Cycles Of Capecitabine Research Articles

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).

573P - Randomized phase II trial of CAPOX with planned oxaliplatin stop-and-go strategy as adjuvant chemotherapy after curative resection of colon cancer (CCOG-1302 study)

BackgroundThe aim of this study was to evaluate the efficacy and safety of CAPOX with planned oxaliplatin stop-and-go strategy compared to continuous use of oxaliplatin as an adjuvant setting for colon cancer. MethodsPatients with curative resection of colon cancerwere randomly assigned to receive eitherCAPOX with continuous use of oxaliplatin (8 cycles of CAPOX; continuous arm) or CAPOX intermittentuse of oxaliplatin (2 cycles of CAPOX – 4 cycles of capecitabine – 2 cycles of CAPOX; intermittentarm).The primary endpoints were frequency of peripheral sensory neuropathy (PSN) at 1-year after surgery and disease-free survival rate at 3-year after surgery. The secondary end points included overall survival (OS), compliance and safety. ResultsA total of 200 patients were enrolled. The intent-to-treat and safety population comprised 100 and 99 patients in the continuous arm,and 100 and 98 patients in the intermittentarm. Compliance: The overall treatment completion rate and relative dose intensity of oxaliplatin were 64% and 71% in the continuous arm vs.92% and 95% in the intermittentarm(p=0.21 and 0.12, respectively). Efficacy: The 3-year DFS was 81.6% in the continuous arm vs.82.4% in the intermittentarm(HR, 0.82; 95% CI, 0.48-1.18). Safety: The incidence of PSN (>grade 2) was 33%in the continuous arm vs.15% in the intermittentarm (p<0.001). The frequencies ofPSF lasting for 1-year and 3-year were 61% and 30% vs. 21% and 6%, respectively. ConclusionsCAPOX withplanned oxaliplatin stop-and-go strategy could be equally effectiveas an adjuvant setting for colon cancer, and substantially reduce long-term PSN and potential improve patient quality of life. Clinical trial identification000012535 (09/December/2013). Legal entity responsible for the studyYasuhiro Kodera (Chubu Clinical Oncology Group, Japan). FundingChubu Clinical Oncology Group. DisclosureAll authors have declared no conflicts of interest.

Sequential Short-Course Radiation Therapy and Chemotherapy in the Neoadjuvant Treatment of Rectal Cancer

We report our single-institution experience with sequential short-course preoperative radiation therapy (5 Gy X 5 fractions) followed by preoperative chemotherapy for the treatment of patients with rectal adenocarcinoma, focusing on short-term oncologic and toxicity outcomes. We reviewed records of 26 patients with stage II or III rectal adenocarcinoma. All patients underwent short course radiation therapy (SCRT: 25 Gy in 5 fractions) followed by mFOLFOX6 or capecitabine plus oxaliplatin. The principle objectives were to assess treatment feasibility, treatment toxicity, and oncologic response. There were five clinical (c) T2, 16 cT3, and five cT4 cases, with 88% cN+. 25 patients received a median of 4 cycles (range 3 to 8) of mFOLFOX6 (with one cycle defined as a two-week period); one patient received 3 cycles of capecitabine and oxaliplatin. All patients completed SCRT; 81% completed the full course of neoadjuvant chemotherapy while 19% required dose reductions in chemotherapy, most commonly due to neuropathy (60%). Nineteen patients underwent post-treatment endoscopic evaluation, and 9 patients were noted to achieve a complete clinical response (CCR). Six patients who achieved CCR opted for a non-operative approach of watch and wait. Twenty patients underwent surgical resection. The median time from the end of SCRT to CCR (for patients followed with non-operative management) or surgical resection was 14.5 weeks (range 11.7 – 25.7 weeks). Negative resection margins were achieved in 18 of 20 patients who underwent surgery, and pathologic complete response was observed in 7 patients (35%) of these 20. The neoadjuvant rectal score was low in 50% of the patients who underwent surgery, and intermediate in 10%. The median follow-up time in the non-operative group was 15.6 weeks (range 2.7 – 42 weeks), and during this time local disease recurrence was noted in one patient at 20 weeks from time of CCR. The median follow-up time in the operative group was 24.3 weeks (range 3.7 – 49.3 weeks), during this time local disease recurrence was noted in one patient at 40 weeks from the time of surgery. The main radiation-associated toxicity was proctitis. CTCAE Grade 2 proctitis was observed in seven patients (27%). Post-operative Clavien-Dindo Grade 3 complications within 30 days of surgery were identified in six patients (30%), with no Grade 4 or 5 adverse events. Median length of hospital stay was 4.5 days (range 2-16 days); three patients were readmitted within a 30 day period. Short-course preoperative radiation therapy followed by chemotherapy was well-tolerated and achieved high rates of tumor response.

Factors Contributing to Cancer-Related Muscle Wasting During First-Line Systemic Treatment for Metastatic Colorectal Cancer.

