bluuebunny/crossref_metadata_2025 huggingface dataset:
Pooled safety results from SPIRITT: A multicenter, open-label, randomized, phase II study of FOLFIRI with panitumumab (pmab) or bevacizumab (bev) as second-line treatment (tx) in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Hecht J. R. , Dakhil S. R. , Saleh M. N. , Piperdi B. , Cline-Burkhardt M. , Kocs D. M. , DeMarco L. C. , Chen L. , Krishnan K. , Cohn A. L.
Published: February 2017

477

Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor (EGFR) approved as monotherapy in pts with chemorefractory mCRC. Many pts with mCRC who have progressed on a bev-containing regimen receive second-line bev + chemotherapy despite the lack of prospective, randomized data supporting this approach. A phase III study recently showed that pmab + second-line FOLFIRI improved progression-free survival (PFS) in pts with wild-type (WT) KRAS tumors vs chemotherapy alone. This study was amended after enrollment began to focus hypothesis testing on the WT KRAS population and is evaluating the safety and efficacy of pmab + FOLFIRI vs bev + FOLFIRI in pts who received first-line therapy with an oxaliplatin-based regimen + bev.

Methods: This is a randomized, phase II, open-label study in pts with mCRC with disease progression or intolerability after ≥ 4 doses of first-line oxaliplatin-based chemotherapy + bev. Pts are randomized 1:1 to receive either 6 mg/kg pmab Q2W + FOLFIRI or bev (given at institutional standard dose Q2W) + FOLFIRI. Tx is administered until disease progression (PD), death, or withdrawal from study. The primary endpoint is PFS in patients with WT KRAS tumors. Other endpoints include objective response rate, overall survival, safety, and patient-reported outcomes.

Results: At the time of data cutoff, 216 of 277 planned pts were enrolled. 175 (81%) pts discontinued study tx and 39 (18%) pts remain on tx. Any grade adverse events (AEs) were reported in 197 (92%) pts. 38 (18%) pts had AEs that led to withdrawal from tx or study. Serious AEs were reported in 66 (31%) pts and included gastrointestinal disorders (13%), infections and infestations (8%), respiratory disorders (7%), and metabolism and nutrition disorders (7%). Fatal AEs were reported in 18 (8%) pts of which 9 (4%) were related to disease progression.

Conclusions: The aggregate safety profile is consistent with expected toxicities of FOLFIRI in combination with an anti-EGFR or an anti-VEGF targeted therapy in second-line mCRC. Detailed pooled safety results will be presented at the meeting.

[Table: see text]
Complete pathologic response after combined-modality treatment for rectal cancer and long-term survivals: A meta-analysis.
Authors: Zorcolo L. , Rosman A. S. , Restivo A. , Pisano M. , Nigri G. R. , Fancellu A. , Melis M.
Published: February 2017

479

Background: Recent literature suggests that a complete pathologic response (CPR) following neoadjuvant chemoradiotherapy (combined modality treatment, CMT) for rectal cancer is associated with improved survivals compared to partial or no response (NPR). However, previous reports have been limited by small sample size and single-institution design. To overcome these limitations, we performed a meta- analysis of studies evaluating the prognostic value of CPR.

Methods: A systematic literature review was conducted to detect studies comparing long-term results of patients with CPR or NPR after CMT for rectal cancer. Variables were pooled only if evaluated by 3 or more studies. Both qualitative and quantitative data were pooled using a random-effects model. Study endpoints included rates of complete pathological response, local recurrence (LR), distant recurrence (DR), as well as 5-year overall (OS) and disease-free survival (DFS).

Results: There were 13 studies suitable for the meta-analysis, that overall reported on outcomes of 2030 patient with rectal cancer treated with CMT. CPR was achieved in 332 patients (16.4%). CPR and NPR patients groups were similar with respect to age, male gender, tumor size, distance of tumor from the anus and pre- treatment stage (p > 0.3 for all comparisons). Median follow-up ranged from 23.5 to 46 months. CPR patients had lower rates of LR (0.7% vs. 2.6%; odds ratio [OR]=0.45, 95% CI 0.22–0.90), DR (5.3% vs. 24.1%; OR=0.15, 95% CI 0.07–0.31) and LR+DR (0.7% vs. 4.8%; OR=0.32, 95% CI 0.13–0.79). OS was 92.6% for CPR vs. 73.2% for NPR (OR=3.6, 95% CI 1.84–7.06), and DFS was 89.1% vs. 64.3% (OR=4.3, 95% CI 1.8-10.1).

Conclusions: Our meta-analysis confirms that a CPR following CMT for rectal cancer is associated with an improved local and distal control as well enhanced OS and DFS.

No significant financial relationships to disclose.
Similarities in treatment (Tx) patterns and clinical outcomes (CO) in patients (pts) with metastatic colorectal cancer (mCRC) initially treated with FOLFOX/BV or FOLFIRI/BV: Results from ARIES, a bevacizumab (BV) observational study.
Authors: Bendell J. C. , Bekaii-Saab T. S. , Cohn A. L. , Hurwitz H. , Kozloff M. , Tezcan H. , Feng S. , Flick E. D. , Sing A. , Grothey A.
Published: February 2017

480

Background: COs associated with varying Tx patterns in mCRC pts are poorly understood because patterns diverge from the randomized trials (RCT). The RCTs of BV (Avastin) plus chemotherapy (CT) in mCRC pts continued BV until progressive disease (PD), even if CT was stopped/changed. Some RCTs of BV+CT in mCRC show ∼50% of pts stopping Tx early for reasons other than PD with possible lessening of benefit. It is unclear if this is due to use of a particular CT regimen or other practice pattern. While the beneficial effect of post-PD BV Tx has been shown in ARIES (HR 0.52 BBP vs No BBP) [A Cohn, ASCO 2010], the effect of stopping BV or CT before PD is unclear. ARIES, a community based observational study with a large cohort of 1st line BV-treated mCRC pts, will assess the COs associated with different 1st line Tx patterns (BV and CT) based on real world practice.

