bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of race and socioeconomic status and outcomes with patients with rectal cancer.
Authors: Nitzkorski J. R. , Willis A. I. , Farma J. M. , Cohen S. J. , Zhu F. , Nick D. M. , Sigurdson E. R.
Published: February 2017

376

Background: Few studies have evaluated disparities of race and SES with outcomes in RC patients. We hypothesize that disparities exist in treatment and outcomes of RC.

Methods: Medical records were retrospectively reviewed of RC patients treated from 2000-2009 at an NCI cancer center and an urban academic center. SES was estimated using census data. Quartiles of income and education based on zip codes were calculated. Lowest vs. other quartiles were compared. Clinicopathologic variables included: initial stage, chemotherapy refusal, sphincter preservation, and overall survival (OS).

Results: 748 patients were included (581 white, 135 black, 6 other, 26 unknown). Patients with Medicaid were more likely to present with advanced disease (Table). Initial stage did not differ by race, income, or education. Non-white (NW) patients and low education were more likely to refuse chemotherapy. 7 patients refused radiation. After excluding stage IVpatients; sphincter preservation was higher among those with higher income. Median OS for all stages was worse for NW patients (31 months vs. 50 months, p<0.001), low income and education and most pronounced among NW patients with advanced disease. Insurance was not associated with survival difference. Advanced age, stage, and NW race (HR 1.49, 95% CI 1.10-2.02, p=0.01) were independent predictors of survival.

Conclusions: Disparity exists in treatment acceptance and outcomes in patients with RC. NW race and lower SES is associated with advanced disease, lower rates of sphincter preservation, chemotherapy refusal, and worse OS in patients with RC.

[Table: see text]

[Table: see text]
Relative impact of chemotherapy with or without bevacizumab on cytokines and angiogenic factors (CAFs) in metastatic colorectal cancer.
Authors: Lieu C. H. , Tran H. T. , Fiorentino S. , Jiang Z. , Mao M. , Overman M. J. , Eng C. , Ellis L. M. , Heymach J. , Kopetz S.
Published: February 2017

401

Background: CAFs were previously shown to be modulated in patients (pts) with metastatic colorectal cancer (mCRC) after bevacizumab-containing chemotherapy. Validation of these prior findings is warranted. In addition, the relative impact of bevacizumab and the cytotoxic chemotherapy components on CAFs has not been previously described.

Methods: Plasma samples from 403 mCRC pts were obtained prior to any chemotherapy (Group A) or after progression on a regimen without or with bevacizumab (Group B and C, respectively) between 2002 and 2008. Samples were matched for number of metastatic disease sites (Groups A, B, C) and for prior chemotherapy duration, and time from last chemotherapy dose to sample collection (Groups B, C). Levels of 48 CAFs were measured by suspension bead multiplex assays (BioRad and EMD). Comparisons of Groups A v C (n=169 pairs) and Groups B v C (n=65 pairs) were by the two-sided, nonparametric Wilcoxon paired test, with p<0.05 significance for confirmation of previous CAF results.

Results: Prior chemotherapy duration (6.5mo, 6.7mo), and time from last chemotherapy dose to sample collection (1.3mo, 1.2 mo) were similar for Groups B and C, respectively. Results were available for 80% of the samples. Compared to Group A, Group B had reductions in multiple CAFs, including IL-8 (-38%, p<0.0001) and PDGF (-62%, p<0.0001). Commensurate with prior results, PlGF, Eotaxin and TRAIL were increased in Group C by 30% (p<0.0001), 23% (p=0.024) and 19% (p=0.008) respectively. Most CAF changes were attributable to chemotherapy alone. However, PlGF (-31%, p<0.0001) and TRAIL (+26%, p=0.037) significantly differed in Groups B v C. In group C compared to A, multiple changes were seen in the EGFR-axis including decreases in EGF (-52%, p=0.032), epiregulin (-25%, p=0.0023), and HB-EGF (-40%, p<0.0001) as well as an increase in sEGFR (+10%, p=0.004).

Conclusions: Most changes in CAFs after treatment with bevacizumab-containing chemotherapy appear to be due to chemotherapy alone and not attributable to anti-VEGF therapy, with several notable exceptions. Chemotherapy-induced changes in the EGFR-axis have not previously been described in mCRC and warrant further investigation.

[Table: see text]
Effect of neuropilin-2 expression on TGF-β1-epithelial-mesenchymal transition in colorectal cancer cells.
Authors: Grandclement C. , Bedel R. , Kantelip B. , Viel E. , Remy Martin J. , Ferrand C. , Pivot X. B. , Tiberghien P. , Borg C.
Published: February 2017

414

Background: Initially characterized as neuronal receptors, Neuropilins (NRPs) were also found to be expressed in endothelial cells and subsequently were shown to play a role in the development of the vascular system. NRP family consists of two genes, neuropilin-1 (NRP1) and neuropilin-2 (NRP2).The multiple functions of NRPs were recently highlighted by the identification of NRP role in oncogenesis. In this study, we first confirmed the role of NRP2 in tumor progression. We also extended the understanding of NRP2 oncogenic functions by investigating the ability of NRP2 to orchestrate epithelial-mesenchymal transition (EMT) in colorectal cancer cells.

Methods: We have generated human colon cancer cell lines transfected with NRP2 transgene or siRNA to investigate NRP2 involvement in EMT. First, the oncogenic functions of NRP2 were studied in vitro by MTT, soft agar, invasion assays and in vivo using xenografts experiments. Ability of NRP2 to orchestrate EMT was then investigated by flow cytometry, immunohistochemical (IHC) staining, western-blotting and quantitative real-time PCR.

