bluuebunny/crossref_metadata_2025_split huggingface dataset:
Screening patients for fluoropyrimidine-related toxicity risk.
Authors: Capitain Olivier , Seegers Valérie , Metges Jean-Philippe , Faroux Roger , Stampfli Claire , Ferec Marc , Matysiak-Budnik Tamara , Senellart Helene , Rossi Valerie , Blouin Nadege , Boisdron-Celle Michele , Dauve Jonathan , Campone Mario 
Published: May 2019

3529 Background: Severe, sometimes fatal, toxicity can occur during the 1st or 2nd course of chemotherapy using fluoropyrimidines (FPs), and poses a serious public health problem. FPs carry a 3-5% risk of grade ≥ 3 early toxicities and 0.2% risk of death linked to Dihydropyrimidine Dehydrogenase (DPD) deficiency. Methods: Of 29,000 patients screened since July 2000, 472 were referred to us due to severe toxicity during 1st round 5-FU, or because pre-screening was done too late. Toxicity evaluation was performed according to the NCI scale of adverse reactions to cancer drugs (0=none, 5=death). Patients were previously 5-FU naïve, had different cancers, and received various protocols, eg. 5FU or Capecitabine; bolus±continuous or per os. The reliability of the following 4 pre-treatment screening tests to predict grade≥ 4 toxicity was assessed: 1) DPYD genotype mutation (*2A,*2B,*7, 13, HapB3) 2) Plasma uracil (U) level, 3) Plasma dihydrouracil/uracil ratio (UH2/U) 4) a multiparametric approach with genotyping, UH2/U ratio and key patient factors (age, sex, etc.). McNemar’s test with Bonferroni correction was used for statistical analysis. Results: Of the 472 referred patients, 169 had grade 4 or 5 toxicity, of which 41 died from toxicity. 98 had one or plus DPYD mutation: 42(42.9%)*2A; 43(43.9%)*2B; 3(3%)*7; 4(4%)*13; 8(8.16%) HapB3; 1 was homozygous *2A. Data below compare the 4 screening methods for predicting grade 4-5 toxicity. Conclusions: The multiparametric approach is statistically (p<0.0001) the most efficient in terms of preventing grade 4 and 5 toxicity (death) due to 5-FU treatment. Around 290,000 patients are treated with 5-FU per year in the USA. Assuming a 0.2% mortality rate due to toxicity, around 580 lives could be saved per year using the multiparametric pre-treatment test. [Table: see text]
Efficacy of retreatment with anti-EGFRs in mCRC is not predictable by clinical factors related to prior lines of therapy: A multi-institutional analysis.
Authors: Rossini Daniele , Pagani Filippo , Pellino Antonio , Dell'Aquila Emanuela , Liscia Nicole , Bensi Maria , Germani Marco Maria , Masi Gianluca , Moretto Roberto , Santini Daniele , Salvatore Lisa , Scartozzi Mario , Lonardi Sara , Zucchelli Gemma , Ongaro Elena , Falcone Alfredo , Pietrantonio Filippo , Cremolini Chiara 
Published: May 2019

3540 Background: Retrospective analyses and phase 2 studies suggest that administering an anti-EGFR in advanced lines may be effective in mCRC pts who achieved benefit from a 1st-line anti-EGFR containing regimen. The identification of clinical features associated with benefit from anti-EGFR re-treatment (re-tx) in pts experiencing PD during 1st-line anti-EGFR (rechallenge) or after its interruption (reintroduction), is a major clinical need. Methods: A real-life data-base including a total of 5530 pts treated at 6 insitutions from December 2010 to October 2018 was queried. Pts retreated with anti-EGFRs, with RAS/ BRAF wild-type status on tissue samples, who had received a 1st-line anti-EGFR-based tx with at least SD as best response, and at least one further line of therapy before anti-EGFR re-tx, were included. The association with RECIST response (RR), PFS and OS was investigated for the following variables: RR (PR or CR vs SD) and PFS