bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I trial of a bi-weekly combination of capecitabine/irinotecan (XELIRI) then capecitabine/irinotecan/oxaliplatin (XELIRINOX) in solid tumors
Authors: Assenat E. , Kramar A. , Poujol S. , Gestin-Boyer C. , Senesse P. , Samalin E. , Portales F. , Thezenas S. , Bleuse J. , Ychou M.
Published: August 2020

e15075

Background: Oral fluoropyrimidines, notably capecitabine, are increasingly replacing IV 5-FU/LV as the backbone of therapy for metastatic colorectal cancer. The bi-weekly combination of capecitabine/irinotecan warrants further examination. Methods: We conducted a phase I trial, in metastatic cancer patients treated for solid tumors, to determine the recommended dose of capecitabine administered orally bid from day 1 to 8 in combination with a bi-weekly fixed-dose of IV irinotecan 180 mg/m2 delivered on day 1 and 14 (FIRST STAGE: XELIRI); and + a bi-weekly fixed-dose of IV oxaliplatin (L-OHP) 85 mg/m2 delivered on day 1 and 14 (Second STAGE: XELIRINOX). Five increasing dose levels (DL1–5) of capecitabine were planned: 1000, 1250, 1500, 1750, and 2000 mg/m2 bid. A pharmacokinetic study of this association was performed. Results: In the first stage, a total of 17 patients were enrolled, with a median age of 60 (range 52–73) years. All patients had an ECOG PS of either 0 (59%), 1 (35%), or 2 (6%). Four patients experienced dose-limiting toxicity: 2 developed grade 4 neutropenia (at DL 1 and 4) and 2 others grade 4 febrile neutropenia (at DL3 and 4). One toxicity-related death occurred following febrile neutropenia (DL4). Maximal tolerated dose (MTD) was DL4, and the recommended dose regimen was bi-weekly irinotecan 180 mg/m2 combined with capecitabine 1500 mg/m2 bid (administered from days 1 to 8). In the second stage, the starting dose level of capecitabine in the bi- weekly association with irinotecan and L-OHP was defined as two dose levels below the MTD level reached in the first stage of the study (DL4 - 2 = DL2). Height patients were enrolled with a median age of 56 (35–75) and ECOG 0 for 62%, ECOG 1 for 38%. Chemotherapy is ongoing for three of them. Three patients experienced dose-limiting toxicity: 1 grade 4 neutropenia ( DL2), 1 grade 4 febrile neutropenia ( DL3) and 1 grade 4 pneumopathy ( DL3). The MTD of XELIRINOX was DL3, and the recommended dose regimen will be presented at the meeting. Conclusions: Bi-weekly combination of capecitabine/irinotecan/oxaliplatin (XELIRI / XELIRINOX) is feasible and could be tested in patients with metastatic colorectal cancer in combination with a targeted therapy.

[Table: see text]
Dose escalation of capecitabine in combination with biweekly cetuximab and hepatic arterial infusion (HAI) of oxaliplatin in patients with liver metastases of colorectal cancer: Preliminary clinical results
Authors: Viudez A. , Zárate R. , Garrido M. , Rodríguez J. , Chopitea A. , Fernández-Troconiz I. , Pardo F. , García-Foncillas J.
Published: August 2020

e15080

Background: To determine the maximum-tolerated dose (MTD) and the doses-limiting-toxicities (DLT) of concurrent capecitabine and cetuximab plus HAI of oxaliplatin (LOHP) in patients with hepatic metastases from colorectal cancer (CCR). Methods: Successive cohorts of 3–6 patients (pts) were treated with HAI LOHP (100 mg/m2), biweekly cetuximab (500 mg/m2) and escalation doses of capecitabine (825 mg/m2 BID d1–7:DL1; 1000 mg/m2 BID d1- 7:DL2; 1250 mg/m2 BID d1–7:DL3; 1500 mg/m2 BID d1–7:DL4) recycled every 14 days. Dose-limiting-toxicities (DLT) were defined as any grade 3–4 events, excepting grade 3–4 skin rash. LOHP and cetuximab PK/PD data were prospectively collected. Results: 19 patients (median age: 60; range: 34–74; 52.9% men, 47.1% females) and ECOG performance status of 1 (range 0–2) were treated at 4 DLs (dose level) as follows: DL: 3 pts, DL2: 6 pts, DL 3: 7 pts and DL 4: 3 pts. All pts were evaluable for toxicity. With a median of follow-up of 21.23 months, ORR was 78.9%, all of them partial response, with 4 pts SD (21.1%). Initially, only 4 pts were considered potentially resectable. Among the remaining 15 pts, 4 (20.6%) could be resected after treatment. Disease progression occurred in 15 pts (78.9%; 3 pts in liver only; 4 pts with extrahepatic metastases; 8 cases with both, hepatic and extrahepatic disease). The TTP was 9.6 months. OS has not been reached. 4 pts have died during the follow-up. Grade ¾ toxicities including Hand-foot Syndrome in 3 pts (1 pt at DL1, other at DL3 and other at DL4), diarrhoea in 3 pts ( one at DL3 and 2 at DL4), anaemia in 2 pts (DL2 and DL4), asthenia in 2 pts (DL2 and DL4) and mucositis in 1 pts (DL3). DLT and MTD were established in DL4 (two pts with diarrhoea grade IV with one of them with grade III HFS) Conclusions: Combination therapy with HAI LOHP plus concurrent capecitabine and cetuximab, can be safely administered to patients with liver metastases from CCR. The MTD and DLT was established in 1500 mg/m2 BID d1 to d7 of capecitabine. The Doses-recommended (DR) has not been obtained yet. oxaliplatin PK/PD is best defined through a bicompartimental model. Mature results of PK/PD analysis will be presented at 2009 ASCO Symposium.