Results: IHC staining revealed that NRP2 is expressed in human colon and breast carcinomas while it is not expressed in healthy tissues. Then, we confirmed that NRP2 increases tumor proliferation, colony formation, invasion and xenograft formation. Moreover, NRP2-expressing cells displayed an immunohistochemical phenotype of EMT characterized by the loss of E-Cadherin and an increase of vimentin. Furthermore, NRP2 expression promotes transforming-growth factor-β1 (TGF- β1) signaling, leading to an increased phosphorylation of the Smad2/3 complex in colorectal cancer cell lines. Specific inhibition of NRP2 using siRNA or treatment with specific TGFβRI kinase inhibitors prevented this phosphorylation and the EMT, suggesting that NRP2 cooperates with TGFRI to promote EMT in colorectal carcinoma.

Conclusions: Our findings have reinforced the essential role of NRP2 in cancer progression and demonstrated that NRP2 expression confers to tumor cell lines the hallmarks of EMT. Moreover, in the current work, we present evidence for the therapeutic value of NRP2 targeting.

No significant financial relationships to disclose.
Relevance of sex and PER2 SNPs for predicting irinotecan tolerability in cancer patients.
Authors: Pirovano M. , Fornasari D. , Nasisi A. , Caronno A. , Innominato P. F. , Garufi C. , Moroni M. , Scaglione F. , Levi F. ,   TEMPO consortium
Published: February 2017

416

Background: Advances in understanding the mechanisms underlying diseases and drug responses are creating increasing opportunities to offer safer and more effective treatments to individual patients (pts). Biomarkers are needed for predicting likelihood of therapeutic safety and efficacy in each individual pt. Down-regulation of core clock gene PER2 in tumors predicted for poor survival in pts with metastatic colorectal cancer (Jacobelli. J Clin Oncol. 26: 2008 May 20 suppl; abstr 11032).

Methods: A clinical data base and tissue bank involving primary tumor (T) and healthy adjacent colon mucosa (C) from 139 pts treated with circadian-shaped or standard infusion of (A)-single-agent irinotecan (63 pts) or (B) in combination with oxaliplatin and 5FU (76 pts) for previously-treated metastatic colorectal cancer was established and tissues were collected. Clinical relevance of constitutive or acquired single nucleotide polymorphisms (SNPs) for 5 metabolism (ABCB1, ABCB2, CES2, TOP1, UGT1A1) and for two PER2 SNP's (A4572G and C3968T).

Results: No acquired mutation in the genes analysed was found (100% T and C concordance). The incidence of grade 3-4 toxic event of any kind was significantly lower in women as compared to men in A population(39% vs 76%, p=0.007) and in A+B population (p=0.05), independently from other factors (p=0.02) this difference is lost if you consider only B population where oxaliplatin is added (p=0.5). No SNP in metabolism genes predicted for toxicity in this cohort. Conversely, SNPs in core clock gene PER2 (1 pt with A4572G and 4 pts C3968T) were significantly associated with higher incidence of G3-4 toxicity (100% in polymorphic pts. vs 17.2% in wild type pts, p=0.01).

Conclusions: Irinotecan tolerability is sex dependent and woman has significative low incidence of toxic effects. We demonstrated for the first time an association between constitutive SNPs in a core clock gene and toxicity, further supporting the relevance of the circadian timing system in chemotherapy tolerability. Moreover, our findings are in good agreement with data in mice, supporting the hypothesis that sex determines two chronotoxicity classes in patients with metastatic colorectal cancer.

No significant financial relationships to disclose.
Folinic acid, 5-fluorouracil, irinotecan (FOLFIRI) plus chemoradiation (CRT) with 5-fluorouracil (5FU) as adjuvant treatment for patients with operable gastric cancer (OGC): A feasibility study with pharmacogenetic analysis.
Authors: Athanasiadis A. , Boukovinas I. , Sfakianaki M. , Saridaki Z. , Papadaki C. , Tzardi M. , Androulakis N. E. , Polyzos A. , Georgoulias V. , Sougklakos I.
Published: February 2017

44

Background: To evaluate the efficacy and safety of FOLFIRI plus CRT with 5FU as adjuvant treatment for patients with OGC.

Methods: Patients received treatment with FOLFIRI (irinotrecan 150 mg/m2, d1, LV 200 mg/m2, d1+2 and 5FU [400 mg/m2/d bolus and 600 mg/m2/d, 22 h infusion, d1+2]) for 2 15-day cycles followed by RT (45Gy) with 5FU continuous infusion (325 mg/m2/d in the 1st and 5th week) administration. Eight additional cycles of FOLFIRI were administered after the completion of CRT. BRCA1, ERCC1, XPD, TOPO-I, TOPO-IIA and B and TS mRNA expression was determined in the primary tumor where available.

Results: The median age of the 171 enrolled patients was 62 years, 114 (66%) were males, 136 (79%) had R0 resections and 152 (89%) had at least a D1 resection. Treatment was completed as per protocol in 107 (63%) of the patients. CRT was completed in all but 5 (3%) patients. The median rate of drug exposure was 93% for irinotecan, 87% for 5FU and 91% for LV. The most common grade 3/4 adverse events were neutropenia (32%), febrile neutropenia (3.5%) and diarrhea (7%). After a median follow-up of 45.7 months 84 had relapsed and 70 were deceased. The median disease-free survival (DFS) was 30 months (95% CI: 18-41 months), while the projected median overall survival (mOS) was 53.7 months (95% CI: 30-77 months). The recurrence free probability at 5 years was 44% while the probability of survival at 5 years was 46%. From the studied pharmacogenetic markers only TS low expression was correlated with a trend towards improved DFS and OS in patients with R0 resections.

