497 Background: In patients (pts) with metastatic colorectal cancer (MCRC), XELOX is non-inferior... more 497 Background: In patients (pts) with metastatic colorectal cancer (MCRC), XELOX is non-inferior to FOLFOX4 in terms of PFS and OS as either first-line (NO16966, Cassidy et al. JCO 2008) or second-line therapy (NO16967, Rothenberg et al. Ann Oncol 2008). In pts with stage III colon cancer (NO16968, Haller et al. ECCO-ESMO 2009), adjuvant XELOX is superior to 5-FU/LV in terms of DFS. While XELOX is generally well tolerated, regional differences in fluoropyrimidine tolerability were noted in a pooled analysis [Rothenberg et al. ASCO GI 2008], leading to use of lower than recommended doses of capecitabine (i.e. 1,000mg/m2 bid d1–15 with oxaliplatin 130mg/m2 d1 q3w) in some countries. Methods: NO16966, NO16967 and NO16968 protocols included standard dose/schedule modifications for capecitabine, 5-FU and oxaliplatin for treatment-related adverse events (AEs). Safety parameters included AEs, deaths, laboratory parameters, exposure to trial medication, and withdrawals. In NO16966 and NO16...
3546 Background: In a previous phase III study, the FUFOX regimen has shown superior response rat... more 3546 Background: In a previous phase III study, the FUFOX regimen has shown superior response rates and progression-free survival compared with bolus 5-FU/FA (Mayo Clinic protocol) in patients with ACRC (Grothey, ASCO 2002). The combination of capecitabine (CAP) and oxaliplatin (OX) has demonstrated good efficacy and safety results in recent phase II studies. In August 2002 we initiated a phase III trial to compare FUFOX and CAPOX as first line therapy in patients with ACRC. Here, we present the results of a planned interim safety analysis. PATIENTS AND METHODS From August 2002 to October 2003 275 (of target 420) patients (m:f = 176:99; median age 66 (range 32-85)) have been randomized to receive either FUFOX (135 pts. arm A: 5-fluorouracil 2000mg/m2 24h infusion, folinic acid 500mg/m2, oxaliplatin 50mg/m2 d1,8,15,22; q5 wks) or CAPOX (140 pts. arm B: capecitabine 1000mg/m2 bid d1-14, oxaliplatin 70mg/m2 d1 and 8; q3 wks). All patients had measurable metastatic disease, ECOG performance status 0-2, normal renal and hepatic function. RESULTS To date 783 treatment cycles (320 FUFOX, 463 CAPOX) are evaluable (median number of cycles per patient: arm A: 4, range 1-8; arm B: 4, range 1-12. Seven deaths occured within the first 60 days (3 (2.2%) in arm A : 1x bowel obstruction, 1x severe diarrhea, 1x unknown cause) and 4 (2.8%) in arm B : 1x stroke, 1x bowel obstruction, 1x severe diarrhea and sepsis, 1x unknown cause). Major toxicities grade 2-4 (NCI-CTC) are listed in the table below. CONCLUSIONS These data show that both FUFOX and CAPOX have a comparable toxicity profile as first line therapy in ACRC and are both well tolerated. Updated toxicity results will be reported at the meeting. At that time, the planned enrollment of 420 patients will have been completed. [Figure: see text] No significant financial relationships to disclose.
ABSTRACT Background: Capecitabine has established efficacy and tolerability profiles in the treat... more ABSTRACT Background: Capecitabine has established efficacy and tolerability profiles in the treatment of colorectal and breast cancer. Dose modification is recommended upon the occurrence of grade 2–4 adverse events (AEs). The effect of dose modification on efficacy was analyzed using data from 6 large, randomized phase III trials of pts treated with capecitabine monotherapy or in combination with oxaliplatin or docetaxel. Methods: Data regarding appropriate modification, interruption or delay of capecitabine dose were prospectively captured during 6 clinical trials (breast cancer: NO17629, NO16853; colorectal cancer: NO16966, NO16967, NO16968 and M66001). Uniform prespecified criteria for dose modification were used across trials. Data were analysed using descriptive statistics. KM curves for DFS (NO16968, M66001 and NO17629) or PFS (NO16966, NO16967 and NO16853) were constructed to assess the effects on pt outcomes. Results: Data from each study show that capecitabine dose reduction for AE management has no detrimental effect on DFS/PFS. Findings were similar across trials, indications and settings (adjuvant/metastatic). Outcomes were numerically worse in pts with no capecitabine dose modifications; a trend observed across indications/settings. The difference was more pronounced in pts receiving combination therapy. Across all studies 57-67% pts had cycle interruptions, delays or capecitabine doses reduced. Median delivered capecitabine dose intensities ranged from 0.67–0.94 across trials. Dose modification reduced the occurrence of subsequent AEs in the only capecitabine monotherapy trial (M66001 [X-ACT]), a trend less apparent in combination regimen trials where initial capecitabine doses were lower. Conclusions: Data from 6 phase III trials show that AEs associated with capecitabine treatment are manageable by appropriately planned dose modification or cycle delay without detrimental effects on efficacy, across indications/settings. Observed reduced performance among pts with no dose modifications in the mCRC setting may suggest underdosing as data indicate treatment may have been stopped due to disease progression rather than AEs.
