bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of an interim analysis of a multinational randomized, double-blind, phase III study in patients (pts) with previously treated metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo (CONFIRM 2)
Authors: Koehne C. , Bajetta E. , Lin E. , Van Cutsem E. , Hecht J. , Douillard J. , Moore M. , Germond C. , Laurent D. , Jacques C.
Published: March 2020

3508

Background: PTK/ZK is a novel, oral, small molecule, antiangiogenic compound that inhibits tyrosine kinase signaling of all known vascular endothelial growth factor (VEGF) receptors. Methods: 855 pts were randomized to FOLFOX4 plus PTK/ZK (1250 mg, qd), or placebo. Eligibility included histologically or cytologically documented mCRC, pretreatment for metastatic disease with irinotecan/fluoropyrimidine-based chemotherapy, measurable disease by RECIST, PS of 0–2 and adequate organ and bone marrow function. The primary endpoint is overall survival (OS). Secondary endpoints included OS and PFS in high LDH pts (stratifiedbybaseline serum LDH levels > 1.5 × ULN). Results: OS was 12.1 mo in the PTK/ZK arm and 11.8 mo in the placebo arm (HR: 0.94; p=0.511). A pre-planned triangular test suggested a low probability of demonstrating an improvement in OS at the final analysis (4Q 2006). The response rates (CR+PR) were 18.5% in the PTK/ZK arm, 17.5% in the placebo arm. PFS was significantly longer in the PTK/ZK arm (5.5 mo vs. 4.1 mo; HR: 0.83; p=0.026). LDH, usually a poor prognostic factor in mCRC, is predictive of the outcome in the PTK/ZK arm. Pts with high LDH showed a strong improvement in PFS when treated with PTK/ZK (5.6 mo vs. 3.8 mo; HR: 0.63; p<0.001) and an improved OS (9.6 mo vs. 7.5 mo; HR: 0.78; p=0.10). Adverse events (AE) were similar to that of the CONFIRM 1 trial (ASCO 2005). Most frequent grade 3/4 AE associated with PTK/ZK were hypertension (PTK/ZK: 21%; placebo: 5%), diarrhea (16%; 8%), fatigue (14.5%; 6.9%), nausea (11%; 5%), vomiting (9%; 5%), dizziness (9%; 1%). AEs were generally reversible. Thrombotic and embolic events of all grades occurred in 6% (PTK/ZK) vs. 1% (placebo) and 4% vs. 1%, respectively. There was no increase in bowel perforations, hematological toxicities or peripheral neuropathy in the PTK/ZK arm. Conclusions: While the primary endpoint for OS was not met, PTK/ZK improves PFS significantly in the overall population, and shows strong activity in patients with high baseline serum LDH.

[Table: see text]
Routine short course pre-op radiotherapy or selective post-op chemoradiotherapy for resectable rectal cancer? Preliminary results of the MRC CR07 randomised trial
Authors: Sebag-Montefiore D. , Steele R. , Quirke P. , Grieve R. , Khanna S. , Monson J. , Holliday A. , Thompson L. , Griffiths G. , Stephens R.
Published: March 2020

3511

Background: Radiotherapy reduces local recurrence (LR) when combined with surgery in resectable rectal cancer. The Medical Research Council CR07 trial was designed to compare two different radiotherapy policies when combined with mesorectal excision. Methods: Patients with operable non-metastatic adenocarcinoma of the rectum were randomised to either routine pre-op short course radiotherapy [25Gy/5F] (PRE) or selective post-op chemoradiotherapy (POST) for patients with involvement of the circumferential resection margin (CRM) - [45Gy/25F + 5fluorouracil]. Results: A total of 1350 patients were randomised from 52 centres in the UK, Canada, New Zealand and South Africa between March 1998 and August 2005. Median follow-up is 3 years. Patients (73% male, median age 65 years, 79% PS0) were well balanced between the 2 arms. 595 of 674 (88%) of the pre-op group received their allocated treatment. Of the 676 patients allocated to the selective post-op chemoradiotherapy arm, 73 (11%) were CRM +ve and 51 of these (70%) received chemoradiotherapy. Post operative chemotherapy was received by 85% of patients with stage III disease. At the time of analysis 23 PRE and 61 POST patients had confirmed LR, 96 and 106 patients respectively distant metastases, and 115 and 146 respectively had died. The 3 year rates for LR (primary end point) were 4.7% and 11.1% for PRE and POST groups respectively (HR 2.47, 95% CI 1.61–3.79), for disease free survival 79.5% and 74.9% (HR 1.31, 95% CI 1.02–1.67) and for overall survival 80.8% and 78.7% (HR 1.25, 95% CI 0.98–1.59. The LR benefit in favour of PRE was consistent for tumours 0–5,5–10 and >10cm from the anal verge (HR 2.00, 2.14 and 4.97 respectively). Further subset analysis based on TNM stage and operation performed will be presented. Conclusions: These preliminary results indicate that routine short course pre-operative radiotherapy results in a signifcant reduction in local recurrence and improved disease free survival at 3 years when compared with a highly selective post operative approach.

No significant financial relationships to disclose.
A genetic signature of relapse in stage II colorectal cancer derived from formalin fixed paraffin embedded tissue (FFPE) tissue using a unique disease specific colorectal array
Authors: Johnston P. G. , Mulligan K. , Kay E. , Black J. , Moore S. , Mc Dermott U. , Wilson R. , Harkin D.
Published: March 2020

