bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal treatment strategy in KRAS wild type (wt) metastatic colorectal cancer (mCRC): Cetuximab plus FOLFIRI followed by FOLFOX4 with or without cetuximab-The Capri trial from the Gruppo Oncologico Dell’Italia Meridionale (GOIM).
Authors: Ciardiello Fortunato , Maiello Evaristo , Pisconti Salvatore , Giuliani Francesco , Barone Carlo , Rizzo Mimma , Bordonaro Roberto , Montesarchio Vincenzo , Cinieri Saverio , Martinelli Erika , Troiani Teresa , Delcuratolo Sabina , Simone Gianni , Normanno Nicola , Febbraro Antonio , Tonini Giuseppe , Colucci Giuseppe
Published: March 2020

e14565

Background: Cetuximab in combination with standard doublet chemotherapy is an effective treatment in KRAS wt mCRC patients (pts). The present study investigated a treatment strategy of cetuximab in combination with FOLFOX4 as a second line therapy for KRAS wt mCRC pts treated in first line with cetuximab plus FOLFIRI. Methods: KRAS wt m CRC pts were treated in first line with cetuximab plus FOLFIRI and at progression were randomized (1:1) to receive FOLFOX alone (Arm A) or in combination with cetuximab (Arm B). Primary endpoint for each treatment line was progression-free survival (PFS), with secondary endpoints overall survival (OS), response rate (RR), disease control rate and safety. 221 events would be required to statistically differentiate PFS between the two arms with 80% power for the second line treatment. Here we report the results of first line cetuximab plus FOLFIRI treatment. Results: From July 2009, 344 pts were enrolled: 58% males, median age 63 years (range, 20-81 years), ECOG performance status, 0 (85%); 1 (15%); synchronous metastasis (75%). For the 319 evaluable patients, median PFS was 10 months; overall response rate (ORR) was 55% with 47% partial responses (PR), 8% complete responses (CR) and 35% stable disease (SD) for a disease control rate (DCR) of 90%. The most common grade 3/4 adverse events were: skin reactions (15%), diarrhea (9%) and neutropenia (6%). As of January 31 2013, 118 pts have progressed and have been enrolled in second line treatment (58 Arm A; 60 Arm B). Conclusions: The results of first line treatment with cetuximab plus FOLFIRI confirm in a multicenter trial in prospectively selected KRAS wt mCRC pts the efficacy and tolerability of this combination. The randomized second line part of the study is currently ongoing. Multiple gene next generation sequencing to characterize a 24 genes mutation profile is currently ongoing. Clinical trial information: 2009-014041-81.
Impact of the Recurrence Score (RS) result and mismatch repair status (MMR) on agreement between oncologists (MDs) for stage II colon cancer (CC) recurrence risk (RR) assessment: A novel clinical utility endpoint for prognostic markers.
Authors: Kelley Robin Katie , Lopatin Margarita , Hwang Jimmy , Crager Michael , Brenner Adrienne A , Kuczma Jane , King Ashley , Chao Calvin , Lee Mark , Venook Alan Paul
Published: March 2020

e14569

Background: Appropriate use of prognostic and predictive markers depends on quality of evidence for clinical utility in addition to clinical validity. In stage II CC, RR assessment is based traditionally on clinicopathologic factors (CP) with limited clinical validation and varies substantially across providers. We hypothesized that the validated Oncotype DX Colon Cancer RS and MMR tests may impact clinical decision-making by decreasing variation in RR assessment across MDs. We conducted a survey to compare the level of MD agreement on stage II CC RR assessment using CP alone vs CP+RS+MMR (CP+). Methods: A clinical trial database was randomly sampled for 100 cases of stage II CC stratified on T-stage, MMR and RS groups. Anonymous internet surveys asked each MD to assess 3-year RR for 10 cases with CP and 10 different cases with CP+. MDs were divided into panels of 5; all members of each panel reviewed the same cases. Agreement in RR among MDs was assessed using within-panel mean squared difference in RR assessments and analyzed using generalized linear models. Results: 30 community (C) and 20 university-based (U) MDs (Assoc of Northern California Oncologists or NCCN, respectively) completed evaluable surveys April-June 2012. For C vs U, median years in practice were 5 and 2; prior use of RS 13% vs 25%; and routine MMR use 21% vs 55%. The standard deviation of the differences (SDD) in RR assessments for CP alone was high overall (7%), and greater for U vs C MDs (8.2% vs 6.4%). CP+ produced higher agreement in RR assessments vs CP for both C (p<.001) and U (p=0.04) MDs, with 23% and 20% proportional reduction in SDD. ForT3 MMR-proficient (P) patients (n=70), CP+ produced higher agreement in RR for both C (p<0.001) and U (p=0.01) MDs with 37% and 29% reduction in SDD. Conclusions: Addition of RS+MMR to CP significantly increased MD agreement on RR assessment in stage II CC, including T3 MMR-P patients. Agreement was higher among C than U MDs. MD agreement on stage II CC RR assessment and Tx decision-making warrants consideration as a novel endpoint for clinical utility of RS, MMR, and other prognostic markers.
Retrospective analysis of dose intensity, toxicity, and clinical outcomes in 5-fluorouracil (5FU)-based regimens in adjuvant treatment of colon cancer.
Authors: Loree Jonathan , Mulder Karen E. , Ghosh Sunita , Spratlin Jennifer L.
Published: March 2020

