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ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 4  |  Page : 558-561
 

A case series of salvage CCNU in high-grade glioma who have previously received temozolomide from a tertiary care institute in Mumbai


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 Publication21-Apr-2017

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


DOI: 10.4103/0019-509X.204774

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 » Abstract 

INTRODUCTION: In our center, we routinely use CCNU (Lomustine) as salvage treatment in high-grade glioma patients who cannot afford bevacizumab. This exploratory analysis was done to report the efficacy and toxicity associated with this regimen. METHODS: Patients who were treated with salvage CCNU (postexposure to temozolomide) between January 2015 and August 2016 were included for this retrospective analysis. SPSS version 16 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 during salvage CCNU was noted in accordance with CTCAE version 4.02. RESULTS: In the stipulated period, 16 patients were selected for the analysis. The median age of patients was 43 years (range 15–63 years), and 12 (80.0%) patients were males. The Eastern Cooperative Oncology Group performance status was 0–1 in 11 patients (73.3%) and 2–4 in 4 patients (26.7%). The tumor histopathology at diagnosis was glioblastoma in ten patients (66.6%), anaplastic astrocytoma in four (26.7%) patients, and anaplastic oligodendroglioma in one patient (6.7%). Grade 3–4 myelosuppression was seen in five patients (33.3%). The median PFS and OS were 192 days (95% confidence interval [CI]: 156.0–227.5 days) and 282 days (95% CI: 190.9–373.1 days), respectively. CONCLUSION: CCNU is associated with modest treatment outcomes in recurrent/relapsed high-grade gliomas. The high rate of myelosuppression is a concern. Urgent efforts are required to improve upon these results.


Keywords: CCNU, glioblastoma, high-grade glioma, salvage


How to cite this article:
Patil V, Abhinav R, Tonse R, Epari S, Gupta T, Jalali R. A case series of salvage CCNU in high-grade glioma who have previously received temozolomide from a tertiary care institute in Mumbai. Indian J Cancer 2016;53:558-61

How to cite this URL:
Patil V, Abhinav R, Tonse R, Epari S, Gupta T, Jalali R. A case series of salvage CCNU in high-grade glioma who have previously received temozolomide from a tertiary care institute in Mumbai. Indian J Cancer [serial online] 2016 [cited 2020 May 30];53:558-61. Available from: http://www.indianjcancer.com/text.asp?2016/53/4/558/204774



 » Introduction Top


The management of recurrent high-grade gliomas is multidisciplinary in nature.[1] However, commonly, the option of maximum safe resection and irradiation has been exhausted or is not feasible. Salvage chemotherapy is offered in such situations.[1] The salvage chemotherapy preferred and recommended is bevacizumab-based therapy. The US Food and Drug Administration in 2009 has approved the use of single-agent bevacizumab in this specific situation.[1] This approval was based on a series of small studies demonstrating an improved efficacy with bevacizumab and irinotecan.[2],[3] However, in developing countries like ours, the access to bevacizumab is limited. Treatment with lomustine (CCNU) is an option in such patients.

CCNU is an alkylating agent and has been used as salvage therapy in glioblastoma (GBM). The results of recently concluded BELOB study confirm its efficacy.[4] CCNU has also been the control arm in multiple studies on salvage chemotherapy or targeted therapy in recurrent high-grade gliomas.[4],[5],[6],[7] The use of CCNU, however, is associated with a high incidence of myelosuppression. In our center, we routinely use CCNU as salvage treatment in patients who cannot afford bevacizumab. This audit was done to report the efficacy and toxicity associated with this regimen.


 » Methods Top


Selection of patients

Patients who were treated with salvage CCNU 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 were selected from this database subjected to following criteria:

  1. Age >15 years
  2. Histological proof of high-grade glioma (either Grade 3 or Grade 4)


    1. Recipient of temozolomide (TMZ) during the treatment of high-grade glioma


  3. Radiological proof of recurrence post-TMZ
  4. Recipient of salvage CCNU as second line (i.e., postadjuvant TMZ).


Dosing and modifications

The selected patients at the suspicion of recurrence were discussed in a multidisciplinary clinic consisting of radiation oncologist, medical oncologist, neurosurgeon, radiologist, pathologist, and physiotherapist. The option of salvage CCNU with or without local treatment was decided in this clinic. Patients were offered CCNU (11–130 mg/m 2) with adequate antiemetic support as per the American Society of Clinical Oncology antiemetic 2011 guidelines. Patients were not offered any prophylactic antibiotic or primary granulocyte colony-stimulating factor prophylaxis. The dose was rounded off to the closet capsule strength available. The capsule was administered on an empty stomach. The cycle was repeated every 6 weeks. The cycle was repeated only when the absolute neutrophil count (ANC) was above >1.5 × 109/L, and platelet count was above 100 × 109/L. Patients were monitored for toxicity during chemotherapy. The dose modifications were done taking into account the myelosuppression in previous cycle and were as follows:

  1. The dose was reduced by 20%–25% in case of decrease in ANC between 1.5 and 1.0 × 109/L or a decrease in platelet count between 80 and 100 × 109/L
  2. The dose was reduced by 40%–50% in case of decrease in ANC below 1.0 × 109/L or a decrease in platelet count below 80 × 109/L.


