bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultrastaging of sentinel lymph nodes (SLNs) compared to non-SLNs in colorectal (CRca) cancer: Do we need both?
Authors: Wiese D. , Saha S. , Ghanem M. , Yestrepsky B. , Patel M. , Bassily N. , Ng P. , Liu W. , Quiachon E. , Badin J.
Published: March 2020

4055

Background: SLN mapping (M) accurately stages many solid tumors including CRca. SLNs are 3–5 times more likely to have metastases (mets) when ultrastaged by microsections and IHC as compared to non-SLNs examined by standard pathological methods. It is unknown whether ultrastaging of initially -ve non-SLNs would lead to higher incidence of +ve nodes. Hence, we retrospectively analyzed all initially -ve non-SLNs by microsections and IHC similar to SLNs in CRca patients (pts) undergoing SLNM to determine its impact on final nodal staging. Methods: All CRca pts underwent SLNM by circumferential subserosal injection of 1% lymphazurin. First 1–4 blue nodes were marked as SLNs and ultrastaged by 4 section with H&E and 1 with IHC. All non-SLNs were initially examined by single H& E section and initial staging was made as per AJCC criteria. We re-examined all initially -ve non-SLNs similar to the SLNs by a senior pathologist blinded to prior results. Results: There were 156 pts with Cca and 44 pts with Rca. SLNM was successful in 100% pts with 94% accuracy rate. A total of 2,755 nodes (13.78/pt) were identified, of which 494 were SLNs and 2,261 were non-SLNs. Nodal positivity was 46% and 16% for Cca and Rca pts respectively. Mets were detected in 20.9% of SLNs vs. 8.6% of non-SLNs (p< 0.0001). The exclusive site of nodal mets was detected in 6.5% of SLNs vs.0.8% of non-SLNs (p< 0.0001). Skip mets were found in 6% of pts. After ultrastaging all initially -ve non-SLNs (n=2,065), only 0.58% (12/2065) nonSLNs became +ve in 12 pts. Of these, 10 pts already had +ve SLNs, hence no change of staging occurred. Only 2/200 pts (1%) with initially -ve non-SLNs were found to have a cluster of tumor cells. Thus, ultrastaging of 2065 initially -ve non-SLNs in 200 pts changed the staging from II to III only in 1% of pts. Conclusions: SLNM is highly accurate in staging CRca. The chance of finding additional mets by ultrastaging of all non-SLNs is extremely low (< 1%), hence of little benefit. Therefore, ultrastaging restricted to SLNs alone will assure accurate staging of CRca.

[Table: see text]

No significant financial relationships to disclose.
Predictors of a true complete response in colorectal liver metastases that disappear radiographically following chemotherapy
Authors: Taylor R. A. , White R. R. , Kemeny N. , Jarnagin W. R. , DeMatteo R. P. , Fong Y. , Blumgart L. H. , D’Angelica M.
Published: March 2020

4058

Background: During chemotherapy for colorectal liver metastases (LM), some lesions disappear by CT scan. This may represent a true complete response (CR) with eradication of tumor or a reduced sensitivity of imaging due to chemotherapy induced hepatic steatosis. This study aimed to determine the significance of radiologic disappearance of LM treated with chemotherapy and factors predictive of a true CR. Methods: Between 2000 and 2003, 435 patients evaluated by a hepatobiliary surgeon were treated with neoadjuvant chemotherapy for LM. Inclusion criteria were fewer than 12 LM initially, disappearance of one or more LM by CT scan and a clinical follow-up of at least 1 year after disappearance. A pathologic CR (pCR) was defined as the absence of a LM in the resected specimen, a durable clinical CR (cCR) was defined as a LM that did not reappear during follow-up imaging. A LM was defined as found if it was detected by other imaging (MRI), at resection, or if it recurred during follow-up. LM that were found were compared to pCR and durable cCR to determine factors predictive of a true CR. Results: During chemotherapy, 39 (9%) patients had a total of 117 LM disappear by follow-up CT scan. The outcome is shown in the Table . Treatment with hepatic arterial infusion (HAI) chemotherapy (n=22) was associated with a significantly higher rate of pCR or durable cCR (42% vs. 14%, p<0.001). LM were also significantly more likely to represent a pCR or durable cCR when the surrounding liver did not demonstrate steatosis (p<0.001), when the patient’s BMI was <30 kg/m2 (p=0.002), and when a preoperative MRI was performed (p=0.01). Conclusions: Among disappearing LM, a pCR occurs in 37% and a durable cCR in 26%, yielding a true CR rate of 63%. The disappearing LM in patients treated with HAI chemotherapy were more likely to a represent true CR when compared to systemic chemotherapy alone. Hepatic steatosis and obesity impaired the ability to detect lesions by CT scan and MRI improved the preoperative detection rate of disappearing LM.

[Table: see text]

No significant financial relationships to disclose.
Effectiveness of neoadjuvant chemotherapy including bevacizumab in patients with resectable colorectal cancer liver metastases
Authors: Gruenberger B. , Scheithauer W. , Tamandl D. , Zielinski C. , Schueller J. , Gruenberger T.
Published: March 2020