e14047 Background: According to the German S3 guidelines (Schmiegel et al., 2008), groups (gr) fo... more e14047 Background: According to the German S3 guidelines (Schmiegel et al., 2008), groups (gr) for suggested tx intensity are defined as based on an outcome-oriented algorithm (Schmoll & Sargent, Lancet 2007): Gr 1: pts with resectable liver mets (CLM), Gr 2: pts with CLM, potentially resectable after conversion tx, Gr 3a/b: pts with incurable disease, with disease related symptoms or at risk for rapid deterioration (3a) or without latter conditions (3b), gr 4: elderly or frail patients. In gr 2 and 3a, intense tx regimes (IT), by triple chemo or with targeted agents (TA), are recommended, whereas in 3b and 4, sequential tx starting with single agent or doublet tx are regarded as an option. METHODS A representative sample of 82 sites was selected with regard to the distribution of treated prevalence in institutions. Pts. characteristics as well as treating physicians suggestion for group distribution (according to guidelines), and tx characteristics were evaluated. RESULTS Data include 636 pts with first-line tx (Q4 '09): Distribution per gr is: 26% gr 1 (immediate surgery); in pts with upfront systemic tx: 16% gr 2, 12% gr 3a, 20% gr 3b, and 26% gr 4. Pts. in gr 2 were significantly (all <0.05) younger, had better performance status (PS), lack of comorbidity, had tx decision in non-university institutions and kras testing, but no more TA or IT. By contrast to the intention, IT and TA were given without statist. diff. in all gr., with the highest number (69% and 64%) in symptomatic pts (gr 3a). In a multivariate cluster analysis, 3 clusters overall including 89% of pts were determined (all p<0,05). In the only cluster with significantly higher use of TA, pts were younger (<70 y.), in better PS (≥80% KI), and asymptomatic (independent whether from tumor or lack of comorbidity). CONCLUSIONS In clinical practice, the use of the complex, outcome-orientated determination system is not generally accepted. The decision making on tx intensity is rather based on pts characteristics and institutional factors. This underlines the need for development of further models.
Goals of work: Comparing antiemetic efficacy of different 5-HT 3-receptor antagonists (5-HT 3 RAs... more Goals of work: Comparing antiemetic efficacy of different 5-HT 3-receptor antagonists (5-HT 3 RAs) is difficult due to inter-study variability. Therefore, a meta-analysis was performed to comparatively evaluate dolasetron, granisetron, ondansetron and tropisetron for acute chemotherapy-induced nausea and vomiting (CINV). Patients and methods: Comparisons between 5-HT 3 RAs were based on 44 randomized studies (including 12,343 patients) identified by MEDLINE, CANCERLIT or EMBASE searches and subcategorized by chemotherapy type (cisplatin-or non-cisplatinbased). Main results: When all studies were combined, granisetron was equivalent to ondansetron (n=27), and showed an advantage vs tropisetron (p=0.018; n=12). Ondansetron vs tropisetron (n=11) and ondansetron vs dolasetron (n=3) revealed equivalence in each comparison. An advantage for 3 mg granisetron vs 8 mg ondansetron was found in non-cisplatin-based studies (p=0.015; n=6). Overall equivalence was seen between ondansetron, 24 or 32 mg, and granisetron, 2 or 3 mg, for all studies (n=13). There was a possible advantage for higher (24 or 32 mg) vs lower (8 mg) ondansetron dose regimens with cisplatin-based trials (n=6). No differences were seen between 3 and 1 mg granisetron doses (n=6). Conclusions: Efficacy of 5-HT 3 RAs for preventing CINV following cisplatin-and non-cisplatinbased chemotherapy is comparable, with the exception of granisetron vs tropisetron. Some differences were noted in dosing subanalyses.
Background Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemot... more Background Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fl uorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment. Methods This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fl uorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50•4 Gy plus infusional fl uorouracil (1000 mg/m² days 1-5 and 29-33), followed by surgery and four cycles of bolus fl uorouracil (500 mg/m² days 1-5 and 29; fl uorouracil group); and an experimental group receiving preoperative radiotherapy of 50•4 Gy plus infusional fl uorouracil (250 mg/m² days 1-14 and 22-35) and oxaliplatin (50 mg/m² days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m² days 1 and 15), leucovorin (400 mg/m² days 1 and 15), and infusional fl uorouracil (2400 mg/m² days 1-2 and 15-16; fl uorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratifi ed by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, effi cacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076. Findings Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fl uorouracil plus oxaliplatin group and 623 in the fl uorouracil group). Preoperative grade 3-4 toxic eff ects occurred in 140 (23%) of 606 patients who actually received fl uorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fl uorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fl uorouracil and oxaliplatin during chemoradiotherapy than in those who received fl uorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fl uorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fl uorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fl uorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fl uorouracil group (odds ratio 1•40, 95% CI 1•02-1•92; p=0•038). In the fl uorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fl uorouracil group. Interpretation Inclusion of oxaliplatin into modifi ed fl uorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS. Funding German Cancer Aid (Deutsche Krebshilfe).