3519

Background: We have developed the first disease specific microarray for colorectal cancer using a transcriptome-based approach. This unique tool has been specially designed and optimised for analysis of gene expression profiles from formalin fixed paraffin embedded tissues (FFPE). To evaluate this tool we are conducting a study in patients with Dukes B (stage II) colorectal cancer (CRC) using FFPE tissues to determine a prognostic genetic signature predicting disease recurrence. Methods: The colorectal array was developed using a high-throughput transcriptome-based approach and encodes over 52,500 transcripts expressed in normal and diseased colorectal tissue. To date, tumours from 32 patients have been selected (mean FFPE tissue block age - 10.4 years) from the stage II CRC cohort of a phase III randomized trial comparing 5-FU/Leucovorin versus no adjuvant treatment (NI240). The patients were from the observation alone arm;19 of whom were disease-free for 5 years post-randomisation, while 13 suffered relapse prior to 3 years. Results: RNA was extracted from all 32 FFPE tissue samples, amplified, labelled and hybridised to the colorectal cancer disease specific array. Raw data was normalised using scalar, median-polish and z-score strategies and scalar was selected as the best strategy in relation to predictive error. Within this data set genes selected by correlation using ANOVA performed best in both KNN and support vector machine algorithms (supervised). Using this approach a gene signature containing 48 genes demonstrated 100% accuracy in the prediction of relapse in stage II CRC (p<0.001). This signature was also able to separate samples at the meta-node level using unsupervised hierarchical clustering. Conclusion: We have developed the first colorectal cancer disease specific microarray and demonstrated its use using FFPE tissues. Using this approach we have derived a gene signature that predicts for a high likelihood of early relapse in stage II CRC.

[Table: see text]
Feasibility of metastasectomy in patients treated with bevacizumab in first-line mCRC - Preliminary results from the First Beat-study
Authors: Michael M. , Vancutsem E. , Kretzschmar A. , Berry S. , Rivera F. , Dibartolomeo M. , Mazier M. , Lutiger B. , Cunningham D.
Published: March 2020

3523

Background: In a phase III pivotal trial in patients (pts) with mCRC, bevacizumab (BEV) increased overall survival by 30% when added to first-line irinotecan, 5FU and leucovorin. The study reported 10% of pts having wound healing complications after major unplanned or elective surgery. The study had limited data on the feasibility and safety of metastastasectomies. First BEAT was opened to evaluate safety events of BEV in a broader pt population using a variety of chemotherapy (CT) regimens. Methods: First BEAT started in June 2004 and aims to enrol up to 2000 mCRC pts in 41 countries. Eligible patients starting with first-line CT are treated until progression with BEV (5mg/kg q2w (5FU based CT) or 7.5mg/kg q3w (Capecitabine (CAP) based CT). In case of major elective surgery, BEV should be stopped 6–8 weeks prior to the planned surgery and could be restarted 28 days after surgery and complete wound healing. At protocol visits, bleeding and wound healing data was collected according to CTC AE grading (v3.0). Results: By Dec 20th, 2005, 31 pts (13 male; median age 55 years; PS 0/1 90%/10%) had undergone metastasectomies. 27 were liver (1 pt had two operations), 3 lung, 1 peritoneal and 1 other resections. 27 were curative, 3 palliative and 2 other resections. 17 reported no residual disease, 5 had residual disease and for 8 resections the outcome was missing or unknown. Median time from first BEV treatment to surgery was 167 days and 54 days from last BEV administration to surgery, respectively. Median follow-up was 12.4 months. One pt died due to disease progression 5.5 months after surgery. CT regimens used with BEV included FOLFOX (N=9), CAPOX (N=9) and FOLFIRI (N=7). No wound healing or bleeding were reported. 21/31 pts reported no complications at all, for 3/31 data was currently missing and 7/31 pts reported the following complications: stomach perforation, right pleural effusion, surgical area infection, thrombosis portal vein/myocardial infarct, bowel-obstruction, ascites, ileus/cornea infection. Updated data will be available in June 06. Conclusions: Preliminary data suggest metastasectomies are feasible after treatment with BEV and CT. Stopping BEV 6–8 weeks before major surgery resulted in no bleeding or wound healing complications.

[Table: see text]
Safety of bevacizumab plus chemotherapy as first-line treatment of patients with metastatic colorectal cancer: Updated results from a large observational registry in the US (BRiTE)
Authors: Hedrick E. , Kozloff M. , Hainsworth J. , Badarinath S. , Cohn A. , Flynn P. , Dong W. , Suzuki S. , Sugrue M. , Grothey A.
Published: March 2020

3536

Background: Bevacizumab (BV) prolongs overall survival and progression-free survival when added to standard chemotherapy for patients with metastatic colorectal cancer (mCRC). BRiTE is a large, community-based observational registry of patients with mCRC receiving BV plus first-line chemotherapy. Safety and efficacy information in unselected patients with mCRC are collected. Chemotherapy regimen choice is at the physician’s discretion. Methods: To facilitate and evaluate enrollment of a typical community-based mCRC population, eligibility criteria were minimized. Cohort demographics were consistent with the NCI Surveillance, Epidemiology, and End Results (SEER) database for mCRC. Patients are followed for up to 3 years, and safety data including targeted BV-associated serious adverse events (SAEs) are updated every 3 months (mo). Results are based on descriptive analyses and are not adjusted for propensity of treatment, baseline characteristics, and treatment effects. Results: 1968 patients were enrolled between Feb 2004 and Jun 2005. Median study follow-up was 10 mo by Nov 4, 2005. SAEs were reported in 12.0% of patients including gastrointestinal perforation (GIP) (1.7%), postoperative bleeding/wound healing complications (1.2%), arterial thromboembolic events (ATE) (2.1%), and grade 3–4 bleeding (1.9%). 3.2% of patients discontinued BV due to a BV-related toxicity, most commonly bleeding. For patients with the respective event(s), median time to first event was 2.1 mo for GIP, 3.5 mo for ATE and 4.0 mo for grade 3–4 bleeding. 8.9% of patients with no history of hypertension (HTN) developed HTN requiring medication and 6.2% of patients who had HTN requiring medication at baseline experienced worsening of their HTN while on study treatment. Conclusions: In this unselected population of patients with mCRC, the safety profile of BV plus various chemotherapy regimens appears consistent with that observed in the pivotal BV trial. Overall discontinuation of BV due to a BV-related toxicity was uncommon. In this large community-based observational registry, no new BV associated safety issues have been identified.

