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.

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.

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.

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.

Neoadjuvant chemotherapy and radiotherapy followed by resection/ablation in stage IV rectal cancer patients with potentially resectable metastases.

BACKGROUND: The optimal treatment of stage IV rectal cancer remains controversial. The purpose of this study was to assess the treatment outcomes and toxicity of neoadjuvant chemotherapy and radiotherapy followed by local treatment of all tumor sites and subsequent adjuvant chemotherapy in stage IV rectal cancer patients with potentially resectable metastases. METHODS: Adult patients diagnosed with locally advanced rectal adenocarcinoma with potentially resectable metastases, who received neoadjuvant chemotherapy and radiotherapy from July 2013 and September 2019 at Sun Yat-sen University cancer center, were included. Completion of the whole treatment schedule, pathological response, treatment-related toxicity and survival were evaluated. RESULTS: A total of 228 patients were analyzed with a median follow-up of 33 (range 3.3 to 93.4) months. Eventually, 112 (49.1%) patients finished the whole treatment schedule, of which complete response of all tumor sites and pathological downstaging of the rectal tumor were observed in three (2.7%) and 90 (80.4%) patients. The three-year overall survival (OS) and progression-free survival (PFS) of all patients were 56.6% (50.2 to 63.9%) and 38.6% (95% CI 32.5 to 45.8%), respectively. For patients who finished the treatment schedule, 3-year OS (74.4% vs 39.2%, P < 0.001) and 3-year PFS (45.5% vs 30.5%, P = 0.004) were significantly improved compared those who did not finish the treatment. Grade 3-4 chem-radiotherapy treatment toxicities were observed in 51 (22.4%) of all patients and surgical complications occurred in 22 (9.6%) of 142 patients who underwent surgery, respectively. CONCLUSIONS: Neoadjuvant chemotherapy and radiotherapy followed by resection/ablation and subsequent adjuvant chemotherapy offered chances of long-term survival with tolerable toxicities for selected patients with potentially resectable stage IV rectal cancer, and could be considered as an option in clinical practice.

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 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.

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.

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.

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.

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.

Prognostic Value of the Cycle Number of Perioperative Chemotherapy in Locoregionally Advanced Rectal Cancer: a Propensity Score Matching Analysis.

Background: Appropriate cycle number of perioperative chemotherapy for patients with locoregionally advanced rectal cancer (LARC) remains unknown. This study aimed to evaluate how cycle number of perioperative chemotherapy influenced the prognosis of LARC patients. Methodology / Principal Findings: In this study, a total of 388 consecutive patients were enrolled and retrospectively reviewed if they were diagnosed with untreated stage cII-III LARC and treated with neoadjuvant chemoradiotherapy plus radical surgery followed by adjuvant chemotherapy or not. After grouping by the postoperative pathologic stage (yp0-I vs. ypII-III), propensity score matching was performed in each group to balance baseline characteristics between the patients treated with chemotherapy cycle ≤ 7 and those treated with chemotherapy cycle ≥ 8. The chemotherapy cycle was analyzed for its association with the survivals of the matched patients in the 2 groups, respectively. And the incidence of treatment-related complications was also compared. Through analysis, chemotherapy cycle ≥ 8 appeared to predict better overall, disease-free and distant-metastasis-free survivals in the whole cohort of matched patients (P values were 0.003, 0.002 and 0.004, respectively) and the ypII-III group (P values were 0.006, 0.005 and 0.014, respectively). But in the yp0-I group, chemotherapy of 8 cycles or more brought no improvement of survivals but only more acute toxicities (83.5% vs. 57.0%, P < 0.001). Conclusions / Significance: Chemotherapy cycle ≥ 8 was proven associated with improved prognosis of LARC patients, especially those with ypII-III disease. But prolonged chemotherapy should be performed with caution in patients with yp0-I stage.

The high pCR rate of sandwich neoadjuvant treatment in locally advanced rectal cancer may translate into a better long-term survival benefit: 5-year outcome of a Phase II clinical trial.

