Oxaliplatin In Patients Research Articles

Three-year outcomes of two phase II studies of adjuvant chemotherapy with S-1 plus oxaliplatin or capecitabine plus oxaliplatin in patients with stage III gastric cancer after D2 gastrectomy.

94 Background: Two phase II trials of oxaliplatin-based adjuvant chemotherapy for patients (pts) with gastric cancer (GC) after D2 gastrectomy have been conducted in Japan; the J-CLASSIC study of capecitabine plus oxaliplatin (CAPOX) and the SOXaGC study of S-1 plus oxaliplatin (SOX). In the current study, we evaluated survival outcomes of the two trials. Methods: The J-CLASSIC, enrolling stage II and III pts from 12 centers between July 2012 and July 2013, evaluated eight cycles of CAPOX. The SOXaGC, enrolling stage III pts from 11 centers between July 2013 and February 2014, evaluated seven cycles of SOX after one cycle of S-1 monotherapy. The two studies were conducted sequentially and most centers (9 centers) participated in both trials. In this pooled analysis, we updated relapse-free survival (RFS) and overall survival (OS) information. The median follow-up time was 49 months in the J-CLASSIC and 39 months in the SOXaGC. Results: Fifty-nine stage III pts treated with CAPOX and 62 stage III pts treated with SOX were analyzed. The 3-year RFS and OS rates of SOX were 70.9% (57.8-80.5%) and 75.7% (63.0-84.6%), respectively, whereas the 3-year RFS and OS rates of CAPOX were 67.8% (54.3-78.1%) and 79.3% (66.5-87.7%), respectively. The hazard ratio (HR) of SOX in comparison to CAPOX was 0.925 (0.498-1.720) for RFS, suggesting the efficacy of the two treatments was similar. Trend of a different efficacy was observed in some particular subgroups; the HR for RFS was 1.732 (0.506-5.927) in the intestinal type and 0.735 (0.353-1.528) in the diffuse type, while that was 2.008 (0.447-9.016) in stage IIIA, 0.872 (0.266-2.857) in stage IIIB, and 0.597 (0.258-1.383) in stage IIIC. Conclusions: This is the first report of survival follow-up in Japanese GC pts with oxaliplatin-based adjuvant chemotherapy, which suggests comparable outcomes in both treatments for stage III GC. Different trend in the treatment effect by histologic type or stage warrants further evaluation in a larger cohort. Clinical trial information: UMIN000026883.

Phase I study of hepatic arterial infusion (HAI) therapy with floxuridine (FUDR) combined with systemic gemcitabine and oxaliplatin in patients with locally advanced intrahepatic cholangiocarcinoma (ICC).

417 Background: The standard of care for unresectable ICC is palliative systemic chemotherapy with cisplatin and gemcitabine. HAI therapy with FUDR in ICC resulted in high response rates [Kemeny 2011]. The use of HAI FUDR with systemic chemotherapy may improve outcomes. We conducted a phase 1 study of HAI FUDR with systemic gemcitabine and oxaliplatin. Methods: We enrolled patients in 3 cohorts: FUDR 0.16mg/kg/day x 14 days (Cohort 1), FUDR 0.12 mg/kg/day x 14 days with gemcitabine 1000mg/m2 on days 1, 8, 15 (Cohort 2), and FUDR 0.10 mg/kg/day x 14 days with gemcitabine 800mg/m2 days 1, 15 and oxaliplatin 85mg/m2 days 1, 15 (Cohort 3). The primary endpoint was the recommended phase 2 dose (RP2D) for Cohort 3. DLTs were assessed during cycle 1. Secondary objectives were response rate and survival. Results: We enrolled 24 patients, 6 male, age range 42-81 years (median 64). No DLTs were observed in Cohort 1 (FUDR). In Cohort 2 (FUDR + Gem), the addition of gemcitabine at 1000mg/m2 days 1, 8, 15 resulted in grade 3 LFT elevation in 2 patients; for subsequent patients, the gemcitabine dose was reduced to 800mg/m2, and no further DLT were noted. No DLT were observed in Cohort 3 (FUDR + GemOx). 10 patients experienced partial responses and conversion to resectable disease occurred in all cohorts. No other significant toxicities occurred. Conclusions: FUDR via HAI with systemic gemcitabine and oxaliplatin is well-tolerated in patients with unresectable cholangiocarcinoma, with a high rate of response and disease control, allowing for resection in some patients. Our RP2D is FUDR 0.10 mg/kg/day x 14 days, with gemcitabine 800mg/m2 days 1, 15 and oxaliplatin 85mg/m2 days 1, 15. Collaboration with MSKCC is ongoing. Clinical trial information: NCT01525069. [Table: see text]