Conclusions: These results show that the administration of FOLFIRI plus CRT with 5FU as adjuvant treatment in OGC is a feasible approach with acceptable toxicity and challenging efficacy which merits further evaluation in a randomized trial.

No significant financial relationships to disclose.
Human epidermal growth factor receptor-2 (HER2) Ile655Val single nucleotide polymorphism (SNP) is associated with gender-specific outcome in patients with metastatic colorectal cancer (mCRC) treated with cetuximab in a phase II study (IMCL-0144).
Authors: Gerger A. , Bohanes P. O. , Yang D. , Winder T. , Ning Y. , Labonte M. J. , Mauro D. J. , Langer C. , Rowinsky E. K. , Lenz H.
Published: February 2017

441

Background: HER2 pathway is an important growth-regulatory pathway in many malignancies. In-vitro data from various cell lines suggest that activation of HER family members predicts resistance to cetuximab. HER2 also interacts with hormone receptors and estrogen, promoting tumor proliferation in breast cancer models. We previously demonstrated that polymorphisms in HER1 and ER-β were associated with gender-specific survival in colorectal cancer patients. HER2 Ile655Val (rs1136201) SNP's functionality was shown in breast cell lines with Val-expressing cells exhibiting increase growth capacity. We tested whether this SNP may predict gender-specific clinical outcome in mCRC treated with cetuximab.

Methods: Tissue samples of 130 patients, 64 males and 66 females, with mCRC, enrolled in a phase II trial of cetuximab monotherapy were analyzed. Genomic DNA was extracted from FFPE tumor tissue. K-Ras mutation status and HER2 Ile655Val (rs1136201) SNP were analyzed using direct DNA-sequencing and PCR-RFLP. 23 out of 130 patients were still alive at the time of data analysis with a median follow-up of 12.3 months.

Results: Females with the low activity HER2 Ile/Ile (n = 41) genotype had better progression-free survival (PFS) when compared to Ile/Val or Val/Val (n = 21) genotypes (median PFS = 2.4 vs. 1.2 months; HR = 2.06 (95% CI: 1.08-3.92), p = 0.0281) based on the multivariable Cox regression model adjusting for KRAS, performance status and severity of skin rash and stratified by race. In KRAS wild-type females, 15 patients out of 20 (75%) with HER2 Ile/Ile genotype responded or had stable disease when compared to 4 out of 12 (33%) Ile/Val or Val/Val genotypes (exact conditional test p = 0.143). In males, HER2 Ile655Val SNP is not associated with outcome. HER2 Ile655Val SNP is not associated with gender-specific overall survival.

Conclusions: Our data suggest that HER2 Ile655Val SNP may identify females with mCRC likely to experience better outcome when treated with cetuximab. Prospective biomarker-embedded clinical trials are needed to validate our results.

[Table: see text]
Chemotherapy-induced neutropenia association with survival in metastatic colorectal cancer (MCC): Schedule dependency.
Authors: Innominato P. F. , Giacchetti S. , Smaaland R. , Focan C. N. , Garufi C. , Bjarnason G. A. , Iacobelli S. , Tumolo S. , Karaboué A. , Levi F. ,   ARTBC International Chronotherapy group
Published: February 2017

454

Background: Circadian clocks control cellular proliferation and drug metabolism over 24 h. However, circadian chronomodulated chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronoFLO4) offered no survival benefit as compared to the non-time stipulated FOLFOX2 in an international randomized trial involving patients (pts) with previously untreated MCC (EORTC05963). We hypothesized that treatment near maximum tolerated dose could disrupt circadian clocks thus impairing the efficacy of chronoFLO4 but not of FOLFOX2.

Methods: Pts with available data (N=556) were categorized into three subgroups according to the worst grade of neutropenia experienced during treatment. Distinct multivariate models were constructed for each treatment schedule.

Results: Neutropenia (all grades) occurred in 39% of the pts on chronoFLO4 as compared to 67% of those on FOLFOX2 (p< 0.0001), with G3-4 being encountered in 7% and 25%, respectively (p< 0.0001). In both schedules, neutropenia was more frequent and more severe in women than in men (p<0.04).The occurrence (but not the severity) of neutropenia was significantly associated with improved objective response rate, progression-free and overall survival in pts on FOLFOX2 (p< 0.0001), confirming previous results by others. In pts on chronoFLO4, the occurrence of neutropenia was not associated with any efficacy advantage (p=0.36), and worst survival was observed in pts developing severe neutropenia.

Conclusions: Neutropenia was more frequent and severe in women than in men, and on FOLFOX2 than on chronoFLO4. Neutropenia was positively correlated with survival in pts on FOLFOX2 supporting intra-patient dose escalation to achieve toxicity for conventional chemotherapy. No survival prolongation was found in pts with neutropenia on chronoFLO4. Thus, reaching maximum tolerated dose was unnecessary to achieve optimal effectiveness of circadian-timed therapy, and should even be avoided.

[Table: see text]

No significant financial relationships to disclose.
Relationship between methylation status of PTEN and point mutation of the EGFR L2 domain and efficacy of cetuximab in metastatic colorectal cancer.
Authors: Ito Y. , Yamada Y. , Asada K. , Ushijima T. , Iwasa S. , Kato K. , Hamaguchi T. , Shimada Y.
Published: February 2017

458

Background: The KRAS mutation has been associated with resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in metastatic colorectal cancer (mCRC). However, the predictive biomarkers of cetuximab resistance in KRAS wild-type mCRC remain unknown. We explored the possible roles of PTEN methylation and mutation of the EGFR L2 domain, which is the site of binding to cetuximab, in cetuximab resistance in KRAS wild-type mCRC.

