bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiotensin converting enzyme inhibitor and angiotensin receptor blocker use and outcomes in patients with colorectal cancer.
Authors: Tuazon Sherilyn Alvaran , King Gentry Teng , Sta. Cruz Joanna Paula Pingol , Ong Kian Koc Jean B. , Chae Young Kwang , Leighton John Charles , Daskalakis Constantine
Published: February 2017

544

Background: Increasing evidence implicates angiotensin in the pathophysiology of carcinogenesis. Both Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) have shown in-vitro activity in Colorectal Cancer (CRC) via inhibition of both VEGF and IGF-1 and present a novel therapeutic strategy. This study aimed to investigate the association of these agents in outcomes of patients with CRC. Methods: We reviewed the medical records of patients with stage I-III CRC from 2004-2008. ACEI and ARB use was defined as consumption for at least 3 months in patients with no evidence of disease after initial diagnosis and treatment. Outcomes were Disease Free Survival (DFS) and Overall Survival (OS). Kaplan-Meier and Cox proportional hazards regression were used. Results: A total of 222 patients were included, with a median follow up of 39 months. A total of 105 (47%) were identified as users of ACEI/ARBs. Multivariate analysis, adjusted to age, sex, race, stage, grade, tumor location, adjuvant chemotherapy, radiotherapy, statin and ASA use showed significantly improved DFS among users of ACEI and/or ARBs compared to non-users (HR = 0.44, p = 0.003). Considered separately, users of ACEIs only and users of ARBs only had better DFS than non-users (HR = 0.43 and 0.53, respectively). Compared directly, users of ACEIs did not have significantly different DFS than users of ARBs (HR = 0.81, p = 0.678). With regards to OS, multivariate analysis showed that, compared to non-users, patients with ACEI or ARB use had better OS, although non-significantly (HR = 0.59, p = 0.219). However, the magnitude of the impact on OS was comparable to that seen for DFS. Conclusions: The use of ACEIs and/or ARBs is associated with improved disease-free survival in CRC patients. There was a statistically insignificant trend toward improved OS, which may be related to the low power to the study. This observation warrants further exploration.
Occurrence and timing of organ space surgical site infections (SSI) in rectal cancer patients: A NSQIP database review.
Authors: Miyagaki Hiromichi , Kumara HMC Shantha , Xiaohong Yan , Cekic Vesna , Whelan Richard L.
Published: February 2017

552

Background: This study’s aim was to determine the incidence and date of presentation of organ space SSI (in this setting most likely due to anastomotic leak or pelvic abscess) in rectal cancer resection patients. A second purpose was to determine which variable(s) impacted the timing of the presentation. Methods: The NSQIP database was queried from 2007 to 2011 for elective rectal cancer resections. Exclusion criteria included; ASA 5 status, preoperative(preop) shock/sepsis, SIRS, and recent surgery. Demographic parameters, comorbidities, lab data, and incidence and timing of organ space SSI were assessed. The statistical methods used were Fisher’s exact test (categorical variables) and Wilcoxon’s rank tests (continuous variables). Results: 8,093 rectal cancer patients were identified (Male/Female; 60.1%/39.9%; median age, 60; APR, 28 %; sphincter saving procedures,72%). The incidence of organ space SSI was 6 % (485 patients; 2.7% presented before and 3.3% after discharge). The rate was significantly greater for men, younger patients (< 60), smokers, sphincter saving resections (vs. APR). Preop radiotherapy (RT) did not increase the rate of and stomas did not protect against the formation of organ space SSI. The mean date of detection was 14.6±7.3 days after surgery (Mean±SD). A further delay was noted in those who had preop RT regardless of the operation performed (n=184, added delay 2.7 days, p<0.05). Significant delays (p<0.05) were also noted in patients that had APR (n=112, mean delay 2.4days), stoma formation (n=285, mean delay 1.6days) and open surgery (n=368, mean delay 1.8 days). Multivariate analysis revealed preop RT (p=0.0002) and APR (p=0.0258) as independent risk factors for delayed presentation. Conclusions: Most organ space SSI after rectal cancer surgery occur after hospital discharge. The mean presentation date is about 2 weeks after surgery. Patients who received preop RT or underwent APR presented about 2.5 days later than the mean date. Rectal cancer patients should be followed closely for 3 weeks as regards organ space SSI.
Comparison of sizes of sentinel and non-sentinel lymph nodes in colorectal cancers (CRCa).
Authors: Saha Sukamal , Koduru Ujwala , Burke Jacob , Korant Alpesh K. , Saha Supriya Kumar , Dhar Vikrom K. , Johnston Gregory , Wiese David , Arora Madan L. , Singh Trevor
Published: February 2017

557

Background: Sentinel lymph node (SLN) mapping (M) in CRCa with ultrastaging of SLNs find more nodes per patient (Pt) and more metastasis in the SLNs than non-SLNs (NSLNs) compared to conventional methods. We hypothesized that SLNs may represent a subset of nodes smaller than those detected by routine pathological exam, and hence missed by conventional methods. Hence, we compared the sizes of SLNs and NSLNs in CRCa pts undergoing SLNM. Methods: 365 pts underwent subserosal peritumoral injections of blue dye for SLNM. Blue stained nodes were tagged as SLNs. SLNs were sectioned at 5 levels, 4 stained with H & E, one with cytokeratin (CK-IHC). The non-SLNs were sectioned at one level and stained with H & E. Greatest diameter of nodes for sizes were measured on glass slides or from gross examination. Results: Of the total of 5,601 LNs (Average 15.3/pt) included, 912 were SLNs and 4689 non-SLNs. Of the total lymph nodes removed, 78% were 5mm or less; 69% of positive LNs and 97% of negative LNs were less than 9mm (Table). On average, the size of SLN was bigger (5.7mm) than NSLN (4.0mm). Both positive and negative SLNs were also bigger than positive and negative NSLNs (Table). Conclusions: Our study confirms that on average, SLNs are bigger than NSLNs whether positive or negative or as a whole. This also highlights diligent efforts needed by the pathologists, as 77% of all lymph nodes were less than 5mm. [Table: see text]
A phase II study of second-line S-1/CPT-11+bev for advanced colon cancer (NCCSG04): Subset analysis by K-ras, EGFR, UGT1A1, and previous bevacizumab.
Authors: Takii Yasumasa , Furukawa Kouichi , Maruyama Satoshi , Yamazaki Toshiyuki , Nishimura Atsushi , Kawahara Mikako , Tomiyama Takemi , Akazawa Kohei , Hatakeyama Katsuyoshi
Published: February 2017

