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New advances in radiotherapy for pancreatic cancer in 2019-2020
New advances in radiotherapy for pancreatic cancer in 2019-2020. Precision radiotherapy technology continues to improve, multi-modal images combined with delineation of the target area, “FLASH” radiotherapy can better protect normal tissues, and the radiotherapy dose mode is developing in the direction of high dose and less fractionation.
The symptoms of pancreatic cancer patients are not obvious at the time of onset, and 67% of them have metastasized at the time of diagnosis. Radiotherapy, surgical resection, chemotherapy, targeted drugs, immunotherapy and many other tumor treatment methods, alone or combined treatment can make the prognosis of pancreatic cancer patients certain Improved, but still inferior compared with other tumors. The 1-year overall survival (OS) rate of patients with pancreatic cancer is 30%, of which 60% is non-metastatic and 15% is metastatic .
The rapid progress of radiotherapy equipment, imaging technology, artificial intelligence and other aspects of the research has made radiotherapy enter the era of precision. Image-guided radiotherapy, multimodal image delineation of the target area, radiotherapy information system and other equipment that mark the characteristics of precision radiotherapy are gradually becoming more and more important. Essential for radiotherapy centers. With the completion of precision “radiotherapy weapons”, the corresponding radiotherapy treatment mode has also changed correspondingly, gradually developing from the conventional dose mode to the direction of macrosegmentation and stereotactic radiotherapy (SBRT), and the target area ranges from large-scale irradiation to visible lesion radiotherapy.
The technology and concept of radiotherapy for pancreatic cancer in some countries is not behind that of foreign countries. As early as the end of the last century, X-knife or Gamma Knife was used to treat pancreatic cancer. The high-dose and low-fractionated radiotherapy dose model was also proposed, and the data results are better than the conventional dose. mode. Reviewing the literature on radiotherapy for pancreatic cancer in the past two years, the content mainly includes five aspects: dose mode, radiotherapy technology, clinical results, combination therapy and prognostic impact. Now we do the following literature review.
1. Advances in radiotherapy technology
The determination of the radiotherapy target area is one of the important links of precision radiotherapy, and the combination of multi-modal images is beneficial to the delineation of the pancreatic cancer target area. Magnetic resonance imaging (MRI) has high soft tissue resolution and can improve the accuracy of pancreatic tumor delineation in radiotherapy plans.
Caravatta et al.  conducted a multi-center pancreatic tumor delineation study to evaluate the consistency of MRI and CT in pancreatic cancer gross tumor volume (GTV) and duodenal delineation, and found that MRI was in the borderline resectable cases CT has a smaller GTV than CT.
The average volumes of CT and MRI-GTV are (21.6±9.0) cm3 and (17.2±6.0) cm3, respectively, which are basically the same between observers. PET is an imaging technology that can quantitatively evaluate the biochemical changes in the body. The image fusion positioning of PET, CT, and MRI is important for the identification of metastatic lymph nodes.
“FLASH” radiotherapy has an ultra-high dose rate. Compared with traditional dose rate radiotherapy, it can reduce normal tissue damage while maintaining tumor efficacy. Diffenderfer et al.  set up a new type of radiotherapy device on this basis, using double-scattering protons for “FLASH” proton radiotherapy, through dosimetry and biological research compared with standard proton radiotherapy, reducing the early response cell Loss and advanced fibrosis without reducing tumor suppression. Bourhis et al.  used “FLASH” to treat the world’s first clinical tumor patient.
The patient suffered from multidrug-resistant CD30+ T-cell lymphoma. The skin lesions were still progressing after receiving systemic treatment, and the lesions had invaded the whole body. The skin has received more than 110 fractions of conventional dose rate radiotherapy. This time I received 15 Gy within 90 ms. After 3 weeks of irradiation, the patient only developed grade I dermatitis and edema. After 5 months, the curative effect was evaluated and tumor control was found. good. However, the determination of the specific pulse dosing method and the irradiation division mode still needs more research results.