e14575

Background: Adjuvant colon cancer treatment relies on 5FU containing regimens as either an IV formulation or as the oral pro-drug, capecitabine, combined with oxaliplatin (FOLFOX6 and CAPOX). We performed a retrospective chart review comparing average relative dose intensity (ARDI), overall survival (OS), disease free survival (DFS), and toxicity profiles of these two regimens. Methods: 233 patients between January 1, 2006 and December 31, 2011 received chemotherapy combining either FOLFOX6 (n= 128) or CAPOX (n=105) in Edmonton, Alberta. ARDI was compared by calculating a percent of target dose achieved in the average cycle for each patient. Data on OS, DFS, baseline demographics, and toxicities were gathered. Survival data was plotted using the Kaplan-Meier method and compared using the log-rank test. Variable comparisons were performed with the Student’s t-test or the Fisher’s Exact test. Follow up was complete until November 1, 2012. Results: Oxaliplatin ARDI was significantly lower in those treated with CAPOX compared to FOLFOX6 (80.72% vs 87.11%, p=0.0033), as was the 5-FU component (87.10% vs 93.60%, p<0.0001). More patients treated with CAPOX had dose limiting toxicities (84.76% vs 73.40%, p=0.039), and there were significantly more Grade 2 and higher toxicities in those on CAPOX (p<0.0001). A similar percentage of goal number of cycles was achieved between CAPOX and FOLFOX6 (87.38% vs 91.80%, p=0.13) and similar neuropathy was noted between groups. Survival analysis demonstrated similar OS and trends towards improved DFS with CAPOX (1 year – 89.55% vs 83.20%, 3 year – 67.13% vs 58.01%, p=0.051). Stage specific analysis showed stage III patients had improved DFS with CAPOX (1 year – 93.36% vs 86.69%, 3 year- 71.58% vs 68.10%, p=0.042) and trends towards improved OS with CAPOX (1 year – 100% vs 95.56%, 3 year – 95.08% vs 80.17%, p=0.16). The groups had similar age, gender, tumor size, and node status, while ECOG was slightly higher with FOLFOX6 (0.589 vs 0.419, p=0.0315). Conclusions: While patients on CAPOX had significantly lower doses of oxaliplatin and the 5-FU component of their treatment they appear to have improved outcomes compared to FOLFOX6.
Palliative chemotherapy in advanced colorectal cancer patients age 80 or older.
Authors: Lai Pamela , Sud Shelly , Zhang Tinghua , Asmis Timothy R. , Wheatley-Price Paul
Published: March 2020

e14598

Background: Colorectal cancer (CRC) is the second most common cancer worldwide, with a median age at diagnosis of 71 years. While there has been significant progress in chemotherapy (CT) options for metastatic CRC (mCRC) patients (pts) over the past decade, there is very little data on outcomes or toxicity from CT in mCRC pts aged ≥80 years. We investigated palliative CT in the 80+ mCRC population, hypothesizing that high rates of hospitalization and toxicity may be observed. Methods: With ethics approval, a retrospective chart review was conducted of pts ≥80 years with mCRC who initiated a CT course between June 2005 and November 2009 at our institution. Baseline data on pt demographics were collected, in addition to CT data. The endpoints included: rates of hospitalization, CT discontinuation due to toxicity, and overall survival (OS). Results: CT was initiated on 88 occasions during the study period. The median age was 83 (range 80-92) and 52% of pts were male. Where data were available, 60% of pts had a good performance status (PS) of ECOG 0-1, 20% PS 2 and 9% PS 3 (10% unknown). 63 pts (72%) lived with family and 23% lived alone. 76% had a Charlson Comorbidity Index (CCI) ≥7 and 31% were taking ≥6 baseline prescription medications. At baseline, 33% of pts were anemic (Hgb <100), 36% had leukocytosis (WBC>11) and 48% had renal impairment (eGFR <60). Palliation was the intent for 95% of cases and 47 pts (53%) were receiving first line CT. The initial CT dose was adjusted from standard of care in 67% of cases. The most common CT was capecitabine monotherapy (45%). In total 19 pts (22%) were hospitalized during or within 30 days of CT; 26 pts (30%) discontinued CT due to toxicity, and 48 pts (55%) required at least 1 dose reduction, delay or omission. The median OS was 14.6 months (95% CI 11.7-18.6). No baseline factors (age, sex, PS, CCI, line of CT, baseline dose adjustment, baseline blood work) were associated with hospitalization, CT discontinuation due to toxicity, or OS. Conclusions: Palliative CT for mCRC in the ≥80 population is feasible, but most pts will require dose adjustments, and a significant minority will be hospitalized or stop CT due to toxicity. Prospective research incorporating geriatric assessment tools is required.
Panitumumab after progression on cetuximab in patients with KRAS wild-TYPE (WT) metastatic colorectal cancer (MCRC): A single institution experience.
Authors: Marino Antonella , Caliolo Chiara , Sponziello Francesco , Nacci Angelo , Quaranta Annamaria , Mazzoni Enrica , Federico Federica , Rizzo Pietro , Calvani Nicola , Orlando Laura , Schiavone Paola , Fedele Palma , D' Amico Maria , Chetrì Maria Concetta , Cinefra Margherita , Ferrara Pasqualinda , Cinieri Saverio
Published: March 2020