No significant financial relationships to disclose.
Variation in enrollment of colorectal cancer patients in clinical trials
Authors: Joubert R. , Raeth U. , Moehler T.
Published: August 2020

e15094

Background: Correct estimation of patient enrollment is an important success factor for planning clinical studies including studies for metastatic colorectal cancer (CRC). Methods: We reviewed all CRC studies published in the Journal of Clinical Oncology and Annals of Oncology between 01/2007 and 10/01/2008. 43 studies were found and the following data were collected from 39 studies: indication, phase, number of sites, number of patients enrolled, mean patient age, recruitment time, sponsor (Industry, NIH, Organization, University), region, line of treatment and type of drug (6 categories). 4 studies were omitted from analysis as recruitment data were largely missing. Our analysis is based on a literature review as information from unpublished trials is unavailable. This implies some limitations regarding the data interpretation. Results: An average enrollment of 0.92 Patient/Site/Month (range 0.10–7.38) was observed for these trials. The highest recruitment efficacy with a median of 4.11 Pt/S/M (range 1.81–7.38) was found in 5 single institution phase II trials. For multi-center phase II and III studies the median enrollment was 1.82 and 0.32 Pt/S/M respectively, with significant higher recruitment in phase II studies. The highest enrollment rate was observed for studies located in Europe or in USA (0.77 and 2.21 Pt/S/M respectively, p=0.03). No correlation was seen with the mechanism of action (targeted drug vs. chemotherapy), sponsor (NIH vs. Industry vs. IIT), line of treatment (first line vs. 2nd and subsequent line). For phase I recruitment analysis we retrieved 2 studies that investigated novel agents in solid tumor patients including advanced or metastatic colorectal cancer patients with a median recruitment of 0.46 Pt/S/M. For phase Ib and I/II recruitment analysis 5 studies were found with a median recruitment of 0.78 Pt/S/M. Conclusions: Single institution phase II clinical trials on novel agents with high potential to change future treatment standard demonstrate almost a tenfold higher than average recruitment rate for multi-center trials (0.45 Pt/S/M). Despite some limitations in the interpretation of results our analysis provides important information to support estimation of patient recruitment in future clinical trials for colorectal cancer.

No significant financial relationships to disclose.
Chemotherapy-free interval following initial chemotherapy in patients with stage IV colorectal cancer
Authors: Melmed G. , Becerra C. , Saracino G. , Bowman E. , McCollum A. D.
Published: August 2020

e15096

Background: Patients with metastatic colorectal cancer (mCRC) have improved survival due to recent advances in systemic therapy. It remains unclear whether patients responding to initial chemotherapy can be offered a chemotherapy free interval (CFI) without compromising survival. An initial CFI is potentially beneficial from a quality of life and health care economics standpoint. Methods: We studied patients with mCRC treated at Baylor University Medical Center (Dallas, TX) who had a CFI after first-line chemotherapy. Eligible patients had unresectable mCRC and had stable or responding disease after initial chemotherapy. Records were analyzed to record patient characteristics, chemotherapy details, initial response, duration of CFI, progression free survival (PFS), and overall survival (OS). Results: We identified 29 eligible patients treated between 11/02 and 11/08. Analyses are based on data from 8/08. Patient characteristics included: median age 63 (range 34–81), M/F 16/13, ECOG PS 0 (9) or 1 (20), and median number of sites of disease 2 (range 1–7). Initial chemotherapy regimens included mFOLFOX6 with or without bevacizumab (10), FOLFIRI/bevacizumab (12), XELOX/bevacizumab (2), 5-fluorouracil/leucovorin/bevacizumab (3), and capecitabine with or without bevacizumab (2). With a median follow-up of 31.1 months, the median duration of CFI was 8.0 months (95% CI: 4.3–9.6). In addition, the median OS was 33.7 months (95% CI: 27.8 -56.3) and PFS was 15.0 months (95% CI: 9.4–21.4). Conclusions: In this selected group of patients with mCRC, we found a CFI of 8 months. The OS nearing 34 months and PFS of 15 months compares favorably with other studies of patients treated for mCRC. An initial CFI may reduce the medical and financial burden of therapy for patients with mCRC without compromising outcomes and warrants further study.

[Table: see text]
Oxaliplatin-based neoadjuvant chemoradiation for locally advanced rectal cancer
Authors: Kazmi S. S. , Azfar M. , Syed A. A. , Yusuf M. A.
Published: August 2020

e15102

Background: Preoperative chemoradiation improves local recurrence in patients with locally advanced rectal cancer1. The survival benefit of 5-FU based chemotherapy with radiation has been questioned2. Oxaliplatin based protocols have shown promise but the optimal regime remains to be defined3,4. We report our experience with addition of Oxaliplatin to neoadjuvant chemoradiation for rectal cancer. Methods: For this retrospective study, thirty-six consecutive patients referred for neoadjuvant chemoradiation for rectal cancer between May 2007 and March 2008 were identified. All patients had histologically proven adenocarcinoma, and were clinical stage T3/T4 or N+, except for one who was T2N0. Outcomes of interest were R0 resection rate and pathological complete response rate(pCR). Neoadjuvant treatment consisted of upto 4 cycles of CapOx(oxaliplatin 130 mg/m2, IV, D1, capecitabine (2,000 mg/m2/day, D1–14, q3 weeks), followed by capecitabine(1650mg/m2/day) with concurrent pelvic radiation(50.4Gy/28 fractions). Restaging to assess resectability was done at 4–6 weeks and definitive TME surgery was undertaken 6–8 weeks after end of chemoradiation Results: Thirty patients(oxaliplatin group) received at least 1 cycle of CapOx(range 1–8). Radical radiotherapy to 50.4Gy/28# was completed in 29/36 patients(81%). Surgical resection was undertaken in 24/36 patients(67%). Resection rate, R0 resection rate, pCR and local recurrence rate were 63%(19/30), 95%(18/19), 32%(6/19), and 5%(1/19) in the oxaliplatin group. In patients with low rectal cancer (0–5cm from anal verge), 16/26(62%) underwent resection. Sphincter sparing surgery was carried out in 7 patients, all of whom had received oxaliplatin, giving a sphincter sparing surgery rate of 64%(7/11) in the oxaliplatin group. Conclusions: Addition of oxaliplatin to neoadjuvant chemoradiation results in a significant number of patients achieving R0 resection, pCR and sphincter sparing surgery, compared to historical controls.