2. Progress in radiotherapy mode
The change of radiotherapy dose mode is a representative sign of the arrival of the era of precision radiotherapy, which is most prominent in the change of radiotherapy mode for pancreatic cancer. Due to the biological characteristics of pancreatic cancer tissues that are not sensitive to radiation, high-dose radiotherapy can be given as much as possible to achieve good results.
45~50.4 Gy, a single 1.8~2.0 Gy conventional fractional radiotherapy (CFRT) is mainly used for auxiliary purposes In treatment, when it is applied to the treatment of visible lesions and radiotherapy and chemotherapy, it is recommended to use high-dose and low-fraction radiotherapy including hyperfractionation and SBRT. Xiang et al.  retrospectively analyzed the data of resectable pancreatic cancer receiving neoadjuvant treatment in the National Cancer Database (NCDB) from 2010 to 2015, and found that 175 cases of SBRT neoadjuvant radiotherapy combined with chemotherapy were longer than 1355 cases of neoadjuvant chemotherapy alone. OS (30 months vs 21 months, P=0.02), also prolonged survival time compared with 552 cases of CFRT (29 months vs 16 months, P=0.002).
Similar results are also confirmed by the meta-analysis results of Tchelebi et al. . The 2-year OS rate of SBRT is higher than that of CFRT (26.9% vs 13.7%, P=0.004). Among them, SBRT mostly adopts 30 Gy/5F model, biological etc. The effective dose (BED) is 1048 Gy. Most of the SBRT patients enrolled in this meta-analysis are receiving neoadjuvant therapy for pancreatic cancer. Therefore, the above report only shows that this SBRT dose mode is dominant in neoadjuvant radiotherapy.
The hyperfractionated radiotherapy mode has recently emerged in the field of pancreatic cancer radiotherapy, and is considered to be superior to the SBRT mode. Dosimetry studies  show that the internal dose of the target area is increased on the basis of the 15-time mode, which is easier to achieve BED10=100 Gy than the 5-time mode . Compared with 3 to 5 times of SBRT, 10 to 15 times of hyperfractionated radiotherapy may be the main method of pancreatic cancer radiotherapy in the future. There is still a lack of clinical trial studies comparing the two modes.
3 clinical progress in each phase
3.1 Preoperative radiotherapy
Neoadjuvant radiotherapy for pancreatic cancer is theoretically superior to postoperative adjuvant radiotherapy, and does not increase the perioperative mortality rate , and recent meta-analysis  shows that neoadjuvant can reduce pancreatic fistula after pancreaticoduodenectomy risks of. Recent clinical reports of pancreatic cancer radiotherapy are preoperative radiotherapy and chemotherapy. Many literatures have reported the results of prospective single-arm studies [11-13]. The radiation dose mode is mainly CFRT, and the research object is resectable or/and borderline.
In patients with resectable pancreatic cancer, the median OS of R0 patients after surgery is 34.8-55.3 months. The results of a phase II prospective clinical trial—ESPAC-5F were released at the ASCO meeting in 2020. The 1-year OS rate of the secondary endpoints of various neoadjuvant regimens for the treatment of borderline resectable patients is better than that of patients with direct surgery (77% vs 42%) ), of which 16 patients received CFRT combined with capecitabine and the 1-year OS rate was 64%. Versteijne et al.  reported the results of the phase III clinical trial PREOPANC.
In the preoperative radiotherapy and chemotherapy group, the radiotherapy dose was 36 Gy/15F, combined with gemcitabine 1 g/m2 chemotherapy, and 119 cases of resectable or borderline resectable pancreatic cancer received preoperative radiotherapy. The median OS of chemotherapy was 16.0 months, 127 patients with immediate surgical resection of the tumor were 14.3 months (P=0.096), the R0 resection rate of patients with preoperative radiotherapy and chemotherapy was 71% (51/72), and the R0 of patients with immediate surgery The resection rate was 40% (37/92) (P<0.001). The above research results confirm that preoperative radiotherapy and chemotherapy can prolong the survival time of patients, and increase the evidence-based medical evidence of preoperative radiotherapy and chemotherapy in the treatment of pancreatic cancer.
