bluuebunny/crossref_metadata_2025 huggingface dataset:
A genetic UGT1A1 polymorphism oriented phase I study of irinotecan (CPT-11) and doxifluridine (5’-DFUR: An intermediate form of capecitabine for metastatic colorectal cancer (MCRC)
Authors: Hazama S. , Nagashima A. , Kondo H. , Shimizu R. , Araki A. , Yoshino S. , Okayama N. , Hinoda Y. , Oka M.
Published: March 2020

3602

Background: 5-Fluorouracil plus CPT-11 is one of the standard 1st-line therapies in patients (pts) with metastatic colorectal cancer (MCRC). Although it has been reported that individuals carrying the (TA) 7 allele in the TATAA promoter of UGT1A1 increased risk of severe toxic event occurrence after CPT-11 administration, there is no report about phase I study based on the polymorphism of UGT1A1. Here we report the results from a genetic UGT1A1 polymorphism oriented phase I study of CPT-11 and 5’-DFUR to determine the maximum tolerated dose (MTD) and the recommend doses (RD) for each UGT1A1 genotypes. Methods: Eligibility criteria were as follows; histologically proven CRC with unresectable metastatic lesions, PS 0–2, age<76, adequate organ functions, and written informed consent. CPT-11 was infused (level 1, 2, 3 and 4: 70, 100, 120, 150 mg/m2, respectively) biweekly and 5’-DFUR was administered orally (800 mg/body, <1.39 m2; 600 mg/body) on 5 consecutive days with 2 days’ rest for more than 12 weeks. DLT were determined as grade 3 hematological and non-hematological toxicities. Genotypes were determined by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from pts. Results: Eighteen pts with wild 6/6 allele and 9 pts with mutated 6/7 allele were registered. In pts with 6/6 allele, MTD was not observed up to level 4 (150 mg/m2). In pts with mutated 6/7 allele, on the other hand, MTD was observed at level 2 (100 mg/m2). We recommend doses of 70 mg/m2 of CPT-11 for pts with mutated 6/7 allele and 150 mg/m2 of CPT-11 for pts with wild 6/6 allele, respectively. Conclusions: The recommended phases II/III starting doses of biweekly CPT-11 administration are 150 mg/m2 for pts with wild 6/6 allele and 70 mg/m2 of CPT-11 for pts with mutated 6/7 allele, and 5’ -DFUR 800 mg/body on every 5 days per week. This combination therapy may be administered safely for all pts according to the TATAA promoter polymorphism of UGT1A1. The gene polymorphism should be taken into consideration to provide more precise information to guess the individual toxicities.

No significant financial relationships to disclose.
Multifactorial prospective study of tumoral factors related to disease-free survival (DFS) in colorectal cancer patients
Authors: Milano G. , Francoual M. , Bourgeon A. , Benchimol D. , Chazal M. , Laurent-Puig P. , André T. , Letoublon C. , Gilly F. N. , Etienne-Grimaldi M. C.
Published: March 2020

3604

Background: There is still a need to identify faithful biological prognostic factors in colorectal cancer, particularly in stage 2, so as to decide upon adjuvant treatment. We thus conducted a prospective multicentric multifactorial study to this end. Methods: Primary colorectal tumors (30 stage 1, 119 stage 2, 107 stage 3) were prospectively collected in 256 patients undergoing total tumor resection (152 men, 104 women ; mean age 69, extremes 29–90). Adjuvant 5FU-based chemotherapy was administered in 92 patients. Median follow-up was 54 months (53 patients developed metastasis or recurrence). Tumors were analyzed for thymidylate synthase (TS), thymidine phosphorylase and dihydropyrimidine dehydrogenase expression (RT-PCR), TS activity (radioenzymatic assay), EGFR level (ligand-binding assay), VEGF (Elisa), DNA content and cell cycle (flow cytometry), p53 mutations (exon 4 to 8), microsatellite instability (bat 25, bat 26), EGFR genotype (CA repeats in intron 1 and -216G>T), TS genotype in 3’ (6 bp deletion) and 5’ (28 bp repeats including the G>C mutation), and methylenetetrahydrofolate reductase genotype (677C>T and 1298A>C). Results: With the exception of tumor TS expression (p = 0.034, the higher the expression, the better the DFS), none of the analyzed parameters were linked to DFS. In multivariate Cox analysis, tumor staging (p = 0.001) and TS expression (p = 0.062) were the sole factors associated to DFS. Focus on tumoral EGFR revealed large inter-patient variability (from 1 to 510 fmol/mg prot) with a significant influence of tumor localisation (p = 0.009, higher in proximal colon) and differentiation status (p = 0.01, higher in poorly differentiated tumors). EGFR within the tumors was 30 % lower than in adjacent normal mucosa (p<0.001). The longer the intron 1 CA repeats, the higher the tumor EGFR (p = 0.044). EGFR -216G>T polymorphism was linked to intron 1 polymorphism, although -216G>T did not influence EGFR levels. Conclusions: The present results underline the major impact of TS expression as a prognostic factor and provide new insights in the knowledge of EGFR in colorectal cancer.

No significant financial relationships to disclose.
Potential role of ERBB-2 and cyclooxygenase-2 expression in human colon carcinomas
Authors: Antonacopoulou A. , Tsamandas A. , Skopa C. , Bonikos D. , Kalofonos H.
Published: March 2020

3608

Background: ERBB2 receptor tyrosine kinase and cyclooxygenase-2 (COX-2) represent promising molecular targets for cancer therapy and/or prevention. This study investigates the relation between ERBB2 and COX-2 expression in human colon carcinomas. Methods: Immunohistochemistry to detect membranous ERBB2 and cytoplasmic COX-2 expression was performed on 124 archived human primary colon carcinomas and matched normal tissues. Results were expressed as % positive cells. In addition, the mRNA levels of ERBB2 and COX-2 were evaluated in a subset of the colonic tissue samples (46 tumor, 7 normal) using real time RT-PCR (expression relative to a calibrator) Results: The results are displayed in the table . ERBB2 and COX-2 expression was higher in well-differentiated tumors (p<0.001 and p<0.05, respectively). However, both ERBB2 and COX-2 protein levels increased in a statistically significant way towards more advanced stages. Linear regression revealed a strong positive correlation between ERBB2 and COX-2 expression in neoplastic populations (r=0.83, p=0.000082 for protein; r=0.411, p=0.00404 for mRNA). Thus, ERBB2 and COX-2 may transcriptionally regulate each other in colon carcinomas. Conclusions: Overexpression of ERBB2 and COX-2 may represent an early dysfunctional event in human colon carcinogenesis regarding tumor differentiation. However, their expression is increased in advanced stages. These markers may constitute important targets for chemoprevention or adjunct therapy of well-differentiated colon carcinomas.

