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TPS3636 Background: KRAS, NRAS, and BRAF mutations are well-established negative predictive biomarkers of response to anti-EGFR monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC) patients (pts). In clinical practice, RAS/BRAF wild-type (wt) patients receive first-line therapy regimens containing anti-EGFR agents. However, tumor heterogeneity might drive primary and acquired resistance to anti-EGFR MoAbs. In fact, circulating tumor DNA (ctDNA) testing reveals RAS/BRAF mutations in approximately 10% of pts who resulted in wt at tumor tissue. In addition, 30% to 50% RAS wt pts develop, during the treatment with anti-EGFR MoAbs, RAS mut can be detected in the ctDNA several weeks before clinical progression. As today, it is not known whether revealing RAS mut in liquid biopsy (LB) earlier than the appearance of a clinical/radiological disease progression, could impact pts’ outcomes. Similarly, there are no data suggesting the best therapeutic approach in patients with RAS/BRAF wt tissue and mutated ctDNA. Methods: This is a phase III, randomized, open-label, comparative, multicenter study to assess the superiority of Bevacizumab (BEV) compared to Cetuximab (CET) plus FOLFIRI in treatment naïve mCRC RAS/BRAF wt on tumor tissue (TT) and mutated in plasma samples. RAS/BRAF wt pts on TT will undergo the first LB, and RAS mut pts will be randomized 1:1 to receive FOLFIRI/CET (control arm) or FOLFIRI/BEV (experimental arm). Instead, RAS wt pts at first LB will be treated with FOLFIRI/CET up to 8 cycles. Pts who have not progressed after 8 cycles of treatment will undergo a second LB. If RAS mut was detected, pts will be randomized 1:1 to continue FOLFIRI/CET or switch to FOLFIRI/BEV. If not, pts will continue FOLFIRI/CET outside the clinical trial. Pts will be treated until disease progression, unacceptable toxicity, or withdrawal of consent. Among 26 pts screened at the first LB, actually 1 KRAS mut and 1 BRAF mut pts were detected. The primary endpoint is the PFS Plasma samples will be analyzed for KRAS, NRAS, and BRAF mutations by Idylla ctKRAS and Idylla ctNRAS-BRAF-EGFGR. All samples will be also analyzed by NGS, in order to better evaluate the correlation of tumor heterogeneity with pts’ outcomes. Clinical trial information: EudraCT Number: 2020-005078-82, NCT04776655.

Purpose To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Patients and Methods Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m2/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m2 weekly × 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here. Results Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014). Conclusion Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.

PURPOSE To determine if fluorouracil (FUra) has different mechanisms of action as a function of the dose schedule used. DESIGN The preclinical and clinical literature relating toxicity and antitumor effects of FUra as a function of its dose schedule, with and without modulating agents, was reviewed. RESULTS The data support the hypothesis that FUra may be considered to be two different drugs, depending on its dose schedule (bolus v continuous infusion [CI]). CONCLUSION These results suggest that additional therapeutic benefit may be obtained from FUra regimens by (1) appropriate schedule-dependent modulation, (2) the sequential or alternating use of cycles of bolus followed by cycles of CI FUra appropriately modulated, or (3) hybrid regimens, ie, those that contain both pulse and CI schedules.

e15149Background: Despite standard preoperative pelvic chemoradiation (CRT) and optimal surgery with total mesorectal excision (TME) leading to local recurrence rates below 5% in locally advanced r...

e14502 Background: The treatment with fluoropyrimidines and concomitant RT is the standard care inLARC preoperative chemoradiation. The aim of RaP/STAR-03 study is to evaluate the activity and safe...