[Table: see text]
Influence of bevacizumab on the plasma disposition of CPT 11 and its metabolites in advanced colorectal cancer patients
Authors: Schueller J. , Czejka M. , Kiss A. , Krexner E. , Aigner K. , Wirth M.
Published: March 2020

3540

Background: The monoclonal antibody (mab) bevacizumab (BEV) inhibits VEGF, downregulates angiogenesis and lowers interstitial pressure, by which blood tissue transfer and metabolism of a drug could be modulated. CPT 11 produced survival benefit combined with BEV and undergoes complex biotransformation by different enzymatic routes: carboxylesterase hCE2 (SN 38), UGT1A1 (detoxificition to SN 38 glucuronide) and CYP 3A4 (APC), the latter enzyme has been described to be reversibly inhibited by mabs. Therefore it seems worthwhile to investigate a potential influence of BEV on plasma disposition and pharmacokinetics (PK) of CPT11 and metabolites. Methods: 10 pts with advanced colorectal cancer (5 first line, 5 second line after FOLFOX) were treated by FOLFIRI schedule (with CPT 11 180 mg/m2 1HR infusion) preceeded by BEV 5 mg/kg (90–60–30 min infusion) every 2 weeks. At cycle 1, CPT 11 was applied before BEV to allow baseline PK analysis of CPT 11 and its metabolites, at cycle 4 (i.e. after 8 weeks) determination of CPT 11 plasma conc was repeated after a 30 min infusion of BEV. Plasma samples were collected every 30 min over 4 HR and analysed by HPLC. Results: PK of CPT 11 remained unaffected by BEV, only a small decrease in cmax and AUC was found. Contrary, SN 38 formation seemed to be delayed and formation rate decreased when combined with BEV, resulting in lower cmax (-24%) and AUC (-20%). SN 38 glucuronide levels were generally found to be higher than those of SN 38, cmax and AUC reduced by 35% when BEV was preadministered. A similar effect was also observed in PK parameters of APC (about 30% reduction of cmax and AUC). Conclusion: A changed plasma disposition of all 3 metabolites - generated by 3 different enzymatic pathways - is unlikely to be caused by BEV influencing CPT 11 metabolism. The observed effect could be explained by increased blood tissue transfer, alteration of microvasculature by BEV may favour tissue uptake of the drug.

[Table: see text]

No significant financial relationships to disclose.
Dose-escalation study using up to twice the standard dose of cetuximab in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST study): Preliminary data
Authors: Tejpar S. , Peeters M. , Humblet Y. , Gelderblom H. , Vermorken J. , Viret F. , Glimelius B. , Ciardiello F. , Kisker O. , Van Cutsem E.
Published: March 2020

3554

Background: Response to the epidermal growth factor receptor (EGFR) inhibitor, cetuximab appears to correlate with the intensity of the associated skin reaction. This randomized multicenter study investigated the effect of cetuximab dose escalation on EGFR activation and downstream signaling in skin and tumor biopsies, on activity and skin reactions in patients (pts) with EGFR-expressing mCRC, failing prior irinotecan (I). Methods: Pts with ≥1 measurable lesion suitable for biopsy were eligible and were randomized 22 days after starting treatment with cetuximab (initial dose 400mg/m2 then 250mg/m2/week(w)) plus I (2-weekly regimen 180 mg/m2) if they had not experienced >grade 1 skin reaction, any other >grade 2 cetuximab-related toxicity and were not intolerant to I. Pts were randomized to standard cetuximab dose (arm A; 250 mg/m2/w) or dose-escalation (arm B; cetuximab dose increased by 50 mg/m2 q 2 w up to 500 mg/m2, until >grade 2 toxicity or tumor response). Pts not randomized (arm C) continued with the standard regimen after day 22. Skin and tumor biopsies were taken pre- and during treatment. Results: Of 273 screenedpts, 221 were EGFR-expressing and 166 were recruited. 45 pts were randomized to arm A, 44 to arm B and 76 were in arm C. By August 2005, 18 pts had reached the highest dose (500mg/m2/w), with no concerns over safety. All baseline and second biopsies are available. Safety results are presented for the first 36 pts in arm B. M/F 23/13, median age 60 y (34–79), median Karnofsky performance score 90 (80–100). All pts reported here had received cetuximab for at least 6 weeks. Maximum dose reached at w 6: 350mg/m2/w (300mg/m2 in 36 pts at w 4; 350mg/m2 in 31 pts at w 6). Relevant grade 3/4 toxicities were diarrhea (2.8%) and fatigue (5.6%). No grade 3/4 skin reactions occurred. Conclusions: Cetuximab at a dose of 350 mg/m2 is well tolerated in pts who have had no or mild skin reactions in response to standard dose treatment. Further dose escalation is possible. No early increase of skin toxicity is observed. Analysis of efficacy and pharmacokinetics/dynamics is ongoing.

[Table: see text]
Phase I/II study of cetuximab, capecitabine and oxaliplatin (CAPOX) combined with standard radiotherapy (RTX) as neoadjuvant treatment of advanced rectal cancer (RC)
Authors: Arnold D. , Hipp M. , Reese T. , Hohenberger W. , Liersch T. , Lordick F. , Sülberg H. , Sauer R. , Rödel C.
Published: March 2020

3574

Background: CAPOX given concurrently to neoadjuvant RTX in RC is well tolerated and yielded high rates of pathologic complete responses in phase II trials. Cetuximab, a monoclonal antibody targeted against the EGF receptor, is active in metastatic colorectal cancer. Furthermore, synergy of cetuximab with RTX was shown in improved survival vs. RTX alone in head and neck cancer. This trial was to evaluate maximal tolerated dose (MTD), feasibility and efficacy of CAPOX + RTX with cetuximab in RC. Method: Patients (pts) had to have unpretreated T3–4 and/or N+ disease, with distant metastases allowed. During a conventionally fractionated RTX (1.8 Gy for 28 days [d]), cetuximab was given in standard dosage (400mg/m2 on d-7, then 6 weekly doses of 250 mg/m2, to d35). CAPOX was given on the basis of a previously examined schedule with oxaliplatin (50 mg/m2 d 1,8,22 and 29) in combination with capecitabine (d1–14 and d22–35) at 3 dose levels: 1000, 1300 and 1650mg/m2 bid. In phase I, a standard 3+3 design was used, allowing for dose escalation in 0/3 or 1/6 pt with dose-limiting toxicity (DLT). Results: 13 pts were enrolled: Median age 58 [35–75] yrs., m/f 7/6 pts. T3 85%, T4 15%; N+ 92%, M1 46%; G2 92%, G3 8%. As on dose level 1 one DLT (diarrhea grade 3) occurred, it was extended to 7 pts. No further DLT was observed as it was on levels 2 and 3 with 3 pts each. Full RTX course was administered in all pts, while CAPOX-cetuximab was stopped in the DLT case and cetuximab in 1 pt with hypersensitivity reaction. Toxicities are displayed in the table . Conclusion: CAPOX can safely be combined with cetuximab without requiring chemotherapy dose reduction. The multicenter phase II part of the trial with 31 pts. included so far is ongoing and updated results (including resectability) will be presented.