564

Background: We planned a phase II trial to evaluate the efficacy and safety of irinotecan, S-1, and bevacizumab (IRIS/Bev) as second-line therapy for patients with metastatic colorectal cancer (mCRC). The result of this study was reported an active and generally well-tolerated 2nd-line treatment for mCRC (Takii et al. ASCO-GI 2013 #496). We analyzed subset of EGFR, K-ras, UGT1A1, and previous Bev. Methods: The study design was multicenter, single-arm, open-label phase II study. Eligible patients had to have mCRC with confirmed diagnosis of adenocarcinoma, history of oxaliplatin containing regimen as first-line therapy, an age from 20 to 80 years, ECOG performance status (PS) of 0-1. S-1 65 mg/m2 daily p.o. was given on days 1-14 and Irinotecan 75mg/m2and bevacizumab 10mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. We retrospectively examined progression-free survival (PFS), overall response rate (OR), overall survival (OS), time to treatment failure (TTF) and safety by K-ras, EGFR, UGT1A1, and previous Bev status. Results: Thirty-four patients were investigated. The OR was 21.1% (7/33) and disease control rate was 84.8% (28/33). Median PFS was 8.9 months, median TTF was 8.2 months and median OS was 23.4 months. Median PFS was 9.9 months on K-ras wild group and 6.6 months on K-ras mutant group (p = 0.517). Median OS was not reached on K-ras wild group and 16.4 months on K-ras mutant group (p = 0.097). The EGFR-negative case was three cases, and it did not become a data to compare because of small number. Median PFS was 8.5 months on previous Bev group and 9.9 months on previous no-Bev group (p = 0.637). Median OS was not reached on previous Bev group and 23.1 months on previous no-Bev group (p = 0.701). Median PFS, TTF and OS was no different between UGT1A1 wild group and mutant group. On safety analysis, there were no different between the two groups, respectively. Conclusions: IRIS/Bev is an active and well-tolerated second-line treatment for patients with mCRC. Only K-ras status influendced OS. Clinical trial information: UMIN000001631.
Peritoneal surface disease (PSD) from appendiceal cancer treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC): Overview of 481 cases.
Authors: Votanopoulos Konstantinos I. , Russell Greg B. , Randle Reese W. , Shen Perry , Stewart John H. , Levine Edward Allen
Published: February 2017

565

Background: Appendiceal cancer PSD treated with CRS/HIPEC has shown significant variability in the obtained survival benefit. Methods: A prospective database of 1,069 procedures was reviewed for primary, grade, nodal and performance status, resection type, morbidity, mortality, and survival. Results: 481 CRS/HIPEC procedures, 317 (77.3%) for low grade (LGA) and 93 (22.7%) for high grade (HGA) appendiceal primaries, were identified. Median follow up was 44.4 months. 30 and 90 day major morbidity were 27.8% and 9.3% while the 30 and 90 day mortality was 2.7% and 5.6% respectively. Median ICU and hospital stay was 1 and 9 days. In multivariate analysis, Clavien III/IV complications, were related to incomplete CRS (p = 0.0037), involved nodes (p < 0.0001) and comorbidities (p = 0.003). Multivariate analysis of the LGA patients indicated survival to be dependent on nodal status (p = 0.003 HR 3.6), complete cytoreduction (p < 0.0001) and preoperative chemotherapy (p = 0.04 HR 2.2). The multivariate survival of HGA was dependent on complete cytoreduction (p = 0.0003 HR 3.8) and preoperative chemotherapy (p = 0.0064 HR 2.5). In patients with complete cytoreduction, median survival for node positive LGA and HGA patients was less than their node negative counterparts. (85 months vs. not reached (82% alive at 90 months) and 30 vs. 153 months respectively p < 0.0001). Conclusions: Positive nodes are associated with decreased survival not only in HGA but also in LGA patients even after a complete cytoreduction. Nodal status is superior to grade of disease as a prognostic indicator of survival. Node negative HGA primaries after complete CRS can obtain a comparable survival benefit to LGA counterparts.
Causes of urban-rural disparities in adjuvant chemotherapy (AC) for rectal cancer (RC).
Authors: Rasool Javaheri Khodadad , Speers Caroline , Cheung Winson Y.
Published: February 2017

