bluuebunny/crossref_metadata_2025 huggingface dataset:
Personalized therapy for metastatic colorectal cancer: A closer possibility?
Authors: Pierobon M. , Calvert V. , Lipsky M. , Sheehan K. , Speer R. , Mammano E. , Belluco C. , Nitti D. , Liotta L. , Petricoin E.
Published: March 2020

4131

Background: Colorectal cancer (CRC) is the second leading cause of cancer related death in the Western world, and survival rate is closely associated with the development of metastases. Personalized targeted therapies promise to have a dramatic impact on the treatment of cancer over the next decade. The molecular fingerprint of a patient’s tumor is the basis for specific targeted therapy. Most often, we are not measuring what we are treating. If we choose therapy based on the primary tumor, but we are treating the metastasis, we are likely giving the wrong therapy if the two microenvironments are not equivalent. In this study we employed reverse phase protein microarrays (RPPA) to compare the protein kinases signal pathway derangements in the primary CRC and in its synchronous liver metastasis. Methods: Pure cell populations of 34 cases of patient-matched CRC and hepatic metastases (collected at the same surgical time) were isolated through laser capture microdissection and then lysed. The lysed cells were evaluated using RPPA technology that allowed us to analyze the activation status of 80 different kinases. Data analysis was performed using commercially available software. Results: Of the 80 kinases only 20 endpoints were significantly (p< 0.05) altered between the two populations. These endpoints were contained within just a few signaling pathways, including the PI3K-AKT prosurvival pathway and the c-kit/PDGFr/c-abl growth factor pathway. We noted a significant increase in phosphorylation of AKT along with a decrease in phosphorylation of PTEN in the liver metastasis compared to the matched primary tumors. This is in keeping with what is known about AKT since phosphorylation of PTEN serves to destabilize the protein, which serves as a natural upstream suppressor of AKT kinase. Conclusions: Specific cell signaling pathways, such as the PI3K-AKT and the c-kit/PDGFr/c-abl growth factor signaling pathway, are significantly altered and activated in hepatic metastasis compared to the primary colorectal site. Since the data reveals elevation in kinase activity increases on a pathway-wide level, a rational hypothesis can be developed whereby combinations of drugs such as an AKT- mTOR inhibitor and/or Gleevec may be an effective and novel therapeutic strategy for the treatment of metastatic CRC.

No significant financial relationships to disclose.
KRAS mutations preclude tumor shrinkage of colorectal cancers treated with cetuximab
Authors: De Roock W. , De Schutter J. , De Hertogh G. , Janssens M. , Biesmans B. , Personeni N. , Geboes K. , Verslype C. , Van Cutsem E. , Tejpar S.
Published: March 2020

4132

Background: A recent study has shown that the presence of a KRAS mutation is associated with the absence of objective response to cetuximab (CTX) in advanced colorectal cancers (mCRC). Our hypothesis was that CTX cannot induce any tumor shrinkage in KRAS mutant mCRC. Methods: We analyzed KRAS exon 2 mutation status by Taqman, PCR and sequencing on 37 available tumor samples from patients with mCRC progressive on chemotherapy. Twenty patients received CTX combined with irinotecan (BOND) and 17 received CTX in monotherapy (7 BOND, 10 SALVAGE). We measured the change in tumor size between baseline and the consecutive evaluations. At week 12 and at week 24, we statistically tested the change from baseline between the groups with KRAS wild type (WT) and KRAS mutation (MUT) using the t-test. RECIST criteria for tumor response were used. Results: 3 patients had progressive disease (PD), 26 stable disease (SD), 8 partial response (PR) and 0 complete response. A KRAS MUT was found in 17 tumors (46%): 2 in PD (66.7%), 15 in SD (57.7%) and none in PR patients (p<0.01; responders vs. non responders). At 12 weeks there was a mean decrease in tumor size of 23.1% (SE=7.38) in the KRAS WT and an increase of 2.6% (SE=4.13) in the KRAS MUT mCRC. At 24 weeks KRAS WT and MUT mCRC had a 45.8% (SE=8.61) and a 1.3% (SE=6.67) mean decrease respectively (p= 0.0081 at 12 weeks; p=0.0015 at 24 weeks). The mean tumor size of the KRAS WT did not decrease further after 24 weeks. In the subgroup of SD tumor size regression was observed but only in WT patients. Mean time to progression was 32 (range 12–96) and 30 weeks (range 12–84) for KRAS WT (SD + PR) and MUT respectively. Conclusion: We confirmed KRAS MUT precludes objective response to CTX in mCRC. In addition we found tumor size regression in SD patients being restricted to WT patients. We observed rapid onset of these differences suggesting an important role of KRAS MUT status in early tumor shrinkage. However the onset of progression was not different according to KRAS MUT status.

[Table: see text]
Simplification of cetuximab (Cet) administration: double dose every second week as a 60 minute infusion
Authors: Pfeiffer P. , Bjerregaard J. K. , Qvortrup C. , Jensen B. V. , Yilmaz M. , Nielsen D.
Published: March 2020