BackgroundIncreasing evidence indicates that loss of muscle mass is associated with adverse outcomes in metastatic colorectal cancer. Here, we investigate which demographic, lifestyle- (smoking), tumor-, and treatment-related factors are associated with muscle loss in patients with metastatic colorectal cancer during first-line palliative systemic treatment.MethodsData from 300 patients with computed tomography scans both at start and after six initial cycles of capecitabine plus oxaliplatin and bevacizumab was used (CAIRO3). From computed tomography, muscle mass normalized for stature (skeletal muscle index [SMI]) was calculated. A priori-selected variables were tested using multivariable linear regression models (P values ≤.05). Two models were developed: Model 1 contained variables measured at start and Model 2 contained variables assessed after initial therapy.ResultsIn Model 1, loss of SMI was statistically significantly associated with a higher initial SMI (−0.32%, 95% confidence interval [CI] = −0.45% to −0.19% per unit increase in initial SMI), smoking status (−2.74%, 95% CI = −5.29% to −0.19% for smokers), and interval of metastases (−3.02%, 95% CI = −5.50% to −0.53%) for metachronous vs synchronous metastases), and primary tumor resection was statistically significantly associated with a gain in SMI (2.17%, 95% CI = 0.13% to 4.21% for resection vs no resection). In Model 2, loss of SMI was statistically significantly associated with response to capecitabine plus oxaliplatin and bevacizumab (−2.48%, 95% CI = −4.33% to −0.62% for stable disease vs partial/complete response).ConclusionsOur results highlight, given the association of sarcopenia and survival, that patients with higher SMI should not be ignored. In addition, smoking is a potentially modifiable factor associated with muscle loss. The association between smoking and muscle loss might relate to worse clinical outcomes in smokers with metastatic colorectal cancer.

Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone for isolated resectable colorectal peritoneal metastases: protocol of a multicentre, open-label, parallel-group, phase II-III, randomised, superiority study (CAIRO6)

BackgroundUpfront cytoreductive surgery with HIPEC (CRS-HIPEC) is the standard treatment for isolated resectable colorectal peritoneal metastases (PM) in the Netherlands. This study investigates whether addition of perioperative systemic therapy to CRS-HIPEC improves oncological outcomes.MethodsThis open-label, parallel-group, phase II-III, randomised, superiority study is performed in nine Dutch tertiary referral centres. Eligible patients are adults who have a good performance status, histologically or cytologically proven resectable PM of a colorectal adenocarcinoma, no systemic colorectal metastases, no systemic therapy for colorectal cancer within six months prior to enrolment, and no previous CRS-HIPEC. Eligible patients are randomised (1:1) to perioperative systemic therapy and CRS-HIPEC (experimental arm) or upfront CRS-HIPEC alone (control arm) by using central randomisation software with minimisation stratified by a peritoneal cancer index of 0–10 or 11–20, metachronous or synchronous PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C. At the treating physician’s discretion, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. The first 80 patients are enrolled in a phase II study to explore the feasibility of accrual and the feasibility, safety, and tolerance of perioperative systemic therapy. If predefined criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint. A total of 358 patients is needed to detect the hypothesised 15% increase in 3-year overall survival (control arm 50%; experimental arm 65%). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histopathological response rates.DiscussionThis is the first randomised study that prospectively compares oncological outcomes of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone for isolated resectable colorectal PM.Trial registrationClinicaltrials.gov/NCT02758951, NTR/NTR6301, ISRCTN/ISRCTN15977568, EudraCT/2016–001865-99.

Mining Small Routine Clinical Data: A Population Pharmacokinetic Model and Optimal Sampling Times of Capecitabine and its Metabolites.

The present study was performed to demonstrate that small amounts of routine clinical data allow to generate valuable knowledge. Concretely, the aims of this research were to build a joint population pharmacokinetic model for capecitabine and three of its metabolites (5-DFUR, 5-FU and 5-FUH2) and to determine optimal sampling times for therapeutic drug monitoring. We used data of 7 treatment cycles of capecitabine in patients with metastatic colorectal cancer. The population pharmacokinetic model was built as a multicompartmental model using NONMEM and was internally validated by visual predictive check. Optimal sampling times were estimated using PFIM 4.0 following D-optimality criterion. The final model was a multicompartmental model which represented the sequential transformations from capecitabine to its metabolites 5-DFUR, 5-FU and 5-FUH2 and was correctly validated. The optimal sampling times were 0.546, 0.892, 1.562, 4.736 and 8 hours after the administration of the drug. For its correct implementation in clinical practice, the values were rounded to 0.5, 1, 1.5, 5 and 8 hours after the administration of the drug. Capecitabine, 5-DFUR, 5-FU and 5-FUH2 can be correctly described by the joint multicompartmental model presented in this work. The aforementioned times are optimal to maximize the information of samples. Useful knowledge can be obtained for clinical practice from small databases.