4060

Background: Chemotherapy including bevacizumab has become the new standard in the first line treatment of patients with metastatic colorectal cancer (mCRC). Response to chemotherapy has been assessed as major prognostic factor for RFS in resectable mCRC patients, but safety concerns have been raised. We conducted a phase II trial to evaluate the safety of neoadjuvant chemotherapy including bevacizumab (Bev). Methods: Patients with resectable mCRC received six cycles (3 months) of neoadjuvant XELOX (capecitabine 3,500mg/m2/day days 1–7 plus oxaliplatin 85mg/m2 day 1) with bevacizumab (5mg/kg) every 2 weeks. The sixth cycle did not include Bev resulting in a gap of 5 weeks between last Bev and surgery. Primary end points were feasibility of neoadjuvant treatment with this regimen and response rate; secondary end points were feasibility of curative liver resection and perioperative morbidity of the surgical procedure. Results: 54 patients (32 male, 22 female) with a median age of 61 years (SD ± 10.6) were included. The median number of preoperative cycles was 6 (SD ± 2). Grade 3/4 side effects were PNP in 13%, H&F in 3%, diarrhea in 38%, anaemia in 3% and neutropenia in 12% of our patients. Thromboembolic events occurred in 4 patients (7%), hypertension grade III in 2 (4%) and perforation in 1 (2%) patients. A dose reduction of chemotherapy was required in 43%. There were no treatment related deaths. The overall objective response rate for all 54 patients was 74% (40 patients) including 11% pCR. 11 additional patients (20%) had stable disease and only 3 (6%) progressed. Potential curative surgery was performed in all but 5 patients (91%). 2 patients were not resected due to PD, 2 because of pulmonary embolism during chemotherapy and 1 patient because of positive hilar lymph nodes. Conclusions: These data provide evidence that neoadjuvant chemotherapy including bevacizumab can be safely administered in patients with resectable mCRC. A high response rate and a disease control rate of 94% suggest that XELOX + Bev is an effective regimen in this treatment setting.

No significant financial relationships to disclose.
Bevacizumab plus XELOX as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer
Authors: Gruenberger T. , Tamandl D. , Puhalla H. , Scheithauer W. , Zielinski C. , Gruenberger B.
Published: March 2020

4064

Background: Patients (pts) with colorectal cancer (CRC) and liver metastases have a poor prognosis and may benefit from perioperative chemotherapy and disease resection. Bevacizumab (BEV) is proven to improve outcomes in patients with metastatic CRC; however, its impact on surgical complications and hepatic regeneration following liver resection needs to be assessed. Methods: Patients with metastatic CRC with liver metastases potentially curable by resection were eligible for this single-centre, nonrandomised phase II trial. Eligibility criteria define pts at high risk of early recurrence: synchronous liver metastases; primary non-optimally resectable disease or multiple liver metastases. Pts received BEV 5mg/kg q2 weeks plus XELOX (capecitabine 3500mg/m2/day days 1–7 plus oxaliplatin 85mg/m2 day 1 of a 2-week cycle) for 6 cycles. The sixth cycle of therapy did not include BEV, resulting in 5 weeks between the last BEV dose and surgery. Therapy with BEV plus XELOX was restarted 5 weeks after surgery for another 6 cycles. Results: 54 patients have been enrolled and are evaluable having received a median of 6 cycles of BEV plus XELOX: 39 pts underwent liver resection alone, 9 pts also had primary tumor resection (2 are awaiting surgery); major liver resections were performed in 17 pts (35%). 40 pts responded (ORR 74%) and 11 had stable disease. To date, peri- and postoperative events are consistent with previous studies evaluating chemotherapy alone: there was no intra-operative increased bleeding, perioperative blood transfusions were required in only 3 pts (6 %); further surgery was necessary in a single patient. Postoperative liver function and regeneration (assessed by CT 3 months after surgery) were normal in all but one patient (prolonged liver dysfunction due to steatohepatitis). No postoperative mortality occurred and morbidity was encountered in 8 pts (17%). Mean postoperative hospital stay was 8 days (SD ± 3.8). Conclusions: These data suggest that BEV can be safely administered until 5 weeks prior to liver resection in patients with mCRC without increasing the rate of surgical or wound healing complications or severity of bleeding. They are the first to show that neoadjuvant BEV does not affect liver regeneration after resection.

No significant financial relationships to disclose.
A phase I study of AEE788, a multitargeted inhibitor of ErbB and VEGF receptor family tyrosine kinases, to determine safety, PK and PD in patients (pts) with advanced colorectal cancer (CRC) and liver metastases
Authors: Xiong H. Q. , Takimoto C. , Rojo F. , Davis D. , Huang J. , Abbruzzese J. L. , Dugan M. , Thomas A. , Mita A. , Steward W. P.
Published: March 2020

4065

Background: AEE788 (AEE) is an oral inhibitor with potent activity against EGFR, ErbB2, and KDR. This phase I study was to assess the safety, PK, PD, and MTD/DLT of AEE in pts with CRC and liver metastases. Methods: AEE was given PO at 25, 50, 100, 250, 300 or 400 mg/day daily in 28-day cycles (C) to 3–6 pt cohorts. 24-hr PK was obtained on C1, days (D)1, 15 and 28. PK parameters of AEE and active metabolite, AQM674 (AQM) were computed by non-compartmental methods. PD markers were analyzed in skin (SK), and tumor (TU) biopsies pre- and post-treatment. Samples were evaluated by both IHC and Laser Scanning Cytometry (LSC). DCE-MRI was performed at baseline (BL), and on C1D2 and 28 and C2D28. Results: 22 pts were treated at doses of 25 (n=4), 50 (n=3), 100 (n=4), 250 (n=1), 300 (n=4), and 400 mg (n=6). No DLT was reported. The most common AE (> 15%): fatigue (55%), vomiting (46%), diarrhea (41%), nausea (36%), dyspnoea (23%), constipation (18%) pyrexia (18%) and rash (18%). 2 pts had reversible gr 3/4 LFTs. Serum concentration of AEE and AQM increases with dose and dose duration. 7 pts had stable disease at the end of C2. Median time on treatment was 56 days (range 7–168). In SK, at doses =100 mg, pEGFR, pMAPK and Ki67 were inhibited by an average of 51, 54 and 41%, respectively by IHC. In endothelial cell (EC) pKDR/KDR was significantly inhibited (4-fold) in the wound-induced SK in a dose-dependent manner by LSC. In TU, inhibition of pEGFR, pMAPK and Ki67 at 400 mg was 100%, 90% and 39%, respectively by IHC. EC pKDR decreased with dose, however, trend was not significant. 1 out 15 pts who had BL and end of C1 DCE-MRI had > 40% Ktrans reduction. Conclusions: A dose dependent inhibition of pKDR, pEGFR, and pMAPK in skin and tumor was observed. However, no significant effects were observed on Ki67 and apoptosis in TU. No dose dependent reduction in Ktrans from DCE-MRI was observed. These findings were consistent with the lack of clinical activity of AEE up to 400 mg in this patient population. The study has been discontinued without reaching DLT due to safety data from other phase I studies and in favor of different dosing schedules.

