CAPOX Regimen Research Articles

Prognostic impact of early treatment discontinuation and early oxaliplatin discontinuation in patients treated with 6 months of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer: an ACCENT/IDEA pooled analysis of 11 trials.

11 Background: Six months of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) remains a standard in high-risk stage III patients. Early treatment discontinuation (ETD) could worsen the prognosis. In addition, there is current lack of data on the prognostic impact of early oxaliplatin only discontinuation (EOD). Methods: We studied the prognostic impact of ETD and EOD in patients with stage III CC who participated in 11 relevant clinical trials of the ACCENT and IDEA databases, where patients were planned to receive 6 months of adjuvant fluoropyrimidine plus oxaliplatin (FOLFOX or CAPOX). ETD was defined as discontinuation of treatment before 75% of cycles of chemotherapy. EOD was defined as discontinuation of oxaliplatin only, while continuing the fluoropyrimidine, before 75% of cycles of oxaliplatin. Association between ETD/EOD and overall survival (OS) and disease-free survival (DFS) was assessed by Cox model adjusted for prognostic factors. Results: ETD analysis included 10,444 patients (FOLFOX n = 7,033; CAPOX n = 3,411), with 20.9% of patients with ETD (17.8% with FOLFOX and 27.2% with CAPOX, p < 0.001). Out of 7,243 patients, 18.8% experienced EOD (17.4% FOLFOX versus 21.4% with CAPOX, p < 0.001). Compared to patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, older, with higher ECOG-PS ≥ 1, and in addition for ETD, a Body Mass Index (BMI) < 18.5 kg/m2. In multivariate analyses, ETD was associated with a decrease in DFS and OS in the overall population (HR: 1.40 95%CI 1.23-1.58, p < 0.001 and HR: 1.51 95%CI 1.31-1.74, p < 0.001, respectively). The same pattern was present with FOLFOX and CAPOX regimen, and also in low-risk and high-risk groups for each regimen with the exception of the CAPOX regimen in the low-risk group for DFS and OS. By contrast, EOD was not associated with reduced DFS or OS in the overall population (HR: 1.10 95%CI 0.77-1.58, p = 0.6 and HR: 0.97 95%CI 0.62-1.52, p = 0.9, respectively), in the low-risk group (HR: 0.97 95%CI 0.56-1.66, p = 0.9 and HR: 0.97 95%CI 0.51-1.82, p = 0.9, respectively) and high-risk group (HR: 1.22 95%CI 0.74-2.02, p = 0.4 and HR: 1.05 95%CI 0.53-2.08, p = 0.9, respectively) and for all subgroups of regimen. Conclusions: In patients treated with 6 months of oxaliplatin-based adjuvant chemotherapy for stage III CC, ETD was associated with a decrease in DFS and OS. By contrast, EOD was not significantly associated with poorer outcomes. In case of relevant neurotoxicity during a 6 months schedule, these data are not in favor of continuing oxaliplatin beyond 75% of planned cycles of adjuvant chemotherapy, and demonstrate that fluoropyrimidines remain the cornerstone of adjuvant chemotherapy in localized CC.

Anlotinib combined with mXELIRI as second-line treatment in advanced colorectal cancer pretreated with bevacizumab plus standard chemotherapy: A single-arm, phase IB/II study.

TPS220 Background: For advanced colorectal cancer (CRC), fluoropyrimidine-based chemotherapy (5-FU or capecitabine combined with oxaliplatin) with VEGF inhibitors (bevacizumab) is standard first-line treatment. However, once this treatment had been used, the second line treatment is limited. Although continuation of bevacizumab after first progression can improve PFS and OS, the benefit of bevacizumab may be reduced compared with who never pre-treated with bevacizumab (the ML18147 study). Anlotinib is an oral small molecule tyrosine kinases inhibitor, targeting VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α/β and c-kit. mXELIRI is a chemotherapy regimen consisting of irinotecan and capecitabine. The trial is to investigate the efficacy and safety of anlotinib combined with mXELIRI as second-line treatment in advanced colorectal cancer pre-treated with bevacizumab plus standard chemotherapy. Methods: This is a multi-center, prospective, single-arm, 2-part, phase Ib/II study. Eligible pts are aged 18-75 years with histologically and radiographically confirmed mCRC who had progressed or intolerant with bevacizumab plus FOLFOX or CAPEOX regimen chemotherapy treatment. ECOG performance status 0 - 1, and adequate organ function. Treatment: anlotinib (8mg, 10mg or 12mg), po, qd, on days 1-14 every 3 weeks; irinotecan 180-200 mg/m2, iv, on day 1 every 3 weeks; capecitabine, 800 mg/m2, po, bid, on days 1-14 every 3 weeks. For the phase 1b segment, a standard 3+3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase 2 dose (RP2D) of anlotinib. 3 patients are enrolled and treated per dose level (8mg,10mg,12mg). If no DLT, dose is escalated for the next cohort of 3 patients; If 1 DLT, 3 additional patients are treated at this level with dose escalation only if no additional DLTs；If ≥ 2 DLTs, prior dose level is defined as MTD. MTD decided when 6 patients are treated at a dose level with < 2 DLTs. Primary endpoint is objective response rate (ORR) according to RECIST v1.1. Secondary endpoints are progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR) and quality of life (QoL). Based on a one-sided one sample log-rank test with 2.5% Type I error, 80% power to detect an improvement in ORR from 5.4% to 15%, there will be 94 patients consider 20% of patients fall off. Research Sponsor: Guangdong Provincial Hospital of Chinese Medicine Clinical trial information: NCT05035914.

Association between the Co-administration of Histamine H2 Receptor Antagonists and the Effectiveness of Capecitabine in Patients with Colorectal Cancer: Propensity Score Analysis.