[Table: see text]

No significant financial relationships to disclose.
Do racial differences predict survival amongst VA patients with colon cancer?
Authors: Safa M. , Atiq M. , Komrokji R. , Nahleh Z. , Pancoast J. , Muhleman A. , Jazieh A. R.
Published: March 2020

3628

Background: Several reports suggested that African-American patients with colon cancer have poor survival. The outcome of colon cancer in patients treated within the VA system is not well studied. Patients treated in the VA usually share common features and socioeconomic class that will allow studying any potential effect of racial difference on outcome. Methods: We used the VA Central Cancer Registry (VACCR) to analyze VA patients with colon cancer diagnosed between 1995–2005. The reference date for data collection and reporting is January 1, 1995. Data are entered by tumor registrars at the VA medical centers. This site aggregates the data collected by the medical centers’ cancer registries. Data was analyzed using bio-statistical software SPSS. Results: There were a total of 14,816 cases with invasive adenocarcinoma.Majority of patients (98%) were males. Median age was 69 years among caucasian patients as compared to 67 years among African- American (p-value <0.005). There was no difference between the two groups with regards to sex, histological grade, histological subtype, use of chemotherapy or radiation therapy. However, African-Americans had less definitive surgery (84% vs. 86%) (p-value 0.003).The staging information was missing or unknown in 59% of the patients. In patients with known stage, no difference was observed.Median survival for caucasians was greater than African-Ameircans (42 months vs. 39 months)(p-value 0.009). Median survival for stage IV patients was not statistically significant between the two groups (8.8 months vs. 8.6 months);(p-value 0.53). Race was not statistically significant independent variable in Cox multiple regression analysis. Conclusions: In the VA system, African-American patients with colon cancer seem to have a trend towards inferior survival. However, race was not an independent prognostic variable. This slight difference could be due to other variables like definitive surgery.

No significant financial relationships to disclose.
Patterns of use and outcomes with irinotecan and oxaliplatin in the treatment of 5-fluorouracil (5-FU) refractory metastatic colorectal cancer: An Australian population based analysis
Authors: Damianovich D. , Adena M. , Tebbutt N.
Published: March 2020

3630

Background: Randomised clinical trials have established an important role for oxaliplatin (O) and irinotecan (I) in the management of advanced colorectal cancer (CRC). However, patients (pts) enrolled in clinical studies represent a restricted population and little is known about the use of O and I in the general population and the subsequent outcomes outside clinical studies. We used the Australian Health Insurance Commission (HIC) database to describe prescribing patterns of O and I and their impact on survival in all patients with 5-FU refractory CRC in Australia in 2002 and 2003. Methods: The Australian HIC database was searched to identify all patients with 5-FU refractory CRC who received initial treatment with either O or I in 2002 and 2003. Survival of patients was determined based on subsequent receipt of any other prescriptions for other medication identified in the HIC database. Results: 2999 patients received initial treatment with O or I in Australia in 2002 and 2003. 62% of pts were male and 23% and 2% were aged ≥70 years and ≥80 years respectively. There was a marked increase in initial treatment with O rather than I; 48% of pts received O first in 2002 versus 66% in 2003 (p<0.001). Overall 40–45% of pts received both O and I, however younger pts were more likely to receive both drugs (p<0.001). After 5-FU failure and treatment with O or I, estimated 6-month and 12-month survival was 0.67 (95% CI 0.66–0.69) and 0.42 (95% CI 0.40–0.44) respectively. Six and twelve month survival was superior for pts who received both O and I, however the sequence of O and I had no impact on survival. Survival of older pts (≥70 years) was inferior to younger pts no matter whether O or I was used as initial treatment. Conclusions: Analysis of the Australian HIC database provides a valuable means of assessing patterns of use and outcomes of new therapies. This type of analysis could also be used to evaluate other new agents.

[Table: see text]
A multicentre analysis of the long-term outcomes of patients with localized rectal cancer treated with chemotherapy and/or radiotherapy alone due to medical inoperability or patient refusal
Authors: Lim L. , Chao M. , Shapiro J. , Millar J. , Kipp D. , Rezo A. , Fong A. , Jones I. , McLaughlin S. , Gibbs P.
Published: March 2020

3633

Background: The outcome for patients with localized rectal cancer treated with chemoradiotherapy (CMT) or radiotherapy alone (RT) and no planned subsequent surgery is unknown. Insights can be provided by study of patients that do not undergo surgery due to excessive operative risk (medically inoperable) as a result of advanced age and/or co-morbidities, or patient refusal. Methods: A retrospective analysis at 6 Australian centers. Patients with recurrent rectal cancer, metastatic disease or primary tumors that were considered unresectable were excluded from the study. Results: We identified 48 patients treated between August 1998 and June 2005 meeting our criteria. There were 13 females and 35 males with a median age of 76 years (range 49 - 94). 24 patients (50%) were deemed medically inoperable and 24 patients refused surgery (the most common reasons were the desire to avoid a stoma or fear of surgery). Treatment was with standard long course radiation plus 5-FU (either bolus or continuous infusion) in 36 patients (75%) and 12 (25%) received RT alone. A complete clinical response was documented in 23 patients (48%) and a partial clinical response was documented in 14 patients (30%). At a median follow-up of 49 months, 18 patients (37.5%) have documented disease progression including 10 of 24 in the medically inoperable group and 8 of 24 in the refused surgery group. The median progression-free survival for all patients was 30+ months. 7 had local progression only, 7 had distant progression only and 4 patients had both local and distant progression. Of the 23 deceased patients, 16 (70%) died from progressive disease and 7 (30%) from non-cancer causes, including 4 from the refused surgery group. The median survival for all patients was 35 + months. Conclusions: In patients who are not suitable candidates for surgical resection due to advanced age and/or comorbidity CRT or RT alone is a safe alternative that results in significant progression-free and overall survival times, with many patients succumbing to co-morbidities rather than progressive disease. Many of these patients refusing surgery will have long periods of disease control after treatment with CRT or RT.