during 1st-line; time from the last anti-EGFR administration to 1st-line PD (i.e. re-introduction vs rechallenge); reason for anti-EGFR discontinuation in 1st-line (PD vs. other); number of anti-EGFR-free lines of therapy before re-tx; anti-EGFR free interval (time between the last anti-EGFR administration in 1st-line and the time of re-tx); primary tumor side; time from the diagnosis of metastatic disease to re-tx (≥ vs. < 18 mos). Results: Data from 86 patients were retrieved, 56 (65%) and 30 (35%) received anti-EGFR rechallenge or reintroduction, respectively. Median anti-EGFR free interval was 15.1 mos. The RR during re-tx was 19.8%, with a DCR of 46.5%. Median PFS and OS were 3.6 and 10.2 mos, respectively. No significant association of investigated features with RR and PFS was observed. No differences in RR or PFS were observed among patients receiving anti-EGFR re-tx as rechallenge or reintroduction (20.4% vs 23.1%, p = 0.99; median PFS: 3.49 vs 4.97 mos, p = 0.61). Patients with left-sided tumors had longer OS (HR: 0.50, 95%CI: 0.26-0.93, p = 0.005). Conclusions: Clinical factors that are generally believed to affect the efficacy of anti-EGFR re-tx are not confirmed in our series. Therefore, clinicians should not rely on those characteristics in their decision-making on anti-EGFR re-tx, and adequate studies for implementing liquid biopsy in clinical practice are urgently needed.
Trifluridine/tipiracil plus bevacizumab in elderly patients with previously untreated metastatic colorectal cancer (KSCC1602): A multicenter, phase II clinical trial.
Authors: Oki Eiji , Makiyama Akitaka , Miyamoto Yuji , Kotaka Masahito , Kawanaka Hirofumi , Miwa Keisuke , Kabashima Akira , Hamanoue Masahiro , Ohchi Takafumi , Kashiwada Tomomi , Shimokawa Mototsugu , Saeki Hiroshi , Akagi Yoshito , Baba Hideo , Mori Masaki 
Published: May 2019

3548 Background: Elderly patients are often intolerable in combination of cytotoxic agents. Recently, Trifluridine/tipiracil plus bevacizumab has been shown as good candidate for the vulnerable patients. We aimed to assess the efficacy and safety of trifluridine/tipiracil plus bevacizumab in elderly patients with metastatic colorectal cancer. Methods: Patients aged 70 years and older with previously untreated, unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were included in this trial. Treatment consisted of trifluridine/tipiracil (35 mg/m2 orally a day on day 1-5 and day 8-12) with bevacizumab (5mg/kg intravenously on day 1 and day 15), given every 4 weeks until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate (ORR), Overall survival (OS) and adverse events (AEs). Results: Between 2017 January and 2018 March, 39 patients were enrolled in this study. The characteristics of patients were male/female : 17/22, median age : 77.5 (range: 70-88) and PS: 0/1 : 31/8. The ORR of 37 patients were assessed by the central review committee. The best response was 40.5(15/37) % (95% CI: 24.8-57.9), and the disease control rate was 86.5 (32/37) % (95% CI: 71.2–95.5). The AEs which were frequent as grade 3 or 4 were leucopenia (71.8 %), neutropenia (48.7 %), anorexia (12.8 %), febrile neutropenia (10.3 %) and fatigue (10.3 %). No treatment related death was reported. Conclusions: The combination of trifluridine/tipiracil plus bevacizumab is an effective and well-tolerated regimen for elderly patients with metastatic colorectal cancer. Hematological adverse events were need for caution. The primary endpoint of PFS will be presented in the end of this year. Clinical trial information: UMIN000025241.
Circulating tumor DNA dynamics, serial testing and evolution on treatment in 322 colorectal cancer patients.