4133

Background: CetIri (Cetuximab and irinotecan (Iri)) is effective in pretreated patients with advanced colorectal cancer (ACRC). Presently it is recommended that Cet is administered weekly. Inspired by a pharmacokinetic study (Tabernero et al, ASCO 2006), and due to long waiting time to begin CetIri in our institutions, we have gradually simplified the administration of CetIri. Methods: From January to September 2005, patients received standard CetIri (Cet loading dose 400 mg/m2 as a 120 minutes infusion and then weekly Cet 250 mg/m2 in 60 minutes. Iri 180 mg/m2 every second week started 1 hour after completion of Cet). From October 2005 we gradually enhanced the simplicity of administration. Presently Cet 500 mg/m2 is administered every 2 weeks. The first course is infused in 120 minutes followed 1 hour later by Iri 180 mg/m2 as a 30 minutes infusion. Subsequent courses of Cet are infused in 60 minutes, immediately followed by Iri - resulting in a total treatment time of only 90 minutes per 2 weeks. Results: All patients had ACRC resistant to 5-FU, Iri and Ox and CetIri was offered independently of EGFR expression. 65 consecutive patients with ACRC received standard CetIri and 57 patients biweekly CetIri. There was no difference in patient characteristics. Duration of therapy (4.7 vs 4.1 months), response rate (20 vs 23 %), TTP (5.4 vs 4.8 months) and survival (10.4 vs 9.8 months) were similar. Grade 3–4 non-hematological toxicity was rare (skin toxicity: 8 vs 7%, diarrhea: 10 vs 8 %, fatigue: 8 vs 5 %). Conclusion: Salvage therapy with simplified CetIri every second week is a convenient, effective and well-tolerated regimen in ACRC patients resistant to 5-FU, Iri, and Ox. To confirm results an ongoing phase II study will include 100 patients.

No significant financial relationships to disclose.
Hereditary diffuse gastric cancer: Natural history, pathology, screening limitations, and prophylactic total gastrectomy in CDH1 mutation carriers
Authors: Lynch H. T. , Caldas C. , Wirtzfeld D. , Vaccaro C. , Rubinstein W. , Weissman S. , Kaurah P. , Boyd N. , Fitzgerald R. , Huntsman D.
Published: March 2020

4500

Background: Hereditary diffuse gastric cancer (HDGC) is a potentially fatal disease that occurs due to mutations in the E- cadherin (CDH1) gene, as discovered in 1998. Its penetrance ranges between 70–80%. Its morbidity and mortality can be altered favorably through genetic counseling, germline mutation testing, and highly-targeted management that includes prophylactic total gastrectomy. Lobular breast cancer has been identified as an integral lesion in HDGC. Methods: This international collaborative group on HDGC is comprised of 56 mutation-positive families, which is the world’s largest resource of such families. Cancer diagnoses were verified with pathology slides/tissue block review when possible, or reports. Genetic counseling covering the pros and cons of mutation testing, screening and its limitations, and the option of prophylactic total gastrectomy was provided. Results: Findings on 56 HDGC mutation-positive families show carrier testing to have been performed on 267 individuals, of which 123 were CDH1 mutation positive. Prophylactic gastrectomies were performed on 14 families involving 50 individuals. Occult cancer was diagnosed in 31 (31/39=79.5%; results are pending on the remaining 11), based upon pathology and verbal reports. Five individuals underwent prophylactic gastrectomy prior to genetic counseling, 3 of whom later tested negative for mutations. In one of these remarkable HDGC families, 11 first cousins who tested positive for the CDH1 mutation underwent prophylactic total gastrectomy. On a post-surgery questionnaire, they each stated that the decision for the prophylactic procedure was the “right one” for them. In each case, a parent had died of HDGC sequelae, adding to the cousins’ acceptance of DNA testing and surgery. They considered their post-operative nutritional programs to have been acceptable. Conclusion: HDGC and its life-threatening sequelae were significantly ameliorated in CDH1 mutation carriers through total prophylactic gastrectomy in patients at enormous lifetime risk for HDGC. Decision for mutation testing and surgery may be more acceptable through intensive education in concert with a compassionate management team.

No significant financial relationships to disclose.
MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study
Authors: Hobday T. J. , Rubin J. , Holen K. , Picus J. , Donehower R. , Marschke R. , Maples W. , Lloyd R. , Mahoney M. , Erlichman C.
Published: March 2020

4504

Background: Treatment options for metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet derived growth factor receptor receptor-β (PDGFR-β). Sorafenib, a small-molecule inhibitor of the VEGFR-2 and PDGFR-β tyrosine kinase domains, is a rational targeted therapy to evaluate in NET. Methods: Eligibility criteria included: ECOG PS = 2, = 1 prior chemotherapy, good organ function and signed informed consent. Prior interferon and prior or concurrent octreotide at a stable dose were allowed. Pts unable to take oral medications, with uncontrolled hypertension or with symptomatic coronary artery disease were excluded. Pts received sorafenib 400 mg po BID. Primary endpoint was response by RECIST in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. Results: 93 pts were enrolled: (50 CT, 43 ICC). For pts evaluable for the primary endpoint, 4 of 41 (10%) CT pts and 4 of 41 (10%) ICC pts had a PR. There were 3 minor responses (MR = 20–29% decrease in sum of target lesion diameters) in CT pts and 9 MRs in ICC pts for PR+MR rate of 17% for CT pts and 32% for ICC pts. For pts evaluable, 6-month progression-free survival was observed in 8/20 CT and 14/23 ICC pts. Grade 3–4 toxicity occurred in 43% of pts, with skin (20%), GI (7%) and fatigue (9%) most common. Translational studies from tumor tissue will be presented. Conclusions: Sorafenib at 400 mg po BID has modest activity in metastatic neuroendocrine tumors, with frequent grade = 3 toxicity. Supported by NOI CM6225.

