Fluoropyrimidine-based Adjuvant Chemotherapy Research Articles

The efficacy of fluoropyrimidine-based adjuvant chemotherapy on biliary tract cancer after R0 resection

BackgroundThe optimal treatment strategy for biliary tract cancer (BTC) after curative-intent resection remains controversial. The purpose of this study was to evaluate the efficacy of fluoropyrimidine-based adjuvant chemotherapy for BTC patients undergoing microscopically margin-negative (R0) resection.MethodsWe retrospectively analyzed the clinical data of BTC patients who underwent curative-intent R0 resection. Patients were eligible if they received either fluoropyrimidine-based adjuvant chemotherapy or observation after R0 resection.ResultsA total of 153 patients were included. In the entire patient cohort, no significant differences were observed in 5-year overall survival (OS) rates (48.4% vs. 39.6%, P = 0.439) or 3-year recurrence-free survival (RFS) rates (49.1% vs. 39.5%, P = 0.299) between patients who received fluoropyrimidine-based adjuvant chemotherapy or observation. However, for patients with stages II and III BTC, chemotherapy significantly improved 5-year OS rate (52.4% vs. 35.6%, P = 0.002) and 3-year RFS rate (55.5% vs. 39.1%, P = 0.021) compared with observation.ConclusionFluoropyrimidine-based adjuvant chemotherapy may prolong the survival of patients with stages II and III BTC after R0 resection.

Survival Impact of Adjuvant Chemotherapy for Resected Locally Advanced Rectal Adenocarcinoma

BackgroundRecent data has created uncertainty regarding the benefit of adjuvant fluoropyrimidine-containing chemotherapy following preoperative chemoradiotherapy and surgical resection for locally advanced rectal cancer (LARC). In particular, patients with a pathologic complete response (pCR) may derive no benefit from adjuvant chemotherapy. Patients and MethodsThis is a retrospective analysis of patients with LARC, diagnosed between January 1, 2003 and December 31, 2014 at 3 Melbourne health services. Patients were identified from the Australian Comprehensive Cancer Outcomes and Research Database, where a defined data set is prospectively collected on consecutive patients. Patient demographics, pCR rates, postoperative treatment, recurrence, and survival were analyzed. ResultsA total of 717 patients with LARC were identified, of whom 555 (77%) had received preoperative long-course chemoradiation followed by surgery. Four hundred fifty-two of 555 patients (81%) subsequently received adjuvant fluoropyrimidine-based chemotherapy. At a median follow-up of 45.9 months, 95 (21%) patients in the adjuvant chemotherapy group and 20 (19%) in the surveillance group had relapsed. Five-year relapse-free survival was 77% in the adjuvant chemotherapy group and 71% in the surveillance group with no significant difference on univariate analysis (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.58-1.51; P = .780). No significant impact on relapse-free survival was seen for either pCR or non-pCR patients. Five-year overall survival (OS) was 85% in the adjuvant chemotherapy group and 74% in the surveillance group with a nonsignificant trend towards OS benefit (HR, 0.62; 95% CI, 0.37-1.05; P = .074). A significant OS benefit favoring adjuvant chemotherapy was seen in the non-pCR subset of patients (HR, 0.49; 95% CI, 0.28-0.86; P = .014). ConclusionA high proportion of patients in this routine practice cohort received adjuvant chemotherapy following preoperative treatment and surgery for LARC. Adjuvant chemotherapy administration was associated with a significant improvement in 5-year OS only in the patients with a non-pCR.

Management of “borderline resectable” and “locally advanced” pancreatic cancer at the Massachusetts General Hospital