No significant financial relationships to disclose.
Prognostic factors for colorectal cancer patients with pulmonary metastases
Authors: Li W. , Zhang W. , Cai S. , Yin J. , Li J.
Published: August 2020

e15107

Background: Pulmonary is the second common metastastic site of CRC with a good survival after metastasectomy, however the general situation of pulmonary metastases from CRC has received little attention, especially for unresectable ones. The aim of this study was to determine factors that may influence survival and disease free interval from primary radical surgery to pulmonary metastases (DFI). Methods: From 01/2000 to 11/2008, a total of 206 pts with pulmonary metastases (colon72, rectal ca131, 3 unknown) were collected retrospectively and the clinical data were analyzed using Kaplan-Meier survival curves, univariate and multivariate analysis. Results: 128 pts (62.1%) had lung disease as the first metastatic site and 33 pts (26.7%) had synchronous liver involvement. Only 17 patients (8.3%) followed pulmonary metastatic resection, and others underwent palliative medical treatment including the chemotherapy and intervention. Median survival was 16.0 months (range 12.240–19.760) with a 18% 5-year survival. Of the totally 160 patients who had synchronous pulmonary metastases after radical primary tumor surgery, the mDFI was 20 months (range 16.738–23.262) months. Rectal cancer had a high chance (65%) for lung recurrence with longer DFI (21 vs 14 mo, P=0.02), but no difference of survival was shown compared to colon cancer. Factors that significantly predicted a poor prognosis on univariate analysis included vessel invasion (P=0.022) and high T stage (P=0.009), but neither of them was the independent prognostic factors after multivariate analysis. The factors influencing the DFI of metachronous pulmonary metastases included primary tumor site, pathological morphology, tumor infiltration stage and regional lymph node stage (P<0.05). There was a trend of better survival of patients receiving resection surgery after pulmonary metastases than receiving chemotherapy alone though no statistical significant was reached (mOS:34 vs 16 mo, P=0.125). But to patients who receiving metastatic site resection, chemotherapy after surgery improved the survival (P=0.042). Conclusions: No independent prognostic factors of survival had been found. The invasive tumor with high stage may have a shorter disease free interval of pulmonary metastases after primary surgery.

No significant financial relationships to disclose.
Downregulation of RIZ1 protein expression in left-sided versus right-sided primary colorectal carcinomas and their distant metastases and the association with NF-B activation
Authors: Torlakovic E. , Marginean E. C. , Torlakovic G. , Geyer R. , Neufeld H. , Decoteau J.
Published: August 2020

e15112

Background: Activation of NF- B leads to enhanced proliferation and the expression of anti-apoptotic proteins, which are cancer phenotypes. RIZ1 inactivation through various molecular events was linked to increased proliferation, migration induction and apoptosis inhibition in human cancer. RIZ1 frameshift mutations were recently reported to be confined to MSI-H colorectal tumors and proximal tumor origin, while its hypermethylation was not limited to MSI-H tumors. However, RIZ1 protein expression has not been evaluated in colorectal carcinoma. Methods: TMAs included 28 left-sided and 12 right-sided primary colorectal adenocarcinomas, their matched normal mucosa and their respective distant metastases. Left-sided tumors were compared to right-sided tumors for expression of RIZ1 protein and NF- B activation. RIZ1 immunostaining was scored semiquantitatively (0–3+). NF- B activation was determined by IHC detecting nuclear translocation of its p65 subunit in more than 30% tumor nuclei. Discrepant results were defined as score difference of 2. Results: RIZ1 was less expressed in tumors than in benign mucosa (p<0.0001, r=- 0.377, Chi-Square). The difference between primary vs. metastatic carcinoma was not significant. Low RIZ1 was associated with NF- B activation (p<0.0001, Linear-by-Linear). Left-sided primary tumors showed less RIZ1 protein expression than right-sided (p=0.03, Chi-Square). NF- B activation was more frequent in left-sided primary tumors and their respective metastases (35% in right vs. 67% in left; p=0.002, Chi-Square Test). RIZ1 expression and NF- B activation were almost identical in primary and their respective metastatic tumors with only 3 discrepant results for NF- B status and 2 discrepant results in RIZ1 expression. Conclusions: While RIZ1 downregulation in colorectal adenocarcinoma due to RIZ1 mutations appears to be associated with MSI-H and proximal origin, its protein expression appears to be downregulated more often in distal tumors. NF- B activation is strongly associated with lower RIZ1 protein expression in colorectal adenocarcinoma.

No significant financial relationships to disclose.
Phase II study of bevacizumab (B), camptosar (I), high-dose 24-hour continuous intravenous infusion of floxuridine (F) and leucovorin (L) in patients with previously untreated metastatic colon cancer. (B-IFL)
Authors: Ardalan B. , Feagans M. , Mezentsev D. , Jones C. , Subbarayan P. R. , Walker G. , Sapp M. , Stephenson K. , Ness J. , Franceschi D. , Livingstone A.
Published: August 2020

