Hypofractionated and Low Dose Radiotherapy Combined with Temozolomide in Naive Unresectable Glioblastoma: A Pilot Study

Silvia Chiesa, Milena Ferro△, Stefano Luzi, Barbara Diletto, Francesco Beghella Bartoli, Nicola Dinapoli, Gian Carlo Mattiucci, Vincenzo Frascino, Francesco Miccichè, Cesare Colosimo, Carmelo Anile, Alessandro Olivi, Vincenzo Valentini, Mario Balducci

(1.Department of Radiation Oncology, Catholic University of the Sacred Heart, L.go A. Gemelli, 8 00168-Rome, Italy; 2.Department of Radiology, Catholic University of the Sacred Heart, L.go A. Gemelli, 8 00168-Rome, Italy; 3.Department of Neurosurgery, Catholic University of the Sacred Heart, L.go A. Gemelli, 8 00168-Rome,Italy)

?國際交流?

Hypofractionated and Low Dose Radiotherapy Combined with Temozolomide in Naive Unresectable Glioblastoma: A Pilot Study

Silvia Chiesa1, Milena Ferro1△, Stefano Luzi1, Barbara Diletto1, Francesco Beghella Bartoli1, Nicola Dinapoli1, Gian Carlo Mattiucci1, Vincenzo Frascino1, Francesco Miccichè1, Cesare Colosimo2, Carmelo Anile3, Alessandro Olivi3, Vincenzo Valentini1, Mario Balducci1

(1.Department of Radiation Oncology, Catholic University of the Sacred Heart, L.go A. Gemelli, 8 00168-Rome, Italy; 2.Department of Radiology, Catholic University of the Sacred Heart, L.go A. Gemelli, 8 00168-Rome, Italy; 3.Department of Neurosurgery, Catholic University of the Sacred Heart, L.go A. Gemelli, 8 00168-Rome,Italy)

Background/Aim: To assess safety of hypo-fractionated radiotherapy (HyRT) followed by low dose radiation therapy (LD-FRT) plus Temozolomide (TMZ) in naive unresectable Glioblastoma. Methods: Patients (ECOG<2, age>18) undergone to biopsy or with gross residual tumor after surgery were enrolled. HyRT (30Gy in ten fraction) plus TMZ was administered. From the second adjuvant cycle of TMZ, patients received LD-FRT (0.40Gy twice daily over 5 days, every 28 days) for two cycles. The primary endpoints were safety and toxicity. Moreover we analyzed response, overall survival (OS) and progression-free survival (PFS). Results: Twenty patients were enrolled. Median dose of LD-FRT was 12Gy. All toxicities were reversible. Four out of 20 patients had Partial Response (PR) and 6 experienced a stable disease (SD). Median OS and PFS were 14 and 11 months, respectively. Conclusions: HyRT followed by LD-FRT plus TMZ is safe and shows good clinical outcomes. A new study is ongoing.

Low-dose Radiation Therapy; Glioblastoma; Hypofractionation; Palliative Treatment

Introduction

Gliomas account for 30% of all brain tumors and 80% of malignant brain tumors[1]. They are among the deadliest of all human cancer[1]. Despite technical advances in diagnosis and therapeutic modalities, the overall prognosis remains dismal with a median survival of 14.6 months and 2 and 5-year survivals of 27.2and 9.8% respectively[2]. Patients submitted to biopsy and patients with gross residual tumor are included in the worst RPA class with median survival time of 7.5 months[3]. The extent of surgical resection has been noted to be the most important prognostic factor. In light of poor outcomes of these patients many authors have questioned the routine use of standard treatment. Alternative fractionation regimens, such as hypofractionated radiation therapy seemed to be more appropriate for this setting of patients[4]. In fact, it has three advantages over standard treatment: (1) total treatment time is shorter; (2) a reduced number of treatment sessions is cheaper; (3) radiobiological advantage of hypo fractionation.

Fractionation in RT relies on tumors behaving like early-responding tissues with high alpha/beta ratios and normal tissues being late responding tissues with low alpha/beta ratios[5]. This implies that a late responding tissue should be more sensitive to a fewer or a higher dose per fraction. Glioblastoma Multiforme (GBM) is relatively radio-resistant and responds more like neural tissue, which is a late responding tissue[6]. Therefore radiation fraction sizes of 3-7Gy have often been utilized[7].