e14605

Background: Cetuximab and panitumumab are monoclonal antibodies that target EGFR, approved for the treatment of KRAS WT MCRC. Few data describe the activity of panitumumabafter cetuximab-irinotecan based regimen failure. Methods: The aim of this study is to assess if panitumumab has some activity in pts with KRAS WT MCRC that has progressed on prior cetuximab. Results: We retrospectively analysed 25 pts with KRAS WT MCRC who received from 07/2009 to 01/2013 panitumumab after progression on cetuximab. Median age: 63 yrs (40-78), primary site tumor: colon 64%, rectum 36%; synchronous metastases 36%, metachronous 64%. Sites of metastases: liver 44%, liver and lung 8%, other sites 48%. All pts had previously received cetuximab associated with irinotecan (20 pts) or oxaliplatin (5 pts) and subsequently received panitumumab. We withdrew cetuximab because of intolerance in 4 pts (16%), while 21 pts (84%) with ECOG PS 0-1 who had previously responded to cetuximab (ORR plus SD lasting more than 5 months) received panitumumab “off-label” after progression on cetuximab because strongly motivated to continue treatment. Median cycles of panitumumab were 7 (1-54). Only eighteen pts were evaluable for ORR (4 pts received 1-2 cycles and then died, 3 pts too early). We observed one PR (5%); five pts (28%) had SD, median duration 9 months. Median PFS was 5 months (3-28) and median OS 8 months (5-41). All pts were evaluable for toxicity. No pts developed anemia, nor neutropenia. One patient (4%) developed grade 2 CTCAE version 4.03 thrombocytopenia. Eight pts (32%) developed grade 2-3 CTCAE version 4.03 dry skin or rash, 2 pts (8%) grade 2 CTCAE version 4.03 nausea-vomiting. Conclusions: Panitumumab has minimal benefit in pts with KRAS WT MCRC who have progressed on prior cetuximab andthis approach up to date should not be adopted in the clinical practice. Our data anyway show a longer PFS and OS as compared to other few series in the same setting. Further confirmatory prospective studies with larger series of pts would be necessary.
Prognostic value of incidental betablockers use in metastatic colorectal cancer patients receiving first-line treatment.
Authors: Del Prete Michela , Giampieri Riccardo , Scartozzi Mario , Maccaroni Elena , Faloppi Luca , Bianconi Maristella , Bittoni Alessandro , Cecchini Luca , Cascinu Stefano
Published: March 2020

e14610

Background: Preclinical and retrospective studies suggested antitumor activity for the incidental use of betablockers in various tumour types. Data regarding colorectal cancer are lacking. We assessed the correlation between the incidental use of betablockers and clinical outcome in colorectal cancer patients receiving first-line therapy. Methods: 235 patients treated with first-line chemotherapy alone (128 patients) and with Bevacizumab (107 patients) were analysed. Patients were stratified for betablockers use, age, sex, site of metastases, previous adjuvant chemotherapy and ECOG performance status. Results: 29 patients (12%) were on treatment with betablockers at the time of first-line therapy: 20 (16%) in the chemotherapy alone group and 9 in the bevacizumab group (8%). In both groups patients receiving or not betablockers were similar for all main clinical characteristics. In the chemotherapy alone group, patients receiving betablockers showed an improved response rate (60% vs. 33%, p=0.044) and overall survival (mOS 41.3 vs 25.7 months, p=0.03, HR:2.26, 95% CI: 1.05-3.24). Only a trend for improved progression free survival was noticed. In the 107 patients receiving chemotherapy with bevacizumab a trend towards a worse overall survival was seen for patients receiving betablockers, although this was not statistically significant (mOS 16 vs 23.7 months, p=0.26, HR:0.64, 95% CI: 0.22-1.49). No significant differences were seen in regards of progression free survival or different response rate patterns between the two groups. Conclusions: Our analysis confirms a potential prognostic role for the use of betablockers in colorectal cancer patients treated with chemotherapy. Our findings are in line with preclinical studies suggesting that beta-adrenergic signalling may regulate cancerogenesis and tumor invasiveness. Our analysis suggests a potential worse outcome for patients on betablockers receiving Bevacizumab-based treatment, although the small number of patients precludes any definitive conclusion. We suggest that in future prospective trials the incidental use of betablockers will be considered a stratification factor for clinical outcome.
Addition of bevacizumab to compensate for the negative influence of attenuated relative dose intensity of cytotoxic agents on the outcome in patients with metastatic colorectal cancer.
Authors: Nakayama Goro , Hayashi Naomi , Tanaka Chie , Fujii Tsutomu , Ando Yuichi , Kodera Yasuhiro
Published: March 2020

e14614

Background: We reported that relative dose intensity (RDI) of key cytotoxic agents, irinotecan (IRI) and oxaliplatin (OX), is a significant predictor of disease control in patients with metastatic colorectal cancer (mCRC). However, in concomitant therapy with bevacizumab (BEV), the influence of adding BEV on the relation between RDI of cytotoxic agents and outcomes are unclear. In this study, we evaluate the impact of BEV on RDI of IRI and OX-based chemotherapy on the outcome of mCRC. Methods: A retrospective analysis of mCRC patients entered into three prospective clinical trials, testing FOLFIRI (CCOG-0502), mFOLFOX6 (CCOG-0704), FOLFIRI plus BEV and mFOLFOX6 plus BEV (CCOG-0801), was performed. RDI was calculated as the delivered dose intensity divided by standard dose intensity calculated for each regimen and compared to response rate (RR), disease control rate (DCR) and progression-free survival (PFS). Results: In FOLFIRI therapy, higher RDI (IRI, >median: 80%) group achieved significant better RR, DCR and PFS than lower RDI (<median) group (RR: 65 vs. 6% [p=0.001], DCR: 100 vs. 41% [p=0.003] and PFS: 9.9 vs. 5.6 months [p=0.002]). The other hand, in FOLFIRI plus BEV therapy, there were no difference between higher and lower RDI (IRI, median: 76%) group in ORR, DCR and PFS (RR: 31 vs. 27% [p=0.779], DCR: 75 vs. 53% [p=0.208] and PFS: 6.2 vs. 7.3 months [p=0.903]). In mFOLFOX6 therapy, higher RDI (OX, >median: 79%) group achieved better disease control than lower RDI group (RR: 47 vs. 33% [p=0.456], DCR: 100 vs. 73% [p=0.032] and PFS: 8.5 vs. 6.2 months [p=0.064]). In addition of BEV, there were no difference between higher and lower RDI (OX, median: 76%) group in any outcomes (RR: 54 vs. 74% [p=0.159], DCR: 88 vs. 91% [p=0.672] and PFS: 11.6 vs. 11.7 months [p=0.797]). Conclusions: RDI of key cytotoxic agents is a significant predictor of disease control, especially in IRI-based regimen. Nevertheless, in concomitant therapy with BEV, there were no relations between RDI of cytotoxic agents and outcomes. These results suggest that BEV could have ‘covering effect’ to reduce the influence of dose modification of cytotoxic agents in mCRC patients.
Metformin and biomarkers relevant to neoplasia in nondiabetic patients.
Authors: Pollak Michael N. , Blouin Marie-Jose , Vasilevsky Carol-Ann , Cefis Luca , Frank Russell , Tao Yuzhen , Li Zhen , Tu Yinggang , Wang Ye , Zakikhani Mahvash , Trifiro Mark , Schwab Matthias
Published: March 2020