Assessment

All patients had undergone contrast-enhanced magnetic resonance imaging with spectroscopy and perfusion before start of therapy. The same investigation was repeated post 3–4 cycles. In case of clinical deterioration or radiological progression, CCNU was discontinued. The radiological progression was defined as an increase in size of solid tumor or infiltrating component of the tumor. The patients' postprogression was treated in accordance with their neurological performance status (PS).

Endpoints

Progression-free survival (PFS) was defined as duration in days from start of CCNU 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 Oct 16, 2016. Overall survival (OS) was defined as duration in days from start of CCNU to the date of death. Patients who did not have these events were censored on Oct 16, 2016. The hematological toxicity was graded in accordance with CTCAE version 4.03. Variables evaluated for hematological toxicity in the current analysis were hemoglobin, ANC, and platelets. The maximum grade of toxicity during salvage CCNU was noted.

Statistical analysis

SPSS version 16 was used for this analysis (Chicago, SPSS Inc). Descriptive statistics were 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. Time-to-event analysis was performed using the Kaplan–Meier method.


 » Results Top


Demographics

In the stipulated period, 16 patients were selected for the analysis. The median age of these patients was 43 years (range 15–63 years), and 12 (80.0%) patients were males. The Eastern Cooperative Oncology Group PS was 0–1 in 11 patients (73.3%) and 2–4 in four patients (26.7%). The tumor histopathology at diagnosis was GBM in ten patients (66.6%), anaplastic astrocytoma in four (26.7%) patients, and anaplastic oligodendroglioma in one patient (6.7%). The patient with oligodendroglioma histology was 1p/19q noncodeleted. The integrated WHO 2016 diagnosis is provided in [Table 1].
Table 1: Baseline characteristics

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Previous treatment details

The previous treatment consisted of maximum safe surgery followed by concurrent radiation with TMZ in all patients. The median number of adjuvant TMZ cycles received was 6 (4–18). The median time-to-failure postlast treatment was 7 months (0–34 months). Seven patients (46.7%) had a time-to-failure postlast treatment of >6 months. At failure, only three patient (20.0%) underwent resection. The histopathology was GBM in all three of them.

Tolerance and toxicity

The dose of CCNU was 110 mg/m 2 in 14 patients (93.3%) and 130 mg/m 2 in 1 patient (6.7%). The median number of cycles of CCNU administered was three cycles (range 1–6 cycles). Dose reductions due to toxicity were seen in four patients (26.7%). The median dose reduction done was 25% (20%–70%). The delay in administration of CCNU was seen in six patients (40.0%). The median days of delay were 14 days (12–30 days). The reasons for delay were toxicity in four patients and noncompliance in two patients. The CCNU had to be stopped due to toxicity in two patients.

Data regarding myelosuppression in each cycle were available for all patients. Any grade myelosuppression was seen in 12 patients (80.0%). Grade 3–4 myelosuppression was seen in five patients (33.3%). [Table 2] provides the details of hematological toxicity seen with CCNU.
Table 2: Adverse event details in accordance with CTCAE version 4.03. The numbers depicted are actual patient numbers and not percentage

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Outcomes

The median follow-up was 173 days. The event for progression occurred in seven patients. All of these five patients had clinical progression. The median PFS was 192 days (95% CI: 156.0–227.5 days). The median OS was 282 days (95% CI: 190.9–373.1 days) [Figure 1].
Figure 1: Panel A depicts progression-free survival and B depicts overall survival

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 » Discussion Top


High-grade gliomas (Grade 3 or Grade 4) are common brain tumors seen in adults. The incidence of brain tumors in India according to GLOBOCAN was 18,831 patients/100,000 population, and the mortality was 15,152/100,000 population in the year 2012.[10] This means that 80.5% of patients diagnosed with this uncommon tumor succumbed to the same. This datum is reflective largely of high-grade gliomas as they contribute to 70%–80% of adult brain tumors.[11] The treatment of high-grade glioma up front has modest success rates, and a majority of patients become candidates for retreatment. Postpublication of seminal studies on the use of TMZ by Stupp et al. in GBM, TMZ has been incorporated in the schema of the treatment for high-grade gliomas.[12],[13],[14],[15] The treatment of patients who have failed such TMZ incorporated treatment is a challenge. The current guidelines suggest the use of repeat TMZ, nitrosoureas, or bevacizumab in recurrent high-grade gliomas who are not amenable for further local treatment.[1] CCNU is one of the recommended options. The result of the current case series confirms its efficacy in our setting. It is heartening to see that the median OS in our study was 9.4 months, which is similar to the OS reported in literature [Table 3].
Table 3: Comparison of outcome of the current study with other studies reporting on single-agent CCNU

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The dose of CCNU used in the current study was 110–130 mg/m 2. However, all except one patient received 110 mg/m 2 dose. The higher dose of CCNU is associated with higher rates of myelosuppression, and it may not provide any benefit in survival. In the study reported by Wick et al., the dose of TMZ was in range of 110–130 mg/m 2, and the median survival was 7.4 months.[6] As opposed to this, in multiple studies, CCNU in a dose of 100–110 mg/m 2 was administered, and these studies had a median survival similar or numerically better than those reported by Batchelor et al.[4],[7],[8] In our series, only a single patient received 130 mg/m 2, and it was this patient in whom CCNU had to be stopped because of Grade 4 thrombocytopenia.

