 case because of side effects, and after 36 months in 1 case because the health insurance company denied cost absorption.

Conclusions: Although no case of tumor regression was detected on MR imaging, the study results indicated that SST analogs can arrest the progression of unresectable or recurrent benign meningiomas of the skull base in some patients. It remains to be determined whether a controlled prospective clinical trial would be useful 3).


1)

Miyagishima DF, Moliterno J, Claus E, Günel M. Hormone therapies in meningioma-where are we? J Neurooncol. 2022 Nov 23. doi: 10.1007/s11060-022-04187-1. Epub ahead of print. PMID: 36418843.
2)

Jensen LR, Maier AD, Lomstein A, Graillon T, Hrachova M, Bota D, Ruiz-Patiño A, Arrieta O, Cardona AF, Rudà R, Furtner J, Roeckle U, Clement P, Preusser M, Scheie D, Broholm H, Kristensen BW, Skjøth-Rasmussen J, Ziebell M, Munch TN, Fugleholm K, Walter MA, Mathiesen T, Mirian C. Somatostatin analogues in treatment-refractory meningioma: a systematic review with meta-analysis of individual patient data. Neurosurg Rev. 2022 Oct;45(5):3067-3081. doi: 10.1007/s10143-022-01849-6. Epub 2022 Aug 19. PMID: 35984552.
3)

Schulz C, Mathieu R, Kunz U, Mauer UM. Treatment of unresectable skull base meningiomas with somatostatin analogs. Neurosurg Focus. 2011 May;30(5):E11. doi: 10.3171/2011.1.FOCUS111. PMID: 21529167.

Glioblastoma recurrence treatment

Glioblastoma recurrence treatment

There is no consensus as to the standard of care as no therapeutic options have produced substantial survival benefit for Glioblastoma recurrences (Glioblastomas) 1) 2).

A purely radiological diagnosis of recurrence or progression can be hampered by flaws induced by pseudoprogressionpseudoresponse, or radionecrosis

There is sufficient uncertainty and equipoise regarding the question of reoperation for patients with Glioblastoma recurrence to support the need for a randomized controlled trial 3).


Based on parameters like localization and tumor volume, patient’s Karnofsky Performance Score, time from initial diagnosis, and availability of alternative salvage therapies, reoperation can be considered as a treatment option to extend the overall survival and quality of life of the patient.

The achieved extent of resection of the relapsed tumor—especially with the intention of having a safe, complete resection of the enhancing tumor—most likely plays a crucial role in the ultimate outcome and prognosis of the patient, regardless of other modes of treatment. Validated scores to predict the prognosis after reoperation of a patient with a Glioblastoma recurrence can help to select suitable candidates for surgery. Safety issues and complication avoidance are pivotal to maximally preserving the patient’s quality of life. Besides a possible direct oncological effect, resampling of the recurrent tumor with detailed pathological and molecular analysis might have an impact on the development, testing, and validation of new salvage therapies 4).

Options include repeat surgical resection, repeat fractionated radiation, radiosurgery.

Bevacizumab (BEV) plus daily temozolomide (TMZ) as a salvage therapy has been recommended for recurrent glioma.


In a study, Hundsberger et al investigated which treatments are currently being used for recurrent Glioblastoma within a single nation (Switzerland) and how clinicians are deciding to use them 5)

The authors surveyed Swiss hospitals with comprehensive multidisciplinary neuro-oncology practices (neurosurgery, radiation therapy, medical neuro-oncology, and a dedicated neuro-oncology tumor board) about treatment recommendations for recurrent Glioblastoma. They identified relevant clinical decision-making criteria, called diagnostic nodes or “dodes,” and compared treatment recommendations using a decision-tree format.

