Cycles Of XELOX Research Articles

Total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC): Real-world experience from a tertiary Asian cancer center.

39 Background: Multiple studies of TNT for LARC have shown improved pathological complete response (pCR) rate and disease-free survival (DFS). However, real-world data in Asia is limited. Methods: Patients (pts) diagnosed with LARC at National University Cancer Institute, Singapore were discussed at a multidisciplinary tumor board. Patients were eligible for TNT if they had cT2/3N+ or cT4Nany, threatened circumferential resection margin (CRM) and adequate organ function. TNT protocol was systemic chemotherapy with 5-6 cycles of mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) or 3-4 cycles of XELOX (capecitabine, oxaliplatin) followed by short- or long-course chemoradiation (CRT), then 3 cycles of mFOLFOX6 or 2 cycles of XELOX. Clinical outcomes included rates of clinical complete response (cCR), pCR, surgery type, R0 resection and DFS. Baseline pt demographics, laboratory results and tumor characteristics were analyzed against these outcomes. Results: 173/205 pts who were diagnosed with rectal cancer between February 2020 and November 2022 had LARC and 47 received TNT. Median age was 65 (range: 33-79), 68.1% male, 78.7% were Chinese, 19.2% had cT4 tumors, 87.2% node positive and 80.9% had CRM involvement. Median tumor distance from anal verge was 6cm (range: 1-15cm) on colonoscopy and 5cm (range: 2-12cm) on magnetic resonance imaging. 95.7% received XELOX, 87.0% had long-course CRT and 83.0% completed all cycles of systemic chemotherapy and CRT. 44.7% had dose reduction of systemic therapy and 4.3% required emergent surgery due to local complications during TNT. After TNT completion, 7 pts did not pursue surgery – 3 achieved cCR (6.4%) and adopted a watch-and-wait approach, 2 had disease progression (PD), and 2 declined. Of those who underwent surgery, 75.0% had sphincter-preserving surgery and 85.0% achieved R0 resection. 2.1% (n =1) achieved pCR. Rates of tumour regression grade (TRG) 0, 1, 2, 3 were 7.5%, 15.0%, 67.5% and 10.0%, respectively. After a median follow up of 21.7 months (range: 9.3 – 41.6 months), 21.3% (n = 10) had disease recurrence and 14.9% (n=7; 5 from PD, 1 from surgery-related complication, 1 unrelated to treatment) passed away. 1-year DFS rate was 88.7% (95% CI 75.0% - 95.2%). Conclusions: This is the first Asian study reporting real-world data of TNT for LARC since its wide-scale adoption. pCR rates appear lower than reported studies. Understanding the limitation of retrospective studies, further analysis is ongoing to determine if factors other than sequence of modality can contribute to the observed findings.

Results of a prospective phase II study of total neoadjuvant therapy for locally advanced rectal cancer.

147 Background: Total neoadjuvant therapy is further accepted for the treatment of locally advanced rectal cancer, which is more valuable for patients with high-risk factors. Optimal schedule of radiotherapy and chemotherapy remains unknown and needs further exploration. Methods: We conducted a multicenter, randomized, phase II trial (ClinicalTrials.gov No.: NCT04543695). Patients aged 18-75 years with initial stage II / III rectal adenocarcinoma (At least one of high-risk factors should be included: mesorectal fascia involvement, T4, N2, positive lateral lymph node, or extramural vessel invasion) were assigned into three groups, 1) Chemoradiotherapy (50 Gy of radiation combined with oral capecitabine) followed by consolidation chemotherapy using six cycles of XELOX(CNCT group), 2) Induction chemotherapy before chemoradiotherapy (INCT group), or 3) Chemoradiotherapy alone (Control group). Then enrolled patients were required to undergo radical surgery after neoadjuvant therapy. Patients in Control group need six cycles of XELOX after surgery. The primary end point was proportion of yp0-II, and watch-and-wait strategy after complete clinical response (cCR) was allowed. Results: Of the 257 patients enrolled, 255 patients were evaluable (Control: CNCT: INCT= 84: 86: 85). Neoadjuvant treatment related grade 3 or 4 toxicity was higher in TNT approach (7.1%, 23.3% and 32.9% in Control, CNCT and INCT, respectively), of with myelosuppression being most common. Compliance of chemoradiotherapy was lower in INCT group (98.8%, 100% and 90.6% in Control, CNCT and INCT, respectively). As to CNCT and INCT, 60.0% and 74.1% of patients completed six cycles of chemotherapy, with 76.7% and 83.5% completing four cycles of chemotherapy, respectively. Proportions of downstage (yp0-II + sustained cCR) were achieved 75.6% in CNCT group and 74.1% in INCT group, respectively, compared to 56.0% in Control group. CR rates (pCR + sustained cCR) were achieved 43.0% in CNCT group and 38.8% in INCT group, respectively, compared to 20.2% in Control group. Both TNT approaches did not increase the incidence of surgical complications (6.0%, 8.1% and 10.9% in Control, CNCT and INCT, respectively), with anastomotic fistula and abdominal infection being of most common. Conclusions: Both TNT approaches increased the probability of ≥ G3 acute toxicities, but most patients could tolerate 4 cycles of neoadjuvant chemotherapy. Both TNT approaches could achieve a higher proportion of downstage and CR rate. Clinical trial information: NCT04543695 .