Relationship between the Asp1104His polymorphism of the nucleotide excision repair gene ERCC5 and treatment sensitivity to oxaliplatin in patients with advanced colorectal cancer in China

OBJECTIVES:To study the relationship between the Asp1104His polymorphism of the nucleotide excision repair gene ERCC5 and treatment sensitivity to oxaliplatin in patients with advanced colorectal cancer (CRC) in China.METHODS:A group of 226 patients in the Department of Gastrointestinal Oncology at Zhejiang Xiaoshan Hospital from July 2011∼December 2016 and a control group of 226 normal healthy individuals were involved in this study. All patients were first diagnosed with advanced CRC and were treated with oxaliplatin-based chemotherapy. The genotype of ERCC5 at the site of amino acid 1104 was determined by a TaqMan probe-based real-time PCR approach.RESULTS:There were no differences in age or gender between the groups, but the percentages of smokers and individuals with a family history of cancer were significantly higher in the patient group than in the control group. Analysis of the G/C polymorphism frequency among the patients and the healthy controls showed that the frequencies of the CC genotype and the CC+GC genotype were significantly related to CRC, but no significant difference in these frequencies was found between genders. The analysis of the relationship between the 5-year survival rate and different genotypes showed that in the total patient group, regardless of gender, the 5-year survival rate was significantly associated with the Asp1104His polymorphism of ERCC5.CONCLUSIONS:The Asp1104His polymorphism of ERCC5 was associated with the risk and 5-year survival rate of CRC as well as treatment sensitivity to oxaliplatin.

A Phase I Study of Irinotecan, Capecitabine (Xeloda), and Oxaliplatin in Patients With Advanced Colorectal Cancer

BackgroundThe objective of the present phase I study was to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of irinotecan, capecitabine, and oxaliplatin given in combination (IXO regimen) to patients with previously untreated, unresectable advanced or metastatic colorectal cancer (CRC). Patients and MethodsPatients received oxaliplatin followed by irinotecan as intravenous infusions on day 1, with oral capecitabine taken twice daily (BID) on days 2 to 15 of a 3-week cycle. The dose ranges were explored as follows: oxaliplatin, 75 to 120 mg/m2; irinotecan, 160 to 230 mg/m2; capecitabine, 750 to 1000 mg/m2 BID. Dose escalation was performed individually for each drug at each dose level according to the type and severity of toxicity encountered in the previous cohort. ResultsA total of 39 patients were enrolled at 7 dose levels and the MTD. The recommended doses for phase II evaluation were oxaliplatin 100 mg/m2, irinotecan 160 mg/m2, and capecitabine 950 mg/m2 BID. Diarrhea and febrile neutropenia were DLTs. Of the 39 enrolled patients, 26 (67%) had confirmed objective responses. The median progression-free survival was 11 months, and the median overall survival was 25 months. The survival rate at 5 years was 23%. ConclusionThe IXO regimen has a manageable toxicity profile with promising antitumor activity as first-line treatment of advanced and metastatic CRC.

5-FU or mitomycin C hepatic arterial infusion after failure of arterial oxaliplatin in patients with colorectal cancer unresectable liver metastases