Recent data has created uncertainty regarding the benefit of adjuvant fluoropyrimidine-containing chemotherapy following preoperative chemoradiotherapy and surgical resection for locally advanced rectal cancer (LARC). In particular, patients with a pathologic complete response (pCR) may derive no benefit from adjuvant chemotherapy.This is a retrospective analysis of patients with LARC, diagnosed between January 1, 2003 and December 31, 2014 at 3 Melbourne health services. Patients were identified from the Australian Comprehensive Cancer Outcomes and Research Database, where a defined data set is prospectively collected on consecutive patients. Patient demographics, pCR rates, postoperative treatment, recurrence, and survival were analyzed.A total of 717 patients with LARC were identified, of whom 555 (77%) had received preoperative long-course chemoradiation followed by surgery. Four hundred fifty-two of 555 patients (81%) subsequently received adjuvant fluoropyrimidine-based chemotherapy. At a median follow-up of 45.9 months, 95 (21%) patients in the adjuvant chemotherapy group and 20 (19%) in the surveillance group had relapsed. Five-year relapse-free survival was 77% in the adjuvant chemotherapy group and 71% in the surveillance group with no significant difference on univariate analysis (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.58-1.51; P = .780). No significant impact on relapse-free survival was seen for either pCR or non-pCR patients. Five-year overall survival (OS) was 85% in the adjuvant chemotherapy group and 74% in the surveillance group with a nonsignificant trend towards OS benefit (HR, 0.62; 95% CI, 0.37-1.05; P = .074). A significant OS benefit favoring adjuvant chemotherapy was seen in the non-pCR subset of patients (HR, 0.49; 95% CI, 0.28-0.86; P = .014).A high proportion of patients in this routine practice cohort received adjuvant chemotherapy following preoperative treatment and surgery for LARC. Adjuvant chemotherapy administration was associated with a significant improvement in 5-year OS only in the patients with a non-pCR.

LGR5 and CD133 as prognostic and predictive markers for fluoropyrimidine-based adjuvant chemotherapy in colorectal cancer

Background: Expression of leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5) gene is associated with a metastatic phenotype and poor prognosis in colorectal cancer (CRC). CD133 expression is a putative cancer stem cell marker and a proposed prognostic marker in CRC, whereas the predictive value of CD133 expression for effect of adjuvant chemotherapy in CRC is unclear.Material and methods: For the study of LGR5 mRNA and CD133 expression, tissue microarrays from 409 primary CRC stage II and III tumors, where patients had been randomized to adjuvant chemotherapy or surgery only, were available. LGR5 mRNA and CD133 expression were assessed by in situ hybridization (ISH) and immunohistochemistry (IHC), respectively. LGR5 mRNA and CD133 expression as prognostic and predictive markers were evaluated by univariate and multivariate analyses.Results: For all CRC patients, positive LGR5 mRNA and CD133 expression were associated with classic adenocarcinoma histology type (p = 0.001 and p = 0.014, respectively). Positive LGR5 mRNA expression was also associated with smaller tumor diameter for CRC stage II (p = 0.005), but not for CRC stage III (p = 0.054). For CRC stage II, lack of LGR5 mRNA expression was associated with longer time to recurrence (TTR) in Kaplan-Meier (p = 0.045) and in multivariate Cox analysis (HR 0.27, 95% CI 0.08–0.95, p = 0.041). For colon cancer stage III patients, lack of CD133 expression was associated with better effect of adjuvant chemotherapy (p = 0.016) in Kaplan-Meier univariate analysis, but the interaction between CD133 and adjuvant chemotherapy was not statistically significant in multivariate analysis (HR 0.59, 95% CI 0.18–1.89, p = 0.374).Conclusion: LGR5 mRNA expression is a prognostic factor for CRC stage II patients, whereas the value of CD133 expression as prognostic and predictive biomarker is inconclusive.

Predictive value of chemotherapy-related high-density lipoprotein cholesterol (HDL) elevation in patients with colorectal cancer receiving adjuvant chemotherapy: an exploratory analysis of 851 cases

BackgroundThe phenomenon of chemotherapy-related lipid alterations has been reported based on a small number of patients and varies among different cancers. However, little is known about these alterations in colorectal cancer (CRC) patients.ResultsPatients in cohort 1, but not in cohort 2, exhibited significantly increased cholesterol, triglyceride, HDL-C, and ApoA-I levels, and decreased LDL-C and ApoB levels after adjuvant chemotherapy. Patients with chemotherapy-related HDL-C elevation exhibited better 3-year DFS (84.5% vs. 73%, P = 0.001) and 7-year OS (82% vs. 70%, P = 0.002) than those without. Similarly, the 3-year DFS (83.3% vs. 77.6%, P = 0.008) and 7-year OS (81% vs. 74.6%, P = 0.040) were superior in chemotherapy-related ApoA-I elevation patients. However, only HDL-C elevation remained an independent prognostic value in the multivariate Cox model.MethodsEight hundred fifty-one CRC patients with curative-intent resection were retrospectively analyzed. Six hundred sixty-seven receiving fluoropyrimidine-based adjuvant chemotherapy for more than 3 months were enrolled in cohort 1. The lipid alterations before and after chemotherapy were studied. Simultaneously, 184 patients not treated with chemotherapy (cohort 2) were included as a control for the comparisons of lipids alterations within 1 month after resection and at half-year follow-up. Furthermore, these significant alterations were investigated with respect to the prognostic value of disease-free survival (DFS) and overall survival (OS). An internal validation was performed.ConclusionWe observed significant changes in the levels of various lipids in CRC patients receiving adjuvant chemotherapy. Furthermore, chemotherapy-related HDL-C elevation was determined to be an independent prognostic indicator for superior DFS and OS.

