Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.

Serum apolipoprotein B to apolipoprotein A-I ratio is an independent predictor of liver metastasis from locally advanced rectal cancer in patients receiving neoadjuvant chemoradiotherapy plus surgery.

BACKGROUND: The ratio of serum apolipoprotein B (apoB) to apolipoprotein A-I (apoAI) had been reported as a prognostic factor in colorectal cancer. This retrospective study aimed to assess the implication of apoB-to-apoAI ratio in predicting liver metastasis from rectal cancer (RC). METHODS: The clinical data of 599 locally advanced RC patients treated with chemoradiotherapy followed by surgery were reviewed. Serum apoAI, apoB and apoB-to-apoAI ratio were analyzed for their correlation with the liver-metastasis-free, other-metastasis-free and overall survivals, together with the pretreatment and postsurgical pathoclinical features of the patients. Univariate and multivariate survival analyses were realized through the Kaplan-Meier approach and Cox model, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for independent predictors. RESULTS: Carbohydrate antigen 19 - 9 ≥ 26.3 U/ml, apoB-to-apoAI ratio ≥ 0.63, tumor regression grade 5 - 3, pT4 and pN + stage emerged as independent predictors of poorer liver-metastasis-free survival. The hazard ratios were 1.656 (95% CI, 1.094-2.506), 1.919 (95% CI, 1.174-3.145), 1.686 (95% CI, 1.053-2.703), 1.890 (95% CI, 1.110-3.226) and 2.012 (95% CI, 1.314-2.077), respectively. Except apoB-to-apoAI ratio, the other 4 factors were also independent predictors of poorer other-metastasis-free and overall survivals. And the independent predictors of poorer overall survival also included age ≥ 67 years old, distance to anal verge < 5 cm. CONCLUSIONS: Serum apoB-to-apoAI ratio could be used as a biomarker for prediction of liver metastasis risk in locally advanced RC.

Beneficiaries of radical surgery among clinical complete responders to neoadjuvant chemoradiotherapy in rectal cancer.

This study aimed to identify patients who benefit from radical surgery among those with rectal cancer who achieved clinical complete response (cCR). Patients with locally advanced rectal cancer (LARC; stage II/III) who achieved cCR after neoadjuvant chemoradiotherapy (nCRT) were included (n = 212). Univariate/multivariate Cox analysis was performed to validate predictors for distant metastasis-free survival (DMFS). A decision tree was generated using recursive partitioning analysis (RPA) to categorize patients into different risk stratifications. Total mesorectal excision (TME) was compared with the watch-and-wait (W&W) strategy in each risk group. Two molecular predicators of CEA and CA19-9 were selected to establish the RPA-based risk stratification, categorizing LARC patients into low-risk (n = 139; CA19-9 < 35 U/mL and CEA < 5 ng/mL) and high-risk (n = 73; CA19-9 ≥ 35 U/mL or CEA ≥5 ng/mL) groups. Superior 5-y DMFS was observed in the low-risk group vs. the high-risk group (92.9% vs. 76.2%, P = .002). Low-risk LARC patients who underwent TME had significantly improved 5-y DMFS compared with their counterparts receiving the W&W strategy (95.9% vs. 84.3%; P = .028). No significant survival difference was observed in high-risk patients receiving the 2 treatment modalities (77.9% vs. 94.1%; P = .143). LARC patients with cCR who had both baseline CA19-9 < 35 U/mL and CEA < 5 ng/mL may benefit from radical surgery.

Neoadjuvant chemoradiotherapy for patients with unresectable radically locally advanced colon cancer: a potential improvement to overall survival and decrease to multivisceral resection.

BACKGROUND: The management of unresectable locally advanced colon cancer (LACC) remains controversial, as resection is not feasible. The goal of this study was to evaluate the treatment outcomes and toxicity of neoadjuvant chemoradiotherapy (NACRT) followed with surgery and adjuvant chemotherapy in patients with unresectable radically LACC. METHODS: We included patients who were diagnosed at our institution, 2010-2018. The neoadjuvant regimen consisted of radiotherapy and capecitabine/ 5-fluorouracil-based chemotherapy. RESULTS: One hundred patients were identified. The median follow-up time was 32 months. The R0 resection rate, adjusted nonmultivisceral resection rate and bladder preservation rate were 83.0, 43.0 and 83.3%, respectively. The pCR and clinical-downstaging rates were 18, and 81.0%%, respectively. The 3-year PFS and OS rates for all patients were 68.6 and 82.1%, respectively. Seventeen patients developed grade 3-4 myelosuppression, which was the most common adverse event observed after NACRT. Tumor perforation occurred in 3 patients during NACRT. The incidence of grade 3-4 surgery-related complications was 7.0%. Postoperative anastomotic leakage was observed in 3 patients. CONCLUSIONS: NACRT followed by surgery was feasible and safe for selected patients with LACC, and can be used as a conversion treatment to achieve satisfactory downstaging, long-term survival and quality of life, with acceptable toxicities.

