bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoadjuvant XELOX vs. XELIRI in combination with concomitant boost 3D-conformal radiotherapy in locally advanced rectal cancer (LARC)
Authors: Privitera G. , Spatola C. , Acquaviva G. , Di Franco G. , Raffaele L. , Salamone V. , Ettorre G. C.
Published: March 2020

3570

Background: While several randomized trials have shown that preoperative chemoradiation reduces local recurrence in LARC, there is no standard chemoradiation schedule. The aim of this study was to compare capecitabine + oxaliplatin (XELOX) vs. capecitabine + irinotecan (XELIRI) in association with high-dose radiotherapy. Methods: Patients (pts) with histologically proven uT3–4 N-/+ or uT2 N+ LARC were randomized to receive capecitabine 1250mg/m2 bid d1–14 before chemoradiation and then 825mg/m2 bid d22–55 plus either oxaliplatin 130mg/m2 d1,22&43 (18 pts) or irinotecan 180mg/m2 d1,22&43 (18 pts). On d22 pts also received radiotherapy administered to the whole pelvis (maximum 45Gy; 1.8Gy/fraction), with a concomitant boost to the CTV (maximum 9Gy; 1.5Gy/fraction) during the last 6d of treatment with a 6h inter-fraction interval. Surgery was carried out 6–8w after chemoradiation by the same surgical team. Results: 36 pts (23M/13F, median age 59 years, ECOG PS 0–1) were enrolled between Jan03 and Jun05. No pt had systemic disease at the time of diagnosis. One pt in the XELIRI group discontinued chemoradiation because of GI toxicity; the other 35 pts (18 XELOX, 17 XELIRI) received 95% and 92% of the planned chemotherapy doses, respectively. The most common adverse event was grade 3/4 diarrhea (6% XELOX, 18% XELIRI). There was no relevant neurotoxicity. 12 pts (67%) on XELOX and 12 pts (71%) on XELIRI had clinical and pathological downstaging. There were no treatment-related deaths. A complete pathological remission was seen in 4 pts (22%) on XELOX and 5 pts (29%) on XELIRI. 25 pts (71%; 13 XELOX, 12 XELIRI) underwent sphincter-saving surgery and 10 pts had Miles abdomino-perineal resection. All pts are alive after a median follow-up of 20 months (range 7–36 months), but 4 (2 in each group) have developed distant metastases. Conclusions: XELOX and XELIRI are feasible and effective, with high efficacy comparable to that observed with other neoadjuvant regimens. XELOX was better tolerated, as diarrhea was seen more frequently in the XELIRI arm. Further studies of these regimens are warranted in this setting.

No significant financial relationships to disclose.
Long-term follow-up of colorectal cancer (CRC) patients treated with neoadjuvant chemotherapy with irinotecan and fluorouracil plus folinic acid (5-FU/FA) for unresectable liver metastases
Authors: Pozzo C. , Basso M. , Quirino M. , Schinzari G. , Astone A. , Trigila N. , D’Argento E. , Sponziello F. , Cassano A. , Barone C.
Published: March 2020

3576

Background: In a prospective study, neoadjuvant therapy with irinotecan and 5-FU/FA (modified FOLFIRI) enabled a significant proportion of CRC patients (pts) with initially unresectable liver metastases (LM) to undergo potentially curative surgical resection (Annals of Oncology 15:933–939, 2004). Here we report data on survival and time to progression (TTP) from long-term follow-up. Methods: Forty patients received irinotecan 180 mg/m2 IV on day 1, FA 200 mg/m2 IV on days 1 and 2, 5-FU IV bolus 400 mg/m2 on days 1 and 2, and 5-FU 48-h continuous IV infusion 1200 mg/m2 on day 1. Treatment was repeated every 2 wks, with response assessed every 12 wks (6 cycles), and continued until an objective response (OR), indicating suitability for surgery, disease progression, or unacceptable toxicity. Pts undergoing liver resection received a further 6 cycles postoperatively. Results: Nineteen (47.5%) of 40 pts had OR; 13 (33%) underwent resection. Treatment was well tolerated, with adverse events typical of agents used. As of June 30, 2005, median follow up was 30.4 months (mo). Median survival for all pts was 30.1 mo; median survival in nonresected pts was 24 mo, and overall survival (OS) in resected pts was not reached. TTP was 14.3 mo for all pts and 5.2 mo for nonresected pts. Disease-free (DF) survival in resected pts was 28.2 mo. Of resected pts, all were alive and 9 were DF at 1 y, all were alive and 6 were DF at 2 y, and 9 were alive and 6 DF at last follow-up. Conclusion: Surgical resection of LM after neoadjuvant treatment with modified FOLFIRI in CRC pts was followed by favorable DF and OS times. These data encourage use of irinotecan in pts with unresectable LM. Forthcoming studies should include arms with irinotecan-based combination regimens.

[Table: see text]
Preliminary results from a phase II study of infusional 5-FU, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab as first-line treatment for metastatic colorectal cancer (mCRC)
Authors: Kopetz S. , Abbruzzese J. L. , Eng C. , Adinin R. B. , Morris J. , Wolff R. A. , Lin E. , Chang D. Z. , Hoff P. , Bogaard K.
Published: March 2020