Neoadjuvant chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer: a feasibility and safety study

BackgroundStandard treatment for colorectal peritoneal carcinomatosis typically involves cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and if possible, postoperative adjuvant chemotherapy. However, a substantial percentage of patients never receive adjuvant chemotherapy because of postoperative complications. Neoadjuvant chemotherapy could be beneficial in this setting, so we assessed its feasibility and safety when used before cytoreductive surgery and HIPEC.MethodsIn this non-randomized, single-center, observational feasibility study, patients were scheduled to receive six cycles of capecitabine and oxaliplatin before cytoreductive surgery and HIPEC. Computed tomography was performed after the third and sixth chemotherapy cycles to evaluate tumor response, and patients underwent cytoreductive surgery and HIPEC if there were no pulmonary and/or hepatic metastases. Postoperative complications, graded according to the Clavien–Dindo classification, were compared with those of a historic control group that received postoperative adjuvant chemotherapy.ResultsOf the 14 patients included in the study, 4 and 3 had to terminate neoadjuvant chemotherapy early because of toxicity and tumor progression, respectively. Cytoreductive surgery and HIPEC were performed in eight patients, and the timing and severity of complications were comparable to those of patients in the historic control group treated without neoadjuvant chemotherapy.ConclusionPatients with peritoneal metastases due to colorectal carcinoma can be treated safely with neoadjuvant chemotherapy before definitive therapy with cytoreductive surgery and HIPEC.Trial registration numberNTR 3905, registered on 20th march, 2013, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3905

A Phase II Prospective Study about the Efficacy and Toxicity of the Locally Advanced Nasopharyngeal Carcinoma Patients Treated with Concurrent Chemoradiotherapy Followed with the Capecitabine Metronomic Chemotherapy

The concurrent chemoradiotherapy is the standard treatment modality for nasopharyngeal carcinoma (NPC), however the adjuvant chemotherapy is still controversial in the treatment of NPC. Metronomic chemotherapy is a new dosing modality of chemotherapy which is in low-dosages with high frequency and continuous administration that has been rising in recent years. We aimed to preliminary evaluate the possible efficacy and toxicity in locally advanced NPC patients treated with concurrent chemoradiotherapy followed with the capecitabine metronomic chemotherapy. Sixty-seven III-IV stage (UICC 8th) locally advanced NPC were included in our study from April 2014 to July 2016. All the patients received definitive concurrent chemoradiotherapy followed with the capecitabine metronomic chemotherapy. For the control group, we selected 75 patients treated with definitive concurrent chemoradiotherapy. Two to 3 cycles of cisplatin-based chemotherapy and 3 cycles of capecitabine (750mg/m2, bid) was used. The Kaplan-Meier method was used to calculate the local control rate (LC), distant metastasis-free survival rate (DMFS), progression-free survival (PFS) and overall survival (OS). The acute and late toxicities were graded according to the CTCAE 3.0 scoring criteria. The median follow-up time was 24 months. The 2-year OS and LC were similar (96.0%, 98.2%; 95.9%, 97.2% respectively). Compared with the control group, the 2-year DMFS and PFS were improved in the observation group (94.9%, 89.5%; 89%, 85.3%). Because of the limited cases, there was no statistical difference about the OS, LC, DMFS and PFS. For the acute toxicities, the incidence of grade 1-2 and grade 3-4 neutropenia in observational and control group were 50.7%, 58.6% and 10.4%, 8%, the grade 1-2 and grade 3-4 thrombocytopenia were 22.4%, 25.3% and 6%, 5.3%, and the grade 1-2 and grade 3-4 oral mucous reaction were 65.7%, 61.3% and 17.9%, 20%, respectively. For the late toxicities, the incidence of grade 1-2 and grade 3-4 xerostomia were 56.7%, 54.7% and 3%, 1.3% in the observational and control group respectively; the grade 1-2 and grade 3-4 hearing impairment were 41.8%, 38.7% and 0%, 1.3%. In addition, for the specific toxicity, the toxicities were all grade 1-2. The incidence of limb numbness, rash, neuropathic headache and anaphylaxis were 32.8%, 28.3%, 17.9% and 3.0%. There was no significant difference about the toxicities between two groups (p>0.05). The concurrent chemoradiotherapy followed with the capecitabine metronomic chemotherapy was a promising modality for locally advanced NPC patients. The 2-year DMFS and PFS was improved compared with the concurrent chemoradiotherapy, and the acute and late toxicity were all tolerable. The more and long follow-up studies should be carried out in the future.