The prognostic impact of preoperative blood monocyte count in pathological T3N0M0 rectal cancer without neoadjuvant chemoradiotherapy.

It remains controversial whether adjuvant therapy should be delivered to pathological T3N0M0 rectal cancer without neoadjuvant chemoradiotherapy. Thus identification of patients at high risk is of particular importance. Herein, we aimed to evaluate whether the absolute peripheral blood monocyte count can stratify the pathological T3N0M0M0 rectal cancer patients in survival. A total of 270 pathological T3N0M0 rectal cancer patients with total mesorectal excision-principle radical resection were included. The optimal cut-off value of preoperative monocyte count was determined by receiver operating characteristic curve analysis. Overall survival and disease-free survival between low- and high-monocyte were estimated by Kaplan-Meier method and Cox regression model. The optimal cut-off value for monocyte count was 595 mm(3). In univariate analysis, patients with monocyte counts higher than 595/mm(3) had significantly inferior 5-year overall survival (79.2 vs 94.2 %, P = 0.006) and disease-free survival (67.8 vs 86.0 %, P < 0.001). With adjustment for the known covariates, monocyte count remained to be associated with poor overall survival (HR = 2.55, 95 % CI 1.27-5.10; P = 0.008) and disease-free survival (HR = 2.63, 95 % CI 1.48-4.69; P = 0.001). Additionally, the significant association of monocyte count with disease-free survival was hardly influenced in the subgroup analysis, whereas this correlation was restricted to the males and patients with normal carcinoembryonic antigen (CEA) level (<5 µg/L), tumor grade II, and with adjuvant therapy. High preoperative monocyte count is independently predictive of worse survival of pathological T3N0M0 rectal cancer patients without neoadjuvant chemoradiotherapy. Postoperative adjuvant therapy might be considered for patients with high-monocyte count.

Surgery with versus without preoperative concurrent chemoradiotherapy for mid/low rectal cancer: an interim analysis of a prospective, randomized trial.

INTRODUCTION: Multimodality therapy, including preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), has effectively reduced local recurrence rates of rectal cancer over the past decade. However, the benefits and risks of the addition of neoadjuvant CRT to surgery need to be evaluated. This study was to compare the efficacy of TME with versus without preoperative concurrent chemoradiotherapy (CCRT) involving XELOX regimen (oxaliplatin plus capecitabine) in Chinese patients with stages II and III mid/low rectal adenocarcinoma. METHODS: We randomly assigned patients to the TME group (TME without preoperative CCRT) or CCRT + TME group (TME with preoperative CCRT). The primary endpoint was disease-free survival (DFS); the secondary endpoints were overall survival (OS), local and distant recurrence, tumor response to CRT, toxicity, sphincter preservation, and surgical complications. An interim analysis of the potential inferiority of DFS in the CCRT + TME group was planned when the first 180 patients had been followed up for at least 6 months. RESULTS: A total of 94 patients in the TME group and 90 patients in the CCRT + TME group were able to be evaluated. The 3-year DFS and OS rates were 86.3 % and 91.5 % in the whole cohort, respectively. The 3-year DFS rates of the TME and CCRT + TME groups were 85.7% and 87.9 % (P = 0.766), respectively, and the 3-year OS rates were 90.7 % and 92.3 % (P = 0.855), respectively. The functional sphincter preservation rates of the TME and CCRT + TME groups were 71.3 % and 70.0 % (P = 0.849), respectively. In the TME group, 16 (17.0 %) patients were proven to have pTNM stage I disease after surgery. In the CCRT + TME group, 32 (35.6 %) patients achieved a pathologic complete response (pCR). CONCLUSIONS: Preliminary results indicated no significant differences in the DFS, OS, or functional sphincter preservation rates between the TME and CCRT + TME groups. However, preoperative CCRT with XELOX yielded a high pCR rate. Newer techniques are needed to improve the staging accuracy, and further investigation is warranted. CLINICAL TRIAL REGISTRATION NUMBER: Chi CTR-TRC-08000122.

Selective use of adjuvant chemotherapy for rectal cancer patients with ypN0.