No significant financial relationships to disclose.
In vivo platform for translational drug development and biomarker discovery in pancreatic cancer
Authors: Hidalgo M. , Rubio-Viqueira B. , Weekes C. , Song D. , Shah P. , Messersmith W. , Messersmith W. , Altiok S. , Kulesza P. , Maitra A. , Jimeno A.
Published: March 2020

4000

While there are many new agents entering clinical development, there is very little data to prioritize which agents should be explored in pancreas cancer. Furthermore, often there is no information on biomarkers that may predict the activity of these drugs in pancreas cancer. In this project, we have generated a cohort of 30 pancreatic cancer xenografts by implanting in nude mice tumor materials from surgical specimens. Molecular studies show that a) these tumors maintain the genetic features of the originator cancer such as KRAS, p53 and DPC4 gene status; b) tumors represent the heterogeneity of pancreatic cancer well (there is not selection of any genotype in the xenograft ) and c) features do not changed over time. We have used this platform to explore the activity of a battery with a total of 10 new anticancer agents including inhibitors of MAPK, EGFR, mTOR, src kinase, Ras oncogene, mitosis regulators, angiogenesis, heat shock protein and hedgehog pathway inhibitors using a methodology similar to a two stage phase II clinical trial. All agents are tested against 10 xenografts. Those inactive are not explored anymore. Active agents are tested against the full set of tumors. Thus far we have shown that inhibitors of mTOR and MAPK have substantial activity in this model while Ras interacting agents and EGFR targeted drugs have no single agent activity. For active agents, we have characterized the tumors for potential strategies and biormarkers that may predict activity using both a target-focus approach as well as general profiling approach. Signaling inhibitors are more active in tumors with evidence of activation of the targeted pathway. In addition, ex vivo assays indicate that the ability to inhibit the targeted pathway is associated with agent activity. This information may help to prioritize agents for clinical development in pancreatic cancer.

[Table: see text]
RTOG 9704 a phase III study of adjuvant pre and post chemoradiation (CRT) 5-FU vs. gemcitabine (G) for resected pancreatic adenocarcinoma
Authors: Regine W. F. , Winter K. W. , Abrams R. , Safran H. , Hoffman J. P. , Konski A. , Benson A. B. , MacDonald J. S. , Willett C. G. , Rich T. A.
Published: March 2020

4007

Background: RTOG 9704 was designed to determine if the addition of G to postoperative adjuvant 5-FU CRT improved survival for patients(pts) with resected pancreatic adenocarcinoma. Methods: In this Intergroup trial involving RTOG, ECOG and SWOG, pts post gross total resection of pancreatic adenocarcinoma (path stage T1 - 4, N0 - 1, M0) were randomized to receive pre and post CRT 5-FU vs pre and post CRT G. 5-FU = continuous (CI) at 250 mg/m2/day. G = 1000 mg/m2 IV weekly. Both were given over 3 weeks pre and 12 weeks post - CRT. CRT = 50.4 Gy 1.8 Gy/fx/day with CI 5-FU, 250 mg/m2/day during RT for all pts. Pts were stratified by nodal status (uninvolved vs involved), primary tumor diameter ( < 3 cm vs ≥ 3 cm) and surgical margins (negative vs positive vs unknown). Survival was the primary endpoint with an original targeted accrual of 330 pts. Rapid enrollment allowed study amendment for increased targeted accrual to add survival among pts with lesions of the pancreatic head as a primary, prospective endpoint. Results: From 7/98 - 7/02, 538 pts were entered; 442 were eligible and analyzable. Major reasons for patient ineligibility were serum not sent for CA-19–9 analysis (n=22) and treatment starting > 8 weeks post surgery (n=19). Treatment arms were well balanced except for T-stage (T3/4 > for G, p=0.013). Pts with pancreatic head tumors(n=380) experienced significantly improved survival, with median and 3-year survival of 18.8 months and 31% respectively for the G arm vs. 16.7 months and 21% for the 5-FU arm (p=0.047; HR=0.79, CI=0.63–0.99). When analysis was inclusive of pts with body/tail tumors(n=442) no significant difference in survival was found (p=0.20). No significant difference in non-hematologic grade ≥ 3 toxicity was seen. The grade 4 hematologic toxicity rate was 14% in the G arm and 2% in the 5-FU arm (p<0.0001) without difference in febrile neutropenia/infection. The ability to complete chemotherapy (86%, 5-FU vs. 90%, G) and RT (85%, 5-FU vs. 88%, G) as per study was similar. Conclusions: The addition of G to postoperative adjuvant 5-FU CRT significantly improves survival in pts with pancreatic head adenocarcinoma.