Short-Term Outcomes and Cost-Effectiveness between Long-Course Chemoradiation and Short-Course Radiotherapy for Locally Advanced Rectal Cancer.

Long-course chemoradiotherapy (LCRT) has been widely recommended in a majority of rectal cancer patients. Recently, encouraging data on short-course radiotherapy (SCRT) for rectal cancer has emerged. In this study, we aimed to compare these two methods in terms of short-term outcomes and cost analysis under the Korean medical insurance system. Sixty-two patients with high-risk rectal cancer, who underwent either SCRT or LCRT followed by total mesorectal excision (TME), were classified into two groups. Twenty-seven patients received 5 Gy×5 with two cycles of XELOX (capecitabine 1000 mg/m² and oxaliplatin 130 mg/m² every 3 weeks) followed by TME (SCRT group). Thirty-five patients received capecitabine-based LCRT followed by TME (LCRT group). Short-term outcomes and cost estimation were assessed between the two groups. Pathological complete response was achieved in 18.5% and 5.7% of patients in the SCRT and LCRT groups, respectively (p=0.223). The 2-year recurrence-free survival rate did not show significant difference between the two groups (SCRT vs. LCRT: 91.9% vs. 76.2%, p=0.394). The average total cost per patient for SCRT was 18% lower for inpatient treatment (SCRT vs. LCRT: $18787 vs. $22203, p<0.001) and 40% lower for outpatient treatment (SCRT vs. LCRT: $11955 vs. $19641, p<0.001) compared to LCRT. SCRT was shown to be the dominant treatment option with fewer recurrences and fewer complications at a lower cost. SCRT was well-tolerated and achieved favorable short-term outcomes. In addition, SCRT showed significant reduction in the total cost of care and distinguished cost-effectiveness compared to LCRT.

Efficacy and safety of sintilimab plus XELOX as neoadjuvant therapy in patients with locally advanced gastric cancer: A single-arm open-label phase II trial.

e16091 Background: Neoadjuvant chemotherapies have been widely recommended by clinical guidelines for patients with locally advanced gastric cancer. However, the evidence of combining neoadjuvant chemotherapy with anti-programmed death 1 (anti-PD-1) antibody therapy for patients with locally advanced gastric cancer is inadequate. Thus, we conducted a single-arm phase II trial to evaluate the efficacy and safety of anti-PD-1 antibody sintilimab and XELOX regimen (capecitabine plus oxaliplatin) in patients with locally advanced gastric adenocarcinoma. Methods: Patients with locally advanced(cT3-4 N+ M0, CY0,P0) were enrolled and received four preoperative cycles of XELOX (oxaliplatin 130mg/m2, IV, d1 with capecitabine 1000mg/m2, bid, d1-d14, q21d) and sintilimab (200mg, IV, q21d). Surgery was performed within 3-4 weeks after completion preoperative therapy. After surgery, patients received four cycles of XELOX. The primary endpoint was the pathological complete response (pCR) rate and the secondary endpoints were major pathologic response (MPR) rate, R0 resection rate, safety, disease-free survival (DFS) and overall survival (OS). This clinical trial is registered at ChiCTR.gov.cn: ChiCTR2000030414. Results: From March 2020 to July 2021, 30 patients were enrolled, with median age 62 years (range30-72), males 18, cT3/T4: 8/22, cN1/2/3: 10/14/6, intestinal diffuse type (Lauren classification):17/13, ECOG PS 0/1/2: 19/8/3. There were 19(63.3%) patients with PD-L1 CPS≥1. All patients were available for preoperative response evaluation, the objective response (ORR) rate was 70.0% (95% CI, 50.6%-85.3%) and the disease control (DCR) rate was 100% (95% CI, 88.4%-100%). All (100%) achieved R0 resection. 10 patients (33.3%) achieved pCR (TRG 0) and 19 patients (63.3%) had MPR (TRG 0-1). Common treatment-related adverse events (TRAEs) were anemia (36.7%), leukopenia (36.7%), neutropenia (30.0%), diarrhea (26.6%), ALT increase (23.3%), AST increase (13.3%), thrombocytopenia (10.0%), vomiting (10.0%). The potential immune-related adverse events (irAEs) were dermatitis (6.7%), hypothyroidism (3.3%), pneumonia (10.0%). Most of the TRAEs and potential irAEs were grade 1 or 2. Grade3 TRAEs and irAEs included ALT increase (3.3%), AST increase (3.3%), dermatitis (3.3%). There were no severe complications and death related to the operation. The median postoperative hospital stay was 8 days (range6-23 days). Conclusions: Sintilimab plus XELOX as neoadjuvant therapy showed an encouraging pCR rate, MPR rate and manageable safety. This combination regimen might provide a new option for patients with locally advanced gastric cancer. Clinical trial information: ChiCTR2000030414.