BACKGROUND: In a Phase II clinical trial, we reported the effectiveness and safety of a sandwich neoadjuvant treatment based on a modified oxaliplatin plus capecitabine (XELOX) regimen for locally advanced rectal cancer (LARC). The pathologic complete response (pCR) rate was 42.2%, and no patient presented Grade 4 acute toxicities. This study was performed to evaluate whether the high pCR rate could translate into an improved long-term survival benefit by analyzing the 5-year follow-up results of the trial. METHODS: Fifty-one patients with LARC were initially enrolled in the trial. Of these, 2 cases were eliminated due to distant metastasis before treatment. In addition, 4 cases were eliminated for refusing surgery after neoadjuvant chemoradiotherapy (NACRT). Finally, a total of 45 patients were treated with the sandwich NACRT plus total mesorectal excision. We followed up these patients and calculated their overall survival (OS) and disease-free survival (DFS) through a Kaplan-Meier approach. A log-rank test and multivariate survival analysis based on a Cox proportional hazard model were performed to explore the risk factors influencing distant metastasis. RESULTS: The median follow-up time was 60.8 months, and among the 45 patients analyzed, 1 (2.2%) patient suffered local recurrence, and 9 (20.0%) suffered distant metastasis. The 3-year OS and DFS were 95.6% and 84.4%, respectively. In addition, the 5-year OS and DFS were 91.1% and 80.0%, respectively. In the multivariate analysis, postsurgical pathological N stage and carbohydrate antigen 19-9 before treatment maintained statistical significance on distant metastasis. CONCLUSIONS: The sandwich NACRT with XELOX regimen might reduce distant metastasis and improve the survival of LARC patients. However, long-term benefits should be verified through further Phase III clinical trials.

Neoadjuvant oxaliplatin and capecitabine combined with bevacizumab plus radiotherapy for locally advanced rectal cancer: results of a single-institute phase II study.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by surgery is recommended as the standard of care for locally advanced rectal cancer, reducing local recurrence but not distant metastasis. Intensified systemic therapy is warranted to reduce the risk of distant metastasis. The present study aimed to evaluate the safety and efficacy of neoadjuvant oxaliplatin and capecitabine (XELOX) combined with bevacizumab plus radiotherapy for locally advanced rectal cancer. METHODS: Patients with stages II to III rectal cancer received one cycle of induction chemotherapy and concurrent chemoradiotherapy with XELOX plus bevacizumab. Surgery was performed 6-8 weeks after completion of radiotherapy, and postoperative chemotherapy with three cycles of XELOX and two cycles of capecitabine were given. The primary endpoints were pathologic complete response (pCR) rate and safety, and the secondary endpoints were 3-year overall survival and progression-free survival. RESULTS: Forty-five patients were enrolled between February 2013 and April 2015. All completed the neoadjuvant therapy. Seven patients (15.6%) refused subsequent surgical therapy for personal reasons, and the other 38 patients received radical resection, with a sphincter preservation rate of 84.2% and a pCR rate of 39.5%. Toxicity was acceptable, with grades 3-4 hematological toxicity and diarrhea observed in six and two patients, respectively. Incidence of anastomotic leak that required surgical intervention was 13.3%. After a median follow-up period of 37 months, five patients developed disease progression and two died of cancer. The 3-year overall survival rate and 3-year progression-free survival rate were 95.3% and 88.6%, respectively. CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemoradiotherapy resulted in a satisfying pCR rate and 3-year survival, but also may increase the risk of anastomotic leak, thus this regimen is not suitable to be considered for regular recommendation for locally advanced rectal cancer. Trial registration Clinicaltrials.govidentifierNCT01818973.

Neoadjuvant chemoradiotherapy followed by surgery in patients with unresectable locally advanced colon cancer: a prospective observational study.

BACKGROUND: The prognosis of locally unresectable colon cancer (CC) is poor. This prospective observational study aimed to further evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy (NACRT) followed by surgery in these patients. PATIENTS AND METHODS: We consecutively enrolled patients who were diagnosed with locally unresectable CC from November 2010 to March 2017, and received NACRT followed by surgery. The data of all the patients were collected prospectively. The R0 resection, down-stage and pathologic complete response (pCR) rates were calculated to evaluate the short-term treatment effects. The overall survival (OS) was used to evaluate the long-term outcome. The incidence of NACRT-related acute toxicities and postsurgical complications were used to assess the safety. RESULTS: A total of 60 patients were eligible for analysis, including 57 (95.0%) patients who attained resectability after NACRT. Among patients managed with surgery, 49 cases (86.0%) achieved R0 resection, and 15 cases (26.3%) achieved pCR. Down T stage was seen in 47 cases (82.5%), and down N stage was seen in 53 cases (93.0%). After a median follow-up time of 26 months, the OS appeared as 76.7%. The most common grade 3/4 NACRT-related toxicity was myelosuppression (incidence, 20.0%). The incidence of grade 3/4 surgery-related complication was 7.0%. CONCLUSION: NACRT might be a safe and effective choice for patients with locally unresectable CC to improve treatment effects, long-term survival and life quality, though further validation is needed.