Clinical efficacy of preoperative SIB-IMRT for 26 cases of locally-advanced low rectal cancer

Objective To evaluate the feasibility and clinical efficacy of preoperative simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with neoadjuvant chemotherapy of capecitabine in patients with locally-advanced low rectal cancer. Methods Between 2015 and 2016, 26 patients admitted to 301 Hospital who were diagnosed with locally-advanced low rectal cancer, which was located within 5 cm from the anal verge, were enrolled in this investigation. Dose fractionation pattern was delivered: 58.75 Gy in 25 fractions (2.35 Gy/fraction) for rectal cancer and lymph node metastasis and 50 Gy in 25 fractions for the pelvic lymphatic drainage area and simultaneously combined with capecitabine chemotherapy (825 mg/m2, bid d1-5 weekly). One cycle of capecitabine (1 250 mg/m2, twice daily, d1-14) was given at one week after the completion of chemoradiotherapy (CRT). Total mesorectal excision (TME) was performed at 6 to 8 weeks after the completion of CRT.The primary endpoints included pathological complete response rate (ypCR) and sphincter-preserving rate. The secondary endpoints included acute toxicity, tumor downstaging rate and postoperative complications. Results Twenty-six patients successfully completed neoadjuvant CRT, 25 of them underwent surgical resection and one patient failed to receive surgery due to perianal edema. Postoperative ypCR rate was 32%(8/25), the sphincter-preserving rate was 60%(15/25), the tumor downstaging rate was 92%(23/25) and the R0 resection rate was 100%.During the period of CRT, grade 1 and 2 adverse events occurred in 24 patients, grade 3 radiation dermatitis was noted in 2 cases. No ≥ grade 4 acute adverse event was observed. Postoperative complications included ureteral injury in one case and intestinal obstruction in one patient. Conclusions Preoperative SIB-IMRT combined with neoadjuvant chemotherapy of capecitabine is a feasible and safe treatment for patients with locally-advanced low rectal cancer, which yields expected ypCR rate, R0 resection rate and sphincter-preserving rate. Nevertheless, the long-term clinical benefits remain to be elucidated. Clinical Trial Registry Chinese Clinical Trial Registry, registration number: ChiCTR-ONC-12002387. Key words: Rectal neoplasm; Anal neoplasm; Neoadjuvant chemoradiotherapy; Sphincter-preserving surgery

Abstract A43: Induction of systemic immune response by oxaliplatin-based neoadjuvant therapy and survival without metastatic progression in high-risk rectal cancer

Abstract In locally advanced rectal cancer (LARC), local recurrence rates are low due to contemporary multimodal treatment regimens involving neoadjuvant chemoradiotherapy (CRT) and surgery. Metastatic progression however, represents a major challenge and is reported by 30-40% of cases in recent trials. Ongoing effort to combine treatment modalities, including immunotherapy, to best target systemic progression of colorectal cancer, would benefit from a better understanding of the biological and immune responses invoked from the different treatment modalities. In this report we investigated systemic immune activity invoked in LARC patients undergoing neoadjuvant regimens containing oxaliplatin (an agent known to cause immunogenic cell death), by assessing circulating levels of the fms-related tyrosine kinase 3 ligand (Flt3L). Flt3L is a potent hematopoietic factor with proliferating effects on mature dendritic cells (DC), whose elevated levels have also been demonstrated to reflect therapy-induced myelosuppression. LARC patients with mainly T3-4 disease from two independent cohorts (Oslo and Copenhagen) received neoadjuvant chemotherapy (NACT) and sequential CRT. All of the Oslo cohort patients underwent NACT consisting of 4 weeks of the Nordic FLOX regimen (oxaliplatin 85 mg/m2 on day 1 and bolus fluorouracil 500 mg/m2 and folinic acid 100 mg on days 1 and 2 every second week) followed by long-course CRT (radiation to a total dose of 50 Gy and concomitant weekly oxaliplatin 50 mg/m2 and capecitabine 825 mg/m2 twice daily), and then surgery 8-12 weeks later. Eighty percent of Copenhagen cohort patients underwent NACT as 6-8 weeks of oxaliplatin 85 mg/m2 every second week and continuous capecitabine 650 mg/m2 twice daily. Less than 90% of patients had concomitant weekly oxaliplatin 50 mg/m2 during the long-course CRT to a total radiation dose of 54 Gy. Finally, 57% of patients received an additional 1-2 cycles of capecitabine with or without oxaliplatin following CRT completion. Patients had surgery 2-19 weeks after CRT completion. In both cohorts, Flt3L levels were measured in serum collected at baseline, following NACT and then the sequential CRT. Serum samples were stored at –80°C until analysis and Flt3L was quantified using ELISA or a customized Luminex Multiplex Assay (both from R&amp;D Systems). In 39 randomly chosen samples covering all three sampling points, a strong correlation (r=0.96, p&amp;lt;0.01) was found between Flt3L levels measured by the single-parameter and multiplex assays. We found that median serum Flt3L levels were elevated upon completion of each sequential modality in both cohorts (n=73 and n=65). In the principal cohort (Oslo), an increase in levels of Flt3L upon NACT completion was correlated with a decline in hemoglobin and neutrophil counts (r=–0.38, p&amp;lt;0.01 and r= –0.36, p=0.01), possibly reflecting the myelosuppressive effect. Progression-free survival (PFS), with the majority of events being metastatic progression, was 68% and 71% in the two cohorts. For T4 cases in the Oslo cohort, a high Flt3L level following NACT was associated with a low risk for a PFS event (HR=0.22, 95% CI=0.06-0.72, p=0.01). Additionally, oxaliplatin dose reduction during CRT, aimed at maintaining patient compliance to radiotherapy, was also associated with advantageous PFS (HR=0.40, 95% CI=0.17-0.92, p=0.03). In conclusion, the neoadjuvant regimens might have caused repetitive myelosuppression resulting in elevated circulating Flt3L levels, thereby enhancing proliferation of mature dendritic cells and mediation of systemic tumor-targeting effects. Oxaliplatin-containing neoadjuvant therapy that causes normal tissue toxicity but does not compromise patient compliance to the radiotherapy, may condition DC to present shed tumor antigens to cytotoxic T cells, and thus enable eradication of occult microscopic tumor at distant sites in LARC patients prone to develop metastatic disease. Citation Format: Erta Kalanxhi, Sebastian Meltzer, Jakob Vasehus Schou, Finn Ole Larsen, Svein Dueland, Kjersti Flatmark, Benny Vittrup Jensen, Knut Håkon Hole, Therese Seierstad, Kathrine Røe Redalen, Dorte Lisbet Nielsen, Anne Hansen Ree. Induction of systemic immune response by oxaliplatin-based neoadjuvant therapy and survival without metastatic progression in high-risk rectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A43.