Efficacy of Different Number of XELOX or SOX Chemotherapy Cycles After D2 Resection for Stage III Gastric Cancer

PurposeWe aimed to explore whether the prognosis of patients treated with capecitabine and oxaliplatin (XELOX) or S-1 and oxaliplatin (SOX) regimens who received fewer cycles of chemotherapy after D2 radical resection for gastric cancer (GC) would be non-inferior to that of patients who received the standard number of cycles of chemotherapy.Materials and MethodsData on patients who received XELOX or SOX chemotherapy after undergoing D2 radical resection at Harbin Medical University Cancer Hospital between January 2011 and May 2016 were collected.ResultsIn patients who received 4, 6, and 8 cycles of chemotherapy, the 5-year overall survival (OS) rates were 59.4%, 64.8%, and 62.7%, respectively. Compared to patients who received 4 cycles of chemotherapy, those who received 6 cycles (hazard ratio [HR], 0.882; 95% confidence interval [CI], 0.599–1.299; P=0.52) or 8 cycles (HR, 0.882; 95% CI, 0.533–1.458; P=0.62) of chemotherapy did not exhibit significantly prolonged OS. The 3-year disease-free survival (DFS) rate of patients who received 4, 6, and 8 cycles of chemotherapy was 62.1%, 67.2%, and 60.8%, respectively. Compared to patients who received 4 cycles of chemotherapy, those who received 6 cycles (HR, 0.835; 95% CI, 0.572–1.221; P=0.35) or 8 cycles (HR, 0.972; 95% CI, 0.606–1.558; P=0.91) of chemotherapy did not show significantly prolonged DFS. However, the 3-year DFS and 5-year OS rates of patients who received 6 cycles of chemotherapy appeared to be superior to those of patients who received 4 and 8 cycles of chemotherapy.ConclusionsFor patients with stage III GC, 4 to 6 cycles of XELOX or SOX chemotherapy may be a favorable option. This study provides a rationale for further randomized clinical trials.

XELOX or mFOLFOX6 chemotherapy combined with resection of primary lesion versus chemotherapy alone for colon cancer with unresectable metastases: A randomized clinical trial.

3590 Background: It is still controversial for colon cancer patients with unresectable metastases whether to resect the primary tumor when there are no symptoms of primary lesion. Methods: This is an open-label, single-center, prospective, randomized, controlled phase II trial. Colon cancer patients aged 18-80 years with unresectable metastases at enrollment will be randomly allocated to either resection group (group A) or chemotherapy group (group B), and stratified by tumor response and number of organ metastases, after receiving induction chemotherapy with 4 cycles of XELOX or 6 cycles of mFOLFOX6, excluding those with disease progression, lesions radically resectable, or primary lesion unresectable. Patients in group A received resection of primary lesion and then continued chemotherapy, and patients in group B just continued chemotherapy, both up to 4 cycles of XELOX or 6 cycles of mFOLFOX6, and capecitabine maintenance afterwards. If progression occurs 3 months after discontinuation of oxaliplatin and toxicity has recovered to grade I, the original regimen can be applied again. The primary endpoint was TFS (time to failure of strategy, defined as the time from randomization to secondary progression in patients received re-introduce of the induction chemotherapy regimen, or to first progression in patients without re-introduce of the original regimen). The secondary endpoints included progression-free survival (PFS, the time from randomization to first progression), overall survival (OS, the time from enrollment to death), and adverse events (AEs). Efficacy data were analyzed on an intention-to-treat (ITT) basis. This study is registered with ClinicalTrials.gov, number NCT02291744. Results: Between April, 2015, and July, 2020, 140 patients were enrolled, and 54 patients withdrew due to colon obstruction (16), perforation (1), disease progression (22), death (1), radical resection (3), or other reasons (11). Finally, 86 patients were randomized into group A (n = 42) or group B (n = 44). The median TFS was 143 days (95%CI: 104.9-181.1) in group A, and 196 days (95%CI: 96.5-295.5) in group B (HR:0.930 95%CI:0.589-1.468, p = 0.755). The median PFS was 147 days (95%CI: 105.7-188.3) in group A, and 206 days(95%CI:180.9-231.1) in group B (HR:0.831, 95%CI:0.522-1.323, p = 0.436). The median OS was 530 days (95%CI: 308.9-751.1) in group A, and 779 days (95%CI:626.3-931.7) in group B (HR:0.948 95%CI:0.554-1.622, p = 0.845). The incidence of treatment-related AEs was similar between two groups. Conclusions: Resection of primary tumor after induction chemotherapy could not bring survival benefits. It’s not recommended for patients without symptoms of primary lesion to receive primary tumor resection, but it also requires individualized treatment as colon obstruction or perforation occurred in some patients. Clinical trial information: NCT02291744.