Purpose Six randomized phase II and III trials have investigated the role of oxaliplatin (OX) in ... more Purpose Six randomized phase II and III trials have investigated the role of oxaliplatin (OX) in combination with capecitabine (CAP) or infusional fluorouracil (FU) in metastatic colorectal cancer. This meta-analysis compared the efficacy of CAP/OX compared with infusional FU/OX. Patients and Methods This analysis compared all published CAP/OX versus infusional FU/OX regimens. A total of 3,494 patients (FU, n = 1,737; CAP, n = 1,757) were analyzed for response rate (RR), progression-free (PFS), overall survival (OS), and toxicity. Results The fixed-effect pooled estimate for RR showed higher RR for FU-based regimens (Odds ratio [OR] = 0.85; 95% CI, 0.74 to 0.97; P = .02) whereas the analysis of chemotherapy-only trials, excluding the bevacizumab containing NO16966 and TREE 2 trials, led to an OR of 0.74 (95% CI, 0.60 to 0.92; P = .007). However, for PFS (hazard ratio [HR] = 1.04; 95% CI, 0.96 to 1.12; P = .17) and OS (HR = 1.04; 95% CI, 0.95 to 1.12; P = .41) all models suggested si...
Purpose This is one of a few studies that have explored the value of baseline symptoms and health... more Purpose This is one of a few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in patients with brain cancer. Patients and Methods Baseline HRQOL scores (from the European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire C30 and the EORTC Brain Cancer Module) were examined in 247 patients with anaplastic oligodendrogliomas to determine the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap resampling procedure and the computation of C indexes and R2 coefficients were used to explore the stability of the models as well as better assess the potential benefit of using HRQOL to predict survival in clinical practice and research. Results Classical analysis controlled for major clinical prognostic factors selected emotional functioning (P = .0016), communication deficit (P = .0261), future uncertainty (P =...
Invited Publications operated on immediately after post-treatment assessment. LR after the first ... more Invited Publications operated on immediately after post-treatment assessment. LR after the first 12 months was almost always amenable to salvage surgery of the time. There were no oncologic differences between patients undergoing immediate radical resection compared to those who sustained a cCR for 12 months or longer.
The optimal treatment of patients with metastatic spinal cord compression (MSCC) is still being d... more The optimal treatment of patients with metastatic spinal cord compression (MSCC) is still being debated. The current observational multicenter study, performed prospectively by the authors, evaluated two radiotherapy (RT) schedules and prognostic factors with respect to functional outcome In the current study, 214 patients with MSCC were irradiated between April 2000 and September 2003 with 30 gray (Gy) per 10 fractions per 2 weeks (n = 110) or with 40 Gy per 20 fractions per 4 weeks (n = 104). Motor function and ambulatory status were evaluated before RT and until 6 months after RT. The following potential prognostic factors were investigated: RT schedule, performance status, age, number of irradiated vertebrae, type of primary tumor, pretreatment ambulatory status, and length of time developing motor deficits before RT. Both groups were balanced for patient characteristics and potential prognostic factors. Motor function improved in 43% of patients after 30 Gy and in 41% of patients after 40 Gy (P = 0.799). Posttreatment ambulatory rates were 60% and 64% (P = 0.708), respectively. A multivariate analysis demonstrated that a slower progression of motor deficits before RT (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), a favorable histology of the primary tumor (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), and being ambulatory before RT (P = 0.035) were associated with a better functional outcome. RT schedule (P = 0.269) and other variables had no significant impact. Acute toxicity was mild, and late toxicity was not observed during the period of follow-up. Follow-up was 12 (6-28) months in patients surviving &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;/= 6 months. Thirty gray per 10 fractions was preferable to 40 Gy per 20 fractions, because it was associated with similar outcome, less treatment time, and lower costs. The type of tumor, pretreatment ambulatory status, and length of time developing motor deficits before RT were relevant prognostic factors and should be considered in future studies.
Background: Central venous access devices in fluoropyrimidine therapy are associated with complic... more Background: Central venous access devices in fluoropyrimidine therapy are associated with complications; however, reliable data are lacking regarding their natural history, associated complications and infusion pump performance in patients with metastatic colorectal cancer. Methods: We assessed device placement, use during treatment, associated clinical outcomes and infusion pump perfomance in the NO16966 trial. Results: Device replacement was more common with FOLFOX-4 (5-fluorouracil (5-FU) þ oxaliplatin) than XELOX (capecitabine þ oxaliplatin) (14.1% vs 5.1%). Baseline device-associated events and post-baseline removal-/placement-related events occurred more frequently with FOLFOX-4 than XELOX (11.5% vs 2.4% and 8.5% vs 2.1%). Pump malfunctions, primarily infusion accelerations in 16% of patients, occurred within 1.6-4.3% of cycles. Fluoropyrimidine-associated grade 3/4 toxicity was increased in FOLFOX-4-treated patients experiencing a malfunction compared with those who did not (97 out of 155 vs 452 out of 825 patients), predominantly with increased grade 3/4 neutropenia (53.5% vs 39.8%). Febrile neutropenia rates were comparable between patient cohorts±malfunction. Efficacy outcomes were similar in patient cohorts±malfunction. Conclusions: Central venous access device removal or replacement was common and more frequent in patients receiving FOLFOX-4. Pump malfunctions were also common and were associated with increased rates of grade 3/4 haematological adverse events. Oral fluoropyrimidine-based regimens may be preferable to infusional 5-FU based on these findings. Fluoropyrimidines form the foundation of the vast majority of chemotherapy regimens used in the treatment of metastatic colorectal cancer (mCRC), and they can take the form of intravenous 5-fluorouracil (5-FU; by continuous or bolus infusion) or oral formulations (capecitabine). Fluoropyrimidine-based regimens include XELOX (oral capecitabine plus infusional oxaliplatin), FOLFOX (infusional leucovorin (LV), 5-FU and oxaliplatin) and FOLFIRI (infusional LV, 5-FU and irinotecan), each of which has a well-established role in the management of patients with mCRC. These regimens are now included in the key