568

Background: While urban-rural differences in cancer care are well described, the etiology for such disparities is unclear. Our aim was to determine whether differences in AC use are mediated through variations in community size (CS) and whether differences in AC use translated into differences in patient survival outcomes (SO). Methods: Patients with stage II/III RC from 1999 to 2009 and referred to any 1 of 5 regional cancer centers in British Columbia were reviewed. Communities were classified as rural (R), small urban (SU), moderate urban (MU), and large urban (LU) based on census data. Using zip codes and a distance matrix application interface, driving distance (DD) to patients’ respective cancer center (CC) was determined and categorized into quartiles. Stepwise logistic regression was used to explore AC use based on urban-rural communities, controlling for DD. Cox regression was used to identify whether variations in CS translated into differences in SO. Results: A total of 2618 patients were identified: median age 67 years (IQR 58-75), 64% men, and 63% received AC. Patients were distributed across various communities: R 37%; SU 11%; MU 13%; and LU 39%. There were no differences in baseline characteristics based on CS (all p<0.05). Compared to patients in LU centers, those living in R, SU and MU areas were less likely to be treated with AC (55 % vs. 49% vs. 71%, respectively, p<0.001). Likewise, DD was shortest for LU and longest for R residents (p<0.001). In multivariate analysis that controlled for confounders, urban-rural disparities in receipt of AC persisted, and these differences were significantly increased after adjusting for DD (Table). In Cox regression analysis which controlled for confounders, patients who lived in R, SU, and MU regions did not have a significantly inferior SO in comparison to those living in LU areas (HR: 0.926, 0.813, 1.006, respectively, p=0.47). Conclusions: There are urban-rural disparities in access to AC independent of patients’ DD to CC. These disparities do not seem to alter patients’ SO. [Table: see text]
Do inflammatory bowel disease patients experience more toxicity after radiotherapy for colorectal and anal cancer?
Authors: Chang Bianca W. , Kumar Aryavarta M. S. , Kiran Ravi P. , Kalady Matthew F. , Lavery Ian C. , Abdel-Wahab May
Published: February 2017

570

Background: Despite potential oncologic gains from using radiotherapy in patients with inflammatory bowel disease (IBD), it has historically been contraindicated due to increased acute gastrointestinal (GI) toxicity. Yet recent published literature is mixed with regards to toxicity outcomes in these patients. In this study, we examine GI, genitourinary (GU), and skin toxicity in IBD patients compared to non-IBD patients both treated with external beam radiation therapy (EBRT) for anal or colorectal cancer (CRC). Methods: Anal and CRC patients who received EBRT were included in this single institutional IRB-approved study. 15 IBD patients and 30 non-IBD patients were matched 1:2 based on age (±5 years), treatment year (±1 year), BMI (±10 kg/m2), and clinical stage. No IBD patients had documented active disease at the time of treatment. All patients had a pathologic diagnosis of anal or CRC and received EBRT either neoadjuvantly or adjuvantly. Acute toxicity occurred within 100 days of EBRT. Data was collected via retrospective review of the treatment charts. Results: All patients received radiation doses between 45-52 Gy in 1.8Gy/fx or 2Gy/fx, delivered using AP/PA, IMRT, 3-field, or 4-field plans. There was no difference in the rate of grade 3 (20% vs 7%, p=0.19) or grade 4 (7% vs 0%, p=0.13) lower GI toxicity. There was also no difference in the incidence of GU (47% vs 30%, p=0.37), upper GI (60% vs 33.3%, p=0.08), or skin toxicity (40% vs 64%, p=0.17). Post-operatively, IBD patients had a significantly higher rate of wound dehiscence (35.7% vs 7.1%, p=0.02); however, there was no difference in the rate of bleeding (29% vs 18%, p=0.43), infection (50% vs 32%, p=0.50), or ileus (36% vs 11%, p=0.06). Conclusions: IBD patients with anal or CRC who received EBRT neoadjuvantly or adjuvantly did not experience more acute GI, GU, or skin toxicity than matched non-IBD patients with similar treatment. Post-operatively, IBD patients were more likely to have wound dehiscence, but were not more likely to have bleeding, infection, or ileus.
Final results of phase II study of S-1, oral leucovorin, oxaliplatin, and bevacizumab combination therapy (SOL+BV; SOLA) in metastatic colorectal cancer (mCRC).
Authors: Yamazaki Kentaro , Nishina Tomohiro , Kato Takeshi , Yoshino Takayuki , Miyata Yoshinori , Esaki Taito , Moriwaki Toshikazu , Boku Narikazu , Hyodo Ichinosuke
Published: February 2017

574

Background: The SOL regimen (S-1, Oral Leucovorin; LV, and Oxaliplatin) demonstrated a promising activity with tolerated toxicities compared to mFOLFOX6 in a randomized phase II study for mCRC. We previously reported the promising results of a phase II study of SOL+BV in Gastrointestinal Cancers Symposium 2012 (Kato T, et al.) focusing on early clinical outcomes, overall response rate (ORR), progression free survival (PFS) and safety. The final follow-up (cut-off date Dec 2012) has been completed, and we report up-dated overall survival (OS) and the impact of early objective tumor response (EOTR) on OS in the present report. Methods: The main inclusion criteria were; (1) metastatic colorectal adenocarcinoma, (2) age ≥20 years, (3) no prior chemotherapy, (4) target lesion (RECIST v1.0), (5) ECOG PS 0-1, 6) written informed consent. Patients (pts) received S-1 (40-60 mg bid) and LV (25 mg bid) orally for one week. Oxaliplatin (85 mg/m2) and BV (5 mg/kg) were administered on day 1. This treatment was repeated every 2 weeks. The primary endpoint was ORR confirmed by the independent review committee according to RECIST v1.0. This trial was supported by Taiho Pharmaceutical CO, LTD. (JAPIC Clinical Trials information Identifier: JapicCTI-090881). Results: From Oct 2009 to Apr 2010, 31 pts were enrolled. Of the eligible 29 pts, median age was 62; PS 0/1 was 24/5; number of metastatic organs 1/≥2 was 15/14. ORR was 86% (95%CI, 68-96), and the median PFS was 15 months (95%CI, 10-26). OS has not reached median with a median follow-up time of 34 months. Two-year survival rate was 72%. EOTR (RECIST sum ≥30% shrinkage) at 6-weeks was observed in 35% of pts. Two-year survival rate in these pts with an EOTR at 6-weeks was 80%, while in other pts without an EOTR at 6-weeks was 68%. The curative resection rate of metastatic lesions was 28%. The incidence (≥10%) of grade 3/4 adverse drug reactions were; neutropenia 20%, hypertension 23%, anorexia 20%, fatigue 17%, diarrhea 10%, and sensory neuropathy 53%. Conclusions: The SOL+BV regimen showed the promising activity for mCRC. The high proportion of EOTR might lead to long survival. Further evaluation of this regimen would be warranted. Clinical trial information: 090881.
Volumetric analysis of anal cancer relapses following radical chemoradiation.
Authors: Muirhead Rebecca , Durrant Lisa , Hyde Katherine , Hawkins Maria
Published: February 2017

