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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 7  |  Page : 1482-1491

Treatment of high-grade gliomas using escalating doses of hypofractionated simultaneous integrated boost-intensity-modulated radiation therapy in combination with temozolomide: A modified Phase I clinical trial


1 Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
2 Department of Oncology, North China Petroleum Bureau General Hospital, Hebei Medical University, Renqiu, China
3 Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, China

Date of Web Publication19-Dec-2018

Correspondence Address:
Xiaoying Xue
Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_51_18

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 > Abstract 


Background: Recent studies have shown that hypofractionated simultaneous integrated boost-intensity-modulated radiation therapy (SIB-IMRT) provided certain survival benefits over other fractionation methods for high-grade gliomas. However, the best hypofractionation mode and its efficacy have not been confirmed. The purpose of this study was to investigate the maximum tolerated dose (MTD) of hypofractionated SIB-IMRT with stepwise escalating doses combined with temozolomide (TMZ) for treating malignant gliomas.
Methods: The patients received concurrent postoperative radiotherapy and chemotherapy. SIB-IMRT was adopted to increase the dose both in the surgical cavity and residual tumor (planning target volume 1). The dose at each fraction was gradually increased from 2.8 Gy/f (total of 20 times), with an escalating dose interval of 0.4 Gy. The planning target volume 2 involved the 2 cm region around surgical cavity, and residual tumor remained unchanged, with 2.5 Gy each time and a total of 50 Gy/20f. TMZ was administered with a dose of 75 mg/m2/day during radiotherapy. Adjuvant TMZ was given at 150–200 mg/m2/day for 5 days every 28 days. A total of 16 patients were enrolled.
Results: Three patients exhibited dose-limiting toxicity (DLT), two cases reported Grade 3 headache in the 3.6 Gy/f and 4 Gy/f dose groups, and one patient developed persistent seizures attacks in the 4 Gy/f dose group. Therefore, 4 Gy/f was considered the DLT and the lower dose level of 3.6 Gy/f was regarded as the MTD in the study, with tolerable adverse reactions. The median overall survival (OS) and median progression-free survival (PFS) in this study were 19 and 16 months, respectively. The 1- and 2-year OS and PFS were 86.7%, 31.0% and 73.7%, 26.7%, respectively.
Conclusions: It showed that the treatment of high-grade gliomas with hypofractionated SIB-IMRT combined with TMZ had an MTD of 3.6 Gy/f (72 Gy/20f). In addition, the results preliminarily showed improved survival.

Keywords: Hypofractionation, intensity-modulated radiation therapy, malignant glioma, maximum tolerated dose, simultaneous integrated boost, temozolomide


How to cite this article:
Ge X, Xue X, Liu H, Wang Y, Xiao Z, Tian L, Chang X, Lin Q, Yu J. Treatment of high-grade gliomas using escalating doses of hypofractionated simultaneous integrated boost-intensity-modulated radiation therapy in combination with temozolomide: A modified Phase I clinical trial. J Can Res Ther 2018;14:1482-91

How to cite this URL:
Ge X, Xue X, Liu H, Wang Y, Xiao Z, Tian L, Chang X, Lin Q, Yu J. Treatment of high-grade gliomas using escalating doses of hypofractionated simultaneous integrated boost-intensity-modulated radiation therapy in combination with temozolomide: A modified Phase I clinical trial. J Can Res Ther [serial online] 2018 [cited 2019 Aug 20];14:1482-91. Available from: http://www.cancerjournal.net/text.asp?2018/14/7/1482/247722




 > Introduction Top


High-grade gliomas present high malignancy and poor prognosis. Surgery combined with postoperative concurrent radiotherapy and sequential temozolomide (TMZ) chemotherapy has been the standard treatment regimen currently.[1],[2],[3],[4] Although overall survival (OS) could be increased by 2.5 months after the addition of TMZ, the 2-year survival rate and 2-year disease-free progression rate have been only 27.2% and 11.2%, respectively.[5] National Comprehensive Cancer Network recommended 60 Gy/30f as the postoperative radiotherapy dose. Unfortunately, most patients would still surfer recurrence and poor survival after receiving this treatment. Studies [6],[7] have shown that glioma recurrence would be usually observed in target region instead of the boundary or distant region. Therefore, it was suspected that glioma recurrence mainly attributed to insufficient local radiotherapy dosing rather than insufficient therapeutic target volume. Thus, optimization of radiotherapy regimens is of great interest in the current research.