e15114

Background: In a previous study, IFL was used in patients (pt) with untreated metastatic colon cancer and a median overall survival (MOS) of 31 months (m). In the current study we added B to IFL to determine toxicity profiles (TP) and the response rate (RR) to the B-IFL regimen. The primary end-point is MOS Methods: Each cycle involved 6 weeks (wks) of treatment. The treatment cycle consisted of a 90 minute infusion of I (110 mg/m2), followed by a 24 hour infusion of F (120mg/kg) and L (500 mg/m2) on wks 1, 2, 4, 5. Pt received B (7.5mg/kg) over 90 minutes on wks 1 and 4 prior to IFL. No therapy was given on wks 3 and 6. Eligible pt received 2 cycles of B-IFL followed by CT scan. Quality of life data and thymidylate synthase expression in peripheral blood mononuclear cells was monitored Results: 22 pt with a median age of 57 (38–82), 11 males and 11 females were enrolled. Median KPS was 90% (50–100). 8 pt (36%) had bilobar liver disease and involvement of 1 other organ, 6 pt (27%) had bilobar liver disease with involvement of ≥ 2 other organs; 5 pt (23.5%) had bilobar liver disease; 2 pt (9%) had abdominal carcinomatosis; 1 pt (4.5 %) had involvement in one liver lobe. Grade (Gr) 4 toxicity: pulmonary embolus 1 pt (5%) incidental CT finding. Gr 3 occurred in 11 pt (50%); DVT, diarrhea (Drh) 3 pt (14%); fatigue (Ftg), infection, port site thrombosis (Pst), small bowel obstruction 2 pt (9%); wound dehiscence 1pt (5%); Gr 2 and 1: constipation; Drh; Ftg; nausea; neutropenia; Pst; alopecia; anorexia; mucositis. 17 pt remain alive with median follow up of 15 m (2–28). 5 pt have died due to progression of disease. The estimated median time to progression was 13 m with corresponding lower 95% confidence bound of 8.4 m. Kaplan-Meier estimate at 2 yr survival is 61% (95% CI 27–83%). RR in 21 pt was 67% (95% CI: 43–85%). Conclusions: B-IFL regimen has a manageable TP. RR and progression free interval were promising. Pt accrual is ongoing. Supported by Pfizer.

No significant financial relationships to disclose.
The relationship and optimal cutoff value between dual phase corrected whole body uptake ratio (CUR) and serum CEA level in recurrent/metastatic colorectal carcinoma: Dual phase whole body protocol using time of flight (TOF) imaging
Authors: Oh S. , Kim S. , Jun Suk K.
Published: August 2020

e15116

Background: We evaluate whether the corrected SUR has a lineal relationship with a serum CEA level, and to determine the cutoff level of SUV and CEA level in metastatic focus of recurrent colorectal carcinoma. Tumor to background contrast in whole body PET/CT at 1 hour and 2 hour The relationship and optimal cutoff value between change max SUV and serum CEA level in metastatic colorectal carcinoma: ROC analysis. Methods: 48 patients (M: F=32:16, mean age 56.1) who were previously operated for primary colorectal carcinoma enrolled for evaluating metastasis / recurrence from April 2007 to Feb 2008. An one hour and two hour whole body PET/CT (brain to foot) (Gemini TF PET/CT, Philips Medical Systems) was performed after injection of 370–555 MBq of F18 FDG. The serum CEA level (CEA) measured. The time interval between the PET/CT and the CEA 6.8 ± 3.1 days. Background (BG) correct uptake ratio (CUR)[CUR/BG]= maximum SUV of the ROI/ background value (mean SUV of the liver) calculated and then change of the CUR at 1 hour and CUR at 2 hour were calculated. Results: Among the 48 patients, recurrence was confirmed in 41patients, and the remaining 9 patients were disease free. A significant lineal correlation between change of the CUR at 1 hour and CUR at 2 hour and CEA was founded using ROC analysis (P<0.05). The optimal cutoff value of the change of the CUR at 1 hour and CUR at 2 hour and CEA were 71 % (sensitivity86.7, specificity 83.3, AUC 0.8780.047) and 9.44ng/ml (sensitivity 73.3, specificity 87.5, AUC 0.857±0.051) respectively. The difference of AUC between the change of the CUR at 1 hour and CUR at 2 hour and CEA was not significantly different (0.022±0.065, P = 0.739). Conclusions: The change of CUR of 70 % and the CEA level of 9.44 ng/ml was best cutoff value in detecting the recurrent/metastatic focus in colorectal carcinoma.

No significant financial relationships to disclose.
Effect of AbGn-7, a glycotope-specific monoclonal antibody, on apoptosis in colon cancer cells and tumor growth in xenograft models
Authors: Lin S. , Chiang E. , Tsai Y. , Lee S. , Kuo B. , Lin R.
Published: August 2020

e15118

Background: While clinical benefit against colorectal cancer has been observed with therapeutic monoclonal antibodies such as bevacizumab, cetuximab and panituzumab, the death rate of advanced colorectal cancer remains high that warrants further development of more potent therapeutics. Methods: A cell-based immunization approach was used to generate monoclonal antibodies against targets expressed on human colorectal cancer cells. A chimeric monoclonal antibody, AbGn-7, was selected and evaluated for the potential clinical use to treat colorectal cancer. Results: Expression of AbGn-7 antigen: Carbohydrate competition assay demonstrated that AbGn-7 recognizes a Lewis-A-like carbohydrate antigen (AbGn-7 antigen). Immunohistochemical studies showed that AbGn-7 antigen is expressed in colorectal cancer tissue. No significant binding could be detected in non-tumor tissues except in the epithelia of GI track. Effector function of AbGn-7: AbGn-7 triggered dose-dependent apoptosis in COLO 205 colon cancer cell. In addition, AbGn-7 elicited potent complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in a dose-dependent manner. Molecular mechanism of apoptosis induced by AbGn-7: Tunel assay, PARP cleavage assay as well as caspase inhibitor studies demonstrated that AbGn-7 induced apoptosis in COLO 205 colon cancer cells via a caspase-independent pathway. Xenograft study: AbGn-7 alone, or in combination with 5FU-Leucovorin, effectively inhibited the growth of COLO 205 xenograft in SCID mice and prolonged their survival. Conclusions: The results of the present study suggest that AbGn-7 is a potential candidate for effective treatment of colorectal cancer.

