1. Radiation therapy for high-grade glioma
The results of two multicenter phase III clinical trials by Kristiansen et al. and Walker et al. showed that the survival time of the radiotherapy group vs. the supportive care group was 9 months vs. 3.5 months; 10.5 months vs. 5.2 months, respectively, and the differences were statistically significant, laying the foundation for postoperative radiotherapy for glioma. Up to 99% resection of high-grade malignant glioma can reduce the tumor cell load from 109 to 107, and postoperative adjuvant radiotherapy can help prolong patient survival (Class I evidence: Stewart 2002).
1.1 Indications for radiotherapy: All high-grade gliomas should be adjuvantly treated with radiotherapy after surgery. For patients with confirmed diagnosis who are inoperable or refuse surgery, radiotherapy alone may also be indicated.
Tumor assessment: The tumor growth site, invasion range, complete extent of surgical resection and resection range determine the dose and target area of postoperative radiotherapy, so the assessment of tumor before and after surgery is very important for the development of radiotherapy plan. Preoperative MRI multi-sequence imaging should be used, and CT plain + enhanced scan should be used when MRI examination is contraindicated to obtain as much tumor imaging information as possible.
To accurately assess the extent of surgical resection, it is recommended to review MRI/CT within 72 hours after surgery, if the quantitative volumetric analysis of preoperative and postoperative imaging is used as the standard to assess the extent of glioma resection. The T1WI-enhanced scan of MRI of high-grade malignant glioma is currently recognized as the “gold standard” for imaging diagnosis.
1.2 Timing of radiotherapy
In a retrospective study by Irwin C et al [iv], the median survival was 58 weeks when radiotherapy was started 2 weeks after surgery and 54 weeks when radiotherapy was started 4 weeks after surgery. The longer the delay, the shorter the survival of patients. Therefore, starting radiation therapy as early as possible after surgical resection is recommended as the standard protocol for comprehensive treatment of malignant glioma.
1.3 Radiotherapy target area
In the past, the conventional radiotherapy technique of whole brain radiotherapy followed by local tumor bed dosing was simple to operate, without localization problems and without the difficulty of determining the CTV range, but whole brain radiotherapy had no survival advantage and increased the toxicity of radiotherapy and significantly decreased the quality of life.
With the rapid development of imaging technology and radiotherapy, there has been a transition to the use of three-dimensional conformal radiotherapy (3D-RT) or intensity-modulated radiotherapy (IMRT), which targets the largest possible recurrence area and increases the therapeutic dose in the target area as much as possible, while better protecting normal brain tissue, reducing acute and long-term reactions to radiotherapy, and improving quality of life.Kita et al. reported the results of RCT There was no difference in survival time between WBRT 40Gy + local supplemental dose of 18Gy and local radiotherapy 56Gy (level I evidence).
The results of Phillips et al [vi] study (RCT): median survival was 10.3 months and 8.7 months (P = 0.13) for 36 cases of local irradiation 60Gy/30 sessions and 32 cases of whole brain irradiation 35Gy/10 sessions, respectively (level I evidence). Therefore, local radiotherapy is currently recommended for the treatment of high-grade gliomas.
The greatest difficulty in local radiotherapy is the identification of the initial clinical target area (CTV1). Current imaging techniques are still unable to accurately locate the true boundaries of the tumor, so the need to include the peritumoral edema area when determining CTV1 has become a point of controversy. Some foreign scholars have shown through needle biopsy observations that tumor cells are infiltrated within the edema zone around glioma tumors with pathological grade II or higher, so the edema zone of glioma is considered to be the actual extent of glioma infiltration.
With the development of MRI techniques, the definition of tumor margins may change. pirzkall et al. showed that metabolically active tumors in 88% of patients could extend beyond the area defined by the MRI-T2 phase. Therefore, for enhanced high-grade gliomas, the initial CTV is the enhanced tumor plus abnormalities on the FLAIR image or T2 image and extends approximately 2 cm, while the later field reduction push includes only 2 cm outside the enhanced tumor. RTOG recommends that CTV1 needs to include the area 2 cm outside the peritumoral edema zone and be given at 46 Gy, and CTV2 for field reduction needs to extend 2 cm outside the GTV and be dosed to 60 Gy.