Authors: Kasi Pashtoon Murtaza , Kamatham Saivaishnavi , Colibaseanu Dorin , Merchea Amit , Shahjehan Faisal , Starr Jason Scott , Mody Kabir 
Published: May 2019

3566 Background: According to the American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) joint review on circulating tumor DNA (ctDNA) issued in March 2018, widespread use of ctDNA assays in most patients with advanced cancer is still an area of ongoing research. However, multiple studies thereafter published and/or presented support its use in patients with metastatic colorectal cancer (CRC). This has led to several institutions adopting it as ‘clinical practice’. The aim of this study is to report on our institution’s adoption of ctDNA testing for every patient at the time of diagnosis and/or time of progression. Methods: We report on results of 322 CRC patients with 607 ctDNA tests at our center from January 2017 to February 2019 using a commercially available platform (Guardant360). Results: Among 322 patients of our cohort, a total of 607 ctDNA tests were done (Table). 127 (39.4%) of these tests were serial analyses. In the CRC patients who had serial testing, at progression, mechanisms of resistance included acquisition of KRAS, NRAS, EGFR mutations; and HER2- and MET-amplifications. The subclonal mutations were noted to disappear when the selective inhibition was stopped. This was seen in patients on targeted therapies/biologics rather than chemotherapy. This was of value in treatment modification, clinical trial selection and/or monitoring of disease progression in these patients. Conclusions: While ctDNA testing may not be ready for primetime in all advanced cancers, it is increasingly being adopted in practice for especially metastatic CRC. Of particular value is the serial ctDNA testing in the RAS/RAF wildtype subset and now BRAF V600E mutant CRC on anti-EGFR based therapies. [Table: see text]
Association between pretreatment Fusobacterium nucleatum and cancer pain at six months postsurgery in newly diagnosed colorectal cancer patients: Results from the ColoCare Study.
Authors: Peoples Anita Roselyn , Gigic Biljana , Ose Jennifer , Holowatyj Andreana Natalie , Mallea Patrick M. , Warby Christy A. , Stephens W. Zac , Hardikar Sheetal , Schrotz-King Petra , Ryan-Wolf Julie , Ulrich Alexis B. , Swanson Eric A. , Schneider Martin , Li Christopher I. , Shibata David , Siegel Erin M. , Figueiredo Jane C. , Toriola Adetunji T. , Round June , Ulrich Cornelia M. 
Published: May 2019

3581 Background: Pain is a prevalent, debilitating symptom in more than half of cancer patients. Accumulating evidence suggests a bi-directional relationship between gut microbiota and pain, potentially via inflammation and oxidative stress. Fusobacterium nucleatum (Fn), a pro-inflammatory anaerobic bacterium, is frequently detected in colorectal cancer (CRC) patients. To date, no study has identified a relationship between Fn and cancer pain in CRC patients. We investigated the associations between pre-treatment Fn and cancer pain at 6 months post-surgery in CRC patients. Methods: We utilized pre-surgery stool samples collected from 80 prospectively followed, newly diagnosed CRC patients recruited from the German site of the international ColoCare Study. Eligible patients were neo-adjuvant treatment naïve and did not use antibiotics for at least 1 month before stool collection. Fn DNA was assessed via quantitative real-time polymerase chain reaction. Patients were median split into Fn-high (>17.27; n=40) or Fn-low (≤17.27; n=40). Cancer pain was assessed using the 2 pain symptom items from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core-30 (lower score=lower pain) at pre- and 6 months post-surgery. Results: Before surgery, 48% of all patients reported any pain. At 6 months post-surgery, we observed a decrease in cancer pain by 33% for Fn-low, while there was an increase in cancer pain by 41% for Fn-high. After controlling for pre-surgery cancer pain in ANCOVA model, we observed significantly higher mean cancer pain at 6 months post-surgery in the Fn-high group vs. the Fn-low group (24.07 vs. 13.44; effect size, ES=0.45; p=0.04). These results were maintained even after controlling for age, sex, tumor stage and site, adjuvant chemotherapy, BMI, physical activity, and any pain medications (29.11 vs. 16.55; ES=0.53; p=0.03). Conclusions: These findings suggest that high Fn is an independent predictor of cancer pain at 6 months post-surgery in colorectal cancer patients. Further research is needed to confirm and understand the mechanisms of these results. Funding: NCI U01 CA206110.