No significant financial relationships to disclose.
Is chemotherapy failure a contraindication for liver resection in liver metastases of colorectal cancer? A multivariate analysis
Authors: Neumann U. P. , Thelen A. , Jonas S. , Riess H. , Neuhaus P.
Published: March 2020

4066

Background: Liver resection is the only curative treatment offering a chance of long-term survival in patients with colorectal liver metastases. Chemotherapy is increasingly proposed as neoadjuvant treatment in patients with irresectable liver metastases. However, a large number of patients show progress while on chemotherapy. Recent data indicated that liver resection in patients receiving chemotherapy with tumor progress is associated with poor outcome. The aim of the study was to identify risk factors for poor outcome in patients with preoperative chemotherapy with resectable colorectal liver metastases (CRM). Methods: We retrospectively analyzed the outcome of 168 consecutive patients who underwent liver resection for CRM after systemic chemotherapy between 1995 and 2004. Overall, 132 (78.6%) patients had first line, 24 (14.3%) patients second line and 12 (7.2%) third or fourth line chemotherapy. Three groups of patients were identified according to the chemotherapy response. 48 patients (28.6%) had a tumor response (group 1), in 20 (11.9%) the condition stabilized (group 2), and 100 (59.5%) patients had tumor progression (group 3). Median follow-up was 1.8 yrs (range (6 days - 9.5 yrs). Results: Demographic data, size of largest node, number of nodes, extent of resection and postoperative course were equally distributed between groups. Overall, survival was 89%, 56%, and 31% at 1, 3, and 5 years, respectively. Five-year survival was similar between groups. In the univariate analysis, only incomplete resection and vascular invasion were associated with poor outcome. In the multivariate analysis, only vascular invasion was significantly associated with fatal outcome. Neither the number of lines nor the chemotherapeutic agent was associated with decreased survival. Conclusions: In a large patient population, liver resection offered long-term survival for patients with multiple colorectal metastases, even in cases with tumor growth whilst receiving chemotherapy. This underlines that, whenever a curative resection is possible, surgical resection of liver metastases is justified even in patients with therapy failure due to chemotherapy.

No significant financial relationships to disclose.
N9741: Survival update and prognostic factor analysis of oxaliplatin (Ox) and irinotecan (Iri) combinations for metastatic colorectal cancer (MCRC)
Authors: Sanoff H. K. , Sargent D. J. , Campbell M. E. , Morton R. F. , Fuchs C. S. , Ramanathan R. K. , Williamson S. K. , Findlay B. P. , Pitot H. C. , Goldberg R. M.
Published: March 2020

4067

Background: N9741 randomized 1691 patients (pts) to seven 5FU, Ox and Iri containing regimens for MCRC. After 20.4 months median follow-up, FOLFOX and IROX improved time to progression (TTP) and overall survival (OS) compared to IFL. Here we update OS and TTP, and report an analysis of factors prognostic of pt outcome. Methods: 5 yr OS and TTP were calculated by Kaplan-Meier per treatment (rx) arm. Pt factors [rx arm, age, gender, prior adjuvant rx, body mass index (BMI), performance status (PS), number of disease sites (#sites), neutrophil count (ANC), hemoglobin, platelets, bilirubin, alkaline phosphatase (ALK), aspartate aminotransferase (AST)] were assessed for univariate association with OS, TTP, response rate (RR), and any grade =3 toxicity. Associated factors were included in multivariate Cox and logistic regression models. Results: After a median follow-up of 4.3 yrs, FOLFOX treated pts were more likely to live 5 yrs, 9.2% versus 5.4% for IROX (p=.016) and 3.8% for IFL (p<.001). Median TTP was also significantly longer in the FOLFOX arm, 9.2 mo vs 6.5 mo for IROX (p=<.001) and 6.0 mo for IFL (p=<.001). The prognostic model found higher PS, ANC and ALK, and more disease sites were prognostic of worse OS (see table ). Age = 70 was associated with poorer survival (HR death 1.33, p=.03), but not TTP, RR, or grade =3 toxicity. FOLFOX rx was the most powerful prognostic factor for TTP and OS. The odds of grade =3 toxicity were significantly higher in FOLFOX treated pts (OR 1.65, p<.001) and lower in men (OR .63, p<.001). No significant interactions between rx arm and pt factors were present, suggesting no factor examined is predictive of rx-specific outcome. Conclusions: 9% 5 yr OS in MCRC pts treated with first-line FOLFOX sets a new benchmark. We confirmed pre-rx PS, WBC, and ALK are prognostic for OS, though FOLFOX rx was the strongest prognostic factor. No factor was associated with differential outcome or toxicity by rx arm, thus these factors cannot be used to guide rx selection.

[Table: see text]

[Table: see text]
Randomized strategical trial of chemotherapy in metastatic colorectal cancer (FFCD 2000–05): Preliminary results
Authors: Bouché O. , Castaing M. , Etienne P. L. , Texereau P. , Auby D. , Bedenne L. , Rougier P. , Gargot D. , Gasmi M. , Ducreux M.
Published: March 2020