The CTV setting recommended by the European Organization for Research and Treatment of Cancer (EORTC) does not emphasize the need to cover all peri-neoplastic edema areas. Many clinical studies have shown that malignant gliomas are characterized by in situ recurrence. Hochberg et al [viii] studied 35 patients who had a CT scan within 2 months prior to death, 78% of GBM recurrent lesions were within 2 cm of the primary tumor bed, 56% were within 1 cm of the tumor shown on CT, and in 42 GBM with serial CT scans, 90% of recurrent lesions were within 2 cm of the primary tumor within the primary tumor.
The results of the latest phase III clinical trial RTOG0525/EORTC26052-22053 showed by COX analysis that overall survival time was independent of the two radiotherapy target setting methods used (EORTC/RTOG) [ix]. Chang EL et al [x] reported that the target setting method at MD Anderson Hospital in the United States was CTV1 for GTV The CTV of the reduced field included only 0.5 cm outside the GTV and was given 10 Gy. As a result, the local failure mode was similar to the RTOG setting method (10% for both field margin and field recurrence).
Sant Andrea Hospital in Italy proposed a set of target area setting method similar to MD Anderson Hospital, CTV1 was also expanded 2cm outside GTV, if CTV1 volume >250cm3, then CTV1 was irradiated to 50Gy and then the field was reduced to 1cm outside GTV (CTV2) dose to 60Gy, and the results were consistent with MD Anderson Hospital.
As a development direction, target area determination will shift from physical to biological outlining. A study of 39 post-operative patients treated with radiotherapy showed that 74% of them had larger tumor volumes found using methionine (MET)-PET than those found by T1-enhanced MRI. Using structural imaging and metabolic imaging parameters to identify biological targets, MET-PET has implications for guiding radiotherapy in terms of active tumor residuals and outlining target areas after malignant glioma surgery (Level II evidence for evidence-based medicine).
1.4 Radiotherapy dose
Walker MD et al [xi] performed a dose-effect analysis of data from 420 patients treated by the Brain Tumor Cooperative Group (BTCG) protocol, and the median survival of patients in the treatment group rose from 28 to 42 weeks when the total dose was increased from 50 to 60 Gy (level I evidence).Bleehen NM et al[xii] analyzed 443 patients with 1-year survival rates of 39% and 29% ( P = 0.04) at a total dose of 60 Gy/30 doses compared with 45 Gy/20 doses, and median survival of 12 months versus 9 months, respectively, P = 0.007 (level I evidence), both studies suggesting a positive dose-dependent correlation between efficacy in the dose interval of 45 Gy to 60 Gy. Administration of 60 Gy was appropriate. For doses above 60Gy can the efficacy continue to improve with higher doses?
RTOG 7401/ECOG 1374 randomized more than 600 patients to the 60Gy and 70Gy groups, with no difference in overall survival and median survival of 9.3 months and 8.2 months, respectively (level I evidence), but decreased in the higher dose group.
In a randomized prospective trial, Souhami et al [xiii] (RTOG9305) analyzed 203 patients with GBM after conventional radiotherapy at 60 Gy supplemented with BCNU chemotherapy, comparing the efficacy of SRS with and without stereotactic radiosurgery, targeting postoperative residual lesions, with irradiation doses ranging from 15 to 24 Gy depending on tumor size, with no median survival significant difference (13.5 and 13.6 months, P=0.57) (level I evidence). The use of 3D-CRT or IMRT to push up the radiotherapy dose also did not show a clinical advantage in terms of efficacy. chan et al. used IMRT to push the dose to 70-90 Gy and did not see a benefit (level II evidence).
Laperriere et al[xiv] used brachytherapy to push doses in patients with malignant glioma after conventional radiotherapy, and randomized patients to two groups, one with external irradiation only (50 Gy, 25 sessions, n=69) and the other with external irradiation followed by temporary stereotactic implantation of 125I, resulting in a minimum dose of 60 Gy around the tumor (n=71). (n=71).