No significant financial relationships to disclose.
Does endoscopy accurately predict response to chemoradiation in patients undergoing esophagectomy?
Authors: Sarkaria I. S. , Rizk N. , Bains M. , Flores R. , Park B. , Ison D. H. , Minsky B. D. , Rusch V. W.
Published: March 2020

4024

Background: Endoscopic biopsy after chemoradiation therapy (CRT) for esophageal cancer has been used to determine response to treatment. To test the validity of this methodology, we conducted a study to determine if endoscopic biopsy can accurately establish evidence of local pathologic complete response (pCR), defined as no residual local disease in the esophagus, in patients undergoing esophagectomy after CRT. Methods: We retrospectively queried a prospectively maintained database for patients seen at Memorial Sloan-Kettering Cancer Center from 1996 to the present who underwent, 1) CRT for esophageal cancer with the intent to proceed to esophagectomy post-treatment, and 2) post-CRT endoscopic biopsy. Data points included the pathology of the post-CRT endoscopy and resected surgical specimens, tumor histology, mean time from end of CRT to endoscopic biopsy, and mean time from endoscopic biopsy to surgery. Correlations were analyzed by the chi-square test and one way analysis of variance. Results: One-hundred thirty seven patients meeting our search criteria were identified. Ninety-percent of patients received cisplatin based chemotherapy and 5040 cGy of radiation. One-hundred four patients had a negative pathology on endoscopic biopsy. A negative pathology at endoscopic biopsy was a poor predictor of pCR (Positive Predictive Value = 37.5%), with 65% of these patients having residual local disease at esophagectomy. This result was not influenced by mean time from completion of CRT to endoscopy (p=0.5), or by mean time from endoscopy to surgery (p=0.47). A positive pathology at endoscopic biopsy was highly predictive of residual disease (p<0.001). When analyzed by histology, a negative endoscopic biopsy better predicted response for squamous cell carcinomas versus adenocarcinomas (p<0.001). Conclusions: Although improved for squamous cell cancers versus adenocarcinomas, a disease free endoscopic biopsy does not appear to be a useful predictor of a complete pathologic response after CRT. Neither the time to endoscopy after CRT, nor the time to surgery after endoscopy, influence this finding.

No significant financial relationships to disclose.
Phase III preliminary results of preoperative fluorouracil (F) and cisplatin (P) versus surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC 94012-FFCD 9703 trial
Authors: Ychou M. , Pignon J. P. , Lasser P. , Conroy T. , Bouché O. , Boige V. , Segol P. , Bedenne L. , Saint-Aubert B. , Rougier P.
Published: March 2020

4026

Background: The combination of 5FU in continuous infusion and cisplatin (FP) is one of the more active regimen in advanced ASLE. The trial was designed to evaluate the impact on survival of 2–3 cycles of preoperative FP in resectable ASLE. Methods: Patients (pts) with resectable adenocarcima of the stomach (S) without cardia involvement, cardia (C) or lower esophagus (LE), age ≤ 75 yrs, WHO performance status (PS) < 2 were eligible. Pts were centrally randomized between surgery alone (arm 1) and preoperative FP (arm 2). Chemotherapy (CT) included 2–3, cycles of P (100 mg/m2) and F (800 mg/m2 d1-d5 continuous infusion) every 28 days. Post-operative FP was recommended in arm 2 in case of response to FP preoperative or stable disease with pN+. The main endpoint was overall survival. Sample size was 250 (20 % vs 35 % 5-year rates, two-sided logrank test, α = 5 %, β = 20 %). Results: Between 1995 and 2003, 224 pts (arm 1 = 111 pts, arm 2 = 113 pts) were randomized from 28 centers with early stopping because of low accrual. Initial pts characteristics were equally balanced for age (61 yrs), gender (83 % male), PS (75 % WHO 0), tumor site (S = 25 %,C = 64 %, LE = 11 %). In arm 2, FP was given before surgery in 109 pts (98 pts > 2 cycles) and after surgery in 54 pts. Preoperative FP toxicity : 41 pts with at least one grade 3–4 toxicity (polynuclear, 22 pts, vomiting 10 pts), 9 treatment interruption, 1 toxic death. The number of patients with no surgery / no tumor resection / macroscopic incomplete resection (R2)/ microscopic incomplete resection (R1) by arm were 1/10/12/6 in arm 1 and 4/7/2/4 in arm 2. The number of postoperative deaths were 5 in each arm. Complete resection (R0) rate were 73 % in arm 1 versus 84 % in arm 2 (p=0.04). Among eligible RO, R1 patients (85 & 98 pts in arm 1 & 2): the numbers of pts with T0–2/N0/M+ were 27/17/6 and 41/32/1 en arm 1 & 2, the corresponding p-value were 0.16, 0.05 and 0.05 respectively; 3 pts with complete response in arm 2. For DFS, 160 events are observed so far with a median follow-up of 5 years. Conclusions: Preoperative chemotherapy was well tolerated and led to an increase in R0 resection rate, and a decrease in N+/M+ tumors. Disease-free survival will be presented at the meeting.

No significant financial relationships to disclose.
A phase II study of gemcitabine (GEM) given at fixed-dose rate (FDR) infusion, low-dose cisplatin (CDDP), and bevacizumab in metastatic pancreatic cancer (PanCa)
Authors: Ko A. H. , Dito E. , Schillinger B. , Hajnal R. , Venook A. P. , Bergsland E. K. , Allen J. , Rajpal S. , Tempero M. A.
Published: March 2020