Isolated splenic metastases from colon cancer: clinical observations

Isolated splenic metastases from colorectal cancer after radical surgical treatment are quite rare. This frequency of metastases is explained by the anatomical, functional and immunological characteristics of the spleen. The literature usually describes single clinical cases followed by accompanied systematic analysis and discussion. Most of the cases are asymptomatic and are accidentally diagnosed, during different types of imaging tests, including increased levels of tumor markers. The progression free survival was 3 144 months after surgical treatment of the primary tumor in most of the patients. By the nature of the lesion, metastases can be synchronous and metachronous, as well as solitary and multiple.&#x0D; Aim. To discuss two clinical observations of isolated splenic metastases in patients after left colic flexure cancer surgical treatment.&#x0D; Materials and methods. We observed 2 female patients, 68 and 70 years old, with isolated splenic metastatic after left colic flexure cancer radical surgical treatment.&#x0D; Results. Both cases are considered to be metachronous and the interval of absence of disease manifestations are 21 and 10 months, respectively. The patients with stage IIB and IIC left colic flexure cancer underwent left hemicolectomy followed by adjuvant polychemotherapy using regimen with 6 cycles of FOLFOX. The histological study revealed a moderately differentiated adenocarcinoma with invasion into all layers of the wall and into the surrounding tissue. There were no lymph node metastases. In the course of dynamic observation, during the next examination with the help of ultrasound examination we revealed splenic metastasis, and confirmed this using positron emission tomography/computed tomography. The disease was without clinical picture. The time interval after the surgery before diagnosis was 21 and 10 months, respectively. Surgery was performed in the volume of splenectomy. Isolated splenic metastases in the absence of other manifestations of the disease were found intraoperatively. The histological study showed the splenic metastasis of the same type of cancer as the primary tumor. The polychemotherapy using regimen with 6 cycles of XELOX was performed during the postoperative period. Patients are alive without signs of the disease over the period of 5 and 26 months, respectively.&#x0D; Conclusion. Isolated splenic metastases are extremely rare, more often when the primary tumor is located in the left side of the colon. The showed cases illustrate the need and importance of the monitoring the patients after surgical treatment for colon cancer. The use of positron emission tomography/computed tomography helps to understand the real prevalence of the tumor process, without using invasive methods. The surgery in the volume of splenectomy followed by chemotherapy are the main therapeutic options. In one clinical case, the metastases were multiple, and in the other one was solitary metastasis. Patients are alive without signs of the disease over the period of 5 and 26 months, respectively.

Short-course radiotherapy with consolidation chemotherapy versus conventionally fractionated long-course chemoradiotherapy for locally advanced rectal cancer: randomized clinical trial.

The trial hypothesis was that, in a resource-constrained situation, short-course radiotherapy would improve treatment compliance compared with conventional chemoradiotherapy for locally advanced rectal cancer, without compromising oncological outcomes. In this open-label RCT, patients with cT3, cT4 or node-positive non-metastatic rectal cancer were allocated randomly to 5 × 5 Gy radiotherapy and two cycles of XELOX (arm A) or chemoradiotherapy with concurrent capecitabine (arm B), followed by total mesorectal excision in both arms. All patients received a further six cycles of adjuvant chemotherapy with the XELOX regimen. The primary endpoint was treatment compliance, defined as the ability to complete planned treatment, including neoadjuvant radiochemotherapy, surgery, and adjuvant chemotherapy to a dose of six cycles. Of 162 allocated patients, 140 were eligible for analysis: 69 in arm A and 71 in arm B. Compliance with planned treatment (primary endpoint) was greater in arm A (63 versus 41 per cent; P = 0.005). The incidence of acute toxicities of neoadjuvant therapy was similar (haematological: 28 versus 32 per cent, P = 0.533; gastrointestinal: 14 versus 21 per cent, P = 0.305; grade III-IV: 2 versus 4 per cent, P = 1.000). Delays in radiotherapy were less common in arm A (9 versus 45 per cent; P < 0.001), and overall times for completion of neoadjuvant treatment were shorter (P < 0.001). The rates of R0 resection (87 versus 90 per cent; P = 0.554), sphincter preservation (32 versus 35 per cent; P = 0.708), pathological complete response (12 versus 10 per cent; P = 0.740), and overall tumour downstaging (75 versus 75 per cent; P = 0.920) were similar. Downstaging of the primary tumour (ypT) was more common in arm A (P = 0.044). There was no difference in postoperative complications between trial arms (P = 0.838). Reduced treatment delays and a higher rate of compliance were observed with treatment for short-course radiotherapy with consolidation chemotherapy, with no difference in early oncological surgical outcomes. In time- and resource-constrained rectal cancer units in developing countries, short-course radiotherapy should be the standard of care.

Correlation of RECIST, Computed Tomography Morphological Response, and Pathological Regression in Hepatic Metastasis Secondary to Colorectal Cancer: The AVAMET Study.

Background: The prospective phase IV AVAMET study was undertaken to correlate response evaluation criteria in solid tumors (RECIST)-defined response rates with computed tomography-based morphological criteria (CTMC) and pathological response after liver resection of colorectal cancer metastases. Methods: Eligible patients were aged ≥18 years, with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and histologically-confirmed colon or rectal adenocarcinoma with measurable liver metastases. Preoperative treatment was bevacizumab (7.5 mg on day 1) + XELOX (oxaliplatin 130 mg/m2, capecitabine 1000 mg/m2 bid on days 1–14 q3w). After three cycles, response was evaluated by a multidisciplinary team. Patients who were progression-free and metastasectomy candidates received one cycle of XELOX before undergoing surgery 3–5 weeks later, followed by four cycles of bevacizumab + XELOX. Results: A total of 83 patients entered the study; 68 were eligible for RECIST, 67 for CTMC, and 51 for pathological response evaluation. Of these patients, 49% had a complete or partial RECIST response, 91% had an optimal or incomplete CTMC response, and 81% had a complete or major pathological response. CTMC response predicted 37 of 41 pathological responses versus 23 of 41 responses predicted using RECIST (p = 0.008). Kappa coefficients indicated a lack of correlation between the results of RECIST and morphological responses and between morphological and pathological response rates. Conclusion: CTMC may represent a better marker of pathological response to bevacizumab + XELOX than RECIST in patients with potentially-resectable CRC liver metastases.