Methods: ARIES enrolled mCRC pts receiving first- or second-line CT+BV. No Tx regimens or assessments are protocol specified. Data are collected prospectively at baseline (BL) and quarterly. Analyses included first-line pts with PD. Tx patterns of pts initially treated with FOLFOX/BV or FOLFIRI/BV are described and preliminary COs (PFS and OS) are estimated from K-M curves. Tx duration is calculated from enrollment date.

Results: As of 2/5/10, 1,548 first-line mCRC pts enrolled (median follow up = 21 m); 1,133 pts had PD. Of 1,133 pts with PD, most had FOLFOX/BV (63%) or FOLFIRI/BV (16%) as first CT. BL characteristics were similar, but the FOLFOX/BV group had more stage 4 pts (74%). Main reasons for stopping BV include AE, max benefit achieved and CT holiday. Tx patterns and COs are in the table.

Conclusions: ARIES first-line mCRC pts treated with FOLFOX/BV or FOLFIRI/BV had similar Tx patterns and COs despite the common opinion that they may differ in tolerability and possibly effectiveness. Additional analyses will assess the impact of stopping BV and/or CT before PD.

[Table: see text]

[Table: see text]
The relationship between the development of rash and clinical and quality of life outcomes by Kras mutation status in patients with colorectal cancer treated with cetuximab in NCIC CTG CO.17.
Authors: O'Callaghan C. J. , Tu D. , Karapetis C. S. , Au H. , Moore M. J. , Tebbutt N. C. , Trudeau M. G. , Price T. J. , Yip D. , Jonker D. J.
Published: February 2017

481

Background: The NCIC Clinical Trials Group CO.17 trial, conducted with the Australasian Gastrointestinal Trials Group, showed cetuximab monotherapy (CET vs. best supportive care [BSC]) improved overall (OS) and progression-free survival (PFS) and maintained quality of life (QoL) in patients previously treated for advanced colorectal cancer. Correlative analyses showed strong relationships between CET benefits and both rash development and Kras mutation status. Association between rash and CET benefits is now presented by Kras mutation status.

Methods: Rash was graded weekly by NCI CTC 2.0 criteria. Landmark-type analyses (LTA) were performed by excluding patients who died within 28 days and then grouping by rash severity (gr 2+ vs. gr 0/1) based both on worst grade ever developed (LTA1) and worst grade on or before day 28 (LTA2). Multivariate Cox models were conducted separately for wild-type (WT) and mutated (MUT) Kras tumors.

Results: More rash of severity gr 2+ was observed in WT than MUT patients treated with CET (57.3% vs. 44.4%; p = 0.08). The median OS, PFS, and HRs from LTA2 are presented for WT and MUT groups (see Table).

Conclusions: Rash severity was positively correlated with PFS and OS in Kras WT patients who received CET, although only for gr 2+ rash did OS significantly exceed that of BSC patients. In Kras MUT patients, neither gr 0/1 nor gr 2+ rash was associated with either improved PFS or OS vs. BSC patients. Quality of life outcomes will also be reported by Kras mutation status.

[Table: see text]

[Table: see text]
Pushing the envelope beyond a centimeter in rectal cancer: Oncologic implications of close but negative margins.
Authors: Fitzgerald T. L. , Brinkley J. , Zervos E. E.
Published: February 2017

487

Background: Advances in surgery, adjuvant therapy and understanding of the natural history of rectal cancer has enabled sphincter preservation surgery for most patients. A 1 cm margin is commonly accepted as minimal distal margin, when not achievable many are relegated to permanent colostomy. Our purpose was to determine if distal margins of < 1 cm is justified by the world's published experience.

Methods: Studies were identified with a MEDLINE search using terms rectal cancer, colorectal cancer, margins and distal margins with an additional manual search. There were no restrictions on data type or year of publication. All studies were retrospective or prospective, none were randomized controlled. Studies were excluded if specific margins, local recurrence rates or case level data could not be extracted. Extracted variables included year of publication, time span, number of patients, standardized surgery, radiotherapy, margins, follow up, local recurrence rates and overall survival. Meta-analysis was performed using a random weighting scheme. Values were aggregated across studies to determine overall impact and p-values.

Results: Seventeen studies reported margins with thirteen studies, 3,232 patients, reporting outcomes when < 1cm. Meta-analysis of all studies indicated a nonsignificant trend favoring greater margins. However, in order to understand distal margins in the context of current standards additional analyses were performed. Of the thirteen studies 4 reported neither TME nor use adjuvant radiotherapy and 9 studies reported use of one or both. When either total mesorectal excision and/or adjuvant radiotherapy was reported there was no significant increase in local recurrence with distal margins < 1 cm. In studies that used neither therapy > 1 cm margins were statistically less prone to recurrence.

Conclusions: Sphincter preservation is possible with < 1 cm distal margin when optimal surgical and adjuvant therapy are applied.

[Table: see text]
Use of class III beta tubulin to predict efficacy from paclitaxel- or docetaxel-based chemotherapy in patients with advanced gastric cancer.
Authors: Ahn J. , Jung M. , Chang H. , Zhang X. , Jeung H. , Kim T. , Roh J. K. , Chung H. C. , Rha S. Y.
Published: February 2017

52

Background: To predict clinical outcome in patients with advanced gastric cancer (AGC) received paclitaxel or docetaxel based chemotherapy, we evaluated expression of class III beta tubulin (bTubIII).

Methods: Expression of bTubIII was evaluated by immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded tumors from the primary gastric cancer. Tumors were classified as bTubIII “low” and “high” according to median of IHC score [intensity (0-3) × portion (0-100)]. The expression of bTubIII was investigated for their association with clinical outcomes of efficacy and toxicity.