No significant financial relationships to disclose.
Randomized phase III study of S-1 alone versus S-1 + cisplatin in the treatment for advanced gastric cancer (The SPIRITS trial) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the treatment for stomach cancer
Authors: Narahara H. , Koizumi W. , Hara T. , Takagane A. , Akiya T. , Takagi M. , Miyashita K. , Nishizaki T. , Kobayashi O. ,   TS-1 Advanced Gastric Cancer (AGC) Clinical TrialGroup
Published: March 2020

4514

Background: S-1 has been widely used against advanced gastric cancer (AGC) not only as monotherapy but also in combination with other cytotoxic compounds. Results of a phase I/II study combining S-1 + cisplatin (CDDP) were very encouraging with a high response rate (RR) of 76%, and the MST (Median Survival Time) of 383 days (Koizumi W et al, Br J Cancer, 2003). Based on these results, a phase III study comparing S-1 alone with S-1 + CDDP has been conducted to further evaluate the efficacy and safety for S-1 + CDDP as a standard treatment for AGC. Methods: This is a randomized, controlled, open-label, parallel, multicenter study. Patients (pts) are randomized to one of two treatment arms. Arm A: Pts receive oral S-1 (40 mg/m2) twice daily 28 days followed by 14 days rest. Arm B: Pts receive oral S-1 (40 mg/m2) twice daily 21 days followed by 14 days rest plus CDDP (60 mg/m2) iv on day 8. Eligibility criteria included unresectable/recurrent AGC, age 20–74, no prior chemotherapy for AGC. Primary endpoint was overall survival (OS). Main secondary endpoints included RR, time to treatment failure (TTF) and toxicity. Based on planned sample size of 284 pts, the trial was designed to have 90% power to detect an improvement in median OS from 8 to 12 months (2-sided log-rank test; significance level 0.05). Results: 305 pts (Arm A/B, 152/153) were randomized between Mar 2002 and Nov 2004. The eligible pts were 299 (Arm A/B, 150/149). Median age was 62.0/61.5 yrs. At a 2 yrs follow-up since last patient in, the MST for Arm A was 335.5 days (95%CI: 292.0 - 402.0) and for Arm B was 396.0 days (95%CI: 342.0 - 471.0). The OS for Arm B was superior to Arm A (log-rank p=0.0366, hazard ratio: 0.774, 95% CI: 0.608 - 0.985). RR was 31.1% for Arm A and 54.0% for Arm B. In Arm A vs Arm B, the most common grade 3/4 toxicities were: leucopenia, 2.0% vs 11.5%; neutropenia, 10.7% vs 39.9%; anemia (decreased Hb), 4.0% vs 25.7%; nausea, 1.3% vs 11.5%; anorexia, 6.0% vs 30.4%. No treatment related death was observed. Conclusions: The combination treatment of S-1 and CDDP met primary endpoint of OS, and was found to be effective and well tolerated in pts with AGC. Accordingly, this regimen can be regarded as one of first-line standard treatment for AGC.

No significant financial relationships to disclose.
Multi-center phase II/III randomized controlled clinical trial using TNFerade combined with chemoradiation in patients with locally advanced pancreatic cancer (LAPC)
Authors: Posner M. , Chang K. J. , Rosemurgy A. , Stephenson J. , Khan M. , Reid T. , Fisher W. E. , Waxman I. , Von Hoff D. , Hecht R.
Published: March 2020

4518

Background: TNFerade is a replication-deficient adenoviral vector carrying the transgene for human TNF-a protein, regulated by the radiation-inducible promoter Egr-1. A 50 patient (pt) phase II dose-escalation study in LAPC showed a possible dose-dependent improvement in survival. To confirm these findings, the randomized Pancreatic Cancer Clinical Trial with TNFerade (PACT) study was developed. PACT is a 330 pt study, powered to detect a 20% absolute increase in the primary efficacy endpoint (overall survival at 1 year) compared to standard of care (SOC) chemoradiation. An interim analysis of safety and efficacy was planned after the first 51 pts were randomized. Survival data to 11/15/06 has been evaluated and are reported here. Methods: The TNFerade arm pts received a five- wk treatment of weekly injections of 4 x 1011 pu TNFerade, continuous infusion 5-FU (200 mg/m2/day x 5 days/wk) and 50.4 Gy radiation. TNFerade was administered by percutaneous CT-guided transabdominal injection. The SOC arm received the same regimen, without TNFerade injections. Patients were randomized 2:1 to the TNFerade and SOC arms. The first 51 randomized pts were assessed for evidence of objective response (OR) and overall survival Results: Assessment of response data is still ongoing. TNFerade + SOC was well tolerated. One year survival, the primary endpoint of the study, was 70.5% in the TNFerade + SOC arm versus 28.0% in the SOC arm, an absolute increase of 42.5%. The median survival for TNFerade + SOC pts was 515 days compared to 335 days for the SOC pts. The logrank statistic for comparison between the two arms is X2 = 2.014 (p=0.16). Conclusions: The interim survival data is preliminary. The magnitude of the difference in survival in favor of the TNFerade + SOC arm, however, is encouraging. The data appears to corroborate previous findings from the dose-escalation study, which showed an apparent survival advantage in the 4×1011 pu dose group compared to 4 x 109 pu group. A second interim analysis is planned with larger patient numbers to determine whether this early positive trend is confirmed.

No significant financial relationships to disclose.
Correlation of RTOG 9704 (adjuvant therapy (rx) of pancreatic adenocarcinoma (pan ca)) radiation therapy quality assurance scores (RTQASc) with survival (S)
Authors: Abrams R. A. , Winter K. A. , Regine W. F. , Safran H. , Hoffman J. P. , Konski A. A. , Benson A. B. , Macdonald J. S. , Rich T. A. , Willett C. G.
Published: March 2020