Several in vitro studies have shown hyper-radio-sensitivity (HRS) of some human malignant glioma cell lines to low radiation doses (<1Gy); this phenomenon is not predicted by the linear quadratic model but it may be correlated with different capacities to repair radiation damage[8-9]. Moreover, ultra-fractionated irradiation at low doses can increase radio-sensitivity of radio-resistant glioma cell lines[10-11]; in rapidly proliferating tissues, ultra-fractionated irradiation might be relevant because cells quickly progress into the cell cycle. In this context Short et al[11]. suggested a 4 h interfraction interval in order to have a cumulative effect on cell survival.

In pre-clinical studies, low dose fractionated radiation therapy (LD-FRT) has been demonstrated to enhance the effectiveness of multiple chemotherapeutic agents in a variety of tumor cell lines[12-13]. These data were confirmed in some clinical studies[13-14]. In our previous study, we assessed toxicity and patient compliance of LD-FRT associated with chemotherapy[14].

In this study, we evaluated the safety and tolerability of a novel palliative schedule in which hypo fractionated and LD-FRT were combined with Temozolomide (TMZ) for adults with newly diagnosed GBM, who underwent only a biopsy or minimal tumor resection.

Material and methods

Eligibility

Patients (>18 yrs, ECOG<2 and who were able to give informed consent) with newly diagnosed histologically confirmed GBM, who had undergone a biopsy or who had gross residual mass after surgery were eligible. A white blood cell count of ≥3.5×109/L, a platelet count of ≥150×109/L, bilirubin and creatinine levels 1.5 times the upper limit of normal; aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≥2.5 times the upper limit of normal were the hematological and chemical criteria.

Although it is better to perform MRI before 72 hours, it was not possible; therefore we defined the extent of residual disease on a post-operative MRI performed 20～30 days after surgery, according to further to the surgeon’s assessment. We defined a "minimal tumor resection" when the residual tumor was more than 50% compared with the initial disease.

Patients who had undergone partial (residual tumor <50%) or complete tumor resection were not eligible. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975 (in its most recently amended version). Informed consent was obtained from all patients included in the study.

Radiotherapy and Concomitant Chemotherapy

Radiotherapy was planned after gadolinium-enhanced MRI. The patients were treated with thermoplastic immobilization masks to ensure adequate immobilization and reproducibility. Image fusion between CT and MRI scans was used for contouring. A radiation oncologist and a neuroradiologist defined, on the T1-weighted image, the clinical target volume (CTV) including tumor or gross residual tumor with a surgical cavity, plus a 30-mm margin. Treatment planning was carried out with Eclipse Treatment Planning Systems (Varian Medical System), and 3 or 4 (coplanar or not) multi-leaf conformed radiation fields were used. Treatment was delivered by LINAC with a nominal energy of 6MeV or more.

The treatment regimen consisted of hypofractionated schedule of 30Gy (3Gy/day from Monday to Friday) with concomitant TMZ (75 mg/m2from the start to the end of the radiotherapy) followed by adjuvant TMZ. This short palliative regimen was selected to reduce overall treatment time. LDFRT (0.4Gy twice daily, over 5 consecutive days, every 28 days) was associated with Temozolomide (200 mg/m2) starting from the second adjuvant cycle (Fig.1).

Dose to organ-at-risk was evaluated according to the constraints described by Emami[15]and QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic)[16].

Figure 1: Treatment planning

The first MRI at the end of RT was performed after the first cycle of adjuvant chemotherapy to exclude progression of the disease, with an MRI after two cycles LD-FRT to evaluate tumor response. If neither progression disease nor unacceptable toxicity were recorded, another 2 treatment cycles were scheduled.

Toxicity

Patients were assessed weekly for tolerance and toxicity during radiation therapy. Baseline examination included a cranial MRI with and without contrast, clinical, neurologic, hematological and chemical examination. The primary endpoints were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. Treatment compliance was evaluated as the percentage of patients who completed at least 2 cycles of concomitant radiochemotherapy with LD-FRT.

Efficacy Outcomes

Clinical response was evaluated through MRI evaluation, every 2 cycles of LD-FRT plus TMZ, according to the RANO Guidelines[17]. When tumor progression occurred, patients were treated with a second line of chemotherapy or supportive care depending on performance status. Overall survival (OS) and Progression-free survival (PFS) were also evaluated.

Statistical Analysis

The primary endpoints of the study were to document the treatment-related toxicity and tolerance of all patients treated with this novel regimen. Secondary endpoints were PFS and OS. Survival analysis was performed by the Kaplan-Meier model, using MedCalc software (www.medcalc.be). OS was calculated from the time of diagnosis until death or last follow-up; PFS was calculated from the time of biopsy or surgery until recurrence or last follow-up.