Hepatic arterial infusion (HAI) chemotherapy with oxaliplatin is an accepted option in the management of colorectal cancer (CRC) with dominant liver metastases (LM). However, despite prolonged control, some patients experience disease progression. On the other hand, oxaliplatin leads to dose-limiting toxicity. In these cases, the use of a second-line HAI with an alternative drug has never been reported to date. We evaluated treatment outcomes in patients receiving second-line HAI with 5-FU or mitomycin C, after first-line HAI of oxaliplatin in heavily pretreated patients. Between March 2010 and June 2016, this observational study included 24 patients with unresectable CRC LM and treated with HAI of 5-FU (17 patients) or mitomycin C (7 patients), after HAI of oxaliplatin. Mean age was 61.7years. Forty-two percent of patients (10/24) had extra-hepatic metastases and 75% (18/24) at least 8 liver metastases. Including HAI of oxaliplatin, all patients had previously received at least 2lines of chemotherapy±targeted agents (100%) and 96% (23/24) received concomitant systemic therapies together with HAI of 5-FU or mitomycin C. The overall objective response rate and disease control rate were, respectively, 42% (10/24) and 71% (17/24). Median progression-free survival and overall survival (OS) were, respectively, 5.6 and 25.8months; hepatic progression-free survival was 8.5months. Thirteen percent (3/24) of the patients received further curative intent treatment after HAI 5-FU and mitomycin C. No toxic death occurred and the toxicity profile was acceptable. HAI of 5-FU or mitomycin C is an alternative option in patients with predominant CRC LM, when they experience disease progression or do not tolerate HAI of oxaliplatin.

Safety of intraperitoneal Mitomycin C versus intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis of colorectal cancer undergoing cytoreductive surgery and HIPEC

BackgroundColorectal peritoneal carcinomatosis (PC) is commonly treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). There is an ongoing international debate about which intraperitoneal chemotherapeutic agent is preferred, Mitomycin C (MMC) or oxaliplatin. We questioned whether the type of chemotherapeutic agent influenced postoperative complication rates or short-term survival. MethodsIn this retrospective cohort study patients with colorectal PC who underwent CRS-HIPEC between January 2010 and December 2016 were included. Until March 2014 patients had preferentially been treated with MMC and thereafter with oxaliplatin in an iso-osmotic glucose/electrolyte dialysis (Dianeal®) carrier solution. Main outcomes were postoperative complications, disease free survival (DFS) and overall survival (OS). Survival analyses and multivariable analyses were performed. ResultsOne hundred four patients received MMC and 73 patients oxaliplatin. Postoperative complications did not differ between groups (44.2% (MMC) versus 43.8% (oxaliplatin); P = 0.958). Median DFS was 12.5 months (IQR 6.4–32.4) in the MMC-group and 13.1 months (IQR 6.1-NA) in the oxaliplatin-group (P = 0.669). Median OS was 37.2 months (IQR 17.2-NA) in the MMC-group and 29.4 months (IQR 17.0-NA) in the oxaliplatin-group (P = 0.764). The type of chemotherapeutic agent did not influence OS in multivariable analysis (oxaliplatin versus MMC HR 1.09 (95%CI 0.58–2.06)). The HIPEC-phase was shorter for oxaliplatin (median 32 (IQR 31–34) versus 91 min (IQR 90–92) for MMC (P < 0.001)). ConclusionIntraperitoneal oxaliplatin reduced the chemoperfusion time when compared to intraperitoneal MMC without adversely influencing complication rates or short-term survival. It may therefore be the preferential drug in CRS-HIPEC procedures for colorectal PC.

Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats.

Histamine H3 receptors are mainly expressed on CNS neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists. The antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin. While S 38093 did not change vocalization thresholds to paw pressure in healthy rats, it exhibited a significant antihyperalgesic effect in the Streptozocin-induced diabetic (STZ) neuropathy model after acute and chronic administration and, in the chronic constriction injury (CCI) model only after chronic administration, submitted to the paw-pressure test. Acute S 38093 administration at all doses tested displayed a significant cold antiallodynic effect in a model of acute or repeated administration of oxaliplatin-induced neuropathy submitted to cold tail immersion, cold allodynia being the main side effect of oxaliplatin in patients. The effect of S 38093 increased following chronic administration (i.e. twice a day during 5days) in the CCI and STZ models except in the oxaliplatin models where its effect was already maximal from the first administration The kinetics and size of effect of S 38093 were similar to gabapentin and/or pregabalin. Finally, the antinociceptive effect of S 38093 could be partially mediated by α2 adrenoreceptors desensitization in the locus coeruleus. These results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent-induced neuropathic pain. S 38093, a new H3 antagonist/inverse agonist, displays antiallodynic and antihyperalgesic effect in neuropathic pain, especially in oxaliplatin-induced neuropathy after chronic administration. This effect of S 38093 in neuropathic pain could be partly mediated by α2 receptors desensitization in the locus coeruleus.