Eight hospitals participated. The most common treatment options for recurrent Glioblastoma were combination repeat surgical resection with temozolomide or bevacizumab, monotherapy temozolomide or bevacizumab, and best supportive care. Alternative therapies, including radiotherapy, were less common. Despite widespread disagreement between centers in clinical decision-making, the decision-tree analysis found agreement (>63%) between most centers for only 4 specific clinical scenarios. Patients without an appropriate performance status were usually managed with the best supportive care. Patients with rapid recurrence, nonresectable tumors, unmethylated O(6)-methylguanine DNA methyltransferase (MGMT) promoter, and high-performance status were usually managed with bevacizumab. Patients with late recurrence, nonresectable tumors, overt clinical symptoms, methylated MGMT promoter, multifocal disease, and high-performance status were usually managed with repeat temozolomide therapy. Patients with late recurrence, nonresectable tumors, no clinical symptoms, methylated MGMT promoter, tumor multifocality, and high-performance status were usually managed with temozolomide. The findings of this study underscore the lack of effective first- and second-line treatments for Glioblastoma, and the interhospital variability in practice patterns is not surprising. It seems likely that similar heterogeneity would also be noted in a study of American neuro-oncology centers. It is interesting to note that despite the availability of an increasing number of molecular markers for Glioblastoma stratification, MGMT promoter methylation appears to be the only biological marker widely used across multiple centers in this study. It remains to be seen when and how broadly other markers such as the epidermal growth factor receptor variant III or isocitrate dehydrogenase mutations will be adopted for clinical decision-making. The authors are to be congratulated for identifying core clinical decision-making criteria that may be useful in future studies of recurrent Glioblastoma. This decision tree is an excellent reference for clinical trial development, and several active clinical trials already target the dudes identified in this study. Subsequent studies may help to determine whether similar decision trees exist in American neuro-oncologic centers now or will exist in the future 6).

Figure. A through F, clinical decision-making tree for Glioblastoma recurrence multiforme (Glioblastoma) based on clinical scenarios that achieved a majority recommendation (ie, at least 5 of 8 Swiss hospitals). BEV, bevacizumab; BSC, best supportive care; rGlioblastoma, Glioblastoma recurrence multiforme; TMZ, temozolomide. Modified with kind permission from Springer Science+Business Media: Journal of Neuro-Oncology, Patterns of care in Glioblastoma recurrence in Switzerland: a multicenter national approach based on diagnostic nodes (published online ahead of print October 12. 2015), Hundsberger T, Hottinger AF, Roelcke U, et al [doi: 10.1007/s11060-015-1957-0. Available at: http://link.springer.com/article/10.1007%2Fs11060-015-1957-0 ].

see Glioblastoma recurrence resection.

Temozolomide rechallenge is a treatment option for MGMT promoter-methylated Glioblastoma recurrence. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation 7).

see Bevacizumab for Glioblastoma recurrence.

Intrarterial chemotherapy is a viable methodology in recurrent Glioblastoma patients to prolong survival at the risk of procedure-related complications and in newly diagnosed patients with the benefit of decreased complications 8).

Low-dose fractionated radiotherapy LD-FRT and chemotherapy for recurrent/progressive Glioblastoma have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted 9).

Second surgery plus carmustine wafers followed by intravenous fotemustine in twenty-four patients were analyzed. The median age was 53.6; all patients had KPS between 90 and 100; 19 patients (79%) performed a gross total resection > 98% and 5 (21%) a gross total resection > 90%. The median progression-free survival from second surgery was 6 months (95% CI 3.9-8.05) and the median OS was 14 months (95% CI 11.1-16.8 months). Toxicity was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia.

This multimodal strategy may be feasible in patients with Glioblastoma recurrence, in particular, for patients in good clinical conditions 10).

The HSPPC-96 vaccine is safe and warrants further study of efficacy for the treatment of recurrent Glioblastoma. Significant pretreatment lymphopenia may impact the outcomes of immunotherapy and deserves additional investigation 11).

see Laser interstitial thermotherapy.

Galldiks et al monitored the metabolic effects of stereotaxy-guided LITT in a patient with a recurrent Glioblastoma using amino acid positron emission tomography (PET). Serial 11C-methyl-L-methionine positron emission tomography (MET-PET) and contrast-enhanced computed tomography (CT) were performed using a hybrid PET/CT system in a patient with recurrent Glioblastoma before and after LITT. To monitor the biologic activity of the effects of stereotaxy-guided LITT, a threshold-based volume of interest analysis of the metabolically active tumor volume (MET uptake index of ≥ 1.3) was performed. A continuous decline in metabolically active tumor volume after LITT could be observed. MET-PET seems to be useful for monitoring the short-term therapeutic effects of LITT, especially when patients have been pretreated with a multistep therapeutic regimen. MET-PET seems to be an appropriate tool to monitor and guide experimental LITT regimens and should be studied in a larger patient group to confirm its clinical value 12).