Background: The association between the effectiveness of capecitabine and the concomitant administration of gastric acid suppressants remains controversial. We aimed to clarify whether the effectiveness of capecitabine is affected by the co-administration of histamine H2 receptor antagonists (H2RAs) in early-stage colorectal cancer (CRC) patients using real-world data.Methods: This multicenter, retrospective, observational study included consecutive patients with stage II-III CRC who received either capecitabine monotherapy or the CapeOX regimen (capecitabine and oxaliplatin) as adjuvant therapy between January 2009 and December 2014 in Japan. Relapse-free survival (RFS) and overall survival were estimated using the Kaplan-Meier method. Additionally, multivariable Cox proportional hazards model, propensity score adjustment, and inverse probability of treatment weighting analyses were performed.Results: In total, 552 patients were included in this study, of which 30 were co-administered H2RAs. RFS at five years was 76.7% (95% confidence interval [CI]: 57.2-88.1%) and 79.8% (95% CI: 76.0-83.0%) in the H2RA and non-H2RA groups, respectively. Multivariable Cox proportional hazards model and propensity score-adjusted analyses showed that the co-administration of H2RAs was associated with a poor RFS among those receiving capecitabine monotherapy (hazard ratio [HR], 2.01; 95% CI: 0.86-4.70 and HR, 1.81; 95% CI: 0.77-4.22, respectively). In contrast, these results were inconsistent with the group receiving the CapeOX regimen.Conclusions: The study findings suggest that the co-administration of H2RAs may not reduce the effectiveness of capecitabine therapy in patients with early-stage CRC. To confirm this relationship, a prospective study with a pharmacokinetic approach is needed.

Short-term outcome of programmed cell death protein1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high risk factors

Objective: Total neoadjuvant chemoradiotherapy is one of the standard treatments for locally advanced rectal cancer. This study aims to investigate the safety and feasibility of programmed cell death protein 1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high-risk factors. Methods: A descriptive cohort study was conducted. Clinicopathological data of 24 patients with locally advanced middle-low rectal cancer with high-risk factors receiving PD-1 antibody combined with neoadjuvant chemoradiotherapy in Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital between January 2019 and April 2021 were retrospectively analyzed. Inclusion criteria: (1) rectal adenocarcinoma confirmed by pathology; patient age of ≥ 18 years and ≤ 80 years; (2) the distance from low margin of tumor to anal verge ≤ 10 cm under sigmoidoscopy; (3) ECOG performance status score 0-1; (4) clinical stage T3c, T3d, T4a or T4b, or extramural venous invasion (EMVI) (+) or mrN2 (+) or mesorectal fasciae (MRF) (+) based on MRI; (5) no evidence of distant metastases; (6) no prior pelvic radiation therapy, no prior chemotherapy or surgery for rectal cancer; (7) no systemic infection requiring antibiotic treatment and no immune system disease. Exclusion criteria: (1) anticipated unresectable tumor after neoadjuvant treatment; (2) patients with a history of a prior malignancy within the past 5 years, or with a history of any arterial thrombotic event within the past 6 months; (3) patients received other types of antitumor or experimental therapy; (4) women who were pregnant or breast-feeding; (5) patients with any other concurrent medical or psychiatric condition or disease; (6) patients received immunotherapy (PD-1 antibody). The neoadjuvant therapy consisted of three stages: PD-1 antibody (sintilimab 200 mg, IV, Q3W) combined with CapeOx regimen for three cycles; long-course intensity modulated radiation therapy (IMRT) with gross tumor volume (GTV) 50.6 Gy/CTV 41.8 Gy/22f; CapeOx regimen for two cycles after radiotherapy. After oncological evaluation following the end of the third stage of treatment, surgery or watch and wait would be carried out. Surgical safety, histopathological changes and short-term oncological outcome were analyzed. Results: There were 15 males and 9 females with a median age of 65 (47-78) years. Median distance from the lower margin of the tumor to the anal verge was 4 (3-7) cm. The median maximal diameter of the tumor was 5.1 (2.1-7.5) cm. Twenty patients were cT3, 4 were cT4, 8 were cN1, 5 were cN2a, 11 were cN2b. Ten cases were MRF (+) and 10 were EMVI (+). All the patients were mismatch repair proficient (pMMR). During the neoadjuvant treatment period, 6 patients (25.0%) developed grade 1-2 treatment-related adverse events, including 3 immune-related adverse events. As of April 30, 2021, 20 patients (83.3%, 20/24) had received surgical resection, including 19 R0 resections and 16 sphincter-preservation operations. Morbidity of postoperative complication was 25.0% (5/20), including 2 cases of Clavien-Dindo grade II (1 of anastomotic bleeding and 1 of pseudomembranous enteritis), 3 cases of grade I anastomotic stenosis. Pathological complete response (pCR) rate was 30.0% (6/20) and major pathological response rate was 20.0% (4/20). None of Ras/Raf mutants had pCR or cCR (0/5), while 6 of 17 Ras/Raf wild-type patients had pCR and 3 had cCR, which was significantly higher than that of Ras/Raf mutants (P<0.01). Nine of 16 patients with Ras/Raf wild-type and differentiated adenocarcinoma had pCR or cCR. Among other 4 patients without surgery, 3 patients preferred watch and wait strategy because their tumors were assessed as clinical complete response (cCR), while another one patient refused surgery as the tumor remained stable. After a median follow-up of 11 (6-24) months, only 1 patient with signet ring cell carcinoma had recurrence. Conclusions: PD-1 antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced rectal cancer has quite good safety and histopathological regression results. Combination of histology and genetic testing is helpful to screen potential beneficiaries.

Efficacy of Aidi Injection and Brucea javanica Oil Emulsion Injection in Rectal Cancer during CapeOX Adjuvant Chemotherapy.

Background Adjuvant chemotherapy with CapeOX regimen is widely used in resected rectal cancer, which brings benefits to patients. But drug-related toxicities are severe during this process; thus, survival outcomes may potentially be affected. This study explored the efficacy of two Chinese herbal injections, Aidi injection (ADI) and Brucea javanica oil emulsion injection (BJOEI), as adjuvant drugs in CapeOX adjuvant chemotherapy on rectal cancer patients. Methods A total of 240 cases were enrolled in this retrospective study. 80 cases received CapeOX with ADI (the ADI group), 80 cases received CapeOX with BJOEI (the BJOEI group), and the rest 80 cases received CapeOX alone (the control group). After four cycles' chemotherapy, adverse reactions (ADRs) and quality of life (QOL) were analyzed. Then, patients received follow-up for at least one year, and the endpoint was disease-free survival (DFS). Results All patients completed at least four cycles' adjuvant chemotherapy. The incidence of leukopenia and thrombocytopenia was significantly lower in the ADI group; the incidence of nausea was significantly lower in the BJOEI group; the incidence of hand-foot syndrome was significantly lower in both the ADI group and BJOEI group. Significant difference was found in the control group regarding the Karnofsky Performance Status (KPS) scores prior and posttreatment. No difference was found among three groups regarding one-year DFS. Conclusion As adjuvant drugs for rectal cancer during CapeOX chemotherapy, ADI shows advantages in decreasing leukopenia and thrombocytopenia, while BJOEI results better in remitting nausea. Both two CHIs had positive impacts on decreasing hand-foot syndrome and the maintenance of patients' QOL. It is worthy of further study and promotion for CHIs.