Methods: The subjects were 247 mCRC patients screened for KRAS status at the National Cancer Center Hospital between September 2008 and April 2010. Genomic DNA was extracted from formalin- fixed paraffin-embedded colorectal cancer tissue samples. Mutation analysis of KRAS and the EGFR L2 domain was performed by direct sequencing. Methylation analysis of PTEN was performed by quantitative real-time methylation-specific PCR with a set of primers specific to the methylated and unmethylated sequences, using sodium bisulfate-modified DNA.

Results: Of the 247 mCRC patients, 136 patients had wild-type KRAS (55%). In 9 of these patients, the quality of the DNA was sufficient for analysis of PTEN methylation levels. Eight of the 9 patients received a cetuximab-based regimen (with irinotecan: 4, monotherapy: 4). The best response was PR in 4 patients (25%), SD in 2 (12.5%), and PD in 2 (12.5%). The best response of the one patient with methylated PTEN treated with cetuximab and irinotecan was SD. Mutation analysis of the EGFR L2 domain was performed in 65 of the 136 patients with wild-type KRAS. All of them received a cetuximab-based regimen (with irinotecan: 50, monotherapy: 15). The best response was PR in 13 patients (20%), SD in 26 (40%), PD in 20 (31%). The one patient who had a mutation at exon 9 showed a partial response to cetuximab and irinotecan.

Conclusions: Methylation of PTEN and mutation of the EGFR L2 domain were analyzed in Japanese mCRC patients. Our findings do not provide sufficient evidence that EGFR L2 domain mutation and methylation of PTEN are correlated with resistance to cetuximab.

No significant financial relationships to disclose.
The effect of tumor response on quality of life (QoL) in patients with KRAS wild-type metastatic colorectal cancer (mCRC): Analysis from the CRYSTAL study.
Authors: Griebsch I. , Lang I. , Sartorius U. , Van Cutsem E.
Published: February 2017

476

Background: In the CRYSTAL study cetuximab (cet) added to first-line chemotherapy (CT) significantly improved tumor response compared with CT alone in patients (pts) with KRAS wild-type (wt) mCRC, confirming existing data in this setting. Response to CT has been reported to lead to a corresponding increase in QoL, and QoL scores to predict overall survival in mCRC. In this exploratory analysis tumor response and QoL was investigated in pts from the CRYSTAL study.

Methods: Pts were classified as responders (Rs) or nonresponders (NRs) according to best overall response. QoL was assessed using single-item symptoms questions from the EORTC QLQ-C30 (q8-10, q12-18). Pts at baseline were considered symptomatic if they answered “quite a bit” or “very much” and asymptomatic if they answered “not at all” or “a little” to either one of the symptoms questions. Analysis was performed in all treatment groups (gps) on the change in symptoms in pts considered symptomatic or asymptomatic at baseline.

Results: 471 of 627 KRAS wt pts assessed for QoL had baseline data showing they were symptomatic or asymptomatic. In pts asymptomatic at baseline (n=278) there were more Rs (58%) than NRs (42%). In pts symptomatic at baseline (n=193), there were less Rs (40%) than NRs (60%). At week 8 in all treatment gps, in pts symptomatic at baseline more Rs than NRs became asymptomatic (Table). In pts asymptomatic at baseline, in the CT + cet gp at week 8, 61% of Rs remained asymptomatic compared with 50% of NRs. Data from week 16 and 24 also showed trends in favor of Rs in symptomatic or asymptomatic pts at baseline and will be presented.

Conclusions: Rs who are symptomatic at baseline experience higher symptom relief than NRs. Furthermore Rs who are asymptomatic at baseline are more likely to remain asymptomatic post baseline than NRs. These findings are independent of treatment.

[Table: see text]

[Table: see text]
A randomized phase II study comparing mFOLFOX-6 combined with axitinib or bevacizumab or both in patients with metastatic colorectal cancer (mCRC).
Authors: Infante J. R. , Cohn A. L. , Reid T. R. , Edenfield W. J. , Cescon T. , Hamm J. T. , Tarazi J. C. , Kim S. , Rosbrook B. , Cartwright T. H.
Published: February 2017

485

Background: Vascular endothelial growth factor receptor inhibitors, including axitinib (AG-013736), may be useful in treating patients with mCRC. The goals of this study were to estimate the objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety in patients with mCRC treated with mFOLFOX-6 combined with axitinib or bevacizumab or both.

Methods: Patients with mCRC untreated with any systemic chemotherapy >12 months prior to enrollment, ECOG PS 0/1, adequate organ function, and controlled hypertension were eligible for this randomized, open-label, phase II study. Patients receiving prior treatment with antiangiogenic agents or those who were pregnant were ineligible. All patients received standard mFOLFOX-6 treatment and were randomized to receive either axitinib 5 mg (Arm A), or bevacizumab 5 mg/kg (Arm B), or axitinib 5 mg + bevacizumab 2 mg/kg (Arm C). Axitinib was administered orally twice daily. Efficacy was determined by RECIST criteria.