[Table: see text]

[Table: see text]
A randomized phase II trial evaluating safety and efficacy of an experimental chemotherapy regimen (CPT-11 + oxaliplatin [IRINOX]) and two standard arms (LV5-FU2 + CPT-11 [FOLFIRI], LV5-FU2 + oxaliplatin [FOLFOX]) in first line metastatic colorectal cancer (MCRC) (FNCLCC Accord 08)
Authors: Becouarn Y. , Ychou M. , Boucher E. , Adenis A. , Cany L. , Jacob J. , Cvitkovic F. , Thezenas S. , Montoto-Grillot C.
Published: March 2020

3586

Background: LV5-FU2 + CPT-11 or oxaliplatin (OHP) are standard therapies in first line MCRC. This phase II trial evaluates an experimental regimen of CPT-11 + oxaliplatin, without 5FU. Methods: First line MCRC evaluable patients (pts) were randomized to receive, every two weeks, either: Arm A = OHP 85 mg/m2 d1 followed by CPT-11 180 mg/m2 (IRINOX), or Arm B = simplified LV5-FU2 (leucovorin 200 mg/m2 as a 2 h-infusion d1, 5FU bolus 400 mg/m2 d1, and 5FU continuous infusion 2400 mg/m2 d1–2) and CPT-11 180 mg/m2 d1 (FOLFIRI), or simplified LV5-FU2 and OHP 85 mg/m2 d1 (FOLFOX). Results were combined for the two standard arms (FOLFIRI + FOLFOX). Results: 80 pts were included between 09/2002 and 04/2005, 40 in IRINOX (arm A), 20 each in FOLFIRI and FOLFOX (arm B). Pts characteristics (A:B): M/F = 27/13:29/11; median age (range): 63 (41–76):61 (47–75); PS (0/1/2): 16/21/3:16/22/2; median number of cycles (range): 8.0 (1–16):12 (1–26). Safety data: no toxic death. IRINOX (318 cycles): NCI G3–4 neutropenia, 43.6% (pts), 14.7% (cycles); G3–4 neurotoxicity, 17.9% (pts), 5.0% (cycles); G3–4 diarrhea, 33.3% (pts), 5.3% (cycles). FOLFIRI (238 cycles) and FOLFOX (186 cycles): G3–4 neutropenia, 40% (pts) and 23.8% (pts) respectively (8.8% and 7.6% of cycles); G3–4 neurotoxicity, 0% and 14.3% (pts), 0% and 2.7% (cycles); G3–4 diarrhea 15% and 0% (pts), 2.1% and 0% (cycles). Median relative dose-intensity was 0.86 (0.57–1.0) for CPT-11, 0.86 (0.57 -1.0) for OHP in the IRINOX arm. We observed 21 PR in the IRINOX arm, 19 PR and 2 CR in the 2 control arms, for an ORR = 52.5%, 90% CI (38–66). Median follow-up: 17 months, median PFS for IRINOX: 8.4 months. Conclusions: The combination of CPT-11 and OHP (IRINOX) at these doses, every 2 weeks, appears safe and active in first line MCRC.

[Table: see text]
Biweekly oxaliplatin plus capecitabine (OXXEL) versus oxaliplatin plus folinic acid-modulated 5-fluorouracil i.v. bolus (OXAFAFU) in metastatic colorectal carcinoma (MCC): Safety interim analysis of a Southern Italy Cooperative Oncology Group (SICOG) phase III trial
Authors: Sandomenico C. , Filippelli G. , Massidda B. , Farris A. , Natale D. , Palmeri S. , Maiorino L. , Condemi G. , Leo S. , Greco E. , Gambardella A.
Published: March 2020

3590

Background: We have previously reported that OXAFAFU regimen significantly prolonged the overall survival of MCC patients (pts) in comparison with IRIFAFU regimen (Comella, Ann Oncol 2005). Moreover, the OXXEL regimen showed promising activity in phase II study (Comella, Cancer Chemother Pharmacol 2005). Comparison of these two regimens in terms of safety and activity is the aim of the present trial. Methods: Pts with MCC were randomly treated with: oxaliplatin 85 mg/m2 iv on day (D) 1, levo-folinic acid 250 mg/m2 plus 5-fluorouracil 850 mg/m2 bolus iv on D 2 (OXAFAFU); or oxaliplatin 100 mg/m2 iv on D 1, Xeloda 1,000 mg/m2 twice daily po from D 1 (evening) to D 11 (morning). Treatment was delivered every 2 weeks up to progression, or for a maximum of 12 cycles. Results: From May 2004 to December 2005, 191 eligible pts were recruited (OXAFAFU, 96 pts; OXXEL, 95 pts). Characteristics of pts were well balanced in OXAFAFU vs OXXEL arm: primary colon, 74% vs 72%; PS 0/1–2, 57/43% vs 65/35%; previous adjuvant CT, 24% vs 20%; liver metastases, 80% vs 83%; ≥ 2 metastatic sites, 54% vs 49%. At this interim analysis, with a median number of 8 (range, 1–12) cycles delivered in both arms, 143 pts (OXAFAFU, 73; OXXEL, 70) were assessed for safety. In OXAFAFU vs OXXEL arm, occurrence of WHO grade ≥ 3 toxicity was: neutropenia, 29% vs 3%; anemia, 2% vs 7%; thrombocytopenia 3% vs 7%; diarrhea, 4% vs 13%; vomiting, 4% vs 3%; hand-foot syndrome, 1% vs 7%. Conclusions: At this interim analysis, the OXXEL regimen appeared to produce significantly less neutropenia than the OXAFAFU regimen, at a price of an acceptable non-hematologic toxicity. Accrual will continue up to reaching the final sample size of 300 pts.