Any grade myelosuppression reported in our series, especially thrombocytopenia is higher than that reported by multiple studies in literature. The reason for this may be multifold. In our country, the CCNU is available in a capsule strength of 40 mg. The capsule with a strength of 10 mg is rarely available. This makes appropriate dosing difficult. The doses available are 120 mg, 160 mg, or 200 mg. This often leads to higher doses per cycle which may have result in excess myelosuppression. Another reason would be the higher cumulative dose of CCNU received in our study. As opposed to patients in literature where median PFS was 1–3 months, limiting the number of CCNU cycles to 1–2; in our study, the median number of cycles was 4.[4],[6],[7],[8] The myelosuppression because of CCNU is a cumulative dose-related delayed phenomenon.[16] Hence, it is not a surprise that a higher percentage of patients had myelosuppression. This is the first report of CCNU in brain tumors from India, and whether an unusually high sensitivity of Indian patients to CCNU is a factor requires further evaluation.

An interesting factor noted in the study was a high median PFS. The median PFS was 192 days (6.4 months), which is higher than that reported in multiple prospective studies where it was 1–3 months. The reason might be that this study included anaplastic astrocytoma while the prospective studies restricted the inclusion criteria to GBM.[4],[6],[7],[8] The results of treatment in GBM are inferior than those of anaplastic astrocytoma. The results of salvage CCNU reported by Chamberlain et al. in anaplastic astrocytoma were a PFS of 4.5 months.[9] Another reason for the perceived higher PFS in our study would be because of the differential frequency of response assessment. The response assessment was planned after 3–4 cycles in our study as opposed to postevery cycle in prospective studies.

The present study has its limitations. It has a small number from a single center. However, the homogenous patient selection and homogenous protocol of treatment potentially overcome these limitations. The data reassure us that CCNU is a viable salvage option in patients with relapsed recurrent high-grade glioma, but further efforts are required for improving upon these results.


 » Conclusion Top


CCNU is associated with modest treatment outcomes in recurrent/relapsed high-grade gliomas. The high rate of myelosuppression is a concern. Further efforts are required to improve upon these results with newer treatment strategies.

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
    
2.
Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007;25:4722-9.  Back to cited text no. 2
    
3.
Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009;27:740-5.  Back to cited text no. 3
    
4.
Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): A randomised controlled phase 2 trial. Lancet Oncol 2014;15:943-53.  Back to cited text no. 4
    
5.
Piribauer M, Fazeny-Dörner B, Rössler K, Ungersböck K, Czech T, Killer M, et al. Feasibility and toxicity of CCNU therapy in elderly patients with glioblastoma multiforme. Anticancer Drugs 2003;14:137-43.  Back to cited text no. 5
    
6.
Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol 2010;28:1168-74.  Back to cited text no. 6
    
7.
Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 2013;31:3212-8.  Back to cited text no. 7
    
8.
Brandes AA, Carpentier AF, Kesari S, Sepulveda-Sanchez JM, Wheeler HR, Chinot O, et al. A Phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma. Neuro Oncol 2016;18:1146-56.  Back to cited text no. 8
    
9.
Chamberlain MC. Salvage therapy with lomustine for temozolomide refractory recurrent anaplastic astrocytoma: A retrospective study. J Neurooncol 2015;122:329-38.  Back to cited text no. 9
    
10.
Globocan 2012 – Home. Available from: http://www.globocan.iarc.fr/Default.aspx. [Last cited on 2015 Aug 19].  Back to cited text no. 10
    
11.
Manoharan N, Julka PK, Rath GK. Descriptive epidemiology of primary brain and CNS tumors in Delhi, 2003-2007. Asian Pac J Cancer Prev 2012;13:637-40.  Back to cited text no. 11
    
12.
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. 12
    
13.
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. 13
    
14.
Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: The Nordic randomised, phase 3 trial. Lancet Oncol 2012;13:916-26.  Back to cited text no. 14
    
15.
Weller M, van den Bent M, Hopkins K, Tonn JC, Stupp R, Falini A, et al. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol 2014;15:e395-403.  Back to cited text no. 15
    
16.
Action MOF. Drug Name: Lomustine. Citeseer. Available from: http://www.citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.737.7997&rep=rep1&type=pdf. [Last accessed on 2016 Oct 28].  Back to cited text no. 16
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]

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1 Lomustine
Reactions Weekly. 2017; 1657(1): 264
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