bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations between county-level surgeon density and colorectal cancer (CRC) mortality.
Authors: Albarrak J. S. , Ho M. Y. , Cheung W. Y.
Published: February 2017

511

Background: Strong associations between surgeon procedure volumes and patient outcomes have been observed for many types of cancers. Whether surgeon density in a population has a similar impact on cancer outcomes is unclear. Our aims were to 1) explore the effect of US county-level surgeon density on CRC mortality and on annual changes in death, 2) compare the relative importance of colorectal surgeon (CS) versus general surgeon (GS) density on these CRC outcomes, and 3) identify other county characteristics associated with reduced mortality.

Methods: Using county-level data from the Area Resource File, US Census and National Cancer Institute, we developed multivariate regression models to determine the effect of a) CS and b) GS on overall CRC mortality and changes in death between 2002 and 2006, while controlling for CRC incidence, county demographics and other socioeconomic factors.

Results: A total of 1,187 US counties were included: mean CRC incidence and death rates were 64.9 and 19.9, respectively; 57% were metropolitan and 43% were rural counties; mean CS and GS densities were 1.23 and 1.94 per 100,000 people, respectively. When compared to counties with no CS and no GS, those with at least of one of these surgeons had a statistically significant decrease in CRC-specific mortality (beta coefficients were -0.035 and -0.051 for CS and GS, respectively; p=0.014). Increasing the county-level density of surgeons improved outcomes, but increasing it beyond 8 CS or 12 GS per 100,000 people did not continue to result in significant reductions in CRC mortality. Similar associations between surgeon density and annual changes in CRC-related death were observed. Counties with a high proportion of Medicare enrollees also showed increased CRC mortality.

Conclusions: The presence of CS and GS at the county level is each associated with lower mortality from CRC. However, there appears to be a ceiling effect at which point further increases in their density do not produce continued improvements in CRC outcomes. A balanced strategy of allocating healthcare resources and distributing the surgical workforce evenly across all counties will likely offer the most substantial population-based improvements in CRC mortality.

No significant financial relationships to disclose.
Phase I study of dasatinib in combination with capecitabine, oxaliplatin, and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer.
Authors: Starodub A. , Cohn A. L. , Arrowood C. , Haley S. , Morse M. , Uronis H. E. , Blobe G. C. , Hsu S. D. , Zafar Y. , Hurwitz H.
Published: February 2017

513

Background: SRC is a non-receptor tyrosine kinase involved in normal and tumor cell signaling functions including cell proliferation, angiogenesis and survival. Dasatinib (D) is a potent inhibitor of SRC kinase activity. Preclinical data suggests the addition of D to standard chemotherapy agents for colon cancer may increase anti-tumor activity. We evaluated D in combination with capecitabine (C), oxaliplatin (O) and bevacizumab (B) in a phase I dose escalation study followed by an expanded cohort in 1st line colorectal.

Methods: For dose escalation, eligible patients had advanced solid tumors with adequate organ and bone marrow function and no increased risk for class-related toxicities. B and O were given intravenously, and C and D were orally administered; cycle length was 21 days. C was dosed at 850 mg/m2 on days 1-14; O was dosed at 130 mg/m2 and B was dosed at 7.5 mg/kg on day one of each cycle. D was dosed at 50 mg twice daily in cohort one and 70 mg once daily in cohort -1. Dose limiting toxicity (DLT) was assessed in cycle 1.

Results: Dose escalation is complete with 10 subjects evaluable for toxicity and 11 subjects evaluable for efficacy. Two DLTs were observed out of 5 evaluable subjects in cohort one. Six evaluable subjects were enrolled in the -1 cohort with 1 DLT. Possible grade ≥ 3 treatment-related adverse events (AEs) included neutropenia, febrile neutropenia, anorexia, diarrhea, fatigue, anemia, hypophosphatemia, hyponatremia and grade 5 GI-perforation. One non-treatment related death was due to disease progression. D-related nausea and fatigue were responsive to low dose oral steroids; fluid retention was responsive to diuretics. Of 10 subjects evaluable for efficacy, 1 subject had a partial response (PR), 2 had a minor response (MR), and 4 had stable disease (SD). Four subjects had disease control (PR, MR, or SD) ≥ 6 months.

Conclusions: D in combination with C, O and B is well-tolerated with a toxicity profile similar to standard C, O and B.The recommended phase II dose is C at 850 mg/m2 on days 1-14, O at 130 mg/m2 and B at 7.5 mg/kg on day one of each cycle, and D at 70 mg once daily. Enrollment in the expanded cohort of 1st line colorectal is ongoing.

[Table: see text]
Randomized, controlled trial comparing UFT with S-1 as adjuvant therapy for curatively resected stage III colorectal cancer.
Authors: Koda K. , Miyauchi H. , Ochiai T. , Yasuda H. , Kaiho T. , Tanaka N. , Yokoi K. , Kobayashi S. , Matsubara H.
Published: February 2017

515

Background: Oral anticancer drug, UFT, has recently been reported to improve both overall survival (OS) and relapse-free survival (RFS) for patients with stage III colorectal cancer in Japan. We conducted a randomized clinical trial to compare S-1 with UFT for adjuvant therapy in patients with stage III colorectal cancer.

Methods: Patients with stage III colorectal cancer (PS, 0 to 1; age, 20 to 80 years) were randomized to take either UFT (400mg/m2/day, 5days per week) or S-1 (80mg/m2/day, 28days per 6weeks) for 1 year started within 6 weeks following curative resection. The primary endpoint was to investigate relations of relapse-free survival (RFS) and tissue mRNA levels of 5-FU metabolism-related enzymes. The secondary endpoint was over all survival (OS) and safety.