671P - Interim safety and clinical activity of nivolumab (Nivo) in combination with S-1/capecitabine plus oxaliplatin in patients (pts) with previously untreated unresectable advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: part 1 study of ATTRACTION-04 (ONO-4538-37)

671P - Interim safety and clinical activity of nivolumab (Nivo) in combination with S-1/capecitabine plus oxaliplatin in patients (pts) with previously untreated unresectable advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: part 1 study of ATTRACTION-04 (ONO-4538-37)

P-176 - Peripheral neuropathy secondary to oxaliplatin in patients treated for colorectal carcinoma

P-176 - Peripheral neuropathy secondary to oxaliplatin in patients treated for colorectal carcinoma

Bevacizumab, eribulin, and oxaliplatin in patients with platinum-resistant ovarian carcinomas: A phase II study with biomarker analysis.

5550 Background: Eribulin is a candidate for paclitaxel-refractory breast cancers, and Bevacizumab (B) is known to enhance efficacy of anti-cancer agents in ovarian cancers. A phase II study to evaluate weekly administration of B with eribulin and oxaliplatin (EriOX) in patients with platinum-resistant and refractory ovarian carcinomas (PR-ROC) was performed. Methods: Eligible patients were as follows: (a) ECOG PS = 0~2 (b) histologically confirmed epithelial ovarian cancer (c) diagnosed as platinum-resistant ovarian cancer (d) written informed consent. Patients were treated with weekly-B-EriOX consisting of B (2mg/kg), eribulin (1mg/m2) and oxaliplatin (30mg/m2), three weeks on and on week off, q4weeks. The study was conducted using two-stage design of Simon (type I error = 0.05, power = 0.9, true response rate = 25%). Biomarker analyses including serum VEGF, BNP, p53, IL-6, and Her-2 were also conducted. Results: A total of 34 patients were enrolled in the present study: 13 cases in the first-stage, and additional 21 cases in the second-stage. There were 3 responders (≧2) in the first-stage, and the protocol was proceeded to the second-stage. Median age of the patient was 58.5 years (range: 35-76), and median number of previous regimen was 4 (range: 2-9). Overall, two patients (6%) had a complete response (CR), 8 patients (24%) had a partial remission (PR) and 16 patients (47%) had a stable disease (SD). The response rate and clinical benefit rate (CR+PR+SD) were 29% and 76%, respectively. Median progression-free survival was 4 months (range: 1-27+). Hematological adverse effects (AE) with grade 3/4 were observed in 4 patients (11%). Non-hematological AE greater than grade2 was observed in one case: hypo albuminemia and edema, which were manageable and tolerable. As there were 10 responders (≧6), the protocol was considered for additional investigation. The Patients with elevated serum mutated p53 / IL-6 showed lower response and worse prognoses. Conclusions: Weekly B and EriOX administration was considered for additional investigation for patients with PR-ROC. Serum mutated p53 protein and/or IL-6 could be biomarkers in PR-ROC patients treated with weekly B and EriOX.

Clinical and neurophysiologic prospective study with time-event and long-term analysis of the chronic neurotoxicity associated with oxaliplatin in patients with colorectal cancer (CRC).

e15150 Background: The sensitive, symmetric, chronic neurotoxicity is a frequent dose-dependent and dose-limiting secondary effect of oxaliplatin (COXALIN). Time-event and long-term studies about COXALIN and its progression after the end of treatment ( coasting) are lacking. Methods: A prospective, translational, clinical and neurophysiologic study was performed in patients (p) with CRC treated with oxaliplatin. We analyzed COXALIN during and after treatment (at the time of initial, maximum coasting, improvement and maximum improvement). We followed p every 3 months the first year and every 6 months thereafter. The NCI-CTC V3.0 sensitive and modified TNSc (without motor and autonomic skills) clinical scales and Quantitave Sensitive Test and ENG were used. Results: 41 chemo naive p with CRC were included, 22 men, median age 60 y (IA:55-73).Oxaliplatin was administrated as adjuvant treatment in 36p. FOLFOX combination was used in 40p. The median cumulative doses was 825,25 mg/m2 (IA: 697-963). The median follow-up was 21,5m (11-27). 38 p developed COXALIN at median 5,5 m (IA: 4,4-6,6) and maximum coasting at median 8,5 m (IA: 7,6-9,5); in multivariant analysis, cumulative dose at 3 months (p = 0,039; OR 2,5; p = 0,027; HR 0,5) was predictive factor and female gender (p = 0,017; OR 0,11) was protective factor. Fine fiber neuropathy was detected in 47,4% p. All p improved at median 8,7m (IA: 7,1-10,2) since COXALIN, reaching the maximum improvement at 13,4 m (IA:16,0-20,4); on multivariate analysis, the COXALIN intensity was the predictive factor (p = 0,03; HR 0,42). 76,6%p showed residual COXALIN (73,9% p subclinical/mild, 17,4% p moderated and 8,7% p severe). A high correlation was found between clinical scales and neurophysiologic studies along the study (p &lt; 0,0001). Sensitive NCI-CTC scale was more sensible than modified TNSc to evaluate COXALIN intensity in our study. Conclusions: We confirm coasting in COXALIN which prolongs 6 months after treatment. About 80% p showed residual COXALIN in the long-term but it was subclinical or mild in most cases. Sensitive NCI-CTC 3.0 scale is a simple and reliable method for the follow-up of COXALIN.