BACKGROUND: The administration of adjuvant chemotherapy for rectal cancer patients with ypN0 is controversial. The purposes of this study were to evaluate the role of adjuvant chemotherapy in ypN0 patients and to optimize its use for these patients. METHODS: We performed a retrospective study of 160 rectal cancer patients who had the final pathology of ypN0 between March 2003 and November 2010. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were compared between patients who did and did not receive adjuvant chemotherapy. Multivariate analysis was performed to explore clinical factors significantly associated with DFS, LRFS, and DMFS. RESULTS: For ypT0-2N0 patients, the 5-year OS, DFS, LRFS, and DMFS were similar between patients who did and did not receive adjuvant chemotherapy (P > 0.05). For patients with ypT3-4N0, those who were given adjuvant chemotherapy exhibited a higher 5-year OS than those who were not (P = 0.026), with also an extended 5-year DFS (P = 0.050). Further analysis indicated that adjuvant chemotherapy could decrease the rates of distant metastases for ypT3-4N0 patients with no impact on local control. In multivariable analysis, both the final pathological stage and adjuvant chemotherapy were independent predictors of DMFS for the whole group. When stratified by pathological stage, adjuvant chemotherapy was still significantly associated with DMFS in the ypT3-4 stratum. CONCLUSIONS: Adjuvant chemotherapy may not improve survival for ypT0-2N0 patients. However, it may be clinically meaningful for ypT3-4N0 patients by decreasing rates of distant metastases. Further randomized controlled clinical trials are needed to address this problem.

[Value of postoperative adjuvant chemotherapy in locally advanced rectal cancer patients with ypT1-4N0 after neo-adjuvant chemoradiotherapy].

OBJECTIVE: The purpose of this study was to investigate the value of postoperative chemotherapy for locally advanced rectal cancer patients who reached pathological ypT1-4N0 after neo-adjuvant chemoradiotherapy. METHODS: We performed a retrospective study of 104 patients treated with preoperative chemoradiotherapy followed by radical resection, who achieved pathological ypT1-4N0, between Mar 2003 and Dec 2010. There were 73 patients who received postoperative adjuvant chemotherapy, and the other 31 patients did not. The distribution of final pathologic stages for these patients was ypT1-2N0 in 39 cases and ypT3-4N0 in 65 cases. RESULTS: The median follow-up was 41 months. The 3-year overall survival rate (OS) and recurrence-free survival rate (RFS) for the whole group (ypT1-4N0) were 93.4% and 85.3%, respectively. The 3-year OS and RFS in the adjuvant chemotherapy group and non-adjuvant chemotherapy group were 95.5%, 88.6% and 88.6%, 77.2%, respectively. There were no significant differences in 3-year RFS (P = 0.108) and OS (P = 0.106) between the two groups. The 3-year local recurrence and distant metastasis rates in the adjuvant chemotherapy group were 4.1% (3/73) and 5.5% (4/73), while for the non-adjuvant chemotherapy group, the 3-year local recurrence rate and distant metastasis rate were 3.2% (1/31) and 16.1% (5/31), respectively. Significant difference was found in distant metastasis rates (P = 0.030) between the two groups, but not in local recurrence rates (P = 0.676).Further subgroup analysis indicated that for the ypT1-2N0 patients, there were no significant differences in 3-year OS (P = 0.296) and RFS (P = 0.939) between the adjuvant and non-adjuvant chemotherapy groups, while negative results displayed in 3-year local recurrence rates (P = 0.676) and distant metastasis rates (P = 0.414). However, for patients with ypT3-4N0, significant differences were showed in both the 3-year OS (P = 0.034) and RFS (P = 0.025), and further analysis revealed that the 3-year distant metastasis rate was significantly higher in the non-adjuvant chemotherapy group than in the adjuvant chemotherapy group (P = 0.010) , but with non-significant difference in the 3-year local recurrence (P = 0.548). CONCLUSIONS: Adjuvant chemotherapy may not improve survival for ypT1-2N0 patients. However, it may be clinically meaningful for ypT3-4N0 patients by decreasing distant metastasis rate. Further randomized controlled clinical trials are needed to confirm our results.

Total neoadjuvant treatment to increase the clinical complete response rate for distal locally advanced rectal cancer (TESS): A study protocol of a prospective, open-label, multicenter, single-arm, phase 2 trial.