Results: A total of 42, 43, and 41 patients were enrolled in Arms A, B, and C, respectively. The ORR was 29%, 49%, and 39% for Arms A, B, and C, respectively. Median PFS was 315 days, 350 days, and 377 days, with 1-year survival of 72%, 79%, and 80% for Arms A, B, and C, respectively. Discontinuations due to adverse events (AEs) were more common in Arm A (36%), than in Arms B (19%) or C (32%). More patients withdrew from Arm A (18%) than from Arms B (5%) or C 12%). The rates of grade 3 AEs were similar across arms, except for hypertension and fatigue which were more common in Arms A (15% and 12%) and C (21% and 29%) compared with Arm B (2% and 12%). Serious AEs were reported by 41%, 40%, and 56% of patients in Arms A, B, and C, respectively; the most common were gastrointestinal disorders (21%, 16%, 15%, respectively).

Conclusions: In combination with mFOLFOX-6 chemotherapy, treatment with axitinib resulted in a lower ORR but comparable survival to bevacizumab and this did not appear to improve significantly in the presence of both agents. This result may have been affected by the higher numbers of discontinuations and withdrawals in Arm A compared with the other 2 arms.

[Table: see text]
Use of a multigene prognostic assay for selection of adjuvant chemotherapy in patients with stage II colon cancer: Impact on quality-adjusted life expectancy and costs.
Authors: Meropol N. J. , Lyman G. H. , Chien R. , Hornberger J. C.
Published: February 2017

491

Background: Uncertainty exists regarding the use of adjuvant therapy in patients with stage II colon cancer. To assist decision making, we compared quality-adjusted life expectancy and costs associated with using a multigene recurrence score (RS) assay with the use of clinicopathological factors currently recommended in clinical guidelines.

Methods: A state-transition (Markov) model was developed to assess outcomes associated with the use of the RS (Oncotype Dx gene expression assay) in adjuvant therapy decisions in stage II colon cancer (excluding T4 tumors and those with deficient DNA mismatch repair). RS test characteristics were based on results reported from a randomized controlled trial (QUASAR, Kerr et al. ASCO, 2009). Current rates of administering adjuvant chemotherapy (aCTX) as a function of age, lymphatic invasion, tumor stage, and number of lymph nodes examined was derived from the NCCN Colon/Rectum Cancer Outcomes study (Earle et al, J Surg Oncol, 2009). Effects of aCTX on recurrence risk were based on published data. Medicare fee schedules were used to estimate cost; toxicities, recurrence, and quality-of-life adjustments were obtained from published studies.

Results: Treatment decisions based on RS and a patient's years of life remaining without cancer recurrence would reduce aCTX use by 17% compared with current treatment patterns, and increase quality-adjusted life expectancy by an average of 0.035 years. With lower use of aCTX, direct medical costs are expected to decrease by an average of $2,971 per patient. One-way sensitivity analysis predicts overall QALY improvement with the RS through a range of variables, with the results most sensitive to the disutility associated with aCTX use. Sensitivity analyses also show the assay to be cost-saving under a variety of conditions.

Conclusions: Clinical use of a multigene RS to assess risk of recurrence in T3 stage II colon cancers with intact mismatch repair is likely to improve quality-adjusted life expectancy and be cost-saving from a societal perspective. Patient age and disutility associated with chemotherapy are important considerations in adjuvant treatment decisions.

[Table: see text]
Comparative clinical efficacy of adjuvant chemotherapy regimens in randomized controlled trials (RCTs) of early-stage colon cancer: Systematic review and meta-analysis.
Authors: Cassidy J. , Schmoll H. , Chu E. , Hawkins N. , Tatt I. , Saini J. P. , Urspruch A.
Published: February 2017

498

Background: A systematic review was conducted to identify RCTs of adjuvant chemotherapy regimens for early-stage colon cancer and a network meta-analysis performed to compare efficacy of oxaliplatin/fluoropyrimidine regimens.

Methods: A systematic review identified RCTs recruiting adult patients with early-stage (adjuvant) stage II/III colon cancer. Outcome measures included hazard ratios for DFS and OS. Only publications in English were considered. Study quality was assessed using the Cochrane Collaboration “risk of bias” assessment tool. A single reviewer screened abstracts/titles using predefined selection criteria, with critical appraisal and data extraction conducted independently by two reviewers. A Bayesian network meta-analysis was used to estimate comparative efficacy of adjuvant chemotherapy across RCTs.

Results: 56 articles describing 40 trials were selected, of which six reported data on regimens accepted as current standard of care (capecitabine/X-ACT, XELOX/NO16968, FOLFOX/MOSAIC, FLOX/C-07) or common comparators: bolus 5FU/LV and LV5FU2 (C-96-1, PETACC-2). Statistical assessment of heterogeneity was not possible due to the limited study network. Baseline characteristics were similar across trials with the exception of three trials recruiting only stage III patients; sub-group analysis on these trials was not possible due to lack of common comparators. There was no significant difference in DFS at a median follow-up of 3-years (or closest reported analysis) for XELOX vs. FLOX (HR=0.99, 95% CI 0.80–1.22) or FOLFOX (HR=1.00, 95% CI 0.72–1.41). There was also no significant difference in OS at a median follow-up of at least 5 years. Taken as a class, oxaliplatin-containing regimens (XELOX, FOLFOX, FLOX) improved DFS vs. non-oxaliplatin-containing regimens (HR=0.80, 95% CI 0.73–0.87). This result was confirmed for OS.

Conclusions: Despite the limited number of available trials, the results of these analyses demonstrate a clear benefit of incorporating oxaliplatin into combination regimens for early-stage colon cancer. XELOX, FOLFOX and FLOX appear to be equivalent in terms of efficacy in this setting.