[Table: see text]
The clinical pathogensis significance associated with mutation of APC MCR in colorectal neoplasms
Authors: Lai R. , Feng L. , Liu L. , Xie L. , Wu X. , Zhang S. , Tang X. , Geng J. , Chen T.
Published: August 2020

e15119

Background: To explore the clinical pathogensis evalution of codon 1493,1367 and 1328 mutations in MCR (mutation cluster region) of exon 15 of APC (Adenomatous polyposis coli) gene in cases of colorectal neoplasm and the family history. Methods: The specimens from 21 colorectal adenoma specimens groups,16 colorectal carcinoma groups, 20 healthy germline groups with positive familial history and 8 healthy germline groups without familial history. MCR of APC gene were extracted and specificly amplified, then sequenced by sequencer, the codon mutations were analyzed between the 4 groups and various genotypes tested with Chi-square. Results: The codon mutations were three variations: 1493(ACG > ACA), 63/69(91.3%); 1367(CAG > TAG), 1/69(1.4%) and 1328(CAG>TAG), 5/69(7.2%). The allele mutations were checked out four genotypes such as 4478(G→A), 41/69(59.4%); 4478(G/A), 22/69(31.9%); 4096(C/T), 1/69 (1.4%) and 3979(C/T), 5/69(7.2%); but the significant groups status (P<0.05) were shown between the adenoma and nonfamily history group on the analysis of 4478(G→A) and (G/A), also the significant differences were tested between the with and without family history on the analysis of 4478(G→A). The significant differences (P<0.05) in pathogensis mutant phenotypes were involved between 4478(G→A) with 4478(G/A), 4096(C/T) and 3979(C/T), respectively; also showed between 4478(G/A) with 4096(C/T) and 3979(C/T); but not between 4096(C/T) and 3979(C/T) (P>0.05). Conclusions: In our data, the highest mutant frequency 4478(G→A) of 1493(ACG>ACA) presented to the significant phenotype of positive history and adenoma, but 4478 (G/A) were associated with colorectal adenocancer, which was discovered in the different effect to candidators despite the same synonymous mutation. In researches, APC MCR codon 1367 and 1328 genotyping were significantly presented in the colorectal cancergenetic phenotypes in somatic cells only.

No significant financial relationships to disclose.
Fixed dose rate (FDR) gemcitabine (G) and capecitabine (C) in patients with metastatic biliary tract cancer (BTC): Final results of phase II trial
Authors: Santini D. , Vincenzi B. , Vasile E. , Catalano V. , Virzì V. , Masi G. , Intagliata S. , Catalano G. , Falcone A. , Tonini G.
Published: August 2020

e15510

Background: The combination of fixed dose rate (FDR) gemcitabine (C) and capecitabine (G) has been demonstrated to be well tolerated in patients with advanced cancers. To determine the activity and safety of this combination in metastatic metastatic biliary tract cancer patients, a phase II trial was conducted. Methods: Patients with unresectable BTC who had pathologically confirmed adenocarcinoma, no prior chemotherapy, ECOG PS < 2 and measurable disease were enrolled. Treatment consisted of FDR G at 800 mg/m(2) infused in 80 minutes on days 1 and 8 every 21 days with C administered orally bid in equal doses (650 mg/m2 bid) for 14 days (28 doses). Results: Between Feb 2005 and Sept 2008, 30 pts were enrolled. Median age was 67 (45–86) with 14 males. 30 pts were evaluable for response and toxicity. A total of 219 cycles were administered (median, 8; range, 2–16). One patient achieved CR and 8 pts achieved PR giving an overall response rate of 30.0% in intention-to-treat population (95% CI, 19.2–42.6%). And 11 pts (36.6%) had stable disease. The median time to progression of all patients was 7.4 months (mo) (95% CI, 3.2–19.5). The median overall survival was 15.3 mo (95% CI, 4.6–27.9). Grade 3/4 neutropenia and thrombocytopenia were noted in 13.3% and 6.6% of the pts, respectively. Grade 2/3 non-hematologic toxicities were asthenia (50.0 % of pts), diarrhea (16.6%), stomatitis (23.3%) and hand-foot syndrome (6.6%). There was no treatment-related death. Gemcitabine was skipped at least once/reduced in 20%/15% of the patients, respectively. Capecitabine was skipped at least once/reduced in 20%/25% of the patients, respectively. Conclusions: The combination of FDR gemcitabine and capecitabine in this three week cycle is safe and seems to have advantages in activity over other regimens in advanced biliary cancer.

No significant financial relationships to disclose.
Efficacy and tolerance of chemotherapy with dacarbazine or temozolomide associated or not with 5-fluorouracil (5-FU) in endocrine carcinomas: A retrospective multicentric study from the Groupe des Tumeurs Endocrines (GTE)
Authors: Pecout S. , Baudin E. , Paoli A. , Maire F. , Terrebonne E. , Mitry E. , Pavel M. , Ruszniewski P. , Cadiot G. , Brixi-Benmansour H.
Published: August 2020

e15523

Background: Small studies have shown that therapy with dacarbazine and temozolomide give up to 34% tumoral response rates in endocrine carcinomas. The aim of this large retrospective multicentric study was to evaluate efficacy and tolerance of chemotherapy with dacarbazine or temozolomide associated or not with 5-FU in endocrine carcinomas. Methods: Patients were recruited in 6 French and 1 German centers. All patients with well (WDEC) or poorly-differentiated endocrine carcinoma (PDEC), whatever the primary, and who have been treated with dacarbazine or temozolomide associated or not with iv 5-FU or capecitabine, were included. Response rates were evaluated according to RECIST criteria by one of the investigator and toxicity according to National Cancer Institute Common criteria. Results: 86 patients were included : 36 women, median age 61.7 years (27.7 - 85.7), 67 WHO-PS 0–1. Primaries were : pancreas (n=34), digestive tract (n=23), thyroid (n=9), lung (n=6), other (n=6), unknown (n=8). 64 patients had WDEC and 11 PDEC (11 not determined). The number of previous systemic treatments (chemotherapy, chemoembolization, radionuclide therapy) was: 0 (n=16), 1 (n=25), 2 (n=25), 3 (n=14), 4 and more (n=6). Treatments received were : dacarbazine (n=3), temozolomide (n=19), dacarbazine + 5-FU (n=48), temozolomide + capecitabine (n=16). Evaluation was impossible in two patients. Tumoral response rates (partial and stabilization) were 61.2% in WDEC and 18.2% in PDEC. The best response rates in WDEC were : partial response (n=6; 9.7%), stabilization (n=32; 51.6%), progression (n=24; 38.7%) without significant differences between regimens and primary location. Response rates in WDEC were 88.9%, 71.4% and 64.7% in first, second and third line therapies, respectively. Median progression free survival in WDEC was 5.7 months (0.1–41.7). Grade 3–4 toxicities were hematologic (n=8), digestive (n=10), infection (n=3). Conclusions: Dacarbazine and temozolomide therapy showed high partial response and stabilization rates up to 3rd line therapy in well-differentiated endocrine carcinoma, with moderate toxicity. MGMT tumoral status is currently investigated.