No significant financial relationships to disclose.
Phase II study of oral S-1 monotherapy in metastatic colorectal cancer after failure of both irinotecan and oxaliplatin-containing regimen
Authors: Cho B. , Choi H. , Jeung H. , Rha S. , Ahn J. , Roh J. , Kim Y. , Chung H.
Published: March 2020

3597

Background: There has been a considerable increase in the number of patients (pts) with mCRC pretreated with both irinotecan and oxaliplatin. Little is known about third-line therapy in this group of pts. We conducted a phase II trial of oral S-1 in pts with advanced colorectal cancer who failed on both irinotecan and oxaliplatin. Methods: This phase II study was designed to evaluate the activity and toxicity of S-1 monotherapy in 31 advanced colorectal cancer pts (P0 = 3%, P1 = 15%; α = 0.05, power = 80%, drop-out rate 10 %). S-1 was administered orally twice daily, 70 mg/m2/day for 14 days followed by 1-week rest. Eligibility criteria included ECOG 0–2; measurable lesion; adequate organ functions; signed informed consent. Results: As of 1st September 2005, 21 pts were enrolled. Median age of all pts 55 years. There were 10 male and 11 females. Thirteen of 21 patients were treated with oxaliplatin-containing regimens as a first-line therapy for metastatic diseases. The median number of treatments was 3 courses (range, 1–10). The relative dose intensity was 1.0 (0.83 - 1.0) with a median dose of120 mg (100 -140 mg). Nineteen out of 21 patients were evaluable. The confirmed response rate was 21.1% (4/19, 1 CR, 3 PR). The median PFS was 11 weeks, and median OS was not reached. The most frequent adverse reaction was skin pigmentation (47.6%). Grade 3 toxicities was skin pigmentation in 1 patients (4.8%), neutropenia in 1 (4.8%), and anemia in 1 (4.8%), respectively. Conclusion: This results shows that S-1 produces a promising response rate with an acceptable safety profile in refractory, mCRC. S-1 has the potential to become a valuable option as a third-line salvage regimen in irinotecan and oxaliplatin pretreated mCRC pts. Clinical trial of combination therapy with S-1 will be warranted.

No significant financial relationships to disclose.
5,10-methylenetetrahydrofolic acid with 5-fluorouracil as first line treatment in metastatic colorectal cancer: Phase II study results
Authors: Reid T. , Spears C. P. , Quadro R. , Subramanian M. , Pawl L. , Jankovic G. , Jelic S. , Milinic N. , Muzikravic L. , Robbins J.
Published: March 2020

3599

Background: 5-Fluorouracil (FU) plus Leucovorin (LV) has historically been the standard first line treatment of colorectal cancer. Although LV modestly enhances FU activity, it can increase systemic toxicity and also must be intracellularly converted in multiple steps to its active metabolite, 5,10-methylenetetrahydrofolate (CoFactor [CO]). Unlike LV, CO directly modulates FU inhibition of thymidylate synthase without the need for metabolic conversion. Preclinical models show reduced hematologic toxicity of CO+FU with enhanced efficacy compared to FU+LV. We evaluated CO+FU chemotherapy in patients with previously untreated mCRC. Methods: Patients (pts) had performance status ECOG 0–2 and objectively measurable mCRC. Prior adjuvant therapy was allowed including FU+LV. Fifty pts were enrolled and treated with CO 60mg/m2 and FU 450mg/m2 (weekly IV bolus) for 6 weeks, followed by 14 day rest. Response was measured at 16 wks (WHO criteria). Results: As of January 2006, 50 pts received at least 1 dose of drug and are no longer on treatment. Patient demographics: median age = 65 (range 42–86), M/F = 60%/40%. Mean number of doses was 18.0 (range 2–41). Overall incidence of grade 3/4 AEs was 14 (28%). No grade 3/4 drug-related hematologic toxicity was observed. There was no significant effect on HCT, Bili, WBC, ALT, and AST during the course of the study. Objective response rate (CR + PR) to first line treatment with CO+FU based on independent blinded review was 35% (2 CR, 14 PR, 23 SD, 7 PD; 95% CI: 21.4–50.2) based on 46 pts evaluable for response. Median time to tumor progression was 163 days (95% CI: 105 -189). Twenty pts are deceased and median survival has not been reached. Conclusions: The results suggest thatCO+FU is safe, well tolerated, and has activity in mCRC. In the optimum treatment strategy afforded by the availability of numerous drugs, the high level of activity and low toxicity of CO+FU suggests that this combination may be a good initial treatment in a sequential strategy of mCRC management, especially among pts who would benefit by minimizing initial toxicity.

[Table: see text]
Gene expression of MLH1 related to microsatellite instability, immuno-histochemistry, and promoter hypermethylation in colorectal cancer
Authors: Jensen L. H. , Jakobsen A. , Kuramochi H. , Liu B. , Stephen C. L. , Crüger D. G. , Aggerholm A. , Lindebjerg J. , Danenberg P. V. , Danenberg K. D.
Published: March 2020