3579

Background: Irinotecan (I) plus bolus 5-FU (F) and leucovorin (L) comprise the IFL regimen, a very active treatment in mCRC when combined with bevacizumab (B). The response rate (RR) for IFL-B given as first-line treatment is 45%, with a median progression-free survival (PFS) of 10.6 months and a median survival of 20.3 months. The IFL regimen is now considered inferior to infusional 5-FU regimens, such as FOLFIRI, which have less toxicity and improved efficacy. Methods: We designed a 43 patient (pt), single-arm phase II trial of FOLFIRI-B with B (5mg/kg), I (180mg/m2), bolus of F (400mg/m2) and L (400mg/m2) followed by a 46-hour infusion of F (2400mg/m2), with a primary endpoint of progression-free survival (PFS). Chemotherapy naïve mCRC patients (pts) with adequate organ function and performance status 0–2 received B alone on Day minus 14, starting FOLFIRI + B on Day 1. DCE-MRI and laboratory correlates were completed before and after B alone and cycle 1. Once cycle is equivalent to two weeks. Results: 21 pts, median age 59 y/o (range 26–75), M:F = 15:6, 4 with prior F in adjuvant setting, have been enrolled to date. 20 pts are evaluable for response. One pt is too early. A total of 215 cycles have been administered (median 11). Median PFS has not been reached after a median follow-up of 8 months. By intent-to-treat analysis, there were 14 PRs (70%), and 5 (25%) pts with stable disease observed (including 1 unconfirmed PR). PRs were observed from 9 to 35 weeks after the first cycle (median: 18 weeks). 9 pts remain on treatment (1–12 months); 12 pts are off study (3 for progressive disease, 1 withdrew, 4 sent for curative surgery, 2 for toxicity, 2 sent for surgery unrelated to cancer). Toxicity included 10 cases of grade 3 neutropenia, including 1 febrile neutropenia, 4 venous thrombi, and 6 cases of hypertension requiring medication change. One pt included in the analysis developed peritonitis, considered a possible microperforation, after B alone and never received FOLFIRI. No ≥ grade 3 diarrhea was observed. Analysis of correlative studies will be presented at a later date. Conclusion: Our preliminary results indicate that FOLFIRI-B is well tolerated and an excellent choice as a first-line treatment for mCRC.

[Table: see text]
Effective salvage therapy of liver-only colorectal cancer metastases with chronomodulated irinotecan-fluorouracil-oxaliplatin via hepatic artery infusion
Authors: Bouchahda M. , Adam R. , Giacchetti S. , Li X. M. , Castaing D. , Gholam D. , Kunstlinger F. , Jasmin C. , Machover D. , Lévi F.
Published: March 2020

3585

Background: Cell cycle and pharmacology genes are controlled by the molecular clock in normal liver but not in tumors (Filipski et al. JNCI 2005). As a result, circadian-based hepatic artery infusions of 3 main active drugs (ChronoHAI) could improve both tolerability and efficacy in patients (pts) with liver metastases from colorectal cancer. Methods: The therapeutic potential of 3-drug chronoHAI was evaluated in 28 heavily pretreated non hospitalized pts with metastatic colorectal cancer (MCC). They received 5-day (d) q21 d courses (c) with d1 irinotecan (160 mg/m2 from 2 to 8 am, peak at 5 am) and d2–5 oxaliplatin (20 mg/m2/d from 10 am to 10 pm, peak at 4 pm) and 5-fluorouracil (600 mg/m2/d from 10 pm to 10 am, peak at 4 am). 149 courses (c) were given (median, 5 ; 1–15) using a multichannel pump (Mélodie, Aguettant, F). Toxicity was assessed q21 d and response q3 c with CT scan. Results: Pt characteristics: prior chemotherapy lines 1/2/3/4+: 3/4/8/13 pts; WHO Performance Status 0/1/2/3 : 12/9/6/1 pts; median age: 63 years (32–73); liver only: 21 pts; liver and lung: 7 pts. Treatment was withdrawn for thrombosis (6 pts) and/or Grade (gr) 3 abdominal pain (3 pts). Grade 3–4 diarrhea and vomiting respectively occurred in 6 pts (21%) and 4 pts (14%) and were the main toxicities. Leucopenia, anemia and thrombocytopenia were respectively encountered in 5, 2 and 1 pt (< 18%). NCIC gr 3 sensory neuropathy occurred in 4 pts and alopecia in 3 pts. Of 25 pts with measurable lesions, disease progressed in 11 pts (exclusively outside the liver for 3 pts) and was controlled in 14 pts (56%), including 8 objective responses - 32% [95% C.L. 13.4 to 50.6]. Partial hepatectomy was performed in 3 pts with measurable disease (12%): R0 (2 PR) and R1 (1 SD). Median Progression free survival is 5 months [2.5 to 7.5] and median survival is 18.4 mo [10.5 to 26.3]. Five pts are alive at 2 to 51 mo. Conclusions: 3-drug chronoHAI is safe in heavily pretreated pts and achieves consistent activity against colorectal cancer liver metastases despite prior failure to oxaliplatin, irinotecan and fluorouracil. The addition of systemic molecular targeted therapy could be useful for preventing extra hepatic dissemination. Supported by ARTBC, Hôpital P. Brousse, Villejuif, France

No significant financial relationships to disclose.
Chemo-immunotherapy regimen with gemcitabine + FOLFOX 4 (GOLF) followed by subcutaneous (sc) granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2). Results from a multicenter phase II trial in colon carcinoma patients
Authors: Correale P. , Remondo C. , Montagnani F. , Rotundo M. S. , Marsili S. , Laplaca M. , Tassone P. , Tagliaferri P. , Venuta S. , Francini G.
Published: March 2020