e14615

Background: Use of the anti-diabetic drug Metformin has been associated with reduced risk or improved prognosis of several cancers in both lab models and retrospective population studies of diabetics. Plausible mechanisms of action include (1) reduction in serum levels of insulin or inflammatory cytokines and (2) direct effects on target cells due to action of the drug as an inhibitor of mitochondrial respiration, including activation of AMPK. Methods: Non-diabetic subjects (n = 47) consented to bloodwork and sigmoid biopsy at screening colonoscopy, metformin administration (500 mg TID) for 10 weeks, and end-of-study sigmoid biopsy and bloodwork. Serum assays were performed on both fasting and post standard oral glucose load specimens. Metformin levels were measured by mass spectroscopy. Anti-phospho-histone-3 immunostaining was used to quantify proliferation. Results: Metformin reduced fasting levels of c-peptide, insulin, and IL-6 levels by < 10%, a magnitude of change that laboratory studies suggest is unlikely to be biologically significant. However, postprandial insulin levels following metformin were reduced by 18 % relative to baseline postprandial levels, a finding of potential physiologic relevance. Serum metformin level showed considerable variation between subjects (1005 ± 769 ng/ml) and this variation was not correlated with effects of metformin on epithelial proliferation. Proliferation index fell from 5.9 to 3.3, (p<0.03), a change greater than predicted by in vitro studies of direct action of metformin at the concentrations measured in serum. Conclusions: Metformin lowers insulin levels even in non-diabetic subjects, and post prandial insulin levels are more sensitive indicators of metformin action than fasting biomarkers. As high insulin level has been linked to increased cancer risk and/or worse prognosis (eg J Natl Cancer Inst. 2004;96:546), this systemic action suggests clinical applications. However, direct exposure of colonic epithelial cells to high luminal concentrations of metformin may also be relevant and is one of several factors that may explain the greater inhibitory effect of the drug on colonic epithelium proliferation than that previously reported for breast or prostate.
Patterns of care of elderly patients with metastatic colorectal cancer.
Authors: Parakh Sagun , Ali Sayed Sahanawaz , Wong Hui-li , Field Kathryn M , Shapiro Jeremy David , Nott Louise M. , McKendrick Joseph James , Gibbs Peter , Yip Desmond
Published: March 2020

e14640

Background: Elderly patients (pts) account for a large proportion of pts with metastatic colorectal cancer (mCRC). Despite this they are underrepresented in clinical trials and often undertreated. The purpose of this study is to review the patterns of care of elderly pts with mCRC in the community setting. Methods: Retrospective analysis of 507 elderly (age ≥ 65 years (yrs)) pts with mCRC on the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) database enrolled between July 2009 and November 2012. Comprehensive clinical data was collected prospectively on pts with mCRC from 14 sites across Australia. In this analysis pts were grouped according to age: 65-75, 75-85 and ≥85 yrs. Treatment patterns and intent, performance status (PS), and overall survival (OS) were analysed by age cohorts. Kaplan-Meier method was used for survival analysis. Results: In this cohort, 213 (42.0%), 216 (42.6%) and 78 (15.4%) pts were aged 65-75, 75-85 and >85 yrs respectively. Older patients were more likely to be female (30.5% vs 42.1% vs 52.6%, p=0.0012) and have worse PS (PS≥2: 18.3% vs 25.9% vs 48.7%, p<0.0001). There were no differences in comorbidity score, primary tumour site or resection rates between age groups. In total, 358 (70.6%) elderly pts received chemotherapy. However, chemotherapy use declined significantly with increasing age (83.1% vs 70.8% vs 35.9%, p<0.0001). Among the very elderly (≥85 yrs) pts who received chemotherapy (n=28), 12 (42.9%) received combination chemotherapy and 6 (21.4%) were given bevacizumab. Median OS was 24.3, 17.7 and 11.3 months in the 65-75, 75-85 and >85 yrs age groups respectively (p<0.0001). Pts receiving chemotherapy had significantly longer OS than those who did not (median OS 22.7 vs 6.4 months, HR 0.28 (95% CI 0.21-0.38, p<0.0001)). Conclusions: This is the largest series of elderly pts with mCRC in Australia. Multiple studies have confirmed the safety and efficacy of fluorouracil and bevacizumab but in our cohort, chemotherapy and bevacizumab appear to be underutilised in the elderly. Chart review is planned to explore reasons for not administering chemotherapy.
Chemotherapy-induced diarrhea in older patients with colorectal cancer receiving fluoropyrimidines: A retrospective review.
Authors: Iyer Laxmi H , Browner Ilene S. , Blackford Amanda L. , Laheru Daniel A. , Azad Nilofer Saba , Diaz Luis A. , Donehower Ross C. , Purtell Michael J. , Zheng Lei , Le Dung T. , Cosgrove David , Rasheed Zeshaan , Kadan Maura , De Jesus-Acosta Ana
Published: March 2020