The association between the duration of fluoropyrimidine-based adjuvant chemotherapy and survival in stage II or III gastric cancer.

BackgroundThis study was conducted to propose the optimal duration of fluoropyrimidine-based adjuvant chemotherapy consisting of fluoropyrimidine derivatives alone or combined with intravenous platinum for stage II or III gastric cancer (GC).MethodsWe analyzed retrospectively the data from 2219 patients with histologically confirmed adenocarcinoma in the stomach, who underwent a curative gastrectomy with lymphadenectomy from 2005 to 2012. Five-year overall survival (OS) and 3-year relapse-free survival (RFS) were analyzed according to the duration of fluoropyrimidine-based adjuvant chemotherapy.ResultsData from 617 patients with stage II or III GC were analyzable; 187 patients (30.3 %) were treated with surgery alone, while 430 patients (69.7 %) were treated with postoperative adjuvant chemotherapy. The duration of adjuvant chemotherapy was less than 6 months [group 1] in 147 patients (34.2 %), 6 months to less than 12 months [group 2] in 94 patients (21.9 %), 1 year to less than 2 years [group 3] in 139 patients (32.3 %), and over 2 years [group 4] in 50 patients (11.6 %). The 5-year OS in groups 1, 2, 3, and 4 was 75.7, 87, 90.3, and 93.4 %, respectively, while 3-year RFS was 52.5, 58.8, 81.4, and 94.0 %, respectively.ConclusionsIn this retrospective study, we did not demonstrate any significant improvement in OS and RFS by longer periods of fluoropyrimidine-based adjuvant chemotherapy in stage II or III GCs. Further prospective randomized studies are needed.

Current topics in the multimodality treatment of locally advanced rectal cancer.

The multimodality approach to the treatment of locally advanced rectal cancer has evolved to include neoadjuvant radiotherapy with or without concurrent chemotherapy, total mesorectal excision and adjuvant fluoropyrimidine-based chemotherapy. Though this broad strategy has yielded improvements in local control compared with historical data, overall survival remains largely unchanged. Current investigations focus on improving patient selection through new imaging modalities, improving surgical techniques, incorporating more aggressive systemic treatment regimens and the selective use of radiation. Here, we review emerging data regarding newer staging techniques, neoadjuvant chemotherapy, optimal timing of surgery, selective use of radiation and nonoperative approaches to the management of locally advanced rectal cancers.

Optimizing Colorectal Cancer Care in Older Patients

Colorectal cancer is a disease affecting mainly older people, a fact that is becoming more apparent with the global population aging. However, this patient group is more likely to be subjected to suboptimal treatment due to a number of factors, but most commonly as a result of the physician’s weakness to recognize those fit for the full spectrum of cancer therapy. In this regard, clinical screening tests, such as the Comprehensive Geriatric Assessment, can be invaluable in guiding treatment decisions. Fluoropyrimidine-based adjuvant chemotherapy clearly confers a survival advantage in older individuals with node-positive disease; however, the benefit from the administration of oxaliplatin-based regimens is less clear. Palliative chemotherapy also has an important role in managing metastatic disease, and with the use of novel targeted agents it can potentially prolong survival and improve quality of life. The management of rectal cancer in this population can present a challenge, since it appears that the optimal treatment of chemoradiation followed by total mesorectal excision can be applied in select few. Indeed, the morbidity and mortality rates in older people treated with these combined modalities can be too high, guiding many physicians to opt for more conservative approaches, directed at providing palliation and local control, especially in those with limited life expectancy. In conclusion, in order to provide the best care in an older colorectal cancer patient, we need to individualize our approach, selecting the right patient for the right treatment.