In the radiotherapy, the cure rate of tumors was positively correlated with the biological doses received by the tumors. Increased total dose is the most commonly applied approach in clinical practice for increasing biological effects of radiotherapy in tumors. Whereas, previous studies [8],[9],[10],[11] did not show a significantly increased survival by increased total dose with hyperfractionation and conventional fractionation.

The other method for improving the biological effects of radiotherapy has been the increased single fractionation dose and reduced treatment time. In recent years, there were some studies exploring the hypofractionated radiotherapy for glioma. In the early stages, some scholars applied the traditional radiotherapy technique and increased the dose of single fractionation, they did not show a clear survival benefit,[12],[13],[14] neither obvious side effect was observed. With the advent of precision radiotherapy, especially the clinical application of simultaneous integrated boost-intensity-modulated radiation therapy (SIB-IMRT), the dose in tumor regions can be precisely increased without increasing the dose in normal tissues at the same time, and the biologically effective dose (BED) on tumor could be increased. Some studies have tried to apply the SIB-IMRT and hypofractionated technique combined with TMZ to treat gliomas and improve patient survival. MonJazeb et al.[15] performed IMRT on malignant gliomas and the local dose was increased to 80 Gy/32f. Unfortunately, patients did not show a significant survival benefit. Chen et al.[16] increased the single dose in the surgical cavity and residue tumors to 6 Gy/f with 10 times in 2 weeks. The results showed that hypofractionated SIB-IMRT resulted in survival advantages compared to other fractionation methods. The median survival period was 16.6 months, but the incidence of radiation necrosis at late stages was higher. To mitigate radiation necrosis, Bevacizumab was adopted in the following study;[17] finally, this study was terminated due to the presumed necrosis of 50%. Iuchi et al.[18] increased the dose to 68 Gy/8f in the surgical area of glioblastoma, and good efficacy was observed. However, 43.5% of patients in this study presented radiation necrosis, and the physical conditions of the long-term survivors were significantly aggravated.

Above studies with small single fractionated dose did not demonstrate survival benefits.[15] However, the following two studies with a larger single fractionated dose showed increased efficacy, as well as a high incidence of radiation necrosis. The single fractionation dose led to more adverse reactions and radiation necrosis at the late stage.[16],[17],[18] To reduce the incidence of necrosis, Jastaniyah et al.[19] adopted the 2.72 Gy/f fractionated regimens concurrent with TMZ for radiotherapy in 25 cases of high-grade gliomas. The results did not show a significant improvement in efficacy, and treatment failure was mainly due to local recurrence. Therefore, the appropriate single fractionated dose still required further studies. To minimize the incidence of radiation necrosis, this study reduced the overly high single fractionated dose, properly increased the radiation fractionation number, adopted a 20-treatment radiotherapy regimen, and gradually increased the dose from 2.8 Gy/f by SIB-IMRT. The subclinical dose remained unchanged, and the dose was stepwise escalated in the residual tumors and the surgical cavity that were the most prone to recur; then, the maximum radiation tolerated dose was obtained.


 > Methods Top


Eligibility

Postoperative Grades III and IV glioma patients were confirmed by pathology (patients with restricted lesions and nondiffuse growth). They received cranial magnetic resonance (MR) examination after 48 h of surgery, and radiotherapy was performed after 2–4 weeks of surgery. The age of patients was between 18 and 70 years, KSP scores were ≥60, blood routine and liver and kidney functions were normal, expected survival period was ≥3 months, maximum diameter of the residual tumor, surgical cavity, and primary tumor bed was ≥6 cm,[16],[20] and lesions were not in the brain stem and thalamus. All patients had not received chemotherapy or brain radiotherapy previously.

The exclusion criteria included pregnant and lactating women, secondary primary malignant tumor, severe pulmonary infection, and combination with mental illness or other diseases that required hospitalization.

This clinical trial was approved by the Ethics Committee of the second hospital of Hebei Medical University. The trial was performed in accordance with the standards for human clinical trials and the principles stated in the Declaration of Helsinki. All patients signed an informed consent form before enrollment in this study.

Baseline evaluation

For all included patients, a detailed medical history was collected, and physical examinations were performed. Auxiliary examinations included cranial MR imaging (MRI) plain and enhanced scanning, electrocardiography, routine blood tests, and complete biochemical tests. All examinations were finished before treatment.