Patients recruitment was prolonged until we got a sufficient median follow up time (17 months with Kaplan-Meier estimation) in order to estimate the difference in median overall survival time and a sufficient level of accuracy in confidence interval estimation of the 12 months OS regard to the cited literature studies that give lower results in terms of OS.

Results

Patient Demographics

Twenty patients with the diagnosis of GBM entered the study between June 2008 and January 2012 (Table1). Thirteen out of twenty patients (65%) were subjected to a biopsy while seven (35%) had a gross residual tumor on MRI images after surgery. Mainly tumors were localized in a deep part of left frontal lobe. The mean volume of residual disease after surgery was 111 cc (range 15～390).

Table 1: Patient’s demographics

The mean volume of CTV for hypofractionation was 169 (range 23～593) and for LD-FRT was 87 cc (range 9～500). Radiotherapy started a median of 28 days (range 8～38) after surgery, Median time from the end of hypofractionation treatment to the beginning of LD-FRT was 60 days (range 56～68). In patients with gross residual tumor, the MGMT promoter was methylated in 5/7 tumors.

In patients subjected only to a biopsy the insufficient material did not allow the MGMT promoter methylation testing.

Toxicity

All toxicity was reversible and no treatment-related death was recorded. The main adverse effect observed was fatigue; however, no interferences on daily activities were reported.

Only 5 out of 20 patients (25%) showed hematologic toxicity: grade 1～2 of leukopenia and thrombocytopenia were recorded in 4 patients (20%), while leuko-thrombocytopenia grades 3～4 was recorded in 1 patient. In one patient pulmonary thromboembolism was observed (Table 2).

Clinical Response

Four out of twenty patients (20%) had a partial response (PR), 6 (30%) a stable disease (SD) and 10 patients (50%) had disease progression (PD), five of them had been submitted only to biopsy.

Table 2: Toxicities

Treatment of Progression

Ten out of twenty patients with initial PR or SD experienced PD: 1 patient retreated with Temozolomide because PD occurred more than 6 months after the end of TMZ; 4 patients (20%) were treated with Cisplatin and Fotemustine; one underwent new surgery and in 4 patients no treatment was prescribed because of a low-performance status.

Survival

Median follow-up time was 25.5 months (range 6-48). At the time of analysis, 8 patients (40%) were alive with disease. The median PFS was 11 months, with PFS at 1 and 2 years of 32 and 11% respectively. Median OS was 14 months, with OS at 1 and 2 years of 50 and 22% respectively. According to the number of cycles, we observed a median OS and PFS of 5 months and 4 months in patients who underwent <2 cycles while a median OS of 26 months and PFS of 14 months when four cycles were administered (P=0.02) (Table 3; Fig. 2～3).

Table 3: Overall survival and PFS of our study vs EORTC/NCIC TMZ/RT vs ultrafractionation.

Figure 2: Overall Survival in group 1 (<2 cycles) and 2 (>2 cycles).

Discussion

Glioblastoma is one of the most resistant brain tumors.Risk stratification of patients with malignant gliomas using recursive partitioning analysis (RPA) was described by Curran et al[18]. Patients subjected to biopsy and patients with gross residual tumor after surgery are included in the worst RPA class. For these poor-prognosis patients, the optimum treatment after surgery is not well defined-some researchers recommend modest forms of therapy, such as a short course of radiotherapy, rather than 6 weeks of daily irradiation[19]. Hypofractionated RT delivers a biologically similar dose of radiation in a shorter period of time by using larger daily fractions. Different radiation fraction sizes have been evaluated[4,8]. Hypofractionation has typically been used as palliative therapy, especially in elderly patients, with no difference in survival, toxicities and performance status compared with standard RT. Several studies suggested that hypofractionation should be used not only as palliative therapy but also as an effective treatment modality for a broad population[20-21]. Low-dose hypersensitivity(HRS) has been investigated since the 1980s, in both in vitro and in vivo studies. Some authors showed that the linear quadratic model may not correctly describe the survival curve in the low-dose region below 1Gy, in which the cell kill per unit dose is increased[22-23]. The mechanism underlying this phenomenon is still unclear, probably due to the different induction of DNA repair: low-doses, in fact, would not enable the repair processes and, therefore cells would be more radiosensitive[24]. Short et al. examined the survival of the radio-resistant cell line, T98G human glioblastoma cells, to low radiation doses (<1Gy), finding a marked HRS[25].