576

Background: Definitive chemoradiotherapy is standard of care in anal squamous cell carcinoma. The ACT II trial set the standard achieving three year overall survival rates of 73%. However patients with locally advanced disease have a ~50% local relapse rate. Studies have failed to demonstrate an improvement in local relapse rate by altering the systemic therapy. Although 2/3 of relapses are local as opposed to regional or distant, there is limited knowledge on the 3D position of these relapses. We aim to retrospectively review the patterns of local failure in three dimensions, relative to the radiotherapy plan. Methods: Between February 2007 and April 2012, 77 patients were treated for squamous cell carcinoma of the anus with radical chemoradiotherapy. Early stage (T0/2) and locally advanced (T3/4) tumours constituted 53% and 44% respectively. 37% of patients had nodal disease. As per ACT II protocol we used a gross tumour volume (GTV) to PTV margin of 3cm and prescribed to a dose of 50.4Gy. In patients with a local recurrence, imaging from the time of recurrence was imported into the radiotherapy planning system. The volume and site of gross recurrence was noted relative to the previous GTV and 95% isodose line. The mean dose delivered to the relapsed area was calculated. Results: Median follow-up was 42 months (range 14 to 78 months). Eight (10%) patients failed to respond. Six (8%) patients developed an isolated local relapse, 2 (3%) distant metastatic disease alone and 1 both local and distant relapse. Of those that relapsed locally, 5 patients were T2N0, one T3N0 and 1 node positive. There were no regional relapses. The entire macroscopic relapse lay within the 95% isodose line of the 50.4Gy in all patients. The median percentage of relapse that lay within GTV was 63% (range 29 to 100%). A GTV to PTV margin of 2cm would have encompassed all macroscopic relapses. The median doses to relapsed area was 52Gy (range 51Gy to 53Gy) with the minimum dose to any relapsed area being 49Gy. Conclusions: The majority of relapses centred on the GTV suggesting the gross tumour was uncontrolled with current doses in these patients. A reduction of GTV to PTV margin may be appropriate, facilitating trials of dose escalation with the aim of improving outcomes.
Preliminary results of preoperative FOLFOX chemotherapy for locally advanced colon cancer patients with therapeutic drug monitoring of 5-FU.
Authors: Rodriguez Javier , Martin Romano Patricia , Aldaz Azucena , Chopitea Ana , Baixauli Jorge , Subtil Jose Carlos , Zufia Laura , Garzon Carlos , Sola Iosu , Castanon Eduardo , Hernandez-Lizoain Jose Luis
Published: February 2017

579

Background: Preoperative chemotherapy is an alternative approach undergoing active clinical research in patients (pts) with locally advanced colon cancer (LACC). The aim of this study was to assess the feasibility and preliminary evidence of activity of a direct monitoring of 5-FU levels based on pharmacokinetically (PK) guided dose adjustments. Methods: LACC pts (T4 or T3 with extramural depth >5mm) diagnosed after a colonoscopy and spiral CT were scheduled to receive 4 cycles of Oxalipatin (85mg/m²), Leucovorin (400 mg/m²), bolus 5-FU (400 mg/m2) and infusional 5-FU (initial dose of 2400mg/m² in 46h and then tailored according to PK monitoring to reach an area under the curve (AUC) between 25-30 mg·h·L-1). Surgery was planned 4 to 6 weeks after the completion of chemotherapy treatment. All pts were staged at baseline and before surgery. Pathological tumor regression was graded according to the MSKCC classification. Toxicity was reported according to the NCI-CTCAE 4.0. Results: From March 2011 to April 2013, 16 pts (M/F: 10/6; median age 56) with LACC were evaluated. Median dose of 5-FU was 4750 mg. 70.6% pts required a 5-FU dose increase to reach the target AUC. Median 5-Fu plasma clearance was 199,58 L/h. Side effect profile included G3 neutropenia (6 pts), G2 diarrhea (5 pts), G2 nausea (3 pts) and G2 asthenia (4 pts). Neoadjuvant treatment was discontinued in 2 pts due to small bowell obstruction requiring surgery. No progressive disease was observed during preoperative chemotherapy. A radiological dowstaging was achieved in 9 pts (56.25%). All pts underwent surgery (laparoscopy-assisted 50%) with an R0 resection rate of 93.75%. There were no treatment-related deaths. Pathological responses (MSKCC score) included grades 4, 3+ and 3 in 12.5%, 12.5% and 25% of pts, respectively. Median number of harvested nodes was 23.5 (7-51) with a ypN0 rate of 75%. Median time to hospital discharge was 7 days. After a median follow-up of 7 months (3-27), the 2-year actuarial median PFS and OS were 67.5% and 100%. Conclusions: Preoperative PK-adjusted FOLFOX in LACC pts achieves major pathological responses in almost 50% the pts and a remarkable R0 resection rate. Further research seems warranted.
Predictors of treatment interruption/dose reduction of neoadjuvant chemotherapy for rectal cancer: A multicenter study.
Authors: Raissouni Soundouss , Armstrong Dawn Elizabeth , Price Hiller Julie A. , Mercer Jamison , Powell Erin Diana , MacLean Anthony , Jiang Maria , Doll Corinne M. , Goodwin Rachel Anne , Batuyong Eugene , Zhou Kevin , Monzon Jose Gerard , Tang Patricia , Heng Daniel Yick Chin , Cheung Winson Y. , Vickers Michael M.
Published: February 2017