Multicentre Randomised Phase III Trial of Capecitabine With or Without Irinotecan Guided by UGT1A1 Status in Patients Undergoing Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer

Background: Our previous study identified irinotecan dose differentiated by UGT1A1 genotype in the neoadjuvant chemoradiotherapy and showed improved pCR. The objective of this phase III study was to further investigate irinotecan combined with capecitabine-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Methods: We underwent a randomized, open-label, multicenter, phase 3 trial in China. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma were randomly allocated to the control arm (CapRT arm): pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine 825 mg/m2 twice daily 5 days per week, followed by a cycle of XELOX two weeks after the end of CRT; or the experimental arm (CapIriRT arm): radiation with capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28, followed by a cycle of XELIRI. The primary endpoint is pathological complete response (pCR). This trial was registered with ClinicalTrials.gov, number NCT02605265. Findings: Of the 360 patients initial enrolled, 356 were evaluated in mITT dataset (both 178 in two arms). Surgery was performed in 87% and 88% of patients in two arms, with 39% and 31% of patients got abdominoperineal resection respectively. The pCR rates were 18% (27/154) in CapRT arm and 34% (53/157) in CapIriRT arm (risk ratio 1.93; 95% CI 1.28–2.89, p=0.001), additional 4 and 6 patients were marked as complete clinical response (cCR). therefore, the overall CR rates were 17% and 33%, respectively. The most common grade 3-4 toxicities during CRT were leukopenia (3% vs. 25%), neutropenia (2% vs. 20%), and diarrhoea (2% vs. 13%). The overall rate of surgical complications were not significantly different between arms (11% vs. 15%). Interpretation: Adding irinotecan guided by UGT1A1 to capecitabine-based neoadjuvant chemoradiotherapy significantly increases complete tumor response. The treatment toxicities were increased but tolerable. Trial Registration: ClinicalTrials.gov, number NCT02605265 Funding Information: This study was funded by grants from Fudan University Shanghai Cancer Center (YJLC201601) and National Natural Science Foundation of China (81773357). We thank the patients, investigators, and institutions involved in this study. Competing Interest Declaration: I/We declare no competing interests. Ethical Approval Statement: The study was approved by the central ethics committee of Fudan University Shanghai Cancer Center (Shanghai, China)

Long-course neoadjuvant chemoradiotherapy with versus without a concomitant boost in locally advanced rectal cancer: a randomized, multicenter, phase II trial (FDRT-002)

BackgroundThis study was designed to explore whether an intensified chemoradiotherapy (CRT) led to a better clinical outcome in locally advanced rectal cancer.MethodsPatients with stage II/III rectal cancer were randomly allocated to receive either pelvic intensity-modulated radiation therapy (IMRT) of 50 Gy/25Fx concurrently with capecitabine and oxaliplatin (Arm A), or pelvic radiation of 50 Gy/25Fx with a concomitant boost of 5 Gy to the primary lesion, followed by a cycle of XELOX 2 weeks after the end of CRT (Arm B). All patients were planned to receive a definitive operation 8 weeks after the completion of CRT and a total of six perioperative chemotherapy cycles of capecitabine and oxaliplatin regardless of pathological result. Pathological complete response (ypCR) was the primary endpoint.ResultsFrom February 2010 to December 2011, 120 patients from three centers were enrolled in this study. Ninety-five percent patients completed a full-dose chemoradiotherapy as planning. Then 53 and 57 patients received a radical surgery, and 8 and 14 cases were confirmed as ypCR in two groups (P = 0.157). The other 10 patients failed to receive a definitive resection because of unresectable disease. Similar toxicities were observed between two groups and more incision healing delay were found in Arm B (3 vs.13, P = 0.011). No statistical differences were observed in local-regional control (P = 0.856), disease-free survival (P = 0.349) and overall survival (P = 0.553). Mesorectal fascia (MRF) involvement was an independent prognostic factor for survival in multivariate analysis.ConclusionsA concomitant boost to oxalipatin-combined preoperative chemoradiotherapy demonstrated a slightly higher pCR rate but delayed incision healing after surgery. The impact of MRF involvement on survival merits further investigations.Trial registrationNCT01064999 (ClinicalTrials.gov).

Oxaliplatin plus Capecitabine in the Perioperative Treatment of Locally Advanced Gastric Adenocarcinoma in Combination with D2 Gastrectomy: NEO-CLASSIC Study.