e14647

Background: Chemotherapy-induced diarrhea (CID) is a common treatment-limiting toxicity of regimens used for colorectal cancer (CRC). Fluoropyrimidines, the backbone of CRC regimens, are associated with diarrhea, but the frequency and severity in older patients are less known due to under-representation of older patients in CRC trials. As life expectancy increases, the prevalence of older CRC patients will increase. We aimed to evaluate if older patients are vulnerable to CID. Methods: We retrospectively studied patients >70 years old who received fluoropyrimidines based therapy for stages II-IV CRC at Johns Hopkins and Bayview Medical Center from 1996-2007. Patient demographics and cancer-specific data were retrieved. Diarrhea was graded per National Cancer Institute Clinical Toxicity Criteria. Results: We included 150 patients > 70 years old. Median age was 75 (range 70-87). 65 (43%) were 70-74 years old, 52 (35%) were 75-79 years and 33 (22%) > 80. Diarrhea occurred in 48% (n=72) of patients. Presence of diarrhea was not significantly associated with increasing age (70-74, 75-79 or >80 years), gender, ECOG performance, number of comorbidities or medications. Severe grade 3-4 diarrhea occurred in 16% (n=24) and was associated with advanced stage (p=0.04). CID (all grades) was more common in cycle 1 than subsequent cycles (p=0.002). Conclusions: Fluoropyrimidines based therapy was tolerated in older patients with CRC. Incidence of CID was not associated with increasing age, gender, performance, comorbidities or polypharmacy. Severe diarrhea occurs in advanced stage and early during therapy. Larger prospective studies are needed to definitively evaluate the impact of age on CID.
Retrospective analysis of 178 patients with stage I rectum cancer.
Authors: Cihan Sener , Ozdemir Nuriye , Urakci Zuhat , Kucukoner Mehmet , Dane Faysal , Yazilitas Dogan , Durnali Ayse , Yuksel Sinemis , Colak Dilsen , Seker Metin , Taskoylu Burcu , Aksahin Arzu , Ozturk Banu , Demirci Umut , Turan Nedim , Aksoy Sercan , Atasoy Ajlan
Published: March 2020

e14662

Background: There is no strong evidence to suggest that type of adjuvant therapy has any role in the management of stage I rectum cancer. The risks of local relapse and distant metastasis are higher in rectal cancer than colon cancer. Due to the more aggressive nature of rectal cancers, we explored the clinical and pathologic factors that could predict the risk of relapse in stage I disease. Methods: This multicenter study was carried out by Anatolian Society of Medical Oncology. 178 patients with rectal cancers who underwent curative surgery between 1994 and 2012 were included. Retrospective analyses were made using data collected from medical records. Results: The median age was 58 years (26-85). Low anterior resection (LAR) was the most preferred surgical method. Most tumors were well or moderately differentiated. After surgery, 13 patients (7.3%) received radiotherapy alone, 12 patients (6.7%) received chemotherapy alone and 15 patients (8.4%) were given chemoradiotherapy. Median follow-up was 29 months (3-225). 41 patients (23%) had relapse; relapses were local in 18 patients (10.1%) and distant in 12 patients (6.7%). 11 patients (6.2%) who had no relapse data were considered to be disease free. The 3-year disease free survival (DFS) was 74% and the overall survival (OS) was 94%. Mucinous histology and adjuvant therapy were found to have statistically insignificant correlations with relapse and survival. Conclusions: There is no strong evidence to support the role of any type of adjuvant therapy after resection in stage I rectal cancer. Approximately ¼ of patients had local or systemic relapse. This is a high rate for stage I tumors. The rates of relapse were slightly higher in the patients who had no adjuvant therapy and those who had mucinous tumors. There may be a role for adjuvant therapy in high-risk stage I rectal tumors. However, there is still a need for prospective studies in this regard. [Table: see text]
Outcomes of oxaliplatin-based adjuvant chemotherapy in pathologically lymph node positive (ypN+) rectal cancer.
Authors: Al Zahrani Ahmad , Brierley James D. , Kennedy Erin Diane , Krzyzanowska Monika
Published: March 2020

e14664

Background: Standard therapy for locally advanced rectal cancer( LARC) with pre-operative chemoradiation(CRT) followed by curative surgery and adjuvant 5-flourouracil (5-FU) has resulted in a 5-year local relapse (LR) rate of less than 10% and incidence of distant metastases of about 36%. Accumulating data suggests that pathological lymph node status post CRT (ypN) is a major prognostic factor for long term outcomes in LARC .The role of adjuvant oxaliplatin-based therapy has not yet been well defined in ypN+ patients and is the focus of this study. Methods: Patients with ypN+ rectal cancer who underwent fluoropyrimidine-based preoperative CRT followed by curative surgery and received adjuvant oxaliplatin- (group 1) or fluoropyrimidine-based (group 2) chemotherapy at Princess Margaret Hospital were retrospectively reviewed.The study end point was comparison of three year disease free survival(DFS) and freedom from distant metastasis (FDM) in group 1 vs 2 using log-rank test. Results: Between 2003 and 2010, 25 pts in group 1 (adjuvant FOLFOX, n=23 and FOLFOX/bevacizumab, n=2) and 38 pts in group 2 ( adjuvant 5-FU/LV, n =37; capecitabine, n=1) were reviewed. Baseline characteristics were similar in both groups except more pts in group 2 had < 12 lymph nodes (LNs) retrieved (p=0.02), whereas more pts in group 1 were female (p=0.03)and had ypN2 vs ypN1 (p=0.01). Median follow-up was 33 months in group 1 and 38 months in group 2 (range: 3-86). Median age: 58 years. Male: 51, 80%. Five pts (8%) in the entire cohort experienced LR and 20 pts (31.7%) had distant metastasis. A trend toward better three-year DFS was observed in favour of oxaliplatin-based therapy (76% in group 1 vs. 51% in group 2; HR=0.4, 95%CI = 0.1-1.0; P=0.05). Corresponding three-year FDM rates were 83% and 58%, respectively (HR=0.23; 95% CI = 0.6-0.8; p= 0.01). In multivariate analysis, number of LNs retrieved of ≥12 and adjuvant oxaliplatin-based therapy were independent prognostic factors for improved DFS and FDM, respectively. Conclusions: Our analysis suggests that in ypN+ rectal cancer, addition of oxaliplatin to adjuvant therapy is associated with better outcomes. A prospective confirmatory randomized trial would be informative.
Locally advanced rectal cancer: The value of magnetic resonance imaging as a predictive tool.
Authors: Connell Louise Catherine , Stuart Charlotte , Daly Norma , Mehigan Brian , Kennedy M. John
Published: March 2020