Results: Between July 2005 and February 2008, a total of 100 patients were registered from 21 centers. There were no clear intergroup differences in background factors. When patients who relapsed within 1 year postoperatively were excluded, the percentages of patients who took expected dosage of medicine were 73% (30/41) and 72% (33/46) in UFT and S-1 groups, respectively. Grade 3 liver dysfunction (4%) or diarrhea (4%) occurred in UFT group, whereas grade3 to 4 myelosuppression (4%), diarrhea (4%), stomatitis (2%) were observed in S-1 group, but all of them were reversible. With a median follow-up period of 1,250 days, OS in patients of UFT and S-1 groups were 86.6% and 95.9%, respectively (p=0.06). The number of patients who relapsed in rectal cancer was significantly higher in UFT group (11/25) than in S-1 group (4/21, p<0.01). In a multivariate analysis, dihydropyrimidine dehydrogenase (DPD) mRNA level was shown as a factor of the recurrences. And S-1 improved RFS in patients with rectum cancer with high orotate phosphoribosil transferase (OPRT) mRNA level.

Conclusions: Oral anticancer drug, S-1, was no less effective than UFT as an adjuvant therapy for stage III colorectal cancer. Tissue levels of both DPD and OPRT mRNA were important parameters for postoperative prognosis in patients with stage III colorectal cancer who take oral 5-FU derivatives for adjuvant therapy.

No significant financial relationships to disclose.
Reproducibility of colon tumor grade and relationship to recurrence in the context of clinical, pathologic, and genomic tumor features in 504 patients with stage II colon cancer treated with surgery alone at the Cleveland Clinic.
Authors: Lavery I. C. , Baehner F. L. , Lopatin M. , Iezza G. , Millward C. , Clark-Langone K. , Lee M.
Published: February 2017

526

Background: High tumor grade is included in practice guidelines as a marker of higher recurrence risk in stage II colon cancer. Multiple systems for tumor grading exist, without a standardized approach. We characterize agreement of 2 methods for tumor grading and association with recurrence in the context of clinical, pathologic, and genomic tumor features including mismatch repair (MMR) and the 12-gene recurrence score (RS).

Methods: Colon tumors were graded independently by 2 academic GI pathologists (P1, P2). Grade was defined by % tumor with gland-like structures: well (> 95%), moderately (50-95%) and poorly (< 50%) differentiated. P1 used this 3-tier system while P2 used 2-tier scheme with well and moderately differentiated tumors defined as low grade and poorly differentiated as high grade. All mucinous tumors were high-grade by P2 but not P1. Relationship to recurrence-free interval (RFI) was assessed by Cox regression.

Results: Primary tumors from 504 stage II colon cancer treated with surgery alone were included. 18% (P1) and 31% (P2) were high grade. High grade tumors were more likely right-sided (≥ 60%) and MMR deficient (≥ 35%) for P1 and P2 (all p < 0.001). Proportion of mucinous tumors was similar for high and low grade by P1 (25% vs. 21%, p = 0.39). P2 high grade trended to lower recurrence (HR = 0.63, p = 0.10) while P1 grade was not associated w/ RFI (p = 0.46). In multivariate analyses including grade and RS, P2 high grade was associated with lower recurrence (p = 0.007) but P1 grade was not associated w/ RFI (p = 0.30). Neither grade was associated w/ RFI (p > 0.30) after controlling for RS, MMR, tumor location and mucinous histology. Using the two-tier scheme, agreement b/w the 2 pathologists was low (kappa = 0.30, 95% CI 0.21-0.39) in all pts and moderate if mucinous tumors were excluded (kappa = 0.52, 95% CI 0.40-0.64).

Conclusions: High tumor grade was not found to be a marker of higher recurrence risk in stage II colon cancer. Other markers validated in stage II colon cancer, such as MMR and RS, should be considered. Interpathologist agreement on colon tumor grade is modest, even with central expert review.

[Table: see text]
Helical tomotherapy for anal cancer: Initial clinical outcomes and organ motion.
Authors: Siker M. L. , Qi X. S. , Hu B. , Wong S. J. , Li X. A. , Erickson B.
Published: February 2017

530

Background: Helical tomotherapy (HT) delivers rotational IMRT with megavoltage CT (MVCT) guidance for patient positioning, offering improved dose conformality and accuracy. We report preliminary clinical outcomes using HT in patients with anal cancer with estimated organ motion and delivered doses.

Methods: From 9/2005-8/2009, 15 patients with anal cancer were treated with HT and concurrent chemotherapy (MMC 10 mg/m2 IV bolus d1 and 29; 5FU 1,000 mg/m2/day CI d1-4 and 29-32). Median doses for primary tumor, involved lymph nodes and uninvolved lymph nodes were 50.5, 50.4 and 45 Gy. Dose specifications and target definitions were per RTOG 0529 for the majority. Treatment plans, daily MVCT, and initial clinical outcomes and toxicity were retrospectively analyzed. Center-of-mass (COM) locations and volumes of the targets and OAR with daily shifts were analyzed on selected patients. Doses actually delivered daily were reconstructed.

Results: At median follow-up of 15 months, all patients were alive without any evidence of recurrence. There were 40% male, 27% HIV+, 13% T3/4, and 47% lymph node positive. Four patients required treatment break of ≤ 1 week. There were no non-hematologic grade 4/5 toxicities. Overall non-hematologic grade 3 toxicity was 33.3% (GI and skin). All other patients had ≤ grade 2 GI or skin toxicity that completely resolved with aggressive supportive care. There was 40% overall hematologic grade 4 toxicity. Overall hematologic grade 3 toxicity was 60%. Daily shifts were 0.6 ± 3.3, 0.4 ± 3.0, and 0.5 ± 2.2 (SD) mm in lateral, longitudinal and vertical directions. Average daily displacements of the COM from their locations on the planning CT were 9 ± 3, 7 ± 4, 9 ± 2, and 7 ± 2 (SD) mm, for anus, rectum, bladder and vulva. Interfractional organ motion and deformation resulted in variations in the dose delivered in each fraction.For example, daily dose covering 95% of PTV varied by 4%, and vulva volume covered by 50 Gy changed by 23% daily.