[Table: see text]
Study on the deterioration of verbal memory in colon cancer patients after receiving adjuvant chemotherapy.
Authors: Martinez Marín V. , Lopez Santiago S. , De Castro J. , Cruzado J. A. , Belda-Iniesta C. , Cano J. , Barriuso Feijoo J. , Feliu M. , Smith J. , Feliu J.
Published: February 2017

509

Background: Usually, patients treated with chemotherapy (CT) complain about memory loss. This was mainly studied on patients receiving adjuvant CT for breast cancer. However there are no data on adjuvant treatment of colon cancer (CC). The aim of this study is to investigate whether adjuvant CT induces in CC patients impaired memory, particularly the verbal one.

Methods: 77 patients diagnosed with stage II-III CC who received adjuvant CT for 6 months with FOLFOX-4 were included between January 2008 and May 2010. Verbal memory was investigated pre-and post-treatment by the Test Barcelona. Peña-Casanova, (1990).

Results: Data of 54 patients who completed the analysis pre-and post-treatment were collected. Population characteristics are: male (61%), mean age of 66, less than 5 years of education (58.3%), stage II/III (43/57%) treated with FOLFOX-4/Xeloda (85/15%). Analysis of verbal memory performance can be seen in the table.

Conclusions: We found a clear verbal memory impairment after adjuvant CT in CC patients, although the number of words Learning decreases without reaching statistical significance. Remembering of stories is significantly deteriorated after the administration of QT, affecting the patient immediate recall of stories, even when given clues. So it is the delayed recall (after 5′). This can have a negative impact on the patient's life in tasks involving immediate or delayed recall of events. This interesting finding must be tested in larger series and placebo controlled randomized trials.

[Table: see text]

No significant financial relationships to disclose.
Six months compared with 12 months of capecitabine as adjuvant chemotherapy for stage III (Dukes' C) colon cancer: Rationale for the open-label randomized phase III study, JFMC37-0801.
Authors: Takahashi T. , Yoshida K. , Hamada C. , Sakamoto J. , Satoh T. , Sadahiro S. , Mishima H. , Watanabe M. , Sugihara K. , Tomita N.
Published: February 2017

517

Background: The standard duration of adjuvant chemotherapy (CT) in patient with stage III colorectal cancer is 6 months. On the other hand, no clinical trial which investigate an optimal duration of oral chemotherapeutic agents has yet been implemented for adjuvant treatments. According to the ACCENT database (Sargent, et al. J Clin Oncol 27: 872- 877, 2009), 83% of recurrences in stage II and III pts have occurred within the first 3 years after surgery and peak was observed around one year after surgery. Also, single-agent FU-based adjuvant CT reduced the hazard rate of OS, DFS, and TTR, although the peak of events around one year was still remained especially for stage III pts. We analyzed the data of recurrent risk of curatively resected colon cancer pts provided by JFMC7-1-7-2-15, X-ACT. Surgery alone group and 6 months CT (5FU/LV or capecitabine [Cape]) showed highest peak between 12 months to 18 months after surgery, but 12 months oral 5-FUs group did not show recurrence peak between 12 months to 18 months after surgery. Therefore, to clarify the benefit of 12 month administration of Cape, we planned a phase III randomized trial for a comparison of 6 months treatment and 12 months treatment.

Methods: JFMC37 is a multicenter, randomized phase III trial. Patients with fully resected stage III colon or recto sigmoid cancer were eligible. Patients were randomized 1:1 to receive Cape of 6 months (arm A) or Cape of 12 months (arm B). Primary endpoint is disease-free survival. The statistical design is based on superiority hypothesis; 5-yrs DFS is 60% in arm A, 67% in arm B; unilateral α=0.05, 1-β=0.8; and planed accrual is 1200 pts.

Results: Between September 2008 to December 2009, 1,304 pts were randomized. Patients characteristics are (armA/armB); number 653/651, gender M352-F301/M343-F308, median age 65 years/65 years, ECOG PS=0-1 620-33/632-19, involvement of lymph nodes=N0-N1-N2 503-130-20/499-128-24. There were no differences in baseline characteristics between arm A and arm B.

Conclusions: This trial is expected to show if 1 year adjutant chemotherapy with capecitabine can reduce the peak of recurrence in 1 year and provide long-term OS benefit.

[Table: see text]
Racial disparity trends in clinical presentation and outcomes in colorectal cancer: Findings from an urban university hospital.
Authors: Mitchell E. P. , Topham A. , Singla R. , Maron S. , Schoenfeld J. , Guiles F. , Goldstein S. , Anne P. R. , Isenberg G. , Maxwell P. J.
Published: February 2017

518

Background: African Americans (AA) have a higher incidence and lower survival rates from colon and rectal cancer than Caucasian Americans (C). This disparity has been attributed to many factors, including diagnosis at later stage, unfavorable histopathologic features, inadequate treatment, and socioeconomic factors. The multidisciplinary management setting ensures similarity in management and treatment planning. In this study, we assessed the pathological features and evaluated survival outcomes in patients with CRC in AA and CA using a large single institutional database.

Methods: We compiled data from 3,826 patients with colon and rectal cancer treated at Thomas Jefferson University Hospital from 1988-2009 and used Surveillance Epidemiology and End Results registry data from 1988-2004 to compare survival rates. Independent variables included age, racial background, site of primary tumor, degree of differentiation, stage at presentation, recurrence-free survival and overall survival rates for colon and rectal cancer and for each stage of disease. We compared survival rates using statistical modeling to account for differences in patient and disease characteristics between the two groups.

Results: At diagnosis, AA pts presented with more advanced stage of disease (p < 0.0001), were more likely to have proximal disease (p < 0.000000528), had worse overall 5-year survival, and worse survival stage-by-stage than C patients. Data also showed that the odds ratio for risk of nodal involvement was greater for AA pts than C pts with lower T tumors. AA pts were more likely to have less well differentiated colon tumors, but more well differentiated rectal tumors, younger age and worse survival stage-by stage than C pts. Although C pts were more likely to have rectal cancer (p < 0.0001), they were less likely to have stage IV disease at presentation.