BACKGROUND: Standard treatment of locally advanced rectal cancer (LARC) was neoadjuvant chemoradiotherapy (CRT), followed by total mesorectal excision (TME). Total neoadjuvant treatment (TNT), a new concept, attempts to deliver both systemic chemotherapy and neoadjuvant CRT prior to surgery. Patients treated with neoadjuvant chemotherapy were more likely to show higher tumor regression. The objective of this trial was to increase complete clinical rate (cCR) for LARC patients by optimizing tumor response, using TNT regimen as compared to conventional chemoradiotherapy. TESS, a prospective, open-label, multicenter, single-arm, phase 2 study, is underway. METHODS: Main inclusion criteria include cT3-4aNany or cT1-4aN+ rectal adenocarcinoma aged 18-70y; Eastern Cooperative Oncology Group (ECOG) performance 0-1; location ≤5 cm from anal verge. Ninety-eight patients will receive 2 cycles of neoadjuvant chemotherapy Capeox (capecitabine + oxaliplatin) before, during, and after radiotherapy 50Gy/25 fractions, before TME (or other treatment decisions, such as Watch and Wait strategy) and adjuvant chemotherapy capecitabine 2 cycles. Primary endpoint is the cCR rate. Secondary endpoints include ratio of sphincter preservation strategy; pathological complete response rate and tumor regression grade distribution; local recurrence or metastasis; disease-free survival; locoregional recurrence-free survival; acute toxicity; surgical complications; long-term anal function; late toxicity; adverse effect, ECOG standard score, and quality of life. Adverse events are graded per Common Terminology Criteria for Adverse Events V5.0. Acute toxicity will be monitored during antitumor treatment, and late toxicity will be monitored for 3 years from the end of the first course of antitumor treatment. DISCUSSION: The TESS trial aims to explore a new TNT strategy, which is expected to increase the rate of cCR and sphincter preservation rate. This study will provide new options and evidence for a new sandwich TNT strategy in patients with distal LARC.

Comprehensive treatment experience of anal squamous cell carcinoma from a tertiary cancer center in South China.

BACKGROUND: Anal squamous cell carcinoma (ASCC) is a rare malignant tumor with increasing incidence. The goal of our study was to analyze the treatment outcome and prognostic factors of ASCC in South China in the past half-century. METHODS: This study retrospectively included 59 patients with ASCC admitted from 1975 to 2018 in Sun Yat-sen University cancer center. The clinical records and follow-up information of all patients were collected. Survival analysis and univariate and multivariate regression analyses were performed using the "survival" and "survminer" packages of R software. RESULTS: In 59 patients, 5 patients had distant metastasis at diagnosis. Among 54 M0 stage patients, 33 patients received chemoradiotherapy (CRT), 19 patients received local surgery, and 2 patients refused curative treatment and received the best supportive treatment (BST). The most common grade 3-4 acute toxicities during treatment were myelosuppression and radiation dermatitis. The median follow-up time was 32 months. For the whole group, the 3-year and 5-year overall survival (OS) rates and disease-free survival (DFS) were 71.1% and 63.6%, and 73.4% and 69.0%, respectively. Multivariate regression analysis showed that the T3-4 stage was an independent prognostic risk factor for OS, progression-free survival (PFS), and DFS. And M1 was an independent prognostic risk factor for PFS and DFS. Patients in stage M0 mainly treated with CRT had better local control than those mainly treated with surgery (p = 0.027). For M0 patients, induction chemotherapy combined with CRT tends to prolong OS compared with CRT alone (p = 0.26). The 3-year colostomy-free survival for the whole group was 81.1%. CONCLUSIONS: CRT is recommended as the first choice for the treatment of M0 stage ASCC. Induction chemotherapy may bring better survival benefits for some patients. Patients with ASCC in China seem to have a better local control rate, which suggested different treatment strategies may be needed in China.

High dose chemoradiotherapy increases chance of organ preservation with satisfactory functional outcome for rectal cancer.

BACKGROUND: High dose chemoradiotherapy offers a curative chance for patients with rectal cancer that are unfit or unwilling to undergo surgical resection, yet its long-term survival and functional outcomes have been rarely investigated. METHODS: Patients with non-metastatic rectal adenocarcinoma who received pelvic radiation for curative intent from April 2006 to July 2017 were retrospectively investigated. Survival rates were analyzed using the Kaplan-Meier method. Quality of life and functional outcomes were evaluated using the EORTC quality of life questionnaire. RESULTS: A total of 57 patients were included, with a median age of 59.0 (range, 29-84) years. The numbers of patients who were diagnosed as stage I, II and III were 5 (8.8%), 16 (28.1%) and 36 (63.2%), respectively. 53 (93.0%) patients had tumor located within 5 cm from the anal verge. All patients received fluorouracil-based concurrent chemoradiotherapy with a median radiation dose of 80 (range, 60-86) Gy. All kinds of grade 3-4 adverse events occurred in 18 (31.6%) patients. 42 (73.7%) patients achieved a clinical complete response after chemoradiotherapy. After a median follow-up of 43.5 (range 14.9-163.2) months, 12 (21.1%) patients had local progression and 11 (19.3%) developed distant metastasis. The 3-year local recurrence-free survival and distant metastasis-free survival were 77.3% (95% CI, 65.7-88.8%) and 79.2% (95% CI, 68.2-90.2%), while the 3-year progression-free survival, cancer-specific survival, overall survival were 61.9% (95% CI, 48.8-75.0%), 93.1% (95% CI, 85.8-100.0%) and 91.4% (95% CI, 83.6-99.2%), respectively. For patients who had tumor located within 3 cm from the anal verge, the sphincter preservation rate was 85.3% at last follow-up. Long-term adverse events mainly were anal blood loss. 21 patients completed the quality-of-life questionnaire and had a score of the global health status of 78.57 ± 17.59. Of them, 95.2% reported no urinary incontinence and 85.7% reported no fecal incontinence. CONCLUSIONS: High dose chemoradiation demonstrated promising survival outcomes with acceptable short-term and long-term side effects, and satisfying long-term functional outcomes and quality of life. It could be considered as a non-invasive alternative for rectal cancer patients who refuse surgery.