Experimental design

This was a prospective phase I clinical trial. The primary study endpoint was the maximum tolerated dose (MTD) for treating malignant glioma patients, with stepwise escalating doses in hypofractionated SIB-IMRT combined with TMZ. The secondary endpoints were OS and progression-free survival (PFS). The classical phase I clinical 3 + 3 mode was adopted. In each dose group, a minimum of three patients was enrolled, if a patient among these three patients had dose-limiting toxicity (DLT), then another three patients were enrolled in the same dose level. If these six patients had two or more cases of DLT or the maximum target dose was achieved, the study was terminated. The study scheme was depicted [Table 1]. We preset the maximum single fractionated dose as 4 Gy, namely if the single fractionated dose reached 4 Gy without DLT, the radiation dose would be no longer increased. The reason for us to preset the maximum target dose was the complex intracranial structure. An overly high single fractionated dose may increase the risk of radiation necrosis, severely affect the quality of life of patients, and even induce severe complications. Therefore, we would like to obtain a hypofractionated radiation regimen that could improve the efficacy without significantly increasing severe adverse reactions of radiotherapy. Some studies have shown that survival could be significantly improved with the BED of radiation higher than or equivalent to 100 Gy to tumor. Therefore, we preset the maximum fractionated dose at 4 Gy; there were 20 fractionations, and the total dose was 80 Gy (BED = 112 Gy). Because we preset the maximum single fractionated dose, our study was different from the classical dose elevation. Therefore, this study was a “modified phase I study.”
Table 1: Study schema and hypofractionated intensity-modulated radiotherapy regimens

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Radiotherapy

Radiotherapy applied the hypofractionated SIB-IMRT with an Elekta Precise linear accelerator and 6MV-X-ray. The Nucletron Plato patient selection system v3.4.0 software (Veenendaal, Netherlands) was applied for optimizing radiotherapy plans. All patients received cranial enhanced MR scanning after 48 h of surgery to confirm whether there was residual tumor. Patients were fixed with face mask, and a Philips Brilliance TM Big Bore computed tomography (CT) was applied for enhanced scanning. The scanning slice thickness was 3 mm. The cranial plain scanning and enhanced MR scanning were performed simultaneously at the same body position. The target area was delineated with a combination of MR and CT scanning images [Figure 1]. The gross tumor volume (GTV) was delineated based on the MR enhanced T1 image. The GTV was defined as the area of the residual tumor and surgical cavity. Planning target volume 1 (PTV1) was defined by expanding GTV by 0.3 cm. The clinical tumor volume (CTV) was the expansion of GTV by 2 cm (not more than the anatomical barrier). Planning target volume 2 (PTV2) was the expansion of CTV by 0.3 cm. The prescription dose of PTV2 was 50 Gy/20 f (2.5 Gy/f). The single dose and total dose of PTV2 remained unchanged. The SIB-IMRT was applied for a concurrent increase of the dose at PTV1. PTV1 was gradually increased from 2.8 Gy/f (a total of 20 times). The interval of the escalating dose between each set of two groups was 0.4 Gy. If two or more cases in the same dose group showed DLT or reached the maximum target dose of 4 Gy/f, the experiment would be terminated. As for the limited dose for organ damage, the maximum limited dose for the brain stem was 54 Gy, and the maximum limited doses for the lens and optic nerve were 9 Gy and 54 Gy, respectively. All patients completed radiotherapy at one time/day and 5 days/week for 4 weeks [Table 1].
Figure 1: The target area and the plan curve. The synthesis scheme demonstrated the target area of the integration of computed tomography and magnetic resonance scanning images (a and b) and the plan curve (c). The yellow line was Planning target volume 1 with 72 Gy/20f, while the purple line was planning target volume 2 with 50 Gy/20f (c)

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Chemotherapy

All patients received oral TMZ chemotherapy at 75 mg/m2/day during the radiotherapy. Oral administration was started on the 1st day until the end of the radiotherapy. One month after the completion of concurrent radiotherapy and chemotherapy, TMZ chemotherapy was sequentially applied for 12 cycles. The dose in the first cycle was 150 mg/m2/day, and the dose in the 2nd–12th cycles was 200 mg/m2/day for 5 days every 28 days. Before chemotherapy, the neutrophil count was ≥1500/mm 3, and the platelet count was ≥75,000/mm 3.