Lessons Learned.The NEO‐CLASSIC study provided valuable insight for the clinical efficacy and tolerability profiles of perioperative chemotherapy with oxaliplatin and capecitabine, plus gastrectomy, in patients with localized resectable gastric cancer.The study was designed to explore the potential survival benefits of an eight‐cycle, perioperative oxaliplatin and capecitabine (XELOX) schedule in the above‐mentioned setting and to explore the feasibility of prolonging the cycles of preoperative chemotherapy. The projected endpoint was not met.Background.This multicenter, open‐label study (NEO‐CLASSIC) evaluated the efficacy and safety of oxaliplatin and capecitabine (XELOX), plus D2 gastrectomy, in localized resectable gastric cancer.Methods.Patients aged 18–75 years with histologically‐confirmed gastric adenocarcinoma (stage T2–4a/N+M0) were given eight cycles of XELOX (four preoperatively, four postoperatively). Each 3‐week cycle comprised capecitabine 1,000 mg/m2 twice daily on days 1–14 and oxaliplatin 130 mg/m2 on day 1. Curative D2 gastrectomy was scheduled 2–4 weeks after the last preoperative cycle. The primary objective of the study was to determine the objective response rate (ORR) of XELOX in the preoperative setting. Sample size was calculated by assuming that a minimum of 47 cases would be required to increase the ORR by 15% (from 40% to 55%). With an estimated 10% dropout rate, 55 patients would have to be recruited.Results.Fifty‐five patients were enrolled, and one was excluded because of screening failure. R0 resections were achieved in 45 of 54 intent‐to‐treat patients (83.3%), and four patients received R1 resections (Fig. 1). There were no complete responses, 27 (50.0%) partial responses, 22 cases (40.7%) of stable disease, and 4 (7.4%) of progressive disease. The objective response rate was 50.0%. Median follow‐up was 52.97 months; 30 patients (55.6%) had disease progression (Table 1), and median progression‐free survival was 20.10 (95% confidence interval: 4.31—35.89) months; median overall survival was 30.77 months (95% confidence interval was not yet available) (Fig. 2). Fifty‐four patients completed 209 cycles of preoperative chemotherapy; 42 patients received 133 cycles of postoperative chemotherapy (Table 3). The rate of grade 3–4 adverse events was 8.5% (29/342 cycles); the most frequent events were neutropenia (9/342 cycles) and leukopenia (4/342 cycles).Conclusion.These findings suggest that combination therapy with capecitabine and oxaliplatin as perioperative chemotherapy, followed by D2 gastrectomy, is effective and safe in late‐stage, locally advanced gastric cancer. Although enrollment exceeded the 47 patients required to identify an increase in the ORR by 15% (from 40% to 55%), results did not meet the primary endpoint.

A multicenter randomized phase III trial of capecitabine with or without irinotecan driven by UGT1A1 in neoadjuvant chemoradiation of locally advanced rectal cancer (CinClare).

3510 Background: Our phase I/II study identified irinotecan dose differentiated by UGT1A1 genotype in the neoadjuvant CRT and showed improved pCR. The objective of this phase III study was to further investigate irinotecan combined with capecitabine-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Methods: We underwent a prospective, randomized, open-label, multicenter, phase 3 trial in China from Nov.2015 to Dec.2017. Eligible patients with clinical stage T3-4 and/or N+ rectal adenocarcinoma were randomly allocated to two arms. The approach in control arm (Arm A, n = 180) was pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine 825 mg/m2 twice daily 5 days per week, followed by a cycle of XELOX two weeks after the end of CRT. The experimental arm (Arm B, n = 180) was pelvic radiation with capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan. The irinotecan dose was used based on UGT1A1 genotype of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28 weekly, followed by a cycle of XELIRI. The primary endpoint is pathological complete response (pCR). This trial was registered with ClinicalTrials.gov, number NCT02605265. Results: Surgery was performed in 86.5% and 88.2% of patients in two groups, with 38.9% and 30.5% of patients got abdominoperineal resection respectively. The pCR rate was 17.5% in Arm A and 33.8% in Arm B (P = 0.001). Four and 6 patients maintained a complete clinical response status at least 12 months and were marked as cCR. The CR rate, including pCR and cCR, was 17.4% in Arm A and 33.1% in Arm B (P = 0.001). The most common grade 3-4 adverse events during preoperative treatment were leucopenia (3.4% vs. 25.3%), neutropenia (1.7% vs. 19.7%) and diarrhea (1.7% vs. 13.5%) in two arms. The overall rate of surgical complications were not significantly different between arms (11.0% vs. 14.6%). Conclusions: Adding irinotecan guided by UGT1A1 to capecitabine-based neoadjuvant chemoradiotherapy significantly increases complete tumor response. The treatment toxicities were increased but tolerable. This treatment can be as an option for ‘watch and wait’ approach. Clinical trial information: NCT02605265.

Occurrence of irreversible sinusoidal obstruction syndrome during adjuvant chemotherapy for colorectal cancer using oxaliplatin: A multi-center study.