Neoadjuvant PD-1 Blockade Combined With Chemotherapy Followed by Concurrent Immunoradiotherapy in Locally Advanced Anal Canal Squamous Cell Carcinoma Patients: Antitumor Efficacy, Safety and Biomarker Analysis.

Background: Anal canal squamous cell carcinoma (ACSCC) is an exceedingly rare malignant neoplasm with challenges in sphincter preservation, treatment toxicities and long-term survival. Little is known concerning the activity of PD-1 antibodies in locally advanced ACSCC. This study reports on the efficacy and toxicities of a neoadjuvant PD-1 blockade combined with chemotherapy followed by concurrent immunoradiotherapy in ACSCC patients, and describes biomarkers expression and mutation signatures. Methods: In this cohort study, patients were treated as planned, including four cycles of neoadjuvant PD-1 antibody toripalimab combined with docetaxol and cisplatin, followed by radiotherapy and two cycles of concurrent toripalimab. Multiplex immunofluorescence staining (mIHC) with PD-L1, CD8, CD163, Pan-Keratin and DAPI was performed with the pretreatment tumor tissue. Whole exome sequencing was performed for the primary tumor and peripheral blood mononuclear cells. The primary endpoint was the complete clinical response (cCR) rate at 3 months after overall treatment. Acute and late toxicities graded were assessed prospectively. Results: Five female patients with a median age of 50 years old (range, 43-65 years old), finished treatment as planned. One patient had grade 3 immune related dermatitis. Two patients had grade 3 myelosuppression during neoadjuvant treatment. No severe radiation-related toxicities were noted. Four patients with PD-L1 expression >1% achieved a cCR after neoadjuvant treatment. and the other patient with negative PD-L1 expression also achieved a cCR at 3 months after radiotherapy. All the patients were alive and free from disease and had a normal quality of life, with 19.6-24 months follow up. Inconsistent expression of PD-L1 and CD163 was detected in 3 and 5 patients, respectively. TTN, POLE, MGAM2 were the top mutation frequencies, and 80 significant driver genes were identified. Pathway analysis showed enrichment of apoptosis, Rap1, Ras, and pathways in cancer signaling pathways. Eight significantly deleted regions were identified. Conclusions: This small cohort of locally advanced ACSCC patients had quite satisfactory cCR and sphincter preservation rate, after neoadjuvant PD-1 antibody toripalimab combined with chemotherapy followed by concurrent immunoradiotherapy, with mild acute and long-term toxicities.

Serum Apolipoprotein A-I Predicts Response of Rectal Cancer to Neoadjuvant Chemoradiotherapy.

BACKGROUND: Serum lipids have been reported as prognosticators for malignancies, including rectal cancer (RC). Yet, their value in predicting the response of RC to neoadjuvant chemoradiotherapy (NACRT) remains unknown. This study aimed to assess the predictive abilities of serum lipids for a bad response, and to build a serum lipid-based prediction model. METHODS: In total, 751 patients diagnosed with stage cII-III RC and treated with NACRT plus surgery from January 2007 to August 2018 were retrospectively reviewed and randomly divided into two data sets, in a ratio of 1:1. Receiver operating characteristics (ROC) analysis was conducted in the development set to select possible predictors of bad NACRT response from pathoclinical factors, including serum lipids. Multivariate logistic regression was conducted to further determine independent predictors, which were then used to develop a prediction index (PI). Finally, the PI was verified in the validation set, through ROC analysis and chi-squared test. RESULTS: Five independent predictors were identified: tumor length ≥4 cm, cT4 stage, carcinoembryonic antigen ≥5.0 ng/mL, irradiation with three-dimensional conformal radiotherapy technique, and apolipoprotein A-I ≤1.20 g/L. Each of them was assigned a number of points. In the validation set, the area under the curve of PI appeared as 0.642 (95% confidence interval 0.586-0.697). The sensitivity, specificity, positive and negative predictive values, and concordance were 72.3%, 52.3%, 63.8%, 61.9%, and 63.0%, respectively. CONCLUSION: Serum apolipoprotein A-I was found to correlate negatively with the RC response to NACRT. It could serve as a biomarker for guiding individualized treatment and a potential target for improving sensitivity to chemoradiation.