3601

Background: The subgroup of highly microsatellite instable (MSI-H) colorectal cancers (CRC), is well described with DNA microsatellite and immuno-histochemistry (IHC) analyses. MSI-H CRCs are most often caused by hypermethylation inactivation of MLH1 or to a lesser extent by hereditary mutations in this or other mismatch repair genes. Microsatellite analysis and IHC are qualitative rather than quantitative methods. Reports showing that MMR deficient CRC has a favorable prognosis and that these cancers may respond less to chemotherapy may be more informative if based on a quantitative method instead. The aim of the present study was to correlate the expression of MLH1 to microsatellite analysis, promoter hypermethylation, and IHC. Methods: Sections of paraffin-embedded tumors from 206 unselected consecutive patients with CRC were microdissected and RNA was isolated and reverse-transcribed to cDNA. The relative gene expression of MLH1 was measured with real-time PCR. DNA from tumor and blood was examined with five standard microsatellite markers to find length mutations indicating instability. Tumor DNA was further analyzed with a methylation specific PCR in the C region of the MLH1 promoter. Protein expression of MLH1 was analyzed with IHC. Results: For all quantifiable tumors the median (and lower and upper quartiles) of the relative MLH1 gene expression was 0.90 (0.68, 1.42). For MSI-H tumors, defined as presense of instability in at least two markers or lack of protein expression with IHC, the median was 0.36 (0.26, 0.56). For microsatellite stable cancers the median was 0.96 (0.73, 1.44), p<0.0001 (Wilcoxon test). Median and quartiles of MLH1 expression in hypermethylated and non-methylated tumors was 0.31 (0.26, 0.45) and 0.96 (0.73, 1.43) respectively (p<0.0001). Relative MLH1 expression in MSI-H tumors range up to 0.64. Fourteen % of MSS tumors are in this range, too. Conclusions: In this large unselcted group of CRC patients we found a significant relation between low gene expression, MSI-H, MLH1-hypermethylation and negative IHC. We further identify a subgroup of MSS patients with low gene expression of MLH1 and suggest this quantitative marker in studies of prognosis and treatment effect.

[Table: see text]
Novel blood biomarker panel detects human colorectal cancer
Authors: Han M. , Liew C. T. , Zhang H. W. , Yip K. T. , Song Z. Y. , Li H. M. , Geng X. P. , Zhu L. X. , Marshall K. W. , Liew C. C.
Published: March 2020

3611

Background: Human colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States, and early detection is critical to improve prognosis. To date, we have applied our unique methodology (the Sentinel Principle) to identify blood-based gene expressed biomarkers for several diseases including osteoarthritis, bladder cancer and psychiatric disorders. In the present CRC study, we identified gene signatures from blood cells and characterized a set of biomarkers able to differentiate patients with CRC from controls. Methods: Microarray: 31 blood RNA sample (15 controls; 16 CRC) were profiled using Affymetrix U133Plus2.0 GeneChips. Differentially expressed genes were identified using the non-parametric, Wilcoxon-Mann-Whitney test. SYBR Green real-time RT-PCR: a subset of identified genes was assayed using 115 samples (57 controls; 58 CRC). Logistic regression was used to assess the ability of linear combinations of specific transcripts to distinguish CRC from controls. The diagnostic power for each combination was evaluated by AUC of the Receiver Operating Characteristic (ROC) curve. Blind Test: 83 samples were assayed (45 controls and 38 CRC). Results: Microarray data: 2,779 probes were significantly different in blood gene expression profiles from controls and those from CRC (p<0.05). Real-time RT-PCR: Two up-regulated genes (cytidine deaminase, 1.3 fold with p<0.001; MGC20553 /FERM domain containing 3, 1.2 fold with p=0.031) and three down-regulated genes were validated (B-cell scaffold protein with ankyrin repeats 1, 0.43 fold with p<0.001; B-cell novel protein 1, 0.44 fold with p<0.001; membrane-spanning 4-domains, subfamily A, member 1, 0.44 with p<0.001). Combination analysis: The AUC was 0.883 (95%, C.I. 0.810–0.935) for the best linear combination of these 5 genes. At a cut-off of -1.1, the sensitivity and specificity were 98% and 51%, respectively. Blind Test: The 5-gene set gave sensitivity of 95% (36/38) and specificity of 42% (19/45) with an overall accuracy of 66%. Conclusions: Gene expression signatures from peripheral blood differentiate between CRC patients and controls. The five-gene panel showed high classification performance and could be used as a novel screening tool for CRC.

[Table: see text]
Benefits, limitations and pitfalls of sentinel lymph node (SLN) mapping (M) for colorectal carcinoma (CRCa): A multicenter trial
Authors: Saha S. , Sehgal R. , Patel M. , Wiese D. , Bilchik A. , Beutler T. , Iddings D. , Espinosa M. , Yee C. , Ghanem M.
Published: March 2020

3621

Background: Clinical application of SLNM in CRCa patients (pts) is controversial due to the variable results in the literature for its success, skip metastases (mets) and accuracy. Hence prospective data from 5 institutions were analyzed to identify the factors associated with failure and skip mets in CRCa pts undergoing SLNM. Methods: SLNM was performed by peri-tumoral injections of 1–3 ml of 1% lymphazurin subserosally. First 1–4 blue nodes marked as SLNs were examined by 4 sections with H & E and 1 for cytokeratin. Rate of failure and skip mets rate along with age, sex, tumor site, size, grade, T & N stages were analyzed. Results: 549 consecutive CRCa pts underwent SLNM; 453 colon (C) and 96 rectal (R) pts. M: F ratio was 48%: 52% and median age of 72 years. The average no. of LNs was 14.5. SLNM failed in 1% of C and 8% of R pts ( Table ). Of the 8 R failures, 7 had neoadjuvant therapy. No correlation was found between failure, size or T-stage. Overall nodal positivity (+ve) rate was 48%. Of the 466 invasive CRCa pts with successful SLNM, rate of skip mets was 7% in C and 4% in R. Age, sex, grade and neoadjuvant therapy had no correlation with skip mets. Of 28 skip mets pts, 79% had tumors >3cm and 93% had advanced (T3, T4) tumors. Higher skip mets also was found in the transverse colon tumor. The success, accuracy, and sensitivity rates were 98%, 95%, and 88% respectively. Of node +ve pts, 47% had mets found only in the SLNs. SLNM upstaged 35% of C and 36% of R pts with micromets. Conclusions: In CRCa, SLNM is highly successful and accurate in predicting the presence or absence of nodal mets. Submucosal fibrosis of the lymphatics due to neoadjuvant therapy may result in higher failure rates for R pts. Skip mets are higher in transverse C tumors and increase in frequency as the T-stage increases. Pts upstaged by SLNM may benefit from adjuvant chemotherapy.