4041

Background: The objectives of this study are to determine safety and efficacy in pts with metastatic PanCa treated with a novel combination consisting of FDR GEM, low-dose CDDP, and BEV. We present here interim results of the first 35 pts. Methods: Chemotherapy-naive pts with histologically confirmed PanCa and documented extrapancreatic metastases received the following: GEM 1000 mg/m2 at FDR infusion (10 mg/m2/min), CDDP 20 mg/m2, and BEV 10 mg/kg, all administered on dd 1 and 15 of a 28-dd cycle. Pts were monitored by CT scans every 2 cycles and monthly serum CA19–9 measurements. Results: 35 pts (15M,20F; median age 60 y.o. [range 39–85]; ECOG PS 0–1) have been enrolled betw 6/2004 and 1/2006 (med f/u, 288 dd; range, 50–542). 18 pts remain alive, with 7 still undergoing study rx. Pts received a median of 4 cycles of rx (range, 0.5–12). Reasons for study discontinuation: 15 pts had progressive dz (med # of cycles, 6; range, 0.5–10); 2 pts completed max # of allowable rx cycles (twelve); 2 pts came off rx 2 o to cumulative asthenia after plateau in response with 8 and 10 cycles of rx. Other major events inc. 2 bowel perforations, one associated with placement of a duodenal stent; 3 major GI bleeds; 1 malignant HTN; and 1 stroke-like sx. 3 pts d/c’ed rx 2o to prolonged rx delays (two persistent bowel obstruction, one grade 3 renal/liver function abnls). Addn grade 3/4 toxicities inc. 7 pts with LFT abnls (20%), 4 with HTN (11.4%), and 3 with thromboembolic events (8.6%). Hematologic toxicities were rare (grade 3/4 neutropenia 5.7%, plts 2.9%). 7 pts (20%) required dose reduction of GEM and 2 required d/c of CDDP. No rx-associated deaths were observed. 7 of 33 evaluable pts (21.2%) have had an unconfirmed response (1 CR, 6 PR) and 15 pts (45.5%) have had stable dz for > 2 cycles, inc. 2 with minor response, for an overall dz control rate of 66.7%. 13 of 21 pts (61.9%) with elev. baseline CA19–9 levels (≥2X ULN) have had ≥50% biomarker decline during rx. Updated efficacy data will be presented at the meeting. Conclusions: The toxicity profile observed in this trial is similar to that previously reported with other BEV-containing regimens. Rates of disease control and CA 19–9 response are encouraging, suggesting this combination is deserving of further study.

[Table: see text]
Use of lymph node ratio improves staging and selection criteria for adjuvant therapy of gastric cancer
Authors: Coburn N. G. , Swallow C. J. , Kiss A. , Law C.
Published: March 2020

4051

Background: Despite 1997 American Joint Commission on Cancer (AJCC) guidelines stipulating assessment of ≥15 lymph nodes (LN) for staging of gastric cancer, only one third of patients in the Surveillance, Epidemiology and End Results (SEER) database from 1998–2002 had ≥15 LN assessed (ASCO 2005 #4004), with resultant understaging and probable under-treatment. In series from Asia and Europe, Lymph Node Ratio (LNR), the ratio of positive to total LN assessed, has been shown to be more accurate for staging than number of positive LN. However, most of these excluded cases with <15 LN assessed. We examined the utility of LNR in a North American population. Methods: Using SEER data, we identified 9503 M0 resected gastric cancer cases from 1988–2002. LNR was categorized as 0%, 1–10%, 11–30%, 31–50% and >50%. For node negative cases (LNR = 0%, n = 3652), we stratified by number of LN assessed (A=1–4; B = 5–9; C = 10–14; D≥15). For each AJCC stage or LNR strata, the degree of understaging in patients with inadequate LN assessment was measured by survival difference on Kaplan-Meier curves. Cox proportional hazard ratio (HR) models determined the effect of stratifying node negative patients and the accuracy of LNR for prognostication. Results: 27% of patients had a LNR > 50%, a high proportion compared to Asian series. Fewer nodes assessed resulted in a higher likelihood of being node negative. In node negative cases, the HR of death increased for those with fewer LN assessed (vs. Group D, with 95% CI): A: HR=1.6 (1.5–1.8); B: HR = 1.3 (1.1–1.5); C: HR = 1.3 (1.1–1.5). Understaging was observed for patients with inadequate LN assessment when AJCC criteria were used (p < 0.0001); this effect significantly decreased by using LNR. LNR had superior prognostic accuracy in Cox models. Conclusions: This study examines LNR in the largest series of resected gastric cancer in the literature, and the only one in which the majority of cases were inadequately staged. LNR significantly decreases understaging and improves prognostic ability. Node negative patients, nearly one third of cases, should be risk stratified by number of LN assessed, and considered for adjuvant therapy on this basis. LNR should be used to stratify node positive patients in clinical trials, and to provide more accurate staging and prognostication.

No significant financial relationships to disclose.
Possible individualized therapy by early assessment of response during neoadjuvant radiochemotherapy in esophageal squamous cell carcinoma patients by 18-FDG-PET
Authors: Brücher B. L. , Wieder H. , Busch R. , Becker K. , Lordick F. , Molls M. , Siewert J. , Schwaiger M.
Published: March 2020

4060

Background: Response evaluation by positron emission tomography with the glucose analog [18F]-fluorodeoxyglucose (FDG-PET) has been used in patients with esophageal squamous cell carcinoma (ESCC) after neoadjuvant radiochemotherapy (RTx/CTx). This prospective study was undertaken to compare FDG-PET assessment of tumor response during RTx/CTx with histopathology in patients with ESCC, and to correlate the findings with survival. Methods: Patients (n=61) with histologically proven intrathoracic ESCC (cT3, cN0/+, cM0) underwent preoperative, simultaneous RTx/CTx followed by esophagectomy between 1996 and 2005. The patients underwent FDG-PET prior to and 2 weeks after the begin of RTx/CTx (20Gray). Histopathological response was quantified as the percentage of residual tumor cells. The threshold pre-therapy-to-during-therapy decrease in standardized uptake value by FDG-PET used to define metabolic responders (ΔSUVR) was -30%. Results: Receiving-operator-curve analysis (ROC) for determination of metabolic response revealed an area-under-curve (AUC) of 7140 (p=0.005) with a sensitivity of 76%, specificity (70%), a positive predictive value of 81% and a negative predictive value of 64% (p<0.0001). Responder by FDG-PET during the neoadjuvant treatment (p=0.016) as well as Histopathology (p<0.0001) showed substantially better survival compared to nonresponders. Conclusions: Changes in tumor metabolic activity by FDG-PET during neoadjuvant RTx/CTx allows an accurate determination of response due to the multimodal approach in patients with ESCC. This stratification may lead to a change of the neoadjuvant into a definitive therapy concept in nonresponders (individualized tumor therapy).