Analysis of Factors Influencing the Tolerability of S-1 plus Oxaliplatin in Patients with Advanced Gastric Cancer

Oxaliplatin (L-OHP) was approved for the treatment of gastric cancer in 2015 in Japan. Cisplatin (CDDP) and L-OHP are used as the first-line therapy for unresectable advanced or recurrent gastric cancer. Compared with CDDP, L-OHP has fewer adverse effects such as nausea and vomiting. Moreover, L-OHP does not need a large amount of hydration. Many outpatients with gastric cancer can use L-OHP. L-OHP is used with S-1 (SOX) for unresectable advanced or recurrent gastric cancer. However, some patients need to take a reduced dose or discontinue therapy. Thus, we evaluated the factors that influence the tolerance to SOX, to improve treatment safety and predict adverse events. The study included 22 patients who were treated with SOX. Intolerant patients were defined as those who required a reduced dose or discontinuation of therapy. Eight patients were defined as intolerant. The factors that influenced tolerance included surgical history of gastric cancer (P = 0.018), body mass index < 18.5 (P = 0.039), low neutrophil count (P = 0.039), low platelet count (P = 0.039), and high aspartate transaminase level (P = 0.036). All intolerant patients underwent surgery for gastric cancer. The duration from surgery to the initiation of SOX in intolerant patients was shorter than that for tolerant patients (P = 0.021). In conclusion, the factors that influence tolerance in patients receiving SOX were short duration from surgery to SOX, low body mass index, low neutrophil count, low platelet count and high aspartate transaminase level. Therefore, patients who have these factors require careful monitoring for adverse events.

S-1 in combination with docetaxel and oxaliplatin in patients with advanced gastro-esophageal adenocarcinoma: two parallel phase 1/2a studies

Background: Docetaxel in combination with cisplatin and 5-fluorouracil (5-FU) is one of several standard chemotherapy regimens for patients with advanced gastro-esophageal adenocarcinoma (aGEA) in Europe. To enable outpatient treatment, we evaluated the maximum tolerated dose (MTD), recommended dose (RD), dose limiting toxicity (DLT) and safety of docetaxel in combination with oxaliplatin (O) and S-1 (DOS) in Caucasian patients with aGEA.Methods: We present final results of two parallel phase 1/2a studies (3 + 3 design). Escalating doses of docetaxel and S-1 with fixed dose O were given for 18 weeks every second week (DOS2w) or every third week (DOS3w) followed by S-1 maintenance therapy.Results: Thirty-four patients (18 in DOS2w and 16 in DOS3w) were enrolled between October 2013 and June 2015. Median age was 65 years (range 49–78). DLT was most often febrile neutropenia. Most common severe non-hematological adverse events were diarrhea (9%) and fatigue (6%). The RD of DOS3w was: docetaxel 50 mg/m2, O 100 mg/m2 and S-1 25 mg/m2 twice daily and of DOS2w was: docetaxel 40 mg/m2, O 70 mg/m2 and S-1 35 mg/m2 twice daily. Overall, response rate was 56%; median progression-free survival was 9.1 months; and median overall survival was 13.2 months in 34 patients.Conclusions: At the RD, DOS2w and DOS3w showed an acceptable safety profile in patients with aGEA.Clinical trials ID: NCT-01928524 and EudraCT 2012-005187-10