580

Background: Neoadjuvant chemoradiation (CRT) is the standard of care for patients with locally advanced rectal cancer. Many patients require dose reduction or chemotherapy interruption due to significant toxicities. To assess the predictors of neoadjuvant chemotherapy treatment (tx) adjustments, we performed a retrospective study in four Canadian provinces. Methods: Cancer Registries identified consecutive patients with clinical stage I-III rectal cancer from the Tom Baker Cancer Center, Cross Cancer Institute, BC Cancer Agency, Ottawa Hospital Cancer Centre and the Dr. H. Bliss Murphy Cancer Centre who received CRT and had curative intent surgery (Sx) from 2005 to 2012. Patient, tumor and tx characteristics were correlated with treatment completion. Results: Of the 891 patients included, 886 patients had tx dose adjustments data available. 738 (83.2%) completed the planned neoadjuvant chemotherapy, while 148 (16.7%) failed to complete planned chemotherapy. Patients who required tx interruption/cessation or dose reduction were more likely to be female, elderly, had higher ECOG PS and were treated with fluorouracil (FU) chemotherapy in univariate analysis (see Table). On multivariable analysis, female gender (OR 1.807, 95% CI 1.02-3.2, p=0.042) and tx with FU (vs capecitabine) (OR 2.7, 95% CI 1.52-4.77, p=0.0007) were associated with dose reduction and tx interruption/cessation. Conclusions: Gender and type of chemotherapy are predictors of neoadjuvant chemotherapy interruption or dose reduction in rectal cancer. Careful monitoring of these patients is warranted during neoadjuvant CRT. [Table: see text]
Does first-line treatment impact the cost-effectiveness of second-line treatment for elderly metastatic colon cancer patients?
Authors: Mullins C. Daniel , Woldemichael Andinet , Zheng Zhiyuan , Onukwugha Ebere , Seal Brian S. , Hanna Nader
Published: February 2017

585

Background: Randomized clinical trials for second line treatment (Tx2) of metastatic colon cancer (mCC) often have strict inclusion/exclusion criteria regarding prior treatment, yet in the real world there is significant variation. This study aims to determine whether cost effectiveness estimates of Tx2 for elderly mCC patients varies by the regimen they received in first-line treatment (Tx1). Methods: We identified 3,211 elderly (age 66+) mCC patients in the SEER-Medicare dataset who received NCCN recommended Tx1 between 2003 and 2009. Patients were categorized by Tx1 based on a previously published algorithm as fluorouracil and leucovorin (5-FU/LV), irinotecan (IRI), oxaliplatin (OX), or “other,” which included IROX or biologics without OX or IRI. Separate 5-year incremental cost-effectiveness of Tx2 were calculated for each Tx1. Approximately 1% of patients with outlier costs were excluded. Patients enrolled in HMOs, lost Part A and/or B, and died of causes other than colon cancer are censored. We adjusted for censoring using the Inverse Probability Weighting (IPW) method. Costs were inflation-adjusted to 2009 dollars using the national monthly medical price index. Results: Among patients who received Tx1, 34% (n=1,090) received 5FU, 17% (n=530) received IRI, 46% (n=1,481) received OX, and 3% (n=110) received other (IROX or Biologics) regimens; 44.5% (n=1,440) proceeded to Tx2. Compared to those who do not receive Tx2, patients who received Tx2 following IROX or Biologics, IRI and 5FU in Tx1 live 292 (se = 4), 224 (se = 2), and 191 (se = 2) days longer and incur added costs of $49,096 (se = $7,137), $83,784 (se = $12,322), and $91,686 (se = $10,312), respectively. Recipients of OX in Tx1 did not receive a survival benefit from Tx2, despite additional costs of $46,849 (se = $10,468). Conclusions: The real-world survival benefit of Tx2 for elderly mCC patients in SEER-Medicare varied based on Tx1 from potential harm to a mean of 292 days of incremental survival. Similarly, the costs and cost effectiveness of Tx2 varied by Tx1. These results underscore the importance of considering prior treatment when evaluating the benefit of subsequent treatment for elderly mCC patients.
Analysis of KRAS/NRAS, PI3CA, and BRAF mutations in the phase II KSCC0901 study of cetuximab plus S-1 as third-line treatment for metastatic colorectal cancer in Japanese patients.
Authors: Emi Yasunori , Oki Eiji , Saeki Hiroshi , Kitao Hiroyuki , Samura Hironori , Takahashi Takao , Sawai Terumitsu , Akagi Yoshito , Tsuji Akihito , Eguchi Susumu , Yoshida Kazuhiro , Baba Hideo , Ogata Yutaka , Natsugoe Shoji , Shimokawa Mototugu , Maehara Yoshihiko ,   Kyushu Study Group of Clinical Cancer (KSCC)
Published: February 2017