Supportive care

When intracranial hypertension symptoms such as headache and dizziness occurred during the radiotherapy period, the patients were given mannitol and corticosteroid drugs for reducing intracranial pressure. If the patients presented nausea and vomiting, it was determined whether they were caused by intracranial hypertension or chemotherapy. If they were induced by intracranial hypertension, drugs that lowered intracranial pressure were administered; if they were caused by chemotherapeutic drugs, antiemetic drugs were given for symptomatic treatment. If patients showed degree 3 or 4 bone marrow suppression, radiotherapy and chemotherapy were temporarily stopped, and colony-stimulating factor was administered for increasing blood. If necessary, symptomatic supportive treatment could be given. Patients with a seizure attack history were treated with antiseizure drugs.

Dose-limiting toxicity and maximum tolerated dose

Adverse reactions were determined with the NCI-CTC3.0 criteria (NCI-The National Cancer Institute of Canada, CTC-Common Toxicity Criteria). DLT referred to severe to life-threatening adverse reactions including Grade 3 or higher nonhematologic toxicity caused by radiotherapy,[16],[20] excluding nausea, vomiting, and weakness. Acute adverse reactions referred to adverse reactions that occurred within 30 days of radiotherapy. Later, adverse reactions were adverse reactions that occurred after 30 days of radiotherapy.[16],[20]

The modified phase I clinical trial regimen was adopted in this study. A minimum of three patients were enrolled in each dose group. If there was no DLT, next three patients would be enrolled in the group of next dose level. If one case in these three patients showed DLT, another three patients were enrolled in the same dose group and observed for at least 30 days. If two or more cases in these six patients showed DLT or the maximum target dose of 4 Gy/f was achieved, the study was terminated, and the previous lower dose level was the MTD. Similarly, if two or more cases in the same dose level presented late-stage DLT and the study of the next dose level had been started, then the MTD was considered as the previous lower dose level that resulted in DLT.

Efficacy assessment

A cranial plain scan and enhanced MRI were performed after completion of the radiotherapy, 1 month after completion of radiotherapy, every 3 cycles during sequential chemotherapy, and after the completion of sequential chemotherapy. If recurrence was suspected, cranial functional MRI was performed again, including perfusion-weighted imaging, diffusion-weighted imaging, and MR spectroscopy. The RESICT1.1 criteria were applied for the efficacy assessment.[21]

Follow-up and statistics

All patients received out- or in-patient re-examinations and telephone follow-up. Follow-up was performed monthly for the first 3 months; afterward, the follow-up was performed once every 3 months, and after a half year, follow-up was performed once every 6 months. Until December 1, 2015, the follow-up rate was 100%. The SPSS17.0 statistical software (SPSS Inc., Chicago, Illinois, America) package was applied for statistical analysis. The Kaplan–Meier method was performed to calculate the survival rate. The survival of patients was calculated from definite diagnosis to death.


 > Results Top


Patient characteristics

A total of 16 patients were enrolled between March 2014 and June 2015. Median age was 49 years (ranged 22–70 years). Among the 16 patients, one patient had two locations of detectable lesions, and the other patients had lesion at one location. However, the sum of lesion diameters at two locations was smaller than 6 cm. All the cases received operations. There were seven cases of complete resection of gross tumors, 8 cases of partial resection, and 1 case of biopsy. According to the radiation therapy oncology group and recursive partitioning analysis (RPA) classification criteria, there were 4 cases of RPA Grade III, 7 cases of Grade IV, and 5 cases of Grade V. The median PTV1 of the whole group was 92.69 cm 3 (ranged 35.65–167.25), and the median PTV2 was 243.57 cm 3 (ranged 115.37–451.82). Patient characteristics were listed [Table 2]. The maximum point doses to the brain stem, lens, and optic nerves were also listed [Table 3].
Table 2: Patient characteristics

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Table 3: Radiation dose to critical structures

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Compliance

All patients received escalating-dose radiotherapy at one of the four dose levels: 2.8 Gy/f, 3.2 Gy/f, 3.6 Gy/f, and 4.0 Gy/f, corresponding to three, three, six, and four patients, respectively. All 16 patients completed the IMRT concurrent with the TMZ chemotherapy regimen. One patient did not receive the sequential TMZ chemotherapy regimen after the concurrent radiotherapy and chemotherapy due to economic reasons. Other patients all received sequential TMZ chemotherapy. The median cycle number of the TMZ chemotherapy was 6 (ranged 0–12).