4069

Background: The survival benefit of using a combination therapy instead of keeping it for a second line (L2) has not been demonstrated in metastatic colorectal cancer. The purpose of this trial was to compare the efficacy of simplified LV5FU2 (s) followed by FOLFOX6 (arm A) to FOLFOX6 followed by FOLFIRI (arm B) on progression-free survival after two lines of chemotherapy. We present here preliminary results relating to toxicity, observance and overall survival. Methods: Inclusion criteria: a) non resectable metastases of histologically proven colorectal adenocarcinoma , b) evaluable disease (WHO criteria), c) absence of previous chemotherapy other than adjuvant. Treatment was as follows: LV5FU2s = at day 1, folinic acid 400 mg/m2, 5-FU bolus 400 mg/m2 and continuous infusion over 46 hours 2,400 mg/m2/2 weeks; FOLFOX6 = LV5FU2s + oxaliplatin 100 mg/m2 at day 1; FOLFIRI = LV5FU2s + irinotecan 180 mg/m2 at day 1. Results: 410 pts out of 570 initially planned (early stopping due to slow accrual and new treatments) were included from 02/2002 to 02/2006 (205 in each arm). Median follow-up was 25 months. The median number (range) of cycles (28 days) in first line (L1) was respectively 5 (1–24) and 6 (1–24) in the arms A and B (p=0.01), and for L2 (152 and 144 pts in the arms A/B): 5 (1–17) and 3 (1–33) (NS). In the arms A and B, 74% and 70% of pts had L2. L1 was stopped for toxicity for 1% and 16% of the pts in arms A and B (p<0.0001); L2 respectively for 15% and 2% pts (p<0.0001). The percentages of pts presenting at least a grade 3–4 hematologic toxicity (mainly neutropenia) by arm were: 6% versus 37% (p<0.0001) for L1 and 30% versus 27% (NS) for L2; grade 3–4 non hematological toxicity (grade 2–4 neurotoxicity): 26% (1%) versus 56% (64%)(p<0.0001; p<0.0001) for L1 and 54% (60%) versus 46% (40%) of the pts for L2 (NS; p<0.01). No toxic death was observed in the arm A against 5 in the arm B: 3 in L1 and 2 in L2. Overall survival medians were 17 and 16 months in arms A/B (logrank p=0.64) (preliminary results, 291 observed deaths). Conclusions: This trial does not show any substantial difference in treatment duration and overall survival between both arms and shows a more important toxicity in the arm with first line combined chemotherapy.

No significant financial relationships to disclose.
Cetuximab (C), oxaliplatin (Ox) and fluoropyrimidine (Fp): Toxicity during the first 12 weeks of treatment for the first 804 patients entered into the MRC COIN (CR10) trial
Authors: Maughan T.
Published: March 2020

4070

Background: COIN is a 3-arm trial comparing continuous chemotherapy (CT) plus C or intermittent CT with standard continuous CT (OxFp) in the first-line treatment of advanced colorectal cancer (ACRC). Methods: Eligible patients have measurable, inoperable ACRC; no prior CT for metastases; PS 0–2; GFR >50; ALP <5 xULN; bili <1.25 xULN. Patients and/or clinicians choose the OxFp regimen, either FOLFOX (Braun,M BJC 89:1155f, 2003) or capecitabine (Cap) with Ox. Thereafter, randomization is 1:1:1 between: (A) OxFp; (B) OxFp plus weekly C; or (C) Intermittent OxFp. In Arms A and B treatment is given until progression, cumulative toxicity or patient choice, in Arm C it is stopped at 12 wks in stable/responding patients and reintroduced following progression off treatment. Primary endpoint is Overall Survival (OS). The trial aims to recruit 2,421 patients over 3.5 years. Release of this preliminary toxicity data has been approved by the independent Data Monitoring Committee (DMC). Results: 804 patients were randomised between 03/05 and 07/06 and 12 week toxicity is available on approx. 85% of patients. 62% of patients received Ox + cap and 38% received FOLFOX. Grade 3 /4 toxicities (%) in the first 12 weeks by regimen are reported below. Conclusions: The addition of cetuximab to OxFp combinations results in increased grade 3/4 toxicities overall and specifically in GI, skin rash and lethargy. Cap combination is associated with more GI toxicity but less neutropenia. Unexpectedly, no hypersensitivity reactions have yet been seen on FOLFOX (with or without C).

[Table: see text]

[Table: see text]
Irinotecan/5-FU/FA (I-FU) or 5-FU/FA (FU) first-line therapy in older and younger patients with metastatic colorectal cancer: Combined analysis of 2,691 patients in randomized controlled trials
Authors: Folprecht G. , Seymour M. T. , Saltz L. , Douillard J. Y. , Stephens R. J. , Van Cutsem E. , Rougier P. , Maughan T. S. , Köhne C. H.
Published: March 2020

4071

Background: Irinotecan containing first line therapy has been shown to improve efficacy in first line therapy. Pooled analyses demonstrated that elderly patients benefit in a similar way as younger patients if 5-FU or 5-FU/oxaliplatin is administered as palliative or adjuvant treatment within clinical trials (Sargent, NEJM 2001, Folprecht, Ann Oncol 2004, Goldberg JCO 2006). Methods: We present an updated metaanalysis using source data of randomized trials (Saltz 2000, Douillard 2000, Köhne 2005 [EORTC 40986] and Seymour 2005 [FOCUS]) and compared the efficacy and toxicity in older (=70 years) and younger (<70 years) patients receiving first line 5- FU/FA with or without irinotecan. Randomized patients who did not receive treatment were excluded. Results: A total of 2,691 pts. was enrolled into the analysis ( table 1 ). There was no imbalance regarding risk factors (ECOG PS, WBC, No. of tumor sites, alkal. phosphatase, LDH) between elderly and younger patients. Older and younger patients had significantly improved response rates and PFS with I-FU compared to FU. Younger patients had significantly longer OS with I-FU, older patients a trend to longer OS with I-FU ( table 1 ). I- FU was associated with more grade >= 3 toxicity in the general population, but there were no significant differences regarding toxicity between older and younger patients ( table 1 ). Conclusion: Patients over 70 yrs who are selected for inclusion in phase III trials derive similar benefits from irinotecan-containing chemotherapy, and with similar risks of toxicity, compared with younger patients.

