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ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 368-371
 

Rechallenge temozolomide in glioma: A case series from India


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. V M Patil
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_173_17

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 » Abstract 

INTRODUCTION: Temozolomide (TMZ) is an integral part of upfront treatment of high-grade gliomas. It is administered postsurgery as concurrent therapy with radiation and subsequently as adjuvant chemotherapy for 6–12 cycles. It is unknown whether rechallenge of salvage TMZ in previously treated high-grade glioma has any efficacy. MATERIAL AND METHODS: Patients treated with salvage rechallenged TMZ between January 2015 and August 2016 were included for this retrospective analysis. SPSS version 20 was used for this analysis. Time to event analysis was performed using the Kaplan–Meier method. Progression-free survival (PFS) and overall survival (OS) were estimated. The maximum grade of toxicity was noted in accordance with CTCAE version 4.02. RESULTS: A total of 23 patients were selected for analysis with the median age being 43 years (range: 26–69 years). The tumor histopathology at baseline was astrocytoma Grade 2 in 1 patient, oligodendroglioma Grade 2 in 3 patients, anaplastic astrocytoma in 7 patients, anaplastic oligodendroglioma in 2 patients, and glioblastoma in 10 patients. All of them had previously received TMZ. The median numbers of previous TMZ cycles received were 6 (4–18). The median time to failure postlast treatment was 24 months (5–72 months). The median number of cycles of rechallenged salvage TMZ administered was 6 cycles (range: 1–18). Grade 3–4 myelosuppression was seen in 3 patients (13.4%). The median PFS was 459 days (95% confidence interval: 212.1–705.9). The median OS was 25 months. Six-month OS and 1-year OS were 81.4% and 75.1%, respectively. CONCLUSION: Rechallenge with TMZ in recurrent glioma that had previously responded to TMZ is associated with improvement in PFS and OS and has a sufficiently long disease-free interval.


Keywords: Glioma, palliative,rechallenge, salvage, temozolomide


How to cite this article:
Patil V M, Tonse R, Kothari R, Chandrasekaran A, Pande N, Epari S, Gupta T, Jalali R. Rechallenge temozolomide in glioma: A case series from India. Indian J Cancer 2017;54:368-71

How to cite this URL:
Patil V M, Tonse R, Kothari R, Chandrasekaran A, Pande N, Epari S, Gupta T, Jalali R. Rechallenge temozolomide in glioma: A case series from India. Indian J Cancer [serial online] 2017 [cited 2020 Mar 31];54:368-71. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/368/219553



 » Introduction Top


The treatment of recurrent high-grade gliomas is a challenge.[1] Although resurgery and reirradiation are described in literature to produce satisfactory survivals, the applicability of these modalities is very limited.[2],[3],[4],[5],[6] Systemic salvage chemotherapy steps up in this situation. Single-agent bevacizumab or in combination with cytotoxic drug is the standard treatment offered in this clinical scenario.[7] However, in low- and middle-income countries, access to bevacizumab is restricted due to financial constraints. Multiple options such as lomustine, temozolomide (TMZ), or PCV (procarbazine, lomustine, and vincristine) regimen are used in this situation.[1]

TMZ is an alkylating agent and has been used as salvage therapy in glioblastoma multiforme. This drug has proven efficacy in this situation and has provided better overall survival (OS) rates in comparison to salvage PCV regimen.[8] However, TMZ is currently an integral part of upfront treatment of high-grade gliomas.[9],[10] It is administered postsurgery as concurrent therapy with radiation and subsequently as adjuvant chemotherapy for 6–12 cycles. Whether rechallenged TMZ has similar efficacy when administered as salvage in recurrent high-grade gliomas is unknown. Hence, this study was contemplated to address this deficiency in literature.


 » Materials and Methods Top


Selection of patients

Patients treated with rechallenged salvage TMZ between January 2015 and August 2016 were included for this analysis. The patients were identified from a medical oncology chemotherapy database maintained in the neuro-disease management group outpatient department. The patients selected from this database were subjected to following criteria.

  1. Age more than 15 years
  2. Histological proof of glioma at the initial surgery
  3. Radiological proof of recurrence
  4. Recipient of salvage TMZ as the second line (i.e., postadjuvant TMZ).


Dosing and modifications

When suspected of recurrence, these patients were discussed in a multidisciplinary clinic consisting of a neurosurgeon, radiation oncologist, medical oncologist, radiologist, pathologist, and physiotherapist. The option of salvage TMZ with or without local treatment was decided in this clinic. Patients were offered TMZ (150 mg/m2) with adequate antiemetic support as per the 2011 ASCO antiemetic guidelines in cycle 1. If patients tolerated the first cycle well, then the dose of TMZ was stepped up to 200 mg/m2. Patients were not offered any prophylactic co-trimoxazole or primary granulocyte macrophage colony-stimulating factor prophylaxis. The dose was rounded off to the closet tablet strength available and administered preprandial. The cycle was administered every 4 weeks, only when the absolute neutrophil count was above 1.5 × 109/L and platelet count was above 100 × 109/L. Patients were monitored for toxicity during chemotherapy.