Conclusions: HT with concurrent chemotherapy is well-tolerated compared to historical reports. Interfractional organ motion is significant and can result in deviations in dose delivery to the target and OAR. Such deviations should be considered in analyzing dose response outcome.

No significant financial relationships to disclose.
Long-term follow-up of a multicenter phase II study of chemo-immunotherapy in the treatment of metastatic colorectal cancer (MCC).
Authors: Recchia F. , Candeloro G. , Necozione S. , Lippe P. , Desideri G. , Rea S.
Published: February 2017

536

Background: The combination of low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA) has been shown to decrease vascular endothelial growth factor (VEGF) of patients with MCC (Anticancer Res, 2005). Moreover, results of various studies have shown that the addition of IL-2 and RA to chemotherapy (CT) increased treatment efficacy, inducing a statistically significant decrease of VEGF, with a low cost.

Methods: Patients with MCC, deemed unresectable, were given the following treatment for two consecutive days (D1-D2): Oxaliplatin 50 mg/m2, Leucovorin (LV), 200 mg/m2, 5-fluorouracil (5-FU) 400 mg/m2, Capecitabine (C) 2,000 mg/m2 (FOCFOX). After 2 weeks Camptothecin, 90 mg/m2 (D1-D2), was administered with the same doses of LV, 5-FU and C (FOCFIRI) as first-line treatment of MCC. Subcutaneous IL-2 1.8 x 106 I.U. and oral RA, 0.5 mg/kg were given 5 days/week. Induction CT was administered for 12 courses, alternating FOCFOX and FOCFIRI, followed by maintenance treatment with the same schedule of IL-2 + RA, for 3 weeks/month. The primary endpoint was the decrease ≥ 30% of VEGF of patients with MCC. Secondary endpoints were the cost of IL-2 and RA with respect to bevacizumab, toxicity, progression- free survival (PFS), and overall survival (OS).

Results: From 08/2000 to 08/2006, fifty-four patients with MCC were entered into the trial. After a median follow up of 64 months (95% CI 62-85%), a statistically significant > 30% (p<0.001) decrease of VEGF was observed. Costs of therapy were $ 304.00/month for IL-2/RA and $ 1,700.00/month for bevacizumab (82% cost reduction). The most common adverse events of CT were grade 3/4 neutropenia, leukopenia, thrombocythopenia, and anemia in 33%, 9%, 2%, and 2% of patients, respectively, peripheral neuropathy in 10% of patients. Mild cutaneous skin rash, fever and autoimmune reactions were observed in the patients who received the maintenance immunotherapy. PFS at 10 months was 76% (95% CI 62-86). Median PFS was 27.8 months, while median OS was 48.8 months.

Conclusions: These data show that maintenance immunotherapy with low-dose IL-2 and oral RA in patients with MCC has a low toxicity profile, is cost effective, decrease VEGF and seems to improve expected PFS and OS.

No significant financial relationships to disclose.
Survival advantage associated with palliative oophorectomy in patients with metastatic colorectal cancer (CRC) to the ovaries (mCRC-O): A single institution retrospective analysis.
Authors: George B. , You Y. , Viswanathan C. , Wen S. , Baladandayuthapani V. , Overman M. J. , Kee B. K. , Kopetz S. , Eng C. , Garrett C. R.
Published: February 2017

539

Background: The ovaries are an uncommon site for secondary spread from metastatic CRC. We hypothesize that palliative oophorectomy improves survival among patients with mCRC-O.

Methods: We undertook a single institution IRB-approved (DR-09-623) retrospective evaluation of women with mCRC-O from 2001-2008; 110 pts with ovarian metastases and follow-up information for survival analysis were identified out of 3,776 female pts with CRC (2.9%). Survival data was calculated from the date of diagnosis of ovarian metastases (by pathology or radiology) to date of death.

Results: Median age of patients was 49 years (range 19-82); median duration of follow-up was 49 months. Twenty patients were identified from 1,758 female patients with CRC seen at our institution from 2001-2004 (1.1%) and ninety patients identified from 2,018 female CRC patients from 2005-2008 (4.5%). KRAS mutation was present in the primary tumor in 23 of 43 (54%). Sixteen evaluable patients who received systemic chemotherapy with mCRC-O and other sites of metastatic disease were identified; five (31%) had a mixed radiographic response (progression in the ovarian metastases with disease response in other sites of metastases). Seventy-one (64.5%) patients had metastatic disease at the time of initial presentation; 39 (35.5%) had completely resected stage II or III CRC with mCRC-O occurring at a later date. 86 (78.2%) underwent unilateral or bilateral oophorectomy for treatment of their disease. Patients who had metastatic disease at presentation and underwent oophorectomy had a median survival of 39.4 months versus 18.2 months for those with ovarian metastases left in situ (p < 0.0001); patients who developed ovarian relapse after prior colectomy and subsequently underwent oophorectomy had a median survival of 50 months versus 12 months for those patients who did not (p = 0.001). Patients with mCRC-O and peritoneal metastases had a significantly worse survival (p = 0.003).

Conclusions: This single institution retrospective data analysis suggests that women with colorectal cancer metastatic to the ovaries may derive a survival benefit from palliative oophorectomy.