587

Background: Exploratory biomarker studies in the randomized phase III PRIME study suggested that patients with mCRC tumors harboring a mutation (MT) in KRAS or NRAS (beyond KRAS exon 2) do not respond to panitumumab-FOLFOX4 (2013 ASCO, JCO 31, #3511). We reported the efficacy and safety of S-1+. Cetuximab (Cmab) in wild-type (WT)-KRAS (exon 2) mCRC patients (pts) as third-line therapy (KSCC0901) (2012 ASCO, JCO 30, s3558). The full spectrum of characterized RAS (KRAS and NRAS), PI3CA, and BRAFMTs may affect efficacy in S-1+Cmab therapy in Japanese patients. Methods: An analysis was conducted to assess the treatment effect of S-1+Cmab, according to RAS (KRAS and NRAS), PI3CA, and BRAF MTs. The treatment protocol of KSCC0901 was as follows: weekly intravenous Cmab administration of 400 mg/m2 (day 1), 250 mg/m2/week (following day 1) and oral administration of 80 mg/m2/day S-1 on days 1–28 of each 42-day cycle. MTs in KRAS codons 12 and 13 (exon 2) were detected using direct sequencing according to the manufacturer’s instructions. MTs in KRAS codons 61 and 146, NRAS codons 12, 13 and 61, BRAF codon 600 and PIK3CA codons 542, 545, 546, and 1047 were detected using the multiplex PCR-Luminex method-based MEBGEN MT Kit (Medical and Biological Laboratories, Nagoya, Japan). Results: 35 pts were eligible for the analysis. Number of MT cases of KRAS, NRAS, BRAF, and PIK3CA were 4, 2, 2, and 5, respectively. One case had MTs of NRAS and PIK3CA. In 37 cases with WT KRASexon2 pts, median progression-free survival (mPFS) was 5.6 [95% CI: 4.4 – 5.7] months; median overall survival (mOS), 13.5 [8.5-16.5] months; and best overall response (ORR), 37.8%. In the all-WT subgroup 23 cases, mPFS was 5.6 [5.1-7.1] months; mOS, 13.5 [9.3-21.2] months; and best ORR, 47.8%. In 12 patients with any MT, mPFS was 4.0 [2.7-7.5] months; mOS, 5.5[2.9- ] months; and best ORR, 16.7%. Conclusions: These results suggest that also in Japanese patients receiving a Cmab containing regimen, RAS, BRAF and PIK3CA MT status beyond KRAS exon2 might predict non-responders to treatment. Clinical trial information: UMIN000002475.
A model of comparative effectiveness research (CER): The impact of biologic agents in a cohort of patients from ethnic minorities with metastatic colorectal cancer (mCRC).
Authors: Shah Umang , Khot Ashish Abhay , Goyal Dharmendra , Guo Shuang , Kaubisch Andreas , Rajdev Lakshmi , Goel Sanjay , Aparo Santiago
Published: February 2017

591

Background: The role of biologic agents in the treatment of mCRC has been studied in clinical trials. These studies included ≥ 90% patients (pts) of white race. Hispanics and blacks were largely underrepresented. CER allows exploration of the impact of biologic agents in a cohort composed largely of pts from minorities. We present the results of a cohort of pts served by Montefiore Einstein Cancer Center (MECC) in Bronx, NY. Methods: Pts diagnosed and treated for mCRC from January 2000 to December 2011 were identified using data from the MECC Cancer Registry. Pts demographic and clinical characteristics were extracted from pts medical records. A Cox proportional–hazard model was used to assess survival differences between pts treated with chemotherapy alone vs. pts treated with chemotherapy plus biologics. Results: A total of 293 pts where identified; 45% were black, 27% were Hispanic, and 28% were white. Of the pts receiving biologics, 90% received bevacizumab and 50% received cetuximab or panitumumab. The median overall survival was 15.2 months in the chemotherapy alone group and 25.6 months chemotherapy + biologics group (p=0.003). Univariate analysis showed that 1 metastatic site vs. ≥ 2, CEA <40 ng/mL, receiving ≥ 2 lines of chemotherapy and exposure to biologics were independently associated with longer survival. Multivariate analysis of the whole cohort (n=290), which included all ethnic groups, showed that exposure to biologics offered a survival benefit (HR of 0.70, 95%CI 0.52–0.93, p=0.02), after adjusting for gender, age, CEA, number of metastatic sites and lines of chemotherapy received. Subgroup analysis based on ethnicity showed survival benefit for Whites (HR of 0.38, 95%CI 0.22–0.66, P=0.001) but not for Hispanics (HR of 0.65, 95%CI 0.35–01.23, p=0.18) nor Blacks (HR of 1.04, 95%CI 0.63–1.70, p=0.87). Conclusions: In this cohort weighted heavily towards ethnic minorities, the addition of biologics to chemotherapy was associated with longer survival, an effect mainly driven by whites. Hispanics and blacks did not seem to benefit from exposure to biologics. An effort should be made to include minority pts in ongoing clinical trials.
Treatment and outcomes of neuroendocrine malignancies (NEMs) of the rectum.
Authors: Tsang Erica , Speers Caroline , Kennecke Hagen F.
Published: February 2017

594

Background: NEMs of the rectum are rare and standard therapy is not well defined. We sought to characterize the clinicopathologic features, locoregional, and systemic management of a series of rectal NEMs and correlated these with outcomes. Methods: Patients referred to the BC Cancer Agency with rectal NEMs between 2005-2011 were included. Well-differentiated tumors with a Ki67 ≤20% and/or mitotic count ≤ 20 per high power field were classified as neuroendocrine tumors (NETs) while poorly differentiated tumors with higher Ki67 and/or mitotic count were classified as neuroendocrine carcinomas (NECs). Results: Of 28 NEMs, 18 (64%) NETs, and 9 (36%) NECs were identified with a median age of 56 and 59, respectively. Of 15 patients with stage I-III NETs, 13 underwent local excision, 2 had a surgical resection and none received pelvic radiation. Univariate analysis demonstrated an association between tumor size (< 1cm, 1-2 cm, > 2cm) and T stage (χ2 = 10.7, p = 0.03). One of 15 NETs developed distant relapse 8.9 months after surgical resection of a T1bN1 tumor. Of 9 NECs, only 2 presented with stage I-III tumors and were treated with radiation (1) or surgery (1). One patient developed distant relapse 4.8 months after radiation. Among all NEMs, liver was the most common site of metastasis (n = 10) followed by bone (n = 3). Median overall survival was 46.5 and 4.8 months for NETs and NECs (p < 0.01), respectively. Conclusions: Rectal NEMs comprise a rare subgroup of rectal tumors and may be classified as NETs or NECs. NETs generally present with early stage disease and are associated with good outcomes with local excision and without pelvic radiation. Rectal NECs frequently present with advanced disease and are associated with poor outcomes.
The efficacy and safety outcomes of bevacizumab and systemic therapy in metastatic colorectal cancer patients with peritoneal disease in the AGITG MAX clinical trial and in nontrial patients in two cancer centers.
Authors: Roohullah Aflah , Sjoquist Katrin Marie , Gebski Val , Ng Weng , Chua Wei , Price Timothy Jay , Tebbutt Niall C. , Chantrill Lorraine A.
Published: February 2017