Hazard rate of tumor recurrence over time: a pooled-analysis of three clinical trials with fluoropyrimidine-based adjuvant chemotherapy for colorectal cancer achieved by the Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC)

Hazard rate of tumor recurrence over time: a pooled-analysis of three clinical trials with fluoropyrimidine-based adjuvant chemotherapy for colorectal cancer achieved by the Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC)

A retrospective study of the association between durations of fluoropyrimidine-based adjuvant chemotherapy and survivals in stage II or III gastric cancer.

e15088 Background: This study was conducted to propose the optimal duration of fluoropyrimidine-based adjuvant chemotherapy, which was consisted of fluoropyrimidine derivatives alone or fluoropyrim...

Pathologic Factors Associated with Prognosis after Adjuvant Chemotherapy in Stage II/III Microsatellite-Unstable Colorectal Cancers.

Background:Although there are controversies regarding the benefit of fluoropyrimidine-based adjuvant chemotherapy in patients with microsatellite instability–high (MSI-H) colorectal cancer (CRC), the pathologic features affecting postchemotherapeutic prognosis in these patients have not been fully identified yet.Methods:A total of 26 histopathologic and immunohistochemical factors were comprehensively evaluated in 125 stage II or III MSI-H CRC patients who underwent curative resection followed by fluoropyrimidine-based adjuvant chemotherapy. We statistically analyzed the associations of these factors with disease-free survival (DFS).Results:Using a Kaplan- Meier analysis with log-rank test, we determined that ulceroinfiltrative gross type (p=.003), pT4 (p<.001), pN2 (p=.002), perineural invasion (p=.001), absence of peritumoral lymphoid reaction (p=.041), signet ring cell component (p=.006), and cribriform comedo component (p=.004) were significantly associated with worse DFS in patients receiving oxaliplatin-based adjuvant chemotherapy (n=45). By contrast, pT4 (p<.001) and tumor budding-positivity (p=.032) were significant predictors of poor survival in patients receiving non-oxaliplatin–based adjuvant chemotherapy (n=80). In Cox proportional hazards regression model-based univariate and multivariate analyses, pT category (pT1-3 vs pT4) was the only significant prognostic factor in patients receiving non-oxaliplatin–based adjuvant chemotherapy, whereas pT category, signet ring cell histology and cribriform comedo histology remained independent prognostic factors in patients receiving oxaliplatin-based adjuvant chemotherapy.Conclusions:pT4 status is the most significant pathologic determinant of poor outcome after fluoropyrimidine-based adjuvant chemotherapy in patients with stage II/III MSI-H CRC.

Is There a Role for Adjuvant Chemotherapy in Rectal Cancer?

Adjuvant chemoradiotherapy trials demonstrated a reduction in local failure and an increase in survival of patients with locally advanced rectal cancer submitted to upfront surgery. The standard-of-care shifted to neoadjuvant chemoradiotherapy when the German Rectal Cancer Study Group Trial demonstrated the benefit of neoadjuvant compared to adjuvant fluoropyrimidine chemoradiotherapy in lower rates of local failure, lower toxicity in patients optimally resected with total mesorectal excision (TME), and higher rate of sphincter-sparing surgery. Overall survival (OS) was equivalent in both arms. The benefit of adjuvant chemotherapy after preoperative chemoradiotherapy has not been clearly demonstrated in randomized trials. This review will discuss the role of fluoropyrimidine-based and oxaliplatin-based adjuvant chemotherapy in patients treated with neoadjuvant chemoradiotherapy.

Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial

The role of adjuvant chemotherapy for patients with rectal cancer is controversial, especially when used after preoperative chemoradiotherapy. Fluoropyrimidine-based adjuvant chemotherapy, including fluorouracil and leucovorin, has been widely used; however, the addition of oxaliplatin to fluorouracil and leucovorin (FOLFOX), a standard adjuvant regimen for colon cancer, has not been tested in rectal cancer. We aimed to compare the efficacy and safety of adjuvant fluorouracil and leucovorin with that of FOLFOX in patients with locally advanced rectal cancer after preoperative chemoradiotherapy. In this open-label, multicentre, phase 2, randomised trial, patients with postoperative pathological stage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after preoperative fluoropyrimidine-based chemoradiotherapy and total mesorectal excision were recruited and randomly assigned (1:1) via a web-based software platform to receive adjuvant chemotherapy with either four cycles of fluorouracil and leucovorin (fluorouracil 380 mg/m(2) and leucovorin 20 mg/m(2) on days 1-5, every 4 weeks) or eight cycles of FOLFOX (oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil bolus 400 mg/m(2) on day 1, and fluorouracil infusion 2400 mg/m(2) for 46 h, every 2 weeks). Stratification factors were pathological stage (II vs III) and centre. Neither patients nor investigators were masked to group assignment. The primary endpoint was 3-year disease-free survival, analysed by intention to treat. This study is fully enrolled, is in long-term follow-up, and is registered with ClinicalTrials.gov, number NCT00807911. Between Nov 19, 2008, and June 12, 2012, 321 patients were randomly assigned to fluorouracil and leucovorin (n=161) and FOLFOX (n=160). 141 (95%) of 149 patients in the fluorouracil plus leucovorin group and 141 (97%) of 146 in the FOLFOX group completed all planned cycles of adjuvant treatment. Median follow-up was 38·2 months (IQR 26·4-50·6). 3-year disease-free survival was 71·6% (95% CI 64·6-78·6) in the FOLFOX group and 62·9% (55·4-70·4) in the fluorouracil plus leucovorin group (hazard ratio 0·657, 95% CI 0·434-0·994; p=0·047). Any grade neutropenia, thrombocytopenia, fatigue, nausea, and sensory neuropathy were significantly more common in the FOLFOX group than in the fluorouracil plus leucovorin group; however, we noted no significant difference in the frequency of these events at grade 3 or 4. The most common grade 3 or worse adverse events were neutropenia (38 [26%] of 149 patients in the fluorouracil plus leucovorin group vs 52 [36%] of 146 patients in the FOLFOX group), leucopenia (eight [5%] vs 12 [8%]), febrile neutropenia (four [3%] vs one [<1%]), diarrhoea (four [3%] vs two [1%]), and nausea (one [<1%] vs two [1%]). Adjuvant FOLFOX improves disease-free survival compared with fluorouracil plus leucovorin in patients with locally advanced rectal cancer after preoperative chemoradiotherapy and total mesorectal excision, and warrants further investigation. Korea Healthcare Technology R&D Project (South Korean Ministry of Health and Welfare).

Pharmacogenetic predictors of outcome in patients with stage II and III colon cancer treated with oxaliplatin and fluoropyrimidine-based adjuvant chemotherapy.

Identifying molecular markers for tumor recurrence is critical in successfully selecting patients with colon cancer who are more likely to benefit from adjuvant chemotherapy. We investigated the effect of single-nucleotide polymorphisms (SNP) within genes involved in oxaliplatin and fluoropyrimidines metabolism, DNA repair mechanisms, drug transport, or angiogenesis pathways on outcome for patients with stage II and III colon cancer treated with adjuvant chemotherapy. Genomic DNA was extracted from formalin-fixed paraffin-embedded samples of 202 patients with stage II and III colon cancer receiving oxaliplatin-based adjuvant chemotherapy from January 2004 to December 2009. Genotyping was performed for 67 SNPs in 32 genes using the MassARRAY (SEQUENOM) technology. Our results were validated in an independent cohort of 177 patients treated with the same chemotherapy regimens. The combination of the selectin E (SELE) rs3917412 G>A G/G and the methylentetrahydrofolate reductase (MTHFR) rs1801133 T/T genotypes was associated with a significantly increased risk for recurrence in both the training [RR = 4.103; 95% confidence interval (CI), 1.803-9.334; P = 0.001] and the validation cohorts (RR = 3.567; 95% CI, 1.253-10.151; P = 0.017) in the multiple regression analysis considering the stage, lymphovascular invasion, and bowel perforation as covariates. The combined analysis of these polymorphisms was also significantly associated with overall survival in both cohorts (RR = 3.388; 95% CI, 0.988-11.623; P = 0.052, and RR = 3.929; 95% CI, 1.144-13.485; P = 0.020, respectively). Our findings suggest that the SELE rs3917412 and MTHFR rs1801133 SNPs could serve as pharmacogenetic predictors of tumor recurrence in patients with early-stage colon cancer treated with oxaliplatin-based adjuvant chemotherapy, thus allowing personalized selection of treatment to optimize clinical outcomes.