Treatment improvement by addition of leucovorin to S-1 plus oxaliplatin in patients with advanced gastric cancer

Regional differences in gastric cancer are observed between Asian and Western countries concerning prevalence, clinicopathologic features, as well as treatment strategies. Cisplatin and fluoropyrimidine based therapies are used as backbone of first-line chemotherapy for advanced gastric cancer treatment, although there is preference for 5-fluorouracil (5FU) or capecitabine in the West while S-1 is mostly used in Asia. REAL-2 and Al-Batran et al . studies have shown that oxaliplatin was as effective as cisplatin in combination with capecitabine or 5FU in Western countries (1,2). In the same way, in Asian countries, Yamada et al . have demonstrated recently that oxaliplatin could replace cisplatin in combination with S-1 for gastric cancer in first-line treatment with favorable safety profile (3). A third agent (docetaxel or epirubicin) may be added (more commonly in Western countries) for patients with good performance status (1,4).

Treatment improvement by addition of leucovorin to S-1 plus oxaliplatin in patients with advanced gastric cancer

Treatment improvement by addition of leucovorin to S-1 plus oxaliplatin in patients with advanced gastric cancer

Safety and Efficacy of a Modified FLOX Adjuvant Regimen for Patients With Stage III Colorectal Cancer Treated in the Community

BackgroundThe efficacy and safety of the combination of a fluoropyrimidine with oxaliplatin for patients with stage III colorectal cancer (CRC) have been evaluated in selected patients who took part in clinical trials. We evaluated the outcomes of FLOX (bolus fluorouracil [5-FU] combined with oxaliplatin) in patients with resected stage III CRC treated in the community in a large cancer center. Patients and MethodsWe performed a retrospective unicenter cohort study of all consecutive stage III CRC patients who received adjuvant chemotherapy with an mFLOX (modified FLOX) regimen. The schedule consisted of 5-FU bolus 500 mg/m2 and bolus of leucovorin 20 mg/m2 per week for 6 consecutive weeks and oxaliplatin 85 mg/m2 in a 2-hour infusion at weeks 1, 3, and 5, every 8 weeks. Logistic regression multivariate analyses were used to evaluate prognostic factors for relapse at 2 years, and to investigate potential predictors of Grade ≥3 toxicity. ResultsA total of 267 consecutive patients were eligible and included. The median age was 59 years and pathological stage was mostly IIIB (68.2%). With a median follow-up of 24 months, n = 67 patients (25.1%) relapsed, representing a 74.9% rate of disease-free survival at 2 years. In multivariable analyses, urgent surgery (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.02-3.48; P = .042), angiolymphatic invasion (OR, 1.92; 95% CI, 1.05-3.52; P = .034), and any interruption or dose reduction of chemotherapy (OR, 2.37; 95% CI, 1.31-4.27; P = .004) were predictors of recurrence or death at 2 years. Nine patients (3.4%) died from any cause within 60 days of starting mFLOX. Grade ≥3 toxicity occurred in 98 (36.7%) patients, with diarrhea (n = 43; 16.1%) and neutropenia (n = 38; 15.3%) being the most frequent ones. Peripheral neurotoxicity Grade ≥3 occurred in 5 patients (1.8%). Age 70 years or older (OR, 5.85; 95% CI, 2.5-13.66; P ≤ .001) was independently associated with a higher risk of a Grade ≥3 adverse events. ConclusionResults suggest that the effectiveness of combining oxaliplatin with bolus 5-FU in patients in the community is reasonably similar to that obtained in clinical trials. However, community patients presented a higher risk of death, especially for those who were older than 70 years. Adjuvant oxaliplatin should be used carefully and probably restricted to fit patients younger than 70 years in this setting.

REOX: Effectiveness evaluation of re-exposure to oxaliplatin in patients with metastatic colorectal cancer.