[Table: see text]
The predictive value of baseline fluoro-deoxy-glucose positron emission tomography (FDG-PET) standardized uptake value (SUV) for overall survival in patients (pts) with locally advanced esophageal and gastroesophageal junction (GEJ) cancer
Authors: Abou-Jawde R. M. , Rybicki L. , Bybel B. , Rice T. , Carroll M. , Mekhail T. , Videtic G. , Adelstein D. J.
Published: March 2020

4062

Background: The predictive value of FDG-PET SUV in pts with esophageal and GEJ cancer has been subject of recent interest. The heterogeneity of disease stages and treatments made interpretation of reported data difficult.We evaluated the value of baseline FDG-PET SUV in a homogeneous patient (pt) population treated in a uniform fashion. Methods: Retrospective analysis of 71 pts with stages II-IVa esophageal and GEJ cancer treated on 2 phase 2 trials at the Cleveland Clinic Foundation. Data was collected on baseline pt and tumor characteristics, baseline SUV uptake, and outcomes. Results: All pts were treated with preoperative concurrent fluorouracil/cisplatin chemoradiotherapy (CRT); 69 pts proceeded to esophagectomy and 58 pts received additional postoperative adjuvant CRT. Median pt age was 60 (range 33–75) years, 86% were male, 89% had adenocarcinoma, 35%, 41% and 24% had stage II, III and IVa disease respectively. Pts have been followed for a median of 14 (range 3–50) months. All pts underwent a baseline FDG-PET scan with a mean primary site SUV of 8.9 (range 0–28.2). Pathological response (complete or partial) was achieved after induction CRT in 54% and was more likely in those with a baseline primary site SUV ≥ 7.3 (OR: 3.95, 1.43–10.9, P=0.008). Recurrence developed in 33 pts (46.5%) with distant metastases identified in 31 of these 33. The Kaplan-Meier 2-year projected overall survival for all 71 pts is 58% with a median of 31 months. Mortality was less in pts with baseline SUV ≥ 5.0 (HR: 0.44, 0.20–0.94, P = 0.033). After adjusting for clinical stage at diagnosis, tumor location and histology, baseline SUV ≥ 5 was still predictive of improved survival in multivariate analysis (HR: 0.35, 0.15–0.85, P = 0.02). Conclusions: In this retrospective analysis, esophageal and GEJ cancer pts with a higher baseline primary site SUV were more likely to respond to induction CRT and had better overall survival. This observation suggests that the subset of pts with more metabolically active tumor may derive greater benefit from multimodality treatments that include CRT. A prospectively designed trial would be required to confirm this hypothesis.

No significant financial relationships to disclose.
Phase II cisplatin, irinotecan, cetuximab and concurrent radiation therapy followed by surgery for locally advanced esophageal cancer
Authors: Enzinger P. C. , Yock T. , Suh W. , Fidias P. , Mamon H. , Choi N. , Lehman N. , Lawrence C. , Lynch T. , Fuchs C.
Published: March 2020

4064

Background: Weekly irinotecan, cisplatin, and concurrent radiation therapy is a well-tolerated, active regimen in locally advanced esophageal cancer. (Ilson. JCO 2003) Cetuximab, an EGFR inhibitor, is a potent radiation sensitizer in head and neck cancer. (Bonner. Proc ASCO 2004) Methods: In this phase II trial, patients (pts) with T2–4N0–1M0–1A esophageal adenocarcinoma (A) or squamous cell carcinoma (S) receive 5040 cGy/28 fractions of radiation therapy (RT) and concurrent weekly cisplatin 30mg/m2 plus irinotecan 65 mg/m2 on weeks 1, 2, 4, and 5, followed by surgery 4–8 weeks after completion of RT. Additionally, pts receive weekly infusions of cetuximab 250 mg during RT, up to one week before surgery, and for 6 months following surgery. Results: Seventeen pts have been entered: male: female = 14:3, median age 54, ECOG PS 0:1 = 6:11, A:S = 17:0, stage IIA:IIB:III:IVA = 6:1:8:2, tumor location-esophagus-mid:lower:gastroesophageal junction = 1:4:12, >10% weight loss-yes:no = 8:9. Of 17 pts entered, 15 pts have proceeded to surgery, 1 pt died from Aspergillus infection resulting in respiratory failure and sepsis, and 1 pt is pending surgery. Of the 15 pts who underwent surgery, 2 (13%) had a complete pathologic response; pathologic stage for other pts: 0 = 1, I = 3, IIA = 3, IIB = 1, III = 4, IV = 1. Grade III/IV toxicity (17 pts) was: diarrhea 9 pts, neutropenia 9 pts, febrile neutropenia 5 pts, anorexia 5 pts, vomiting 4 pts, fatigue 3 pts, mucositis 1 pt. Chemotherapy dose attenuation was required for diarrhea in 5 pts, for neutropenia in 4 pts, and for folliculitis in 1 pt. One patient was removed from study during week 6 for prolonged diarrhea/ dehydration. Due to the 2-step design of the trial, accrual is on hold pending a 3rd required pathologic CR in the first 17 patients. Conclusions: Compared to other trials of irinotecan, cisplatin, radiation therapy, and surgery in similar groups of esophageal cancer patients, early results for this combination with cetuximab suggest a lower complete response rate and higher overall toxicity. Additional data will be available at ASCO. Supported by Bristol-Myers Squibb.