Background: This randomized phase II trial investigated the efficacy and safety of capecitabine/o... more Background: This randomized phase II trial investigated the efficacy and safety of capecitabine/oxaliplatin (CapOx) plus bevacizumab and dose-modified capecitabine/irinotecan (mCapIri) plus bevacizumab as first-line therapy in patients with metastatic colorectal cancer (mCRC). Patients and methods: Patients received bevacizumab 7.5 mg/kg with oxaliplatin 130 mg/m 2 /day 1 plus capecitabine 1000 mg/m 2 bid/days 1-14 or with irinotecan 200 mg/m 2 /day 1 plus capecitabine 800 mg/m 2 bid/days 1-14 both every 21 days. The primary end point was 6 months progression-free survival (PFS). Results: A total of 255 patients were enrolled. The intent-to-treat population comprised 247 patients (CapOxbevacizumab: n = 127; mCapIri-bevacizumab: n = 120). The six-month PFS rates were 76% (95% CI, 69%-84%) and 84% (95% CI, 77%-90%). Median PFS and OS were 10.4 months (95% CI, 9.0-12.0) and 24.4 months (95% CI, 19.3-30.7) with CapOx-bevacizumab, and 12.1 months (95% CI, 10.8-13.2) and 25.5 months (95% CI, 21.0-31.0) with mCapIri-bevacizumab. Grade 3/4 diarrhea as predominant toxic effect occurred in 22% of patients with CapOx-bevacizumab and in 16% with mCapIri-bevacizumab. Conclusions: Both, CapOx-bevacizumab and mCapIri-bevacizumab, show promising activity and an excellent toxic effect profile. Efficacy is in the range of other bevacizumab-containing combination regimen although lower doses of irinotecan and capecitabine were selected for mCapIri.
Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the las... more Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence
This two-part phase Ib/II study investigated the feasibility of administering cetuximab in combin... more This two-part phase Ib/II study investigated the feasibility of administering cetuximab in combination with oxaliplatin and infusional 5-fluorouracil (5-FU)/folinic acid (FA) in a weekly schedule (AIO FUFOX protocol) as firstline treatment in patients with epidermal growth factor receptor-detectable advanced colorectal cancer. Patients and methods: Cetuximab was administered weekly: 400 mg/m 2 initial dose, then 250 mg/m 2 and FUFOX: oxaliplatin 50 mg/m 2 , FA 500 mg/m 2 and 5-FU as a 24-h infusion at either 1500 or 2000 mg/m 2 administered for 4 weeks followed by a 1-week rest (one cycle). Results: Dose-limiting toxicity (grade 3 diarrhea) occurred in 3 of 14 assessable patients receiving 5-FU at standard 2000 mg/m 2 . This dose was administered to a further 25 patients. Cetuximab combined with FUFOX was generally well tolerated with the most common grade 3/4 adverse events being diarrhea (27%) and paresthesia (16%). The confirmed response rate for patients receiving 5-FU at standard 2000 mg/m 2 (N = 41) was 56%, with a median duration of 9.3 months. Median progression-free and overall survival times including all 49 patients were 8.1 (95% confidence interval 6.0-9.7) and 28.2 months, respectively. Cetuximab pharmacokinetics seemed not to be different for combination with FUFOX compared with cetuximab/irinotecan combinations. This protocol is well tolerated and shows promising efficacy supporting further investigation.
ABSTRACT Background: The PETACC-6 trial investigates whether the addition of oxaliplatin to preop... more ABSTRACT 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 report on pathological staging and sphincter preservation following preoperative CRT. 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, were randomly assigned to receive 5 weeks of preoperative CRT (45 Gy in 25 fractions with an optional boost to a total dose of 50.4 Gy) with capecitabine (825 mg/m 2 twice daily), followed by 6 cycles of adjuvant CT with capecitabine (1000 mg/m2 twice daily/days 1-15 every three weeks) (arm 1) or to receive the same regimen with the addition of oxaliplatin before (50 mg/m 2 /days 1, 8, 15, 22, 29) and after surgery (130 mg/m 2 /day 1, every three weeks) (arm 2). Pathological down-staging (ypT0-2N0) rate, complete remission (ypT0N0) rate and tumor regression grade according to Dworak were secondary endpoints. The assessment was based on the review of the specimen and scoring by the local pathologist. Patients not operated or not resected were scored as failures (intent-to-treat analysis). 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 2. More than 90% of full dose concurrent CT was delivered in 91% and 63% of patients in arm 1 and 2 respectively. R0 resection rate was 92.0% in arm 1 and 86.3% in arm 2. The ypT0N0 rate was equal in both arms with 11.3% in arm 1 and 13.3% in arm 2 (p = 0.31). There was no difference in pathological down-staging rate (43.5% in arm 1 vs. 41.5% in arm 2). In arm 2, the tumor regression according to Dworak was minimal in 13.7% of patients, moderate in 35.5%, good in 20.5% and total in 13.5%. In arm 1, the percentages were 19%, 36.2%, 19.4% and 12.4% respectively. The anal sphincter was preserved in 70% vs. 65% (p = 0.09) in arm 1 and 2. Definitive numbers will be presented at the congress. Conclusion: The addition of oxaliplatin to preoperative fluoropyrimidine-based CRT led to decreased treatment compliance and did not result in any improvement in tumour down staging or in anal sphincter preservation.