[Table: see text]

[Table: see text]
Magnitude of progression-free survival (PFS) improvement and treatment (Tx) duration in metastatic colorectal cancer (mCRC) for bevacizumab (BV) in combination with oxaliplatin-containing regimens: An analysis of two phase III studies
Authors: Giantonio B. J. , Meropol N. J. , Catalano P. J. , Ng V. , Oliver R. , Sirzen F. , Leonard S. , Cassidy J. , Benson A. B.
Published: March 2020

4073

Background: In trials of BV with FOLFOX (fluorouracil, leucovorin, oxaliplatin) for mCRC, variability in the magnitude of PFS improvement has been reported [HR=0.61 in E3200 vs HR= 0.83 (FOLFOX or CAPOX (capecitabine and oxaliplatin)) in NO16966]. We propose that differences in rates of treatment discontinuation (D/C) for adverse events (AE) between these studies may have resulted in differences in the observed benefits associated with BV. We explored Tx duration (proportion of patients on Tx) and Tx D/C data at median PFS for the BV containing arms of each study. Methods: ECOG study E3200 randomized previously treated patients with mCRC to FOLFOX ± BV (10 mg/kg). NO16966 employed a 2x2 design that randomized previously untreated patients with mCRC to CAPOX vs FOLFOX and to BV (5 mg/kg) or placebo. In both trials, study Tx was defined as any component of the prescribed regimen. PFS was estimated from Kaplan-Meier curves, and hazard ratios (HR) for PFS were estimated by Cox regression. Results: Median PFS for the BV containing arm of the study: 30 weeks for E3200; 42 weeks for NO16966 Conclusion: These data suggest possible differences between the two studies in Tx duration and Tx D/C patterns with a greater proportion of patients on NO16966 discontinuing Tx for any AE. Duration of study Tx might have affected both the incidence of AEs and the magnitude of PFS benefit observed for the addition of bevacizumab to oxaliplatin-based chemotherapy in these studies. Attention to Tx duration and Non-PD Tx D/C in future clinical trials will be important when considering PFS as a primary efficacy endpoint.

[Table: see text]

No significant financial relationships to disclose.
Cost comparison of XELOX compared to FOLFOX4 with or without bevacizumab (bev) in metastatic colorectal cancer
Authors: Garrison L. , Cassidy J. , Saleh M. , Lee F. , Mena R. , Fuloria J. , Chang V. , Ervin T. , Stella P. , Saltz L.
Published: March 2020

4074

Background: A recent randomized 2x2 phase III trial compared oral capecitabine + IV oxaliplatin (XELOX); IV 5FU/LV/oxaliplatin (FOLFOX4), XELOX+bev, and FOLFOX4+bev. FOLFOX4 was the regulatory control. XELOX was non-inferior to FOLFOX4 for progression-free survival, and bev-containing regimens were superior to comparison arms. This economic analysis compared expected costs in XELOX vs. FOLFOX4 arms in a US setting from a payer and societal perspective. Methods: Direct medical and indirect cost estimates (for patient time and travel) were compared. Resource use and patient time were estimated based on trial data and protocols. Data collected during the trial and used in the analysis were as follows: no. of visits / duration of drug administration, central venous access management, treatment of adverse events (AE), including hospital days for treatment-related AEs and total hours of ambulatory encounters. Unit costs were based on government fee schedules (i.e. Medicare reimbursements) and other published sources. Results: Total direct medical cost estimates were similar for bi-weekly FOLFOX4 and 3-weekly XELOX: $45,800 vs. $44,500. XELOX had higher drug costs while FOLFOX had higher drug administration costs, with about 15 more visits. Costs for hospitalization and ambulatory encounters were slightly lower for FOLFOX4; other medications and venous access were slightly higher for FOLFOX4. Similar patterns held for FOLFOX4+bev vs. XELOX+bev (total direct medical cost estimates $76,100 vs. $79,200). Indirect time cost estimates were lower with XELOX due to fewer cycles and visits: estimated savings range from $1000-$5000 depending on assumptions used. Conclusion: XELOX is estimated to have similar total direct medical costs and lower indirect costs compared with FOLFOX4.

[Table: see text]

No significant financial relationships to disclose.
Waterfall plots provide detailed information on magnitude of response to conventional chemotherapy in advanced colorectal cancer (ACRC) - lessons learned from N9741
Authors: Campbell M. E. , Grothey A. , Sargent D. J. , Goldberg R. M.
Published: March 2020

4080

Background: Waterfall plots have been used to capture the anti-tumor efficacy of both biologic agents (Ratain JCO 2006), which mainly exhibit a cytostatic effect, but also of chemotherapeutic agents. We are not aware of an application to therapeutic studies in CRC. We conducted waterfall plot analyses on the data of N9741 which compared IFL, FOLFOX4, and IROX as first-line therapy in ACRC (Goldberg JCO 2004). Methods: 634 (IFL 215, FOLFOX 215, IROX 204) of the 795 pts presented in the published analysis had measurable disease, and are included. The percentage change in tumor measurements from baseline to 12 wks was calculated, allowing for a time window of assessment from 6 to 20 wks for those without a 12 wk measurement. Pts with progression before the 12 wk assessment were assigned a 100% increase. The average reduction in tumor burden (ARTB) was calculated as difference in waterfall AUC divided by the number of pts. ARTB captures the average percentage reduction in tumor measurements at 12 wks for a patient entering the trial. Results: Waterfall plot analysis demonstrated some tumor growth at 12 wks in 23.7% (IFL), 15.8% (FOLFOX), and 26.9% (IROX) of pts. In contrast, tumor shrinkage was observed in 67.9% (IFL), 71.6% (FOLFOX), and 61.4% (IROX) of pts. Total differential AUC was -34.4 (IFL), -61.6 (FOLFOX), and -30.4 (IROX) resulting in an ARTB of 16.0% (95% Confidence Interval (CI) (23.7%, 8.2%)) for IFL, 28.7% (35.1%, 22.2%) for FOLFOX, and 14.9% (22.5%, 7.3%) for IROX. Conclusions: Waterfall plot analyses are feasible in this and likely other CRC trials using conventional chemotherapy. Our analysis confirms the published results of N9741, but suggests a larger degree of benefit for individuals based on anti-tumor activity than captured by conventional response analysis. Waterfall plots provide a potentially useful new efficacy metric, the average reduction of tumor burden per pt, which should be validated in future trials.