compared with 16% of patients experiencing grade 3-4 events. This might depend on differences in drug and RT scheduling. The interval between OXA administration and delivery of RT prescribed in CALGB 89901 might have resulted in more effective RT sensitization and, therefore, toxicity. However, the similar antitumor activity observed between the two studies argues against this explanation. Similarly, although the shortened duration of OXA infusion in the US study (1 hour) might theoretically affect toxicity, a selective effect on gastrointestinal toxicity is unlikely. Neurotoxicity rates were in fact slightly higher in our study (grade 1-2, 80% v66%). This difference may have other explanations. While patients in our study were accrued and treated at a single institution, patientsintheUSstudywererecruitedatseveralcenters.Different toxicity grading systems may have also been used. While in our study toxicity was scored according to the Nation Cancer Institute Common Toxicity Criteria version 2, the scoring system used in theUStrialwasnotspecified.Despitethehigherincidenceofgrade

e17533 Background: Detection of soluble mesothelin-related peptide (SMRP) levels in serum has been proposed to help the diagnosis of malignant pleural mesothelioma (MPM). In this study we evaluated the SMRP levels in pleural effusions of MPM (MPM-PE), the clinical importance and usefulness of SMRP detection in MPM-PE and whether it can have an additional value to cytological analysis (Cyt). Methods: We studied 52 MPM-PE, 129 benign PE (B-PE) and 94 non-MPM pleural metastasis PE (Mts-PE). In all PE samples, both cytology and SMRP detection were performed. SMRP levels were estimated by means of the MesoMark ELISA kit (Fujirebio Diagnostic, Malvern, PA). Diagnostic performance parameters were estimated through the ROC analysis, Youden's index was applied to obtain the best cut-off level and the degree of correlation was estimated by Diagnostic Odds Ratio (DOR) and by P-value (P) with Chi-square test. Results: The median SMRP levels were significantly higher in MPM-PE (28.2 nM) than in B-PE (3.2 nM) or Mts-PE (3.8 nM). MPM-PE vs B-PE yielded an AUC of 84.5 (P

8234 Background: Cancer patients with moderate-severe pain often require opioid analgesics. Methods: From October 2002 to November 2003, 62 outpatients underwent transdermal treatment with Fentanyl (TDF). All pts had been previously treated with other drugs according to the WHO analgesic scale. Pts characteristics: median age 64 years (range 44–84), M/F 29/33, median ECOG PS 0 (range 0–2). Primary tumors: 24 breast, 8 lung, 9 colorectal, 7 pancreas, 7 prostate, 7 others. Somatic pain was reported in 35/62 pts (56%), visceral pain in 12/62 pts (19%), 15/62 pts (24%) showed both types, with neuropatic features in 10%. Breakthrough pain was present in 24/62 pts (38%) requiring rescue medication. 47/62 pts (75%) received palliative chemo-radiotherapy. All pts were evaluated weekly with VAS (Visual Analogic Scale) and TIQ (Therapy Impact Questionnaire). A Geriatric Assessment with CIRS (Comorbility Index), ADL and IADL was performed for pts aged over 65 years (23/62; 37%) at the beginning of treatment and afte...

3637 Background: We have recently demonstrated that OXA, given weekly at the dose of 60 mg/m2, may be safely combined with infusional FU and preoperative pelvic RT for LARC resulting in rates of pathological complete responses (pCR's) approaching 30 %. Replacing infusional FU with an oral fluoropyrimidine might reduce the inconvenience and some of the potential complications of this regimen. Methods: Since June 2002, 15 patients (10 males, 5 females; median age 63, range 33–75 years) with LARC (cT3-T4 and/or N+; one patient also had a potentially resectable liver metastasis) were thus accrued in a phase I study aimed at defining the maximum tolerated dose (MTD) of UFT (200–250-300–350 mg/m2/day, monday through friday for all the duration of RT) combined with weekly OXA (60 mg/m2) and standard pelvic RT (50.4 Gy - 28 fractions). Oral LV (90 mg/day, fixed dose) was administered with the same schedule as UFT. Results: No grade III-IV toxicity was observed at the first dose level (n=4; UFT 200 mg/m2/day). At ...

3577 Background: Sequential combinations of FU and IRI or OXA are currently used as 1st and 2nd line therapy for advanced CRC. Multiple trials are also investigating the concomitant use of the thre...