Results: One hundred twenty-four AGC pts who were treated with paclitaxel or docetaxel combined with an infusional 5-fluorouracil and low-dose leucovorin as first and second-line palliative chemotherapy were enrolled. Thirty-three patients (26.7%) were confirmed to have high expression of bTubIII. The patients with high expression of bTubIII showed higher disease control rate (DCR) and longer progression-free survival (PFS) than those with low expression in patients treated with paclitaxel (79.3 % vs. 57.3 %, p = 0.039, and 3.0 months vs. 1.5 months, p = 0.073). By contrast, there was no difference of DCR and PFS according to expression of bTubIII in patients treated with docetaxel. The expression of bTubIII was not associated with toxicity in both patients treated with paclitaxel or docetaxel.

Conclusions: The expression of bTubIII may be a predictive marker in AGC patients received paclitaxel based chemotherapy, but not docetaxel.

No significant financial relationships to disclose.
A randomized phase II trial of chemoradiotherapy with oral fluoropyrimidine inhibitory for dihydropyrimidine dehydrogenase for low rectal cancer: An interim report.
Authors: Nishioka M. , Shimada M. , Kurita N. , Iwata T. , Morimoto S. , Yoshikawa K. , Higashijima J. , Miyatani T. , Kashihara H. , Mikami C.
Published: February 2017

524

Background: Preoperative chemoradiotherapy (CRT) has been widely used to improve local control of disease and to preserve anal sphincter in the treatment of rectal cancer. However, the response to CRT differs among individual tumors. In ASCO 2008 Gastrointestinal Cancers Symposium, we reported that the patients with up-regulation of 17 genes were suggested to be good responder of CRT. Our purpose of this study was to evaluate the toxicity and efficacy of CRT using UFT versus S-1 and explore biomarkers for response in patients with locally advanced rectal cancer.

Methods: Fifty patients who received preoperative CRT (40Gy radiotherapy) were randomly assigned to either UFT or S-1. UFT and S-1 were administered during the radiotherapy course. S-1 was a novel oral fluoropyrimidine inhibitory for dihydropyrimidine dehydrogenase and had potent radiosensitizing property. Biopsy specimens were obtained from rectal cancer before preoperative CRT and were analyzed by focused DNA microarray (132 genes). To pick up the predictive factors, the 132 genes were selected in the view of sensitivity of 5FU. Response to CRT was determined by RECIST and histopathologic examination of surgically resected specimens and classified as responders (CR, PR and grade 2, 3) or nonresponders (SD, PD and grade 0, 1).

Results: UFT group (n=25) and S-1 group (n=25) were enrolled. Response rate (grade 2 or 3) to CRT determined by histopathologic examination of surgically resected specimens was 58% in the UFT group and was 75% in the S-1 group. Response rate evaluated by RECIST criteria was 62% in the UFT group and was 77% in the S-1 group. National Cancer Institute Common Toxicity Criteria grade 2 or 3 toxicity was observed in 8% of the patients in the UFT group and 23% of patients in the S-1 group. Grade 2 or 3 toxicity in the UFT group was neutropenia and was diarrhea, neutropenia and dermatitis in the S-1 group. In ASCO 2010, we will report each candidate biomarker genes for response to CRT in the UFT and S-1 group.

Conclusions: The results have suggested that CRT using UFT or S-1 is feasible and effective for patients with locally advanced rectal cancer.

[Table: see text]
Treatment patterns and health care resource utilization of metastatic colorectal cancer (mCRC) patients who received bevacizumab or cetuximab in second-line regimen.
Authors: Yang H. , Yu A. P. , Yim Y. , Yu E. , Wu E.
Published: February 2017

525

Background: Targeted therapies such as bevacizumab (BV) and cetuximab (CX) are important treatment options in mCRC. Real-world treatment patterns and resource utilization of mCRC patients (Pts) receiving BV and CX in second-line (2L) treatment are not well studied.

Methods: Pts with mCRC were identified from the PharMetrics pharmacy and medical insurance claims database (2002-2009). Included Pts received BV or CX in 2L therapy. 2L was defined as change in therapy from first-line (1L) at least 4 weeks after 1L initiation. Healthcare resource utilization and costs were evaluated during the 6 months following 2L start.

Results: A total of 2,188 Pts were included in the analysis, including 1,808 2L BV Pts and 380 2L CX Pts. Demographic and baseline characteristics were similar between groups. Pts' mean age was 61 years and 56% were male. Among all study Pts, 34.1% and 2.7% received BV and CX in 1L, respectively. 60.1% of Pts received oxaliplatin-based regimens in 1L. In 2L, irinotecan and oxaliplatin containing regimens were most commonly used. During the 6 months period following 2L therapy start, BV vs. CX Pts incurred significantly lower risk-adjusted total costs (difference: -$10,231, p=0.020) and inpatient costs ($-3,681, p<0.001). Mean targeted therapy cost was significantly higher for CX ($33,425) than BV ($23,622) (-$10,260, p<0.001). BV Pts incurred significantly less inpatient visits (0.5 vs. 0.7, p<0.001) compared to CX Pts and shorter duration of total hospital stay (3.6 vs. 5.6 days, p=0.007).

Conclusions: In 2L treatment of mCRC Pts in the real world setting, BV was most used with oxaliplatin- and irinotecan-based regimens, whereas CX was commonly used with irinotecan-based regimens. Overall, less healthcare resource utilization and costs were observed in patients treated with 2L BV compared to 2L CX. Use of BV in 2L treatment of mCRC was associated with lower number of claims for targeted agents, lower healthcare costs and fewer hospitalizations than CX.