3587

We have recently described a poly-chemotherapy (GOLF) regimen that: A) is active in colon carcinoma patients as second line of therapy; B) induces high levels of necrosis and apoptosis in colon cancer cells; C) up-regulates the expression and release of heat shock proteins (HSP)-70 and -90 and tumour-associated antigens (2,3); and D) down-regulates tumour cell resistance to the death signals of cytotoxic-T-lymphocytes.These effects represented the rationale for projecting GOLFIG regimen. Here we describe the results of a multi-center translational phase II trial designed to evaluate the toxicity, anti-tumour activity of a novel regimen designated as GOLFIG-1, composed by the GOLF poly-chemotherapy followed by the subcutaneous (sc.) administration of GM-CSF and low-dose IL-2 in colorectal carcinoma patients. The study involved 37 patients (21M and 16F, mean age 62.5 years), 24 of whom had received a previous line of treatment, and 24 had liver involvement. All the patients received biweekly chemotherapy with gemcitabine (1g/m2, day 1 and 15), oxaliplatin (85 mg/m2, day 2 and 16), levo-folinic acid (100 mg /m2, day 1, 2, 15, 16) and 5-Fluorouracil (400 mg/m2 as a bolus, and 800 mg/m2 as 24 hour infusion, days 1, 2, 15, 16). These patients also received sc GM-CSF (100 μg, day 3 to 8) followed by sc IL-2 (0.5 X 106 IUs twice a day from day 9 to 14 and from 17 to 29). The treatment was well tolerated and very active in colon carcinoma patients, with high objective response (64.9%) and disease control rates (97.3%), with an average time to progression of 12.94 months (CI 95%: 9.98–15.91). An immunological study confirmed the immunological response to colon carcinoma antigen, a significant reduction in suppressive regulatory T lymphocytes (CD4+CD25+T-reg) and a significant reduction of VEGF levels reported in a previous study. In conclusion, these results suggest that the GOLFIG regimen exerts strong immunological and anti-tumour activity in colorectal cancer patients. A randomized phase III trials aimed to compare the efficacy of GOLFIG-1 with FOLFOX-4 regimen in patients with advanced colorectal carcinoma is presently ongoing.

No significant financial relationships to disclose.
Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms associated with overall survival in women with metastatic colon cancer
Authors: Press O. A. , Zhang W. , Yang D. , Haiman C. A. , Gordon M. , Schultheis A. M. , Nagashima F. , Sherrod A. , Iqbal S. , Lenz H.
Published: March 2020

3600

Background: Methylenetetrahydrofolate Reductase (MTHFR) is a key enzyme regulating intracellular folate pool, which affects DNA synthesis and methylation. Recent studies found folate deficiency induces DNA damage because of impaired nucleotide-excision repairs in mouse model. Two MTHFR gene polymorphisms, C677T and A1298C are linked to altered enzyme activity. Numerous studies have shown these two polymorphisms associated with colon cancer risk and response to fluorouracil-based treatment in advanced colon cancer patients. One epidemiology study also demonstrated 1298CC genotype to be associated with a significantly lower risk of colon cancer in women, but not men. We tested whether these two polymorphisms were associated with clinical outcome in metastatic colon cancer patients treated with 5-FU/Oxaliplatin. Methods: Between 1992 and 2003, a total of 318 patients with metastatic colon cancer treated at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC) or the Los Angeles County/University of Southern California Medical Center (LAC/USCMC), were eligible for this study. Peripheral blood samples were collected from each patient and genomic DNA was extracted from white blood cells using the QiaAmp kit (Qiagen, Valencia, CA). Two MTHFR gene polymorphisms (C677T, A1298C) were tested by PCR-RFLP method. Results: MTHFR A1298C gene polymorphism showed statistically significant differences in overall survival (OS) in female patients with metastatic colon cancer (P=0.025, logrank test). Patients with the AA genotype had an 18.7 months median OS compared with the heterozygous AC genotype, which had a 14.3 months median OS and the CC genotype, which had a 15.9 months median OS. Conclusions: There is no significant difference in clinical outcome in male patients. However, female metastatic colon cancer patients with a MTHFR A1298C polymorphism AA genotype have significantly better overall survival than those with heterozygous AC genotype or CC genotype. This data supports the role of MTHFR polymorphisms as an independent prognostic marker in female patients with metastatic colon cancer. Further prospective study is needed to confirm these preliminary findings.

[Table: see text]
Impact of biomarker dynamic profile and pathological response induced by neoadjuvant chemoradiotherapy in rectal cancer
Authors: Gentile A. L. , Pinto C. , Ceccarelli C. , Di Fabio F. , Funaioli C. , Longobardi C. , Tardio M. L. , Cuicchi D. , Iacopino B. , Martoni A. A.
Published: March 2020

3614

Background: The aim of this study was to evaluate the correlation among biomarkers, pathological response and clinical outcomes in patients (pts) with rectal cancer submitted to neoadjuvant chemoradiotherapy. Methods: Pts entering the study had rectal adenocarcinoma, uT3/4N-/+ or uT2N-/+ with inferior location. Chemotherapy consisted of oxaliplatin 60 mg/m2 weekly infusion IV for 6 times and 5-fluorouracil 225 mg/m2/die continuous infusion IV d 1–38. Radiotherapy was delivered up to a dose of 50.4 Gy in daily fractions of 1.8 Gy d 1–38. Rectal surgery with TME was performed 6–8 weeks after neoadjuvant treatment. Immunohistochemical determination of Ki67, p53, bcl2, TS, EGFR, MLH1 and MSH2 was performed in pretreatment biopsy and operative specimen. Results: Between March 2002 and May 2005, 32 pts had completed neoadjuvant therapy and surgery. Pt characteristics: 24 (75%) men and 8 (25%) women; median age 64 (33–80) years; stage uT2N-M0 3 (9.4%) pts, uT3N-M0 14 (43.8%), uT3N+M0 10 (31.2%), uT3NXM0 2 (6.2%), uT4N+M0 3 (9.4%). Surgery consisted of abdominal-perineal amputation in 12 (37.5%) and low-anterior resection in 17 (53.1%) pts, with negative circumferential resection margins in 86.2%. Laparoscopic local excision was performed in 3 (9.4%) pts. Pathological down-staging occurred in 18 (56.2%) pts, including 7 (21.9%) pT0N0, with sphincter preservation in 40%. Tumor Regression Grade (TRG) (according to Mandard) evaluation of operative specimen was: 7 TRG1, 11 TRG2, 11 TRG3 and 3 TRG4. Expression mean value in pretreatment biopsy and operative specimen was: Ki67 88.8% and 31.7%; p53 49.7% and 40.7%; TS 12.6% and 10.0%; MLH1 89.7% and 76.4%; MSH2 84.3% and 72.2%. The evaluation of biomarker profile in operative specimen of TRG2 pts vs TRG3–4 showed: Ki67 16.6% vs 46.2% (p=0.03); TS 4.5% vs 12.9% (ns); MSH2 82.3% vs 65.6% (ns); p53 52.3% vs 34.8% (ns). Median DFS was 19 (3–35) months. At a median follow-up of 22 (5–41) months, 100.0% of TRG1 pts, 90.9% of TRG2, 73.3% of TRG3–4 had no-evidence of disease relapse. Conclusions: These preliminary results suggest a correlation between Ki67 and pathological response in rectal cancer pts treated with neoadjuvant therapy. Moreover, DFS appears to be related to TRG.