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

A Randomized Phase 2 Trial of Consolidation Chemotherapy After Preoperative Chemoradiation Therapy Versus Chemoradiation Therapy Alone for Locally Advanced Rectal Cancer: KCSG CO 14-03

Preoperative chemoradiation therapy (CRT) followed by total mesorectal excision (TME) in locally advanced rectal cancer is the standard of care. To date, the role of consolidation chemotherapy after CRT has rarely been addressed through randomized trials. This study aimed to evaluate the efficacy of CRT followed by consolidation chemotherapy compared with CRT alone. This study enrolled patients with adenocarcinoma of the rectum and cT3 or cT4 disease with any N category and no metastasis.In arm A (control arm), we planned CRT (50.4Gy in 28 fractions) with capecitabine followed by TME. In arm B, 2 cycles of capecitabine and oxaliplatin were administered 1week after the completion of CRT before TME (capecitabine, 1700mg/m2 per day from day 1 to 14, and oxaliplatin, 100mg/m2 on day 1, every 3weeks). The downstaging rate (the proportion of ypT0 to ypT2 and ypN0M0) was the primary endpoint, which was to be tested with a 1-sided type I error of 15% and with 85% power. From September 2014 to February 2016, 110 patients (56 in arm A and 54 in arm B) were randomized and 108 (55 in arm A and 53 in arm B) started CRT. TME was conducted per protocol in 96 patients (52 in arm A and 44 in arm B). In arms A and B, downstaging was achieved in 21.2% and 36.4% (P=.077), respectively, and the pathologic complete response rate was 5.8% and 13.6% (P=.167), respectively. Grade ≥3 adverse events occurred in 3.6% of patients in arm A and 9.4% of patients in arm B during the preoperative treatment phase and in 1.9% and 9.0%, respectively, during the postoperative recovery phase. Consolidation chemotherapy with 2 cycles of capecitabine and oxaliplatin demonstrated a marginal improvement in the downstaging rate. However, a phase 3 trial of this strategy is discouraged because of the high dropout rate and safety issues.

Abstract P5-21-13: Olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: Asian subgroup analysis from the phase III OlympiAD trial