497 Background: In patients (pts) with metastatic colorectal cancer (MCRC), XELOX is non-inferior... more 497 Background: In patients (pts) with metastatic colorectal cancer (MCRC), XELOX is non-inferior to FOLFOX4 in terms of PFS and OS as either first-line (NO16966, Cassidy et al. JCO 2008) or second-line therapy (NO16967, Rothenberg et al. Ann Oncol 2008). In pts with stage III colon cancer (NO16968, Haller et al. ECCO-ESMO 2009), adjuvant XELOX is superior to 5-FU/LV in terms of DFS. While XELOX is generally well tolerated, regional differences in fluoropyrimidine tolerability were noted in a pooled analysis [Rothenberg et al. ASCO GI 2008], leading to use of lower than recommended doses of capecitabine (i.e. 1,000mg/m2 bid d1–15 with oxaliplatin 130mg/m2 d1 q3w) in some countries. Methods: NO16966, NO16967 and NO16968 protocols included standard dose/schedule modifications for capecitabine, 5-FU and oxaliplatin for treatment-related adverse events (AEs). Safety parameters included AEs, deaths, laboratory parameters, exposure to trial medication, and withdrawals. In NO16966 and NO16...
3546 Background: In a previous phase III study, the FUFOX regimen has shown superior response rat... more 3546 Background: In a previous phase III study, the FUFOX regimen has shown superior response rates and progression-free survival compared with bolus 5-FU/FA (Mayo Clinic protocol) in patients with ACRC (Grothey, ASCO 2002). The combination of capecitabine (CAP) and oxaliplatin (OX) has demonstrated good efficacy and safety results in recent phase II studies. In August 2002 we initiated a phase III trial to compare FUFOX and CAPOX as first line therapy in patients with ACRC. Here, we present the results of a planned interim safety analysis. PATIENTS AND METHODS From August 2002 to October 2003 275 (of target 420) patients (m:f = 176:99; median age 66 (range 32-85)) have been randomized to receive either FUFOX (135 pts. arm A: 5-fluorouracil 2000mg/m2 24h infusion, folinic acid 500mg/m2, oxaliplatin 50mg/m2 d1,8,15,22; q5 wks) or CAPOX (140 pts. arm B: capecitabine 1000mg/m2 bid d1-14, oxaliplatin 70mg/m2 d1 and 8; q3 wks). All patients had measurable metastatic disease, ECOG performance status 0-2, normal renal and hepatic function. RESULTS To date 783 treatment cycles (320 FUFOX, 463 CAPOX) are evaluable (median number of cycles per patient: arm A: 4, range 1-8; arm B: 4, range 1-12. Seven deaths occured within the first 60 days (3 (2.2%) in arm A : 1x bowel obstruction, 1x severe diarrhea, 1x unknown cause) and 4 (2.8%) in arm B : 1x stroke, 1x bowel obstruction, 1x severe diarrhea and sepsis, 1x unknown cause). Major toxicities grade 2-4 (NCI-CTC) are listed in the table below. CONCLUSIONS These data show that both FUFOX and CAPOX have a comparable toxicity profile as first line therapy in ACRC and are both well tolerated. Updated toxicity results will be reported at the meeting. At that time, the planned enrollment of 420 patients will have been completed. [Figure: see text] No significant financial relationships to disclose.
ABSTRACT Background: Capecitabine has established efficacy and tolerability profiles in the treat... more ABSTRACT Background: Capecitabine has established efficacy and tolerability profiles in the treatment of colorectal and breast cancer. Dose modification is recommended upon the occurrence of grade 2–4 adverse events (AEs). The effect of dose modification on efficacy was analyzed using data from 6 large, randomized phase III trials of pts treated with capecitabine monotherapy or in combination with oxaliplatin or docetaxel. Methods: Data regarding appropriate modification, interruption or delay of capecitabine dose were prospectively captured during 6 clinical trials (breast cancer: NO17629, NO16853; colorectal cancer: NO16966, NO16967, NO16968 and M66001). Uniform prespecified criteria for dose modification were used across trials. Data were analysed using descriptive statistics. KM curves for DFS (NO16968, M66001 and NO17629) or PFS (NO16966, NO16967 and NO16853) were constructed to assess the effects on pt outcomes. Results: Data from each study show that capecitabine dose reduction for AE management has no detrimental effect on DFS/PFS. Findings were similar across trials, indications and settings (adjuvant/metastatic). Outcomes were numerically worse in pts with no capecitabine dose modifications; a trend observed across indications/settings. The difference was more pronounced in pts receiving combination therapy. Across all studies 57-67% pts had cycle interruptions, delays or capecitabine doses reduced. Median delivered capecitabine dose intensities ranged from 0.67–0.94 across trials. Dose modification reduced the occurrence of subsequent AEs in the only capecitabine monotherapy trial (M66001 [X-ACT]), a trend less apparent in combination regimen trials where initial capecitabine doses were lower. Conclusions: Data from 6 phase III trials show that AEs associated with capecitabine treatment are manageable by appropriately planned dose modification or cycle delay without detrimental effects on efficacy, across indications/settings. Observed reduced performance among pts with no dose modifications in the mCRC setting may suggest underdosing as data indicate treatment may have been stopped due to disease progression rather than AEs.