546 Background: Oxaliplatin reduces the recurrence rate after curative surgery for stage III colorectal cancer. However, it can cause hepatic sinusoidal obstruction syndrome (SOS), an adverse effect that creates morbidity after liver resection for recurrence. SOS has conventionally been diagnosed by liver biopsy, which is invasive. We have reported that a 10% increase in splenic volume (SV) indicates SOS (J Surg Oncol 2017). In this multi-center study, we measured SV to evaluate SOS caused by adjuvant chemotherapy. Methods: This multi-center study included the participants of the FACOS study, which included patients with Stage III colon cancer. Participants received 12 cycles of mFOLFOX6 or eight cycles of XELOX as adjuvant chemotherapy. We used multi-detector raw CT to measure SV three times; before surgery, on completion of adjuvant chemotherapy, and 1-year after completing adjuvant chemotherapy. CT images were taken in 5-mm slices. SV was calculated by using a volume calculator SYNAPSE VINCENT v3.0(Fujifilm, Japan). Results: The FACOS study included 130 patients, 16.9% of whom discontinued treatment. The mean relative dose intensity (RDI) of oxaliplatin was 80.3%. Grade 3 neutropenia, thrombocytopenia, and neuropathy were observed in 28.5%, 6.2%, and 4.6% of patients, respectively. The 3 year DFS was 82.2%. We analyzed data of 75 patients (57.7%) for whom the three CT studies were available. SV on completing chemotherapy (median 181 cm3) and SV 1-year after completing chemotherapy (141 cm3) were significantly higher than that before surgery (128 cm3) (P &lt; 0.001). SV increased by more than 10% after chemotherapy in 72% and was still increased 1 year after chemotherapy in 51% of patients. Conclusions: In our previous single center study, SV had increased in 84% on completing chemotherapy and was still increased in 47% 1 year after completing chemotherapy. Adjuvant chemotherapy without oxaliplatin induced SV increases in only 20% of patients on completing chemotherapy. Thus, these results are reproducible and show the potential of oxaliplatin to induce SOS. Oxaliplatin frequently induces SOS and this SOS persists for over 1 year in half of affected patients. Clinical trial information: UMIN000005427.

Image-guided high-dose-rate interstitial brachytherapy for recurrent rectal cancer after salvage surgery: a case report

Treatment options for patients with recurrent rectal cancer in pelvis represent a significant challenge because the balance of efficiency and toxicity needs to be pursued. This case report illustrates a treatment effect of image-guided high-dose-rate interstitial brachytherapy (HDR-ISBT) for locally relapsed rectal cancer after salvage surgery. A 61-year-old male who underwent laparoscopic high anterior resection (LAP-HAR) with D3 lymph node dissection as a primary treatment for rectal cancer (pT3N0M0, well-differentiated adenocarcinoma) had relapsed locally 8 months after initial surgery, for which he underwent salvage abdominal perineal resection (APR), followed by adjuvant 8 cycles of XELOX (capecitabine and oxaliplatin) chemotherapy. He developed pelvic recurrence 1 year after the second surgery. Image-guided HDR-ISBT was performed (30 Gy/5 fractions/3 days) followed by external beam radiation therapy with 39.6 Gy in 22 fractions. There were no severe complications related to salvage radiotherapy. CEA was decreased from 24.5 ng/ml to 0.7 ng/ml, 4 months after the salvage radiotherapy. Complete response was noted on follow-up MRIs done on 2, 5, 8, and 14 months after the treatment. Hence, HDR-ISBT appears to be effective for locally recurrent rectal cancer even after salvage surgery.

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

BackgroundNeoadjuvant 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.MethodsPatients 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.ResultsForty-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.ConclusionsThe 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

Advances in colorectal cancer research from 2017 annual meeting of Chinese Society of Clinical Oncology

There are several progresses in colorectal cancer research from 2017 annual meeting of Chinese Society of Clinical Oncology (CSCO). (1) Phase Ⅲ multi-center trial FRESCO and TERRA study have showed domestic new drug Fruquintinib and Japanese oral combination anti-cancer drug TAS-102 significantly improved overall survival (OS) comparing to placebo in third-line metastatic colorectal cancer (mCRC) patients. (2) Preoperative neoadjuvant chemotherapy with mFOLFOXIRI and selective radiotherapy or concomitant boost neoadjuvant chemoradiotherapy (nCRT) followed by one cycle of XELOX, can improve short-term outcome for locally advanced rectal cancer, and clinical and pathological features can be used to predict complete response following nCRT. (3) In asymptomatic elderly population, the specificity of septin9 methylation detection in plasma cfDNA as colorectal cancer screening is low, but the probability of negative predictions as non-colorectal cancer is high. And integrated signature of the gut microbiome and metabolome serves as diagnostic biomarkers in patients with colorectal cancer. (4) Immunoscore system predicts prognosis after liver metastasectomy in colorectal metastases, and the immune signature difference between right and left colon cancer could explain the difference of targeted therapy. Key words: Colorectal neoplasms; Third-line treatment; Neoadjuvant chemoradiation; Screening; Immune signature

Self-Reported Adherence to Capecitabine on XELOX Treatment as Adjuvant Therapy for Colorectal Cancer.