764 Background: Colorectal cancer has high incidence and mortality rates. Treatment of metastatic colorectal adenocarcinoma has evolved since the approval of irinotecan, oxaliplatin and monoclonal antibodies with survival surpassing 30 months in contemporary trials. Nevertheless there is paucity of effective options after failure of these protocols. Thus re-exposure to previously used drugs became a treatment strategy. We aimed to evaluate the efficacy of retreatment with oxaliplatin in mCRC and its correlation with clinicopathological features. Methods: We retrospectively analyzed 83 patients with mCRC who underwent REOX treated at a single cancer center in Brazil. REOX was defined as a second trial of an oxaliplatin containing regimen after a previous failure. Primary endpoint was time to treatment failure (TTF) after REOX. Results: Median age of our cohort was 53.5y. Female/Male: 51.8%/48.2%. Primary colon was found in 67.5% while 32.5% had primary rectal adenocarcinoma. KRAS status was wild type in 57.8% and mutated in 39.8%. Exclusive hepatic metastasis was found in 19.3%. Median follow-up after REOX was 31m. Main chemotherapy regimen was mFOLFOX6 (84.3%). Bevacizumab and Cetuximab were used in 42.2% and 6% respectively. Most patients underwent REOX in third and fourth lines, 48.2% and 25.3% respectively. Median time to treatment failure (mTTF) after REOX was 6.04m. Overall survival was 10.04m. Disease control (CR + PR + SD) was observed in 56.6%, while 42.2% had progressive disease (PD). Reasons for interruption were as follows: PD (68.7%), toxicity (19.3%) and metastasectomy (2.4%). Patients who attained disease control had better OS (14.5m) compared with patients who had PD (14.5m versus 6.24m, p &lt; 0.0001). Patients with exclusive hepatic metastasis had a trend to a better TTF compared to other metastasis sites (8.96m X 6.01m, p = 0.2). Regarding KRAS status, there was no difference in mTTF (wt 6.68m, mut 6.04m, p = 0.14). Conclusions: In the setting of pretreated mCRC patients where there are few options available, REOX remains an effective treatment, with mTTF of 6.04m in our cohort. This could be related to progression of cell clones sensitive to the drug after a time lapse since the previous exposure.

Phase II study of bevacizumab combined with capecitabine and oxaliplatin in patients with advanced adenocarcinoma of the small bowel or ampulla of vater.

144 Background: Capecitabine with oxaliplatin (CAPOX) is used in front-line management of metastatic small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC). In a prior single arm phase 2 study (n = 30), CAPOX showed an overall response rate (ORR) of 52%. The purpose of this study was to evaluate safety and activity of bevacizumab and CAPOX in this population. Methods: We conducted a single-center open-label single arm phase 2 study in patients with treatment naïve metastatic SBA and AAC between 8/2011 to 11/2014. Prior fluoropyrimidine-based adjuvant therapy was allowed if completed ≥ 52 weeks. Bevacizumab-CAPOX was administered as a 21-day cycle with capecitabine 750 mg/m2 orally twice daily on days 1-14, oxaliplatin 130mg/m2intravenously on day 1 and bevacizumab 7.5mg/kg intravenously on day 1. The primary endpoint was progression-free survival (PFS) at 6 months. Secondary objectives included ORR, overall PFS, overall survival (OS) and toxicity. Results: A total of 30 patients with median age of 63 years (range 33-78) were enrolled. Six (20%) patients had AAC and 24 (80%) had SBA (duodenal: 18). Treatment was well tolerated and most common grade 3/4 toxicities included fatigue (23%), hypertension (23%), neutropenia (30%), and diarrhea (10%). Common grade 2 toxicities included anorexia (50%), fatigue (47%), and nausea (37%). 4 patients remain on study treatment to date. In 29 evaluable patients the ORR was 48.3% (1 complete and 13 partial responses). Eleven (37.9%) patients had stable disease. The PFS at 6 months was 68% (95% CI: 52%-88%). The median PFS and median OS were 8.7 (95% CI: 6.6-13.4) and 14.98 (95% CI: 10.2-21.3) months, respectively. Comparing the current study to a subset of 25 patients with metastatic disease from our prior phase 2 CAPOX study demonstrated similar ORR, 48.3% vs. 52% (p = 0.79) and PFS 8.7m vs. 6.6m (p = 0.73). Conclusions: In patients with untreated metastatic SBA and AAC, therapy with bevacizumab and CAPOX was well-tolerated and showed efficacy comparable to published regimens. Further studies are warranted to evaluate the benefit of targeting angiogenesis in this rare tumor.

