I. Selection of appropriate population in neoadjuvant radiotherapy for rectal cancer
The controversy of population selection in neoadjuvant radiotherapy is mainly in patients with T3NO. Different scholars have analyzed and studied the relevant clinical characteristics, including the location of tumor, the significance of nerve invasion, etc. on the recurrence of rectal cancer. For pT3NO patients without high risk factors such as nerve invasion, Peng et al. showed that their 5-year local recurrence rate was only 7.9%, which was 2.5 times lower than that of patients with nerve invasion (22.7%, P=0.017), suggesting that the role of neoadjuvant radiotherapy may be limited for this group of T3NO patients without high risk factors for recurrence.
Tumors located in different parts of the rectum have different odds of local recurrence, and the risk of recurrence after surgery alone is significantly lower for high-grade rectal cancer >lO cm from the anal verge compared with low and intermediate sites, and the role of neoadjuvant radiotherapy may likewise be limited for this group of patients, but there is no confirmation from large-scale randomized clinical studies that have focused on the clinical features associated with T3 tumors, while another concern is For T3 tumors themselves, there are different subgroups, i.e., differences in the depth of tumor invasion in the intestinal wall that have an impact on treatment selection.
1. Current status of research in 3 subgroups
Studies have shown that the prognosis of patients becomes significantly worse as the depth of tumor infiltration increases. t3 tumors are defined as invasion beyond the intrinsic muscular layer of the rectum, but the distance of their invasion in the intestinal wall varies greatly. a study by Merkel et al. showed that the 5-year tumor-related survival rate was 85% for patients with t3 tumor infiltration depth <5 mm, significantly higher than t3, regardless of lymph node metastasis, and 54% for patients with infiltration depth ≥5 mm percent (p< Shin et al. analyzed 291 patients with T3 rectal cancer and divided T3 into 4 subgroups according to the depth of invasion T3a,<1mm; t3b, 1.5mm; t3c, 5-15mm; t3d>15mm, and 5-year DFS was 86.5%, 74.2%, 58.3%, and 29% in the 4 subgroups of the population, respectively (p<0.ool) The classification of t3 subgroups has been applied in the preoperative mri assessment of rectal cancer, but the tnm staging criteria have not been formally incorporated in the postoperative pathological assessment. Two classification systems, esmo criteria and rsna criteria, have been used for the assessment of preoperative mri infiltration depth in rectal cancer. < p=""> ESMO criteria (T3a, <1mm; t3b, 1-5mm; t3c, 5-15mm; t3d>15mm) are more accurate than RSNA criteria (T3a, <5mm; t3b, 5-lomm; t3c>15mm), but increase the difficulty of measurement, have low reproducibility, and are currently The infiltration depth of 5 mm is a more general cut-off value, and the RSNA criteria are more clinically applicable in clinical applications. the MERCURY study showed that for patients with no invasion of the rectal mesenteric space, no cancer thrombus in the vasculature, and an infiltration depth of <5 mm, the local recurrence rate after surgery alone was only 1.7% for patients with mri evaluation of no high-risk factors. < p=""> 2. Treatment recommendations based on recurrence risk groups The 2013 ESMO guidelines recommended that for the first time, rectal cancer should be stratified according to the risk of recurrence, with the stratification based on pre-treatment MRI assessment, including depth of tumor infiltration (T stage), number of lymph node metastases (N stage), distance from the anus, mesorectal fascia (MRF), and the risk of recurrence. fascia (MRF) and extramural vascular invasion (EMVI). invasion (EMVI) invasion, etc., then according to the risk of recurrence into very low risk group, low risk group, intermediate risk group and high risk group, the stratified treatment mode after the traditional single mode is different and more refined, in these four groups, the very low risk group can be operated directly without neoadjuvant radiotherapy, and the other three subgroups are treated as Low-risk group: including T1-2 rectal cancer; early stage T3NO patients with MRI assessment of tumor infiltration depth <5mm, mrf and emvi not invaded, and tumor located above the anal raphe, can be operated directly, and then supplemented with radiotherapy or chemotherapy if there are adverse prognostic factors such as the presence of lymph node metastasis or positive circumferential margins in the postoperative pathology report. < p=""> Intermediate-risk group: including low-grade T2, T3 tumor infiltration depth ≥5mm and MRF is not invaded, there are lymph node metastasis, or part of T4a (such as only part of the invasion of the peritoneum) patients, neoadjuvant radiotherapy can effectively reduce the local recurrence rate for these patients, the specific choice of radiotherapy long course or short course is still controversial, but long course radiotherapy can bring higher pCR rate, which is the current majority of radiotherapy. It is the first choice of the center. In the high-risk group: including patients with MRF-invasive T3 rectal cancer, and patients with post-T4a and T4b parietal lymph node metastases, long course radiotherapy followed by 6-8 weeks of surgery is the preferred mode of treatment, and it is also the currently accepted treatment modality, and for patients of advanced age or those who cannot tolerate long course radiotherapy, 5*5Gy short course radiotherapy