e14047 Background: According to the German S3 guidelines (Schmiegel et al., 2008), groups (gr) fo... more e14047 Background: According to the German S3 guidelines (Schmiegel et al., 2008), groups (gr) for suggested tx intensity are defined as based on an outcome-oriented algorithm (Schmoll & Sargent, Lancet 2007): Gr 1: pts with resectable liver mets (CLM), Gr 2: pts with CLM, potentially resectable after conversion tx, Gr 3a/b: pts with incurable disease, with disease related symptoms or at risk for rapid deterioration (3a) or without latter conditions (3b), gr 4: elderly or frail patients. In gr 2 and 3a, intense tx regimes (IT), by triple chemo or with targeted agents (TA), are recommended, whereas in 3b and 4, sequential tx starting with single agent or doublet tx are regarded as an option. METHODS A representative sample of 82 sites was selected with regard to the distribution of treated prevalence in institutions. Pts. characteristics as well as treating physicians suggestion for group distribution (according to guidelines), and tx characteristics were evaluated. RESULTS Data include 636 pts with first-line tx (Q4 '09): Distribution per gr is: 26% gr 1 (immediate surgery); in pts with upfront systemic tx: 16% gr 2, 12% gr 3a, 20% gr 3b, and 26% gr 4. Pts. in gr 2 were significantly (all <0.05) younger, had better performance status (PS), lack of comorbidity, had tx decision in non-university institutions and kras testing, but no more TA or IT. By contrast to the intention, IT and TA were given without statist. diff. in all gr., with the highest number (69% and 64%) in symptomatic pts (gr 3a). In a multivariate cluster analysis, 3 clusters overall including 89% of pts were determined (all p<0,05). In the only cluster with significantly higher use of TA, pts were younger (<70 y.), in better PS (≥80% KI), and asymptomatic (independent whether from tumor or lack of comorbidity). CONCLUSIONS In clinical practice, the use of the complex, outcome-orientated determination system is not generally accepted. The decision making on tx intensity is rather based on pts characteristics and institutional factors. This underlines the need for development of further models.
Goals of work: Comparing antiemetic efficacy of different 5-HT 3-receptor antagonists (5-HT 3 RAs... more Goals of work: Comparing antiemetic efficacy of different 5-HT 3-receptor antagonists (5-HT 3 RAs) is difficult due to inter-study variability. Therefore, a meta-analysis was performed to comparatively evaluate dolasetron, granisetron, ondansetron and tropisetron for acute chemotherapy-induced nausea and vomiting (CINV). Patients and methods: Comparisons between 5-HT 3 RAs were based on 44 randomized studies (including 12,343 patients) identified by MEDLINE, CANCERLIT or EMBASE searches and subcategorized by chemotherapy type (cisplatin-or non-cisplatinbased). Main results: When all studies were combined, granisetron was equivalent to ondansetron (n=27), and showed an advantage vs tropisetron (p=0.018; n=12). Ondansetron vs tropisetron (n=11) and ondansetron vs dolasetron (n=3) revealed equivalence in each comparison. An advantage for 3 mg granisetron vs 8 mg ondansetron was found in non-cisplatin-based studies (p=0.015; n=6). Overall equivalence was seen between ondansetron, 24 or 32 mg, and granisetron, 2 or 3 mg, for all studies (n=13). There was a possible advantage for higher (24 or 32 mg) vs lower (8 mg) ondansetron dose regimens with cisplatin-based trials (n=6). No differences were seen between 3 and 1 mg granisetron doses (n=6). Conclusions: Efficacy of 5-HT 3 RAs for preventing CINV following cisplatin-and non-cisplatinbased chemotherapy is comparable, with the exception of granisetron vs tropisetron. Some differences were noted in dosing subanalyses.
Background Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemot... more Background Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fl uorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment. Methods This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fl uorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50•4 Gy plus infusional fl uorouracil (1000 mg/m² days 1-5 and 29-33), followed by surgery and four cycles of bolus fl uorouracil (500 mg/m² days 1-5 and 29; fl uorouracil group); and an experimental group receiving preoperative radiotherapy of 50•4 Gy plus infusional fl uorouracil (250 mg/m² days 1-14 and 22-35) and oxaliplatin (50 mg/m² days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m² days 1 and 15), leucovorin (400 mg/m² days 1 and 15), and infusional fl uorouracil (2400 mg/m² days 1-2 and 15-16; fl uorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratifi ed by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, effi cacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076. Findings Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fl uorouracil plus oxaliplatin group and 623 in the fl uorouracil group). Preoperative grade 3-4 toxic eff ects occurred in 140 (23%) of 606 patients who actually received fl uorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fl uorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fl uorouracil and oxaliplatin during chemoradiotherapy than in those who received fl uorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fl uorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fl uorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fl uorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fl uorouracil group (odds ratio 1•40, 95% CI 1•02-1•92; p=0•038). In the fl uorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fl uorouracil group. Interpretation Inclusion of oxaliplatin into modifi ed fl uorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS. Funding German Cancer Aid (Deutsche Krebshilfe).