3.2 Postoperative radiotherapy
The role of postoperative radiotherapy is still being questioned. Recent research reports are all retrospective studies. Through comparison and stratified analysis, it is believed that patients with R1 resection and positive lymph nodes may benefit from postoperative radiotherapy. Lutsyk et al.  retrospectively analyzed the prognosis of 134 patients with pancreatic cancer who received chemotherapy or radiotherapy after surgery, 41 cases of R1 resection, of which 26 patients received radiotherapy and chemotherapy, the median OS was 23 months, and the median of 15 patients with chemotherapy alone The OS was 12 months, and the difference was statistically significant (P=0.01). Kamarajah et al.  calculated the data of R0 patients after pancreatic cancer resection in the NCDB for 10 years, and analyzed the significance of postoperative radiotherapy on the prognosis of patients.
After matching, there were 3860 cases in the postoperative radiotherapy group and the non-radiotherapy group. The survival time was statistically different. The median OS was 25.8 months and 23.9 months, and the 5-year OS rate was 27% and 24%, respectively. Stratification and multivariate interaction analysis showed that the survival benefit was limited to patients with lymph node-positive disease: N1 (HR=0.68, 95%CI: 0.62~0.76, P=0.007) and N2 (HR=0.59, 95%CI: 0.54 ~0.64, P=0.04).
3.3 Radiotherapy for locally advanced patients
Currently, reports of locally advanced pancreatic cancer radiotherapy mostly use the SBRT radiotherapy mode, but the overall radiation dose is not high, and it has not reached the real high-dose, low-fractionated radiotherapy mode. Shen et al  reviewed the prognostic results of 56 cases of locally advanced pancreatic cancer receiving SBRT in a single center. The median dose of radiotherapy was 40 Gy/5F, combined with gemcitabine and capecitabine chemotherapy, the median OS and median progression-free survival (PFS) ) It was 19 months and 12 months from the time of diagnosis, and the 1-year and 2-year OS rates were 82.1% and 35.7%, respectively. Two patients (3.6%) had acute grade 3 duodenal obstruction symptoms, 3 Cases (5.4%) developed advanced grade 3 gastrointestinal toxicity, and 2 cases (3.6%) developed grade 4 advanced radiation enteritis and intestinal perforation. Arceli et al.  reviewed the use of SBRT technology to treat locally advanced pancreatic cancer with a median dose of BED1048Gy alone or in combination with chemotherapy. The results showed that the 2-year median OS rate was 33.8%, the local control rate was 55.8%, and the radiation dose was Independent prognostic factors of patient OS and local control rate.
3.4 Radiotherapy for metastatic pancreatic cancer
In addition to the therapeutic effects of metastatic pancreatic cancer, in addition to pain relief and reduction of tumor compression, for patients with isolated metastasis or recurrence, on the basis of improving local control, there is the possibility of prolonging the survival of patients . Scorsetti et al.  retrospectively analyzed the results of 41 cases of solitary metastatic pancreatic cancer receiving SBRT treatment. The median local control time was 39.9 months, the median OS was 23 months, and the 1-year and 2-year OS were 79.9% and 46.7, respectively. %. Shi et al.  retrospectively analyzed the results of 31 cases of isolated local recurrence after radical operation of pancreatic cancer receiving radiotherapy and chemotherapy. The median total dose was 56.0 Gy, 1.8-2.15 Gy/time, and the median local regional progression-free time was 12.0 months. The median OS was 23.6 months, 3 cases of grade 3 acute toxicity (9.7%), and 1 case (3.2%) in the late stage.
4-system drug combination
The local curative effect of pancreatic cancer after receiving radiotherapy is obvious, but because the tumor progresses rapidly, most patients will have distant metastasis. If the risk of metastasis is not reduced, the local curative effect of radiotherapy will be transformed into a limited result of long-term survival. Some studies  found From 2010 to 2014, compared with 1988 to 1996, the total OS of locally advanced pancreatic cancer patients receiving radiotherapy in the United States was prolonged by 3 months. A study reviewing NCDB data  showed that radiotherapy and multi-drug combined with neoadjuvant therapy are factors influencing the degree of postoperative pathological remission of patients. For this reason, it is recommended to combine systemic treatment with radiotherapy for pancreatic cancer.