can be considered. Therefore, for rectal cancer, especially T3 tumors, the assessment of high local risk factors for recurrence is essential for stratified treatment, which also depends on the development of high-resolution MRI technology. For patients with low-risk T3 tumors, whether direct surgery can achieve the same effect as neoadjuvant radiotherapy while avoiding the toxic side effects of radiotherapy deserves confirmation from future prospective studies. Evaluation of the efficacy of neoadjuvant radiotherapy for rectal cancer After neoadjuvant radiotherapy, some patients can obtain complete tumor regression, whether the subsequent surgical treatment can be changed according to the therapeutic effect of the tumor, some scholars have proposed “minor surgery” or “wait-and-see” (wait-and-see) for local resection. However, due to the exploration of local excision, wait-and-see, etc. to reduce the scope of surgery or non-surgical means after neoadjuvant treatment for rectal cancer, the clinical efficacy assessment after neoadjuvant treatment is in line with the postoperative pathology, especially for the complete remission after treatment. The assessment is crucial. The evaluation after neoadjuvant therapy includes anal finger diagnosis, imaging and colonoscopy, etc. Traditional imaging examinations such as ultrasound endoscopy, CT or conventional MRI are mostly for morphological assessment of efficacy, and the accuracy of prediction is between 30% and 60%, therefore, exploring new imaging technologies or detection methods for the evaluation of efficacy after neoadjuvant radiotherapy for rectal cancer is the current hot spot of research . 1.MRI
MRI plays an important role in the staging and diagnosis of preoperative neoadjuvant radiotherapy, and therefore its application to the evaluation of efficacy after radiotherapy has also been reported by several studies. MRI has been used to assess its conformity with the pathological findings after radiotherapy, especially the value of clinical judgment of complete remission. However, the value of MRI in assessing the efficacy of radiotherapy varies widely among reports, and conventional sequences of MRI have less value in determining efficacy. harly reported on five centers that used MRI reassessment before and after radiotherapy to examine its predictive value, but found its role to be more limited. With the advancement of MRI technology, diffusion-weighted, high-resolution imaging techniques are now mostly used in the evaluation of the efficacy of neoadjuvant radiotherapy for rectal cancer, and multiple MRI-related parameters are used to predict the efficacy of radiotherapy and improve its prediction accuracy. A multicenter study showed that combining DWI with conventional MRI helped to improve the accuracy and consistency of pCR diagnosis by different evaluators. However, it has also been suggested that the edema, necrosis, and fibrosis that occur in the tumor bed after treatment may decrease the ADC value and thus affect the accuracy of assessment. T2WI with high-resolution imaging sequences can clearly wet show the structure of each layer of the rectal wall. In the study of MERCURY, tumor regression grading of MRI after radiotherapy with high-resolution imaging sequences ( mr Tumor regression grade, mrTRC.) and circumferential margins can make a more accurate prediction of patients’ long-term survival; and the compliance with pathological TRG is high. shihab et al. showed that good mrTRC scores tend to be associated with lower local recurrence rates. Therefore, the application of high-resolution MRI for tumor reassessment of TN descending stage and TRG score after radiotherapy is of good clinical value to guide the next treatment and prognosis. 2.PET/CT functional imaging MRI using new technology has advantages in evaluating the efficacy of tumor radiotherapy, but its effectiveness in distinguishing pCR and microscopic micro lesion residue is still low, but it needs to be evaluated together with other information.18F-FDG PET/CT has its advantages in predicting the sensitivity of pCR. The decrease in glucose metabolism uptake can be demonstrated in rectal cancer when tumor volume reduction occurs two weeks after radiotherapy, suggesting that metabolic changes can predict radiotherapy efficacy at an early stage. van Stiphout et al. established a model to predict pCR after radiotherapy for locally progressive rectal cancer using several indicators, including tumor length, maximum uptake of 18F-FDG by tumor cells before and after radiotherapy and its changes, and achieved good accuracy (AUC=0.86). In addition, a study by Sun [25] showed that in a group of patients with better response to neoadjuvant radiotherapy, 18F-FDG The metabolic tumorvolume (MV) and total lesion glycolysis (TLG) measured by PET/CT in a group of patients with a better response to neoadjuvant radiotherapy were significantly higher than those with a better response, TLG) were more significantly different before and after radiotherapy, suggesting that these parameters may also serve as predictors of efficacy. In contrast, analysis of patients who tested negative for 18F-FDGPET/CT after neoadjuvant radiotherapy revealed 5-year overall and tumor-free survival rates of 9l% and 81%, respectively, which were close to those reported clinically for pCR patients, 83% and 73%, respectively. It is suggested that the magnitude and variation of the SUV maxima of PET/CT functional images may not only be a predictor of response to radiotherapy, but may also have a prognostic value. However, PET/CT as a means of evaluating the