Adverse reactions

The median follow-up time was 18 months (ranged 8–25). The major adverse reactions were mild headache, nausea, and vomiting. Among these patients, only 3 patients developed Grade III adverse reactions, of which there were 2 cases of headache and 1 case of persistent seizure attacks. After symptomatic treatment for dehydration and seizure, these symptoms were relieved. In the third dose group, one patient had decreased vision combined with a partial defect of the visual field after surgery, as well as mild reduction of vision during the radiotherapy. These symptoms were not significantly aggravated after 1 year. The lesion of this patient was located at the occipital lobe, the PTV1 was approximately 94.2 cm 3 with a local dose of 72 Gy/20f, and the PTV2 was approximately 231.0 cm 3 with a local dose of 50 Gy/20f. This region was mainly considered to control vision; thus, these symptoms were caused by local nerve cell ischemia induced by surgery and radiotherapy. The long-term adverse reactions were mainly mild weakness and headache. One patient (6.25%) in the second dose group suffered from radiation necrosis combined with tumor recurrence, 4 patients (25%) were treated with hormone therapy for more than 7 days to relieve symptoms. Acute and late toxicities were listed [Table 4].
Table 4: Distribution of toxicity

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The determination of the maximum tolerated dose

This study enrolled 3 patients in each of the 2.8 Gy/f and 3.2 Gy/f dose groups, and no DLT was observed. The first case of DLT was in the 3.6 Gy/f dose group; DLT occurred after 8 radiotherapy treatments and was a serious Grade III headache. During the whole process, the patient was treated with dehydration measures (such as hormones) for reducing intracranial pressure. After the completion of the radiotherapy, the dose of hormones was gradually reduced and eventually withdrawn. Afterward, other patients were additionally enrolled in the 3.6 Gy/f dose group (a total of 6 patients). There was no Grade III adverse reaction in further observation. The second case of DLT was in the 4.0 Gy/f dose group; it was a persistent seizure attack after 12 radiotherapy treatments, which was combined with a Grade II headache. The lesion of this patient was at the right temporal lobe. The MR showed obvious edema combined with a midline shift. The radiotherapy was temporarily suspended for 2 days, and the symptom was relieved after the patient was treated with dehydration to reduce intracranial pressure and sedatives were provided. Moreover, the subsequent radiotherapy was completed with the assistance of intracranial pressure reduction by dehydration and antiseizure drugs during the whole process. When the radiotherapy was completed, the dehydration therapy and anti-seizure drugs were gradually stopped. The third case of DLT was in the 4.0 Gy/f dose group. It was a Grade III headache, which occurred on the 20th day after radiotherapy. The symptoms were headache combined with mild limb activity disorders. MR showed that the disease lesion did not progress but that edema surrounding the lesions was significantly increased. The effects of reducing intracranial pressure with hormone-based dehydration were not good. During the sequential chemotherapy, Bevacizumab was administered for 2 cycles, and the symptoms were significantly relieved.

Among the three cases of DLT in this study, two patients were in the 4.0 Gy/f dose group, and one case was in the 3.6 Gy/f dose group. Although there was one DLT patient in the 3.6 Gy/f dose group, there were no Grade III adverse reactions after another three patients were additionally enrolled in this group. Therefore, 4 Gy/f (80 Gy/20f) was considered as the DLT, and the previous level dose of 3.6 Gy/f (72 Gy/20f) was regarded as the MTD of malignant gliomas.

Survival

Until the last follow-up, the median follow-up time was 18 months. Among the 16 patients, 10 cases were dead, and 6 cases survived. Among the 10 died patients, 8 patients died of intracranial tumor progression, 1 patient died of intracranial tumor progression combined with lung tumor, and 1 patient died of recurrence combined with cerebral infarction. There were 11 patients with recurrence, including 6 cases showed recurrence in situ (2 cases were in the first dose group, and the other 4 cases were in the second and third dose groups); 2 cases in the second and third dose groups exhibited recurrence in the edge of radiation field; 1 case in the fourth dose group had recurrence outside the radiation field; 2 cases, which were in the first and third dose groups, had local recurrence combined with intraventricular diffusion.

