EXTENSION OF TMZ MAINTENANCE THERAPY BEYOND SIX CYCLES: TWO CASES REPORT WITH A GOOD RESPONSE

Glioblastoma is an aggressive cerebral tumor characterized by increased morbidity and/or mortality. In 2005, concomitant chemoradiotherapy with temozolomide (TMZ), followed by adjuvant 6 cycles, became the standard-of-care therapy following tumor resection or biopsy. We present two cases, newly diagnosed with glioblastoma, which received more than 6 maintenance cycles after surgical resection and radiotherapy with TMZ. In both cases, the drug was well tolerated. The optimal duration of maintenance therapy is still not clear. In both cases, the extended administration of TMZ therapy, had a signifi cant activity and excellent tolerability.


INTRODUCTION
Glioblastoma (WHO grad IV) is the most frequent and most aggressive primary malignant tumor in adult central nervous system.
Despite multimodal treatment the prognosis remains grim, with median survival of 12-15 month since diagnosis (1,2). Unfortunately, only 3-5% of patients are surviving 3 years or more (3,4). In many cases, the reasons of discordant results remain unknown.
Standard care for new glioblastoma diagnosed patient, was established by European Organization for Research and Treatment of Cancer (EORTC)/ National Cancer Institute of Canada (NCIC), published in 2005: -Radiotherapy (RT): fractionated focal irradiation, 2 Gy per fraction given once daily 5 days per week over 6 weeks (total dose of 60 Gy). -Concomitant chemotherapy: temozolomide 75 mg/m 2 daily, from the fi rst day of radiotherapy until the last day (no longer than 49 days). -Adjuvant Temozolomide: 6 cycles of 5-day schedule every 28 days; 150 mg/m 2 for the fi rst cycle and was increased to 200 mg/m 2 beginning with the second cycle (2) . Maximal surgery of the tumor improves glioblastoma patients prognosis, and this became possible by introducing intra-operator ultrasonography, neuro-navigation and intra-operator coloration. Temozolomidum (TMZ) is an alkylating agent which links with DNA molecule and is afecting DNA replication/transcription and is leading to apoptosis (5).
TMZ has the ability to cross blood-brain barrier and to be spontaneously transformed in active metabolite inside of central nervous system (6).
One of the mechanisms involved in TMZ resistance of glioblastoma is increased expression of O6-methyl-guanine DNA methyltransferase, -a DNA reparation protein through alkyl group removal from O6 position of guanine -a target situs for alkylating cytotoxic agents.
We present here 2 new glioblastoma diagnosed cases, which received more than 6 cycles of chemotherapy with TMZ after surgery and standard radiochemistry treatment.

Case report 1
The patient was a 69-year-old female with medical history of hypertension who was admitted to the hospital with headache, dizziness, and confusion.
Her clinical examination and neurologic exam was almost normal. Blood laboratory data were within normal range. A brain magnetic resonance imaging (MRI) was performed on February 24 th 2015 and showed a mass measuring 50,1/47,8/43 mm within the right frontal lobe, with signifi cant vasogenic edema, seen as a contrast enhancing heterogeneous mass with solid, cystic, and necrosis areas.
On February 26 th 2015, she underwent a right frontal craniotomy with maximal safe resection of the tumor.
Her postsurgical course unfolded without complications.
Histological examination showed the neoplasia to be a giant cells glioblastoma.
After 4 weeks from surgery, the patient underwent adjuvant radiotherapy using image modulated radiotherapy (IMRT) technique in a conventional fraction schedule, 2 Gy per fraction daily over 6 weeks up to a total dose of 60Gy concurrent chemo- therapy with TMZ (75 mg/m 2 daily. from the fi rst day of radiotherapy until the last day) was administrated Fig. 1,2.
One month following chemotherapy and radiotherapy, the patient was neurologically evaluated, and she performed a cerebral MRI, and there were no signs of disease recurrence. Chemotherapy was continued with Temozolomide 150 mg/sqm days 1-5 (1 st cycle), q4w, followed by 200 mg/sqm days 1-5 (for 2 years) without essential toxicity. Last chemotherapy cycle was in 2017, March. She was followed-up for one year (neurological evaluation, MRI, blood tests every 4 months) without any sign of tumor relapse.
In 2018, March, 7th, MRI evaluation showed a relapse, a new tumor in the same area as the previous one and another lesion in left capsulo-lenticular area with a mass effect and its size was 30/25/16 mm.
The multidisciplinary team decided for reirradiation and reintroduction of chemotherapy. Therefore, the patient underwent 2 cycles of chemotherapy with Temozolomide, but due to very unfavorable evolution, the radiotherapy did not start. On 2018, May 5 th , the patient deceased.