No significant financial relationships to disclose.
Phase II study evaluating trimodal therapy with cetuximab intensity modulated radiotherapy (IMRT) and gemcitabine for patients with locally advanced pancreatic cancer [ISRCTN56652283]
Authors: Krempien R. C. , Münter M. W. , Timke C. , Huber P. E. , Friess H. , Heeger S. , Herfarth K. K. , Abdollahi A. , Hartung G. , Buchler M. W. , Debus J.
Published: March 2020

4100

Background: The induction of EGFR targeting with cetuximab in radiation based therapy of solid tumors has yielded promising results. Thus, we initiated a prospective Phase II trial designed to analyze the feasibility and effectivity of trimodal therapy with gemcitabine-based chemoradiation and cetuximab in locally advanced inoperable pancreatic cancer. Methods: In this phase 2 study, pts with locally advanced pancreatic cancer without prior cytotoxic therapy were treated with radiotherapy (RT), gemcitabine weekly (300 mg/m2), and cetuximab weekly (loading dose 400 mg/m2 day 1, and concomitant with radiation day 8,15,22,29,36 250 mg/m2). RT was delivered by using an integrated IMRT boost concept (54 Gy GTV, 45 Gy CTV) over 5 weeks. RT was followed by gemcitabine (1000 mg/m2) weekly × 3 in 4 weeks. Response evaluation using computed tomography followed at week 12. All amenable patients were intended for surgical treatment between week 12–15. Results: 24 pts were enrolled until now. Preliminary results are presented on 20 pts with the following characteristics: pancreatic adenocarcinoma c2 T4 N1 20/20, median age = 63.5 (range 51–79); M/F = 13/7; ECOG PS 0/1/2 = 2/12/6; median days on treatment: 90 (range 70–100). Treatment-related toxicities were observed in 16 pts. Grade 3 toxicities included diarrhea (n = 4), fatigue (n = 2), nausea (n = 3), neutropenia (n = 6), thrombocytopenia (n = 2), and vomiting (n = 2). 18/20 pts developed some acneiforme rush during therapy. No omittance of cetuximab therapy was necessary. 1 patient died during RT due to tumor bleeding. Median follow-up at present is 6 month, median survival has not been reached. Partial remissions 8/20, stable disease 9/20, progressive disease 3/20. 12/20 patients were amenable for secondary potentially curative resection. 4 patients could be resected, while 3 patients were found to have abdominal metastatic spread. Conclusions: Early data from trimodal therapy in pancreatic adenocarcinoma with chemoradiation (IMRT), gemcitabine, and cetuximab indicate feasibility without increased toxicity profile. The local response appears to be very promising in pancreatic cancer, potentially allowing neoadjuvant treatment.

[Table: see text]
Combined modality therapy for pancreatic carcinoma: An Australian Pancreatic Cancer Group study of the addition of gemcitabine (G) to concurrent infusional 5-fluorouracil (CI 5FU) and 3D conformal radiotherapy (RT)—Final outcomes
Authors: Goldstein D. , Spry N. , Van Hazel G. , Underhill C. , Kotasek D. , Harvey J. , Links M. , Shapiro J. , Iacopetta B. , Australia Eli Lilly
Published: March 2020

4104

Background: This open-label Phase II study (B9E-AY-S168) examined whether CI 5FU plus 3D conformal planning RT is well tolerated and may be combined with G pre and post chemoradiotherapy in patients (pts) with pancreatic cancer (PC). Methods: Eligible pts were enrolled in two strata: (1) inoperable PC in head or body without metastases (LAD) or (2) resected PC at high risk of relapse (Surg). G was given at 1000 mg/m2 weekly for 3 wks followed by 1 wk rest and a 5–6 wk period of RT and concurrent CI 5FU (200 mg/m2/day). The defined target volume was treated to 54Gy in 30# of 1.8Gy (LAD) or 45Gy in 25# (Surg). After 4 wks rest, G was given for 12 wks. Results: 63 pts were enrolled: 39 females, 24 males; mean age 61 yr, range 31–79; 43% ECOG PS 0, 51% PS 1, 5% PS 2. Follow-up was 2 yr. 1- and 2-yr survival (KM) were 46% and 10% (LAD) and 59% and 27% (Surg). 1- and 2-yr local control (KM) were 48% and 21% (LAD) and 80% and 80% (Surg). The % planned dose delivered was (i) G pre RT: 87.6% (LAD)/94.6% (Surg); (ii) 5FU: 100.7%/96.4%; (iii) RT: 96.2%/99.5%; (iv) G post RT: 67.4%/65.3%. The baseline CA 19.9 level was significantly associated with a shorter TTPD (p=0.0002) and a shorter survival time (p=0.0071). Using Time Dependent Covariate analysis, CA 19.9 levels were strongly associated with TTPD and survival (both p < 0.0001); a person with a 10-fold higher level has a 1.95-fold higher risk of death over the next time period than their counterpart (95% CI: 1.53–2.49-fold). In 22 pts we found no statistically significant associations between outcome and mutations in K-RAS or TP53 or with microsatellite instability. Grade 3/4 hematological and non-hematological toxicity was reported by 29 (46%) and 42 pts (67%), respectively. There was one treatment-related death. Conclusions: This approach to treatment is safe and promising, with good local control for a substantial proportion of patients, and merits testing in a randomized trial.

[Table: see text]

[Table: see text]
Phase I study of oral fluoropyrimidine anticancer agent (S-1) with concurrent external-beam radiotherapy for unresectable pancreatic cancer
Authors: Shinchi H. , Takao S. , Maemura K. , Noma H. , Aikou T.
Published: March 2020