4523

Background: RTOG 9704 demonstrated a marginal S advantage (p=0.054) in multivariate analysis (MVA) of Gemcitabine (G) over 5FU before and after 5FU+RT for patients (pts) with pan ca resected for cure from the pan head but not from non-head sites (ASCO 2006, ASTRO 2006). This analysis was undertaken to assess the impact of RTQASc on S, S by treatment (rx) arm, and toxicity by rx arm. Methods: This is a secondary analysis of a prospective, randomized, phase III trial of the RTOG, ECOG, and SWOG. RTQASc was graded as per protocol (PP) or less than (<) PP. Using prospectively defined guidelines, <PP scores were variation acceptable (VA), variation unacceptable (VU), or incomplete/not evaluable (I/NE). I/NE pts were excluded from further analysis. Toxicities were scored by CTC, v 2.0. S is expressed as median S in yrs. Results: 416 pts had RTQASc of PP (216, 52%) or <PP (200, 48%; 42% VA, 6% VU). Frequency of PP and <PP did not differ by rx arm (PP = 55% on 5FU arm and 48% on G arm). Looking at PP vs <PP frequency of Grade 3+ Heme and Non- Heme toxicity did not vary significantly on the 5FU arm but did show a trend of < toxicity for PP pts on the G arm ( Table ). In contrast, S was increased for all (head, non-head) PP pts (median S 1.74 vs 1.47 yrs, p=0.019) and, in MVA, score of PP significantly impacted on S (p=0.02) but rx arm did not. PP and <PP S curves began to diverge at 14–15 months post surgery. For head pts, in MVA, RTQASc (PP superior to  than S of VA (1.41yrs) and VU (1.37yrs) pts. Conclusions: In this study prospectively defined RTQASc significantly correlated with S and effect of rx arm on S and showed a weaker effect on toxicity (G arm only). Timing of appearance of RTQASc effect on S implies effect on tumor control. In this context failure to consider RTQASc may confound observed outcomes and confuse correct understanding of the importance of RT.

[Table: see text]

No significant financial relationships to disclose.
Irinotecan plus S-1 (IRIS) versus S-1 alone as first line treatment for advanced gastric cancer: Preliminary results of a randomized phase III study (GC0301/TOP-002)
Authors: Chin K. , Iishi H. , Imamura H. , Kobayashi O. , Imamoto H. , Esaki T. , Kato M. , Tanaka Y. , Furukawa H.
Published: March 2020

4525

Background: Irinotecan has single agent activity and combination activity with S-1 reportedly in phase I/II studies with advanced gastric cancer patients (pts). S-1, oral fluoropyrimidine, also has activity on gastric cancer. A multicenter, randomized phase III trial comparing IRIS to S-1 alone in advanced gastric cancer was conducted. Methods: Pts with previously untreated gastric cancer were randomized to Arm A (oral S-1 80 mg/m2/day from day 1 to 28 followed by a 14-day rest period), or Arm B (oral S-1 80 mg/m2/day from day 1 to 21 and intravenous irinotecan 80 mg/m2 on days 1 and 15 followed by a 14-day rest). Treatment was continued unless disease progression was observed. Inclusion criteria: PS (ECOG) of 0 to 2; adequate major organ functions. Primary endpoint was overall survival. Results: From June 2004 to November 2005, 326 pts were randomized to arm A (162 pts) and arm B (164 pts). Pts characteristics (arm A vs. arm B) were as follows: median age: 63 vs. 63 years, PS 0–1: 97% vs. 97%, and distribution of subtype of intestinal/diffuse/others: 44%/55%/1% vs. 41%/58%/1%. Among 187 RECIST-evaluable pts (93 vs 94) reviewed by independent review panel, best response rates were 26.9% for arm A and 41.5% for arm B(p=0.035). Among 319 toxicity-evaluable patients (161 vs 158), grade 3 or 4 toxicities for arm A vs arm B (% of pts) were as follows: neutropenia 9.3% vs 26.6%, diarrhea 5.6% vs 15.8%, anorexia 9.9% vs 15.8%, nausea 3.7% vs 7.0%, vomiting 0.6% vs 2.5%. Conclusions: IRIS is effective, and well tolerated in pts with advanced gastric cancer. Survival analysis is underway.

No significant financial relationships to disclose.
Cetuximab plus weekly oxaliplatin/5FU/FA (FUFOX) in 1st line metastatic gastric cancer. Final results from a multicenter phase II study of the AIO upper GI study group
Authors: Lordick F. , Lorenzen S. , Hegewisch-Becker S. , Folprecht G. , Wöll E. , Decker T. , Endlicher E. , Röthling N. , Fend F. , Peschel C.
Published: March 2020

4526

Background: Cetuximab and oxaliplatin-5FU/FA are active in first-line metastatic colorectal cancer. Here we report on the final results from a trial assessing the efficacy of this combination in advanced gastric cancer. Methods: Pts received cetuximab 400mg/m2 at first infusion followed by weekly 250mg/m2 combined with the FUFOX regimen (oxaliplatin 50mg/m2 plus 5FU 2,000mg/m2 plus DL-folinic acid 200mg/m2 d1,8,15,22 qd36). The primary endpoint was response according to RECIST. Toxicity was reported according to NCI.CTC v3.0. Results: From 4/05 until 03/06 we included 52 pts at 7 study centers: 13 women and 39 men; median age 63 years (38–80). ECOG-PS 0/1/2 in 19/25/8 patients. Median number of involved organ sites 3 (1–5), 46% liver and 31% peritoneal involvement. EGFR was detectable by immunohistochemistry (IHC) in 59.5%. 5 pts (9.6%) died within 60 days after study inclusion, two deaths were treatment-related (1 hypersensitivity reaction, 1 septic diarrhea). One patient withdrew consent during the first infusion cycle and is therefore excluded from the following analyses. Reported grade 3/4 adverse events in 51 evaluable pts were: leukopenia 2.0%, febrile neutropenia 5.9%, thrombocytopenia 2.0%, nausea 5.9%, diarrhea 33.3%, fatigue 9.8%, sensory neuropathy 3.9%, hand-foot-syndrome 5.9%, skin-reactions 23.5%. Response is evaluable in 46 patients showing an overall response rate of 65.2% [CI 95%: 49.8; 78.6] including 4 complete and 26 partial responses. Eighteen (39.1%) responses have been confirmed. The reponse rate according to the EGFR-status is 76.5% in undetectable and 54.2% in detectable tumors. Intention-to-treat analysis reveals a time to progression (TTP) of 7.6 months [CI 95% 5.0; 10.1] and an overall survival (OS) of 9.5 months [CI 95%: 7.9; 11.1]. Conclusions: Cetuximab plus FUFOX is highly active in metastatic gastric cancer, irrespective of the EGFR detection by IHC.