Zanidatamab, an anti-HER2 bispecific antibody, plus chemotherapy with/without tislelizumab as first-line treatment for patients with advanced HER2-positive breast cancer or gastric/gastroesophageal junction adenocarcinoma: A phase 1B/2 trial-in-progress.

TPS2656 Background: Zanidatamab is a novel HER2-targeted antibody that binds two distinct extracellular domains of HER2, allowing for multiple mechanisms of action including enhanced binding, clustering, receptor internalization and downregulation; this results in inhibition of ligand-dependent and -independent proliferation and potent activation of antibody-dependent cellular cytotoxicity. Zanidatamab monotherapy is well tolerated and has shown promising anti-tumor activity in patients (pts) with pre-treated advanced HER2-positive cancers, and was well tolerated in a Phase I trial (NCT02892123). Tislelizumab is an investigational anti-programmed death-1 (PD-1) antibody engineered to minimize binding of FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, which is a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy. Tislelizumab is well tolerated and has anti-tumor activity alone and in combination with chemotherapy in pts with advanced solid tumors. The highly immunogenic nature of HER2 tumors has led to the development of therapies combining anti-HER2 therapies with immune checkpoint blockade. Methods: This open-label, two cohort Phase 1B/2 study (NCT04276493) is designed to evaluate zanidatamab as a first-line therapy with chemotherapy in pts with HER2-positive metastatic breast cancer (mBC; cohort 1) or with chemotherapy + tislelizumab in pts with HER2-positive advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC; cohort 2). Weight-based dosing (cohorts 1a and 2a) and flat dosing (cohorts 1b and 2b) regimens of zanidatamab are being investigated. In cohort 1 (n = 20), pts with treatment-naïve HER2-positive (IHC3+ or ISH amplified) mBC will receive intravenous (IV) zanidatamab 30 mg/kg (cohort 1a) or 1800 mg (cohort 1b), plus IV docetaxel 75 mg/m2 once every 3 weeks (Q3W). In cohort 2 (n = 30), treatment-naïve pts with HER2-positive (IHC3+ or IHC2+ with ISH amplification) advanced GC/GEJC will receive IV zanidatamab 30 mg/kg (cohort 2a), or 1800 mg (pts &lt; 70kg; cohort 2b) or 2400 mg (pts ≥ 70kg; cohort 2b), plus IV tislelizumab 200 mg and chemotherapy (CAPOX regimen: oral capecitabine 1000 mg/m2 twice daily [days 1–14] and IV oxaliplatin 130 mg/m2 [day 1]) Q3W. For cohort 2 there is a six pt safety lead-in phase, followed by dose expansion after approval by the safety monitoring committee. Primary endpoints are the safety profile and objective response rate. Secondary endpoints include duration of response, time to response, progression-free survival, disease control rate, and overall survival. Clinical trial information: NCT02892123.

The updated five-year overall survival and long-term oxaliplatin-related neurotoxicity assessment of the FACOS study.

We previously reported the first evidence of oncological benefits from a Japanese phase II trial of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (the FACOS study). We herein report the long-term survival and persistent oxaliplatin-related peripheral sensory neuropathy (PSN) for patients enrolled in this trial. Patients were scheduled to receive the mFOLFOX6 or CAPOX regimen in the adjuvant setting. The five-year overall survival (OS) rate and persistent PSN were evaluated. A total of 130 patients (mFOLFOX6, n = 73; CAPOX, n = 57) were eligible. The 5-year OS rate was 91.4%. No significant difference in the OS rate was observed between regimens (mFOLFOX6, 94.4%; CAPOX, 87.4%; P = 0.25). The incidence of PSN during adjuvant treatment was 55.4% in grade 1 (G1), 30.0% in G2, and 4.6% in G3. No patients showed G3 PSN at 12months, but G1 or G2 residual PSN after 5years was observed in 21.8% (G1, 20%; G2, 1.8%). Updated results from the FACOS study support the benefits of oxaliplatin-based adjuvant chemotherapy in terms of the long-term survival among Japanese patients with stage III colon cancer. However, long-term persistent PSN occurs in about 20% of survivors, counterbalancing the favorable OS.

Intentional Watch &amp;amp; Wait or Organ Preservation Following Neoadjuvant Chemoradiotherapy Plus Consolidation Capeox for Mri-Defined Low-Risk Rectal Cancer: Findings from a Prospective Phase 2 Trial (PKUCH-R01 Trial, NCT02860234)