595

Background: Metastatic colorectal cancer with peritoneal disease (PmCRC) represents a phenotype that may derive a greater clinical benefit from bevacizumab (BEV) due to the effect of VEGF on peritoneal spread and ascites production. However, there is concern of greater adverse events, in particular GI perforations. We investigated the clinical benefit and safety of adding BEV to chemotherapy in PmCRC in clinical trial and nontrial populations. Methods: We compared PFS and OS in PmCRC patients receiving first-line chemotherapy with and without BEV in: (1) the AGITG MAX trial (capecitabine [CAP] vs CAP/BEV +/- mitomycin C) and (2) two cancer centers in New South Wales between Jan 2005 and Dec 2012 (any regimen +/- BEV). Secondary endpoints included chemotherapy duration and GI adverse events. Time to event outcomes were estimated using the method of Kaplan-Meier and comparisons made using the logrank test. Proportional hazards models were used to obtain hazard ratios for regression analysis. Results: See Table. 84 MAX and 69 nontrial pts had PmCRC and there was a 37% reduction in the risk of progression in those receiving BEV, which is similar when compared to the nonperitoneal disease pts (HR= 0.63 95% CI 0.52-0.79 p value < 0.001). OS in the PmCRC group was significantly worse than the nonperitoneal group (14.3 months vs 18.8 months p value = 0.02). Chemotherapy duration was similar across the groups. The rate of notable GI adverse events, including GI perforation was not increased in the PmCRC group receiving BEV in either cohort. One pt had a GI perforation after receiving CAP+BEV. Conclusions: Pts with mCRC and peritoneal disease receiving first-line therapy in trial and nontrial populations appear to derive a similar proportional benefit when BEV is added to systemic therapy without an increase in GI adverse events. However, this subgroup of patients continues to have a worse prognosis. [Table: see text]
Association of the prognostic role of FGFR4 Gly388Arg polymorphism with treatment outcomes after chemoradiotherapy in esophageal cancer.
Authors: Cho Sanghee , Shin Min-Ho , Hwang Jun-Eul , Shim Hyung-jung , Kim Min-Jee , Chung Ik-Joo
Published: February 2017

60

Background: Fibroblast growth factor receptor 4 (FGFR4) has been associated with increased risk, staging, and metastasis in several type of cancer. The purpose of this study was to evaluate the prognostic role of FGFR4 Gly388Arg polymorphism in esophageal cancer after chemoradiotherapy. Methods: Peripheral blood samples from 250 patients who were treated with chemoradiotherapy were used for this study. Patients were diagnosed as a stage of I in 12 (5%), II in 54 (21%), III in 115 (46%) and IV in 69 (28) patients. All of the patients were received chemotherapy using cisplatin and fluorouracil or docetaxel. Results: The overall response was 85%, with 21% complete response and 64% partial response. The overall survival (stage II, 34months; stage III, 23.3 months; stage IV, 19.3 months, p=0.005) and progression survival (stage II, 23.8 months; stage III, 12.8 months; stage IV, 9 months, p=0.001) was significantly improved according to stage. In FGFR4 genotypic analysis, 96 patients (38.6%) were homozygous for Gly388 allele, with 113 heterozygous (45.4%) and 40 (16.0) homozygous for Arg388 allele. There was no significant association between FGFR4 genotype and stage. However, Gly388 allele patients show better overall response rate (90.6%) than Arg388 carriers (82.4%, p=0.050). In early stage (I, II, n=66), Gly388 allele patients tendted to have a better OS (p=0.898) or PFS (p=0.597) than Arg388 carriers. However, in advanced stage (III, IV), the survival outcomes was similar between genotypes. Conclusions: Present study shows that FGFR4 Gly388 allele has a prognostic role in response after chemoradiotherapy in esophageal cancer. Especially in early stage of esophageal cancer, FGFR4 might have an important role in disease progression and survival outcomes. It suggests that the possibility of new therapeutic target for esophageal cancer treatment.
Work satisfaction at a multidisciplinary gastrointestinal oncology fast-track outpatient clinic.
Authors: Basta Yara , Vogel Jantien A. , Molenaar J. , Tytgat Kristien M. A. J. , Klinkenbijl Jean H. G.
Published: February 2017