e14666

Background: Magnetic Resonance Imaging (MRI) of pelvis stratifies patients (pts) with rectal cancer (ca) according to locally advanced disease (dx) & risk of local recurrence. By determining the extent of lymph node (LN) positivity, it enables the appropriate selection of pts for neoadjuvant therapy (NAT) prior to curative surgical resection (Sx). We assessed our institution’s experience of NAT versus upfront Sx in stage I-III rectal ca to ascertain the utility of MRI as a predictive tool in LN status evaluation. Methods: We retrospectively reviewed a prospectively maintained database for all pts with a diagnosis of stage I-III rectal ca from January 2006 to September 2012 in a specialist colorectal cancer centre. We analysed data with respect to preoperative MRI staging & definitive histopathological confirmation of LN stage. Results: A total of 210 pts were identified that had Sx for rectal ca with curative intent. Of these, 112 pts received NAT while 98 had upfront Sx. Of those who proceeded directly to Sx, there were 41 females & 57 males. Average age in this group was 73.4 years (range 33 -90). LN staging by MRI was accurate in 45.9% (n=45). LN status could not be evaluated (Nx) in 17.3% (n=17). In 19.4% (n=19) more advanced LN staging was apparent on histology while in 17.3% (n=17) LN stage was deemed more aggressive by MRI. Of those who had NAT, there were 75 males & 37 females. Average age was 62.3 years (range 26-82). In this cohort, 81.3% (n=91) had both a preoperative MRI & pathology report available for comparison. MRI in this group matched histology in 61.5% (n=56). Nx was recorded in 3.3 % (n=3). In 17.6% (n=16) more aggressive LN involvement was evident at histology while 17.6% (n= 16) had less advanced dx at tissue sampling. Overall in this study, MRI accurately predicted LN status in 53.4% (n=101). Conclusions: While MRI is a valuable tool in determining those pts with rectal ca that would benefit from NAT, its predictive value has limitations. With further analysis of the dataset at our institution, we aim to identify other factors involved & create a predictive nomogram for the rectal ca pt with locally advanced dx. We plan to validate this work by including data from other Irish cancer centres.
The role of AP-1 in colon cancer stem cells.
Authors: Chatziioannou Marina , Apostolou Panagiotis , Toloudi Maria , Ioannou Eleni , Kopic Asir , Komiotis Dimitrios , Papasotiriou Ioannis
Published: March 2020

e14699

Background: The AP-1 transcription factor is a heterodimeric protein, which regulates gene expression in response to a variety of stimuli. The above factor also regulates cellular processes including differentiation, proliferation and apoptosis. The AP-1 heterodimeric protein is consisted of the combination of c-Jun and c-Fos proteins. The c-Jun is activated through phosphorylation, but it has also phosphorylation independent function. The c-FOS is a cellular proto-oncogene, which is up-regulated in response to many extracellular signals. The present study aim to find out the effect of c-FOS gene in Colon CSCs according to stemness. Methods: In all experiments there have been used established human colon cancer stem cells (CelProgen). Experiments for suppression of c-FOS expression, by using specific siRNA were performed and the transfection was evaluated with qPCR assays. The stemness transcription factors Nanog, Oct3/4 and Sox2 were tested with gene expression assays, and a relative quantification was performed according to Livak method. The CD44 and CD26 genes were used as positive markers in colon cancer in all procedures. Results: The results indicated that the c-FOS proto-oncogene affects the gene expression of transcription factors, which are essential for the maintenance of stemness. However the results were different, depending on the rate of suppression. The suppression of c-FOS by 65% led to increase in gene expression of stemness transcription factors, with higher rates for Nanog, smaller for Sox2 and minimum for Oct3/4. Unlike results were observed when the expression was suppressed by 85%. In this case there was observed higher decrease in Oct3/4 and less in the other markers. Conclusions: Up to now studies have demonstrated the significant role of c-JUN in stem cells, but little is known about the other half of AP-1 complex, the c-FOS gene. In the first part of the study it was confirmed the effect of c-FOS in stemness, as it was observed change in gene expression of stemness’s significant transcription factors. However it is indicated that there is a cross-talk between JNK pathway and stemness. Further studies in more samples are needed to demonstrate all the above, so that it can be used at clinical level.
On-chip drug testing of an aggressive intra-abdominal variant of inflammatory myofibroblastic tumor by kinase activity profiling.
Authors: Ruijtenbeek Rob , van den Berg Adrienne , Hilhorst Riet , Kueffer Stefan , Gaiter Timo , Kievits Tim , Ebert Matthias
Published: March 2020

e14702

Background: A patient presented with an expansivetumor of the liver, which infiltrated diaphragm, duodenum, gastric wall, pancreas and gall bladder. Pathological examination revealed a tumor dominated by infiltrating sheets of epithelioid-to-round cells with a prominent inflammatory infiltrate. Immunohistochemistry showed a positive reaction for vimentin but stained negative for S100, HMB45, Aktin, Desmin, CD117, DOG1, WT1, CDK4, mdm2 and ALK. Diagnosis of an ALK negative aggressive intra-abdominal variant of Inflammatory Myofibroblastic Tumor (IMT) was established. While it is know that approximately 50% of IMTs contain clonal rearrangements involving the ALK gene (Am. J. Surg. Pathol. 2011 135-144), little is known about the ALK-negative variant. The aim of the current study was to gain insights in potential aberrant signaling pathways in this rare tumor and potentially identify alternative druggable pathways. Methods: Kinase activity profiles of the tumor lysate were generated on PamChip peptide microarrays in the presence and absence of a concentration series of the protein kinase inhibitors (PKIs) erlotinib, imatinib, sorafenib, masitinib, crenolanib and tivozanib. Inhibitor effects on this IMT tumor lysate were compared to those on lysates from other tumor types, followed by bioinformatic analysis. Results: Comparing the different kinase inhibition profiles, erlotinib was the least effective inhibitor, while sorafenib and imatinib inhibited phosphorylation of a set of peptides that are known to be substrates for their kinase targets c-KIT, PDGFRα and PDGFRβ. The degree of inhibition in the IMT sample was higher than in tumor samples where these drugs are approved like CML and RCC (as well as in non-approved indications like CRC and AML). In the closely related sarcoma GIST, these kinases are successful targets. Additional prove of their involvement in this IMT variant was found in the positive inhibition profiles using crenolanib and masitinib. Conclusions: c-Kit and PDGFR and corresponding kinase inhibitors would be a pathway/drug combination of choice for drug development in this variant of IMT.
Long-course targeted therapy with bevacizumab to predict better survival in patients with advanced colorectal cancer.
Authors: Deng Yanhong , Tang Yuting , Xiao Jian , Ling Jiayu , Cai Yue , Hu Huabin , Zhang Yan , Lin Yiheng , Chen Dianke
Published: March 2020