CP-673451 for glioblastoma recurrence.

Adjuvant lomustine to other chemotherapy may provide no obvious benefits for the glioblastoma recurrence treatment 13).

A more favorable prognosis following surgery for recurrence or progression is associated with younger age, smaller tumor volume (~50%), motor speech-middle cerebral artery scoring and preoperative Karnofsky performance score (KPS) >80% 14) 15).

Optimal treatment for recurrent High-grade glioma continues to evolve. Currently, however, there is no consensus in the literature on the role of reoperation in the management of these patients.

An analysis, of reoperation in patients with World Health Organization grade III or IV recurrent gliomas, focusing on how reoperation affects outcome, perioperative complications, and quality of life. An extensive literature review was performed through the use of the PubMed and Ovid Medline databases for January 1980 through August 2013. A total 31 studies were included in the final analysis. Of the 31 studies with significant data from single or multiple institutions, 29 demonstrated a survival benefit or improved functional status after reoperation for recurrent high-grade glioma. Indications for reoperation included new focal neurological deficits, tumor mass effect, signs of elevated intracranial pressure, headaches, increased seizure frequency, and radiographic evidence of tumor progression. Age was not a contraindication to reoperation. Time interval of at least 6 months between operations and favorable performance status (Karnofsky Performance Status score ≥70) were important predictors of benefit from reoperation. Extent of resection at reoperation improved survival, even in patients with subtotal resection at initial operation. Careful patient selection such as avoiding those individuals with poor performance status and bevacizumab within 4 weeks of surgery is important. Although limited to retrospective analysis and patient selection bias, mounting evidence suggests a survival benefit in patients receiving a reoperation at the time of high-grade glioma recurrence 16).

Twenty patients with recurrent glioma were treated with BEV (5-10 mg/kg, i.v. every 2 weeks) plus daily TMZ (daily, 50 mg/m2). The treatment response was evaluated via the RANO criteria. HRQL were measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (QLQ-C30) and Brain Module (QLQ-BN20).

Twenty patients received a total of 85 cycles of BEV with a median number of 4 cycles (range: 2-10). No patients showed complete response (CR) to treatment. Twelve patients had partial response (PR), stable disease (SD) in 5 patients with, and 3 patients showed progressive disease (PD). In the functioning domains of QLQ-C30, physical functioning, cognitive functioning and emotional functioning significantly improved after the second cycle of BEV compared to baseline, with the mean score of 45.0 vs. 64.0 (p = 0.020), 55.8 vs. 71.7 (p = 0.020) and 48.3 vs. 67.5 (p = 0.015), respectively. In the symptom scales, the scores of pain and nausea/vomiting significantly decreased compared to baseline from the mean score of 39.1 to 20.0 (p = 0.020) and 29.2 to 16.7 (p = 0.049), respectively. Score of global health status also increased from 47.5 to 63.3 (p = 0.001). As determined with the QLQ-BN20, motor dysfunction (43.3 vs. 25.0, p = 0.021), weakness of legs (36.7 vs. 18.3, p = 0.049), headache (38.3 vs. 20.0, p = 0.040), and drowsiness (50.0 vs. 30.0, p = 0.026) after the second cycle of BEV also significantly improved compared to baseline.

BEV plus daily TMZ as a salvage therapy improved HRQL in patients with recurrent glioma 17).

Quick-Weller et al. performed tumour resections in seven patients with rGlioblastoma, combining 5-ALA (20 mg/kg bodyweight) with iMRI (0.15 T). Radiologically complete resections were intended in all seven patients.

They assessed intraoperative fluorescence findings and compared these with intraoperative imaging. All patients had early postoperative MRI (3 T) to verify final iMRI scans and received adjuvant treatment according to interdisciplinary tumour board decision.

Median patient age was 63 years. Median KPS score was 90, and median tumour volume was 8.2 cm(3). In six of seven patients (85%), 5-ALA induced fluorescence of tumour-tissue was detected intraoperatively. All tumours were good to visualise with iMRI and contrast media. One patient received additional resection of residual contrast enhancing tissue on intraoperative imaging, which did not show fluorescence. Radiologically complete resections according to early postoperative MRI were achieved in all patients. Median survival since second surgery was 7.6 months and overall survival since diagnosis was 27.8 months.