P-0208 - Combination of Oxaliplatin + Fluorouracil Compared to Fluoropyrimidine Single Agent in Adjuvant Treatment of Young Patients with Colon Cancer

Introduction: Colon cancer in young individuals is increasingly common problem in Egypt with more aggressive disease and worse 5-years survival compared to their older counterpart. Thus we carried a retrospective analysis for patients with colon cancer who received Adjuvant therapy aiming to evaluate the magnitude of benefit adding Oxaliplatin to Fluoropyrimidine-based chemotherapy according to patient's age. Methods: We retrospectively identified patients with colon cancer presenting to Kasr al-ainy oncology center in period between January 2009 – Decemer 2013 who were candidate for adjuvant chemotherapy. Files were reviewed for patient's age, gender, pathological subtype, grade, stage, type of chemotherapy received date and site of relapse. All data were tabulated and statistically studied by descriptive analysis as well as survival analysis in relation to different prognostic factors. Comparison between groups was done using Student t test for continuous data and Chi square test for categorical data. Survival analysis was done according to Kaplan-Meier method and compared by log-rank test for significance. Results: One hundred forty patients were included in our analysis of which 55 patients were less than 40 years old, 29 were males (53%) and 26 females (47%). Thirty four patients were treated with combination of oxaliplatin and fluorouracil, and 21 patients received single agent fluorouracil. The Median overall survival (OS) was 43 months, five years disease free survival (DFS) was 37%. Using multivariate analysis, factors significantly affecting overall survival were gender (p= 0.001), Stage (p= 0.002) and combination of oxaliplatin and fluorouracil (p= 0.001). The magnitude of benefit from combination chemotherapy was more significant in patients younger than 40 years compared to those older than 40 years. Conclusion: According to our study, adding Oxaliplatin to fluoropyrimidine-based adjuvant chemotherapy significantly improves overall survival especially in patients younger than 40 years of age.

O-0017 - Preoperative Chemoradiotherapy and Postoperative Chemotherapy with Capecitabine and Oxaliplatin Vs. Capecitabine Alone in Locally Advanced Rectal Cancer: Disease Free Survival at Interim Analysis

Introduction: The PETACC-6 trial investigates whether the addition of oxaliplatin to preoperative oral fluoropyrimidine-based chemoradiation (CRT) followed by postoperative adjuvant fluoropyrimidine-based chemotherapy (CT) improves disease-free survival (DFS) in locally advanced rectal cancer.

Fluoropyrimidine-based adjuvant chemotherapy in patients with resected biliary tract cancers.

e15108 Background: The role of adjuvant therapy is controversial in patients with resected biliary tract cancers(BTC). There are few data regarding the benefit of adjuvant chemotherapy in BTC. Meth...

Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: Disease-free survival results at interim analysis.

3501 Background: The PETACC-6 trial investigates whether the addition of oxaliplatin to preoperative oral fluoropyrimidine-based chemoradiation (CRT) followed by postoperative adjuvant fluoropyrimidine-based chemotherapy (CT) improves disease-free survival (DFS) in locally advanced rectal cancer. Methods: Between 11/2008 and 09/2011, patients with rectal adenocarcinoma within 12 cm from the anal verge, T3/4 and/or node-positive, with no evidence of metastatic disease and considered either resectable at the time of entry or expected to become resectable, were randomly assigned to receive 5 weeks of preoperative CRT with capecitabine, followed by 6 cycles of adjuvant CT with capecitabine with (arm 2) or without (arm 1) the addition of oxaliplatin before and after surgery. 440 DFS events were required to have 80% power to detect an improvement in 3-year DFS from 65% with capecitabine alone to 72% with capecitabine and oxaliplatin (HR=0.763) using a two-sided alpha of 5% and owing for an interim analysis for early efficacy at 200 events. The primary analysis was intent-to-treat and adjusted for stratification factors (clinical T category, nodal status, distance from the tumor to the anal verge and method of locoregional staging) except the center. Results: 1094 patients were randomized (547 in each arm). 543 eligible patients in arm 1 and 526 in arm 2 started their allocated treatment of whom 67.4% completed protocol treatment in arm 1 vs. 53.8% in arm 2. An independent data monitoring committee reviewed the interim data and recommended the early release of the results. At median follow-up of 31 months, respectively 124 and 121 DFS events were observed in arm 1 and 2 (adjusted HR=1.036, 95% CI: 0.806 -1.331, P=0.781). 3-year DFS was 74.5% (95% CI: 70.1% - 78.3%) in arm 1, which is higher than anticipated vs. 73.9% (95% CI: 69.5% - 77.8%) in arm 2. Conditional power under HR=0.763 is only 7%. Conclusions: Interim results indicate that the addition of oxaliplatin to capecitabine plus radiotherapy does not improve DFS. Careful follow-up should continue until the planned 440 events to document any late treatment difference. Clinical trial information: NCT00766155.