e14704

Background: Bevacizumab has been the standard treatment in first-line treatment of advanced colorectal cancer. This study explored whether the short-course and long-course use of bevacizumab could influence overall survival (OS). Methods: A total of 74 patients with advanced colorectal cancer who had received at least one cycle of bevacizumab-based regimens were included. The primary endpoint was OS defined as from the date of first diagnosis of advanced colorectal cancer to death. Results: The P value among the median OS of initiating bevacizumab in first-line group (n = 47), in the second-line group (n = 18), and the third-or more-line group (n = 9) was not reached statistically significance(P = 0.349). In the first-line initiating bevacizumab group, the irinotecan arm showed a trend of better activity than the oxaliplatin arm, but the significance was not reached(P = 0.128). For patients in the first-line initiating bevacizumab group who had received at least four courses of bevacizumab (n = 36), the median PFS and OS was 11 m and 29m respectively and for those receiving less than four courses of bevacizumab (n = 10), it was 3.9 m (P = 0.005) and 13m (P=0.003) respectively. Conclusions: The delayed use of bevacizumab has no negative effect on the OS of patients with advanced colorectal cancer. Long-Course targeted therapy with bevacizumab favors better survival in patients with advanced colorectal cancer.
The efficacy and safety of first-line and salvage therapies with bevacizumab combination chemotherapy regimens in metastatic colorectal cancer: A retrospective ASMO experience.
Authors: Yildiz Ramazan , Buyukberber Suleyman , Koca Dogan , Koral Lokman , Ciltas Aydin , Unal Olcun Umit , Gumus Mahmut , Ozdemir Nuriye , Dane Faysal , Berk Veli , Kaplan Mehmet Ali , Elkiran Tamer , Boruban Melih Cem , Coskun Ugur , Aydin Dincer , Uncu Dogan , Ozkan Metin , Isikdogan Abdurrahman , Benekli Mustafa ,   Anatolian Society of Medical Oncology (ASMO)
Published: March 2020

e14705

Background: The addition of bevacizumab to chemotherapy significantly shows survival advantage in metastatic colorectal cancer (mCRC), but with limited data about irinotecan combination in salvage therapy. Efficacy and toxicity of bevacizumab combination regimens were assessed in first-line and salvage therapies. Methods: Total of 1011 (659 in first-line and 352 in salvage) patients were retrospectively evaluated. Results: In first-line therapy, the ORR was 36.4%. Median PFS was 7 months for FOLFIRI, 6 months for IFL and 6 months for other chemotherapy regimens with a median overall PFS of 7 months. Median survival was 29 months for FOLFIRI, 28 months for IFL and 21 months for others with a median overall survival of 28 months. In salvage therapy, the ORR was 25.2%. Median PFS was 7 months for FOLFIRI, 7 months for IFL and 6 months for others with a median overall PFS of 7 months. Median survival was 19 months for FOLFIRI, 13 months for IFL and 21 months for others with a median overall survival of 19 months. The main toxicities in first-line and salvage therapy were neutropenia, febrile neutropenia, nausea and vomiting, diarrhea, mucositis, bleeding, hypertension, thromboembolism, fistulization and bowel perforation. Conclusions: Bevacizumab combination chemotherapy regimens are effective with a tolerable safety profile in mCRC patients in first-line and salvage therapy.
Chemoradiotherapy for squamous cell carcinoma of the anal canal: Comparison of one versus two cycles mitomycin-C.
Authors: White Evan Carl , Erickson Kelly , Aleshin Alex , Lien Winston Wei , Rao Aroor R.
Published: March 2020

e15001

Background: Concurrent chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and mitomycin-C (MMC) is standard treatment for squamous cell carcinoma of the anal canal. Randomized clinical trials in Europe have used 1 cycle MMC, while American studies use 2 cycles. This study sought to determine any difference in treatment outcomes between patients treated with either 1 or 2 cycles of concurrent MMC. Methods: 217 consecutive patients were treated definitively with CRT from 2003 to 2012 in an integrated health system. All patients received radiotherapy at a single regional facility. Concurrent chemotherapy regimen depended on the referring provider’s practice, and consisted of 2 cycles 5-FU (1,000mg/m2/day on days 1-4 and 29-32), along with MMC (10mg/m2), given on either day 1 alone (n=154), or days 1 and 29 (n=63). Outcomes were progression-free (PFS), cancer-specific (CSS), overall (OS), and colostomy-free survival (CFS), as well as acute toxicity criteria. Toxicity scored using CTCAE version 4. Survival analysis was via Kaplan-Meier method, and multivariate Cox proportional hazards modeling was performed. Results: Median age: 60 years. 70% female. T3-T4: 52%. 40% node-positive (N1: 7%, N2: 17%, N3: 16%). Median follow-up: 26 months. At last follow-up, PFS was 79%, CSS was 87%, OS was 81%, and CFS was 88% for the entire cohort. There were no differences in clinical/treatment factors between patients who received 1 cycle MMC (MMC1) vs 2 cycles (MMC2). There was no difference in PFS (HR 0.92, 95% CI 0.41-2.08), CSS (HR 0.36, 95% CI 0.08-1.62), OS (HR 0.73, 95% CI 0.27-2), or CFS (HR 0.91, 95% CI 0.31-2.67) between the MMC1 and MMC2 groups. On multivariate analysis, stage and male gender were predictive of worse PFS, CSS, OS, and CFS. Acute grade ≥2 toxicities for the MMC2 vs MMC1 group were: Skin: 97% vs 84% (p=0.006); Heme: 89% vs 73% (p=0.01); Leukopenia: 86% vs 68% (p=0.01); Neutropenia: 71% vs 53% (p=0.02). There were 3 treatment related deaths, all in the MMC2 group. Conclusions: This study provides evidence that MMC1 results in similar outcomes to MMC2 in patients with anal cancer treated with definitive CRT, with less acute treatment-related toxicity. Randomized trials comparing these 2 regimens could be considered.
Activity and survival benefit of second-line chemotherapy (2L-Ctx) in advanced pancreatic adenocarcinoma (APC): Pooled analysis of the literature.
Authors: Teo MinYuen , McDermott Raymond S.
Published: March 2020