No significant financial relationships to disclose.
Safety and pharmacokinetics (PK) of AMG 706 with panitumumab plus FOLFIRI or FOLFOX for the treatment of patients (pts) with metastatic colorectal cancer (mCRC)
Authors: Schwartzberg L. S. , Hurwitz H. , Stephenson J. , Kotasek D. , Goldstein D. , Tebbutt N. , McGreivy J. , Sun Y. , Yang L. , Burris H.
Published: March 2020

4081

Background: AMG 706 is an oral, investigational multikinase (MKI) inhibitor with antiangiogenic and direct antitumor activity, selectively targeting VEGF, PDGF and Kit receptors. Methods: This is an ongoing phase 1b, open-label, dose-finding study of AMG 706 with panitumumab plus FOLFIRI or FOLFOX in pts with mCRC. Objectives are to establish safety, PK, and the maximum tolerated dose of AMG 706 with this regimen. Pts =18 yrs with mCRC, ECOG 0–1, =1 prior chemotherapy for advanced disease and no prior oral VEGFr MKIs or anti-EGFR therapy, received either FOLFIRI or FOLFOX (based on prior therapy) plus panitumumab (6mg/kg IV day 1 of each 2-wk cycle), and escalating doses of AMG 706 (50, 75, 125mg QD; 75mg BID) given continuously from day 3 of cycle 1. Assessments included dose-limiting toxicities (DLT) during the first 2 cycles and tumor response (every 6–8 wks from wk 6). Results: As of Nov 2006, 45 pts were enrolled and received at least 1 dose of AMG 706 (FOLFIRI/FOLFOX n=33/12); 64% had prior chemotherapy. There were 6 DLTs: FOLFIRI n=4, all grade 3 (diarrhea n=2: 50mg QD, 75mg BID; deep vein thrombosis n=1: 75mg QD; high GI output n=1: 75mg BID); FOLFOX n=2 (all fatigue, grade 3: 50mg QD). Treatment-related adverse events (AE) occurring in =10% of pts included: any AE, FOLFIRI/FOLFOX 88/92% of pts (grade 3, 21/58%); fatigue 55/58% (12/33%), anorexia 24/50% (0/0%), diarrhea 24/33% (0/8%), epistaxis 27/0% (0/0%) and hypertension 15/8% (0/0%). There were no grade 4/5 AEs. 2 cases of cholecystitis (grade 3, n=1) occurred. Preliminary data showed that AMG 706 PK at 50mg QD (FOLFOX) and 50–125mg QD (FOLFIRI) was comparable to data from monotherapy studies at the same dose levels. AMG 706 did not markedly alter the PK profiles of irinotecan or its metabolites. Objective tumor response per RECIST is shown in the table . Conclusions: In this study of pts with mCRC, AMG 706 was tolerable when combined with panitumumab and FOLFIRI or FOLFOX, with little effect on AMG 706 PK.

[Table: see text]

No significant financial relationships to disclose.
Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: an open-label, multicenter Phase I study
Authors: Saunders M. , Van Cutsem E. , Wilson R. , Peeters M. , Smith R. , Godwood A. , Oliver S.
Published: March 2020

4085

Background: Vandetanib (ZD6474) is a once-daily oral agent in Phase III development that selectively targets key signaling pathways in cancer by inhibiting VEGF, EGF and RET receptor tyrosine kinases. Methods: Patients with metastatic colorectal adenocarcinoma who were eligible for 1st- or 2nd-line chemotherapy received once-daily oral doses of vandetanib (100 mg) in combination with standard 14-day treatment cycles of FOLFIRI (irinotecan 180 mg/m2 1.5-hr and leucovorin 400 mg/m2 2-hr i.v. infusions, followed by 5-fluorouracil [5-FU] 400 mg/mg2 i.v. bolus and 5-FU 2400 mg/m2 46–48-hr i.v. infusion). If <2 of 6 evaluable patients (i.e., having completed 6 weeks of treatment) experienced a vandetanib- related dose-limiting toxicity (DLT), an additional cohort received vandetanib 300 mg + FOLFIRI. The primary objective of the study was to establish the safety and tolerability of vandetanib + FOLFIRI. Secondary objectives included an assessment of any pharmacokinetic (PK) interaction between vandetanib, irinotecan (SN-38) and 5-FU, and preliminary evaluation of efficacy (RECIST). Results: Twenty- one patients (12 male/9 female; mean age 53 years, range 33–72) received vandetanib 100 mg (n=11) or 300 mg (n=10) + FOLFIRI. Combination therapy was well tolerated at both vandetanib dose levels. There were no DLTs in the vandetanib 100 mg cohort, with one DLT of hypertension (CTC grade 3) with QTc prolongation in the 300 mg cohort. The most common adverse events (AEs; all grade 1/2) were diarrhea (n=20), nausea (n=12), fatigue (n=10) and alopecia (n=9); AEs =grade 3 reported in more than one patient were neutropenia (n=4, all grade 3), hypertension (n=3, all grade 3), catheter-related complication (n=2, both grade 3) and pulmonary embolism (n=2, both grade 4). There was no apparent PK interaction between vandetanib and irintotecan (SN-38) or 5-FU. Best overall responses in the 14 patients evaluable for efficacy were partial response (n=2), stable disease =8 weeks (n=9), and progressive disease (n=3). Conclusions: In patients with advanced colorectal adenocarcinoma, combining once-daily vandetanib (100 or 300 mg) with a standard FOLFIRI regimen was generally well tolerated. ZACTIMA is a trademark of the AstraZeneca group of companies.