Assessment

All patients underwent contrast-enhanced magnetic resonance imaging with spectroscopy and perfusion before start of therapy which was then repeated after 6 cycles. In case of clinical deterioration or radiological progression, TMZ was discontinued. Radiological progression was defined as an increase in size of solid tumor or infiltrating component of the tumor. The patients postprogression were treated in accordance with their neurological performance status.

Endpoints

Progression-free survival (PFS) was defined as duration in months from start of TMZ to the date of progression or death or change in treatment due to toxicity whichever was earlier. Patients who did not have these events were censored on January 30, 2017. OS was defined as duration in months from start of TMZ to the date of death. Patients who did not have these events were censored on January 30, 2017. The myelosuppressive toxicity was graded in accordance with CTCAE version 4.02. The myelosuppressive toxicity accounted for the current analysis was anemia, neutropenia, thrombocytopenia, and lymphopenia. Lymphopenia was included as it is a known side effect of TMZ.

Statistical analysis

RStudio and SPSS version 16 were used for this analysis. Descriptive statistics was performed. The median with their respective range was provided for continuous variables while proportion with their respective 95% confidence interval (CI) was provided for noncontinuous variables. Kaplan–Meier survival estimates were used for estimation of PFS and OS. As there were less number of patients, multivariate analysis was not performed. The impact of IDH mutation on median PFS and OS was studied.


 » Results Top


Demographics

In the stipulated period, 23 patients satisfying the inclusion criteria were selected for the analysis. The median age of these patients was 43 years (range: 26–69 years) and 18 patients were male. The ECOG PS was 0–1 in 19 patients and 2 in 4 patients. The tumor histopathology at diagnosis was astrocytoma Grade 2 in 1 patient, oligodendroglioma Grade 2 in 3 patients, anaplastic astrocytoma in 7 patients, anaplastic oligodendroglioma in 2 patients, and glioblastoma in 10 patients. The histopathology in accordance with the WHO 2016 classification is shown in [Table 1].
Table 1: Baseline characteristics

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Previous treatment details

Previous surgery was in 23 patients while exposure to radiation was present in 20 patients. All 23 had previously received TMZ. The median number of previous TMZ cycles received was 6 (4–18). The median time to failure postlast treatment was 24 months (5–72 months). At failure, 11 patients underwent surgery. The diagnosis in operated patients was glioblastoma in 6 patients, anaplastic oligodendroglioma in 3 patients, and anaplastic astrocytoma in 2 patients.

Tolerance and toxicity

The median number of cycles of TMZ administered was 6 cycles (range: 1–18). Grade 3–4 myelosuppression was seen in 3 patients (13.4%). [Table 2] shows the details of hematological toxicity seen with TMZ. Dose reductions due to toxicity were seen in none of the patients. The delay in administration of TMZ was seen in 3 patients. The median number of delay was 9 days (7–14 days). The reasons for delay were toxicities in 2 patients and noncompliance in 1 patient. TMZ had to be stopped due to toxicity in 1 patient.
Table 2: Adverse event details in accordance with CTCAE version 4.03

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Outcomes

The median PFS was 15.3 months (95% CI: 7.1–23.5) [Figure 1]. The median OS was 25 months [Figure 2]. Six-month OS and 1-year OS were 81.4% and 75.1%, respectively. The relationship between IDH mutation and outcomes is shown in [Table 3]. IDH status was not a statistically significant factor affecting PFS and OS on log-rank test.
Figure 1: Estimated progression-free survival curve

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Figure 2: Estimated overall survival curve

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Table 3: The differential progression-free survival and overall survival according to isocitrate dehydrogenase and MGMT status

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 » Discussion Top


Rechallenge of the same chemotherapy drug in same dose and schedule is not new in oncology. Rechallenge of paclitaxel–carboplatin in relapsed ovarian cancer,[11] estrogen receptor agonist (tamoxifen), or aromatase inhibitors (anastrozole, letrozole, or exemestane) in relapsed breast cancer are examples of such rechallenge treatments.[12] In general, such rechallenges of chemotherapeutic regimens are done when there has been a relative long progression- or disease-free interval with previous use. Unfortunately, no such data is available for TMZ in treatment of glioma.