Median survival was not significantly different between the two groups (13.8 months versus 13.2 months, p=0.49) (level II evidence). another randomized prospective trial reported by Selker et al [xv] (Brain Tumor Cooperative Group National Institutes of Health) BTCG8701 The results, too, support these findings (level I evidence). There are also a few studies showing the benefits of high doses, such as Tanaka et al[xvi] who used conformal radiotherapy divided into 60Gy and 70Gy-80Gy high dose groups, with 2-year survival rates of 11.4% and 38.4% for GBM; and 44.1% and 78.1% for AA and 14.7% and 51.3% for 5-year survival, respectively (Class III evidence).
A survival advantage could be obtained by increasing the irradiation dose within a certain dose range, but no benefit was shown after a total conventional radiotherapy dose greater than 60 Gy. Although 3D-CRT or IMRT has the advantage of improving target conformality, better protection of normal tissues, and giving higher radiotherapy doses without increasing the risk to surrounding tissues, the efficacy of these methods of pushing higher doses has not been proven and should be applied with caution and limited to clinical studies.
Therefore, the current recommended total radiotherapy dose is 54-60Gy with 30-33 fractions. Stereotactic radiotherapy should only be used as a local push dose after conventional external irradiation or as an option for the treatment of recurrent tumors.
1.5 Dose fractionation The change in fractionation modality has no effect on survival. Carsten et al[xvii] performed a meta-analysis of 21 clinical studies of hyperfractionation or accelerated hyperfractionation published from January 1997 to June 2002 and did not show an advantage of changing the fractionation modality over conventional fractionated radiotherapy in improving survival (level I evidence).
The RTOG83-02 study was a prospective randomized phase I/II trial of 747 patients with malignant glioma treated with hyper-segmentation/accelerated hyper-segmentation radiotherapy at total doses of 64.8 Gy, 72 Gy, 76.8 Gy and 81.6 Gy, respectively, all at 1.2 Gy twice daily, while accelerated hyper-segmentation radiotherapy gave The total doses were 48 Gy, 54.4 Gy, twice daily at 1.6 Gy, respectively, with no significant difference in median survival between treatment groups in the final outcome (Level I evidence), and this result from RTOG8302 in 1998 led to a phase III clinical trial comparing conventional radiotherapy of 60 Gy, once daily, for a total of 30 sessions with hyperfractionated radiotherapy of 72 Gy, twice daily, at 1.2 Gy Again, no survival difference was found (Class II evidence).
Based on the above studies, neither short course macro-segmentation nor accelerated hyper-segmentation significantly improved the OS of high-grade glioma compared with conventional segmentation for fractionated doses; therefore, conventional segmentation radiotherapy is recommended for high-grade glioma.
1.6 Simultaneous radiotherapy
A large phase III clinical trial by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) demonstrated that patients with glioblastoma multiforme (GBM) treated with standard postoperative radiotherapy in combination with temozolomide (TMZ) followed by 6 cycles of TMZ adjuvant chemotherapy increased median survival from 12 to 15 months and 2-year survival rate from 10.4% to 26.5%. This result was confirmed by a series of studies. The National Comprehensive Cancer Network (NCCN) guidelines, European guidelines for malignant glioma, and Canadian GBM consensus all regard postoperative radiotherapy for malignant glioma as the standard of care for malignant glioma (Level I evidence, highly recommended). The regimen is specifically: the entire course of radiotherapy should be accompanied by chemotherapy with oral temozolomide 75 mg/m2 for 42 days.
It should be given approximately 1 hour before radiotherapy; during radiotherapy, it should still be administered at the same time on days when not receiving irradiation. Adjuvant temozolomide should be administered 4 weeks after the end of radiotherapy at 150 mg/m2 for 5 consecutive days, 28 days as a course of treatment, while detecting hematologic complications and increasing the dose to 200 mg/m2 if well tolerated. clinical and imaging evaluation should generally be performed after 3 courses of adjuvant chemotherapy, and if there is pseudo-progression, continuation of the drug for up to 6 courses is recommended. An extension of the treatment cycle may be considered for patients with sustained improvement on treatment. If there is recurrence after 3 courses of treatment, reoperation or change to another chemotherapy regimen is recommended.