Abstract Background In the Phase III OlympiAD trial (NCT02000622, D0819C00003), olaparib (Lynparza™) showed a significant progression-free survival (PFS) improvement compared with chemotherapy treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm) (Robson et al. NEJM 2017). Here, we present data from a subgroup analysis of Asian pts. It is not yet known whether Asian pts, in comparison with the global patient population, may experience instances of differential toxicity with olaparib therapy. Methods OlympiAD, an open-label, multicenter, Phase III trial, randomized (2:1) pts with HER2-negative mBC and a gBRCAm to olaparib tablets (300 mg twice daily) or single-agent TPC (21-day cycles of capecitabine, eribulin or vinorelbine). Pts must have received ≤2 lines of chemotherapy for mBC and prior anthracycline and taxane in the adjuvant, neo-adjuvant or metastatic setting. Primary endpoint was PFS by blinded independent central review (BICR). Region (Asia, Europe, North America, South America) was a pre-defined subgroup for PFS. Results The Asian subgroup analysis included pts randomized at centers in China, Japan, Korea and Taiwan. Of 87 Asian pts randomized (median age 46 years), 86 received study treatment (n=59, olaparib; n=27, TPC). In the olaparib group, 29/59 (49%) had estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) tumors, and 30/59 (51%) had triple negative breast cancer (TNBC). In the TPC group, 13/28 (46%) had ER+/PR+ tumors and 15/28 (54%) had TNBC. The primary endpoint, PFS by BICR, favored olaparib with a hazard ratio (HR) of 0.53 (95% confidence interval [CI] 0.29–0.97; median 5.7 vs 4.2 months; 77% maturity), and was supported by investigator-assessed PFS (HR 0.29, 95% CI 0.16–0.55). In the overall OlympiAD study population (N=302), the PFS by BICR favored olaparib with a HR of 0.58 (95% CI 0.43–0.80; P=0.0009). Within the Asian subgroup, objective response rate (ORR) (RECIST) was 64% for olaparib versus 38% for the TPC group. Time to second progression, PFS2, was longer for pts receiving olaparib versus TPC (HR 0.43, 95% CI 0.22–0.84; 57% maturity). Grade ≥3 adverse events (AEs) occurred in 46% and 59% of pts receiving olaparib and TPC, respectively. The most common grade ≥3 AE was anemia (olaparib, 20%; TPC, 15%). In both treatment groups, 7% of pts discontinued study treatment due to AEs (n=4, olaparib; n=2, TPC). The tolerability profile of olaparib between the subgroup of Asian pts and the overall OlympiAD population will be examined in our data presentation. Conclusion Olaparib demonstrated an efficacy benefit compared with TPC in pts with HER2-negative mBC and a gBRCAm in this subgroup analysis of Asian pts from the Phase III OlympiAD trial. Discontinuation rates due to toxicity were low, highlighting that olaparib was generally well-tolerated. The efficacy of olaparib within the subgroup of Asian pts was consistent with that shown for the full OlympiAD dataset; consistent hazard ratios were shown in favor of olaparib using the primary endpoint of PFS by BICR, and for the key secondary endpoints of PFS by investigator assessment, PFS2, and ORR. Citation Format: Im S-A, Xu B, Li W, Robson M, Ouyang Q, Yeh D-C, Iwata H, Park Y-H, Sohn JH, Tseng L-M, Goessl C, Wu W, Runswick S, Masuda N. Olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: Asian subgroup analysis from the phase III OlympiAD trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-13.

Health-related quality of life in patients with advanced colorectal cancer treated with dose reduced capecitabine.

237 Background: The goal of palliative chemotherapy is to prolong survival and decrease the symptomatic disease burden while minimizing treatment toxicities to preserve or improve quality of life. We recently reported a trial of dose reduced capecitabine in elderly or frail patients with advanced colorectal cancer, demonstrating that dose reduced capecitabine was a safe and efficacious treatment option. We herein report the health related quality of life (HRQoL) outcomes for the trial. Methods: A single arm multi-centered phase I/II trial of dose reduced capecitabine assessed capecitabine in 221 patients in at least one of the following subgroups: Age &gt; 65, ECOG-PS ≥1, elevated LDH, and prior pelvic RT. Capecitabine was given at 2000 mg/m2 days 1-14 q21 days; or 1500 mg/m2 for patients with prior pelvic RT, as determined in the phase I portion of the study. Phase II participant (182 pts) were asked to complete FACT-G questionnaires at enrollment, after each cycle of capecitabine and once after cessation of the study drug, if possible. Results: 157 pts completed a baseline questionnaire (86%), and 137 pts (75%) completed a baseline and at least one subsequent questionnaire. The mean baseline score was 81.6, out of a possible 108. The mean score peaked at 92 after cycle 10. The mean change from baseline was always positive, with the maximum change (4.0), occurring after cycle 12. The number of patients who achieved the minimal important difference, a meaningful improvement in HRQoL, ranged from 30% to 45% during treatment cylces. The differences in HRQoL between capecitabine doses were minimal and did not reach significance. Patients who did not achieve disease control also reported an improvement in mean score from baseline (+3.9) after cycle 2. Changes in subscale mean scores for physical and social/family wellbeing were minimal (-1.2 to +0.5) while emotion and function subscale mean scores never decreased with the peak subscale change from baseline being +3.5. Conclusions: HRQoL improved on capecitabine therapy at 2000 or 1500 mg/m2 daily, further supporting its use in elderly and less fit patients with advanced colorectal cancer.