Background: Clinical T2 or early T3 rectal cancers can be managed by definitive rectal resection and achieve high clinical complete response (cCR) with chemoradiation, thereby facilitating an intentional watch-and-wait (W&W) or organ-preservation strategy. We assessed the efficacy of neoadjuvant chemoradiation plus consolidation CAPEOX in MRI-defined low-risk rectal cancer to ascertain the proportion of patients who can achieve cCR and receive a W&W or organ-preservation approach. Methods: This prospective, single-arm, phase 2 trial enrolled patients with cT2/T3a/T3b low-risk rectal cancers that were pre-staged by magnetic resonance imaging (MRI), after excluding patients with local or systemic high-risk factors, such as mesorectal fascia, extramural vessel invasion, or mucinous differentiation. All patients concurrently received chemoradiation, followed by four 3-week cycles of the CAPEOX regimen. Following reassessment by the multidisciplinary team, patients with cCR or near-cCR received W&W/organ-preservation surgery. The primary endpoint was the 3-year organ-preservation rate. Findings: Of the 64 participants, 58 completed the treatment, with 6·4% and 33·9% grade 3–4 toxicities in the radiotherapy and consolidation CAPEOX phases, respectively, during a median follow-up of 32·7 (interquartile range [IQR] 4·3–60·3) months. Initial cCR, near-cCR, and non-cCR occurred in 33 (51·5%), 13 (20·3%), and 18 (28·2%) patients, respectively. Of the 31 cCR and seven near-cCR cases managed by WW 8 and 20 patients received local excision and radical resection, respectively, including six of seven patients with local regrowth salvage. One patient died of postoperative complications. Lung metastasis occurred in one patient with W&W and one patient with local excision, with no local recurrence and an estimated 3-year organ-preservation rate of 68·8%. The estimated 3-year CSS, non-regrowth disease-free survival, and stoma-free survival were 95·8%, 93·8%, and 84·3%, respectively. Interpretation: Chemoradiotherapy with consolidation CAPEOX for MRI-defined low-risk rectal cancer achieves high cCR and organ-preservation rate. Intentional W&W might be a safe strategy for this patient subgroup. Trial Registration: This study is registered at ClinicalTrials.gov with the identifier NCT02860234. Funding: Supported by The Beijing Municipal Science & Technology Commission Capital Clinical Research Special Fund (Z151100004015105); National Natural Science Foundation of China (81773214); Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support, code: (ZYLX202116) Declaration of Interest: None to declare. Ethical Approval: The protocol and the later amendments were approved by the ethics committee of Peking University Cancer Hospital on August 06, 2016 and on December 17, 2018, respectively.

Chemotherapy-Induced Nausea and Vomiting (CINV) with GI Cancer Chemotherapy: Do We Need CINV Risk Score Over and Above Antiemetic Guidelines in Prescribing Antiemetic Regime?

Background Various predictive models have been developed which incorporates patient risk factors into the selection of optimal antiemetic therapy, one of which is chemotherapy-induced nausea and vomiting (CINV) risk scoring system developed by Multinational Association of Supportive Care in Cancer (MASCC). Patients and Methods Consecutive patients with gastrointestinal malignancy who had not received previous chemotherapy were eligible for enrollment in the study if they were scheduled to receive at least one cycle of chemotherapy. The CINV risk assessment tool was used to collect the study data and to assess CINV risk score. Results Ninety-eight patients fulfilling the eligibility criteria were included in this study, out of which 57% were males, median age was 48 years (range: 28–77). Colorectal cancer (32.7%) was the most common diagnosis followed by gastric cancer (27.6%). Gemcitabine/cisplatin and CAPOX regimen were the most common regimen being administered in 19.4% each. As per MASCC guidelines, 19.4% patients received highly emetogenic chemotherapy, 69.4% moderately emetogenic chemotherapy, while 11.2% received regimen with low emetogenicity. CINV risk module characterized 52% patients to have high risk for CINV, while 48% to have low risk of CINV, thus, 52% had the discrepancy in risk assigned by two methods, and this was statistically significant ( p = 0.025). In subgroup analysis, although patient cohort with acute nausea had no statistically significant discrepancy ( p = 0.123), but statistically significant discrepancy was found in patient cohort with delayed nausea ( p = 0.001), acute ( p = 0.038), and delayed ( p < 0.001) vomiting. Conclusion A significant percentage of patients who receive chemotherapy continue to experience nausea and vomiting despite receiving antiemetic treatment as per standard guidelines. The study generates a hypothesis for future large randomized studies looking at change in antiemetic prophylaxis based on CINV risk tool, leading to improvement in complete response rates of acute and delayed CINV.

ANALYSIS OF SAFETY OF NEOADJUVANT CHEMORADIOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED GASTRIC CANCER (RESULTS OF A MULTICENTER RANDOMIZED TRIAL)

The purpose of the study was to immediate results of neoadjuvant chemoradiotherapy in patients with locally advanced gastric cancer were analyzed in a multicenter randomized trial. Material and Methods . The comparative analysis of neoadjuvant chemotherapy regimens, toxicity and postoperative complications was carried out. Patients of the study group received conformal radiation therapy (46 Gy in 2 Gy daily fractions) concurrently with chemotherapy with Capecitabine at a dose of 1850 mg/m 2 divided in two equal doses during the course of radiation therapy, and Oxaliplatin at a dose of 85 mg/m 2 on days 1 and 21. After an interval of 4–6 weeks and a control examination, in the absence of evident disease progression, patients were scheduled for surgery (gastrectomy or subtotal gastrectomy with D2 lymph node dissection) and 4 cycles of adjuvant chemotherapy according to the FOLFOX4 or CAPOX regimen. The treatment program for patients in the control group included surgery (gastrectomy or subtotal gastrectomy with D2 lymph node dissection) after randomization, and 6 cycles of adjuvant chemotherapy using the same regimens. The study included 70 patients with an equal distribution between groups. Results . Among the patients of the study group, grade 1 and 2 toxicity was the most common; grade 3 toxicity occurred in 9 cases; grade 4 and 5 toxicity was not observed. Among the manifestations of hematological toxicity, thrombocytopenia and leukopenia were the most common (57–60 % of patients), and grade 3 hematological toxicity was observed in 6 (17.1 %) cases. Among the manifestations of gastrointestinal toxicity, nausea, vomiting and decreased appetite prevailed; grade 3 toxicity was observed only in 3 (8.6 %) cases. The radiation component of neoadjuvant therapy was completed in 32 (91 %) patients. Both protocol-prescribed oxaliplatin infusions were performed in 34 (97 %) patients. Changes in capecitabine administration were required in 8 patients. Immediately before surgery, some patients had grade 1–2 toxicity, which did not prevent performing surgery. There were no statistically significant differences in the frequency and severity of complications in the early postoperative period between the comparison groups. Grade 1–2 postoperative complications were the most common.

ZW25, an anti-HER2 bispecific antibody, plus chemotherapy with/without tislelizumab as first-line treatment for patients with advanced HER2-positive breast cancer or gastric/gastroesophageal junction adenocarcinoma: A phase 1B/2 trial-in-progress.