efficacy of radiotherapy has its uncertainties, as shown by the fact that the time point of PET/CT review after radiotherapy has been chosen differently in different studies, and there is no consensus on what is the best time for efficacy evaluation and the frequency of evaluation. The maximum uptake value SUV variation is the most used in PET/CT functional imaging studies, but there are no uniform regulations on how to standardize the uptake value, and the joint assessment value with other parameters such as uptake range volume variation all deserve further study. The combination of MRI and PET/CT will be more helpful in evaluating the efficacy of rectal cancer after radiotherapy and in guiding the next treatment strategy. The key is. The effect of neoadjuvant radiotherapy on the follow-up treatment 1.Impact on surgery The degree of tumor regression after neoadjuvant radiotherapy is related to the prognosis. The tumors that achieved complete regression had a significant survival benefit over those with poor regression.Maas et al. reported a meta-analysis that included 3105 patients with locally progressive rectal cancer who received neoadjuvant radiotherapy and radical surgery, of whom 484 achieved pCR, and the 5-year disease-free progression survival (DFS) rates were 83.3% and 65.6% in the pCR and non-pCR groups, respectively ( P<0.000I), and 5-year overall survival (OS) rates were 87.6% and 76.4% in the two groups, respectively ( P<0.0001). pcr patients showed a better prognosis, so some scholars explored whether the intensity of subsequent treatment could be reduced for resting patients in complete remission. in terms of surgery, local excision and non-surgical treatment modalities were proposed, and in terms of postoperative adjuvant chemotherapy, different treatments were proposed according to different degrees of tumor regression. < p=""> H Habr-Cama et al. showed that clinical complete plete regression (cCR) was achieved after radiotherapy. Habr-Cama et al. showed that patients who achieved clinical complete remission (cCR) after radiotherapy achieved 83% and 92% of 5-year OS and DFS, respectively, using observational means. There was no significant difference with 88% and 100% in the pCR group, and her latest report in 2014 showed that the local recurrence rate was 31% in patients with the wait-and-see approach after clinical complete remission, so caution is needed for the use of wait-and-see non-surgical treatment for tumors in clinical complete remission after radiotherapy. Belluco et al. retrospectively analyzed 139 patients with stage T3NO-1 rectal cancer treated with neoadjuvant radiotherapy, and among those who achieved pCR, there was no difference in survival between those who underwent radical TME or local resection, and this evidence suggests the possibility of reducing the intensity of subsequent treatment if clinical complete remission is achieved after radiotherapy, but attention must be paid to the indicated population for the application, and The assessment of the efficacy of neoadjuvant radiotherapy should be multifaceted, and the accuracy of the efficacy assessment should be improved as much as possible. 2.Impact on the adjuvant chemotherapy program In the study of EORTC22921, it was suggested that patients with ypT0-2 with good postoperative pathology showing tumor regression after neoadjuvant radiotherapy benefited from postoperative adjuvant chemotherapy, while patients with ypT3-4 with poor regression failed to benefit from postoperative adjuvant chemotherapy. , there was little benefit from postoperative adjuvant chemotherapy, leading to the suggestion that postoperative adjuvant chemotherapy may be overtreatment in patients with pCR. These studies analyzed 5-FU as a regimen for adjuvant chemotherapy, and whether FOLFOX regimen chemotherapy could be improved in patients with poor regression, the 2014 ASCO meeting, Korean scholars reported randomized phase II study comparing XELOX with capecitabine (Siroda) single-agent adjuvant chemotherapy in patients with poorly regressed postoperative pathology of yp stage II/III after neoadjuvant radiotherapy, the The 3-year DFS of the two was 71.6% and 62.9%, respectively (P=0.047) Therefore, postoperative adjuvant chemotherapy regimens can be stratified based on the different scenarios of tumor regression after neoadjuvant radiotherapy to attenuate therapeutic toxicity. patients suggestive of pCR, adjuvant radiotherapy may not be required, patients not in complete remission but with better regression may be treated with single agents, while in patients with poor regression, combination chemotherapy may improve disease-free survival. IV. Neoadjuvant chemotherapy After an exploratory small sample reported 30% pCR with neoadjuvant FOLFOX in combination with bevacor for upper rectal tumors reported for neoadjuvant treatment of rectal cancer, especially where the lesion is located in the upper rectum and the clinical features suggest a relatively good prognosis There are more treatment centers exploring the application of neoadjuvant chemotherapy application, but no results have been reported yet. There are more options studied, including neoadjuvant chemotherapy, neoadjuvant chemotherapy combined with radiotherapy, neoadjuvant chemotherapy combined with short-course radiotherapy, etc., which are worth exploring. In the era of individualized treatment, we need to accumulate more tumor clinical information and radiotherapy and biological information to establish predictive models that can guide the treatment of tumor patients, while achieving individualized treatment.