4109

Background: S-1 is an oral fluorouracil anticancer agent that was recently reported to demonstrate a response rate of 21% in 19 patients with advanced pancreatic cancer. Concurrent external-beam radiotherapy (EBRT) and 5-FU has been generally accepted as the standard treatment for locally advanced pancreatic cancer. However, there are no published data regarding the efficacy of combination therapy of S-1 and radiation in patients with pancreatic cancer. Our purpose of this study was to evaluate the safety of S-1 combined with EBRT and determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of S-1 in patients with locally advanced and unresectable pancreatic cancer. Methods: Eligible patients had UICC stage III or IV pancreatic cancer (either advanced unresectable or metastatic), adequate organ function, and no anticancer therapy in the preceding 4 weeks. S-1 was given orally at a dose of 60 mg/m2/day or 80 mg/m2/day in two divided doses after breakfast and supper. External-beam radiotherapy was delivered using a conformal technique in fraction of 1.25 Gy X 2/day, 5 days per week, totaling 50 Gy/40 fraction for 4weeks. S-1 at a dose of 60 mg/m2/day was given on days 1–7 and 15–21 in level 1, on days 1–14 in level 2, on days 1–21 in level 3a, respectively. S-1 at a dose of 80 mg/m2/day was given on days 1–21 in level 3b and on days 1–28 in level 4. DLT was defined as NCI-CTC grade 3/4 toxicity. Results: 18 patients were entered in this phase I trial: level 1 (4 patients), level 2 (5 patients), level 3a (3 patients), level 3b (3 patients), level 4 (3 patients). There were 1 of 5 patients with DLT in level 2: grade 3 vomiting. There were no DLT in levels 1, 3a, and 3b, respectively. Two of 3 patients in level 4 showed DLT: one patient developed grade 3 neutropenia and another patient developed grade 3 diarrhea. Clinical effects by CT scan included one PR, 15 SD and 2 PD. Reduced CA19–9 level less than a half of that at starting time was observed in 6 of 18 patients. Conclusions: S-1 at a dose of 80 mg/m2/day given on days 1–21 is safe and may be recommended for phase II study in patients with locally advanced and unresectable pancreatic cancer. This regimen appears to be a promising and well-tolerated approach with consideration of application to outpatients.

No significant financial relationships to disclose.
Phase II study of volociximab (M200), an α5β1 anti-integrin antibody in metastatic adenocarcinoma of the pancreas (MPC)
Authors: Valle J. W. , Ramanathan R. K. , Glynne-Jones R. , Anthoney A. , Berlin J. , Yazji S. , Evans T.
Published: March 2020

4111

Background: Tumor angiogenesis occurs when pro-angiogenic growth factors are released, stimulating endothelial cell proliferation and migration to form neovessels. A critical survival step for angiogenesis is the ligation of fibronectin in the extracellular matrix to α5β1 on endothelial cells. M200 is an IgG4 chimeric monoclonal antibody targeting α5β1, thereby inducing apoptosis of proliferating endothelial cells. M200 activity is independent of growth factor stimulus, suggesting that binding of fibronectin to α5β1 occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. Methods: This is a multicenter, open label, single cohort pilot Phase II study of 40 patients (pts) in MPC. Pts received M200 10 mg/kg IV every 2 weeks with Gemcitabine (Gem) 3 weeks on 1 week off for up to 13 cycles or disease progression. Pts were evaluated for efficacy every 8 weeks by objective response using RECIST criteria. An independent data safety monitoring board was utilized to review safety data. Results: A total of 20 pts have been enrolled. All pts were evaluable for safety and 16 pts for objective response (to date) using ITT population. Median age was 59.8 years. ECOG score was 0–1 in 19 (95%) and 2 in 1 (5%) pts. The most frequent side effects for M200 were vomiting in 7 (35%) pts and nausea in 8 (40%) pts and for (Gem) were nausea in 8 (40%) pts and vomiting in 8 (40%) pts. Eight pts died in the study, seven with progressive disease and 1 with GI perforation (possibly related to M200). One partial response was noted to date. Best overall response was (PR) 1/16 and stable disease in 8/16 pts. Median time to progression was 112+ days. Conclusions: M200 appears to be well tolerated at 10 mg/kg Q2W in combination with (Gem). Based on preliminary data from this trial and safety data from other trials, a higher dose level of M200 will be explored.

[Table: see text]
A randomized phase II study comparing gemcitabine plus nadroparine versus gemcitabine in patients with locally advanced or metastatic pancreatic carcinoma: The GEMFRAX trial
Authors: Voorthuizen T. V. , Vervenne W. L. , Van Daalen E. H. , Phoa S. S. , Gouma D. J. , Bruno M. J. , Richel D. J.
Published: March 2020

4112

Background: Gemcitabine is considered to be the standard chemotherapy regimen for advanced pancreatic cancer. The advantage of gemcitabine over best supportive care however is limited. Preclinical and clinical data have shown that low molecular weight heparin (LMWH) has an inhibitory effect on tumor progression. Two years ago provoking and promising results were presented at ASCO in a pancreatic cancer population. In this study we wanted to confirm these promising results, in which 6-month survival was the primary endpoint. Methods: Patients (pts) with advanced pancreatic carcinoma were randomized to either gemcitabine 1000 mg/m2 on day 1, 8 and 15 every 4 weeks (arm A) or gemcitabine plus nadroparine 5700 IU twice daily from day 1 to 21 every 4 weeks (arm B). Simon’s optimal two-stage design was applied to each arm to assess the treatment efficacy within each arm. This design required to enter 10 pts in the experimental arm in the first stage with the hypothesis that 70% instead of the expected 45% would be alive at 6 months. If 5 or less pts were alive at 6 months, the trial would be stopped and the regimen would be declared as ineffective. Results: 27 pts, all with metastatic disease, have been enrolled to date, 16 in arm A and 11 in arm B. Of the first 10 pts in the experimental arm only 4 were alive at 6 months (arm A: 6 of 10 pts alive).The median overall survival (OS) of these pts was 5.6 months and the median progression free survival (PFS) was 4.1 months (in arm A 8.7 and 5.1 months, respectively). The best response was stable disease (80%). No bleeding complications were seen. Conclusions: This small sized study was designed to detect a large, clinically relevant, difference in 6-month survival in pts with advanced pancreatic cancer treated with a combination of gemcitabine plus nadroparine compared to gemcitabine alone. Adding nadroparine to gemcitabine was feasible and gave no serious toxicity attributable to nadroparine. According to Simon’s two-step design a planned analysis after entering 10 pts in the experimental arm rejected the assumption that the combination induced an absolute increase in 6-month survival of 25% (5% type I error rate and 80% power).

No significant financial relationships to disclose.