Tumor–stroma ratio predicts recurrence in patients with colon cancer treated with neoadjuvant chemotherapy

Background: Neoadjuvant chemotherapy represents a new treatment approach to locally advanced colon cancer. The aim of this study was to analyze the ability of tumor–stroma ratio (TSR) to predict disease recurrence in patients with locally advanced colon cancer treated with neoadjuvant chemotherapy.Material and methods: This study included 65 patients with colon cancer treated with neoadjuvant chemotherapy in a phase II trial. All patients were planned for three cycles of capecitabine and oxaliplatin before surgery. Hematoxylin and eosin stained tissue sections from surgically resected primary tumors were sampled and analyzed by conventional microscopy. Patients were divided into stroma-high (>50%, i.e. TSR low) and stroma-low (≤50%, i.e. TSR high) for the comparison with clinical data.Results: A low TSR was found in 47% of the surgically resected primary tumors and correlated to a significantly higher T- and N-category compared, to tumors with a high TSR (p < .01). A low TSR was also significantly associated with disease recurrence (p = .008), translating into significant differences in disease free survival (DFS) and overall survival, p < .002. The 5-year DFS rate for patients with a low TSR was 55%, compared to 94% in the group of patients with a high TSR.Conclusions: TSR assessed in the surgically resected primary tumor from patients with locally advanced colon cancer treated with neoadjuvant chemotherapy provides prognostic value and may serve as a relevant parameter in selecting patients for post-operative treatment.

Phase I/II trial of dose-reduced capecitabine in elderly patients with advanced colorectal cancer.

Combination chemotherapy is associated with improved outcomes in trials of selected fit patients with advanced colorectal cancer (acrc). For older or less-fit patients, combination chemotherapy is associated with greater toxicity and less benefit. Capecitabine monotherapy is a reasonable option for those patients, but the optimal dose remains controversial. A multicentre phase i/ii trial of reduced-dose capecitabine (2000 mg/m2, days 1-14 every 21 days) was conducted in 221 patients representing one or more of the following subsets: age greater than 65 years (n = 167), Eastern Cooperative Oncology Group (ecog) performance status of 1 or greater (n = 139), elevated lactate dehydrogenase (ldh) (n = 105), or prior pelvic radiation (n = 54). Based on phase i results, patients with prior pelvic radiation received capecitabine 750 mg/m2 twice daily. The goal was to ascertain efficacy in a design that was unlikely to cause high levels of toxicity. Median age in the patient cohort was 72 years. A median of 5 and a mean of 8 capecitabine cycles were given (range: 0-50 cycles). Grade 3 or 4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand-foot syndrome, 7.7% diarrhea). The response rate was 13.6%, with a 69.7% disease control rate. Median progression-free survival (pfs) was 5.6 months. Post progression, 56 patients received further capecitabine monotherapy (median of 4 additional cycles). Median overall survival duration for the patients was 14.3 months. Median survival was significantly higher for those who, at baseline, had an ecog performance status of 0 (compared with 1 or more) and normal ldh (compared with elevated ldh). Toxicity is less with dose-reduced capecitabine than with historical full-dose capecitabine, with only a small trade-off in efficacy, seen as a lower objective response rate. The improved tolerability could lead to an increased number of cycles of therapy, and pfs appears to be consistently higher at the lower dose. Those observations should, in the absence of a head-to-head clinical trial, be viewed as compelling evidence that 1000 mg/m2, or even 750 mg/m2, twice daily is an appropriate dose in elderly or frail patients with acrc.

Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine–Induced Hand-Foot Syndrome

ImportanceHand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment.ObjectiveTo compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS.Design, Setting, and ParticipantsThis single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers.InterventionsPatients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine.Main Outcomes and MeasuresPrimary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays.ResultsIn this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P < .001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P < 5 × 10−8), including a novel DPYD variant (rs75267292; P = 1.57 × 10−10), and variants in the MACF1 (rs183324967, P = 4.80 × 10−11; rs148221738, P = 5.73 × 10−10) and SPRY2 (rs117876855, P < 1.01 × 10−8; rs139544515, P = 1.30 × 10−8) genes involved in wound healing.Conclusions and RelevancePyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS.Trial Registrationclinicaltrials.gov Identifier: NCT00486213

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

TPS3632 Background: Irinotecan is an effective drug for rectal cancer. Early small sample size trials have assessed the addition of irinotecan to standard CRT with fluoropyrimidines in neoadjuvant phase of locally advanced rectal cancer, in which pCR rates varied from 13.7 to 37%. ARISTOTLE trial, a multicentre UK-based phase III trial, will complete recruitment in autumn 2016. However, all patients in case group were prescribed with weekly irinotecan dose of 60mg/m2 guided by UGT1A1*28 6/6 and 6/7 genetypes in neoadjuvant chemoradiation. Therefore, this phase III trial was designed to confirm the potential improvement in outcomes seen with the addition of irinotecan to CRT. Methods: Eligible patients are randomly allocated to either radiotherapy 50 Gy with concurrent capecitabine, followed by a cycle of capecitabine and oxaliplatin two weeks after the end of CRT (Control arm) or radiotherapy 50 Gy with concurrent capecitabine and irinotecan, followed by a cycle of capecitabine and irinotecan (Case arm). Capecitabine is prescribed with 825mg/m2 The primary end point is ypCR. The hypothesis is to increase ypCR from 12% in the control group to 25% in the case group. To detect such a difference, with alpha = 0.05 (two-tailed) and belta = 0.15, 360 randomly assigned patients are required. Secondary end points are toxicities, surgical complications, local control, progression-free survival and overall survival. Clinical trial information: NCT02605265.