605

Background: Physician and nurse satisfaction is positively correlated with patient satisfaction. In our university centre we have established the Gastrointestinal Oncology Clinic Amsterdam (GIOCA), a patient centred multidisciplinary one day diagnostics and fast track treatment planning outpatient clinic for gastrointestinal malignancies. The GIOCA team consists of dedicated surgeons, gastroenterologists, medical oncologists, radiation oncologists, radiologists, nuclear radiologists, pathologists, and specialized nurses. We have measured a high patient satisfaction. However to our knowledge there are no studies that focus on the satisfaction of physicians and nurses working within a multidisciplinary team. Our aim was to evaluate the experience and work satisfaction of the physicians and nurses at GIOCA. Methods: A qualitative observational study was performed to compose a questionnaire. This questionnaire was then sent to every physician (specialist, fellow, and resident) and nurse (n=77) working at the outpatient clinic. Answers were given on a 5-point Likert scale. Data were analysed using non-parametric tests. Results: The questionnaire was answered by 73 respondents, of whom 8.2% were nurses and 91.8% were physicians (95% overall response rate). Overall satisfaction with the fast track outpatient clinic was high for all groups (4; 3-5). The workload was experienced as average by physicians and high by nurses (p<0.001). The highest emotional strain was reported by nurses and residents. The emotional strain reported by residents was significantly higher compared to the level of emotional strain reported by specialists (p=0.034). The quality of the multidisciplinary meeting was rated high by both physicians and nurses. The importance of a multidisciplinary one day diagnostics outpatient clinic was invariably rated high to very high by all physicians and nurses. Conclusions: The overall work satisfaction at GIOCA is high. A patient centred one day diagnostics and fast track treatment outpatient clinic for gastrointestinal malignancies is indispensible according to the physicians and nurses. This may have contributed to a high patient satisfaction and a high overall work satisfaction.
Retrospective cohort study of patients with anal cancer treated over a 12-year period at a large Canadian cancer center.
Authors: Abunassar Michael J. , Reinders Jordan , Jonker Derek J. , Asmis Timothy
Published: February 2017

606

Background: While optimal management of anal cancer has become better defined in light of recent clinical trials including selected patients, the outcomes in an unselected population are less well defined. We reviewed the outcomes of anal cancer patients in a population referred to a sole-provider regional cancer program at the Ottawa Hospital over a 12 year period (2000 to 2011). Methods: Patient data was collected from hospital records, including demographic, treatment and outcome. Outcomes of interest included overall and recurrence free survival, as well as colostomy free survival. Results: Patients were 72% (n = 130) female and 28% (n = 50) male, 6.6% (n = 12 males) HIV positive, 60% (n = 108) ever smokers, mean age 62 [range 35-90] years. Most frequent presenting symptoms were blood per rectum (87%) and anal pain (80%). Treatment intent was curative in 87%. Treatment included radiotherapy (94%), brachytherapy (26%), chemotherapy (73%). Combined chemoradiotherapy was received by 71%, including MMC-5FU (n = 87) and cisplatin+5FU (n = 41). Among patients treated with curative-intent, 72% had a complete response, 31% local/regional recurrence, 16% required salvage surgery and 21% had distant recurrence. Colostomy rate was 23%. 5 year overall survival (OS) was not significantly different for patients by HIV status; 52 vs. 60% for HIV positive vs negative, respectively, HR 1.36, p = 0.47. Survival was superior if MMC+5FU was used first vs. Cisplatin+5FU; 5yOS 73 vs 46% respectively, [HR 0.45 (95%CI 0.25 – 0.83), log rank p = 0.013]. Conclusions: The outcomes of patients in this large retrospective cohort study are similar to the outcomes of patients in highly selective clinical trials. Five year overall survival and colostomy free survival are encouraging. MMC +5FU was found to be superior to Cisplatin +5FU. Further study is required to improve outcomes for patients with metastatic disease.
Preoperative radiotherapy combined with simultaneous chemotherapy with capecitabine plus oxaliplatin versus surgery alone: A single-centered, phase II study in patients with mid/low rectal cancer.
Authors: Wang Fulong , Lu Zhen-Hai , PAN Zhizhong , Gao Yuan-Hong , Chen Gong , Wu Xiaojun , Ding Pei-Rong , Zeng Zhi-Fan , Wan Desen
Published: February 2017

609

Background: Though total mesorectal excision (TME) has proved to effectively decrease local recurrence rate of mid/low rectal cancer, the efficacy of preoperative radiotherapy in Asian patients remains unclear. The present study aimed to compare the efficacy of TME alone versus TME after preoperative radiotherapy and simultaneous chemotherapy with capecitabine plus oxaliplatin in Chinese patients with stage II and III mid/low rectal adenocarcinoma. Methods: Patients (n=192) aged between 18 and 70 years enrolled from March 23, 2008 to August 2, 2012 were randomly divided into two groups. Group A (n=97) received preoperative radiotherapy and simultaneous chemotherapy [46-50 GY/23-25 with oxaliplatin 100 mg/m2 (D1) and capecitabine 1,000 mg/m2 (bid, D1-15), repeated since D22], which was followed by TME; while patients in group B (n=95) underwent TME alone. While disease free survival (DFS) was the primary endpoint; the following were evaluated as secondary endpoints: pathological response rate, pathologic complete response (PCR) rate, anal preservation rate, local recurrence rate, distant metastasis rate, acute toxic effects, and late toxic effects. Results: Excluding the drop outs, 90 and 94 patients were analyzed in group A and B, respectively. The median follow-up time was 29 (range: 0 to 59) months. PCR was achieved for 32 patients (35.6%). The median survival time and overall survival (OS) rate in group A were 24 months and 92.5% (95% CI: 88.3-96.7), respectively; while the same were 34 months and 88.7% (95% CI: 84.8-92.6) in group B. The median DFS time was 22 and 31 months in group A and B, respectively; and the overall DFS was 86.1% (95% CI: 81.6-90.6%) and 80.6% (95% CI: 74.8-85.4%) in both groups. No significant differences were observed between groups in OS rate (p=0.323), overall DFS, (p=0.612), and anal preservation rate (p=0.849). Conclusions: Preoperative radiotherapy combined with chemotherapy of capecitabine plus oxaliplatin could result in higher PCR rate. However, studies with long follow up and large sample are recommended to demonstrate the efficacy of this treatment strategy over TME alone. Clinical trial information: ChiCTR-TRC-00000122.