[Table: see text]

[Table: see text]
Phase I results of the randomized, placebo controlled, phase I/II study of the novel oral c-Met inhibitor, ARQ 197, irinotecan (CPT-11), and cetuximab (C) in patients (pts) with wild-type (WT) KRAS metastatic colorectal cancer (mCRC) who have received front-line systemic therapy.
Authors: Eng C. , Bendell J. C. , Bessudo A. , Gabrail N. Y. , Diamond J. , Pande A. U. , Gorbatchevsky I.
Published: February 2017

527

Background: ARQ 197 selectively inhibits the c-Met receptor tyrosine kinase (RTK), which has been implicated in tumor cell migration, invasion, proliferation, and angiogenesis. CPT-11 plus C is a standard of care for CPT-11-refractory mCRC pts with WT KRAS tumors. Resistance to C has been associated with activation of alternative RTK pathways including c-Met. We hypothesize that adding ARQ 197 to CPT-11 plus C may decrease resistance to C therapy and improve pt outcomes.

Methods: The primary objectives of phase I were to evaluate safety and tolerability of ARQ 197 administered in combination with CPT-11 plus C, and to define a recommended phase II dose (RPTD). Pts with surgically unresectable locally advanced or mCRC who received at least 1 prior line of chemotherapy, KRAS WT and ECOG performance status < 2 were eligible. Cohorts of 3 pts each were treated with CPT-11 (180 mg/m2) and C (500 mg/m2) every 2 weeks along with escalating doses of ARQ 197 (120, 240, 360 mg) PO BID. Blood and tissue were collected for PK, biomarker, and other analyses. If no DLTs were observed during the first 28-day cycle in 3 pts treated in cohort 3, 360 mg BID would be defined as the RPTD. Responses were assessed every 8 weeks per RECIST v1.1.

Results: Nine pts were treated in 3 cohorts. Median age: 53 yrs (range 30-77); ECOG PS 0/1: 4/5; median prior therapies: 2 (range 1-4). No DLTs were observed. The RPTD for ARQ 197 was 360 mg BID. To date, two pts have discontinued (1 disease progression and 1 withdrew consent after achieving complete response) and 7 pts remain on study. The reported grade 3/4 adverse events were: neutropenia (3/4: 1/1), and one case each of grade 3 fatigue, leucopenia, acneiform rash, vomiting, anemia and syncope. Preliminary efficacy data in 9 evaluable pts include 1 CR (after 4 cycles), 2 PR (after 2 cycles), 5 SD, and 1 PD as best response.

Conclusions: The combination of ARQ 197 and CPT-11 plus C was well tolerated with encouraging preliminary antitumor activity. The RPTD for ARQ 197 was 360 mg BID. The randomized phase II portion of the study continues accrual.

[Table: see text]
Racial/ethnic differences in use of surgery and adjuvant chemotherapy for nonmetastatic colon cancer: Where's the rub?
Authors: Yang J. , Mauldin P. , Ebeling M. , Hulsey T. , Thomas M. B. , Esnaola N. F.
Published: February 2017

529

Background: Disparities in receipt of recommended medical therapy for colon cancer have been reported. The objective of this study was to determine the independent effect of black race and Hispanic ethnicity on use of surgery/adjuvant therapy in patients (pts) with nonmetastatic colon cancer, controlling for surgical/medical oncology consultation

Methods: Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified 26,946 pts aged 66 and older with resected stage I-III colon cancer diagnosed between 1999-2004. Surgical/medical oncology consultation and receipt of chemotherapy were ascertained from Medicare claims. The relationships between patient/tumor characteristics, surgical/medical oncology consultation, and use of surgery/adjuvant therapy were analyzed using chi square tests. Odds ratios (OR) of receipt of surgery/chemotherapy were calculated using logistic regression analysis.

Results: We identified 23,834 white, 2,022 black, and 1,090 Hispanic pts with stage I (7,088 pts), stage II (9,510 pts), and stage III (7,236 pts) colon cancer. Blacks and Hispanics were more likely to be younger, less educated, of lower income, and have greater comorbidity compared to whites. Rates of surgical resection were lower among blacks than Hispanics (86.6% vs. 88.8% vs. 92.0% in whites, all p < 0.001). Blacks with stage III colon cancer (but not Hispanics) were also less likely to receive adjuvant chemotherapy (48.2% vs. 54.7% in whites, p < 0.001). After controlling for socioeconomic status, comorbidity, and surgical/medical oncology consultation, black race (but not Hispanic ethnicity) was independently associated with underuse of surgery (adjusted OR, 0.68; 95% confidence interval [CI], 0.51-0.89) and adjuvant chemotherapy (adjusted OR, 0.71; 95% CI, 0.60-0.85).

Conclusions: Black race, but not Hispanic ethnicity, is a powerful, independent predictor of underuse of surgery and adjuvant chemotherapy in pts with nonmetastatic colon cancer. Qualitative studies are needed to determine whether patient misperceptions about colon cancer surgery/chemotherapy or suboptimal physician-patient interactions may underlie these observations.

No significant financial relationships to disclose.
Clinical outcomes in patients age 40 or younger at diagnosis of synchonous metastatic colorectal cancer.
Authors: Lowery M. A. , Gallagher D. J. , Kemeny N. E.
Published: February 2017

531

Background: The impact of age ≤ 40 at diagnosis of colorectal cancer on outcome is unclear. The higher incidence of tumor microsatellite instability (MSI) in young patients may confound the estimation of survival in this population due to the more favorable biology associated with MSI cancers.

Methods: All pts diagnosed with metastatic colorectal adenocarcinoma at ≤ 40 years old between Jan 2000-Jan 2010 were identified from the institutional database with prior IRB approval. Clinical and pathology records were reviewed. Only patients with synchronous metastases at presentation were included. Immunohistochemistry for DNA mismatch repair proteins (MMR) was performed in 40 pts of whom 5 had loss of MMR and were excluded from the analysis.