[Table: see text]

No significant financial relationships to disclose.
lymphadenectomy for liver tumors: A safe procedure in a tertiary center which improves the staging of the disease
Authors: Ravaioli M. , Ercolani G. , Grazi G. , Cescon M. , Varotti G. , Del Gaudio M. , Vetrone G. , Zanello M. , Tuci F. , Pinna A.
Published: March 2020

3622

Background: the role of regional lymphadenectomy for liver metastases and primary liver tumors, but not extra-hepatic bile duct cancer, is debated. Methods: from April ’99 to December ’04, we prospectively evaluated 142 patients treated with liver resections and with the following pre-operative diagnosis: 63 (44.4%) colorectal metastases (M-CR), 48 (33.8%) hepatocellular carcinoma (HCC), 16 (11.3%) non-colorectal metastases (M-NCR) and 15 (10.6%) intra-hepatic cholangiocellular carcinoma (CCC). The regional lymphadenectomy of the hepato-duodenal ligament and of the common hepatic artery was performed in all cases. The incidence and the influence on survival of lymph node metastases were analyzed. Results: 42 “wedge” resection (29.6%), 55 segmentectomies (38.7%) and 45 major hepatectomies (31.7%) were performed. The mean operative time was 292±131 minutes and 96 cases (67.6%) had no blood transfusions during the procedures. Operative mortality (within 30 days) was 3.5%, 48 cases (33.8%) developed post-operative complications and the most common was ascites. The mean hospital stay was 9±5 days. The mean number of nodes (LN) removed were 6.5±5 (range 6–30) and 63 LN (6.5%) had micro-metastases. The incidence of lymph node metastases (LN+) according to the pre-operative diagnosis was: 15.9% M-CR, 4.2% HCC, 37.5% M-NCR and 40% CCC. The mean follow-up was 37.4±22.6 months, 107 patients (75.4%) are alive and 44 (31.7%) developed tumor recurrence, which was more frequent in LN+ (54.2% vs. 27%, p<0.05). The 1-and 3-years patient survival was significantly affected by lymph node metastases: 92% and 85% LN- vs. 79% and 64% LN+, p<0.05. Conclusions: the regional lymphadenectomy for liver tumors is a safe procedure in tertiary referred centers. The presence of lymph node metastases was an important prognostic factor, which should be evaluated to improve the treatment strategies.

No significant financial relationships to disclose.
Colorectal cancer patient utilization of an internet based clinical trials matching system
Authors: Bui C. , Hampshire M. , Vachani C. , Metz J.
Published: March 2020

3624

Background: Colorectal cancer patients are increasingly looking to the Internet for information on clinical trials; however, services offering clinical trials recruitment have not been well defined. This study describes one of the first web-based cancer clinical trials matching resources and the demographics of the colorectal cancer patient user base. Methods: Oncolink ( http://www.oncolink.org ) is the web-based educational resource at the University of Pennsylvania and serves between 1.5–2 million pages per month to over 385,000 unique IP addresses. Oncolink, in conjunction with EmergingMed (New York, NY), launched one of the first clinical trials matching resources on the Internet. Patients input demographic and tumor-specific information via secure Internet-only registration or via the Internet with assistance from a call center, to match to trials. As of 12/2005, there were 112 total colorectal trials in the database. Results: Between 12/2000 and 9/2005 a total of 41,970 individual profiles were created, with 3289 (7.8%) by colorectal cancer patients. Other GI tumors accounted for 15% of profiles. Of the 3289 patients, 54% were male and 46% were female, and the median age was 55 (range 19–96). Most patients reported their disease as having spread to another organ (62%) or to lymph nodes (15.4%). Most patients were previously treated with surgery (81%), radiation (26%), chemotherapy (74%), and/or biological therapies (21%) (bevacizumab, cetuximab, interferon or interleukin). Patients who used the call center with the Internet were more likely to apply for enrollment in a clinical trial after review of the matches (77% vs. 10%, p<0.001). The median number of trial matches in the system was 7 per patient. Of the 3289 colorectal patients, 681 patients (21%) went on to apply for enrollment to trials based on their matches. Conclusions: This report demonstrates that a significant percentage of colorectal cancer patients are willing to use the Internet to match to clinical trials. Contact with a call center greatly increases the likelihood of application to trials. Internet based clinical trials resources should maintain options for personal communication to increase the likelihood of enrollment to clinical trials.

No significant financial relationships to disclose.
Intergroup RTOG 98–11: A phase III randomized study of 5-fluorouracil (5-FU), mitomycin, and radiotherapy versus 5-fluorouracil, cisplatin and radiotherapy in carcinoma of the anal canal
Authors: Ajani J. A. , Winter K. A. , Gunderson L. L. , Pedersen J. , Benson A. B. , Thomas C. , Mayer R. J. , Haddock M. G. , Willett C. , Willett C. , Rich T. A.
Published: March 2020

4009

Background: An ∼65% 5-year disease-free-survival (DFS) rate from 5-FU/mitomycin/radiation for anal carcinoma needs improvement. Methods: A phase III randomized trial compared 5-FU (1,000mg/m2 days 1–4 and 29–32) plus mitomycin (10mg/m2 days 1 and 29) and radiation (45 to 59 Gy) (Arm A) to 5-FU (1,000mg/m2 days 1–4, 29–32, 57–60 and 85–88) plus cisplatin (75mg/m2 on days 1, 29, 57 and 85) and radiation (45 to 59 Gy; start day=57) (Arm B) in anal carcinoma patients. Stratification included gender, clinical N status and tumor diameter. Primary endpoint was DFS. Statistical power was 80% with two-sided test to detect 10% DFS increase for Arm B. Results: Of 682 patients accrued, 598 were analyzable. Most unanalyzed patients’ data are early. Patient characteristics were balanced. Median age was 55 years, women predominated (69%), 27.5% had >5 cm tumor diameter and 26% had clinically N+ cancer. Preliminary 5-year estimated DFS was 56% for Arm A and 48% for Arm B (p=0.28) and 5-year estimated overall survival was 69% for both arms (p=0.24). Men(p=0.04), clinically N+ cancer (p<0.0001) and tumor diameter >5 cm (p=0.005) independently prognosticated DFS in a multivariate analysis. 5-year colostomy rate was 10% for Arm A and 20% for arm B(p=0.12). Grade 3/4 toxicity rates: non-hematologic=76% for Arm A and 75% for Arm B but hematologic=67% for Arm A and 47% for Arm B(p=0.0004). Conclusions: In Intergroup-98–11, induction 5-FU/cisplatin followed by 5-FU/cisplatin/radiation failed to improve DFS compared to the standard treatment, 5-FU/mitomycin/radiation. Supported by RTOG U10 CA21661, CCOP U10 CA37422, Stat U10 CA32115.