No significant financial relationships to disclose.
Identification of chemosensitivity markers for postoperative adjuvant chemotherapy using cellular, molecular, and immunohistochemical profiles of advanced carcinomas from gastrointestinal tract.
Authors: Nishizuka S. , Ishida K. , Uesugi N. , Matsuo T. , Chiba T. , Ikeda M. , Sugai T. , Otsuka K. , Koeda K. , Wakabayashi G.
Published: February 2017

55

Background: The prediction of chemotherapeutic efficacy is a fundamental problem. We have developed an effective system to identify prediction markers based on an in vitro approach using a quantitative matrix of chemosensitivity assay (CSA) and protein expression by reverse-phase protein lysate microarrays (RPA), followed by tissue microarrays (TMA). In the present study, we attempted to identify predictive markers by extracting candidate proteins from the “chemosensitivity x protein expression matrix” of 12 cancer cell lines and 12 chemotherapeutic agents, followed by examination using TMA in post-operative adjuvant chemotherapy for advanced gastric and colorectal carcinomas.

Methods: The “chemosensitivity x protein expression matrix” was constructed using quantitative data from CSA and RPA. TMA was constructed from parafin-embedded, formalin-fixed surgically removed tissues from 30 gastric and 49 colorectal carcinomas. All subjects had received post-operative adjuvant chemotherapy. Expression and/or localization of candidate marker proteins on TMA were evaluated for the comparison of time to relapse (TTR) between the groups based on the score of each candidate marker protein.

Results: TTR was compared in each binary score for a candidate marker that showed a moderate to high correlation coefficient of the “chemosensitivity x protein expression matrix” of 144 combinations. Among these candidate combinations, it was found that the presence/absence of NFkB protein nuclear localization and the TTR of those patients who received 5-FU based adjuvant chemotherapy differed significantly. The three-year relapse rate was 28% in NFkB absent cases, whereas it was 84% in the present cases.

Conclusions: We identified NFkB nuclear localization as an effective 5-FU based chemotherapeutic prediction marker in the context of gastrointestinal post-operative adjuvant chemotherapy. The combination of CSA, RPA, and TMA technologies may allow rapid identification of chemotherapeutic prediction markers.

No significant financial relationships to disclose.
Self-report of neuropathy from oxaliplatin-based regimens in the treatment of colorectal cancer: With or without bevacizumab.
Authors: Wang X. S. , Eng C. , Fogelman D. R. , Malekifar M. , Liao K. E. , Glover K. Y. , Cleeland C. S.
Published: February 2017

551

Background: Neuropathy attributed to oxaliplatin-based chemotherapy is a dose limiting factor in the administration of chemotherapy. With premising clinical outomes, bevacizumab (BV) has been added with colorectal cancer (CRC) patients in first line and second- line therapy. Although toxicity been well documented, there is no evidence of the impact of adding BV to oxaliplatin-based chemotherapy on patient's neuropathy development during therapy.

Methods: The study enrolled 66 colorectal cancer patients naïve to oxaliplatin or to any microtubule stabilizing agents scheduled for oxaliplatin-based chemotherapy, 29 (44%) of whom also received BV. From first therapy cycle start date, patients rated symptoms weekly during chemotherapy via the M. D. Anderson Symptom Inventory (MDASI), and continued symptom assessment every two weeks for up to 48 weeks. Longitudinal symptom responses were analyzed by mixed-effect modeling which controlled for age, sex, staging, prior diabetes, and total cycles of chemotherapy received. All cases completed at least 2 cycles chemotherapy.

Results: A third of the sample was female; 24% were older than 65 years; 59% with stage IV disease. The five most severe symptoms were numbness, fatigue, sleep disturbance, drowsiness, and distress on MDASI symptom items. The severity of patient-reported numbness/tingling, rated on MDASI, increased overtime in following 48 weeks after started therapy (p < 0.0001). Oxaliplatin-based therapy plus BV, compared to no BV in the regimen, resulted a significant lower severity on numbness/tingling during the study period (estimate = -1.1325, p = 0.0005). Older patients reported more numbness/tingling. In contrast, pain severity remained low during the initial cycles of therapy, but significantly increased over time during therapy. Therapy with or without BV did not produce differences in pain development.

Conclusions: This prospective study suggests that adding BV to standard oxaliplitin-based therapy for CRC was associated with significantly reduced numbness/tingling development. This observation needs to be confirmed in larger studies. The mechanism(s) by which neuropathy could be attenuated by BV are unknown.

No significant financial relationships to disclose.
Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines.
Authors: Yuki S. , Shitara K. , Yoshida M. , Takahari D. , Utsunomiya S. , Yokota T. , Sato Y. , Tajika M. , Muro K.
Published: February 2017

561

Background: Weekly cetuximab and irinotecan is a standard regimen in heavily pretreated patients with metastatic colorectal cancer (MCRC). The aim of this study was to prospectively evaluate the efficacy of combination chemotherapy with biweekly cetuximab and irinotecan in patients with pretreated MCRC harboring wild-type KRAS.

Methods: Patients with wild- type KRAS MCRC that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included in this study. Cetuximab was administered at 500 mg/m2 biweekly with irinotecan. The primary endpoint was response rate. The secondary endpoints included adverse events, progression-free survival, and overall survival. The pharmacokinetics of cetuximab was also evaluated in five patients.

Results: From May, 2009 to February, 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 assessable patients, ECOG PS was 0 in 12, 1 in 16, and 2 in two patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7-49.4), and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95%CI, 61.4-92.3). The median progression-free survival was 5.3 months (95%CI, 3.4-7.3). Grade 3 skin toxicity was observed in 3 patients (10%), and treatment related death due to pneumonia occurred in one patient.

Conclusions: The efficacy data are similar to those of standard dose of cetuximab plus irinotecan. Combination chemotherapy with biweekly cetuximab and irinotecan is effective for pretreated metastatic wild-type KRAS MCRC.