Adjuvant Chemotherapy in Rectal Cancer after Chemoradiotherapy

The aim of this overview was to investigate whether adjuvant chemotherapy has a favourable effect on the outcome of patients with rectal cancer who had preoperative (chemo)radiotherapy. A review of randomised clinical trials that allocated patients between fluorouracil-based and observation or between fluorouracil-based and oxaliplatin-based adjuvant chemotherapy after preoperative (chemo)radiotherapy was carried out, including their corresponding meta-analyses. None of the five randomised trials has shown a significant benefit of fluorouracil-based adjuvant chemotherapy for overall survival or disease-free survival. Also, the three corresponding meta-analyses failed to show a benefit of adjuvant treatment. Of three randomised trials – two phase III and one phase II with a 3-year disease-free survival end point – two showed a small benefit of adding oxaliplatin to fluorouracil, one failed. The corresponding meta-analyses showed that the pooled difference was not significant. In conclusion, the use of postoperative 5-fluorouracil-based chemotherapy with or without oxaliplatin in patients with rectal cancer after preoperative (chemo)radiotherapy is not scientifically proven.

S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial

Although leucovorin enhances the efficacy of fluorouracil, the anti-tumour activity of S-1 and leucovorin and their combination with oxaliplatin for patients with advanced gastric cancer is unknown. We compared the activity and safety of S-1 plus leucovorin, S-1 plus leucovorin and oxaliplatin, and S-1 plus cisplatin as first-line chemotherapy for advanced gastric cancer. In this multicentre, randomised, open-label, phase 2 trial, we recruited chemotherapy-naive patients with unresectable or recurrent gastric cancer with measurable lesions aged 20 years or older from 25 general hospitals and specialist centres in Japan. Patients were randomly assigned (1:1:1) centrally to receive S-1 plus leucovorin (S-1 40-60 mg orally plus oral leucovorin 25 mg twice a day for 1 week, every 2 weeks), S-1 plus leucovorin and oxaliplatin (S-1 plus leucovorin and intravenous oxaliplatin 85 mg/m(2) on day 1, every 2 weeks), or S-1 plus cisplatin (S-1 40-60 mg orally twice a day for 3 weeks, plus intravenous cisplatin 60 mg/m(2) on day 8, every 5 weeks). Randomisation was done with the minimisation method using performance status (0 vs 1) and tumour stage (stage IV vs recurrent) as stratification factors. The primary endpoint was independently reviewed overall response in the full analysis set. This trial is registered with Japic CTI, number 111635. Between Oct 20, 2011, and Dec 17, 2012, we enrolled and randomly assigned 145 patients: 49 patients were assigned to S-1 plus leucovorin, 47 to S-1 plus leucovorin and oxaliplatin, and 49 to S-1 plus cisplatin. An objective response assessed by the independent review committee was achieved in 20 (43% [95% CI 28·3-57·8]) of the 47 patients in the S-1 plus leucovorin group, 31 (66% [50·7-79·1]) of the 47 patients in the S-1 plus leucovorin and oxaliplatin group, and 22 (46% [31·4-60·8]) of the 48 patients in the S-1 plus cisplatin group (Fisher's exact test, p=0·84 for S-1 plus leucovorin vs S-1 plus cisplatin, p=0·063 for S-1 plus leucovorin and oxaliplatin vs S-1 plus cisplatin, and p=0·038 for S-1 plus leucovorin and oxaliplatin vs S-1 plus leucovorin). The most common grade 3-4 adverse events were neutropenia (three [6%] of 48 patients in the S-1 plus leucovorin group vs 12 [26%] of 47 patients in the S-1 plus leucovorin and oxaliplatin group vs 17 [35%] of 49 patients in the S-1 plus cisplatin group), decreased appetite (six [13%] vs 14 [30%] vs 12 [24%]), anaemia (five [10%] vs seven [15%] vs 13 [27%]), and hyponatraemia (two [4%] vs two [4%] vs nine [18%]). S-1 plus leucovorin and oxaliplatin was more active than S-1 plus leucovorin or S-1 plus cisplatin with acceptable toxic effects for patients with advanced gastric cancer. A phase 3 trial comparing S-1 plus leucovorin and oxaliplatin with S-1 plus cisplatin is underway. Taiho Pharmaceutical.