Good Tumor Response to Chemoradioimmunotherapy in dMMR/MSI-H Advanced Colorectal Cancer: A Case Series.

Purpose: Immune checkpoint blockade has led to a significant improvement of patient survival in metastatic colorectal cancer (CRC) with DNA mismatch repair-deficiency (dMMR)/microsatellite instability-high (MSI-H). However, not all these patients are sensitive to monoimmunotherapy. We firstly presented a case series of advanced dMMR/MSI-H CRCs treating with PD-1 inhibitor-based chemoradioimmunotherapy (CRIT). Methods and Materials: We assessed the short-term efficacy and safety of CRIT in advanced dMMR/MSI-H CRCs, and also did next-generation sequencing (NGS) assays. Results: Our analysis included five advanced dMMR/MSI-H CRCs who have received toripalimab-based CRIT. Toripalimab was given 240mg every three weeks, and the radiation dose was 45-50 gray in 25 fractions. Chemotherapy regimens consisted of CAPOX in three patients, capecitabine in one patient, and mFOLFOX6 in one patient. Initially, two patients displayed complete response (CR), and three patients achieved partial response (PR) on imaging findings. Afterwards, one PR patient was confirmed pathological complete response after surgery, leading to three CR cases in total. Hematological toxicity was the most common adverse effect, and only two patients developed mild immune-related adverse effects besides. All the treatment-related adverse events were under control. Based on the NGS results, the median intratumor heterogeneity was 0.19 (range 0-0.957), which was less in CR patients than PR patients (P = 0.019). Genetic mutations at DNA damage repair genes and the JAK1 gene were also observed. Conclusions: For advanced dMMR/MSI-H CRC, anti-PD-1 based CRIT is effective and safe. Further studies are required to better clarify the potential role and mechanism of CRIT as a viable therapeutic strategy in this population.

Nomogram to Predict Distant Metastasis Probability for Pathological Complete Response Rectal Cancer Patients After Neoadjuvant Chemoradiotherapy.

PURPOSE: This study aimed to predict the risks of distant metastasis (DM) of locally advanced rectal cancer (LARC) patients with pathological complete response (pCR) after neoadjuvant chemoradiotherapy (NACRT) and total mesorectal excision (TME), and to find the association between adjuvant chemotherapy (ACT) and their survival outcomes. METHODS AND MATERIALS: A total of 242 patients with LARC achieving pCR after NACRT were enrolled in this retrospective study. We developed a nomogram model using logistic regression analyses for predicting risk of DM. The model performance was evaluated by the concordance index and calibration curve. Survival was determined using Kaplan-Meier survival curve. RESULTS: Age, pre-operative CEA, pre-treatment CEA and distance of tumor to anal verge were identified as significantly associated variables that could be enrolled in the model to predict the risk of DM for pCR patients. The nomogram we created had a bootstrapped-concordance index of 0.731 (95% CI = 0.627 to 0.834) and was well calibrated. The high risk group was more likely to develop DM than low risk group (total score) (95% CI = 1.439 to 6.493, P = 0.0036). The 1-year, 3-year, and 5-year distant metastasis-free survival (DMFS) for the low and high risk groups (total score ≤ 90 vs > 90) was 97.8%, 94.2%, 94.2% and 91.3%, 83.4%, 81.8%, respectively (P = 0.0036). DM occurred within 1 and 2 years after TME surgery was 33.3% and 55.6% for the low risk group, and 47.3% and 84.2% for the high risk group. The value of ACT was assessed among the whole cohort, patients with cT3-4, with cN+ or with either DM risk group, but no significant difference was observed concerning DMFS whether ACT was given or not (all P > 0.05). Active treatment after DM was more beneficial than palliative treatment (P < 0.001). CONCLUSION: The nomogram model, including age, pre-operative CEA, pre-treatment CEA and distance to anal verge, predicted the probability of DM among LARC patients achieving pCR after NACRT. The effects of ACT were not seen in different subgroups, while closer clinical follow-up may have greater contribution to pCR patients in the first 2 years, especially for patients with relatively higher risk to develop DM. It is suggested that timely active treatment can bring survival benefit for pCR patients developing DM after NACRT.