Preoperative chemoradiotherapy creates an opportunity to perform sphincter preserving resection for low-lying locally advanced rectal cancer based on an oncologic outcome study.

Low-lying locally advanced rectal cancer (LARC) after preoperative chemoradiotherapy (CRT) can be surgically removed by either abdominperineal resection (APR) or sphincter preserving resection (SPR). This retrospective cohort study of 251 consecutive patients with low lying LARC who underwent CRT followed by radical surgery in a single institute, between March 2003 and November 2012, aimed to compare the oncological benefits between the two groups. 3-year disease free survival (DFS), overall survival (OS), cumulative incidence of recurrence and postoperative complications were compared between the two approaches. With median follow-up of 48.6 months, SPR group had higher 3-year DFS rate (86.4% vs 73.6%, P=0.023) and lower incidence of distant recurrence (12.0% vs 23.7%, P=0.026). The postoperative complications, incidence of local recurrence and the 3-year OS were comparable between the two groups. Pathologic T and N stage were the independent predictors for 3-year DFS (P=0.020 and P<0.001). In conclusion, our study suggest that low-lying LARC patients with a significant response to preoperative CRT can benefit from the advantage of SPR in preserving the anal sphincter function without compromising their oncologic outcome.

Outcomes of preoperative chemoradiotherapy followed by surgery in patients with unresectable locally advanced sigmoid colon cancer.

BACKGROUND: Complete resection of locally advanced sigmoid colon cancer (LASCC) is sometimes difficult. Patients with LASCC have a dismal prognosis and poor quality of life, which has encouraged the evaluation of alternative multimodality treatments. This prospective study aimed to assess the feasibility and efficacy of neoadjuvant chemoradiotherapy (neoCRT) followed by surgery as treatment of selected patients with unresectable LASCC. METHODS: We studied the patients with unresectable LASCC who received neoCRT followed by surgery between October 2010 and December 2012. The neoadjuvant regimen consisted of external-beam radiotherapy to 50 Gy and capecitabine-based chemotherapy every 3 weeks. Surgery was scheduled 6-8 weeks after radiotherapy. RESULTS: Twenty-one patients were included in this study. The median follow-up was 42 months (range, 17-57 months). All patients completed neoCRT and surgery. Resection with microscopically negative margins (R0 resection) was achieved in 20 patients (95.2%). Pathologic complete response was observed in 8 patients (38.1%). Multivisceral resection was necessary in only 7 patients (33.3%). Two patients (9.5%) experienced grade 2 postoperative complications. No patients died within 30 days after surgery. For 18 patients with pathologic M0 (ypM0) disease, the cumulative probability of 3-year local recurrence-free survival, disease-free survival and overall survival was 100.0%, 88.9% and 100.0%, respectively. For all 21 patients, the cumulative probability of 3-year overall survival was 95.2% and bladder function was well preserved. CONCLUSION: For patients with unresectable LASCC, preoperative chemoradiotherapy and surgery can be performed safely and may result in an increased survival rate.

Prediction of tumor response after neoadjuvant chemoradiotherapy in rectal cancer using (18)fluorine-2-deoxy-D-glucose positron emission tomography-computed tomography and serum carcinoembryonic antigen: a prospective study.