Purpose Six randomized phase II and III trials have investigated the role of oxaliplatin (OX) in ... more Purpose Six randomized phase II and III trials have investigated the role of oxaliplatin (OX) in combination with capecitabine (CAP) or infusional fluorouracil (FU) in metastatic colorectal cancer. This meta-analysis compared the efficacy of CAP/OX compared with infusional FU/OX. Patients and Methods This analysis compared all published CAP/OX versus infusional FU/OX regimens. A total of 3,494 patients (FU, n = 1,737; CAP, n = 1,757) were analyzed for response rate (RR), progression-free (PFS), overall survival (OS), and toxicity. Results The fixed-effect pooled estimate for RR showed higher RR for FU-based regimens (Odds ratio [OR] = 0.85; 95% CI, 0.74 to 0.97; P = .02) whereas the analysis of chemotherapy-only trials, excluding the bevacizumab containing NO16966 and TREE 2 trials, led to an OR of 0.74 (95% CI, 0.60 to 0.92; P = .007). However, for PFS (hazard ratio [HR] = 1.04; 95% CI, 0.96 to 1.12; P = .17) and OS (HR = 1.04; 95% CI, 0.95 to 1.12; P = .41) all models suggested si...
Purpose This is one of a few studies that have explored the value of baseline symptoms and health... more Purpose This is one of a few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in patients with brain cancer. Patients and Methods Baseline HRQOL scores (from the European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire C30 and the EORTC Brain Cancer Module) were examined in 247 patients with anaplastic oligodendrogliomas to determine the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap resampling procedure and the computation of C indexes and R2 coefficients were used to explore the stability of the models as well as better assess the potential benefit of using HRQOL to predict survival in clinical practice and research. Results Classical analysis controlled for major clinical prognostic factors selected emotional functioning (P = .0016), communication deficit (P = .0261), future uncertainty (P =...
Invited Publications operated on immediately after post-treatment assessment. LR after the first ... more Invited Publications operated on immediately after post-treatment assessment. LR after the first 12 months was almost always amenable to salvage surgery of the time. There were no oncologic differences between patients undergoing immediate radical resection compared to those who sustained a cCR for 12 months or longer.
The optimal treatment of patients with metastatic spinal cord compression (MSCC) is still being d... more The optimal treatment of patients with metastatic spinal cord compression (MSCC) is still being debated. The current observational multicenter study, performed prospectively by the authors, evaluated two radiotherapy (RT) schedules and prognostic factors with respect to functional outcome In the current study, 214 patients with MSCC were irradiated between April 2000 and September 2003 with 30 gray (Gy) per 10 fractions per 2 weeks (n = 110) or with 40 Gy per 20 fractions per 4 weeks (n = 104). Motor function and ambulatory status were evaluated before RT and until 6 months after RT. The following potential prognostic factors were investigated: RT schedule, performance status, age, number of irradiated vertebrae, type of primary tumor, pretreatment ambulatory status, and length of time developing motor deficits before RT. Both groups were balanced for patient characteristics and potential prognostic factors. Motor function improved in 43% of patients after 30 Gy and in 41% of patients after 40 Gy (P = 0.799). Posttreatment ambulatory rates were 60% and 64% (P = 0.708), respectively. A multivariate analysis demonstrated that a slower progression of motor deficits before RT (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), a favorable histology of the primary tumor (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), and being ambulatory before RT (P = 0.035) were associated with a better functional outcome. RT schedule (P = 0.269) and other variables had no significant impact. Acute toxicity was mild, and late toxicity was not observed during the period of follow-up. Follow-up was 12 (6-28) months in patients surviving &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;/= 6 months. Thirty gray per 10 fractions was preferable to 40 Gy per 20 fractions, because it was associated with similar outcome, less treatment time, and lower costs. The type of tumor, pretreatment ambulatory status, and length of time developing motor deficits before RT were relevant prognostic factors and should be considered in future studies.
Background: Central venous access devices in fluoropyrimidine therapy are associated with complic... more Background: Central venous access devices in fluoropyrimidine therapy are associated with complications; however, reliable data are lacking regarding their natural history, associated complications and infusion pump performance in patients with metastatic colorectal cancer. Methods: We assessed device placement, use during treatment, associated clinical outcomes and infusion pump perfomance in the NO16966 trial. Results: Device replacement was more common with FOLFOX-4 (5-fluorouracil (5-FU) þ oxaliplatin) than XELOX (capecitabine þ oxaliplatin) (14.1% vs 5.1%). Baseline device-associated events and post-baseline removal-/placement-related events occurred more frequently with FOLFOX-4 than XELOX (11.5% vs 2.4% and 8.5% vs 2.1%). Pump malfunctions, primarily infusion accelerations in 16% of patients, occurred within 1.6-4.3% of cycles. Fluoropyrimidine-associated grade 3/4 toxicity was increased in FOLFOX-4-treated patients experiencing a malfunction compared with those who did not (97 out of 155 vs 452 out of 825 patients), predominantly with increased grade 3/4 neutropenia (53.5% vs 39.8%). Febrile neutropenia rates were comparable between patient cohorts±malfunction. Efficacy outcomes were similar in patient cohorts±malfunction. Conclusions: Central venous access device removal or replacement was common and more frequent in patients receiving FOLFOX-4. Pump malfunctions were also common and were associated with increased rates of grade 3/4 haematological adverse events. Oral fluoropyrimidine-based regimens may be preferable to infusional 5-FU based on these findings. Fluoropyrimidines form the foundation of the vast majority of chemotherapy regimens used in the treatment of metastatic colorectal cancer (mCRC), and they can take the form of intravenous 5-fluorouracil (5-FU; by continuous or bolus infusion) or oral formulations (capecitabine). Fluoropyrimidine-based regimens include XELOX (oral capecitabine plus infusional oxaliplatin), FOLFOX (infusional leucovorin (LV), 5-FU and oxaliplatin) and FOLFIRI (infusional LV, 5-FU and irinotecan), each of which has a well-established role in the management of patients with mCRC. These regimens are now included in the key