No significant financial relationships to disclose.
Nurse-lead clinics for capecitabine: A prospective audit evaluating changes in toxicity profile and efficacy.
Authors: Samuel L. M. , Lynch D. , Christie G. , Collie J. , McLachlan N. , Jordan J. , Macdonald A. , Gent P.
Published: February 2017

564

Background: Oral chemotherapy offers patients equal efficacy but fewer visits to hospital and less time spent traveling, but there are concerns about toxicity and compliance. Nursing and physician interactions with patients are different, and when a nurse-lead oral chemotherapy service was developed in NE Scotland in 2003 a prospective audit was begun to monitor safety and efficacy.

Methods: Patients with colorectal cancer who declined or were not eligible for appropriate clinical trials had their course of adjuvant or palliative capecitabine chemotherapy prospectively monitored through a nurse-lead clinic. At every clinic visit data was collected on patient demographics, blood and imaging results, and adverse events (AEs). Any decision to change dose was made by the colorectal oncology medical staff.

Results: From September 2003 to November 2006 there were 177 patients prospectively monitored through the nurse-lead clinics. Palliative patients (n = 100), median age 69 (range 43-89) and majority PS 0 or 1. Initial dose reduction in 30% due to low GFR and 13% due to being >75 years old. Overall 77% of patients completed on the starting dose. AE's, shown in table, and efficacy compared with capecitabine registration data (younger age group). Median overall survival 47.7 weeks (cf 56.6 weeks). Adjuvant patients (n = 77), median age 64 (range 40-88) and all PS 0 or 1. Initial dose reduction in 19% due to low GFR and 2% due to being >75 years old. Overall 58% completed on the starting dose (= X-ACT study). AEs, other than 5% G3/4 lethargy, and efficacy similar when compared with X-ACT data, including 3 year DFS of 64% (cf X-ACT 64%).

Conclusions: Using nurses to assess patients receiving capecitabine does not seem to significantly alter efficacy but does alter the AE profile compared with the registration data, particularly in the palliative patients. Differences in the nurse-patient relationship with nurses seen as less busy, more approachable and not taking treatment decisions can improve the quality of care in patients receiving capecitabine chemotherapy.

[Table: see text]

[Table: see text]
The role of UGT1A1 polymorphisms (*28 and *6) in Japanese cancer patients.
Authors: Morimoto S. , Shimada M. , Kurita N. , Iwata T. , Nishioka M. , Yoshikawa K. , Miyatani T. , Mikami C. , Kashihara H.
Published: February 2017

570

Background: Combination protocol using FU-LV with irinotecan (FOLFIRI) is currently regarded as standard first-line therapy in advanced colorectal cancer (CRC). Although irinotecan prolongs survival, it causes severe diarrhea and neutropenia. Recent pharmacogenetic studies on irinotecan have revealed significant associations of UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms *28 and *6, the latter being specifically detected in East Asians resulting in severe toxicity. It is necessary that the dose-finding trial that decided the optimal dose according to the gene polymorphism to draw out the maximum therapeutic effect while evading the side effect. Here we present the result of prospective trial of the safety about FOLFIRI therapy according to each gene type of UGT1A1 for Japanese patients with advanced CRC.

Methods: From 2008, 250 Japanese patients in TOKUSHIMA University were enrolled in this study. Homo group (*6/*6 and *28/*28 or a both hetero types), hetero group (It was *28 and either *6 was hetero type), and wild group (*28 and *6 were wild types) were defined. On the 23 patients with advanced CRC treated with FOLFIRI after standard chemotherapy, wild and homo groups were administered 150mg/m2 irinotecan, and homo group was 100mg/m2.

Results: On the 23 patients, the genotypes of UGT1A1 *28 were homozygous in 1 (0.5%) and heterozygous in 5 (28%), *6 were homozygous in 0 and heterozygous in 6 (26%). In *6 heterozygous patients, severe toxicities (grade 3 or more) were found (33%), but in *28 heterozygous patients were not (0%). There was no decrease of irinotecan doses in each group. In Japanese people, UGT1A1 *6 polymorphisms were higher than *28 (*6 homo 3%, hetero 27% vs *28 homo 0.5%, hetero 13%).

Conclusions: When the dosage of irinotecan is decided, it is necessary to consider the UGT1A1 *6 heterozygous in Japanese cancer patients.

[Table: see text]
Predictors of survival in patients with refractory metastatic colorectal cancer.
Authors: Kim S. , Lee H. , Baek J.
Published: February 2017

583

Background: The survival of patients (pts) with metastatic colorectal cancer (mCRC) refractory to three active drugs including fluoropyrimidine, oxaliplatin and irinotecan is very limited but highly variable. Since estimating life expectancy is important for palliative intervention and advanced care planning, we aimed to suggest a model for improved prognostication of pts with mCRC.

Methods: We retrospectively reviewed 185 pts with mCRC who had been treated with fluoropyrimidine, oxaliplatin and irinotecan with no response to treatment since 2008.

Results: Of 185 pts, there were 104 (56.2%) males and 81 (43.8%) females. The median age was 58 years (range, 23-84 years). Additional cetuximab treatment was given in 43 (23.2%) pts. The median overall survival was 4.82 months. There were seven independent variables with a relationship to survival: performance status (hazard ratio [HR], 1.78; 95% confidence interval [CI], 1.31 to 2.42; p<0.001), resection of primary tumor (HR, 1.55; 95% CI, 1.04 to 2.31; p=0.033), histologic type (HR, 2.54; 95% CI, 1.59 to 4.06; p<0.001), neutrophil/lymphocyte ratio (HR, 1.62; 95% CI, 1.14 to 2.30; p=0.007), serum hemoglobin level (HR, 1.42; 95% CI, 1.02 to 1.96; p=0.035), serum albumin level (HR, 2.33; 95% CI, 1.38 to 3.92; p=0.001) and sum of metastasis site (HR, 2.00; 95% CI, 1.39 to 2.86; p<0.001). By combining these risk factors, pts with mCRC could be categorized into three different groups (Table). There was a significant difference in survival duration between the groups. (p<0.001).