PURPOSE: To investigate the association between (18)fluorine-2-deoxy-D-glucose positron emission tomography-computed tomography ((18)F-FDG PET/CT) parameters, serum carcinoembryonic antigen (CEA), and tumor response in patients with rectal cancer receiving neoadjuvant chemoradiotherapy (nCRT). METHODS: Sixty-four patients with T3-4 and/or node-positive rectal cancer receiving nCRT followed by surgery were prospectively studied. PET/CT was performed before, and in 28 patients, both before and after nCRT. The pre-/post-nCRT maximum standardized uptake (SUVmax) values, differences between pre-/post-nCRT SUVmax (∆SUVmax), response index of SUVmax (RI-SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and CEA were measured. The ability of PET/CT parameters and CEA to predict Mandard's tumor regression grade (TRG) and pathological complete remission (pCR) were evaluated. RESULTS: 31 patients were identified as responders (TRG 1-2), and 19 exhibited pCR. For responders, significant differences were found for ΔSUVmax (24.88 vs. 15.39 g/ml, p = 0.037), RI-SUVmax (0.76 vs. 0.63, p = 0.025), ΔSUVmean (14.43 vs. 8.65 g/ml, p = 0.029), RI-SUVmean (0.77 vs. 0.63, p = 0.011), CEA-pre (6.30 vs. 27.86 µg/L, p < 0.001), CEA-post (2.22 vs. 5.49 µg/L, p = 0.002), ΔCEA (4.08 vs. 23.13 µg/L, p < 0.001), and RI-CEA (0.25 vs. 0.55, p = 0.002). Differences between pCR and non-pCR patients were noted as RI-SUVmean (0.77 vs. 0.65, p = 0.043), MTV-pre (9.87 vs. 14.62 cm(3), p = 0.045), CEA-pre (5.62 vs. 22.27 µg/L, p = 0.002), CEA-post (1.95 vs. 4.72 µg/L, p = 0.001), and ΔCEA (3.68 vs. 17.99 µg/L, p = 0.013). Receiver operating characteristic analysis revealed that RI-SUVmean exhibited the greatest accuracy in predicting responders, whereas CEA-post and ΔCEA exhibited the greatest accuracy in predicting pCR. CONCLUSIONS: (18)F-FDG PET/CT parameters and CEA are accurate tools for predicting tumor response to nCRT in rectal cancer.

Pathological Assessment of the AJCC Tumor Regression Grading System After Preoperative Chemoradiotherapy for Chinese Locally Advanced Rectal Cancer.

We used American Joint Committee on Cancer (AJCC) Staging Manual system to assess the prognostic significance of tumor regression grading (TRG) for locally advanced rectal cancer (LARC) (T3/4 or N+) patients who were treated with preoperative chemoradiotherapy (CRT).The 4 AJCC-TRG classifications were evaluated on surgical specimens from 295 LARC patients receiving CRT. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were estimated using Kaplan-Meier method and Cox regression model.Classifications of TRG 0, 1, 2, and 3 were found in 27.5%, 19.3%, 45.7%, and 7.5% of the resected specimens, respectively. Three-year OS was 95.5% for TRG0, 91.5% for TRG1, 84.8% for TRG2, and 85.7% for TRG3 (P = 0.035). Three-year DFS was 89.0% for TRG0, 74.4% for TRG1, 70.9% for TRG2, and 62% for TRG3 (P = 0.018). By multivariate analysis, AJCC-TRG (P = 0.033), residual lymph node metastasis (ypN+) (P < 0.001) and pretreatment CA19-9 level (P = 0.035) were significant predictors of OS. Pathological T category (P = 0.006) and nodal status (P < 0.001) after CRT were the most important independent prognostic factors for DFS.AJCC-TRG is a prognostic factor for LARC patients receiving CRT, independent of pathological staging.

Tumor deposits: markers of poor prognosis in patients with locally advanced rectal cancer following neoadjuvant chemoradiotherapy.

BACKGROUND: Tumor deposits (TDs) were reported to be poor prognoses in colorectal carcinoma, but the significance in locally advanced rectal cancer (LARC) (T3-4/N+) following neoadjuvant chemoradiotherapy (neo-CRT) and surgery is unclear. Since adjuvant chemotherapy showed no benefit for LARC following neo-CRT, it is of great value to investigate whether TDs can identify the subgroup of patients who may benefit from adjuvant chemotherapy. METHODS: Between 2004 and 2012, 310 LARC patients following neo-CRT and surgery were retrospectively reviewed. Overall survival (OS), disease-free survival (DFS), distant metastasis free survival (DMFS) and local recurrence free survival (LRFS) were evaluated by Kaplan-Meier method, log-rank test and Cox models. RESULTS: TDs-positive patients showed adverse OS, DFS and DMFS (all P ≤ 0.001), but not LRFS (P = 0.273). In multivariate analysis, TDs continued to be associated with poor OS (HR = 2.44, 95% CI 1.32-4.4, P = 0.004) and DFS (HR = 1.99, 95% CI 1.21-3.27, P = 0.007), but not DMFS (HR = 1.77, 95% CI 0.97-3.20, P = 0.061) or LRFS (HR = 1.85, 95% CI 0.58-5.85, P = 0.298). Among TDs-positive patients, adjuvant chemotherapy significantly improved OS (P = 0.045) and DMFS (P = 0.026), but not DFS (P = 0.127) or LRFS (P = 0.862). CONCLUSIONS: TDs are predictive of poor survival in LARC after neo-CRT. Fortunately, TDs-positive patients appear to benefit from adjuvant chemotherapy.