e15019

Background: Many clinicians adopt a nihilistic approach to the management of APC. Delivery of 2L-Ctx is relatively uncommon and no recognized standard exists. We sought to examine the published activity of chemotherapy in the 2nd line setting, and the rate of 2L-Ctx delivery and its influence on reported overall survival in 1st line trials. Methods: 1st and 2L-Ctx randomized trials published between 2000 and 2012 were identified from Pubmed, and manuscripts were obtained for data extraction. Pooled weighted objective response rates (ORR) and disease control rates (DCR) were calculated. For 1st line studies, the percentage of patients who received 2L-Ctx were extracted and plotted against reported median overall survival (OS) and post-progression survival (PPS), defined as arithmetic difference between median OS and progression-free survival. Spearman correlation and linear regression were performed. Results: Sixty nine 2L Ctx studies (77 arms, n=2859) were identified. Majority received prior gemcitabine-based chemotherapy. Pooled ORR was 6.6% (95% CI 5.6 – 7.6%) and DCR was 36.7% (34.5 – 38.0%). When only prospective studies were evaluated (42 studies, 48 arms, n=1546), ORR was 5.0% (3.8 – 6.2%) and DCR was 33.9% (31.0 – 36.9%). Exploratory analysis suggested that intensification of gemcitabine-based therapy (ORR: 10.0%; DCR: 54.7%) might be marginally more active than fluoropyrimidine (7.6%; 32.2%) or taxane based 2L-Ctx (5.2%; 33.6%). 28/52 identified 1st line studies (54%) reported the percentage of patients treated with second-line chemotherapy (11 phase II, 28 arms, n=1450; 17 phase III, 33 arms, n=5051). Percentage of 2L-Ctx delivery ranged from 14 – 68% and correlated with OS (r=.49 [.26 – .67], p<.01) and PPS (r=.57 [.36 – .72], p<.01). When phase II studies were excluded, correlation was improved for OS (r=.63 [.35 – .81], p<.01) and PPS (r=.79 [.59 – .89], p<.01). Percentage of locally advanced disease did not correlate with OS/PPS nor affect prior analysis. Conclusions: Whilst awaiting further advancement in the 1st line setting, increased delivery of 2L-Ctx to patients with APC and maintained performance status may offer a survival benefit.
Changes in the tumor glucose-uptake measured by 18F-FDG PET with two weeks of single-agent cetuximab in localized squamous cell carcinoma of the esophagus.
Authors: Philipp-Abbrederis Kathrin , Herrmann Ken , Beer Ambros , Hapfelmeier Alexander , Peschel Christian , Lordick Florian
Published: March 2020

e15042

Background: Cetuximab (CET), an antibody directed against epidermal growth factor receptor (EGFR) has proved efficacy in squamous cell cancer (SCC) of the head and neck in vitro and in vivo by enhancing the activity of chemo- and radiotherapy. The aim was to investigate the early metabolic response in esophageal SCC induced by single agent CET. Methods: Patients with cT3 Nx esophageal SCC received single agent CET for two weeks (400mg/m2 i. v. d -15 followed by 250mg/m2 d -8) before entering a neoadjuvant dose escalation protocol of weekly cetuximab plus weekly oxaliplatin (starting dose level 45mg/m²; d1,8,15,22,29), plus 5-FU cont. i.v. (starting dose level 180mg/m²/d; d1-5, 8-12, 15-19, 22-26, 29-33) and radiotherapy (45Gy cumulative dose; 1.8Gy/d). Surgery was scheduled 4-6 weeks after chemoradiation (CRT). Tumor FDG uptake was assessed by PET at baseline, two weeks after start of CET and two weeks after start of CRT. Standard uptake values (SUV) of the two response PETs were compared with SUVs measured at baseline and correlated with the histopathological response data. Results: 11 patients are assessable for metabolic and histopathological response. Decreases in the SUVs two weeks after the start of CET compared with baseline SUV ranged from -16% to -70% (median -24%) and from 0% to -72% (median -39%) two weeks after start of CRT. Three patients were classified as complete histopathological responders. One patient had a subtotal (<10% residual tumor) and three patients a moderate response (10-50% residual tumor). No histopathological response was seen in 4 patients. We found an association between FDG uptake decreases both after single agent CET and after two weeks of CRT and a favourable histopathological response with no statistical significance due to the low number of cases. Conclusions: This study shows that single agent CET can lead to a marked and early decrease in tumor glucose uptake. Our findings suggest that there may be an association between the early decrease in FDG uptake during CET monotherapy, indicating a growth dependency of some tumors from the EGFR signal pathway. These preliminary observations require confirmation in a larger patient cohort. Clinical trial information: 2006-001097-24.