Results: 185 pts were identified; median age at diagnosis was 36 years (range 18–40) Primary site was in the right colon in 50 cases (27%). All pts received at least one line of systemic chemotherapy. For pts receiving systemic therapy median survival was 23.4 months and for those receiving hepatic arterial infusion (HAI) plus systemic the median survival was 48.2 months. Median survival for those who underwent liver resection (78 pts) was 54.6 months. Other factors such as race, post partum and KRAS mutation impacted on survival as shown below.

Conclusions: Overall survival in this cohort of young pts is similar to that observed in clinical trials of modern combination therapy for metastatic CRC. African American race, presence of a KRAS mutation, and presentation following pregnancy may be associated with reduced survival in this group.

[Table: see text]

No significant financial relationships to disclose.
Phase Ib study of drozitumab combined with cetuximab (CET) plus irinotecan (IRI) or with FOLFIRI with or without bevacizumab (BV) in previously treated patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Baron A. D. , O'Bryant C. L. , Choi Y. , Royer-Joo S. , Portera C. C.
Published: February 2017

532

Background: Drozitumab is a monoclonal antibody that triggers tumor cell apoptosis by selective agonistic interaction with the Apo2 ligand/TNF-related apoptosis-inducing ligand death receptor 5. This study assessed the safety of drozitumab combined with two standard IRI- containing regimens in previously treated mCRC pts.

Methods: Multicenter, open-label, dose-escalation study with treatment until disease progression or treatment intolerance. For CET+IRI regimen (Cohorts 1-4), a 21-day cycle (cy) = drozitumab on Day 1 at escalating doses of 1, 4, 10, or 15mg/kg, IRI on Day 1, and CET on Days 1, 8, and 15. For FOLFIRI (Cohort 5), a 14-day cy = drozitumab on Day 1 given as a 10 mg/kg loading dose followed by 7 mg/kg in continuing cys, with FOLFIRI (plus BV in pts not previously treated with BV) on Day 1. Dose-limiting toxicity (DLT) was assessed through 2 doses of drozitumab (29 days for CET+IRI; 28 days for FOLFIRI). Adverse events (AE) were recorded through all cys. Response was assessed by RECIST.

Results: 14 pts received a median of 6.5 cys (range 2-21) of drozitumab with CET+IRI and 6 pts received a median of 12 cys (range 3-21) of drozitumab with FOLFIRI. No DLTs occurred at the time of dose escalation. The most frequent AEs were diarrhea (85%), fatigue (80%), nausea (80%), alopecia (70%), neutropenia (70%), and decreased appetite (50%). Most of the toxicities were grades 1-2. The most frequent grade ≥3 AEs were neutropenia (60%), diarrhea (15%), hypokalemia (15%), and leukopenia (15%). Two pts discontinued due to AEs: 1 grade 2 fatigue, 1 grade 3 pyrexia. Among the 20 total pts, best responses included 3 partial responses (2 confirmed, 1 unconfirmed), 12 stable disease and 5 progressive disease. The study enrollment was stopped early by the sponsor for reasons unrelated to safety or efficacy.

Conclusions: The addition of drozitumab to two standard second-line IRI-containing regimens (CET+IRI or FOLFIRI ± BV) was well tolerated in mCRC pts. AEs were similar to those previously reported for the chemotherapy alone. Tumor responses suggest no adverse interactions between drozitumab and the chemotherapy evaluated in this study.

[Table: see text]
The extent of lymphadenectomy and overall survival depend on the timing of radiotherapy for rectal cancer.
Authors: Le M. N. , Mailey B. A. , Lee W. , Duldulao M. P. , Garcia-Aguilar J. , Kim J.
Published: February 2017

540

Background: Accurate staging and local disease control depend on the extent of lymphadenectomy (LAD) in rectal cancer. Previous studies suggest that lymph node (LN) number varies with neoadjuvant therapies. Our objectives were to measure the impact of timing of radiotherapy on extent of LAD and to determine the prognostic role of LN number in rectal cancer.

Methods: Patients undergoing curative-intent surgery for rectal adenocarcinoma (1988-2006) in Los Angeles County were identified from the Cancer Surveillance Program. Patients were grouped according to radiotherapy timing (neoadjuvant, adjuvant, or none). To measure prognostic significance, an optimal cutoff was assessed for patients with N0 disease by dichotomizing LN numbers from 3-7.

Results: Query of the registry identified 6,358 patients. Of these, 20% (n = 1,280), 25% (n = 1,573), and 55% (n = 3,545) received neoadjuvant, adjuvant, and no radiotherapy, respectively. There was no difference in LN number in patients with and without radiotherapy (7 vs. 8 LNs, p = NS). However, within the radiotherapy cohort, there was significantly lower LNs in the neoadjuvant group (5 vs. 9 LNs, respectively; p < 0.001). Survival differences favored the groups with higher LN number. The optimal LN cutoff with no survival difference was 7 in the adjuvant radiotherapy group; there was no optimal cutoff for neoadjuvant therapy patients.

Conclusions: From our population-based cohort, we observed that patients receiving neoadjuvant radiotherapy had decreased LN retrieval and that LN number was non-prognostic. In contrast, the extent of LAD is a prognostic factor for overall survival in patients receiving adjuvant radiotherapy.

[Table: see text]

No significant financial relationships to disclose.
How to reduce the risk of recurrence after surgical treatment of colorectal liver metastases?
Authors: Benhaim L. , Goárá D. , Bonnet S. , Dumont F. , Malka D. , Ducreux M. , Eveno C. , Elias D.
Published: February 2017

544

Background: After surgery with curative intent for colorectal liver metastases (MHCCR), liver recurrence occurs in more than 60% of patients, despite the administration of adjuvant systemic chemotherapy. The objective of this study was to compare the prognosis of patients operated on MHCCR with high risk of recurrences in the liver, treated by postoperative chemotherapy hepatic arterial infusion (HAI) by oxaliplatin, to that obtained after adjuvant systemic chemotherapy.