5-ALA and iMRI are important surgical tools to maximise tumour resection also in rGlioblastoma. However, not all rGlioblastomas exhibit fluorescence after 5-ALA administration. They propose the combined use of 5-ALA and iMRI in the surgery of rGlioblastoma 18).

In some case series reoperation extends survival by an additional 36 weeks in patients with glioblastoma, and 88 weeks in anaplastic astrocytoma 19) 20) (duration of high-quality survival was 10 weeks and 83 weeks, respectively, and was lower with pre-op Karnofsky score < 70). In addition to Karnofsky performance score, significant prognosticators for response to repeat surgery include: age and time from the first operation to reoperation (shorter times → worse prognosis) 21). Morbidity is higher with reoperation (5–18%); the infection rate is ≈ 3x that for first operation, wound dehiscence is more likely


1)

Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of Glioblastoma recurrence–are we there yet? Neuro Oncol. 2013 Jan;15(1):4-27. doi: 10.1093/neuonc/nos273. Epub 2012 Nov 7. Review. PubMed PMID: 23136223; PubMed Central PMCID: PMC3534423.
2)

Lukas RV, Mrugala MM (2017) Pivotal trials for infiltrating gliomas and how they affect clinical practice. Neuro Oncol Pract 4:209–219
3)

Patel M, Au K, Davis FG, Easaw JC, Mehta V, Broad R, Chow MMC, Hockley A, Kaderali Z, Magro E, Nataraj A, Scholtes F, Chagnon M, Gevry G, Raymond J, Darsaut TE. Clinical Uncertainty and Equipoise in the Management of Glioblastoma recurrence. Am J Clin Oncol. 2021 Mar 29. doi: 10.1097/COC.0000000000000812. Epub ahead of print. PMID: 33782334.
4)

Dejaegher J, De Vleeschouwer S. Recurring Glioblastoma: A Case for Reoperation? In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 14. Available from http://www.ncbi.nlm.nih.gov/books/NBK469991/ PubMed PMID: 29251867.
5)

Hundsberger T, Hottinger AF, Roelcke U, et al.. Patterns of care in Glioblastoma recurrence in Switzerland: a multicentre national approach based on diagnostic nodes [published online ahead of print October 12, 2015]. J Neuro Oncol. doi: 10.1007/s11060-015-1957-0. Available at: http://link.springer.com/article/10.1007%2Fs11060-015-1957-0.
6)

Zussman BM, Engh JA. Patterns of Care and Clinical Decision Making for Glioblastoma recurrence Multiforme. Neurosurgery. 2016 Feb;78(2):N12-4. doi: 10.1227/01.neu.0000479889.72124.20. PubMed PMID: 26779791.
7)

Weller M, Tabatabai G, Kästner B, Felsberg J, Steinbach JP, Wick A, Schnell O, Hau P, Herrlinger U, Sabel MC, Wirsching HG, Ketter R, Bähr O, Platten M, Tonn JC, Schlegel U, Marosi C, Goldbrunner R, Stupp R, Homicsko K, Pichler J, Nikkhah G, Meixensberger J, Vajkoczy P, Kollias S, Hüsing J, Reifenberger G, Wick W; DIRECTOR Study Group. MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial. Clin Cancer Res. 2015 May 1;21(9):2057-64. doi: 10.1158/1078-0432.CCR-14-2737. Epub 2015 Feb 5. PubMed PMID: 25655102.
8)

Theodotou C, Shah AH, Hayes S, Bregy A, Johnson JN, Aziz-Sultan MA, Komotar RJ. The role of intra-arterial chemotherapy as an adjuvant treatment for glioblastoma. Br J Neurosurg. 2014 Jan 16. [Epub ahead of print] PubMed PMID: 24432794.
9)

Balducci M, Diletto B, Chiesa S, D’Agostino GR, Gambacorta MA, Ferro M, Colosimo C, Maira G, Anile C, Valentini V. Low-dose fractionated radiotherapy and concomitant chemotherapy for recurrent or progressive glioblastoma : Final report of a pilot study. Strahlenther Onkol. 2014 Jan 17. [Epub ahead of print] PubMed PMID: 24429479.
10)