Literature related to effectiveness and toxicity of salvage TMZ is available [Table 4].[1],[8] However, a lot of treatment paradigms in treatment of glioma have changed since the publications of these reports. TMZ now is an integral part of upfront treatment of glioblastoma, anaplastic glioma, and high-risk low-grade glioma.[13] Hence, the effectiveness of TMZ, when there is an recurrence and patient previously received it, is largely unknown. Gwak et al. had published results of salvage TMZ in 72 patients out of which 43 had exposure to chemotherapy. The median PFS was 8 months, and the 1-year OS was 81%. The study had included patients with anaplastic astrocytoma or anaplastic oligoastrocytoma. In this study, previous exposure to chemotherapy was not independently affecting the PFS or OS. The median time to recurrence was 9 months.[14] In another study reported by Franceschi et al., only patients with previous exposure and response to TMZ were selected. The median PFS was 3 months, and OS was 6 months. The results are explained by the fact that 9 out of 14 patients had glioblastoma.[15] As opposed to this, in our study, median PFS was around 15 months and 1-year OS was 81.3%. The reason for higher PFS and OS seems to be the selection of patients. More than half of patients were intermediate-grade gliomas, all had previous response to TMZ, the median time to failure was 24 months, and a high proportion had IDH mutated (14 out of 23). The study suggests that with proper case selection patients can be rechallenged with TMZ.
Table 4: Selected studies comparing conventional dose temozolomide rechallenge in glioma patients

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TMZ is an alkylating agent. Cumulative dose toxicities are known with this class of drug. However, in our experience, the rate of Grade 3–4 hematological complications with this drug was low (13.4%). This implies that rechallenge TMZ can safely be administered.

The current study is not without limitations. It is a single-center, retrospective analysis with limited patient numbers. However, on the basis of these results, we would suggest rechallenge of TMZ in recurrent gliomas that have previously responded to the same and have a prolonged disease-free interval of 4 months or more.


 » Conclusion Top


Rechallenge of TMZ is associated with an improvement in PFS and OS in recurrent gliomas that have previously responded to TMZ and have a sufficiently long disease-free interval.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Kirkpatrick JP, Sampson JH. Recurrent malignant gliomas. Semin Radiat Oncol 2014;24:289-98.  Back to cited text no. 1
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2.
Ammirati M, Galicich JH, Arbit E, Liao Y. Reoperation in the treatment of recurrent intracranial malignant gliomas. Neurosurgery 1987;21:607-14.  Back to cited text no. 2
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3.
Hoover JM, Nwojo M, Puffer R, Mandrekar J, Meyer FB, Parney IF. Surgical outcomes in recurrent glioma: Clinical article. J Neurosurg 2013;118:1224-31.  Back to cited text no. 3
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4.
Biswas T, Okunieff P, Schell MC, Smudzin T, Pilcher WH, Bakos RS, et al. Stereotactic radiosurgery for glioblastoma: Retrospective analysis. Radiat Oncol 2009;4:11.  Back to cited text no. 4
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Combs SE, Thilmann C, Edler L, Debus J, Schulz-Ertner D. Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: Long-term results in 172 patients treated in a single institution. J Clin Orthod 2005;23:8863-9.  Back to cited text no. 5
    
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Combs SE, Widmer V, Thilmann C, Hof H, Debus J, Schulz-Ertner D. Stereotactic radiosurgery (SRS): Treatment option for recurrent glioblastoma multiforme (GBM). Cancer 2005;104:2168-73.  Back to cited text no. 6
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Møller S, Grunnet K, Hansen S, Schultz H, Holmberg M, Sorensen M, et al. Aphase II trial with bevacizumab and irinotecan for patients with primary brain tumors and progression after standard therapy. Acta Oncol 2012;51:797-804.  Back to cited text no. 7
    
8.
Brada M, Stenning S, Gabe R, Thompson LC, Levy D, Rampling R, et al. Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol 2010;28:4601-8.  Back to cited text no. 8
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9.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.  Back to cited text no. 9
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Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-66.  Back to cited text no. 10
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11.
Mahner S, Meier W, du Bois A, Brown C, Lorusso D, Dell'Anna T, et al. Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in very platinum-sensitive ovarian cancer patients: Results from a subset analysis of the CALYPSO phase III trial. Eur J Cancer 2015;51:352-8.  Back to cited text no. 11
    
12.
Reinert T, Barrios CH. Optimal management of hormone receptor positive metastatic breast cancer in 2016. Ther Adv Med Oncol 2015;7:304-20.  Back to cited text no. 12
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Nabors LB. Central nervous system: Notable developments in the management of primary and recurrent gliomas. J Natl Compr Canc Netw 2016;14 5 Suppl:681-4.  Back to cited text no. 13
    
14.
Gwak HS, Yee GT, Park CK, Kim JW, Hong YK, Kang SG, et al. Temozolomide salvage chemotherapy for recurrent anaplastic oligodendroglioma and oligo-astrocytoma. J Korean Neurosurg Soc 2013;54:489-95.  Back to cited text no. 14
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15.
Franceschi E, Omuro AM, Lassman AB, Demopoulos A, Nolan C, Abrey LE. Salvage temozolomide for prior temozolomide responders. Cancer 2005;104:2473-6.  Back to cited text no. 15
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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