No significant financial relationships to disclose.
A phase I study of bortezomib in combination with 5FU/LV plus oxaliplatin in patients (pts) with advanced colorectal cancer (CRC): EORTC 16029
Authors: Lacombe D. A. , Caponigro F. , Anthoney A. , Bauer J. , Govaerts A. , Milano A. , Marréaud S. , Twelves C.
Published: March 2020

4090

Background: Bortezomib is a potent and reversible inhibitor of the ubiquitin-mediated proteasome pathway, whose inhibition results in the stabilization of p53, p21Cip1, p27Kip1, Bax, in cell-cycle dysregulation and, finally, apoptosis. A phase I study of the combination of 5FU/LV and bortezomib has shown a significant stable disease rate in advanced CRC (Iqbal, ASCO 2004). Methods: In this phase I study bortezomib was given as an IV push over 3 to 5 seconds on days 1, 8 and 15 in combination with standard FOLFOX-4 every 28 days in chemo-naïve pts with advanced CRC. Bortezomib starting dose level was 1.3 mg/m2. A 3+3 study design was utilized at predefined dose levels (DL). Dose-limiting-toxicity (DLT) was assessed during cycle 1. Exploratory pharmacogenetics research was conducted. Results: 15 pts were treated and 46 cycles given. At DL2 (1.6 mg/m2), 2/4 pts experienced a DLT: G3 febrile neutropenia causing treatment delay and bortezomib dose reduction in 1pt and one bortezomib dose skipped due to persistent G2 peripheral neuropathy and myalgia in 1pt. At DL1 (1.3 mg/m2), 2/6 pts had a DLT. Both pts experienced a G3 neutropenia on day 15, which prevented treatment from being given as scheduled. DL-1 (1 mg/m2) was therefore investigated and no DLT was observed among 5 pts. The most frequently reported toxicities in cycle 1 were γGT (64%), nausea, fatigue and sensory neuropathy (53%), pain (33%), diarrhea and fever (27%), vomiting (20%), anorexia, dyspnea and mucositis (13%) and neutropenia 29% (G2,3). 12 pts are currently evaluable for response; 6 had a partial response, 3 stable disease and 3 disease progression. Conclusion: The toxicity profile of this combination is predictable and early evidence of clinical activity has been observed. The recommended bortezomib dose for further investigation within this regimen is 1 mg/m2.

No significant financial relationships to disclose.
Phenotypic and genotypic characteristics of epidermal growth factor receptor (EGFR) in colorectal cancer patients
Authors: Milano G. A. , Etienne-Grimaldi M. C. , Francoual M. , Benchimol D. , Chazal M. , Letoublon C. , André T. , Gilly N. , Delpero J. , Formento J. L.
Published: March 2020

4110

Background: Colorectal tumors express EGFR and are responsive to anti-EGFR therapies. However, there is no tumoral predictive factor for anti-EGFR therapy in colorectal cancer and EGFR gene copy number is currently a good candidate. The aim of this study was to examine relationships between EGFR germinal polymorphisms, EGFR gene copy number and EGFR expression. Methods: Eighty primary colorectal tumors were analyzed along with 39 normal mucosas. Tumor staging was : 4 stage 0, 13 stage I, 22 stage II, 23 stage III and 18 stage IV. EGFR -216G>T and -191C>A genotypes were analyzed by PCR-RFLP, CA-repeats polymorphism in intron 1 by fluorescent genotyping and gene copy number was measured by PCR amplification. EGFR expression was quantified with the reference Scatchard binding assay giving high- and low-affinity sites along with Kd values (Francoual M et al. Ann Oncol 17, 2006). Results: The number of CA- repeats varied from 14 to 21. Considered genotypes were superimposable between tumoral and normal tissues. A linkage disequilibrium was noted between -216G>T and -191C>A genotypes (p = 0.011). CA-repeats polymorphism and -216G>T genotype were not independent (p = 0.002). No relationship was observed between any of the analyzed EGFR genotypes and EGFR expression. EGFR expression was not related to gene amplification. EGFR gene amplification in tumor and normal tissue varied over a 4.7- and 2.9-fold range, respectively, and were not correlated. The mean value of the tumor/normal mucosa amplification ratio was 1.16 (range 0.55–2.68) and 14% of patients exhibited lower amplification in the tumor relative to the normal mucosa (ratio < 0.75). The mean ratio of high-affinity sites between tumor and normal mucosa was 1.20 (range 0.03–13.33). Conclusions: In colorectal tumors, neither EGFR gene amplification nor EGFR germinal gene polymorphisms influenced EGFR expression quantified with a specific ligand-binding assay.

No significant financial relationships to disclose.
Identification of prognostically-relevant signature genes differentially expressed between primary colorectal carcinoma and hepatic metastasis
Authors: Lin A. Y. , Chua M. , Choi Y. L. , Yeh W. , Kim Y. H. , Azzi R. , So S. K. , Pollack J. R.
Published: March 2020

4116

Background: Colorectal cancer (CRC) is the third most common cancer in the US. Hepatic metastasis (HM), the most common distant metastasis from CRC and occurring in about 60% of CRC patients during the course of their treatment, is a significant clinical problem. Although several clinical prognostic factors for HM from CRC have been identified, little is known about its molecular aspect. Methods: Under IRB approved protocols, we profiled gene expression in a set of 30 specimens from primary CRC and 31 unmatched specimens of HM from CRC. To survey the molecular variations between the two groups, we used cDNA microarrays containing ∼22,000 human genes, and identified differentially expressed genes using the Significance Analysis of Microarrays (SAM) method. To further characterize the clinical relevance of differentially expressed genes, we used immunohistochemistry (IHC) on tissue microarrays of tumor tissues obtained from an independent dataset of 154 patients with primary CRC. Results: Supervised analysis using SAM identified >200 genes with significantly higher expression in HM from CRC compared to primary CRC (and also compared to normal liver), with a false discovery rate (FDR) of <1%. IHC staining of two highly ranked differentially expressed signature genes, SPP1 (osteopontin) and LEF1 (lymphoid enhancer factor-1; a transcriptional mediator of Wnt pathway activation), showed protein overexpression (OE) in 60% and 44% of CRC cases, respectively; with a significant correlation with liver involvement in LEF1 expression (chi-square p=0.04) vs. SPP1 OE (p=0.14). Kaplan Meier analysis revealed significantly worsening survival in patients with LEF1 OE (p<0.01), but not SPP1 (p=0.14). Multivariate analysis identified several relevant prognostic markers: stage (p<0.001), nodal status (p <0.01) and LEF1 OE (p=0.02). Conclusions: Among signature genes differentially expressed between CRC and HM, we demonstrate LEF1, not SPP1, OE to be a poor prognostic factor for survival. Further studies are needed to characterize other signature genes, and to refine our understanding of the role of altered LEF1 expression in CRC tumorigenesis.