Efficacy of preoperative neoadjuvant simultaneous integrated boost intensity-modulated radiotherapy combined with preoperative chemotherapy for locally advanced rectal cancer: a phase II clinical study

Objective To investigate the feasibility, safety, and short-term efficacy of preoperative capecitabine and simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) followed by one cycle of neoadjuvant capecitabine in patients with locally advanced rectal cancer (LARC). Methods From March 2015 to April 2016, a total of 37 patients with LARC were enrolled in this study. They received capecitabine (825 mg/m2 orally twice daily for 5 weeks, days 1-5 weekly) and SIB-IMRT (58.75 Gy in 25 fractions for rectal lesion and positive lymph nodes and 50.00 Gy in 25 fractions for pelvic lymphatic drainage area). After the concurrent chemoradiotherapy, they were allowed to rest for one week. And then they received one cycle of induction chemotherapy with capecitabine (1250 mg/m2 orally twice daily for 14 days). And total mesorectal excision (TME) was scheduled at 6-8 weeks after the concurrent chemoradiotherapy. The primary endpoint was pathologic complete response (pCR) rate, and the secondary endpoints included tumor and nodal (TN) downstaging rate, the rate of sphincter-preserving surgery, and adverse events. Results All the 37 patients successfully received the preoperative concurrent chemoradiotherapy. Only 32 patients underwent the surgical resection, 4 patients refused surgery due to symptom relief, and 1 patient delayed surgery due to perianal edema after radiotherapy. The pCR rate was 34%(11/32); the TN downstaging rate was 91%(29/32); the R0 resection rate was 100%; 24 patients (75%) underwent the sphincter-preserving surgery. During the period of chemoradiotherapy, most of the patients experienced grade 1/2 acute adverse events and grade 3/4 adverse events occurred in 3 patients. The postoperative complications included ureteral injury (1 patient) and intestinal obstruction (1 patient), and no death occurred in the perioperative period. Conclusions For patients with LARC, preoperative SIB-IMRT combined with one cycle of capecitabine followed by TME is safe and feasible, and has good short-term efficacy and mild acute adverse events. Key words: Rectal neoplasms/intensity modulated radiotherapy; Intensity modulated radiotherapy, boost; Rectal neoplasms/chemotherapy; Capecitabine

599TiP - A randomized phase III trial of capecitabine with or without irinotecan driven by UGT1A1 in neoadjuvant chemoradiation of locally advanced rectal cancer (CinClare)

Irinotecan is an effective drug for rectal cancer. Early small sample size trials have assessed the addition of irinotecan to standard CRT with fluoropyrimidines in neoadjuvant phase of locally advanced rectal cancer, in which pCR rates varied from 13.7 to 37%. ARISTOTLE trial, a multicentre UK-based phase III trial, will complete recruitment in autumn 2016. However, all patients in case group were prescribed with weekly irinotecan dose of 60mg/m2 for four times, regardless of the genetype of UGT1A1, which has been regarded in favor of predicting toxicities. In our previous phase I trial, the weekly dose of irinotecan was escalated to 65mg/m2 and 80mg/m2 guided by UGT1A1*28 6/6 and 6/7 genetypes in neoadjuvant chemoradiation. Therefore, this phase III trial was designed to confirm the potential improvement in outcomes seen with the addition of irinotecan to CRT. Trial design: Eligible patients are randomly allocated to either radiotherapy 50 Gy with concurrent capecitabine, followed by a cycle of capecitabine and oxaliplatin two weeks after the end of CRT (Control arm) or radiotherapy 50 Gy with concurrent capecitabine and irinotecan, followed by a cycle of capecitabine and irinotecan (Case arm). Capecitabine is prescribed with 825mg/m2 twice daily from first day of radiotherapy and given 5 days per week during radiotherapy in control group. In the other group, capecitabine dose is 625mg/m2 twice daily and additional weekly irinotecan dose is 80mg/m2 or 65mg/m2 guided by UGT1A1*28 6/6 or 6/7 genetypes (total of five times). Stratification was performed by center, UGT1A1*28 genetype (6/6, 6/7), T stage (cT3, cT4), and distance from anal verge (<= 5cm, >5cm). Surgery is schedule 8 weeks after the end of CRT, then, five cycles of XELOX are recommended during the course of adjuvant chemotherapy. The primary end point is ypCR. The hypothesis is to increase ypCR from 12% in the control group to 25% in the case group. To detect such a difference, with alpha = 0.05 (two-tailed) and belta = 0.15, 360 randomly assigned patients are required. Secondary end points are toxicities, surgical complications, local control, progression-free survival and overall survival. Clinical trial identification: NCT02605265, released on December 24, 2015 Legal entity responsible for the study: Fudan University Shanghai Cancer Center