No significant financial relationships to disclose.
Randomized phase II trial of neoadjuvant vs. adjuvant docetaxel plus cisplatin in patients with locally advanced gastric carcinoma: An interim analysis
Authors: Chun J. , Park S. , Kim H. , Kim Y. , Ryu K. , Lee J. , Lee J. , Kim C. , Lee J. , Bae J.
Published: March 2020

4030

Background: The perioperative treatment strategy for locally advanced gastric cancer (LAGC) has not been clearly established. We conducted a randomized phase II study of neoadjuvant vs. adjuvant docetaxel/cisplatin (DC) chemotherapy in LAGC. Methods: LAGC was radiographically defined by CT and PET. Pts were randomized to receive neoadjuvant or adjuvant DC (docetaxel 36 mg/m2 + cisplatin 40 mg/m2 on D1, D8, q 3 wks X 3 cycles) according Japanese staging system (IIIa, IIIb, IV M-, and IV with a single M+ node). Results: All planned 88 pts in 44 per each arm were enrolled between Jan 2003 and Nov 2005. One pt was not eligible. The median age was 57 yrs vs. 58 yrs, PS 1 90.7% vs. 84.1%, and stage III/IV 72.1%/27.9% vs. 70.5%/29.5% in the neoadjuvant and adjuvant arm, respectively. Clinical response rate of 42 evaluable pts in neoadjuvant arm according to WHO criteria was 64.3% (95% CI 49.8–78.8%) with CR 2.4%, PR 61.9%, SD 31.0%, and PD 4.7%. There was no treatment related death. Comparison of G3/4 adverse events in neoadjuvant vs. adjuvant arm were; leukopenia 14.0% vs. 32.4% (p=0.04), neutropenia 37.2% vs. 62.2% (p=0.02), febrile neutropenia 0% vs. 2.7%, diarrhea 2.3% vs. 10.8%, stomatitis 2.3% vs. 8.1% (p=NS). There were no difference in the postoperative morbidity and the duration of hospital stay between both arms, but surgery was delayed in one pt who developed tuberculosis during neoadjuvant chemotherapy. Downstaging of the T stage could be obtained in 6 (14.3%) among 42 evaluable pts in neoadjuvant arm, according to EUS. Conclusions: Both neoadjuvant and adjuvant DC chemotherapy were relatively well tolerated in LAGC, with the lower incidence of G3/4 toxicities in neoadjuvant arm. Neoadjuvant DC showed a high response rate and a modest downstaging effect. (Supported by National Cancer Center Grant; Docetaxel was provided by Sanofi Aventis Korea)

[Table: see text]

No significant financial relationships to disclose.
Impact of PTEN/AKT/PI3K signal pathway on the chemotherapy for gastric cancer
Authors: Oki E. , Kakeji Y. , Tokunaga E. , Nishida K. , Koga T. , Egashira A. , Morita M. , Maehara Y.
Published: March 2020

4034

Background: Growth factor receptor-mediated signal transduction has been recently implicated in conferring resistance to conventional chemotherapy on cancer cells. We have described a pathway that involves AKT/PI3K to mediate chemoresistance in gastric cancer patients. The phosphatase activity of PTEN is crucial in controlling the phosphatidylinositol-3 (PI-3) kinase signal transduction pathway and in the activation of the protein kinase B(PKB/Akt) proto-oncogene. This indicates that PTEN exerts its tumor-suppressor function by negatively regulating the anitapoptotic PI3-kinase/AKT signaling pathway. Methods: Primary gastric carcinoma tissues and corresponding normal mucosa were obtained from 119 gastric cancer patients who underwent surgery in the Department of Surgery II in Kyushu University Hospital from the years 1996 to 2000. Methylation of PTEN was studied with methylation-specific PCR and LOH (loss of heterozygosity) of PTEN was studied using a DNA sequencer with D10S796 and D10S1173 microsatellite marker in the same samples. AKT activation was investigated by immunostaining with a phosphorylation-specific antibody. The chemotherapeutic sensibilities of these patients were investigated using an MTT assay. Results: We found that methylation of PTEN was rarely recognized, However, the gastric cancer patients who had a higher AKT phosphorylation (activated AKT) appeared to have LOH of PTEN (p < 0.0008), and the prognosis of the patient who has LOH of PTEN was significantly poor. When the chemotherapeutic sensibilities of these patients were studied in an MTT assay, it was found that the activated AKT was associated with increased resistance to multiple chemotherapeutic agents, which included those currently used on gastric cancer patients (5-fluorouracil, adriamycin, mitomycin C, and cis-platinum). Conclusions: The results of this study indicate that AKT activation and LOH of PTEN plays an important role in conferring a broad-spectrum chemoresistance in gastric cancer patients. It also indicates that clinical trials for an appropriate chemotherapy combination with conventional drugs and a new generation of signal transduction inhibitors that inhibit the PTEN/AKT pathway should be considered in treating gastric cancer in the near future.