Two patients received the second surgery because the MR showed tumor progression combined with obvious intracranial hypertension, including one patient in the first dose group developed confirmed tumor recurrence after the second surgery and the other patient in the second dose group showed extensive necrosis combined tumor recurrence at the edge by postoperative pathology. Both patients received the maximum degree of tumor and necrotic tissue resection with preserved neural functions. Four patients with recurrence and intracranial spread received the TMZ intensive dose regimen for chemotherapy, of which one patient had temporary tumor shrinkage, and the progression-free period after the intensive regimen was 2 months. The other patients did not show clear efficacy. One patient received the bevacizumab and irinotecan chemotherapy regimen, and the tumor had partial remission. One patient received cisplatin, nimustine, and vincristine chemotherapy for 6 cycles, and the tumor basically disappeared. Three patients only received symptomatic dehydration for reducing intracranial pressure after progression, without receiving antitumor therapy.

The median survival and median progression-free survival in this study were 19 and 16 months, respectively. The 1-year and 2-year OS were 86.7% and 31%, respectively [Figure 2]. The 1-year and 2-year PFS were 73.7% and 26.7%, respectively [Figure 3]. The 1-year and 2-year OS were 66.7%, 100%, 100%, 66.7% and 33.3%, 66.7%, corresponding to the first, second, third and fourth dose groups, respectively (χ2 = 8.793, P = 0.032). The 1-year and 2-year PFS were 66.7%, 66.7%, 100%, 66.7% and 0%, 66.7% in the first, second, third and fourth dose groups, respectively, (χ2 = 10.523, P = 0.015), while the 2-year OS and PFS have not been achieved in the third and fourth dose groups. Although there were some differences, it was unable to determine the better group due to the few cases in each group. Among the 6 surviving patients, 1 patient in the fourth dose group survived with a tumor. The other 5 patients survived without tumor, including 3 cases in the second dose group, 2 cases in the third dose group, and 1 case in the fourth dose group.
Figure 2: Kaplan–Meier curve of overall survival. The median overall survival in this study was 19 months. The 1-year and 2-year overall survival were 86.7% and 31.0%, respectively

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Figure 3: Kaplan–Meier curve of progressionfree survival. The median progression-free survival was 16 months. The 1-year and 2-year progression-free survival were 73.7% and 26.7%, respectively

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 > Discussion Top


High-grade glioma is one of the most common and highly malignant tumors which primarily develops in the central nervous system. The main failure cause of treatment has been the loss of local control. However, because of its growth characteristics, as well as the intracranial-specific structure and function, it was difficult to achieve complete curative effects with the surgery. Therefore, postoperative radiotherapy plays very important roles, but the effects of current conventional radiotherapy regimens are not excellent, and most patients die of recurrence in situ.

The cure rate of radiotherapy is positively correlated with the biological dose received by the tumor. In recent years, there have been many studies investigating the relationship between the total dose and efficacy. They have attempted to increase the total dose without changing the single fractionated dose for increasing the efficacy. Unfortunately, no local control or survival benefit was obtained in these studies.[8],[9],[10],[11],[22] The reason for the local recurrence of tumor was the repopulation of residual tumor stem cells in subclinical lesions. The potential cell doubling time of glioblastoma and anaplastic astrocytoma was ≤10 days,[23] with fast cell proliferation speed. In the past, the total dose was increased with conventional fractionation; however, this method prolonged the total treatment time and led to accelerated repopulation of glioma cells, thus reducing the efficacy.