Furthermore in a successive study Short et al. suggested clinically exploiting the ultra-fractionation in glioblastoma therapy[26], being careful to deliver a fractionated course of very low doses appropriately separated, in order to increase the cell kill. In 2002 Short et al. found a relationship between HRS phenomenon and the phase of the cell cycle, demonstrating that HRS is most expressed in the G2 phase[27]. An alternative to increasing cell killing at a low dose of radiation is to use the chemo-sensitizing effect of LD-FRT. Recently the results of pre-clinical studies demonstrated a synergistic effect between low doses of radiotherapy and chemotherapy; “in vitro” studies showed an apoptosis increase when low doses were used as a chemopotentiator of multiple chemotherapeutic agents as carboplatin, cisplatin, docetaxel, etoposide, gemcitabine and paclitaxel in different tumors cell lines, because low doses induce pro-apoptotic pathways selectively[7-10,28]. Results of clinical trials combining chemotherapy with low-dose radiation have recently shown that this treatment can be both feasible and effective[29].

In our Institution several analyses about low dose radiotherapy are ongoing. We prospectively evaluated concurrent palliative chemotherapy and LDFRT in patients with a various type of epithelial tumors, observing an overall response rate of 45%[30]. To our knowledge, this study is the first in which hypofractionated regimen was combined with LDFRT and concomitant chemotherapy in na?ve patients affected by GBM who underwent only a biopsy or who had a gross residual tumour.

Our data showed a good toxicity profile and high patients’ compliance; in fact leukothrombocytopenia G3～4 was recorded only in 5% of the patients and compliance was 85%. Acute or late neurological toxicity were never recorded. Median PFS and OS were 11 and 14 months respectively. These data increase when four LD-FRT’s cycles are administered.Even if it is hazardous to compare two studies outside a randomized trial, when we compared our results with those obtained in the EORTC/NCIC trial[2]on patients with biopsy only and those obtained in the Beauchesne’s study[31]using ultra-fractionation in inoperable glioblastoma, we found a better outcome (Table 3).

In this context, our data could seem attractive and could support the hypothesis that hypofractionated RT and LD-FRT in combination with TMZ is safe and it may improve outcomes for this setting of patients. This conclusion obviously has much more to be carried out because of the small sample size and study type. We stopped the recruitment at 20 patients because at a median follow-up time higher than 17 months we observed a median overall survival time of 14 months; this follow-up time has a sufficient level of accuracy in confidence interval (C.I. OS at 17 months: 32.7%～84.2%). Another limit of our study is the absence of the MGMT test. As is known, patients with a methylated MGMT promoter have a better PFS and OS than unmethylated. Due to the type of surgery, these dates were only available in few patients. Therefore we cannot exclude that our results may be favored by a major presence of methylated patients.

Conclusions

This data suggest that hypofractionation and LD-FRT in association with TMZ might represent a new well-tolerated palliative schedule, with good clinical outcomes. The number of LDFRT’s cycles seems to increase the survival in this setting of patients. In the light of these results we planned a new study with higher dose level both in hypofractionated and LD-FRT phase.

Conflict of Interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

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2016- 12- 20

△Milena Ferro, MD， Fax: +39- 06- 30155908

四川省腫瘤醫院放療中心

郎錦義

10.3969/j.issn.1674- 0904.2017.01.003

導讀:

膠質瘤是最常見的顱內原發腫瘤，占腦部惡性腫瘤的80%。多形性膠質母細胞瘤的預后很差，中位生存期不超過24月，而對于僅行活檢或大部分殘留的患者平均生存期更短。目前的國際標準治療模式是最大限度的手術切除，聯合術后同步放化療和輔助化療。近年來分子病理學得到快速進展，很多分子預測指標獲得廣泛運用，也為綜合治療策略的制定提供了依據。大分割放療，殘留病灶的局部推量，分子靶向藥物的運用，長療程替莫唑胺化療等治療方式的探討層出不窮，但仍缺乏較好的療效，難以突破瓶頸。多形性膠質母細胞瘤對放療抗拒，其對大分割放療3～7Gy更敏感。而體外細胞實驗已經證實低劑量放療(<1Gy)對某些惡性膠質瘤細胞株具有高放射敏感性。多項臨床前研究也發現，低劑量放療能選擇性誘導凋亡前通路，與化療有協同作用，能增加化療療效。基于此，作者納入20例無法切除的初治多形性腦膠質瘤患者，探索性地運用大分割放療序貫低劑量放療聯合替莫唑胺進行治療，縮短了治療時間，降低了治療費用，同時也取得了較好的生存獲益，為晚期患者提供了一條嶄新的治療思路，值得更加深入的研究和探討。

Running title: LDFRT and Hypofractionation