No significant financial relationships to disclose.
Use of microsatellite instability in non-hereditary advanced colorectal cancer to predict response to chemotherapy and overall survival: A study of the Dutch Colorectal Cancer Group (DCCG)
Authors: Koopman M. , Kortman G. A. , Mekenkamp L. , Ligtenberg M. J. , Hoogerbrugge N. , Mol L. , Antonini N. F. , Punt C. J. , van Krieken J. H.
Published: March 2020

4118

Background: Microsatellite instability (MSI) is present in 10–20% of patients (pts) with non-hereditary colorectal cancer (CRC) and is generally associated with improved overall survival. The effect of chemotherapy in such pts is uncertain, and most data are derived from early stage CRC. Therefore the outcome of treatment in relation to presence or absence of MSI was studied in pts with non- hereditary advanced CRC. Methods: Data were collected from previously untreated advanced CRC pts randomized between 1st line capecitabine (Cap), 2nd line irinotecan (Iri), and 3rd line Cap + oxaliplatin (CapOx) vs 1st line CapIri and 2nd line CapOx. Formalin-fixed, paraffin embedded blocks of primary tumors and normal tissue were collected and tissue microarrays were made. Expression of the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 was examined by immunohistochemistry. Additionally MSI analysis and hypermethylation of the MLH1-promoter were performed. Pts with a tumor showing MSI caused by hypermethylation of the MLH1-promoter were included to study the correlation between MSI status and response to 1st line treatment and overall survival. Results: MSI caused by hypermethylation of the MLH1-promoter was found in 14 (3%) of 512 eligible pts. In 461 evaluable pts, disease control (CR+PR+SD=4 months) in 12 pts with MSI was 58% [95% CI 28%- 85%] and in 449 without MSI 83% [95% CI 79%-86%, p= 0.03].The median OS in pts with MSI was 7 months [95% CI 4–17] and in pts without MSI 18 months [95% CI 16–19, log rank p=0.08]. Conclusions: MSI in advanced non-hereditary CRC is very rare, and predicts a significantly worse outcome in terms of response to chemotherapy with a trend towards a decreased OS.

No significant financial relationships to disclose.
Immunohistochemical test for MLH1 and MSH2 is an independent prognostic factor in sporadic colorectal cancer
Authors: Öhrling K. , Edler D. , Hallström M. , Karlberg M. , Ragnhammar P.
Published: March 2020

4126

Background: Microsatellite instability (MSI) is the hallmark of a defective DNA mismatch repair (MMR) and occurs in 10- 20 % of sporadic colorectal cancer (CRC). The loss of the MLH1 protein is the cause of MSI in almost all sporadic colorectal MSI tumours. The second most common protein to be lost is MSH2. There is evidence that MSI is a prognostic factor in CRC. The role of MSI status as a predictive factor of benefit from adjuvant 5-fluorouracil (5-FU) based chemotherapy is controversial. Methods: Monoclonal antibodies that recognize the mismatch repair protein by immunohistochemistry (IHC) have been commercially available for several years. Previous reports have found a strong correlation between MMR results obtained by immunohistochemical and genetic analysis. This study included 1006 CRC patients (488 Stage II and 518 Stage III) with a median follow-up of 5 years. The patients were included in Nordic trials randomised between surgery alone and surgery plus adjuvant 5-FU. The MMR status was retrospectively assessed on paraffin-embedded formalin-fixed samples using IHC. Results: One hundred fifty seven patients (15.6 %) showed a loss of MMR protein expression (139 MLH1 negative, 15 MSH2 negative and 3 MLH1+MSH2 negative) and were classified as MMR protein negative. A normal MMR protein expression was found in 851 patients who were defined as MMR protein positive. The median overall survival (OS) was 84 months (range 2–181 months). MMR protein expression was a significant prognostic marker in the entire study group where a better OS was seen among patients with MMR protein negative carcinomas compared to patients with MMR protein positive tumours (p=0.005). In multivariate analysis the MMR protein expression was significantly associated with OS, (hazard ratio for death, 0.67 [95 per cent confidence interval, 0.38 to 0.96]; p=0.008). However, in this study the MMR status did not predict response to 5-FU adjuvant chemotherapy. Conclusions: This study reveals that immunohistochemical analysis of MLH1 and MSH2 expression can yield important prognostic information but is not a predictive factor in sporadic CRC.

No significant financial relationships to disclose.
Bevacizumab 5mg/kg can be safely infused over 10 minutes
Authors: Reidy D. L. , Chung K. Y. , Timoney J. P. , Park V. , Hollywood E. , Sklarin N. , Muller R. , Saltz L.
Published: March 2020

4135

Background: Bevacizumab is a humanized monoclonal antibody that targets VEGF. Due to concerns for potential infusion- related hypersensitivity reactions (HSRs), initial phase I trials used an initial 90, 60, 30 minute infusion sequence. We sought to determine if the initial prolonged infusion was still necessary and in addition, if, on the basis of available clinical experience, an infusion time of less than 30 minutes could be safely used. Methods: We used computerized pharmacy records to identify all patients who received bevacizumab at our institution in the first two years of commercial availability (2/1/04- 6/30/06). Our institutional adverse drug reaction reporting program was utilized to identify any infusion reactions possibly related to bevacizumab and patient medical records were reviewed for confirmation Results: A total of 1,077 patients were treated with 10,606 doses of bevacizumab, and 765 of these patients received a 5 mg/kg dose (total of 8,494 doses). No HSRs occurred with the 90, 60, 30 minute infusion sequence in the first 202 patients. The standard infusion rate was then modified to 30 minutes for all bevacizumab doses. No HSRs were encountered. The infusion was again modified to a rate of 0.5 mg/kg/min. Of the 370 patients who received a total of 2,311 doses of bevacizumab at 5 mg/kg over 10 minutes, six (1.6 %) experienced events of minor clinical consequence that were felt to be possibly consistent with non-serious HSRs Conclusions: 90 and 60 minute initial infusion times are unnecessary. Use of a standard infusion rate of 0.5 mg/kg/min is safe, logical, justifiable, and is the current policy at our institution.

No significant financial relationships to disclose.