TPS3145 Background: ZW25 is a novel HER2-targeted antibody that binds two distinct extracellular domains of HER2, allowing for multiple mechanisms of action, including activation of ADCC and inhibition of ligand-dependent and -independent cellular growth. ZW25 is well tolerated and showed single-agent antitumor activity in patients (pts) with advanced HER2-positive cancers. Previous reports suggested that tislelizumab, an investigational anti-PD-1 antibody engineered to minimize binding of FcgR on macrophages in order to abrogate antibody-dependent phagocytosis, was generally well tolerated and had antitumor activity alone and in combination with chemotherapy in pts with advanced solid tumors. Combining HER2-targeted agents with chemotherapy has resulted in improved survival; the highly immunogenic nature of HER2 tumors has led to the development of therapies combining anti-HER2 therapies with immune checkpoint blockade. Methods: This open-label, two cohort phase 1B/2 study is designed to evaluate ZW25 plus chemotherapy ± tislelizumab as first-line therapy in pts (n≈50) with HER2-positive metastatic breast cancer (mBC; cohort 1) or advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC; cohort 2). In cohort 1, pts with HER2-positive (IHC3+ or ISH amplified) mBC must be treatment-naïve for metastatic disease and will receive intravenous (IV) ZW25 30 mg/kg plus docetaxel 75 mg/m2 IV once every 3 weeks (Q3W). In cohort 2, treatment-naïve pts with HER2-positive (IHC3+ or IHC2+ with ISH amplification) advanced GC/GEJC will receive ZW25 30 mg/kg plus tislelizumab 200 mg IV and chemotherapy (CAPOX regimen: capecitabine 1000 mg/m2 twice daily and oxaliplatin 130 mg/m2 IV) Q3W. A safety lead-in phase is designed for the first six pts in cohort 2, followed by dose expansion after a safety monitoring committee review. Primary endpoints are the safety/tolerability profile and objective response rate; secondary endpoints include duration of response, time to response, progression-free survival, disease control rate, and overall survival. Clinical trial information: Registered, NCT number pending will provide as soon as available .

Rectum-preserving surgery after consolidation neoadjuvant therapy or totally neoadjuvant therapy for low rectal cancer: a preliminary report

Objective: To investigate the feasibility and safety of sphincter-preserving surgery after neoadjuvant chemoradiotherapy (nCRT) with consolidation chemotherapy in the interval period or total neoadjuvant therapy (TNT) for low rectal cancer. Methods: A descriptive case series study was carried out. Clinical data of patients with locally advanced low rectal cancer (LALRC) who achieved complete clinical response (cCR) or nearly cCR (near-cCR) after nCRT at the Department of Colorectal Surgery of Fujian Medical University Union Hospital from May 2015 to February 2019 were retrospectively analyzed. Case inclusion criteria: (1) Low rectal adenocarcinoma within 6 cm from the anal verge. (2) After nCRT, tumor presented markedly regression as mucosal nodule or abnormalities, superficial ulcer, scar or a mucosal erythema (< 2 cm); no regional lymph node metastasis or distant metastasis was found in rectal ultrasonography, pelvic MRI and PET-CT; MRI showed obvious fibrosis in the original tumor site; and post-treatment CEA was normal. (3) The patient and the family members adhered to receive the transanal full-thickness local excision with informed consent. (4) When the residual lesions were difficult to detect after nCRT, patients received the watch and wait (W&W) strategy. Exclusion criteria: (1) Before nCRT, pathological results showed poorly differentiated or signet-ring cell carcinoma; lateral lymph node metastasis was suspected. (2) When the residual lesion size was more than 3 cm after nCRT, it was difficult to perform local excision. The consolidation nCRT group received 3-4 cycles of CAPOX regimen (oxaliplatin and capecitabine) or six cycles of mFOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil) combined with the long-course radiotherapy (intensity-modulated radiation therapy with a total dose of 50.4Gy). Patients with concurrent chemotherapy more than or equal to five cycles of CAPOX or eight cycles of mFOLFOX6 were defined as total neoadjuvant therapy (TNT) group. Local resection was recommended for patients who were near-cCR according to modified MSKCC criteria 8-33 weeks after the end of radiotherapy. Patients with a near-cCR, who were judged as ycN0 according to PET-CT and MRI and were ypT0 after local excision, could enter the W&W strategy. Patients with pathologic stage more advanced than ypT1, and those with positive resection margin, or lymphovascular invasion were recommended for salvage radical surgery after local excision. The ypT1 patients with a negative resection margin and without lymphovascular invasion might receive the W&W management carefully if they refused radicalsurgery to sacrifice the sphincter for low rectal cancer. Results: Of 32 patients, 14 were males and 18 were females with the average age of 59 years old. Twenty-three patients underwent consolidation nCRT, and 9 received TNT. The first evaluation after treatments showed 19 cases with cCR and 13 with near-cCR. Twenty-nine patients received local excision while 3 patients with undetectable lesions received W&W policy. Four cases (12.5%) underwent salvage radical surgery with abdominoperineal resection. After local excision, 3 cases underwent salvage radical surgery immediately, and the final pathologic result was ypT3N0, ypT2N0, and ypT2N0 respectively, of whom 2 cases were in the group of consolidation CRT and 1 was in the TNT group. Of these 3 cases, 1 case with an initial cT3 stage showed a pathologic stage of ypT1 and a negative circumferential resection margin after consolidation nCRT and local excision, however, the final pathologic stage was ypT3 with fragmented tumor deposits in the mesorectum after the salvage radical surgery. Meanwhile 1 patient in the TNT group receiving W&W suffered from intraluminal regrowth after 7.4 months follow-up and underwent salvage abdominoperineal resection. One patient in the consolidation nCRT group died of stroke 42.5 months after local resection. Another patient in the TNT group had cerebral metastasis 10 months after the W&W policy, but no local recurrence was found in the pelvic cavity, then received resection of the metastatic tumors. The average follow-up for all the patients was 23 (5-51) months. The cumulative local regrowth rate was 5.0%. The overall survival rate was 85.7%, and the sphincter-preservation rate was increased from 25.0% (28/32) in the original plan to 87.5% (28/32) actually. The 3-year disease-free survival rate was 89.7%. The 3-year organ-preserving survival rate was 85.7%, and the 3-year stoma-free survival rate was 82.5%. At present, 31 patients still survived. Conclusions: After nCRT with consolidation chemotherapy or TNT for low rectal cancer, patients with cCR, ycN0 according to PET-CT and MRI, and ypT0 after local excision, can consider the W&W strategy. Strict patient selection with a near-cCR for local resection and sphincter-preserving strategy can reduce the local regrowth of cancer, and the short-term outcomes are satisfactory.