No significant financial relationships to disclose.
A phase II trial of gefitinib in patients (pts) with progressive metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study
Authors: Hobday T. J. , Holen K. , Donehower R. , Camoriano J. , Kim G. , Picus J. , Philip P. , Lloyd R. , Mahoney M. , Erlichman C.
Published: March 2020

4043

Background: Systemic treatment options for progressive metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express the epidermal growth factor receptor (EGFR). Gefitinib, a small-molecule inhibitor of the EGFR tyrosine kinase, has been shown to inhibit the growth of NET cell lines. Methods: Eligibility criteria included: radiographic progression by RECIST criteria, ECOG PS ≤ 2, ≤ 1 prior chemotherapy, and good organ function. Prior interferon and prior or concurrent octreotide (if disease progression documented on stable dose) were allowed. Pts received gefitinib 250 mg po daily. We evaluated 6 month (mos) progression-free survival (PFS) in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. 6 mos PFS rates of 30% (CT) and 10% (ICC) were considered promising. Results: 96 pts were enrolled: (57 CT, 39 ICC). For pts evaluable for the primary endpoint, 23 of 38 (61%) CT pts and 9 of 29 (31%) pts with ICC were progression-free at 6 mos. 1 PR and one minor response (MR = 20–29% decrease in sum of target lesion diameters) were observed in 40 CT pts; 2 PR and 1 MR in 31 ICC pts. In addition, 32% (12/38) of CT and 14% (4/29) of ICC pts had stable disease on study for a duration that exceeded by at least 4 months the time to progression documented prior to study entry. Grade 3–4 toxicity was infrequent with fatigue (6%), diarrhea (5%) and rash (3%) most common. Evaluation of markers of the EGFR pathway on tumor tissue will be presented. Conclusions: Gefitinib is well-tolerated and results in prolonged disease stabilization in pts with prior documented objective progression of CT and ICC, with rare objective responses. Supported by NOI CM17104.

No significant financial relationships to disclose.
Improving the quality of surgery for gastric cancer—Are surgeons aware of the relevant quality indicators?
Authors: Helyer L. K. , O Brien C. , Coburn N. G. , Swallow C. J.
Published: March 2020

4048

Background: Gastric cancer survival in the West is inferior to that achieved in Asian centers. While differences in tumor biology may play a role, poor quality surgery contributes to understaging. In our evaluation, adequate lymph node (LN) assessment (≥15) was achieved in only one third of patients and independently predicted survival across Surveillance, Epidemiology and End Results (SEER) regions (ASCO 2005, Abstract # 4004). The standard proximal margin of resection is recommended to be ≥5 cm; revision based on intraoperative frozen section is of benefit. We hypothesize that the majority of surgeons performing gastric cancer surgery in a North American setting are unaware of the recommended standards. Methods: Using the Ontario College of Physicians and Surgeons registry, surgeons who potentially include gastric cancer surgery in their scope of practice were identified. A questionnaire was mailed to 559, 55% responded. 203surgeons reported managing gastric cancer. Results were evaluated by chi-square and logistic regression; p<0.05 was considered significant. Results: 86% of respondents were male; 59% in urban non-academic practice, and 30% in academic. 42% of surgeons operate on 2–5 cases/yr and 18 % on >5. One third of surgeons identified ≤ 4 cm to be the desired proximal margin. Frozen section is used by 52% to evaluate proximal margin status. 20% were unsure of the number of LN needed to accuratly stage, the median number reported by the remainder was 10 (range 0 - 30). 99% refer for adjuvant therapy. This was less likely for patients in poor medical condition, poor nutritional status, or age >70 years. Young patients, those with bulky LN or positive margins were more likely to be referred. Overall, only 16 of 203identified the need for both a ≥5 cm proximal margin and ≥15LN; this was too small a group to analyze for demographic associations. Surgeons who do >5 gastric resections/yr were more likely to report performing a D2 resection (p = 0.008). Conclusions: The majority of surgeons operating on gastric cancer in Ontario did not identify standard quality indicators of gastric cancer surgery. A continuing medical education program should be designed to address the knowledge gap, aiming to improve the quality of surgery and outcome of multidisciplinary management.

No significant financial relationships to disclose.
A phase II study of oral S-1 with pharmacokinetics and pharmacogenomic investigation in advanced or recurrent gastric cancer
Authors: Rha S. Y. , Jeung H. C. , Kim H. K. , Kim S. Y. , Kim S. Y. , Lim H. Y. , Kong S. J. , Chung H. C.
Published: March 2020

4072

Background: Present study describes the first phase II study of S-1 including pharmacokinetic and pharmacogenomic evaluation for extra-Japanese Asian population with advanced gastric cancer. Methods: Chemo-naive advanced gastric cancer with measurable disease was enrolled. Initial dose of S-1 was b.i.d. at 35, then 40 mg/m2 according to devised dosing method (range, 90–160 mg/day) for 28 days every 6 weeks. Pharmacokinetic study was performed after 28-day administration at cycle 1 and 3. Microarray based CGH was performed with genomic DNA from peripheral mononuclear cells to detect the toxicity-related genetic changes. Results: When first 31 patients were enrolled, protocol was amended to conduct the study by two steps for additional patients at 40 mg/m2 without dose escalation in initial 31 patients of 35 mg/m2, because these patients showed neither significant nor cumulative toxicity. Of 62 patients enrolled, median relative dose intensity was 0.99. Overall response rate was 19.3% (95% CI, 9.2–29.5). With 558-day follow-up duration, median TTP and OS were 126 and 264 days, respectively. One-year survival rate was 33.9%. Toxicity increased with dose escalation, but there was no grade 4 toxicity. The most common significant toxicity was anemia. Pharmacokinetics parameters were similar to those of Japanese population. In microarray-CGH, we selected 18 genes with different copy numbers of 13 amplified and 5 deleted genes in patients with anemia. Conclusions: Our phase II study showed the feasibility of S-1 in gastric cancer at the dose of 35 mg/m2, and we suggested that selected 18 genes might be candidate markers for predicting anemia with S-1 treatment.