No significant financial relationships to disclose.
Phase I dose escalation study of pomalidomide in combination with gemcitabine in patients (pts) with untreated metastatic carcinoma of the pancreas
Authors: Infante J. R. , Jones S. F. , Bendell J. , Spigel D. , Barton J. , Zubkus J. , Byrne C. , Griner P. , Weekes C. , Messersmith W. A. , Burris H. A.
Published: August 2020

e15539

Background: Pomalidomide is an IMiD immunomodulatory compound that is synergistic with gemcitabine in preclinical models. Pomalidomide has immuno-stimulatory properties and effects on the tumor microenvironment including inhibition of inflammatory mediators, stromal cell support, endothelial cell function, and angiogenesis. The primary objective is to determine the maximally tolerated dose (MTD) and evaluate the safety profile of pomalidomide in combination with gemcitabine. Methods: Eligibility included pts with untreated metastatic pancreatic cancer, adequate organ function, ECOG 0–1, and willingness to take prophylactic anticoagulation with aspirin, low-dose coumadin, or low molecular weight heparin. Gemcitabine 1,000 mg/m2 was given as a 30 min IV infusion on days 1, 8, and 15 of a 28 day cycle. Pomalidomide was given orally, daily for 21 days of a 28 day cycle. 3–6 pts were enrolled to increasing dose cohorts of pomalidomide (2, 3, 5, 7, and 10 mg/day) until dose-limiting toxicity (DLT) was seen in ≥2 of 6 pts. Results: As of 15-Dec-2008, 22 pts received ≥ 1 dose of pomalidomide. No DLT's were observed for 2–7 mg and 3 pts are currently on study in the 10 mg cohort. Neutropenia occurred in 12 pts, 8 were grade 3–4 events. There was 1 DLT of grade 3 neutropenic fever in the 10mg cohort. Thrombocytopenia events (9) were grade 1–2. Non- hematologic events were grade 1–2, the most common being rash (11), fatigue (10), nausea (6), and diarrhea (6). The rash is mild, erythematous, nonpruritic, of limited distribution, and reversible. 2 pts developed DVT (1 during cycle 2 and 1 cycle 4). Of the 16 pts evaluable for response, 1 pt has a confirmed PR and a CA 19–9 that normalized from 157 to <3. 4 additional pts have had minor radiographic responses between 10 and 29%. 10 of 16 pts have had a ≥ 60% decrease in CA19–9 from baseline. Only 2 pts came off study for early progression at the end of cycle 2. Conclusions: Dosing of pomalidomide daily for 21 days in combination with gemcitabine 1,000 mg/m2 given IV on day 1, 8, and 15 of a 28 day cycle was well tolerated and has promising clinical activity in patients with metastatic pancreatic cancer. The RP2D of pomalidomide in combination will be 7 or 10 mg.

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Phase II trial of second-line chemotherapy in metastatic pancreas cancer with the combination of oxaliplatin (Ox) and capecitabine (Cp)
Authors: Gasent Blesa J. , Alberola Candel V. , Giner Marco V. , Juan O. , Provencio Pulla M. , Llorca C. , Gravalos C.
Published: August 2020

e15561

Background: Gemcitabine (G) based chemotherapy is the standard treatment for patients (Pt) with pancreatic cancer. In spite of an active first line chemotherapy, second-line chemotherapy treatment is yet an unmet medical need. Ox and Cp have shown activity in different settings of the disease. We performed this prospective phase II trial to evaluate the efficacy and safety of the combination of Ox and Cp in second-line pancreatic cancer chemotherapy. Methods: From May 2007 to October 2008 15 Pt PS0–2 were included. All Pt had received G 1000 mg/sqm D1, D8 and D15 every 28 days as adjuvant (2 Pt) or first- line therapy (13 Pt). Gender: male/female 8/7, mean age was 64.1 years (47–82), in Pt with elevated CA-19.9 at diagnosis mean CA-19.9 was 337.6 (47–689). Mean time from diagnosis to initiation of second line chemotherapy was 219.3 days (121–457). Metastases (Mt): 11 liver Mt and 8 Pt liver and other Mt sites. Mean number of G cycles received was 6.8 (3–14). All Pt ended G treatment because of disease progression. After progression, all patients received second-line chemotherapy consisting of Ox 100 mg/sqm D1 and Cp 1000 mg/sqm bid D1-D14, every 21 days (XELOX). Results: Median number of cycles of XELOX administered was 4.5 (1–16). Mean CA-19.9 at start of second-line chemotherapy was 714.6 UI/ml (154–1536). Best radiological response was: complete response 1 Pt, stable disease 5 Pt, progressive disease 9 Pt. Median PFS was 124 days (21–480, censored data). Median OS was 301 days (censored data; 150–760). Median survival since the beginning of second line chemotherapy, was 163 days (censored data). In the responding-stable disease patients CA 19.9 level at the beginning of the chemotherapy changed from a median of 241 UI/ml (67–457) to 44.26 (9–86) at the last evaluation with a median decrease of 81.5 %(72–88%). Reported toxicity was the following: Diarrhea G1 in 1 Pt and G2 in 1 Pt, paresthesia G1 in 2 Pt, and hematological toxicity G1 in 1 Pt. Conclusions: As a second-line therapy after standard G treatment, XELOX offers clinical activity that warrants further investigation in this unmet medical need.