Clinical factors related to severe enterocolitis after adjuvant CAPOX for colorectal cancer: a retrospective analysis.

BackgroundCAPOX regimen is a standard option in stage III adjuvant colon cancer. Gastrointestinal toxicity is well described with fluoropyrimidine regimens and can be life-threatening. Identification of risk factors associated with severe gastrointestinal toxicity may help clinicians when choosing the adjuvant regimen.Materials and MethodsWe retrospectively analysed 61 patients treated with adjuvant CAPOX. Our primary objective was to estimate the incidence of severe chemotherapy-induced enterocolitis among patients treated with CAPOX. A secondary objective was to describe the main demographic and clinical characteristics of these patients. A univariate logistic regression was performed to estimate the odds ratio (OR) with a 95% CI to identify a predictor for severe enterocolitis.ResultsGrade 3 diarrhoea was reported in 10 patients (16.3%). Admissions to hospital due to toxicity occurred in nine cases. Reasons for hospitalisation were severe enterocolitis in eight cases (13.1%) and rectal bleeding plus thrombocytopenia in one case. Age > 70 years (OR 9.6; 95% CI 1.81–50.6; p = 0.008), primary surgery involving right/transverse colon (OR 16.8; 95% CI 2.88–98.8; p = 0.002) and Angiotensin II Receptor Blocker (ARB) use (OR 8.14; 95% CI 1.64–40.3; p = 0.010) were associated with severe enterocolitis.ConclusionOur data showed that adjuvant CAPOX induced severe enterocolitis in 13.1% of patients. In addition, we found that advanced age, right colectomy and concurrent use of ARB were statistically associated with these events. Awareness of these factors could be easily incorporated into the treatment decision and patient orientation.

Treatment patterns for metastatic colorectal cancer in Spain

PurposeThe primary aim of this retrospective study was to describe the treatment patterns according to the type of treatment received by patients with metastatic colorectal cancer (mCRC) in Spain.MethodsThis was a retrospective, observational, multicenter study performed by 33 sites throughout Spain that included consecutive patients aged 18 years or older who had received or were receiving treatment for mCRC.ResultsAt the time of inclusion, of the 873 evaluable patients, 507 (58%) had received two lines, 235 (27%) had received three lines, 106 (12%) had received four lines, and the remaining patients had received up to ten lines. The most frequent chemotherapy schemes were the FOLFOX or CAPOX regimens (66%) for first-line treatment, FOLFOX, CAPOX or FOLFIRI (70%) for second-line treatment, and FOLFOX, FOLFIRI or other fluoropyrimidine-based regimens for third- and fourth-line (over 60%) treatment. Sixty percent of patients received targeted therapy as part of their first-line treatment, and this proportion increased up to approximately 70% of patients as part of the second-line of treatment. A relevant proportion of patients were treated with unknown KRAS, and especially the BRAF, mutation statuses.ConclusionsThis study reveals inconsistencies regarding adherence to the recommendations of the ESMO guidelines for the management of mCRC in Spain. Improved adherence to the standard practice described in such guidelines for the determination of RAS and BRAF mutation statuses and the use of targeted therapies in first-line treatment should be considered to guarantee that patients can benefit from the best therapeutic approaches available.

Laparoscopic Posterior Pelvic Exenteration (Complete and Supralevator) for Locally Advanced Adenocarcinoma of the Rectum in Females: Surgical Technique and Short-Term Outcomes.

Background: Laparoscopic posterior exenteration (total and supralevator) is a complex and rarely done procedure. In this study we describe the surgical technique and short-term perioperative outcomes in 7 female patients of locally advanced carcinoma rectum operated with laparoscopic pelvic exenteration. Materials and Methods: We report 7 cases of carcinoma rectum involving either posterior wall of the uterus or vagina, which were operated with a laparoscopic procedure. All perioperative and intraoperative data were collected retrospectively from prospectively maintained electronic data. Results: Nine female patients with the diagnosis of nonmetastatic locally advanced lower rectal adenocarcinoma were selected. In MRI 4 patients had uterus-cervix involvement and 3 patients had a posterior vaginal wall and anal sphincter involvement. Four patients were operated with laparoscopic supralevator posterior exenteration and 3 patients were operated with laparoscopic complete posterior exenteration. Three patients underwent vaginal reconstruction, which was done with bilateral V-Y plasty. All 7 patients received neoadjuvant chemoradiotherapy (NACTRT), 3 patients also received additional chemotherapy (CAPOX regimen) due to poor response to NACTRT. Mean body mass index (BMI) was 23.85 (range 19-27.20). Mean duration for complete posterior exenteration was 9.63 hours (range 7-12 hours). Mean duration for supralevator posterior exenteration was 6.81 hours (range 6.25-7.5 hours). The mean postoperative stay was 10.71 days (range 7-16 days). Mean blood loss was 700 mL (range 200-1800 mL). On postoperative histopathology, all margins were free of tumor in all cases. Conclusion: Laparoscopic approach for locally advanced carcinoma rectum in female patients is feasible with less morbidity and safe short-term oncological outcomes. Careful selection of patients based on MRI is a must before undertaking the minimally invasive surgery approach. Long-term outcomes are still unknown and will require long-term follow-up.