No significant financial relationships to disclose.
HtrA1 expression as a predictive factor of response to cisplatin-based regimen in patients with advanced gastric cancer
Authors: Catalano V. , Baldi A. , Shridhar V. , Staccioli M. P. , Chien J. , Giordani P. , Rossi D. , Baldelli A. M. , Alessandroni P. , Muretto P. , Catalano G.
Published: March 2020

4077

Background: Human HtrA1 is a member of the HtrA (High temperature requirement) family of serine proteases. Recent reports suggest that htrA1 plays a protective role in varous malignancies due to its tumour suppressive properties. This study was performed to estimate HtrA1 expression as a predictor of the response to chemotherapy of patients with gastric cancer. Methods: HtrA1 was measured immunohistochemically on archival specimens of primary gastric cancer from 51 patients treated consecutively at our institution with a weekly chemotherapy including cisplatin 40 mg/m2, epirubicin 35 mg/m2, 6S-leucovorin 100 mg/m2, 5-fluorouracil 500 mg/m2, with the support of filgrastim 5 μg/Kg from the day 2 to 7 (PELF regimen), or cisplatin 40 mg/m2, epirubicin 35 mg/m2, 6S-leucovorin 100 mg/m2, 5-fluorouracil 500 mg/m2 (PLF regimen). Response to chemotherapy was assessed after 8 weekly treatments according to the WHO criteria. Results: our population consisted of M/F 32/19; median age 64 years (range, 46–79). The prevalent metastatic sites were liver (17 pts), peritoneum (13 pts), lymph nodes (21 pts), locoregional disease (16 pts); 31/16/4 pts had 1/2/3 or more sites of disease. 23 pts had a low expression of HtrA1 (0/1+) versus 28 patients with higher expression (2+). Of the total 51 patients, there were 28 responders: 8 showing complete response (CR) and 20, partial response (PR). Of the 28 responders, 20 were in the higher HtrA1 staining group (2+), while of the 23 non-responders, 15 were in the higher HtrA1 staining group (0/1+). A statistically significant correlation between HtrA1 expression (HtrA1 2+ versus HtrA1 0/1+) and the clinical response was observed (response rate in patients with 2+ and 0/1+: 71.4% versus 34.8%, P < 0.01, respectively). Interestingly, among 16 pts with locoregional disease (stomach, gastric bed, anastomosis), 1/6 pts had HtrA1 1+ expression compared to 8/10 pts with HtrA1 2+ (17% versus 80%, respectively; p = 0.025). Conclusions: The immunohistochemical identification of HtrA1 on the primary gastric cancer prior to chemotherapy may be a useful predictor for choice of potentially responders to a cisplatin-based chemotherapy.

No significant financial relationships to disclose.
A phase II study of DJ-927 as second-line therapy in patients (pts) with advanced gastric cancer (GC) who have failed a 5-FU non taxane based regimen
Authors: Evans T. , Dobrila R. , Berardi R. , Sumpter K. A. , Wall L. R. , Oyama R. , Anthoney D. A.
Published: March 2020

4081

Background: Most 1st-line combination chemotherapy regimens in pts with advanced GC include 5-FU. Taxanes are also active agents in GC, either alone or in combination. However, there is no recognized 2nd-line regimen for use in pts with advanced GC. DJ-927 is a semi-synthetic novel taxane with in vitro activity against GC cells lines. It is administered orally, with hematologic dose-limiting toxicity (DLT) in Phase I studies. The primary objective of this study was to determine the objective response rate of DJ-927 as 2nd-line therapy in pts with advanced GC. Methods: Eligible pts had confirmed advanced GC with no more than 1 prior systemic 5-FU-containing regimen for advanced disease, with adequate hematologic, renal and liver function, and with measurable disease. The starting dose in the 1st cohort of 6 pts was 27 mg/m2 orally, every 3 weeks. If < 2 DLTs occurred at this dose, the next cohort of 6 pts would start at a dose of 35 mg/m2, every 3 weeks, and all subsequent pts would be treated at the optimal dose level. Measurable disease was assessed after every 2 courses. Pharmacokinetic sampling was performed during course 1 only. Sample size based on a 3-outcome 1-stage design was calculated to be 27 pts evaluable for response, with ≥ 4 responses of 27 pts indicating that DJ-927 has activity in advanced GC. Results: 36 pts (male=25; female = 11), KPS ≥ 60%, with GC (n = 23) or OG junction cancer (n = 13), received 104 courses (median = 2; range 1–9) of DJ-927. 2 DLTs (febrile neutropenia; Grade 4 neutropenia > 5 days) occurred at 35 mg/m2, and the optimal starting dose was confirmed as 27 mg/m2. 6 of 36 pts were not evaluable for response (< 1 complete treatment course) due to early disease progression (3), toxicity (2), and drug not given (1). Response data is available for 26 of 30 evaluable pts with confirmed PR (n = 5), SD (15), and PD (6). Toxicity, ≥ grade 3, in evaluable pts (n = 33) included neutropenia (17), anemia (5), thrombocytopenia (4), diarrhoea (7), fatigue (5), lethargy (4), neutropenic sepsis (5). Conclusions: DJ-927 has modest activity in pts with GC who have failed a 5-FU non-taxane based regimen. Toxicities include neutropenia ± sepsis, diarrhoea and lethargy. Further studies of DJ-927 in combination with other active agents are warranted in pts with GC.