Association of PIK3CA mutations (mut) with immune engagement and clinical benefit from immunotherapy in microsatellite stable (MSS) colorectal cancer (CRC) patients (pts).
Authors: Nusrat Maliha , Roszik Jason , Katkhuda Riham , Menter David , Raghav Kanwal Pratap Singh , Morris Van K. , Sharma Padmanee , Allison James Patrick , Blando Jorge M. , Maru Dipen M. , Lizee Gregory , Janku Filip , Overman Michael J. , Kopetz Scott 
Published: May 2019

3604 Background: PI3K pathway alterations, PIK3CA mut or PTEN loss, are known to modulate anti-tumor immune microenvironment. MSS CRC pts respond infrequently to immunotherapy, suggesting the presence of a rare MSS immunogenic subset. We investigated the immune repertoire and outcomes on immunotherapy trials in PIK3CA mut MSS CRC pts. Methods: Immune infiltrates and checkpoints were evaluated using quantitative immuno-histochemistry (IHC) on primary CRC. Mutations were assessed by next generation sequencing. PIK3CA mut neoepitopes and HLA allele affinities were predicted using NetMHC 4.0 Server. Outcomes of MSS CRC pts enrolled in 7 immunotherapy trials were assessed. Clinical benefit (CB) was defined as CR, PR or SD of 24 weeks. Time to progression (TTP) was calculated using Kaplan-Meier Method. PIK3CA mut vs wild type (wt) groups were compared using Mann-Whitney U, Fisher’s exact, or Log-Rank tests as appropriate. Results: PI3K alterations were present in 14/40 MSS CRC pts in IHC cohort (7 PIK3CA mut, 33 wt; 7 PTEN loss, 33 intact). The center of PIK3CA mut MSS CRC had higher median densities of CD3+ cells [1112 (IQ range 865-1421) vs 435 (300-744) cells/mm3; P=0.037] and CD8+ cells [554 (331-1200) vs 185 (60-473) cells/mm3; P=0.037] as compared to PIK3CA wt tumors. Intratumoral immune infiltrates did not differ by PTEN IHC staining in MSS CRC. PD-L1 H-scores were also higher in PIK3CA mut MSS CRC [85 (34-114) vs 29 (11-60); P=0.01]. Several activating PIK3CA mut (E542K, E545K, H1047R) were predicted to generate true neoepitopes with high binding affinity to common HLA types. Indeed, among MSS CRC pts enrolled in 7 immunotherapy trials, half (4/8) of PIK3CA mut pts derived CB as compared to 3/35 (8.6%) PIK3CA wt pts (P=0.015). PIK3CA mut pts had trend towards longer TTP (3.8 months in mut vs 2.1 months in wt; P=0.08). CB or TTP did not differ by colon sidedness, monotherapy / combination therapy, number of mut, or mut in other key genes ( APC, SMAD4, TP53, KRAS, NRAS or BRAF). Conclusions: PIK3CA mut MSS CRC are associated with increased cytotoxic T cell infiltration, higher PD-L1 expression, and greater clinical benefit from immunotherapy. Further investigation of immunotherapy outcomes in the context of neoepitope-HLA allele interaction may help identify a subset of PIK3CA mut MSS CRC pts who are likely to benefit from immunotherapy.
Stage-based variation in the impact of colon cancer surveillance.