In order to improve the treatment effect of the whole body, the researches recently reported mostly focus on the powerful chemotherapy regimen combined with multi-drug combination before radiotherapy. Thanikachalam et al.  carried out a prospective phase II resectable or borderline resectable neoadjuvant chemotherapy for pancreatic cancer. After 24 patients received 2 cycles of FOLFOX chemotherapy, 13 patients received CFRT concurrent gemcitabine chemotherapy, 11 patients The patients (84.6%) had R0 resection, the median OS was 34.8 months, and the 2-year OS rate was 75%. Garnier et al.  prospectively studied the prognostic results of 187 cases of locally advanced pancreatic cancer with concurrent radiotherapy or continued chemotherapy after induction chemotherapy. The induction chemotherapy regimen was also FOLFIRINOX and concurrent capecitabine during radiotherapy 54 Gy/30F. The statistical results found that despite There was no difference in OS between concurrent chemoradiation and chemotherapy alone, but they had a longer PFS (13.3 months vs 9.6 months, P<0.01).
Targeted drugs for pancreatic cancer are effective in a small number of patients through genetic testing, and most patients do not have effective targeted drugs. The microsatellites of pancreatic cancer are extremely unstable, the tumor mutation load is generally low, and immune cells are lacking in the microenvironment. So far, no effective results have been reported for its immunotherapy. However, some scholars speculate that radiotherapy can release more antigens from the tumor and change the pancreas. The cancer immune microenvironment is more conducive to the effect of immune drugs, and related research is ongoing.
5 Image prognosis prediction
5.1 CT imaging omics
The currently available clinical prediction models cannot predict the treatment outcome of pancreatic cancer well. Radioomics can achieve tumor prognosis prediction by extracting high-throughput information from images for deep mining and analysis. Parr et al.  used the radiological characteristics of pancreatic cancer CT to make a prognostic prediction model and compared it with traditional clinical models. They extracted and analyzed the enhanced CT image data of 74 pancreatic cancer patients who received SBRT before radiotherapy. More than 800 radiomic features were screened, and the radiological feature prediction model formulated achieved better overall OS prediction performance than the clinical model (average agreement index: 0.66 vs 0.54), and it predicted recurrence better than the clinical model (average AUC is 0.78 vs 0.66).
5.2 MRI imaging omics
In order to explore the possibility of MRI imagingomics in predicting the efficacy of SBRT in pancreatic cancer, SimPson et al.  collected low-field strength (0.35T) MRI-guided MRI images before each treatment of pancreatic cancer patients during SBRT, and extracted the radiological characteristics. Calculating the relationship between these characteristics and the curative effect after radiotherapy, it was initially found that these radiological characteristics of MRI can be used as predictive information of patients’ response to treatment. MRI images have more radiomic features than CT, and how to effectively use these features is worthy of further research in the future.
5.3 PET Metabolism Index
There are many reports on the prediction or prediction of the efficacy of PET for pancreatic cancer after radiotherapy. Su et al.  found that when PET 40% metabolic tumor volume (MTV) is less than 5.6 cm3, patients with pancreatic cancer after SBRT have longer OS and PFS. MTV is an independent prognostic factor of OS and PFS. Incerti et al.  believe that the total glycolysis of the lesion (ΔTLG) 50 is related to OS, PFS, and survival without local recurrence.
recision radiotherapy technology continues to improve, multimodal images combined with delineation of the target area, “FLASH” radiotherapy can better protect normal tissues, and the radiotherapy dose mode is developing in the direction of high dose and less fractionation.
Radiotherapy runs through all stages of pancreatic cancer, and the role of neoadjuvant radiotherapy has been further confirmed. The powerful chemotherapy regimen of multi-drug combination is the main combination of radiotherapy.
The radiomic characteristics of CT and MRI can be used as predictive methods to predict the outcome of pancreatic cancer radiotherapy. In addition, PET metabolic indexes and quantitative ultrasound contrast parameters can also predict or predict the effect of pancreatic cancer radiotherapy.
(source:internet, reference only)