Conclusions: Seven prognostic factors predicting survival were identified and used to categorize mCRC Pts who had been treated with fluoropyrimidine, oxaliplatin and irinotecan into three prognostic groups.

[Table: see text]

No significant financial relationships to disclose.
Effect of the addition of bevacizumab to first-line FOLFOX on efficacy, including response rate, progression-free survival, and overall survival, in patients with metastatic colorectal cancer.
Authors: Suenaga M. , Mizunuma N. , Matsusaka S. , Shinozaki E. , Ogura M. , Kuboki Y. , Watanabe T. , Ozaka M. , Chin K. , Hatake K.
Published: February 2017

588

Background: Bevacizumab (BV) is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor. Used in combination with chemotherapy, BV has been shown to improve survival in both first- and second-line treatment for metastatic colorectal cancer (mCRC). However, it was reported that addition of BV to FOLFOX conferred only little survival benefit (Saltz et al. JCO2008). The aim of this study was to assess the efficacy of addition of BV to FOLFOX in first-line treatment for patients with mCRC.

Methods: Bevacizumab was approved for mCRC in July 2007 in Japan. This study was conducted at a single institution and comprised 217 consecutive patients receiving first-line treatment for mCRC between 2005 and 2009. The primary objective was to compare survival benefit in patients treated with FOLFOX4 (FF) between 2005 and 2007 with that in patients receiving FOLFOX4+BV 5 mg/kg (FF+BV) between 2007 and 2009.

Results: Total number of patients in the FF and FF+BV groups was 132 and 85, respectively. Characteristics of patients were as follows (FF vs. FF+B): median age, 62 yrs (range 28-76 yrs) vs. 60 yrs (range16-74 yrs); ECOG PS0, 98.8% vs. 81.8%; and median follow-up time, 20.8 months vs. 24.4 months. Median progression-free survival (PFS) in the FF and FF+BV groups was 10 months (95% CI, 8.7-11.3) and 17 months (95% CI, 10.2-14.1), while median overall survival (OS) was 21 months (95% CI, 17.9-24.1) and not reached, respectively. Response rate was 46% (95% CI, 37- 54) in FF, and 62% (95% CI, 51-73) in FF+BV. Addition of BV to FOLFOX4 significantly improved PFS (p=0.002) and OS (p<0.001).

Conclusions: The additive effect of BV for first-line FOLFOX was reconfirmed. These data indicate potential survival benefits from the addition of BV to FOLFOX in first-line treatment of mCRC. In addition, PFS may be a sensitive indicator of outcome prior to post-treatment.

No significant financial relationships to disclose.
Observational transversal study to relate functional status and age with the doublet or triplet chemotherapy based on capecitabine in advanced gastric cancer patients.
Authors: Martinez Amores B. , Alsina M. , Jiménez E. , Jorge M. , Martin Valades J. , López P. , Falcó E. , Hinojo C. , Llorca C. , Molins C.
Published: February 2017

59

Background: The available evidence suggests that selection of treatment for advanced gastric cancer (AGC) correlates with age and ECOG PS. This study was conducted to analyze whether previously mentioned variables are relevant for the choice of doublet or triplet regimens with capecitabine and determining prognosis.

Methods: Multicenter, cross-sectional, observational study in patients with AGC who received at least 2-cycles of capecitabine-based doublet or triplet chemotherapy, with or without measurable disease. The age, as a continuous and categorical (> 64 vs ≤ 64) variable, and ECOG PS were analyzed by logistic regression.

Results: A total of 175 patients were evaluated. Median age 65.5 (56-72) years, male: 68% ECOG 0/1/2: 32.7%/55.6%/11.1%. 33% underwent doublet and 67% triplet chemotherapy. Tumour histology: signet-ring cell carcinoma (29%), papillary (13%), mucinous (12%) and tubular (3.5%). Most common sites of metastases: lymph nodes (48%), peritoneum (41%), liver (38%) and lung (12%). Multivariante analysis demonstrated that age ≤ 64 (OR 2.326; p = 0.016) and ECOG 0 (vs 2) (OR 3.937; p = 0.016) were risk factors for the choice of triplet chemotherapy, and failed to show an association between ECOG 1 and regimen. While in patients underwent triplet regimen 51% were aged ≤ 64 and 49% > 64, in those treated with doublet these rates were 32% and 68% respectively; (p = 0.016, Chi-square test). A statistical difference was found for ECOG 0/1/2/4 and regimen chosen. Concretely, among patients who received triplet regimen, 15% had ECOG 2 and 85% ECOG 0 while in case of doublet regimen these rates changed to 43 and 57%; (p = 0.01, Fisher's exact test). Main grade 1/2 capecitabine-related toxicities: diarrhea (10%), mucositis (7%), hand-foot syndrome (5%) and emesis (4%). Most frequent grade 3 were diarrhea in 5% and emesis, asthenia and febrile neutropenia in 2%. No toxicity grade 4 occurred.

Conclusions: Age ≤ 64 years and ECOG 0 are risk factors of choice of capecitabine-based triplet chemotherapy in AGC. These results support previous reports showing that age and ECOG PS are associated with treatment choices for AGC.

No significant financial relationships to disclose.
Characteristics and treatment effect of senior patients with metastatic colorectal cancer (mCRC): A retrospective analysis.
Authors: Boudreault J. , Aubin F. , Ayoub J. M. , Sylvestre M. , Richard C. S. , Tehfe M. A.
Published: February 2017

600

Background: Colorectal cancer affects many elderly patients as approximately 50% of cases are diagnosed in patients older than 70 years of age. We retrospectively studied characteristics, presentation, treatment and clinical course of our senior patients with (mCRC).