Authors: Gately Lucy , Semira Christine , Jalali Azim , Faragher Ian , Ananda Sumitra , Kosmider Suzanne , Field Kathryn M. , Lok Sheau Wen , Steel Malcolm , Lee Margaret , Wong Rachel , Wong Hui-Li , Gibbs Peter 
Published: May 2019

3609 Background: Multiple meta-analyses have demonstrated that routine surveillance following curative intent colorectal cancer surgery improves overall survival. This benefit is largely driven by early detection and curative intent resection of oligometastatic disease. Intuitively, any surveillance benefit should be proportional to recurrence risk, leading some to question the value of surveillance for stage I patients where recurrence rates are low. However, the survival benefit of surveillance has not previously been reported by stage. Methods: We explored data from a multi-site cohort of colorectal cancer patients (pts) diagnosed from 1 January 2001 to 31 December 2016. Pts were followed according to standard protocols with a standardized comprehensive outcome data captured prospectively. Pts with a rectal primary or metastatic disease at presentation were excluded from the analysis. We examined the correlation of stage at diagnosis with tumor recurrence and subsequent outcomes. Results: Of 3608 colon cancer pts, 690 (19%) had stage 1, 1580 (44%) had stage 2, and 1338 (37%) had stage 3 disease. Median follow-up was 7.8 years. Stage at diagnosis impacted recurrence rate (4% stage I vs 12% stage II vs 28% stage III, p < .0001) but not median time to recurrence. Recurrence patterns varied with stage (e.g. distant nodal disease 5% vs 7% vs 16%, p = .003; liver metastases 90% vs 53% vs 42%, p = 0.001). In pts with recurrence, resection of oligometastatic disease varied significantly by stage (58% vs 42% vs 30%, p < .0001) as did post-resection 5 year survival (91% vs 66% vs 43%, p < 0.001). In pts with recurrence treated with palliative intent, stage at diagnosis also impacted post-recurrence 5 year survival (11% vs 7% vs 5%, p < 0.03). Conclusions: Colon cancer stage at diagnosis substantially impacts the proportion of pts able to undergo curative intent surgery for surveillance detected recurrent disease, potentially driven by stage specific metastatic patterns. Stage at diagnosis also has a significant impact on post-resection survival outcomes potentially driven by stage specific biology. Our data indicate a far greater survival impact of surveillance for stage I colon cancer than would be anticipated based on recurrence rate alone.
Long-term outcomes after high-dose chemoradiotherapy for non-surgical management of distal rectal cancer.
Authors: Dizdarevic Edina , Appelt Ane L , Hansen Torben , Ploeen John , Jensen Henrik , Lindebjerg Jan , Rafaelsen Soeren Rafael , Jakobsen Anders Kristian Moeller 
Published: May 2019

3611 Background: Surgery is standard treatment for rectal cancer, but neoadjuvant chemoradiotherapy (CRT) may result in clinical complete response (cCR) in selected patients, allowing for non-surgical management (NSM). Prospective studies of NSM strategies are sparse however, and long-term data on quality of life (QoL) are limited. We conducted a single-arm phase II trial of high-dose CRT for NSM of distal rectal cancer; we report secondary long-term patient-reported outcomes (PROs), local regrowth and overall survival (OS) in patients managed non-surgically. Methods: Fifty-one patients with resectable, T2 or T3, N0–N1, low adenocarcinoma received 65Gy (IMRT, brachytherapy boost) and oral tegafur-uracil. Patients with cCR 6 weeks after treatment (clinical examination, MRI, biopsy) were referred for observation, and followed closely with clinical examinations, endoscopies, PET-CTs, and PROs for 5 years. Overall colorectal cancer specific QoL and specific symptom scores were compared between timepoints using paired Wilcoxon tests. Local regrowth was estimated using cumulative incidence; overall survival using Kaplan-Meier estimates. Results: Forty patients achieved cCR after treatment; 28 were in follow-up at 24m, 21 at 36m, 18 at 60m. Patients left the trial due to local tumor regrowth (n=12), distant metastases (n=3), new primary cancers (n=6) and loss to follow-up (n=1). Average QoL score did not differ between baseline (median 11.1) and 24m (13.7), 48m (11.1,) or 60m (6.9). See Table for individual scores; only rectal bleeding deteriorated from baseline (significantly worse at 24m). At median follow-up of 5.0 years, local regrowth rate and OS were 31% (95 CI 15%-47%) and 85% (95 CI 75%-97%), respectively. Conclusions: Long term follow-up after NSM of early rectal cancer showed excellent general colorectal cancer QoL and local symptom scores. (NCT00952926). EORTC QLQ – CR 29. Proportion reporting ‘quite a bit’ or ‘very much’ on symptom scales. Clinical trial information: NCT00952926. [Table: see text]
S-1 plus oxaliplatin versus S-1 plus cisplatin as first-line treatment for advanced diffuse-type or mixed-type gastric/gastroesophageal junction adenocarcinoma: A randomized, phase 3 trial.