Background: This randomized phase II trial investigated the efficacy and safety of capecitabine/o... more Background: This randomized phase II trial investigated the efficacy and safety of capecitabine/oxaliplatin (CapOx) plus bevacizumab and dose-modified capecitabine/irinotecan (mCapIri) plus bevacizumab as first-line therapy in patients with metastatic colorectal cancer (mCRC). Patients and methods: Patients received bevacizumab 7.5 mg/kg with oxaliplatin 130 mg/m 2 /day 1 plus capecitabine 1000 mg/m 2 bid/days 1-14 or with irinotecan 200 mg/m 2 /day 1 plus capecitabine 800 mg/m 2 bid/days 1-14 both every 21 days. The primary end point was 6 months progression-free survival (PFS). Results: A total of 255 patients were enrolled. The intent-to-treat population comprised 247 patients (CapOxbevacizumab: n = 127; mCapIri-bevacizumab: n = 120). The six-month PFS rates were 76% (95% CI, 69%-84%) and 84% (95% CI, 77%-90%). Median PFS and OS were 10.4 months (95% CI, 9.0-12.0) and 24.4 months (95% CI, 19.3-30.7) with CapOx-bevacizumab, and 12.1 months (95% CI, 10.8-13.2) and 25.5 months (95% CI, 21.0-31.0) with mCapIri-bevacizumab. Grade 3/4 diarrhea as predominant toxic effect occurred in 22% of patients with CapOx-bevacizumab and in 16% with mCapIri-bevacizumab. Conclusions: Both, CapOx-bevacizumab and mCapIri-bevacizumab, show promising activity and an excellent toxic effect profile. Efficacy is in the range of other bevacizumab-containing combination regimen although lower doses of irinotecan and capecitabine were selected for mCapIri.
Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the las... more Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence
This two-part phase Ib/II study investigated the feasibility of administering cetuximab in combin... more This two-part phase Ib/II study investigated the feasibility of administering cetuximab in combination with oxaliplatin and infusional 5-fluorouracil (5-FU)/folinic acid (FA) in a weekly schedule (AIO FUFOX protocol) as firstline treatment in patients with epidermal growth factor receptor-detectable advanced colorectal cancer. Patients and methods: Cetuximab was administered weekly: 400 mg/m 2 initial dose, then 250 mg/m 2 and FUFOX: oxaliplatin 50 mg/m 2 , FA 500 mg/m 2 and 5-FU as a 24-h infusion at either 1500 or 2000 mg/m 2 administered for 4 weeks followed by a 1-week rest (one cycle). Results: Dose-limiting toxicity (grade 3 diarrhea) occurred in 3 of 14 assessable patients receiving 5-FU at standard 2000 mg/m 2 . This dose was administered to a further 25 patients. Cetuximab combined with FUFOX was generally well tolerated with the most common grade 3/4 adverse events being diarrhea (27%) and paresthesia (16%). The confirmed response rate for patients receiving 5-FU at standard 2000 mg/m 2 (N = 41) was 56%, with a median duration of 9.3 months. Median progression-free and overall survival times including all 49 patients were 8.1 (95% confidence interval 6.0-9.7) and 28.2 months, respectively. Cetuximab pharmacokinetics seemed not to be different for combination with FUFOX compared with cetuximab/irinotecan combinations. This protocol is well tolerated and shows promising efficacy supporting further investigation.
ABSTRACT Background: The PETACC-6 trial investigates whether the addition of oxaliplatin to preop... more ABSTRACT 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 report on pathological staging and sphincter preservation following preoperative CRT. 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, were randomly assigned to receive 5 weeks of preoperative CRT (45 Gy in 25 fractions with an optional boost to a total dose of 50.4 Gy) with capecitabine (825 mg/m 2 twice daily), followed by 6 cycles of adjuvant CT with capecitabine (1000 mg/m2 twice daily/days 1-15 every three weeks) (arm 1) or to receive the same regimen with the addition of oxaliplatin before (50 mg/m 2 /days 1, 8, 15, 22, 29) and after surgery (130 mg/m 2 /day 1, every three weeks) (arm 2). Pathological down-staging (ypT0-2N0) rate, complete remission (ypT0N0) rate and tumor regression grade according to Dworak were secondary endpoints. The assessment was based on the review of the specimen and scoring by the local pathologist. Patients not operated or not resected were scored as failures (intent-to-treat analysis). 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 2. More than 90% of full dose concurrent CT was delivered in 91% and 63% of patients in arm 1 and 2 respectively. R0 resection rate was 92.0% in arm 1 and 86.3% in arm 2. The ypT0N0 rate was equal in both arms with 11.3% in arm 1 and 13.3% in arm 2 (p = 0.31). There was no difference in pathological down-staging rate (43.5% in arm 1 vs. 41.5% in arm 2). In arm 2, the tumor regression according to Dworak was minimal in 13.7% of patients, moderate in 35.5%, good in 20.5% and total in 13.5%. In arm 1, the percentages were 19%, 36.2%, 19.4% and 12.4% respectively. The anal sphincter was preserved in 70% vs. 65% (p = 0.09) in arm 1 and 2. Definitive numbers will be presented at the congress. Conclusion: The addition of oxaliplatin to preoperative fluoropyrimidine-based CRT led to decreased treatment compliance and did not result in any improvement in tumour down staging or in anal sphincter preservation.
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