Conclusions: AA pts with CRC are more likely to present at a younger age with later stage, more proximal tumors, have higher nodal involvement with lower T lesions, and less well differentiated tumors than C. Additional studies on biological feature sand molecular markers are ongoing to and will be presented.

No significant financial relationships to disclose.
Rapid 5-fluorouracil plasma quantification by immunoassay: Validation with FOLFOX6 clinical samples.
Authors: Salamone S. J. , Benfield C. N. , Courtney J. B. , Harney R. L. , Kozo D. R. , Li Y. , Lundell G. D.
Published: February 2017

563

Background: 5-fluorouracil (5-FU) is one of the most widely used chemotherapy agents in the treatment of colorectal cancer. Studies over the last 30 years have demonstrated wide pharmacokinetic variability of 5-FU which can lead to undue toxicity and suboptimal treatment. Recent clinical studies have demonstrated that managing plasma 5-FU levels and adjusting doses to target steady state concentrations effectively minimizes toxicity and improves outcome.

Methods: An existing immunoassay using a novel antibody to 5-FU was modified to directly quantify 5-FU in patient plasma samples without any sample pretreatment. The assay was adapted to Beckman Coulter AU analyzers and to Roche COBAS c 111 analyzer. Method comparison to LC-MS/MS, limit of detection (LoD), lower limit of quantitation (LLoQ), precision, and linearity of the assay were evaluated. The assay was also validated by testing samples of patients being treated by modified FOLFOX6 from an on-going clinical trial ( NCT00943137 ).

Results: The modified immunoassay was confirmed to have a linear reportable range from 85 to 18,000ng/mL and a LoD of 52ng/mL. The immunoassay was established to have good precision (CV<6%) around the medical decision points for FOLFOX and FOLFIRI regimens. Method comparison of the immunoassay obtained by testing 58 clinical samples from patients under 5-FU treatment provides excellent correlation to LC- MS/MS: Deming slope 1 ± 0.05, R > 0.98. Another 82 samples of patients on modified FOLFOX6 regimen from clinical trial (( NCT00943137 ) were tested using the immunoassay and range of these sample were reported to be from 95 to 2,970 ng/mL.

Conclusions: The assay provided the performance required to rapidly quantify 5-FU plasma concentrations. It was fast (time to 1st result < 10 minutes), precise, correlated well to a physical method, required only 100uL sample on the analyzer and 7ul for actual testing per assay, and was easily adapted to a variety of clinical analyzers. Clinical and pharmacokinetic laboratories could use this assay to introduce an evidence-based approach to optimize 5-FU dosing that would have higher throughput, simpler methodology, and require less labor, space or expense than the physical methods.

[Table: see text]
Incidence of FOLFOX induced amenorrhea in women age 40 and younger with colorectal cancer.
Authors: Cercek A. , Reidy D. L. , Saltz L.
Published: February 2017

567

Background: The effects of oxaliplatin-based chemotherapy on female fertility are largely unknown. Studies have indicated that the incidence of young women diagnosed with colorectal cancer is on the rise, thus there is an increasing number of female colorectal cancer survivors of child-bearing age. Adjuvant FOLFOX chemotherapy is the most widely used standard treatment for stage III and high- risk stage II colon cancer. The objective of this analysis was to evaluate the incidence of amenorrhea as a crude measure of potential fertility in women age 40 and younger treated with FOLFOX.

Methods: A search of computerized pharmacy records identified 45 women age 40 or younger who received adjuvant FOLFOX chemotherapy at Memorial Sloan-Kettering for stage II or III colorectal cancer from January 2002 and January 2009. Fourteen patient s had received pelvic radiation and 3 developed metastatic disease and were thus ineligible. A total of 28 patients were eligible and were mailed an anonymous questionnaire asking their age at time of diagnosis and specific questions regarding their menses pre-, during, and post-chemotherapy. The returned surveys were reviewed and the results tallied.

Results: Of the 28 patients that met the eligibility criteria and were mailed the survey 16 (57%) returned the questionnaire. One patient had undergone bilateral oophorectomy and was ineligible. The majority of patients were 31-35 years old (range 21-40). All but one patient had regular pretreatment menses. Of the 15 eligible patients, 7 maintained their usual menses throughout chemo, 3 noted a change in their menses, and 6 lost their cycles. Only 1 (6%) did not regain her menstrual cycle 6 months after stopping chemotherapy.

Conclusions: In this small retrospective study, the incidence of amenorrhea in young women treated with FOLFOX chemotherapy is quite low. Prospective studies are planned to more accurately characterize the impact of FOLFOX on female fertility.

[Table: see text]
Bidirectional intraperitoneal chemotherapy with oxaliplatin in the context of CRS and HIPEC in patients with peritoneal carcinomatosis.
Authors: Glockzin G. , Schlitt H. J. , Piso P.
Published: February 2017

568

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide a promising therapeutic option for selected patients with peritoneal carcinomatosis. The use of oxaliplatin as an intraperitoneal cytostatic agent seems to further improve the efficacy of the combined treatment concept. Nevertheless, additional toxicity in comparison to mitomycin C and/or doxorubicin might be exspected.