Methods: Medical records of all patients ≥70 years with mCRC treated in our institution from 2006-2009 were reviewed. A multivariate Cox's proportional hazards model was applied to estimate the effect of chemotherapy (CT) on survival, while adjusting for other factors measured at time of diagnosis (age, sex, comorbidity, and number of metastases).

Results: Ninety-four patients (48 men and 46 women) ≥70 year-old with mCRC were identified. Abdominal pain, fever, lower GI bleed and anemia were the most common presenting symptoms. Fifty-seven patients didn't receive CT mainly because of patient/family refusal, alteration of general status and presence of comorbidity. CT (N=37) was associated with an improved median survival (13.5 months) compared to non-treated group (2 months), with hazard ratio (0.20; 95% CI, 0.09 to 0.43; p<0.00001). In the multivariate analysis, age (70-74 vs 75-79 vs ≥80 years), sex, comorbidity (0 vs 1 vs 2 vs ≥3), and number of metastatic sites (1 vs ≥2) were not independently associated with survival. ECOG-PS was not mentioned in the medical record of most patients. Sixty- three percent of the 70-74 year-old patients, 34% of the 75-79 year-old group, and only 23% of the ≥80 year-old patients received CT. Treatment benefit was seen with either 5-FU monotherapy (HR: 0.30; 95% CI, 0.12 to 0.77), Irinotecan-based (HR: 0.24; 95% CI, 0.07 to 0.74), or Oxaliplatin-based CT (HR; 0.07; 95% CI, 0.01 to 0.30). None of the patients had geriatric assessment prior to treatment.

Conclusions: Most elderly patients with mCRC do not receive CT, yet treatment was associated with a clear survival benefit. The presence of multiple comorbidities did not affect treatment benefit. Although performance status could not be ascertained in this retrospective study, it likely influenced survival and the decision to treat with CT or not. Oncogeriatric assessment may be useful in better selecting elderly patients for systemic treatment.

No significant financial relationships to disclose.
Topical application of hangeshashinto (TJ-14) in the management of chemotherapy-induced oral mucositis: A preliminary study.
Authors: Kono T. , Satomi M. , Ebisawa Y. , Chisato N. , Suno M. , Asama T. , Matsubara K. , Furukawa H.
Published: February 2017

603

Background: Oral mucositis is a common toxicity associated with cytotoxic chemotherapy used for cancer treatment and results in severe discomfort and impairs patients' ability to eat, swallow, and talk. The treatment of chemotherapy-induced oral mucositis is not well established. The cyclooxygenase pathway mediates tissue injury and pain through upregulation of pro-inflammatory prostaglandins. Recent study showed that one of the Japanese traditional medicines (kampo), hangeshashinto (TI-14), may be useful for periodontal disease via downregulation of pro-inflammatory prostaglandins in human. The aim of this study was to evaluate the effect of TJ-14 on chemotherapy- induced oral mucositis.

Methods: Fourteen patients with chemotherapy-induced oral mucositis during mFOLFOX6 or FOLFIRI treatment for requiring to the metastasis of advanced colorectal cancer were received topical application of TJ-14. Topical TJ-14 was applied to the oral mucositis three times a day. Patients were asked to make 50 mL of TJ-14 solution (2.5 g) with a tap water and were advised to rinse the TJ-14 solution on the oral mucosa for 10 seconds and then to spill it. Additionally, TJ-14 was topically applied with a cotton pellet on the oral mucositis. The above treatment was advised throughout the course of chemotherapy. Patients were evaluated for the oral mucositis using the Common Terminology Criteria for Adverse Events (CTCAE) version 4 before and after 2-weeks TJ-14 treatment.

Results: Thirteen of the fourteen patients (92.8 %) responded to the TJ-14 therapy. There was significant reduction in the grade 3/4 mucositis from 3.2 to 1.8 (p=0.02) as well as in the grade 1/2 mucositis from 1.6 to 0.6 (p=0.034). There is no patient showed worse than before. The compliance of TJ-14-treatment was good.

Conclusions: Topical application of TJ-14 may have therapeutic effects on chemotherapy-induced oral mucositis via downregulation of pro-inflammatory prostaglandins.

No significant financial relationships to disclose.
Capecitabin (Cap) compared with flurorouracil (5FU)-leucovorin (LV) as concurrent chemotherapy for preoperative chemoradiation (preop CRT) in rectal cancers: A retrospective study.
Authors: Schipman B. , Nguyen T. , Mercier M. , Borg C. , Miny J. , Bosset J.
Published: February 2017

606

Background: The aim was to compare acute toxicities, compliance to treatment and tumor response after preoperative chemoradiation between two different regimen of concurrent chemotherapy, Cap or 5FU-LV, for the treatment of locally advanced rectal cancers.

Methods: Patients with a resectable rectal cancer (T3-4, N0-2) treated from 1993 to 2006 were included. We compared two groups of patients. One treated with preop CRT including 5FU-LV (5FU 350 mg/m2 short IV infusion daily for 5 days - week 1 and 5. LV IV push 20mg/m2 with 5FU. RT 45 Gy 1.8 Gy/F over 5 weeks). The second group received the same RT scheme. 5FU-LV were substitute for Cap 850 mg/m2 twice daily along the RT except week-end.