Methods: From January 2000 to December 2009, 113 patients who underwent curative resection of more than 3 MHCCR, were selected from a prospective database. Among these 113 patients, 47 had received postoperative HAI associated with systemic chemotherapy (HAI+) and 66, systemic chemotherapy alone (HAI-).

Results: The two groups were comparable in age, sex, stage of primary, rates of synchronous (> 75%), and bilobar (> 90%) MHCCR. The number of MHCCR was significantly higher in the group HAI+ (p < 0.0001). Twenty-seven patients (57%) received more than 6 courses of HAI. HAI was discontinued in 6 patients (12%) due to technical problems with the catheter. After a median follow up of 75 months (7-125), the overall survival and recurrence-free survival at 5 years were higher for patients HAI+ compared to those HAI-, respectively 52.9% vs. 12.3% (p = 0.06) and 30.8% vs. 2% (p < 0.0001).

Conclusions: The postoperative administration of oxaliplatin-based HAI associated to systemic chemotherapy after cure of MHCCR, improves recurrence-free survival of patients at high risk of hepatic recurrence, compared to systemic chemotherapy alone.

No significant financial relationships to disclose.
Feasibility of intensity-modulated radiation therapy (IMRT) with PET-defined simultaneous integrated boost (SIB) for distal rectal adenocarcinoma (DRA).
Authors: Valakh V. , Kirichenko A. V. , Betler J. , Leicher B. , Werts E. D. , Medich D. , Parda D. S.
Published: February 2017

550

Background: PET/CT guided preoperative IMRT is being used with increasing frequency in standard practice but reports of methods, efficacy, and toxicity are limited. We report the AGH experience from 2007-2010 of IMRT with SIB for DRA.

Methods: 22 pts with stage IB–IV DRA (8 with anal canal involvement) were treated with preoperative concurrent IMRT with SIB, 5FU-based chemotherapy. 15 received weekly oxaliplatin. All had PET/CT simulation. The planned target volume included PET-avid primary tumor and LNs with median margins of 3mm (range, 0–13), in a median of 24 fx (range, 20–28), a median dose of 2.25 Gy/fx (range, 1.9–2.4 Gy) to a median total dose of 53.3 Gy (range, 50.6–57.2 Gy). Clinical target volume included non PET-avid 1st echelon LNs with a median dose of 2.0 Gy/fx (range, 1.6–2.3 Gy) to a total median dose of 47 Gy (range, 40.7–54.04 Gy). Median follow-up was 18 mos (range, 4–35). Late toxicities were scored using CTCAE v. 3.0.

Results: 17 of 22 patients (TNM stages IB (3), IIA (3), IIB (1), IIIA (2), IIIB (7), IV (1)) were treated curatively. The remaining 5 pts were treated palliatively. The median length of time from completion of radiation to surgery was 81 days (range, 48–398). 5 pts did not have surgery due to advanced metastatic disease (3), death (1) or biopsy proven complete response (CR) (1). R0 resection was accomplished in 15 of 17 surgical pts including 13/14 curative and 2/3 palliative cases. R1 resection occurred in 2 pts; 1 with stage IIIB and 1 with stage IV. No pts had R2 resection. 6 pts (5 with T2 lesions and 1 with a T4 lesion) had a pathologic CR. 2 of 3 non-surgical pts with metastatic disease had LRF at 5 and 11 mos. 9/22 pts had no late toxicity, 9/22 ≤ grade 2 and 4/22 had grade 3 late toxicity. No patients with T2 tumors had grade 3 late toxicity, and this appeared to be related to lower GTV. Kaplan-Meier freedom from grade 3late toxicity was 85% at 18 mos.

Conclusions: IMRT with SIB is an accurate targeting technique in pts with DRA that showed a pathologic CR in 100% of T2 lesions. Advanced T stage and larger GTV were possible risk factors for grade 3 late toxicity.

[Table: see text]

No significant financial relationships to disclose.
Efficacy of darbepoetin alfa in colorectal cancer patients: Data from the CHOICE study.
Authors: Van Belle S. , Urbanski K. , Orfeuvre H. , Foucher P. , Wheeler T. , Pujol B.
Published: February 2017

552

Background: To evaluate adherence to hemoglobin (Hb) values recommended by the updated European (EU) product label for darbepoetin alfa (DA) and describe hematological response in patients (pts) receiving DA for the treatment of chemotherapy-induced anemia in clinical practice. Data of colorectal cancer (CRC) pts are reported.

Methods: A prospective, multicenter, observational study assessed DA use in CRC, breast, ovarian and lung cancer pts in 11 EU countries. Data (such as Hb levels and need for red blood cell (RBC) transfusions) were extracted from medical records on an electronic case report form.

Results: This interim analysis included 1,290 pts. 192 pts had CRC: 1% had stage I, 6% stage II, 18% stage III and 75% stage IV cancer. The most-used chemotherapy regimens were 5-fluoruracil or capecitabine (33%), ironotecan- (27%) and oxaliplatin-based (24%). Baseline (BL) Hb values were available for 189 pts; the mean (standard deviation, SD) Hb value at BL was 9.8 (0.8) g/dL; 60% of CRC pts had BL Hb values of <10 g/dL and 90% values of <11 g/dL. Of the 119 pts still on study at week (wk) 9, 60% (95% CI: 51, 68) achieved a Hb level of 10-12 g/dL at wk 9 (primary outcome measure). With increasing BL Hb values, more pts achieved Hb ≥10 g/dL (see table). The mean (SD) Hb at the end of treatment period (EOTP) was 11.0 (1.5) g/dL. The Kaplan-Meier (K-M) % of pts with Hb levels ≥10 g/dL at EOTP was 91% (only pts with BL Hb <10 g/dL included). The K-M % of pts with Hb levels >13 g/dL at EOTP was 10% for pts with BL Hb <10 g/dL. Of pts in the study for ≥29 days after start of DA, the K-M % of pts needing RBC transfusions after wk 5 was 21% at EOTP. No treatment-related adverse drug reactions were reported.