No significant financial relationships to disclose.
Serum proteomic profiling of advanced gastric cancer and identification of proteomic changes following response to epirubicin, cisplatin and capecitabine chemotherapy as diagnostic and predictive biomarkers
Authors: Helgason H. H. , Engwegen J. Y. , Cats A. , Boot H. , Kuiper M. , Zapatka M. , Joerger M. , Beijnen J. H. , Schellens J. H.
Published: March 2020

4537

Background: Gastric cancer is the fourth most commonly diagnosed cancer and is the second leading cause of cancer death worldwide. Prognosis is highly dependent on stage at diagnosis making early diagnosis mandatory. By using SELDI - TOF mass spectrometry we compared serum protein profiles of gastric cancer patients with healthy controls and those of gastric cancer patients responding to first-line ECC chemotherapy with those with no response or early progressive disease. Methods: Serum from patients with advanced gastric cancer (GC) was obtained, according to a predefined schedule, prior to start of first-line epirubicin (50 mg/m2 day 1), cisplatin (60 mg/m2 day 1) and capecitabine (1,000 mg/m2 d1–14) chemotherapy (ECC) and serially before each treatment cycle every 3 weeks and analyzed by standardized SELDI-TOF MS/MS. Serum proteomic profiles of GC patients were compared with those of matched healthy controls and proteomic profile changes in responding and non-responding patients were analyzed. Results: In total 82 patients (mean age 57 years) were treated with mean 5 ECC cycles resulting in a response rate of 35%, mean time to progression of 7.1 months and mean overall survival of 12.4 months (95% CI: 10.7 - 14.1). By comparing GC patients and healthy controls we identified 18 m/z values that significantly (p < 0.00001) differentiated between the two groups (m/z 2.7 - 66.6 kDa). Comparison of responding and non-responding patients identified 2 proteins, m/z 3109 and 7559 Da, potentially predicting response (p < 0.001). Serial analysis of proteins changing differently during chemotherapy according to response will be performed. Conclusions: We identified 18 m/z values/proteins that highly (p < 1.0 E-05) discriminated between gastric cancer patients and healthy controls serving as candidate biomarkers of gastric cancer and 2 m/z values that significantly predicted response to chemotherapy.

No significant financial relationships to disclose.
A randomized phase II trial of adjuvant chemotherapy with uracil / tegafur (UFT) and gemcitabine (GEM) vs. gemcitabine alone in patients with resected pancreatic cancer
Authors: Yoshitomi H. , Togawa A. , Kimura F. , Shimizu H. , Yoshidome H. , Miyazaki M. ,   Chiba study group of adjuvant chemotherapy for pancreatic cancer (CSAP)
Published: March 2020

4542

Background: GEM is now the standard therapy for patients with advanced pancreatic cancer (PC). However, there have been few randomized studies of adjuvant chemotherapy with GEM in patients with resected PC. Methods: Patients with invasive ductal pancreatic cancer who underwent radical surgery were enrolled. Within 8weeks after operation, pts were randomized to receive UFT and GEM (GU) or GEM alone (G). GEM was administrated at a dosage of 1g/m2 IV weekly X3 out of 4weeks and UFT at a dosage of 200mg/body/day orally continuously. Eligibility included histological residual tumor (R) 0 or 1, and no previous chemo- or/and radiation therapy. Primary endpoint was 1y disease free survival (DFS) rate and secondary endpoints included overall survival (OS) and side effects in both groups. Results: Between 05/02 and 12/05, 100 patients were randomized into the two arms of the trial (50 pts to GU and 50 to G). No pts were found to be ineligible. Pts characteristics were well balanced (GU/G) with regard to median age (62/63y), tumor status (T3+4 88/94%), nodal status (N positive 77/72%), histological residual tumor status (R0 76/68%). Until 03/06, 1y DFS rate was 50.3% in GU and 45.5% in G and there was no significant difference between two groups. The median OS was 20m in GU and 28m in G (Log rank test: N.S.). Grade 2 or more toxicities were observed in 67.3% of GU pts and 56.3% of G pts (N.S.). No grade 4 or more toxicity was observed in either groups. Leucocytopenia was the most frequently observed side effect in both groups (Grade 2 or more GU/G 49/46%). Conclusion: Preliminary results confirm the efficacy and safety of GEM based adjuvant chemotherapy for pts with resected PC, but addition of UFT with GEM dose not improve DFS as compared with GEM alone, so far. Final results will be presented at the meeting.

No significant financial relationships to disclose.
RAS peptide vaccination in resected pancreatic cancer patients - persistence of anti tumour response and long term survival
Authors: Buanes T. , Bernhardt S. , Lislerud K. , Gladhaug I. , Moeller M. , Eriksen J. A. , Gaudernack G.
Published: March 2020

4543

Background: K-RAS mutations are found in most adenocarcinoma of the pancreas, and targeting mutant RAS by vaccination may be of clinical importance. The present follow-up study was performed to determine whether or not mutant RAS specific T cells were still present in long term survivors seven to nine years after postoperative adjuvant vaccination with synthetic mutant RAS peptides Methods: During 1995–98, all together 23 patients were recruited into two clinical studies. The patients in CTN95002 (n = 10) were given a single mutant RAS peptide (100μg) corresponding to the RAS mutation identified in the patient’s tumor. Patients in CTN98010 (n = 13) were given a mixture of seven mutant RAS peptides, (700μg), corresponding to the most common mutations in pancreatic adenocarcinoma, in a 10 week vaccination regimen, using GM-CSF as an adjuvant, and boosters for an extended period. Immune responses were measured as skin reaction (DTH) and/or in vitro T-cell response. Blood samples from the five patients, still alive in 2006, were investigated by in vitro T-cell proliferation assay for immunological memory. Results: The five surviving patients were all immune responders during the primary vaccination period. Analysis of T-cell reactivity was performed seven (one patient), eight (one patient) and nine years (three patients) after resection/vaccination. Three patients still showed immune responses against the vaccine given previously. T cell reactivity against the Gly12Val mutation was observed in one patient receiving this peptide. In another patient a strong T cell reactivity against all seven peptides present in the vaccine, was observed. Conclusions: Long term survival beyond seven to nine years was only found in patients who primarily responded immunologically on the RAS-vaccination. Long term immunological memory can be induced by peptide vaccination.