Results: 101 patients received 5 FU-LV and 51 patients Cap. Patients and tumour characteristics were similar. Grade 3-4 acute toxicities rates (especially leucopenia and diarrheas) after chemoradiation were 4 and 9.8% for 5 FU-LV and Cap respectively (p=0.16). Chemotherapy was modified for toxicities (dose reduction or interruption) in 5.9 and 17.6% of patients receiving 5 FU-LV and Cap respectively (p=0.04). Radiotherapy was stopped in 7.9 and 3.9% of patients treated by 5 FU-LV and Cap respectively (p=0.50). Complete histological response rates were 10.3 and 6% (p=0.54), tumour regression (downstaging) rates were 44.3 and 41.2% (p=0.73) for patients treated by 5 FU-LV and Cap respectively.

Conclusions: In this retrospective analysis CRT with Cap obtained a similar tumor effect to the 5 FU-LV scheme. However the Cap scheme induced more grade 3-4 toxicities had no impact on the RT compliance but conducted to modify more frequently the chemotherapy scheme.

No significant financial relationships to disclose.
Distress in gastrointestinal cancer: Distress thermometer (DT, NCCN)—Validation to Brazilian Portuguese.
Authors: Dettino A. A. , Pontes L. L. , Pagano T. , Fanelli M. F. , Chinen L. T. , Costa C. L.
Published: February 2017

608

Background: Distress is psychological suffering, and DT is its efficient screening scale. Objectives: 1) Translate,culturally adapt,and validate DT to Brazilian Portuguese. 2) Evaluate distress in gastrointestinal cancer patients.

Methods: Inclusion: >=200 patients with advanced gastrointestinal cancer, age>=18. Exclusion criteria: uncontrolled psychiatric disorder, not knowing diagnosis, difficulty in understanding informed consent. They answered Brazilian Portuguese translated version of DT, and Hospital Anxiety and Depression Scale (HADS). Obtained data used to calculate validity and reliability of the DT (cutoff <=4 represents significant distress), using HADS as gold-standard evaluation of distress (cutoff <=14, and 7 for subscales).

Results: Preliminary relevant results (n=85) shown in the table.

Conclusions: Data confirm importance of emotional assistance to patients with oncologic diseases and need of interdisciplinary palliative care. We plan to present updated data in ASCO GI Meeting, and be able to show validation of DT to Brazilian Portuguese.

[Table: see text]

[Table: see text]
Completion and toxicity rates of adjuvant chemotherapy in rectal cancer patients previously treated with neoadjuvant therapy and resection.
Authors: Oxner C. R. , Choi S. , Hein M. J. , Lim D. , Shibata S. , Pigazzi A.
Published: February 2017

609

Background: Adjuvant chemotherapy is recommended after rectal cancer surgery. Yet the success and complication rates of this adjuvant treatment are poorly studied. The purpose of this study is to determine the success rate and define the toxicity profile of adjuvant chemotherapy in rectal cancer patients previously treated with neoadjuvant chemotherapy.

Methods: Study design is a retrospective review of patients from December 2002-December 2007 from the City of Hope database. Data is available with 66 patients diagnosed with locally advanced rectal cancer treated with neoadjuvant chemo radiation and resection. Data points analyzed included demographics, chemotherapy-related toxicity and survival.

Results: Adjuvant chemotherapy was started in 35/66 (53%) of patients. In 31 cases chemotherapy was not given because of patient refusal or physician preference. 9 patients were lost to follow-up. Follow-up ranged from 9-59 months with median follow-up of 27 months. In the 26 patients with adequate follow up there were a total of 165 episodes of toxic events 3a grade 1. Most of the events were mild to moderate grade 1-2. In 10 patients (28%) 22 major toxicities 3a grade 3 episodes were observed. The median Karnofsky performance scale (KPS) showed no significant difference in patients before and after adjuvant chemotherapy (p = 0.071). The rates of 1-year, 3-year and 5-year survival were 100%, 90%, and 60%, respectively; corresponding disease-free survival was 88%, 83%, and 69% respectively.

Conclusions: These preliminary data suggest that only a fraction of rectal cancer patients previously treated with neoadjuvant CRT complete a full course of adjuvant chemotherapy. Future studies will help confirm these preliminary findings and generate an outcome comparison between patients receiving and not receiving adjuvant therapy.

No significant financial relationships to disclose.
A novel approach to manage skin toxicity caused by cetuximab and panitumumab.
Authors: Berardi R. , Campanati A. , Onofri A. , Bittoni A. , Pierantoni C. , Giuliodori K. , Ganzetti G. , Scartozzi M. , Offidani A. , Cascinu S.
Published: February 2017

616

Background: Inhibition of the EGFR represents one of the most important fields for research and development in cancer therapy. Skin rash has been documented as one of the most common adverse reactions in patients receiving EGFR inhibitors. Several approaches have been attempted to manage skin toxicity. Nicotinamide has been shown to be an effective treatment for skin inflammation in various conditions, since nicotinamide inhibits IL-8 production through the NF-kB and MAPK pathways in an in vitro keratinocytes/P. acnes model of inflammation. Furthermore green tea polyphenols could be useful in attenuation of solar UVB light-induced oxidative stress-mediated and MAPK-caused skin disorders in humans.

Methods: Therapy protocol for skin toxicity consisted of: topic applications of green tea and a mostouizer and orally given nicotinamide. Patients were monitored weekly and data regarding skin toxicity (NCI-CTC grade, the Dermatology Life Quality Index (DLQI), a global score evaluating all the parameters) were recorded.

Results: Between September 2009 and September 2010, 13 colorectal cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab) and developing skin toxicity, were treated by a multidisciplinary team including oncologists, dermatologists, a pathologist, and a nurse. All the patients experienced a significative eduction of erythema, papulo-pustular rash, paronychia, fissuring, xerosis, and itching. A significative improvement of the global score and of DLQI was evident. No toxicity related to the treatment of skin toxicity was observed.

Conclusions: Treatment with nicotinamide, green tea, and moisturizer represents a novel effective approach to manage skin toxicity caused by cetuximab and panitumumab.

No significant financial relationships to disclose.