Conclusions: Most CRC pts were treated in accordance with the EU product label. The high K-M % of pts with Hb values ≥10 g/dL suggests DA is effective. Hb levels >13 g/dL were rare for pts with BL Hb <10 g/dL. Sponsored by Amgen (Europe) GmbH.

[Table: see text]

[Table: see text]
Safety and efficacy of first-line XELIRI with or without bevacizumab in patients with metastatic colorectal cancer: Analysis of two phase II studies.
Authors: Garcia-Alfonso P. , Alvarez S. , Munoz A. , Lopez P. , Riesco C. , Adeva J. , Martin M.
Published: February 2017

560

Background: The safety and efficacy of first-line XELIRI (capecitabine in combination with irinotecan) and XELIRI plus bevacizumab (BEV) have been evaluated in patients with metastatic colorectal cancer (mCRC). To date, however, no randomized studies comparing these regimens have been performed. This retrospective analysis compared efficacy and safety data for the two regimens from separate phase II studies performed at a single institution.

Methods: Patients with histologically documented metastatic or recurrent CRC and no prior treatment for advanced disease received irinotecan 175 mg/m2 on day 1 and oral capecitabine 1,000 mg/m2 twice daily on days 2-8 every 2 weeks (XELIRI study). For patients age ≥65 years, the starting doses of irinotecan and capecitabine were reduced to 140 mg/m2 and 750 mg/m2, respectively. In the second study, patients received the same regimen plus BEV 5 mg/kg on day 1 (XELIRI + BEV study).

Results: A total of 53 and 46 patients were entered into the XELIRI and XELIRI + BEV studies, respectively. Patient characteristics were generally similar in both groups. Efficacy results for the ITT populations are summarized in the Table. Patients treated with XELIRI + BEV had a significantly higher ORR and longer median TTP vs. XELIRI alone and a numerically longer median OS was observed (p=NS). The overall incidence of adverse events (all grades or grade 3/4) was similar in the two groups, although alopecia, mucositis, hand–foot syndrome, and haemorrhage were more common with XELIRI + BEV vs. XELIRI alone (all p<0.05).

Conclusions: In this retrospective comparison of two studies, the addition of BEV to XELIRI appeared to improve outcome relative to XELIRI alone in the first-line treatment of patients with mCRC. The overall incidence of adverse events was similar in the two groups.

[Table: see text]

No significant financial relationships to disclose.
Pelvic malignancies undergoing exenteration.
Authors: Chokshi R. J. , Arrese D. , Kuhrt M. P. , Routt M. , Kocak E. , Martin E. W.
Published: February 2017

579

Background: Pelvic exenteration is reserved for patients with locally invasive and recurrent pelvic malignancies. The literature demonstrates a high morbidity and mortality associated with this operation. At our institution, a high volume of pelvic exenterations are undertaken and their outcomes have been studied.

Methods: The medical records of 53 patients with varying pelvic pathologies who underwent pelvic exenteration between 2004 and 2010 were reviewed. Demographics, histologies, periprocedural events, and outcomes were analyzed.

Results: Patients were divided into a colorectal (n = 37) and noncolorectal (n = 16) group for analysis based on histology. The two groups were similar in demographics, perioperative events, and length of stay. Resection status, chemotherapy use, and intraoperative radiation therapy showed no statistical difference. Complications showed a difference in perineal abscesses in the colorectal group. The colorectal group showed a survival difference when comparing R0 resection versus R1/R2, however no difference was seen in primary versus recurrent tumors. The median survival was 20.3 months in the colorectal group and 4.8 months in the noncolorectal group.

Conclusions: Patients undergoing exenteration for colorectal histology have improved survival when compared to pelvic malignancies of other origins. The greatest effect on long term survival is seen in the colorectal group undergoing a R0 resection. Despite pelvic exenterations carrying a high morbidity and mortality, careful patient selection can optimize outcomes.

[Table: see text]

No significant financial relationships to disclose.
Intensity-modulated radiation therapy (IMRT): Differences in target volumes and improvement in clinically relevant doses to small bowel in rectal carcinoma.
Authors: Mok H. , Crane C. H. , Briere T. , Beddar S. , Delclos M. E. , Krishnan S. , Das P.
Published: February 2017

586

Background: In the treatment of rectal cancer, a strong dose-volume relationship exists between the amount of small bowel receiving low- to intermediate-doses of radiation and the rates of acute, severe gastrointestinal toxicity. Highly conformal treatment approaches, such as intensity-modulated radiation therapy (IMRT), may reduce dose to adjacent organs-at-risk (OAR). We performed a dosimetric evaluation of IMRT compared to 3-dimensional conformal radiation therapy (3DCRT) in standard, preoperative treatment for rectal cancer.

Methods: Using RTOG consensus contouring atlas, treatment volumes were generated for ten patients treated preoperatively, with IMRT plans compared to 3DCRT plans derived from classic anatomic landmarks, as well as modified 3DCRT plans treating the RTOG consensus volume. The patients were all T3, were node-negative (N=1) or node–positive (N=9), and were planned to a total dose of 45-Gy. Bowel displacement was achieved using a carbon-fiber bellyboard apparatus with prone positioning.

Results: IMRT plans had superior PTV coverage, dose homogeneity, and conformality in treatment of the gross disease and at-risk nodal volume, in comparison to 3DCRT. Additionally, in comparison to the modified 3DCRT plans, IMRT achieved a concomitant reduction in doses to the bowel, bladder, pelvic bones, and femoral heads, with an improvement in absolute volumes of small bowel receiving dose levels known to induce clinically-relevant acute toxicity. In the six patients with the highest volume of small bowel (range: 209-537-cc), the volume of bowel receiving 15-Gy was reduced from a median of 224-cc in the modified 3DCRT plans to 185-cc with IMRT. Also, the IMRT volumes were typically larger than that covered by classic 3DCRT fields, without incurring penalty with respect to adjacent OAR.