No significant financial relationships to disclose.
Modified FOLFOX in combination with docetaxel for patients with metastatic adenocarcinoma of the stomach or gastroesophageal junction: A multicenter phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
Authors: Al-Batran S. , Hartmann J. T. , Hofheinz R. , Mahlberg R. , Homann N. , Probst S. , Stoehlmacher J. , Fritz M. , Rethwisch V. , Seipelt G. , Jäger E.
Published: March 2020

4545

Background: The combination of docetaxel, cisplatin, and fluorouracil (DCF) is clearly superior to CF in the treatment of patients (pts) with advanced gastric cancer (AGC). DCF is, however, associated with significant toxicity, including neutropenia, febrile neutropenia, diarrhea and mucositis. This study evaluated a biweekly, oxaliplatin-based modification of DCF. Methods: Pts with measurable, locally advanced or metastatic adenocarcinoma of the stomach or GE-junction and no prior chemotherapy received mFOLFOX (oxaliplatin 85 mg/sqm, leucovorin 200 mg/sqm, and fluorouracil 2.6 g/sqm via 24hr infusion) in combination with docetaxel 50 mg/sqm on day 1 every 2 weeks (FLOT-regimen). Prophylactic G-CSF was not administered. Overall response rate (RR) was the primary endpoint (power 80% to detect a RR of >40%) and toxicity profile the main secondary endpoint. The study was externally monitored according to GCP and data were reviewed by an independent safety board. Results: 59 pts (male, 41; female, 18) were enrolled. At the time of analysis, 53 pts were evaluable for toxicity and 51 pts for response. Median age was 60 (range, 29–76), median ECOG PS was 1, and almost all (93%) pts had metastatic disease. Of 51 pts, 2 had a CR and 25 pts attained a PR, adding to an overall RR of 53% (ITT-analysis). Stable disease was observed in 12 (23.5%) and progressive disease in 6 (11.8%) pts. Six (11.8%) pts were not evaluable for response. NCI-CTC grade 3 or 4 hematologic toxicity included leukopenia in 12 (22.6%), neutropenia in 23 (43%), and anemia in 2 (3.8%) pts. Febrile neutropenia was observed in 1 (1.9%) pt only. Other grade 3 or 4 toxicities included peripheral neuropathy in 4 (7.5%), nausea in 3 (5.7%), vomiting in 2 (3.8%) as well as diarrhea and fatigue in 5 (9.4%) pts each. No treatment related deaths were observed. Conclusions: FLOT is active and has a favorable toxicity profile in the treatment of pts with AGC. It may show activity also in perioperative treatment settings and may be considered as a useful treatment option for elderly pts. Survival data will be presented at the meeting.

[Table: see text]
A randomized multi-center phase II trial of capecitabine (X) versus S-1 (S) as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer
Authors: Kang Y. , Lee J. , Min Y. , Lee K. , Zang D. , Ryoo B. , Kim J. , Park S. , Kang W. , Shin D.
Published: March 2020

4546

Background: Although the combination chemotherapy is the standard of care for young patients (pts) with advanced gastric cancer (AGC), single agent chemotherapy may be a good alternative for elderly pts. Recent introduction of two new generation oral fluoropyrimidines, capecitabine and S-1, prompted us to investigate the activity and safety of these agents in elderly pts with AGC in a randomized multi-center phase II design. ( NCT00278863 ) Methods: Elderly chemo-naïve pts (= 65 years) with measurable metastatic or recurrent gastric cancer were randomly assigned to receive capecitabine (1,250 mg/m2 bid, D1–14 every 3 weeks, arm X) or S-1 (40∼60 mg bid according to BSA, D1–28 every 6 weeks, arm S). The primary endpoint was the response rate (RR). Results: From Oct 2004 to Apr 2006, 96 pts were enrolled. Excluding 5 pts who did not fit inclusion criteria, 91 pts were randomized to arm X (N=46) or arm S (N=45). Median age was 70.5 years for arm S and 71.0 years for arm X. Other clinical and tumor characteristics were well balanced across the two treatment arms. Among 44 assessable pts in arm X, 13 attained partial response (PR, 29.5%), 17 stable disease (SD, 38.6%) and 10 progressive disease (PD); 4 pts were not evaluable (NE). The corresponding disease responses in the 45 assessable pts in arm S were: 1 complete response (2.2%), 12 PR (26.7%), 18 SD (40.0%), 10 PD, and 4 NE. The incidence of grade 3–4 granulocytopenia was 6.8% in arm X and 4.8% in arm S. One episode of febrile neutropenia was observed in arm X. Grade 3–4 non-hematologic toxicities were as follows (arm X vs. S): asthenia (0% vs. 7.2%), anorexia (6.8% vs. 9.5%), diarrhea (2.3% vs. 0%), and HFS (6.8% vs. 0%). With a median follow up of 13.5 months (mo) for survivors (range, 8.1∼21.9), median time to progression and time to treatment failure were 4.8 mo (95% CI, 3.0–6.5) and 4.4 mo (3.6–5.3) for arm X and 4.2 mo (1.5–6.9) and 3.0 mo (1.5–4.5) for arm S. Median overall survival was 10.0 mo (8.0–12.0) for arm X and 7.9 mo (4.1–11.7) for arm S. Conclusions: Both treatments were active and tolerable as a 1st line treatment for elderly pts with AGC.