Methods: Between 02/2008 and 08/2010 40 patients underwent CRS and HIPEC with oxaliplatin at a concentration of 300 mg/sqm at the University Medical Center Regensburg. Thirty-five of these patients received bidirectional chemotherapy with additional intravenous application of 5FU/LV and 5 patients intraperitoneal oxaliplatin only. Perfusion time was 30 and 60 minutes, respectively. A matched-pair analysis was performed to compare IP oxaliplatin to our former standard HIPEC with mitomycin C and doxorubicin. Matching criteria were operating time, age and sex.

Results: The mean operating time in the OX and the MMC group was 315 and 313 minutes, respectively. The mean age was 52 and 51 years, and 15 versus 16 patients were female, respectively. Median hospital stay was 15.5 days in the OX group and 17 days in the MMC group. The median stay on ICU was one day in both groups. The grade 3/4 morbidity rate was 42.5 % versus 37.5 % (p = 0.648). Five versus six patients had to be reoperated. Perioperative morbidity was 2.5 % versus 0 %. Main complications in the OX group were pleural effusion (5), thrombosis (2), cardiac arrhythmia (2), and abscess (2). In the MMC group postoperative morbidity was mainly caused by ileus (4), anastomotic leakage (3), pulmonary embolism (2), and wound infection (2).

Conclusions: Our data suggest that the use of IP oxaliplatin in the context of CRS and HIPEC does not increase perioperative morbidity and/or mortality rate. Nevertheless, randomized controlled trials are required to determine the best intraperitoneal chemotherapeutic regimen regarding toxicity and oncological outcome.

No significant financial relationships to disclose.
Role of thrombospondin 1 (THBS1) expression in peritoneal metastasis of gastric cancer treated with taxanes.
Authors: Kurita N. , Shimada M. , Iwata T. , Nishioka M. , Morimoto S. , Yoshikawa K. , Miyatani T. , Mikami C. , Kashihara H.
Published: February 2017

57

Background: To clarify the utility of taxanes and to pick up the prognostic factors in the treatment with 5FU- based chemotherapy for peritoneal metastasis of gastric cancer.

Methods: Responder analysis: 18 patients with peritoneal metastasis of gastric cancer were enrolled in phase I study. The regimen consists of S-1 (80-120 mg) for 14 days and intraperitoneal infusion of PTX (dose escalation: 40 - 100 mg/m2) at day 1 and 14, which was repeated 2 cycles. To pick up the predictive factors, the 137 genes, which were selected in the viewpoint of sensitivity of 5FU, CPT11 and taxanes, were analyzed using focused DNA microarray for the 12 patients. Role of THBS1 expression: THBS1 expressions were evaluated in immunohistochemical (IHC) staining of surgical specimens of 59 patients with peritoneal metastasis of gastric cancer who were administered 5FU-based chemotherapy. THBS1 positive was defined > 30% of the population stained moderate to strong.

Results: Responder analysis: Expressions of THBS1 gene of the 6 patients who had clinical benefits (2: partial response, 2: positive adenocarcinoma cells in peritoneal cytology became negative, 2: remarkable decrease of ascites) were more than 2 folds higher than those of no responders. THBS1 expression was confirmed in 5 (83.3%) using IHC staining, who had significantly higher survival rate compared with that of the negative. Role of THBS1 expression: 17 patients (28.8%) was THBS1 positive and had significantly better prognosis compared with negative patients (1year survival: 64.7% vs 34.7%). 38 patients treated with regimes including taxanes revealed a tendency of improved overall survival rates (p=0.05). Overall survival of 15 patients with THBS1 positive administered taxanes was significantly higher than that of the negative patients. (1 year survival: 66.7% vs 42.4%)

Conclusions: PTX could improve the survival of peritoneal metastasis of gastric cancer. THBS1 is a prognostic factor especially in the patients treated with taxanes, which leads to tailor-made therapy.

[Table: see text]
Phase II trial of cetuximab plus irinotecan for FOLFOX and FOLFIRI-refractory patients with EGFR-positive advanced and/or metastatic colorectal cancer: Evaluation of the efficacy and safety based on KRAS mutation status (T- CORE0801).
Authors: Shimodaira H. , Soeda H. , Gamoh M. , Andoh H. , Yamaguchi T. , Watanabe M. , Isobe H. , Sudo T. , Kato S. , Ishioka C. ,   T-CORE
Published: February 2017

573

Background: Activating mutation of the KRAS gene is a predictive biomarker for loss of efficacy to anti-EGFR antibody therapy. However, this was mainly established by the evidences of Caucasian studies. Then, this prospective study investigated the role of KRAS mutations on efficacy and safety to cetuximab plus irinotecan in Japanese patients with metastatic colorectal cancer (mCRC).

Methods: We conducted a prospective study to analyze objective response to cetuximab plus irinotecan in molecularly defined KRAS wild-type (WT) or mutant subgroups of chemotherapy-refractory mCRC. KRAS mutations were detected by direct sequence on DNA from formalin-fixed, paraffin-embedded tissue of patients treated in 11 centers in Japan. Additional EGFR related genes such as BRAF, PIK3CA etc. and antibody-dependent cellular cytotoxicity related polymorphism in FCγRIIa and RIIIa genes were also examined.

Results: Forty-three patients were enrolled. KRAS mutations were found in 31.7% of 41 eligible patients. Response rate (RR) to cetuximab plus irinotecan, the primary endpoint of the study, was 17.9% and 0% for the patients with tumor harboring WT and mutant KRAS, respectively. No significant differences in toxicity were observed between the KRAS WT and mutant groups. Detail statistical analyses are ongoing.

Conclusions: We confirmed that KRAS status is a useful predictive maker for the efficacy to cetuximab plus irinotecan therapy in Japanese mCRC patients, even though the response rate in the KRAS WT group was lower than expected.

[Table: see text]