The other approach for enhancing the BED of radiotherapy is to increase the single fractionated dose and then reduce the treatment time, which has been confirmed in lung cancer radiotherapy. The same efficacy could be obtained with hypofractionated radiotherapy on peripheral lung cancer as surgery.[24] While center nervous tissue belonged to late-reacting tissue thus the long-term adverse reactions may be increased with hypofractionation. Maybe it was the reason why hypofractionated radiation was seldom applied for treating the large volume brain tumors. For all that, some scholars have tried the hypofractionation strategy for high-grade gliomas because of its poor survival. Hasegawa et al.[25] introduced a human glioma xenograft model in mice to compare the biological effects of 5 different fractionated radiation regimens performed in 2 weeks on solid tumors. The results showed that hypofractionation made better antitumor effects on glioma. Hulshof et al.[12] divided 155 cases of malignant glioma patients into three groups, and patients in group 1 were given conventional radiotherapy, and patients in the other two groups were administrated with two different hypofractionated radiotherapy regimens. The dose fractionations were 5 Gy/f with a total of 40 Gy/17d and 7 Gy/f with a total of 28 Gy/7–11d. The results showed no significant difference was observed in the median survival period among the three groups. Similarly, McAleese et al. enrolled 184 cases of patients with malignant glioma, and then performed conventional radiation at 60 Gy, as well as dose fractionated radiotherapy three times/week at 5 Gy/f for a total of 30 Gy/2 weeks. The observed results showed that the hypofractionated radiotherapy did not show any benefit. The median survival periods were 8 and 5 months, respectively, while the 1-year survival rates were 19% and 12%, respectively.[26] Ciammella et al.[27] and Sultanem[13] performed IMRT on high-grade glioma patients at the radiation dose of 25 Gy/5f and 60 Gy/20f, respectively. The median survival period was not extended in their studies. In the above studies, although hypofractionated radiation was introduced for increasing the single dose, there was no survival benefit. The reason may because the BED was not significantly increased with the low total radiation dose. The highest BED in the above studies was only 78 Gy, and the BED of 60 Gy/30f was 72 Gy (BED = nd [1 + d/(α/β)]), α/β was commonly assumed for normal tissue and tumor by 3 Gy and 10 Gy, respectively.[20]

IMRT technology can protect normal tissues and maximize the radiation dose specific to tumor. In addition, SIB-IMRT can be applied to obtain a higher single dose in tumor bed area; therefore, when increasing the BED, the total treatment time can be shortened to overcome the accelerated repopulation of tumor cells. In recent years, some studies have applied hypofractionated SIB-IMRT combined with TMZ for the treatment of high-grade gliomas. MonJazeb et al. performed field-in-field IMRT to increase the local dose to 80 Gy/32f. The patients did not show a significant survival advantage compared to patients with equivalent prognostic factors, with the 1-year and 2-year survival rates of 57% and 19%, respectively.[15] Iuchi et al. performed SIB-IMRT concurrent with TMZ chemotherapy on 25 cases of patients with high-grade glioma. The single fractionated dose was 6 Gy-8 Gy, and the local total dose in the surgical cavity was increased to 48 Gy-68 Gy/8f. The 1-year and 2-year survival rates (71.4% and 55.6%) were significantly higher than those of with traditional radiation (54.6% and 19.4%).[28] The subsequent phase II study also obtained better survival, achieving 1-year and 2-year survival rates of 69.6% and 42.8%, respectively.[18] However, 43.5% of the patients in this study developed radiation necrosis. Chen et al.[16] and Reddy et al.[20] adopted hypofractionated SIB-IMRT combined with TMZ to perform phase I and phase II clinical studies for treating glioblastoma. They increased the single dose in the surgical cavity and residual tumor to 6 Gy/f. The total dose was 60 Gy/10f, the dose in the subclinical lesions was 30 Gy/10f, and the median survival period was 16.6 months. This study obtained good median survival. However, the incidence of radiation necrosis in patients of this group was 25%, and 92% of patients required long-term oral hormones to relieve symptoms. Afterward, Reddy et al.[29] reported that a 33-month total median survival period was obtained with the same regimen, samely, higher incidence of necrosis was also observed. To mitigate radiation necrosis, bevacizumab was adopted in the latter study, Ney DE used SIB-IMRT (60 Gy/10f) combined with TMZ and BEV to treat 30 cases of postoperative high-grade glioma patients, but bevacizumab did not prevent hypofractionated radiation regimen-related radiation necrosis and the study was closed early due to the presumed necrosis of 50%.[17]

Above small-dose single fractionated studies did not bring survival benefits.[15] In addition, despite the increased efficacy, other studies [16],[18],[29],[30] involving large fractionated dose have also significantly increased the incidence of radiation necrosis. Furthermore, most patients required long-term administration of hormones to relieve symptoms, and some patients required a second surgery, which greatly affected the quality of life. The single fractionated dose had large effects on late-stage adverse reactions. Currently, there was no evidence that the MTD of conventional fractionated radiotherapy in normal tissues would be equivalent to the MTD of hypofractionated radiotherapy. Although normal tissues could be better protected with IMRT, its dose gradient still cannot be reduced very rapidly. In Iuchi's study, the 50 Gy dose volumes accounted for 80%, and the 60 Gy dose volumes accounted for 50% in the subclinical lesion area (PTV2). Calculation according to α/β = 3 Gy in normal tissues showed that the BED of approximately 80% of the normal tissues in PTV2 was 155 Gy, which may still cause the severe radiation necrosis in this study.