Neoadjuvant chemoradiotherapy in patients with unresectable locally advanced sigmoid colon cancer: clinical feasibility and outcome.

BACKGROUND: Patients with locally advanced sigmoid colon cancer (LASCC) have limited treatment options and a dismal prognosis with poor quality of life. This retrospective study aimed to further evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy (NACRT) followed by surgery as treatment for select patients with unresectable LASCC. METHODS: We studied patients with unresectable LASCC who received NACRT between November 2010 and April 2019. The NACRT regimen consisted of intensity modulated radiotherapy (IMRT) of 50 Gy to the gross tumor and positive lymphoma node and 45 Gy to the clinical target volume. Capecitabine­based chemotherapy was administered every 2 (mFOLFOX6) or 3 weeks (CAPEOX). Surgery was scheduled 6-8 weeks after radiotherapy. RESULTS: Seventy­two patients were enrolled in this study. Patients had a regular follow-up (median, 41.1 months; range, 8.3-116.5 months). Seventy­one patients completed NACRT, and sixty-five completed surgery. Resection with microscopically negative margins (R0 resection) was achieved in 64 patients (88.9%). Pathologic complete response was observed in 15 patients (23.1%), and multivisceral resection was necessary in 38 patients (58.3%). The cumulative probability of 3-year overall survival (OS) and progression-free survival (PFS) were 75.8 and 70.7%, respectively. CONCLUSIONS: For patients with unresectable LASCC, neoadjuvant chemoradiotherapy is feasible, surgery can be performed safely and may result in increased survival and organ preservation rates.

The watch-and-wait strategy versus surgical resection for rectal cancer patients with a clinical complete response after neoadjuvant chemoradiotherapy.

BACKGROUND: The watch-and-wait strategy offers a non-invasive therapeutic alternative for rectal cancer patients who have achieved a clinical complete response (cCR) after chemoradiotherapy. This study aimed to investigate the long-term clinical outcomes of this strategy in comparation to surgical resection. METHODS: Stage II/III rectal adenocarcinoma patients who received neoadjuvant chemoradiotherapy and achieved a cCR were selected from the databases of three centers. cCR was evaluated by findings from digital rectal examination, colonoscopy, and radiographic images. Patients in whom the watch-and-wait strategy was adopted were matched with patients who underwent radical resection through 1:1 propensity score matching analyses. Survival was calculated and compared in the two groups using the Kaplan-Meier method with the log rank test. RESULTS: A total of 117 patients in whom the watch-and-wait strategy was adopted were matched with 354 patients who underwent radical resection. After matching, there were 94 patients in each group, and no significant differences in term of age, sex, T stage, N stage or tumor location were observed between the two groups. The median follow-up time was 38.2 months. Patients in whom the watch-and-wait strategy was adopted exhibited a higher rate of local recurrences (14.9% vs. 1.1%), but most (85.7%) were salvageable. Three-year non-regrowth local recurrence-free survival was comparable between the two groups (98% vs. 98%, P = 0.506), but the watch-and-wait group presented an obvious advantage in terms of sphincter preservation, especially in patients with a tumor located within 3 cm of the anal verge (89.7% vs. 41.2%, P < 0.001). Three-year distant metastasis-free survival (88% in the watch-and-wait group vs. 89% in the surgical group, P = 0.874), 3-year disease-specific survival (99% vs. 96%, P = 0.643) and overall survival (99% vs. 96%, P = 0.905) were also comparable between the two groups, although a higher rate (35.7%) of distant metastases was observed in patients who exhibited local regrowth in the watch-and-wait group. CONCLUSION: The watch-and-wait strategy was safe, with similar survival outcomes but a superior sphincter preservation rate as compared to surgery in rectal cancer patients achieving a cCR after neoadjuvant chemoradiotherapy, and could be offered as a promising conservative alternative to invasive radical surgery.

A Genotype Signature for Predicting Pathologic Complete Response in Locally Advanced Rectal Cancer.