Case report 2
This case discusses a 38-year-old woman presenting with progressive intracranial hypertension syndrome.
Brain MRI revealed a tumor in the right frontal cerebral lobe, measuring 45/37/41 mm, associated with midline deviation with minimal mass effect and perilesional edema.
A radical surgical removal of the tumour was done in 2016, January 29 th .
A CT of the head was done in the immediate post-operative period, and it didn't revealed any trace of residual tumor.
After one month after surgery, there was performed a computer tomography (CT) simulation of the head, and it revealed 2 subcortical tumoral nodes in the proximity of resection cavity , measuring 20 and 12 mm.
Our patient also underwent adjuvant chemoradiotherapy with temozolomide in the Stupp regimen (Fig. 3).

DISCUSSIONS
In a randomised phase III study comparing concurrent chemoradiotherapy with TMZ and adjuvant six cycles TMZ 150-200 mg/m 2 every four weeks, Stupp R et al., showed increased median overall survival (OS) of 14.6 months compared 12.1 months in the RT only arm. The two-year survival rate was 26.5% with radiotherapy plus Temozolomide and 10.4% with radiotherapy alone (1).
The 5 years survival rate was 9.8% in RT with TMZ group, compared to 1.9% in RT alone group, showing a long-term benefi t for the combination treatment (7).
Several changes are being attempted to further improve survival over that conferred standard protocol: extending the adjuvant TMZ doses, use daily metronormic doses or adding new cytotoxic agent.
According to the WHO classifi cation of brain tumors giant cell glioblastoma (GCG) is an uncommon subtype of glioblastoma multiforme accounting for 1-5% of them (8-10).
GCG tended to occur in younger patients the mean age is 51 years, 11 years less than glioblastoma multiforme (GBM) (8).
The combination of factors such as younger age at presentation, extension of the surgical resection and the immune histochemical and genetic differences are suggested to be responsible for longer survival.
Studies have shown that extent of resection has prognostic importance, patients without residual tumor survived longer (16.7 versus 11.8 mo, P < 0.0001) (15).
Extensive and complete surgical resection of GBM though representing the most effective way to increase survival of GBM patients but this goal is still diffi cult to achieve because these tumors are invasive, and are most often located, in neurologically eloquent areas or with extension to these areas (16).
However, neurologic function should not be compromised by surgical efforts at resection, because the Karnofsky performance index remains an important prognostic factor.
The decision to extend the chemotherapy with TMZ for more than 6 cycles, was mainly taken by patiens and their relatives, and also by neurosurgeons and oncologists, as a result of neurological evaluation of toxicity and tumor response to TMZ.
Extended adjuvant therapy was not associated with increased toxicity for the patients we discussed about.
The treatment started with dexamethasone for vasogenic edema and levetiracetam for seizure prophylaxis.
Extended TMZ use more than 6 standard adjuvant cycles is preferred by an increasing number of oncologists.
Seiz and colleagues published a study with 114 patients in a single institution who received the standard of treatment (surgery-total resection, subtotal resection or biopsy, radiotherapy and concomitant Temozolomide) followed by adjuvant TMZ for stable and responsive patients.
Number of adjuvant TMZ cycles ranged from 1-57 (received a median of 6 cycles).
OS in all patients was 15 months (95% CI: 13-18 months). Time to tumor progression (TTP) and OS directly correlate with the amount of chemotherapy cycles (each P < 0.0001) (17).
Barbagallo GMV et al compared data obtained from the group of patients undergoing long-term TMZ treatment (Group A n=19) with data from patients treated with a standard TMZ protocol (Group B n =18).
The patients treated with more than 6 TMZ cycles had OS and PFS that was signifi cantly longer than patients receiving standard treatment (median OS 28 months vs 8 months, respectively; p = 0.0001; median PFS 20 months vs 4 months, respectively; p = 0.0002) (18).