[Table: see text]
The prognostic significance of IL-1-B and GST T1/M1 polymorphisms in non-metastatic gastric cancer
Authors: Al-Moundhri M. S. , Al-Bahrani B. , Al-Nabhani M. , Burney I. , Al-Kindy M. , Ganguly S. S. , Tanira M.
Published: March 2020

4084

Background: Gastric cancer is the most common malignancy in Oman. The proinflammatory cytokine IL-1-B polymorphisms have been associated with increased gastric cancer risk and shown to be of a prognostic value in advanced gastric cancer. Our aim is to study the prognostic significance of IL-1B- 31, -3954, IL-1RN- and GST T1/M1 polymorphisms in non-metastatic gastric cancer and correlate it with clinicopthological features. Methods: Genomic DNA was extracted from peripheral blood of 40 gastric cancer patients treated with adjuvant chemotherapy or chemoradiotherapy. The DNA samples were analyzed using TaqMan real-time polymerase chain reaction and 5’ nuclease assay. The deletion of GST T1/M1 genes was assessed by PCR. Results: The pathological stages were stage I = 1, stage II = 13, stage III = 22, stage IV = 3. The median follow up was 17 months. There was no prognostic significance for all the above polymorphisms in isolation. However, IL-1RN 2/2 IL-31 C/C genotypes (n = 13) were associated with worst outcome compared with IL-1RN L/L or 2/L and IL-31 T/T and T/C genotypes (n = 27). The median survival of IL-1RN 2/2 IL-31 C/C genotype was 16 months versus 63 months for IL-1RN L/L or 2/L and IL-31 T/T and T/C genotypes (p = 0.035). The IL-1RN 2/2 IL-31 C/C genotype correlated with signet ring pathology (p = 0.01) and non-distal gastric cancer location (p = 0.01). There was no significant association with T, N, or overall stage. Conclusion: These preliminary results suggest a prognostic value for IL-1-B polymorphisms in non-metastatic gastric cancer.

No significant financial relationships to disclose.
Correlation between HER2/neu overexpression/amplification and clinicopathologic parameters in advanced gastric cancer (AGC) patients (pts): A prospective study
Authors: Gravalos C. , Marquez A. , Colomer R. , Garcia-Carbonero R. , Sastre J. , Rivera F. , Saenz-Cusi A. , Velasco A. , Guzman C. , Jimeno A.
Published: March 2020

4089

Background: Trastuzumab is widely used in the treatment of HER2/neu overexpressing breast cancer pts and also exhibits activity in human gastric cancer cells that overexpress HER2/neu. We are conducting a phase II trial to assess the efficacy and tolerance of trastuzumab in combination with cisplatin as first line chemotherapy (CT) in HER2/neu positive AGC. Objectives: To determinate prospectively the frequency of HER2/neu expression and to evaluate the relationship with clinicopathologic characteristics in advanced gastric adenocarcinoma pts. Methods: Pts were screening for HER2/neu expression/amplification. Immunohistochemistry (IHQ) was performed using herceptest. A fluorescence in situ hybridization (FISH) assay was done when IHQ was = 2. HER2/neu expression was considered negative if IHQ = 0, 1 or IHQ = 2 and FISH negative; and positive if IHQ = 2 and FISH positive or IHQ = 3. Results: A hundred and twenty six pts were tested for HER2/neu status between 2/2004 and 12/2005. 96 (76%) males, median age 61 years (range 29–84). Histological characteristics: all were adenocarcinomas and 47% type intestinal, 33% diffuse, 20% unknown. Primary tumor localization was 101 (80%) gastric and 25 (20%) gastroesophageal junction (GEJ). 115 (91%) pts had metastases (47% liver; 45% lymph nodes; 27% peritoneum; 10% lung; 27% others) and 11 (9%) locoregional advanced disease. Prior therapies: 67 pts surgery, 18 adjuvant/neoadjuvant CT and 14 adjuvant irradiation. HER2/neu expression was negative in 109 (86.5%) cases. The positive cases were: type intestinal (15.5%); type diffuse (10%) (p = 0.54); 9% gastric localization and 29% GEJ tumors were HER2/neu positive too (p = 0.01). Conclusions: HER2/neu overexpression/amplification was found in 13.5% of AGC and is more common in gastroesophageal junction cancers. The study is ongoing.

[Table: see text]
Association of VEGF expression with poor prognosis among patients with low-grade neuroendocrine carcinoma
Authors: Phan A. T. , Wang L. , Xie K. , Zhang J. , Rashid A. , Evans D. , Vauthey J. , Abdalla E. , Abbruzzese J. L. , Yao J. C.
Published: March 2020

4091

Background: Low-grade neuroendocrine carcinomas (LGNET) can arise from neuroendocrine cells throughout the body and have a wide range of aggressiveness. Reliable predictive and prognostic markers of outcome are lacking. Angiogenesis is critical for metastasis and tumor growth beyond a small tumor size and VEGF is a powerful mediator of tumor angiogenesis. Methods: LGNET tissue from 50 patients (24 with local-regional disease, 26 with metastasis) who underwent tumor resection at the University of Texas M.D. Anderson Cancer Center was evaluated for expression VEGF by immunohistochemistry. Chi-square and Fisher’s exact test were used to test the association between study parameters. Kaplan-Meier analysis was used to assess the affect of study parameters on progression free survival (PFS). Results: Strong, weak, and negative VEGF expression was observed in 32%, 54%, and 14% of cases respectively. Larger tumor size was observed among patients with strong VEGF expression. Mean tumor sizes in patients with strong, weak and negative VEGF were 4.8, 2.8, and 2.9 cm. Compared to the group with negative VEGF expression, VEGF (weak/strong) expression was associated with metastasis (14% v 58%; P = .045). The median PFS durations of patients with strong and weak VEGF expression were 29 months and 81 months respectively. With a median follow-up duration of 50 months, the median PFS duration for the group with negative VEGF expression has not been reached. Compared by log rank test VEGF expression was associated with poor PFS (P = .022). Conclusions: This study suggests that tissue VEGF expression is associated with aggressive tumor growth and metastasis among patients with LGNET. VEGF expression may serve as a useful prognostic marker following tumor resection.