No significant financial relationships to disclose.
Final results of a multicenter phase II study of irinotecan (CPT), cisplatin (CIS), and bevacizumab (BEV) in patients with metastatic gastric or gastroesophageal (GEJ) adenocarcinoma (NCI #6447)
Authors: Shah M. A. , Ramanathan R. K. , Ilson D. , Randazzo J. , Schwartz G. K. , Tse A. , D’Adamo D. , Levner A. , Capanu M. , Kelsen D. P.
Published: March 2020

4020

Background: BEV improves survival in several solid tumors when combined with chemotherapy. CPT/CIS is active in gastric and GEJ cancers with a median time to progression(TTP) of 4.2 months, response rate(RR) of 30%, and median survival of ∼7 months (Pozzo Ann Onc 2004). Anti-angiogenic therapy for upper GI cancers is of concern due to a potential increased risk of perforation or GI bleed. We evaluated the efficacy and safety of the combination of CPT, CIS, and BEV in the treatment of gastric and GEJ cancers. Methods: 47 patients with previously untreated metastatic gastric or GEJ adenocarcinomas were treated with BEV 15mg/kg day 1, CPT 65mg/m2 and CIS 30mg/m2 days 1 and 8, every 21 days. The primary endpoint was TTP, with 90% power to demonstrate a 50% improvement in TTP (eg. from 5 to 7.5 months) over historical control. Safety, response, and survival were secondary endpoints. Results: Patient characteristics: median age 59 (range 25–75), KPS 90% (70%-100%), Male 34, Gastric/GEJ 27:20. With a median follow up of 9.0 months, median TTP is 9.9 months (95%CI: 6.5–11.8 months). In 33 patients with measurable disease, the RR (partial + complete) is 66.7% (95%CI: 51–83%). Median survival is 12.6 months (95%CI: 10.1–17.1 months). We observed no change in expected CPT/CIS related toxicity: eg. grade 3/4 neutropenia (29%), nausea/vomiting (10%), and diarrhea (13%). Possible BEV related toxicity includes 2 gastric perforations, 1 grade 3 peri-rectal fistula, 2 cardiac events(1 ischemia, 1 reduced ejection fraction), and 10 patients with grade 3/4 hypertension. Although the primary tumor was unresected in 35 patients, we observed only 1 patient with an upper GI bleed. Grade 3/4 thromboembolic events occurred in 25%. Conclusions: The combination of CPT/CIS/BEV is active in gastric and GEJ cancers. The toxicity profile is acceptable. The primary endpoint of improving TTP was exceeded by 100% with median TTP 9.9 months. Despite the majority of patients having their primary tumor unresected, GI bleeding was not significant. The thromboembolic and perforation rates with CPT/CIS are similar with or without BEV (Shah et al JCO 2005). Further development of BEV in gastric and GEJ cancers is clearly warranted.

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Interim results of preoperative gemcitabine (gem) plus cisplatin followed by rapid fractionation chemoradiation for resectable pancreatic adenocarcinoma
Authors: Varadhachary G. R. , Evans D. B. , Crane C. , Xiong H. Q. , Lee J. E. , Pisters P. W. , Abdalla E. K. , Lee J. H. , Tamm E. P. , Wolff R. A.
Published: March 2020

4037

Background: Over 80% of pts who undergo potentially curative pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma develop local or distant recurrence. Chemotherapy and external-beam radiation therapy (EBRT) prior to surgery maximizes the number of pts who receive multimodality therapy and undergo a complete (R0) resection. Methods: Pts with biopsy proven, stage I/II adenocarcinoma of the pancreatic head or uncinate process received systemic therapy with 4 infusions of gem (750 mg/m2) + cisplatin (30 mg/m2) every 2 wks followed by 30 Gy of EBRT (3 Gy/Fx, M-F over 2 wks) and 4 weekly doses of gem (400 mg/m2). Pts underwent complete restaging 4–6 wks after the last dose of gem. Those without disease progression and with acceptable PS underwent surgery. Results: This study has currently enrolled 87 pts over 4 years. Median age is 65 yrs (38–80), most pts (96%) had ECOG-PS (0–1) at study entry. Median CA19–9 is 170. Six pts were excluded from analysis and 4 are currently on treatment. Of the 77 pts who finished chemoradiation, 72 completed restaging (3 await restaging, 2 drop outs). Of these 72 pts, 10 had disease progression, 1 had a decline in PS, and 61 (79 %) went to surgery. 49 of 61 pts (64 %) underwent a successful PD and metastatic or locally advanced disease was found in 12 (15 %). 44 (90 %) of 49 pts underwent R0 resection. Pathologic PR rate (>50 % tumor kill) was 61 %. The predominant toxicity prompting hospitalization during preoperative therapy was biliary stent occlusion (44 %). Gastrointestinal toxicity ≤ grade 3 was common but controllable. Grade 3 and 4 neutropenia was seen in 19 (25 %) and 3 pts (4 %) respectively. Grade 3–4 thrombocytopenia was rare. Median survival for resected pts was ∼ 21 months. Conclusions: This study, builds on our previous gem-based preop chemoradiation program ( ASCO 2002, Abs # 516) producing good local treatment effect and a high R0 resection rate. However, interim analysis suggests that the addition of systemic chemotherapy delivered prior to preoperative chemoradiation does not appear to improve survival. Optimal treatment sequencing of chemoradiation, systemic therapy and surgery needs further refinement. Supported in part by Eli Lilly and Co.

[Table: see text]