Lombardi G, Della Puppa A, Zustovich F, Pambuku A, Farina P, Fiduccia P, Roma A, Zagonel V. The combination of carmustine wafers and fotemustine in recurrent glioblastoma patients: a monoinstitutional experience. Biomed Res Int. 2014;2014:678191. doi: 10.1155/2014/678191. Epub 2014 Apr 9. PubMed PMID: 24812626.
11)

Bloch O, Crane CA, Fuks Y, Kaur R, Aghi MK, Berger MS, Butowski NA, Chang SM, Clarke JL, McDermott MW, Prados MD, Sloan AE, Bruce JN, Parsa AT. Heat-shock protein peptide complex-96 vaccination for Glioblastoma recurrence: a phase II, single-arm trial. Neuro Oncol. 2013 Dec 12. [Epub ahead of print] PubMed PMID: 24335700.
12)

Galldiks N, von Tempelhoff W, Kahraman D, Kracht LW, Vollmar S, Fink GR, Schroeter M, Goldbrunner R, Schmidt M, Maarouf M. 11C-methionine positron emission tomographic imaging of biologic activity of a Glioblastoma recurrence treated with stereotaxy-guided laser-induced interstitial thermotherapy. Mol Imaging. 2012 Jul-Aug;11(4):265-71. PubMed PMID: 22954142.
13)

Fu X, Shi D, Feng Y. The Efficacy and Safety of Adjuvant Lomustine to Chemotherapy for Recurrent Glioblastoma: A Meta-analysis of Randomized Controlled Studies. Clin Neuropharmacol. 2022 Nov-Dec 01;45(6):162-167. doi: 10.1097/WNF.0000000000000525. PMID: 36383914.
14)

Barbagallo GM, Jenkinson MD, Brodbelt AR. ‘Recurrent’ glioblastoma multiforme, when should we reoperate? Br J Neurosurg. 2008 Jun;22(3):452-5. doi: 10.1080/02688690802182256. Review. PubMed PMID: 18568742.
15)

Park JK, Hodges T, Arko L, Shen M, Dello Iacono D, McNabb A, Olsen Bailey N, Kreisl TN, Iwamoto FM, Sul J, Auh S, Park GE, Fine HA, Black PM. Scale to predict survival after surgery for Glioblastoma recurrence multiforme. J Clin Oncol. 2010 Aug 20;28(24):3838-43. doi: 10.1200/JCO.2010.30.0582. Epub 2010 Jul 19. PubMed PMID: 20644085; PubMed Central PMCID: PMC2940401.
16)

Hervey-Jumper SL, Berger MS. Reoperation for recurrent high-grade glioma: a current perspective of the literature. Neurosurgery. 2014 Nov;75(5):491-9; discussion 498-9. doi: 10.1227/NEU.0000000000000486. PubMed PMID: 24991712.
17)

Liu Y, Feng F, Ji P, Liu B, Ge S, Yang C, Lou M, Liu J, Li B, Gao G, Qu Y, Wang L. Improvement of health related quality of life in patients with recurrent glioma treated with bevacizumab plus daily temozolomide as the salvage therapy. Clin Neurol Neurosurg. 2018 Mar 27;169:64-70. doi: 10.1016/j.clineuro.2018.03.026. [Epub ahead of print] PubMed PMID: 29631109.
18)

Quick-Weller J, Lescher S, Forster MT, Konczalla J, Seifert V, Senft C. Combination of 5-ALA and iMRI in re-resection of Glioblastoma recurrence. Br J Neurosurg. 2016 Jun;30(3):313-7. doi: 10.3109/02688697.2015.1119242. Epub 2016 Jan 8. PubMed PMID: 26743016.
19)

Harsh GR, Levin VA, Gutin PH, et al. Reoperation for Glioblastoma recurrence and Anaplastic Astrocytoma. Neurosurgery. 1987; 21:615–621
20)

Ammirati M, Galicich JH, Arbit E, et al. Reoperation in the Treatment of Recurrent Intracranial Malignant Gliomas. Neurosurgery. 1987; 21:607–614
21)

Brem H, Piantadosi S, Burger PC, et al. Placebo- Controlled Trial of Safety and Efficacy of Intraoperative Controlled Delivery by Biodegradable Polymers of Chemotherapy for Recurrent Gliomas. Lancet. 1995; 345:1008–1012