No significant financial relationships to disclose.
Gastric adenocarcinoma in young patients: A population-based appraisal
Authors: Al-Refaie W. B. , Pisters P. W. , Chang G. J.
Published: March 2020

4547

Background: While gastric adenocarcinoma is uncommon in young patients, reports of their outcomes remain inconsistent. We performed a population-based study of survival outcomes for gastric cancer in young adults (<45 years). Methods: Patients with gastric adenocarcinoma who underwent cancer directed surgery were identified from the Surveillance Epidemiology and End Results registry from 1991 to 2002. Patient demographics, tumor grade, AJCC stage and use of radiation were categorized by age to <45 years, 45 to 70 years and >70 years old. Cancer-specific survival (CSS) was evaluated using Kaplan-Meier analysis with log rank comparisons. Cox multiple regression analysis was performed to adjust for confounder effects. Results: A total of 20,830 patients were identified: 1,051 (5%) <45 years old [Grp 1], 8,456 (40.6%) 45–70 years old [Grp 2], and 11,323 (54.4%) >70 years old [Grp 3]. Grp 1 was more likely than Grp 2 to have advanced nodal disease (multinomial odds ratio [OR]=1.5 for N2 vs N0, 95% confidence interval [CI] 1.14–2.0, p=0.004; OR=2.0 for N3 vs N0, CI 1.4–3.0, p=0.0002) and more likely to have metastases at presentation (OR 1.5, p<0.00001). Stage-stratified 3-year cancer- specific survival [CSS] was not associated with age at diagnosis except for stage IV disease ( Table ). On Cox regression, young age did not impact survival (OR 0.95, CI 0.87–1.03, p=0.19). However, female gender, Asian race, earlier disease stage, lower grade, cancer- directed surgery and use of radiotherapy were predictors of better outcome (all p=0.003). Conclusions: Although young patients with gastric cancer in this population-based study present with more advanced disease, their stage-stratified cancer specific survival is similar to that of older patients. Stage-dependent, but not age-dependent, treatment should therefore be performed in young patients with gastric cancer.

[Table: see text]

No significant financial relationships to disclose.
Docetaxel, cisplatin and leucovorin/fluorouracil in first-line advanced gastric cancer and adenocarcinoma of the esophagogastric junction: Results of the phase II GASTRO-TAX-1 trial
Authors: Lorenzen S. , Weigert N. , Heinemann V. , Hentrich M. , Schuster T. , Seroneit T. , Röthling N. , Peschel C. , Lordick F.
Published: March 2020

4561

Background: Phase II and III trials combining docetaxel, cisplatin and fluorouracil (DCF) every 3 weeks (wks) have shown superior efficacy but high rates of hematological toxicity in advanced gastric cancer. To reduce toxicity while containing the efficacy of DCF, we conducted a protocol using split doses of docetaxel (T), cisplatin (P), leucovorin (L), fluorouracil (F) (T-PLF). Methods: Chemo-naive patients (pts) with advanced gastroesophageal adenocarcinomas received T 50 mg/m2, P 50 mg/m2 day 1, 15, 29 and L 500 mg/m2 plus F 2,000 mg/m2 d1, 8, 15, 22, 29, 36 qd49. Because significant reductions to <80% of initial drug doses became necessary in 80% of pts, the regimen was amended after the first 15 pts. After the amendment the agents were administered as follows: T 40 mg/m2, P 40 mg/m2, L 200 mg/m2, F 2,000 mg/m2. The primary objective was the overall response rate (ORR) according to RECIST. Results: From 03/04 to 08/05 we included 60 pts: median age 53 yrs, (26–76); 24 pts had locally advanced tumors (LA) and 36 pts had metastatic disease (MET). Pts received a median of 2 (range 0–4) cycles. Reductions to <80% of drug doses were reported in 80% versus 60% of pts pre/post amendment. Reported adverse events were: neutropenia 23%, febrile neutropenia 5%, diarrhea 20%, nausea 8%, emesis 8% and fatigue 20%. The ORR according to RECIST was 46.6% (95%CI 33.3–61.4). Only 6.6% were primarily progressive. 23/24 pts with LA underwent secondary resection (96%). Complete resections (R0) were achieved in 87%. After a median follow-up of 25.5 months, median overall survival (OS) is 17.9 months (95%CI 11.5 -24.3). Median TTP is 9.4 months (95% CI 8.3–10.5). For pts with MET, median TTP is 8.1 months and median OS is 15.1 months. Conclusion: The T-PLF regimen is highly active, safe and has a favorable toxicity profile.

[Table: see text]
Randomized phase II trial of irinotecan, leucovorin and 5-fluorouracil (ILF) versus cisplatin plus ILF (PILF) for advanced gastric cancer
Authors: Shin D. , Lee S. , Park S. , Park J. , Cho E. , Lee J. , Lee W.
Published: March 2020