No significant financial relationships to disclose.
A retrospective analysis of tumor size (TS) as a continuous rather than discrete variable in advanced pancreatic cancer
Authors: Dhani N. C. , Tu D. , Parulekar W. , Seymour L. , Moore M. J.
Published: August 2020

e15565

Background: Objective “response rate” (RR) dichotomizes patients into categories of “response” (complete or partial) and “non-response”. This ignores a lot of data captured within the trial on tumor size changes, and may miss clinically important effects on tumor growth may occur in the absence of a response. Analyzing TS as a continuous variable (TS-CV) has been suggested as a more robust indicator of efficacy. Methods: Tumor size data from 2 randomized controlled trials in advanced pancreatic cancer conducted by NCIC.CTG were analyzed; NCIC.PA1 randomized patients to BAY12–9566 (MMPI) or Gemcitabine (Gem) and demonstrated a large and significant survival (OS) benefit for Gem (6.7 vs 3.4 months), NCIC.PA.3 randomized patients to Gem ± Erlotinib and showed a modest OS benefit for the combination (HR =0.81). In PA1, an early interim analysis (IA) using absence of progression as the primary measure did not halt accrual. Measures of TS at baseline and 8 wks were transformed and represented as a logarithm of the sum of the longest diameters. The difference in logarithms (d-LTS) from baseline to 8 weeks was calculated to indicate change in tumor size. Groups were compared using Wilcoxon rank-sum test. Results: In PA1, TS was significantly decreased in the Gem arm (mean d-LTS 0.087 on MMPI vs. -0.066 on Gem; p<0.0001), in keeping with the OS benefit (p<0.001). The decrease was also significant in the interim analysis cohort (p=0.007) and this result would, if used, have halted accrual earlier. In PA3, for all patients, decrease in TS was significantly larger for the combination arm (mean d- LTS -0.148 on combination vs. -0.114 on Gem; p=0.04), consistent with the OS benefit (p=0.038). Analysis on the 1st 130 patients yielded similar results (p=0.02) Conclusions: Tumor size changes may be a reasonable endpoint for screening efficacy trials in advanced pancreatic cancer. These results support further assessment of this alternate efficacy endpoint.

No significant financial relationships to disclose.
A phase II trial of oral fluoropyrimidine anticancer agent (S-1) with concurrent external-beam radiotherapy for locally advanced pancreatic cancer
Authors: Shinchi H. , Maemura K. , Mataki Y. , Kurahara H. , Natsugoe S. , Takao S.
Published: August 2020

e15570

Background: S-1 is a new oral fluoropyrimidine anticancer agent and has shown a good efficacy for pancreatic cancer. In the phase I trial, we evaluated the safety of S-1 combined with external-beam radiotherapy (EBRT) to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) in unresectable pancreatic cancer patients (H. Shinchi et al,, Br J Ca 2007;96:1353). The phase I trial determined the recommended of S-1 for the phase II chemoradiotherapy trial to be 80mg/m2/day given on days 1–21. This phase II trial was conducted to evaluate the efficacy and toxicity of EBRT combined with S-1 for locally advanced pancreatic cancer. Methods: Eligible patients had locally advanced and unresectable pancreatic cancer without distant metastases, ECOG PS 0–1, adequate organ and marrow function, and no prior anticancer therapy. EBRT was delivered in fractions of 1.25Gy twice daily, totaling 50Gy per 40 fractions for 4 weeks. S-1 was given orally at a dose of 80mg/m2/day twice a day on days 1–21. The primary end-point of this trial was objective tumor response and secondary end-points included toxicity and overall survival. Results: Forty patients were enrolled in this phase II trial. Of the 40 patients, 39 (97%) completed the scheduled course of chemoradiotherapy. The objective tumor responses by RECIST criteria included 13 PR (33%), 20 SD (50%) and 7 PD (17%). The median survival time was 14 months and 1-year survival rate was 67%. Although grade 3 rash and anorexia occurred in one patient each, no grade 4 toxicities were observed. Conclusions: Combination therapy of S-1 and radiation shows favorable efficacy for locally advanced pancreatic cancer and was well tolerated with no severe toxicities.

No significant financial relationships to disclose.
Comprehensive analysis of Excision repair complementation group 1, Glutathione S-transferase, Thymidylate synthase, and Uridine diphosphate glucuronosyltransferase 1A1 polymorphisms predictive for treatment outcome in patients with advanced gastric cancer treated with FOLFOX or FOLFIRI
Authors: Kim H. , Seo B. , Kim J. , Oh S. , Lee S. , Kim S. , Kwon H.
Published: August 2020

e15580

Background: Pharmacogenetic advances in cancer chemotherapy have the potential to predict clinical benefit to particular regimens. Oxaliplatin and irinotecan have shown to be effective in the treatment of gastric cancer. We assessed whether single nucleotide polymorphisms (SNPs) in ERCC1, GST, TS, and UGT1A1predicted overall survival in gastric cancer patients receiving FOLFOX and/or FOLFIRI chemotherapy. Methods: Total genomic DNA was extracted from whole blood of patient. The PCR- restriction fragment length polymorphism (RFLP) method was applied to detect the known variant sites of ERCC1, GST, TS, and UGT1A1. Results: Response rate of FOLFOX (N=75) was 24%. Grade 3–4 neutropenia and neurotoxicity were observed 34.7% and 16%, respectively. TTP and OS of 1st line administration of FOLFOX (N=35) was 3.1 months (95% CI, 0.1–6.1 months) and 13.9 months (95% CI, 12.2–15.6 months). Only the GSTM1 positive genotype showed a significantly better time to progression (P=0.023). But significant genotype variation of TS, GST and ERCC1,which assumed to affect to activity of oxaliplatin was not observed to RR, toxicity, and overall survival. Response rate of FOLFIRI (N=74) was 23%. Grade 3–4 neutropenia and diarrhea were observed 55.4% and 9.5%, respectively. TTP and OS of 1st line administration of FOLFIRI (N=33) was 4.9 months (95% CI, 3.5–6.4 months) and 19.0 months (95% CI, 8.5–29.5months). Low expression type (2R/2R, 2R/3C, and 3C/3C) of TS was associated with high incidence of grade ≥3 neutropenia. But significant genotype variation of UGT1A1,which assumed to affect to toxicity of irinotecan was not observed to RR, toxicity, and survival. Conclusions: In this study, GSTM1 positive genotype showed a significantly better time to progression in the advanced gastric cancer treated with FOLFOX. Low expression type (2R/2R, 2R/3C, and 3C/3C) of TS was associated with high incidence of grade ≥3 neutropenia in the advanced gastric cancer treated with FOLFIRI. Well designed prospective trial will be clearly identifying relations between chemotherapy and genetic variations.