85P - Which is the best partner for capecitabine-based neoadjuvant chemoradiotherapy in locally advanced rectal cancer? A retrospective analysis of a comprehensive cancer center

BackgroundThe purpose of this study was to compare the oncological outcomes of three preoperative chemotherapy regimens, capecitabine alone (Cap), capecitabine plus oxaliplatin (CapOx) and capecitabine plus irinotecan (CapIri), concurrent with long-course pelvic radiotherapy for patients with locally advanced rectal cancer (LARC) at a Chinese comprehensive cancer center. MethodsLARC (T3/4 and/or LN+) cases receiving neoadjuvant treatment between Mar 2006 and Feb 2018 were reviewed. Preoperative chemoradiotherapy consisted standard fractionated pelvic radiotherapy concurrently with chemotherapy of capecitabine alone, CapOx or CapIri. Total mesorectal excision was planned 6-10 weeks after the completion of chemoradiotherapy. Tumor response, neoadjuvant treatment toxicity and surgical complications of the three cohorts were compared analyzed. ResultsA total of 1165 patients were included in the study. 445 patients received concurrent capecitabine alone, 353 received CapOx and 367 received CapIri. An abdominoperineal resection or Hartmann’s procedure was performed in 46.4%, 59.8% and 47.2% of the patients who underwent surgery in the Cap, CapOx and CapIri cohorts, respectively (P = 0.001). The complete response (CR) rate (including pathological CR and clinical CR) was 20.7%, 18.7% and 28.6% in three cohorts (P = 0.003). Multivariate analysis showed that a lower tumor location, normal baseline CEA levels and the CapIri regimen were associated with a higher CR rate. Significantly more grade 3-4 toxicity was reported in the CapIri cohort than in the other two cohorts. Patients in the CapOx cohort were more likely to report surgical complications than the other patients (Cap vs CapOx vs CapIri: 13.4% vs 21.1% vs 13.3%, P = 0.005). ConclusionsConcurrent CapIri chemotherapy during preoperative pelvic radiotherapy significantly improved the CR rate but added toxicity compared with capecitabine alone or CapOx regimen. Long-term follow-up will determine if this short-term benefit translates into an improved survival. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Long Course Neoadjuvant Concurrent Chemo-Radiotherapy with or Without Pre-Radiation Induction Chemotherapy in the Management of Rectal Cancers: A Mono-Institutional Retrospective Analysis

Long course neoadjuvant chemo-radiotherapy (NACRT) followed by total mesorectal excision (TME) with/without adjuvant chemotherapy (ACT) is the standard treatment modality for locally advanced rectal (T3/4; T1-4N1-2) cancers (LARC). While the loco-regional control (LRC) rates have become better with this approach, distant metastasis rates are to the tune of 20-30%. Of several approaches to circumvent this, one is the incorporation of neoadjuvant chemotherapy (NACT) prior to NACRT. This approach may also yield better tumor downstaging and pathological complete response (pCR) rates. At our institution, we have shifted in our approach from NACRT alone (Arm A) to NACT followed by NACRT (Arm B). We aimed to evaluate the outcomes with this novel approach and compare it with the former approach in our cohort of patients. Details of 62 patients of LARC (Jan 2013 – Sep 2018) treated with NACRT or NACT followed by NACRT were retrieved. NACT in Arm B consisted of 2 cycles of CAPOX [oxaliplatin (130 mg/m2 day 1) and capecitabine (1000 mg/m2 twice daily for 14 days) repeated every 3 weeks]. Radiotherapy (RT) in both the arms was 50 Gray in 25 fractions with concurrent capecitabine 825 mg/m2 twice daily. All the patients underwent TME by either low anterior resection (LAR) or abdominal perineal resection. ACT consisted of CAPOX regimen. pCR was defined as no viable tumor cells either at primary or regional lymph nodes. LRC was defined as time from registration to local/regional recurrence. Overall survival (OS) was defined as time from registration to death from any cause. Kaplan Meier method was used for all outcome analysis. 44 patients were in Arm A and 18 were in Arm B. Median age was 45 years with 13 females. Patient characteristics are described in the table. The median number of NACT cycles in Arm B was two. Median follow up was 28 months (range 4-42). Median duration from completion of NACRT to surgery was 5 months (range 4 -10). pCR rates were 17% (3/18) in arm B and 10% (4/44) in arm A (p=0.40). 41% and 39% patients in arm A and B received ACT, respectively [median number of cycles was 6 (range 4-8)]. 18-month LRC rate in Arm A versus B were 88.9% vs. 100% (p=0.46). 18-month OS in arm A and B was 70.6% vs 71.4% (p= 0.865), respectively. There were fifteen deaths, 11 in arm A and 4 in arm B. The crude distant metastasis rates were 11% for both arms (5 in arm A & 2 in arm B). Intensification of neo-adjuvant treatment with pre-radiation chemotherapy and NACRT followed by TME in LARC may achieve better pCR rates and possibly better loco-regional control and survival as compared to NACRT alone. This approach needs to be evaluated further in a prospective randomized trial.Abstract 2394; Table 1Patient characteristicsArm A(n=44)Arm B (n=18)TNM Staging (II: III)28:1610:8Lympho-vascular invasion16(36%)6(33%)Tumor grade (1: 2: 3)14:26:44:12:2Median tumor size at Surgery4 cm4 cmPathological stage (T2:T3:T4:N1:N2)7:25:3:10:23:7:3:5:3Circumferential resection margin positive3(7%)4(22%)LAR:APR24:2012:6 Open table in a new tab

"Watch and wait" strategy after neoadjuvant therapy for rectal cancer: status survey of perceptions, attitudes and treatment selection in Chinese surgeons