4580

Background: Irinotecan, in combination with 5-fluorouracil (FU) or cisplatin, clearly demonstrated efficacy against gastric cancer. We compared the combination of irinotecan, leucovorin and FU (ILF) with cisplatin plus ILF (PILF) as first-line chemotherapy in patients with advanced gastric cancer (AGC). Methods: Patients with chemotherapy-naïve, histologically-confirmed, metastatic gastric adenocarcinoma were randomized to receive irinotecan 150 mg/m2 on day 1, leucovorin 20 mg/m2 and a 22-h infusion of FU 1,000 mg/m2 on days 1 and 2 (ILF), or ILF plus cisplatin 30 mg/m2 on day 2 (PILF). Treatment was repeated every 2 weeks until disease progression, unacceptable toxicity, or patients’ refusal. Primary endpoint was response rate which assessed every 4 cycles of chemotherapy. With a single-stage phase II design, the required number of patients was at least 35 per each arm. Results: Of 91 patients registered, 46 patients were treated with ILF and 44 with PILF. For both arms, 635 chemotherapy cycles were delivered (median, 6 for ILF and 8 for PILF; p=0.46). Both ILF and PILF were generally well tolerated. However, PILF was associated with, although statistically insignificant, substantially more grade 3 or 4 toxicities than ILF (46% and 38%, respectively). In the ILF and PILF arm, 11% and 25% of patients, respectively, discontinued treatment because of toxicity. Treatment duration was similar for both arms (4.3 for ILF v 5.6 months for PILF; p=0.13). Four patients died during treatment: one in the ILF arm and 3 in the PILF arm. The objective response rate was 37% for both arms. Disease control (response plus stable disease) was achieved in 59% and 73% (p=0.02) of patients treated with ILF and PILF. There were no significant differences in therapeutic efficacy between ILF and PILF with respect to progression-free (4.8 v 6.2 months; p=0.60) and overall (10.9 v 10.4 months; p=0.93) survival. Conclusions: Both ILF and PILF appear to be active as first-line chemotherapy for AGC, with acceptable safety profiles. Given the comparable efficacy results, ILF could be a reasonable standard chemotherapy for untreated AGC patients.

No significant financial relationships to disclose.
Somatic mutations of EGFR signal transducers and expression of tumor suppressor PTEN in biliary tract carcinoma
Authors: Aglietta M. , Pignochino Y. , Cavalloni G. , Sarotto I. , Penachioni J. , Zanon C. , Migliardi G. , Piacibello W. , Risio M. , Bardelli A. , Leone F.
Published: March 2020

4582

Background: Biliary tract carcinomas express EGFR and are potential candidates to EGFR target therapies. We recently described somatic mutations of EGFR that can enhance MAPK or Akt activation (Clin Cancer Res, 2006). Some of them are identical to those previously reported to confer sensitivity to some tyrosine kinase inhibitors (TKIs) like erlotinib or gefitinib in lung cancer. Here we report a molecular analysis of EGFR transducers potentially involved in TKI response. Methods: In 49 samples of biliary tract carcinoma we performed mutational analysis of exons from 18 to 21 of EGFR, exons 9 and 20 of phosphatidylinositol 3’-kinase (PI3K), exon 2 of K-Ras, exon 15 of B-Raf and exons from 5 to 8 of PTEN. Nuclear PTEN expression was analyzed by immunohistochemistry and the expression in cancer cells was compared to that of normal cholangiocites. Results: Mutations of EGFR have been detected in 7 out of 49 samples (14.3%). One of them was a new stop-codon mutation. Five hotspot mutations of PI3K (codon 545, 546, 1048 and 1059) were found in 4 cases (8.2%); 3 cases (6.1%) had single mutations in K-Ras and 4 (8.2%) had the V599E mutation in B-Raf. In some samples, mutations of multiple trasducers were present simultaneously. PI3K mutations were significantly more frequent in EGFR mutated samples compared to wild type (28% vs. 4.7% respectively, p<0.05). A single F271L mutation of PTEN was observed (2%). We did not find loss of nuclear PTEN in biliary tract carcinoma cells; rather, a stronger labelling intensity (score 2+ or 3+) was present in biliary tract carcinoma compared to normal cholangiocites (score 1+). Moreover, the median percentage of PTEN labeled nuclei in tumor cells was 31.8%, but in samples with activating EGFR mutation was 60%, suggesting that a compensatory change in the level of the phosphatase might counteract the EGFR activition. Conclusions: These results corroborate our previous finding of EGFR pathway activation in EGFR mutated biliary tract carcinoma and suggest that an accurate analysis of the entire series of EGFR transducers may be done before planning treatments with TKIs.

No significant financial relationships to disclose.
A phase II study of pegylated liposomial doxorubicin (PLD) and gemcitabine (G) in the treatment of hepatocellular carcinoma (HCC) not suitable for loco-regional therapy
Authors: Pastorelli D. , Cartei G. , Zustovich F. , Zovato S. , Artioli G. , Ceravolo R. , Nicoletto M. , Binato S. , Mattiazzi M.
Published: March 2020

4585

Background: There is no gold standard pharmacological treatment for HCC not suitable for loco-regional therapy. Antracyclines have been often used for the chemotherapy of HCC with low efficacy and well known toxicity. Availability of new drugs and in particular of PLD could enhance the chance of treatment and contain side-effects. Gemcitabine is active against the most solid tumors. Patients and Methods: We enrolled 35 patients (PTS) with histological diagnosis of HCC not suitable for loco-regional treatment and adequate haematological function.; median age was 63.2 (range 44.0–77.4); male/female=29/6; PS=0 in 30 PTS, PS=1 in 4 PTS and PS=2 in 1 PT. Eighteen PTS had metastatic disease. Prior treatments were TACE in13 PTS, PEI in 9, surgery in 12, RFTA in 5 and chemotherapy in 3. Nineteen patients had Child-Pough A-B cirrhosis HBV-HCV related. PLD was administered at the dose of 30mg/m2 over a 60’ infusion every 28 days and G at the dose of 1,000mg/m2 over 30’ infusion days 1 and 8 every 28 days. Instrumental response evaluation was performed every 3 cycles and treatment was continued until disease progression or major toxicity evidence. Results: All PTS were valuable for toxicity: G1–2 toxicity was neutropenia in 5 PTS, thrombocytopenia in 7, mucositis in 3 and PPE in 3. G3–4 toxicity was neutropenia in 6 PTS and thrombocytopenia in 1. Thirty-four PTS were valuable for response with CR in 2, PR in 6, SD in 12 and PD in 14. Thirty-four PTS were valuable for TTP: median was 6.2+ months (range 1.9–31.7+). All PTS were valuable for OS: median was 8.8+ months (range 1.9–36.5+). Conclusions: The combination of PLD and G is safe and effective in treatment of HCC. No life-threatening toxicity was experienced and disease control rate was about 60%.

No significant financial relationships to disclose.