No significant financial relationships to disclose.
Downsizing after palliative systemic chemotherapy with weekly high-dose 5-fluorouracil (5-FU) as a 24h-infusion and sodium folinic acid (AIO regimen) plus irinotecan in patients with metastatic adenocarcinomas of the stomach or the gastro-esophageal junction followed by secondary metastatic resection
Authors: Koucky K. , Boxberger F. , Albrecht H. , Maennlein G. , Wolff K. , Ostermeier N. , Schildberg C. , Golcher H. , Hohenberger W. , Hahn E. G. , Wein A.
Published: August 2020

e15585

Background: Due to the positive experience with combined AIO plus irinotecan (iri.) in a phase II trial (Möhler M et al, Br J Cancer 2005), this combination has been applied as first-line treatment in our department since 1999. Methods: 76 chemonaive patients (pts.) with histologically proven metastatic adenocarcinomas of the stomach or AEG tumours (tum.) (UICC IV), deemed to be non-resectable by the Interdisciplinary Tumour Board (ITB), were enrolled from 08/99 to 12/08. Chemotherapy (chemoth.) schedule: iri. (80 mg/m2 i.v. as 1h-infusion (inf.); d1, 8, 15, 22, 29, 36, qd 57) followed by 5-FU (2000 mg/m2 i.v.) with sodium folinic acid (500 mg/m2; d1, 8, 15, 22, 29, 36, qd 57) as 24h-inf. via port-a-cath. After downsizing the patients were again presented at the ITB. In 16 out of 76 pts. (21%) a secondary (sec.) metastatic resection (res.) with curative intent was taken into account. This collective is presented here evidencing the efficacy of this interdisciplinary procedure in palliative (pall.) treatment of gastric cancer. Results: Last date of evaluation: Dec/31/2008; median age: 58,7 years; men/women: n=12/4; res. of the primary tum. prior to pall. chemoth.: yes/no: n=2/14, ECOG 0/1: n=5/11; primary tum. localisation: AEG tum.: n=7; gastric carcinoma: n=9, elevated CEA yes/no: n=5/11, elevated CA19–9 yes/no: n=5/11. Number of metastatic localisations: 1/2/3: 69%/19%/12%, chemoth. application: total number:267; average value/patient:17 cycles altogether: 46, median cycles/pt.: 3, higher grade tox. (grade 3–4): anaemia 4%; diarrhea 2%, vomitus 2%, fever/infection 2%; response: PR 32%; SD 56 %; PD 6%; not evaluable 6 %; tum. control (PR, SD) 88 %; sec. res.: R0: 82 %; R1: 6 %, R2: 6 %; RX: 6%; gastrectomy with peritonectomy (R0): n=4 (25%), gastrectomy with lymph node dissection (D4,R0): n=6 (38%); HIPEC: n=4 (25%); 1-year survival:81%, 2-year survival: 44%, 3-year survival: 25%; deceased pts.: n=9 (56%), NED 19% (n=3). Conclusions: In our trial curative resections could be achieved in 82 % of the pts. During a follow-up of 20 months a NED status could be documented in 19% of the patients.

No significant financial relationships to disclose.
A retrospective review of squamous cell carcinoma of the anal canal in HIV-positive and HIV-negative patients
Authors: Hammad N. , Philip P. A. , Shields A. F. , Heilbrun L. K. , Venkatramanamoorthy R. , El-Rayes B. F.
Published: August 2020

e15586

Background: Human immunodeficiency virus (HIV) infected patients (pts) are at increased risk for squamous cell carcinoma of the anal canal (SCCAC) and the incidence of SCCAC has increased in the era of HAART (highly active antiretroviral therapy). The outcome of SCCAC in HIV (+) pts has not been evaluated in prospective trials and the published literature is limited to small retrospective case series. The aim of this study is to describe the outcome, tolerability, and overall survival (OS) in pts with and without HIV infection treated at Karmanos Cancer Institute, at Wayne State University from 1991 to 2007. Methods: We performed a retrospective chart review. We collected data regarding HIV status, demographics (age, gender, race), stage at diagnosis, treatment, response to treatment, toxicity, and survival. Results: Fifty pts with SCCAC were identified, of whom 18 were HIV (+) and 32 were HIV (−), 26% Caucasians, 68% African American, 56% males and 44% females. HIV (+) pts had significantly better stage (p = 0.011) and less frequent reduced chemotherapy dose (p = 0.001). There were no significant differences by HIV status in type of chemotherapy received, frequency of reduced radiotherapy dosage, use of diverting colostomy, or frequency of relapse. Diverting colostomy was required in 29% of HIV (+) pts and 18% of HIV (−) pts. The major toxicities observed in HIV (+) and (−) pts were diarrhea (36% vs. 64%), neutropenia (27% vs. 21%), and skin toxicity secondary to radiotherapy (XRT: 82% vs. 100%; p = 0.034). Median (OS) was 62.6 months for HIV (+) pts and 71.8 months for HIV (−) pts (p = 0.787). Conclusions: HIV (+) pts had better stage, received standard chemotherapy dose more often, and had more frequent XRT dermatitis than HIV (−) pts. Otherwise, there was no major difference in treatment toxicities. A higher proportion of HIV (+) pts required diverting colostomy. Survival is somewhat shorter among HIV (+) patients.

No significant financial relationships to disclose.