No significant financial relationships to disclose.
Survival of resectable pancreatic cancer patients with diabetes
Authors: Busaidy N. L. , Yazbeck C. F. , Shah P. , Evans D. B. , Li D. , Geraci J. M. , Weiser M. A.
Published: March 2020

4098

Background: Pancreatic cancer is the fourth leading cause of cancer mortality in the United States. Determining modifiable prognostic factors may be a key step in improving outcomes of these patients with overall poor survival. Pancreatic adenocarcinoma is often associated with diabetes. Our aim is to determine whether diabetes worsens disease specific mortality in resectable pancreatic cancer patients. Methods: In this study, we reviewed 298 patients with resected pancreatic adenocarcinoma in our surgical database at MD Anderson Cancer Center between August 1992 and July 2003. Patients were classified into diabetics (N = 87) (defined as those carrying the diagnosis of diabetes (DM) at time of presentation or on long term therapy for DM) and nondiabetics (N = 211). Univariate (log-rank) and Multivariate (Cox Regression) analyses were performed. Results: Compared to nondiabetics, patients with DM had a poorer overall survival with a median survival of 19.8 vs 29.2 months (p = 0.01). On multivariate analysis, correcting for known poor prognosticators in resectable patients: staging, histologic tumor differentiation and retroperitoneal margin status, diabetes was a significant independent risk factor for increased overall mortality (OR 1.55, 95% CI 1.15–2.07, p = 0.004). Disease-specific mortality was also higher in diabetics vs. non-diabetics with a median survival of 29.87 vs. 21.47 months (OR 1.37 95% CI 1.00–1.89 p = 0.048). Stage specific mortality was also higher among diabetics. Potential etiologies will be discussed. Conclusions: Diabetes worsens disease specific and overall mortality in patients with pancreatic cancer. Diabetes may be a modifiable risk factor and should be considered while prognosticating patients with resectable pancreatic cancer. Further studies are needed to determine whether treatment of diabetes improves outcomes.

No significant financial relationships to disclose.
NCCTG phase II trial of bevacizumab, gemcitabine, oxaliplatin in patients with metastatic pancreatic adenocarcinoma
Authors: Kim G. P. , Oberg A. , Kabat B. , Sing A. , Hedrick E. , Campbell D. , Alberts S.
Published: March 2020

4113

Background: The combination of gemcitabine and oxaliplatin (GemOx) is a highly active regimen in pancreatic cancer. A recent study with the biologic agent, bevacizumab, and gemcitabine has also demonstrated significant activity. A phase II study is ongoing to evaluate whether combining an active cytotoxic doublet with an effective targeted agent improves 6-month survival and is tolerable in previously untreated patients (pts) with metastatic pancreas cancer. Methods: Treatment consists of gemcitabine 1000 mg/m2 IV over 100 minutes and bevacizumab 10 mg/kg IV given on day 1 and 15; oxaliplatin 100 mg/m2 IV is given on day 2 and 16. A treatment cycle consists of 28 days. Eligibility includes: no prior chemotherapy, ECOG PS 0–2, bili < 2× UNL, AST < 5× UNL. Pts with stable full-dose anticoagulation are eligible. Bevacizumab specific exclusions include no recent stroke, heart attack, embolus, tumor invasion or significant proteinuria. CT scans are obtained every 2 cycles. Treatment continues until disease progression, toxicity or patient refusal. Results: Sixty-three patients of a planned 75 were enrolled from 7/05 to 1/06; 2 cycles of toxicity data are available on 31 of the first 32 consecutive pts. The overall grade 3+ toxicity rate is 52% (16/31); more specifically, the grade 3 toxicities were 42% (13/31) and the grade 4 rate is 10% (3/31). Grade 3 adverse events are nausea (4), vomiting (4), alk phos (3), dehydration (3), thrombosis (2), leukopenia (2), neutropenia (4), abdominal pain (2), hypokalemia (4), and one each of the following: anorexia, low consciousness, pneumonia, rectal pain, diarrhea, and proctitis. There was one patient death due to cerebral ischemia (grade 5: 1/31 or 3%). Conclusions: Early assessment of toxicity in this trial reveals a reasonably tolerable regimen. Addition of bevacizumab to GemOx appears to have grade 3/4 toxicity rates similar to historical observations (ECOG 6201). Toxicity data for all patients, after at least 2 cycles of treatment, will be presented.

[Table: see text]
Gemcitabine-based polychemotherapy for advanced pancreatic cancer (APC): Is it ready for prime time? A pooled analysis of 3,682 patients (pts) enrolled in 12 phase III trials
Authors: Milella M. , Carlini P. , Gelibter A. , Ruggeri E. , Ceribelli A. , Pino M. , Terzoli E. , Cognetti F. , Giannarelli D. , Bria E.
Published: March 2020

4118

Background: Since the introduction of gemcitabine (G), attempts have been made to develop G-based combination regimens to improve the dismal outcome of APC pts. Results of randomized trials, however, have been conflicting and single-agent G presently remains the standard of care for such pts. Methods: All prospective phase III trials comparing single-agent G with G-based polychemotherapy regimens (poly-G) were considered eligible. A pooled analysis was performed and event-based relative risk ratios (RR) with 95% CI were derived through both a fixed- and a random-effect model approach, exploring OS as the primary outcome and PFS and ORR as secondary outcomes. Heterogeneity between different trials was also taken into account. Results: Twelve trials involving 3682 pts were identified. The analysis was conducted considering three different subgroups: 1) overall population (3682 patients, 12 trials), 2) platinum-containing poly-G (PG) vs G (768 pts, 5 trials), and 3) fluoropyrimidine-containing poly-G (FG) vs G (1640 pts, 4 trials). As shown in the table, no significant differences in the primary outcome (OS) were observed in any of the three groups analyzed. Conversely, a significant advantage for poly-G was evident with regard to both PFS and ORR in the overall population as well as in the PG vs G subgroup, although with some heterogeneity. A heterogeneous non-significant trend towards a better PFS and ORR outcome was also observed in the FG vs G subgroup. Conclusions: Single-agent G remains the treatment of choice in APC pts. However, the addition of platinum compounds to G appears to significantly improve PFS and ORR, possibly justifying the use of platinum-based poly-G in younger and fit patients.

[Table: see text]

No significant financial relationships to disclose.