Conclusions: For rectal carcinoma, IMRT, compared to 3DCRT, yielded plans with superior target coverage, homogeneity, and conformality, while lowering dose to adjacent OAR. This is despite treating larger volumes, raising the possibility of a clinically-relevant improvement in the therapeutic ratio through the use of IMRT with a belly-board apparatus.

No significant financial relationships to disclose.
Effect of PSK on FOLFOX4-induced peripheral neuropathy and bone marrow suppression in patients with metastatic colorectal cancer.
Authors: Shibata M. , Shimura T. , Gonda K. , Nakamura I. , Ohki S. , Takenoshita S.
Published: February 2017

596

Background: FOLFOX4 has been confirmed as an effective treatment for metastatic colorectal cancer and is used as a postoperative adjuvant therapy. However adverse effects such as cold-sensitive paresthesia and bone marrow suppression are common and may necessitate changes in chemotherapy regimen despite FOLFOX effectiveness. PSK, a polysaccharide derived from a species of mushroom, has been developed in Japan as an immune-enhancing agent and is widely used in patients with gastric, colorectal and pulmonary cancer. PSK has also been reported to decrease some adverse effects of chemotherapy.

Methods: FOLFOX4 combined with PSK was administered to patients with metastatic colorectal cancer and the results were evaluated. Eight cycles of FOLFOX4 and PSK (3.0 g/day, p.o.) were given to 25 patients with metastatic colorectal cancer (19 hepatic, 3 pulmonary and 3 peritoneal).

Results: No patients showed CR (complete response, 0%) while PR (partial response), SD (stable disease) and PD (progressive disease) were seen in 48%, 36% and 16% of patients, respectively. Response rate was 48% and disease control rate was 84%. Frequency of adverse effects was significantly lower than described in the published data. Grades 1 and 3 neutropenia occurred in 48% and 24% of patients, respectively; grades 1 and 3 nausea in 48% and 4%, respectively; and grades 1, 2 and 3 sensory neurotoxicity in 52%, 4% and 0%, respectively. No patient dropped out due to adverse effects in this study.

Conclusions: PSK plus FOLFOX4 seems as effective as FOLFOX4 monotherapy, and significantly less toxic. These results suggest that this combination therapy may be more effective when given for a longer period, with lower incidence of adverse effects.

No significant financial relationships to disclose.
Application of Western patients-based Adjuvant! Online (AOL) model on Korean colon cancer patients.
Authors: Jung M. , Kim G. , Ahn J. , Kim N. , Chang H. , Rha S. Y. , Chung H. C. , Roh J. K. , Shin S.
Published: February 2017

599

Background: Adjuvant! Online (AOL) is a web-accessible risk-assessment model that predicts the mortality and the benefits of adjuvant therapy ( www.adjuvantonline.org ). AOL has never been validated for Asian colon cancer patients.

Methods: Using the Yonsei Tumor Registry (YTR) database, we calculated the survival for the patients with T1-4, N0-2, M0 colon cancer who were treated at the Yonsei Cancer Center between 1990 and 2005. Observed and predicted 5-year survival was compared for each patient.

Results: The median age of the study population was 60 years (range, 15-87 years) and the median follow-up duration was 7.9 years (range, 0.06-19.8 years) for all 1,431 patients. While AOL underestimate overall survival (OS) (predicted-observed=-1.02%, P=0.008), it overestimate colon cancer-specific survival (CCSS) (predicted-observed=3.8%, P<0.001) in Korean patients. Especially, AOL underestimated OS and CCSS in younger patients than age 50 years (predicted-observed=-4.3%, P<0.001 and predicted-observed=-3.5%, P<0.001, respectively). We conducted an internal model validation by using a Korean version of AOL (KAOL), which was a new model for prognosis based on AOL's parameters. 5-year OS and CCSS between the observed and the KAOL predicted survival were not different (77.25 vs. 77.15, P=0.873 and 77.4% vs. 77.6%, P=0.78, respectively). The concordance indexes about OS and CCSS were 0.75 and 0.74, respectively.

Conclusions: KAOL model for Korean colon cancer patients is more suitable to predict 5-year outcomes compared to ALO model for Western patients.

No significant financial relationships to disclose.
Radiation oncologist density and colorectal cancer mortality.
Authors: Aneja S. , Yu J. B.
Published: February 2017

605

Background: Although the use of radiation therapy is increasing, there exists geographic variation among the distribution of radiation oncologists. The impact of this variation on colorectal cancer (CRC) outcomes remains unexplored. The goal of this study was to determine the effect of radiation oncologist density on CRC mortality.

Methods: Using county-level data from the 2008 Area Resource File, National Program for Cancer Registries, and US Centers for Disease Control, a regression model was constructed for CRC mortality, controlling for county-level categorized radiation oncologists density, demographics, socioeconomic status and existing healthcare facilities.

Results: There was a statistically significant reduction in CRC mortality (reduction in mortality ranging from 12% to 47%, p<0.001) associated with counties that possessed at least one radiation oncologist. However, increasing the county density to greater than two radiation oncologists per 100,000 people had no statistically significant reduction in CRC mortality.

Conclusions: The presence of a radiation oncologist is associated with lowered mortality for CRC within that county, but increasing radiation oncologist density does not yield further improvements. Therefore, as the use of radiation therapy to treat CRC increases, a detailed understanding of distribution of the radiation oncologists is essential for providing the greatest improvement in cancer mortality outcomes.

[Table: see text]

No significant financial relationships to disclose.