Temozolomide adverse effects

Temozolomide adverse effects

Check with your doctor immediately if any of the following side effects occur:

Amnesia

black, tarry stools

blood in the urine or stools

convulsions

cough or hoarseness

fever or chills

lower back or side pain

muscle weakness or paralysis on one or both sides of the body

painful or difficult urination

pinpoint red spots on the skin

swelling of the feet or lower legs

unusual bleeding or bruising

Abdominal or stomach pain or tenderness

blistering, peeling, or loosening of the skin

chest pain

clay colored stools

cough

decreased appetite

diarrhea

difficulty with swallowing

dizziness

fast heartbeat

headache

hives, itching, or skin rash

joint or muscle pain

nausea or vomiting

puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue

red skin lesions, often with a purple center

red, irritated eyes

sneezing

sore throat

sores, ulcers, or white spots in the mouth or on the lips

tightness in the chest

troubled breathing

unusual tiredness or weakness

yellow skin or eyes

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your healthcare professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Constipation

Anxiety

blurred or double vision

breast pain (in females)

burning or prickling feeling on the skin

confusion

diarrhea

difficulty with speaking

drowsiness

increased urge to urinate

loss of appetite

loss of muscle coordination

mental depression

runny or stuffy nose

trouble sleeping

unusual weight gain

The most common side effect is bone marrow suppression.

The most common non-hematological adverse effects associated with temozolomide are nausea and vomiting, which are either self-limiting or readily controlled with standard antiemetic therapy. These latter effects are usually mild to moderate (grade 1 to 2). The incidence of severe nausea and vomiting is around 4% each. Patients who have pre-existing or a history of severe vomiting may require antiemetic therapy before initiating temozolomide treatment. Temozolomide should be administered in the fasting state, at least one hour before a meal. Antiemetic therapy may be administered before, or following, administration of temozolomide.

Temozolomide is genotoxicteratogenic and fetotoxic and should not be used during pregnancy. Lactating women should discontinue nursing while receiving the drug because of the risk of secretion into breast milk. One study indicated that women that have taken temozolomide without concomitant fertility preservation measures achieve pregnancy at a lesser rate later in life, but the study was too small to show statistical significance in the hypothesis that temozolomide would confer a risk of female infertility 1). In male patients, temozolomide can have genotoxic effects. Men are advised not to father a child during or up to six months after treatment and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to temozolomide therapy.

In male patients, temozolomide can have genotoxic effects. Men are advised not to father a child during or up to six months after treatment and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to temozolomide therapy.

There are minimal reports of temozolomide-induced DRESS syndrome. The diagnosis can be life-threatening, which makes the glioblastoma treatment with no alternative treatment option challenging. The use of de-sensitization therapy to temozolomide has been proposed for the management of severe adverse cutaneous drug reaction2).


Mehta et al reported a Temozolomide-induced drug rash with eosinophilia and systemic symptoms syndrome 3).

Temozolomide Hepatotoxicity.


1)

Sitbon Sitruk L, Sanson M, Prades M, Lefebvre G, Schubert B, Poirot C (November 2010). “Chimiothérapie à gonadotoxicité inconnue et préservation de la fertilité: Exemple du témozolomide” [Unknown gonadotoxicity chemotherapy and preservation of fertility: example of Temozolomide]. Gynécologie, Obstétrique & Fertilité (in French). 38 (11): 660–2. doi:10.1016/j.gyobfe.2010.09.002. PMID 21030284.
2)

Ambur A, Ambur L, Khan L, Nathoo R. Drug-induced hypersensitivity syndrome following temozolimide for glioblastoma multiforme and the role of desensitization therapy. J Oncol Pharm Pract. 2022 Apr;28(3):733-735. doi: 10.1177/10781552211062569. Epub 2021 Nov 26. PMID: 34825610.
3)

Mehta H, Gendle CS, Kumaran MS, Vinay K. Temozolomide-induced drug rash with eosinophilia and systemic symptoms syndrome. Indian J Dermatol Venereol Leprol. 2022 Aug 27:1-4. doi: 10.25259/IJDVL_754_2021. Epub ahead of print. PMID: 36332091.
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