PURPOSE: To construct and validate a predicting genotype signature for pathologic complete response (pCR) in locally advanced rectal cancer (PGS-LARC) after neoadjuvant chemoradiation. METHODS AND MATERIALS: Whole exome sequencing was performed in 15 LARC tissues. Mutation sites were selected according to the whole exome sequencing data and literature. Target sequencing was performed in a training cohort (n = 202) to build the PGS-LARC model using regression analysis, and internal (n = 76) and external validation cohorts (n = 69) were used for validating the results. Predictive performance of the PGS-LARC model was compared with clinical factors and between subgroups. The PGS-LARC model comprised 15 genes. RESULTS: The area under the curve (AUC) of the PGS model in the training, internal, and external validation cohorts was 0.776 (0.697-0.849), 0.760 (0.644-0.867), and 0.812 (0.690-0.915), respectively, and demonstrated higher AUC, accuracy, sensitivity, and specificity than cT stage, cN stage, carcinoembryonic antigen level, and CA19-9 level for pCR prediction. The predictive performance of the model was superior to clinical factors in all subgroups. For patients with clinical complete response (cCR), the positive prediction value was 94.7%. CONCLUSIONS: The PGS-LARC is a reliable predictive tool for pCR in patients with LARC and might be helpful to enable nonoperative management strategy in those patients who refuse surgery. It has the potential to guide treatment decisions for patients with different probability of tumor regression after neoadjuvant therapy, especially when combining cCR criteria and PGS-LARC.

Efficacy of X-ray stereotactic radiotherapy on brain metastases and prognostic analysis.

BACKGROUND AND OBJECTIVE: X-ray stereotactic radiotherapy (SRT) is one of the effective treatments for brain metastases (BM). This study was to evaluate the efficacy of SRT on BM, and investigate prognostic factors. METHODS: Between July 1999 and December 2004, a total of 122 intracranial lesions in 78 patients with BM were treated using SRT in our Center. Forty-nine patients had a solitary lesion and 29 had multiple (2-6) lesions. The median SRT dose was 15 Gy (11-24 Gy) in single fraction for 38 lesions, and 24 Gy (11-40 Gy) in 2-6 fractions for 84 lesions. SRT was combined with whole brain radiotherapy (WBRT) of 30-40 Gy for 39 patients. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Univariate and multivariate analyses were performed by the log-rank test and Cox model, respectively. RESULTS: The median survival time was 12.9 months (1.7-77.4 months). The 1-year intracranial PFS rate was 87.4%. The 1-and 2-year OS rates were 53.9% and 25.8%, respectively. Univariate analysis showed that the 1-year OS rates were higher in the patients with pretreatment KPS of >/= 70, extracranial lesions controlled, or SRT combined with WBRT than in those with KPS of < 70 (60.7% vs. 29.4%, P = 0.002), extracranial lesions uncontrolled (69% vs. 44.9%, P = 0.005), or SRT alone (64.1% vs. 43.4%, P = 0.03). The benefit of treating with WBRT in combination was mainly achieved in the patients with extracranial lesions controlled or with more than one intracranial lesion. Multivariate analysis showed that KPS score and status of extracranial lesions were independent prognostic factors for OS. CONCLUSIONS: SRT is an effective and safe modality for BM. SRT combined with WBRT may prolong the survival time of the patients with extracranial lesions controlled or multiple intracranial lesions. Independent prognostic factors for OS are KPS score and status of extracranial lesions.

Total mesorectal excision with or without preoperative chemoradiotherapy for resectable mid/low rectal cancer: a long-term analysis of a prospective, single-center, randomized trial.

BACKGROUND: The preliminary results of our phase II randomized trial reported comparable functional sphincter preservation rates and short-term survival outcomes between patients undergoing total mesorectal excision (TME) with or without preoperative concurrent chemoradiotherapy (CCRT). We now report the long-term results after a median follow-up of 71 months. METHODS: Between March 23, 2008 and August 2, 2012, 192 patients with T3-T4 or node-positive, resectable, mid/low rectal adenocarcinoma were randomly assigned to receive TME with or without preoperative CCRT. The following endpoints were assessed: cumulative rates of local recurrence and distant metastasis, disease-free survival (DFS), and overall survival (OS). RESULTS: The data of 184 eligible patients were analyzed: 94 patients in the TME group and 90 patients in the CCRT + TME group. In the whole cohort, the 5-year DFS and OS rates were 84.8% and 85.1%, respectively. The 5-year DFS rates were 85.2% in the CCRT + TME group and 84.3% in the TME group (P = 0.969), and the 5-year OS rates were 83.5% in the CCRT + TME group and 86.5% in the TME group (P = 0.719). The 5-year cumulative rates of local recurrence were 6.3% and 5.0% (P = 0.681), and the 5-year cumulative rates of distant metastasis were 15.0% and 15.7% (P = 0.881) in the CCRT + TME and TME groups, respectively. No significant improvements in 5-year DFS and OS were observed with CCRT by subgroup analyses. CONCLUSIONS: Both treatment strategies yielded similar long-term outcomes. A selective policy towards preoperative CCRT is thus recommended for rectal cancer patients if high-quality TME surgery and enhanced chemotherapy can be performed. Trial registration ChiCTR-TRC-08000122. Registered 16 July 2008.