Objective: To understand the perceptions, attitudes and treatment selection of Chinese surgeons on the "watch and wait" strategy for rectal cancer patients after achieving a clinical complete response (cCR) following neoadjuvant chemoradiotherapy (nCRT). Methods: A cross-sectional survey was used in this study. Selection of subjects: (1) Domestic public grade III A (provincial and prefecture-level) oncology hospitals or general hospitals possessing the radiotherapy department and the diagnosis and treatment qualifications for colorectal cancer. (2) Surgeons of deputy chief physician or above. Using the "Questionnaire Star" online survey platform to create a questionnaire about cognition, attitude and treatment choice of the "watch and wait" strategy after cCR following nCRT for rectal cancer. The questionnaire contained 32 questions, such as the basic information of doctor, the current status of rectal cancer surgery, the management of pathological complete remission (ypCR) after nCRT for rectal cancer, the selection of examination items for diagnosis of cCR, the selection of suitable people undergoing "watch and wait" approach, the nCRT mode for promotion of cCR, the choice of evaluation time point, the willingness to perform "watch and wait" approach and the treatment choice, and the risk and monitoring of "watch and wait" approach. A total of 116 questionnaires were sent to the respondents via WeChat between January 31 and February 19, 2019. Statistical analysis was performed using Fisher's exact test for categorical variables. Results: Forty-eight hospitals including 116 surgeons meeting criteria were enrolled, of whom 77 surgeons filled the questionnaire with a response rate of 66.4%. "Watch and wait" strategy was carried out in 76.6% (59/77) of surgeons. Seventy surgeons (90.9%) were aware of the ypCR rate of rectal cancer after preoperative nCRT and 49 surgeons (63.6%) knew the 3-year disease-free survival of patients with ypCR in their own hospitals. Fifty-five surgeons (71.4%) believed that patients with ypCR undergoing radical surgery met the treatment criteria and were not over-treated. Three most necessary examinations in diagnosing cCR were colonoscopy (96.1%, 74/77), digital rectal examination (DRE) (90.9%,70/77) and DWI-MRI (83.1%, 64/77). Responders preferred to consider a "watch and wait" strategy for patients with baseline characteristics as mrN0 (77.9%, 60/77), mrT2 (68.8%, 53/77) and well-differentiated adenocarcinoma (68.8%, 53/77). Sixty-six surgeons (85.7%) believed that long-term chemoradiotherapy (LCRT) with combination or without combination of induction and/or consolidation of the CapeOX regimen (capecitabine + oxaliplatin) should be the first choice as a neoadjuvant therapy to achieve cCR. Forty-one surgeons (53.2%) believed that a reasonable interval of judging cCR after nCRT should be ≥ 8 weeks. Forty-four surgeons (57.1%) routinely, or in most cases, informed patient the possibility of cCR and proposed to "watch and wait" strategy in the initial diagnosis of patients with non-metastatic rectal cancer. Thirteen surgeons (16.9%) would take the "watch and wait" strategy as the first choice after the patient having cCR. Fifty-two surgeons (67.5%) would be affected by the surgical method, that was to say, "watch and wait" approach would only be recommended to those patients who would achieve cCR and could not preserve the anus or underwent difficult anus-preservation surgery. Sixteen surgeons (20.8%) demonstrated that "watch and wait" strategy would not be recommended to patients with cCR regardless of whether the surgical procedure involved anal sphincter. Eleven surgeons (14.3%) believed that the main risk of "watch and wait" approach came from distant metastasis rather than local recurrence or regrowth. Twenty-nine of surgeons (37.7%) did not understand the difference between "local recurrence" and "local regrowth" during the period of "watch and wait". Twenty-six surgeons (33.8%) thought that the monitoring interval for the first 3 years of "watch and wait" strategy was 3 months, and the follow-up monitoring interval could be 6 months to 5 years. Surgeons from cancer specialist hospitals had higher approval rate, notification rate, and referral rate of "watch and wait" strategy than those from general hospitals. Thirty-one surgeons (42.5%) considered that the difficulty and concern of carrying out "watch and wait" approach in the future was the disease progress leading to medical disputes. Twenty-six surgeons (35.6%) demonstrated that their concern was lack of uniform evaluation standard for cCR. Conclusions: Chinese surgeons seem to have inadequate knowledge of non-operative management for rectal cancer patients achieving cCR after nCRT and show relatively conservative attitudes toward the strategy. Chinese consensus needs to be formed to guide the non-operative management in selected patients. Chinese Watch & Wait Database (CWWD) is also needed to establish and provide more evidence for the use of alternative procedure after a cCR following nCRT.

Duration of Adjuvant Chemotherapy in Colon Cancer: Current Standards and New Updates

Adjuvant therapy for 6 months is the standard of care for stage III colon cancer. The use of oxaliplatin-based therapy over fluoropyrimidine alone increases toxicity, including dose-dependent peripheral neuropathy. Evaluation of a shorter duration of adjuvant therapy was therefore warranted, aiming to reduce toxicity while maintaining clinical efficacy. The International Duration Evaluation of Adjuvant chemotherapy (IDEA) collaboration was a pivotal prospective pooled analysis of 6 randomized phase III trials across 12 countries. IDEA evaluated the non-inferiority of 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy. The 3-year disease-free survival was very similar between the 3-month and 6-month study arms. Despite this, non-inferiority was not confirmed. However, important differences were observed between FOLFOX and CAPOX regimens, and risk groups within stage III disease, which allow for greater individualization of adjuvant therapy. The IDEA results suggest 3 months of therapy is reasonable in most patients with stage III disease, especially those with low-risk disease. Importantly, 3 months of therapy is associated with a dramatic reduction in peripheral neuropathy. A thorough discussion of the risks and benefits with patients regarding the duration of therapy is required. In this review, we discuss the IDEA findings and the optimal duration of adjuvant chemotherapy in stage III colon cancer.

Gut microbiome associated with chemotherapy-induced diarrhea from the CapeOX regimen as adjuvant chemotherapy in resected stage III colorectal cancer

BackgroundChemotherapy induced diarrhea (CID) is a common side effect in patients receiving chemotherapy for cancer. The aim of our study was to explore the association between gut microorganisms and CID from the CapeOX regimen in resected stage III colorectal cancer (CRC) patients.ResultsAfter screening and identification, 17 stool samples were collected from resected stage III CRC patients undergoing the CapeOX regimen. Bacterial 16S ribosomal RNA genes was sequenced, and a bioinformatics analysis was executed to screen for the distinctive gut microbiome and the functional metabolism associated with CID due to the CapeOX regimen. The gut microbial community richness and community diversity were lower in CID (p < 0.05 vs control group). Klebsiella pneumoniae was the most predominant species (31.22%) among the gut microbiome in CRC patients with CID. There were 75 microorganisms with statistically significant differences at the species level between the CRC patients with and without CID (LDA, linear discriminant analysis score > 2), and there were 23 pathways that the differential microorganisms might be involved in.ConclusionsThe gut microbial community structure and diversity have changed in CRC patients with CID. It may provide novel insights into the prevention and treatment of CID.