1.7 Evaluation of the efficacy of radiotherapy
After radiotherapy or simultaneous radiotherapy, malignant glioma may show various imaging changes, such as no progression, early progression, pseudo-progression, recurrence, radiation necrosis, etc. Among them, pseudo-progression often appears during or soon after treatment, and should be paid attention to in the clinical treatment process.
(1) Pseudo-progression: After radiotherapy for malignant glioma, especially after combined TMZ treatment, there is often a phenomenon that the original enhancing lesions become larger in size, or even new enhancing lesions appear, but they can gradually subside without any treatment, and this phenomenon is called pseudo-progression because it resembles tumor progression in imaging. This phenomenon is called Pseudo-Progression (PsPr).
(2) Clinical characteristics of pseudo-progression
Pseudo-progression is mostly seen within 2 months after the end of treatment and is a treatment-related response, unrelated to tumor progression. The incidence is related to radiotherapy dose and chemotherapy, and whether it is related to age and irradiation volume is not clear. It is mostly without clinical symptoms and signs, and compared with the traditional concept of radiation necrosis, it can shrink or remain stable even without treatment.
(3) Differentiation of PsPr/ PD
Changes in clinical signs and symptoms cannot predict and determine recurrence and pseudo-progression. Since multiple responses such as pseudoprogression, recurrence and necrosis after radiotherapy for glioma often coexist, but current imaging tools such as MR perfusion, MRS, DWI, FDG-PET are not very helpful in their differentiation, the importance of the physician’s clinical experience is particularly emphasized. New tracers with amino acids such as 11C-methionine, 18F-ethyl tyrosine are more helpful for their identification.
(4) Incidence of pseudoprogression
Pseudoprogression occurs in 9% of patients after radiotherapy alone; pseudoprogression occurs in 21%-31% of patients with temozolomide combined with radiotherapy, and the incidence of pseudoprogression is higher with combined radiotherapy than with radiotherapy alone, and the incidence of pseudoprogression is also significantly higher in those with low MGMT expression or MGMT methylation, suggesting that the occurrence of pseudoprogression means prolonged survival time.
(5) Management of early disease progression after temozolomide combined with radiotherapy
If patients develop progressive disease without clinical symptoms after combined chemotherapy/radiotherapy, in principle, adjuvant chemotherapy with temozolomide should be continued. If a patient has clinical symptoms or an enhancing lesion with rapid short-term enlargement biopsy or surgery should be considered. If intraoperative lesions are found to be predominantly necrotic foci, continuation of temozolomide adjuvant chemotherapy is warranted.
Summary of radiation therapy techniques for high-grade glioma
1. It is recommended to start synchronous radiotherapy with TMZ 75 mg/m2/d as soon as possible after surgery and continue the whole course of radiotherapy;
2.Recommended local radiotherapy with conformal or intensity-modulated technique, the target area GTV is the postoperative residual tumor and/or operative cavity as shown by MRI T1 enhancement image, the first stage clinical target volume (CTV1) is 2-3 cm outside GTV 3D, which need not include the whole edema zone, the second stage clinical target volume (CTV2) is 1~1.5 cm outside GTV 3D, PTV1/PTV2 is CTV1/CTV2 three-dimensional exenteration of 0.3cm to 0.5cm (combined with the positional situation of each unit). In important areas, such as the brainstem and visual cross, GTV is appropriately outwardly placed so that the high-dose area cannot fall in important areas.
3, irradiation dose: choose 6-8MV-X-ray irradiation, 95% of equal dose line to meet PTV1 = 45-50Gy/25-28 times, PTV2 = 60Gy/30-33 times, 1.8Gy-2Gy each time, 5 times a week. Critical organ limit: brainstem, optic cross, pituitary gland maximum amount not more than 54Gy.
4.In units that do not have 3D conformal or intensity modulated radiotherapy, conventional general radiotherapy is still the necessary treatment choice. For local radiotherapy, it is recommended to protect the normal structure on one side, adopt one field + top field, use wedge plate technique to improve the dose distribution, and for tumors located in the midline area, adopt three-field irradiation technique, and the irradiation dose and segmentation mode are the same as that of 3D conformal or intensity-modulated radiotherapy. Stereotactic radiotherapy (FSRT/SRS) is only recommended as an option for treatment of smaller tumors after conventional external irradiation for push-up or recurrent tumors.