Hypofractionated radiotherapy can improve local control of malignant gliomas, as well as survival. However, a large single fractionated dose has made great adverse reactions at late stages in the normal tissue. Because of the special intracranial neural structure and function, the quality of life would be severely affected with the late-stage radiation necrosis. Therefore, for high-grade glioma patients with a poor prognosis, the proper single fractionated dose still required further exploration, and the safety required further validation. The conclusion could still not be unified on the efficacy of the hypofractionated SIB-IMRT for treating high-grade gliomas. Different studies have used varying single fractionated doses and total doses.[15],[16],[18],[31],[32],[33] The single doses ranged from 2.5 to 8.5 Gy/f. The physique between eastern and western people was different, and our previous concurrent radiotherapy and chemotherapy studies [34],[35],[36] showed that the tolerated dose obtained in Western population was not necessarily applicable to the Eastern population. Based on the above conditions, this study was designed to reduce the incidence of radiation necrosis and increase the proper frequency of radiotherapy to 20 times. Using the SIB-IMRT, based on the unchanged subclinical dose, the dose of the residual tumors and surgical cavity which were prone to recur was gradually increased. The dose was started from 2.8 Gy/f, and the MTD of radiotherapy in treating high-grade gliomas was obtained with stepwise escalating of doses in hypofractionated SIB-IMRT combined with TMZ.

This study was a prospective phase I clinical study. The dose in the residual tumor and surgical cavity was gradually increased from 2.8 Gy/f to the maximum target dose of 4 Gy/f (80 Gy/20 f). All the patients completed the SIB-IMRT concurrent with a TMZ chemotherapy regimen according to the treatment plan. The median cycle number of the sequential TMZ chemotherapy was 6 cycles. Relatively mild hematologic toxicity was observed. The nonhematologic toxicity was mainly headache caused by Grades 1–2 intracranial hypertension. GRADE 4 adverse reaction was not observed. Three patients were observed to have DLT, including 2 cases of Grade 3 headache (each in the 3.6 Gy/f and 4 Gy/f dose groups), and 1 case of persistent seizure attack (one patient in the 4 Gy/f dose group). Therefore, 4 Gy/f (80 Gy/20f) was considered as the DLT, while the dose at a lower level of 3.6 Gy/f (72 Gy/20f) was considered as the MTD of malignant gliomas. The MTD obtained in this study was 72 Gy/20f (BED = 98 Gy), it was equivalent to that of the maximum target dose 60 Gy/10f (BED = 96 Gy) reported by Chen et al.[16],[20] and was lower than that of 68 Gy/8 f (BED = 124 Gy) reported by Iuchi et al.[28] While in Iuchi's study, they found that survival could be significantly improved with BED ≥ 96 Gy. Our results were consistent with those obtained in previous studies. In this study, the BED of the MTD was 98 Gy. The median OS and median PFS obtained in this study were 19 and 16 months, respectively. The 1-year and 2-year PFS and OS were 73.7%, 26.7% and 86.7%, 31.0%, respectively. The survival was significantly improved compared to the conventional fractionation of 60 Gy/30f [5] and some hypofractionated researches.[13],[15],[26],[27] It was consistent with the survivals presented by the studies of Reddy et al.[20] and Iuchi et al.[18] which reported the highest rates of survival currently. However, the incidence of radiation necrosis was 25%, and 92% for patients requiring long-term oral hormones to relieve symptoms in Reddy's et al. study.[20] In Iuchi's et al. study, radiation necrosis was observed in 43.5% of patients, and the physical status of the long-term survivors was significantly aggravated.[18] While milder adverse reactions were found in this study, only one patient (6.25%) suffered from radiation necrosis, 4 patients (25%) were treated with hormone therapy to relieve symptoms for more than 7 days. Summarily, more obvious benefit of survival could be obtained than conventional fractionation and some hypofractionated researches, as well as milder side effects than other hypofractionated SIB-IMRT.


 > Conclusions Top


Our study applied hypofractionated SIB-IMRT combined with concurrent TMZ to treat patients with malignant glioma. The results showed that the MTD was 3.6 Gy/f (72 Gy/20f) and the adverse reactions were tolerable. In addition, the results preliminarily showed improved survival. Based on this phase I trial, this regimen was recommended for a phase II clinical trial.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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



 

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