Authors: Xu Rui-hua , Wang Zhi-Qiang , Shen Lin , Wang Wei , Lu Jian-Wei , Dai Guanghai , Xu Jian-Ming , Zhang Yan-Qiao , Chen Xiao-Bing , Deng Yan-Hong , Zhao Yun-Bo , Fan Nan-Feng , Yu Gengsheng , Liao Wangjun , Yuan Xia , Lin You-En , Liu Guo-Long , Zou Qing-Feng 
Published: May 2019

4017 Background: Diffuse-type or mixed-type gastric adenocarcinoma is associated with poor prognosis, and more effective treatment is needed. In Asia, S-1 plus cisplatin (SP) is the standard first-line chemotherapy regimen for advanced gastric cancer. Nevertheless, some clinical data suggested that oxaliplatin-based chemotherapy might be more efficacious and more tolerant than cisplatin-based chemotherapy. Methods: This trial is a multicenter, randomized, parallel-group, open-label, phase 3 trial in China. Patients aged 18-75 years, with PS 0-2, adequate organ function, histology confirmed, unresectable, advanced diffuse-type or mixed-type gastric adenocarcinoma/GEJA were randomized 1:1 to S-1 plus oxaliplatin group (SOX) (S-1: 40-60mg bid on d1-14, q3w; oxaliplatin: 130 mg/m2 on d1, q3w) or SP group (S-1: 40-60mg bid on d1-14, q3w; cisplatin: 60 mg/m2 d1, q3w). The primary endpoint was overall survival (OS) in the full analysis set (FAS). The secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF) and safety. Results: Between Jul 2013 and Jul 2018, 576 patients were randomized and 558 initiated treatment (279 patients/group). The median number of chemotherapy cycles was four in each group. In the FAS, the SOX group showed improved OS (13.0 vs. 11.8 months, HR = 0.764, 95% CI: 0.636-0.918), PFS (5.7 vs. 4.9 months, HR = 0.752, 95%CI: 0.632-0.895), and TTF (5.2 vs. 4.7 months, HR = 0.763, 95%CI: 0.641-0.909) compared with the SP group. In terms of grade≥3 adverse events, SOX showed lower occurrences of neutropenia (10.0% vs. 22.9%), leukopenia (9.7% vs. 21.9%), anemia (4.3% vs. 14.3%),vomiting (3.9% vs. 10.4%), nausea (2.2% vs. 10.4%), anorexia (2.2% vs. 6.8%), and febrile neutropenia (2.5% vs. 6.8%) than SP (all P < 0.05). The occurrence of grade≤2 sensory neuropathy(41.6% vs. 12.2%, P < 0.001)was higher with SOX than with SP. Conclusion: Compared with SP, SOX was more effective and less toxic (except neurosensory toxicity ) in patients with previously untreated advanced diffuse-type or mixed-type gastric adenocarcinoma/GEJA. Clinical trial information: NCT01824459.