Adherence has become an important issue in modern oncology treatment. Most studies have included heterogeneous target tumor types, regimens, and therapy settings. Our study focused on capecitabine during capecitabine plus oxaliplatin (XELOX) treatment as an adjuvant therapy for colorectal cancer. The main aims of this study were to evaluate real-life adherence to capecitabine and to investigate candidate factors that might decrease adherence. We studied 338 consecutive patients who received XELOX treatment between December 1, 2011, and April 30, 2015, at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. Our study assessed adherence to capecitabine through patient-reported treatment diaries and interviewed nonadherents to determine the reasons for not taking capecitabine at a pharmaceutical outpatient clinic. We calculated the adherence rate in a cycle as: number of times the patient took capecitabine/28. Relative dose intensities and factors associated with deteriorating adherence to capecitabine were retrospectively surveyed from electronic patient records. Uni- and multivariate logistic regression analyses were used to investigate factors associated with optimal adherence. The study covered 282 patients who received 2,055 cycles of XELOX. Median adherence rate was 94.0% in the first cycle, and median relative dose intensity of capecitabine was 77.8%. The most common reasons for nonadherence were nausea/vomiting and diarrhea. The presence of the following factors was not significantly associated with adherence: ECOG performance status ≥1 (p = 0.715), clinical stage (p = 0.408), primary tumor site (p = 0.576), age ≥70 years at study entry (p = 0.757), female gender (p = 0.504), and not living alone (p = 0.579). The adherence rate from this study was significantly higher than the adherence from metastatic settings. Adherence-enhancing interventions for capecitabine in XELOX treatment as adjuvant therapy comprised management of nausea/vomiting and diarrhea.

Comparison of two different neoadjuvant chemoradiatiotherapy regimens for locally advanced rectal cancer: Results of a phase II, multicenter, randomized trial.

3614 Background: The aim of this study is to compare clinical outcomes between two groups of different chemoradiation Regimens. Methods: Eligible patients were randomly assigned to Patients received either IMRT to the pelvis of 50 Gy/25Fxs concurrent with oxaliplatin 50 mg/m2 weekly and capecitabine 625 mg/m2 bid d1–5 weekly (Arm A), or IMRT to the pelvis of 50 Gy/25Fxs and a concomitant boost of 5 Gy to the primary tumor in 25 fractions, followed by a cycle of XELOX two weeks after the completion of chemoradiotherapy (Arm B). Surgery was scheduled eight weeks after the completion of CRT. All patients were recommended to receive adjuvant CT regardless of pathological stages. A total of six cycles of XELOX chemotherapy was recommended including neoadjuvant and adjuvant period. The primary end point was pCR. Results: From February 2010 to December 2011, a total of 120 patients were randomly assigned to Arm A (n = 60) or Arm B (n = 60). One hundred and ten patients (Arm A = 53, Arm B = 57) underwent surgery, the other 10 patients didn’t receive surgery because of unresectable disease. Eight and 14 cases were evaluated as pCR in two groups respectively ( p= .157). Tumor response was further classified into good response and poor response, the former was defined as ypT0N0, ypT1-2N0 and ypT0N1a. The rate of good responses were 30.0% and 55% ( p= .006). No significant differences were found in grade 3 or 4 acute adverse events during the treatment between the two groups. However, number of patients who had delayed incision healing was 13 and 3 patients ( p= .007). There were no statistical differences in OS ( p= .553), DFS ( p= .349) and local-regional control ( p= .856) between the two groups. In the univariate analysis, N stage, MRF involvement and tumor response had significant impacts on OS, DFS and LC. In the multivariate analysis, MRF involvement had significant impacts on OS ( p= .02), DFS ( p= .01) and LC ( p= .01). Conclusions: A dose-intensified radiotherapy in neoadjuvant chemoradiotherapy demonstrated contribution to tumor regression with acceptable toxicity, but led delayed incision healing after surgery. The impact of MRF involvement on survival merits further investigation. Clinical trial information: NCT01064999.

Patients with pathological stage N2 rectal cancer treated with early adjuvant chemotherapy have a lower treatment failure rate

BackgroundIn this era of oxaliplatin-based adjuvant therapy, the optimal sequence in which chemoradiotherapy should be administered for pathological stage N2 rectal cancer is unknown. The aim of this study was to investigate this sequence.MethodsIn the primary adjuvant concurrent chemoradiotherapy (A-CRT) group (n = 71), postoperative concurrent chemoradiotherapy was administered before adjuvant chemotherapy. In the primary adjuvant chemotherapy (A-CT) group (n = 43), postoperative concurrent chemoradiotherapy was administered during or after adjuvant chemotherapy. Postoperative radiotherapy comprised 45–50.4 Gy in 25–28 fractions. Concurrent chemotherapy comprised two cycles of oral capecitabine (1,600 mg/m2) on days 1–14 and 22–35. Patients receiving adjuvant chemotherapy with four or more cycles of XELOX (oxaliplatin plus capecitabine) or eight or more cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) were included.ResultsBetween June 2005 and December 2013, data for 114 qualified rectal cancer patients were analyzed. The percentages of patients in whom treatment failed in the A-CRT and A-CT groups were 33.8% and 16.3%, respectively (p = 0.042). More patients had distant metastases in the A-CRT group than in the A-CT group (32.4% vs. 14.3%, p = 0.028). Multivariate analysis indicated that the sequence in which chemoradiotherapy was administered (A-CT vs. A-CRT) was an independent prognostic factor for both estimated disease-free survival [hazard ratio (HR) 0.345, 95% confidence interval (CI) 0.137–0.868, p = 0.024] and estimated distant metastasis-free survival (HR 0.366, 95% CI 0.143–0.938, p = 0.036).ConclusionsIn pathological stage N2 rectal cancer patients, administering adjuvant chemotherapy before chemoradiotherapy led to a lower rate of treatment failure, especially with respect to distant metastasis. Adjuvant chemotherapy prescribed as early as possible might benefit this cohort of patients in this era of oxaliplatin-based adjuvant therapy.