Optimal cycles of fluoropyrimidine-based adjuvant chemotherapy for patients with resectable gastric cancer.

e15160 Background: Although several clinical trials have suggested that postoperative adjuvant chemotherapy could improve survival, there has no study on the optimal cycles of treatment. This retrospective analysis was carried out to evaluate the outcomes of gastric cancer patients treated with 5-6 cycles of FU-based treatment as compared to a cohort treated with 3-4 cycles or 7-8 cycles. Methods: We retrospective identified 254 patients with stage IB-IIIC gastric cancer who received 3-8 cycles of adjuvant chemotherapy after gastrectomy with D1 or D2 lymphadenectomy. The endpoint was overall survival. Factors associated with prognosis were also analyzed. Results: Of the 254 patients, 74 patients treated with 3-4 cycles, 112 patients treated with 5-6 cycles and 68 patients treated with 7-8 cycles. The 3-year OS rates for 3-4 cycles, 5-6 cycles and 7-8 cycles cohort was 56.6%, 73.9% and 67.7%, respectively. Patients who received 5-6 cycles were more likely to have better OS than those received 3-4 cycles (p=0.003), two further cycles of treatment did not improved OS (p=0.885). In the multivariate analysis, cycles of chemotherapy were associated with OS independent of clinical covariates (p=0.008). Subgroup analysis was suggested that for patients with older adult (age ≥60), FU-platinum combined chemotherapy, stage III, poorly differentiation, and gastrectomy with D2 lymph node dissection, 5-6 cycles of adjuvant chemotherapy was associated with a statistically significant benefit of OS (P&lt;0.05). Conclusions: Our result indicated that 5-6 cycles of adjuvant chemotherapy may lead to a favorable outcome for gastric cancer patients following primary surgical treatment. In view of the limited resources of medication, reduced incidences of toxicity and better quality-of-life with shorter duration of treatment, optimal cycles of adjuvant treatment should be explored further.

Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: First results of the PETACC-6 randomized phase III trial.

3531 Background: The PETACC-6 trial investigates whether the addition of oxaliplatin to preoperative oral fluoropyrimidine-based chemoradiation (CRT) followed by postoperative adjuvant fluoropyrimidine-based chemotherapy (CT) improves disease-free survival (DFS) in locally advanced rectal cancer. We present results of the early secondary endpoints. Methods: Between 11/2008 and 09/2011, patients with rectal cancer within 12 cm from the anal verge, T3/4 and/or node-positive, with no evidence of metastatic disease and considered either resectable at the time of entry or expected to become resectable after preoperative CRT, were randomly assigned to receive 5 weeks of preoperative CRT (45 Gy in 25 fractions) with capecitabine (825 mg/m² twice daily), followed by 6 cycles of adjuvant CT with capecitabine (1000 mg/m2twice daily/days 1-15 every three weeks) (arm 1) or to receive the same regimen with the addition of oxaliplatin before (50 mg/m²/days 1, 8, 15, 22, 29) and after surgery (130 mg/m²/day 1, every three weeks) (arm 2). Additional RT before surgery (5.4 Gy/days 36-38) using the same fields or as a boost with capecitabine was an option. Primary endpoint is DFS. Results: 1094 patients were randomized (547 in each arm). 98% and 92% of patients, respectively, received at least 45 Gy of preoperative RT in arm 1 and arm 2. More than 90% of full dose concurrent CT was delivered in 91% and 63% of patients, respectively, in arm 1 and arm 2. Preoperative grade 3/4 toxicity occurred in 15.1% of patients in arm 1 vs. 36.7% in arm 2; 1 vs. 3 patients died before surgery. R0 resection rate was 92.0% in arm 1 and 86.3% in arm 2. The pCR rate (ypT0N0) was equal in both arms with 11.3% in arm 1 and 13.3% in arm 2 (p=0.31). The anal sphincter was preserved in 70% vs. 65% (p=0.09) in arm 1 and 2. Postoperative complications were not different between arms (38% vs. 41%; 5 vs. 4 patients died following surgery). Definitive numbers will be presented at the congress. Conclusions: The addition of oxaliplatin to preoperative fluoropyrimidine-based CRT led to decreased treatment compliance and increased toxicity, but did not improve surgical outcome. Clinical trial information: NCT00766155.