bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final skin toxicity (ST) and patient-reported outcomes (PRO) results from PRIME: A randomized phase III study of panitumumab (pmab) plus FOLFOX4 (CT) for first-line metastatic colorectal cancer (mCRC).
Authors: Douillard Jean Yves , Siena Salvatore , Tabernero Josep , Burkes Ronald L. , Barugel Mario Edmundo , Humblet Yves , Cunningham David , Xu Feng , Zhao Zhongyun , Sidhu Roger 
Published: February 2017

531^ Background: Final PRIME results showed that pmab + CT significantly improved progression-free survival (PFS) and objective response rate vs CT alone for first-line wild type (WT) KRAS mCRC. Efficacy and PRO by ST severity from the final descriptive analysis of PRIME are presented. Methods: Patients (pts) had no prior chemotherapy for mCRC, ECOG performance status ≤ 2, and tumor tissue available for biomarker testing. The final analysis occurred 30 months after the last pt was enrolled; the primary endpoint was PFS; secondary endpoints included OS, objective response, and safety. Pts who received treatment and were alive without progression at day 28 were included in the ST analysis. Results: 1183 pts were randomized. 1057 pts with WT or MT KRAS mCRC met the criteria for inclusion in the ST analysis. Maximum grade ST was observed by day 28 in > 50% of pts. Results are shown ( table ). Overall differences in change from baseline of the least square means from a mixed effects model of the EQ-5D Overall Health Rating for pmab + CT (n = 285) minus CT alone (n = 294) and for ST gr 0-1 (n = 53) minus ST gr 2-4 (n = 232) were −1.069 (95% CI: −3.6277 to 1.4896) and 0.8971 (95% CI: ‐4.0224 to 5.8167), respectively. The overall safety profile was broadly comparable across ST groups and treatment arms. Conclusions: Pts with WT KRAS mCRC receiving pmab with ST gr 2-4 had longer PFS and OS vs pts receiving CT alone. PRO were not adversely affected by ST severity. [Table: see text]
Association between delays in adjuvant chemotherapy for stage III colon cancer and increased mortality.
Authors: Haynes Alex Bernard , Chiang Yj , Feig Barry W. , Xing Yan , Chang George J. , You Y. Nancy , Cormier Janice N. 
Published: February 2017

541 Background: Administration of adjuvant chemotherapy is the standard of care for stage III adenocarcinoma of the colon. There are conflicting data regarding the optimum interval for the initiation of adjuvant therapy and whether this affects survival. Methods: Patients were identified from the National Cancer Database (1998-2002) who received adjuvant chemotherapy after resection of stage III colon cancer. Multivariate analyses were performed to examine the associations between time interval from surgery to chemotherapy initiation and overall and relative survival. Relative survival was used as a surrogate for disease-specific survival. Results: 32,327 stage III colon cancer patients who received chemotherapy after surgery were identified. The relationship between timing of adjuvant chemotherapy and survival is reported in Table 1. Delay of chemotherapy beyond 8 weeks postoperatively was associated with an increased likelihood of death in a relative survival model, with a hazard ratio for death of 1.19 (95% CI: 1.11, 1.28) in the 8 to 12 week interval. Longer delays were associated with worse outcomes, with a 7.6% absolute decrease in relative survival. Other independent factors associated with reduced survival included gender, race, type of insurance, margin status, and tumor grade. Conclusions: Delay in the initiation of adjuvant therapy beyond eight weeks is an independent predictor of increased mortality. While other factors contribute to the risk of death from disease, chemotherapy delays may be preventable. Policy interventions should be developed to encourage the administration of chemotherapy within eight weeks of resection when indicated. Further effort should be expended to understand the etiology of and mitigate these delays. [Table: see text]
Preoperative radiation therapy with concurrent capecitabine, bevacizumab, and erlotinib for rectal adenocarcinoma: A phase I trial.
Authors: Das Prajnan , Eng Cathy , Rodriguez-Bigas Miguel A. , Chang George J. , Skibber John Michael , Maru Dipen , Munsell Mark F. , Clemons Marilyn V. , Kopetz Scott , Garrett Chris R. , Shureiqi Imad , Krishnan Sunil , Delclos Marc E. , Crane Christopher H. 
Published: February 2017

544 Background: The goal of this phase I trial was to determine the maximal tolerated dose (MTD) of concurrent capecitabine, bevacizumab and erlotinib with preoperative radiation therapy (RT) for rectal cancer, with a secondary objective of evaluating pathologic complete response (pCR). Methods: Eligibility criteria included patients with clinical stage II-III rectal adenocarcinoma within 12 cm from the anal verge. Exclusion criteria included uncontrolled hypertension, recent myocardial infarction or angina, coagulopathy, impaired renal function, and history of gastrointestinal perforation. Patients were treated in cohorts of 2, in 4 escalating dose levels (DL), using the continual reassessment method, as shown in the table. Patients underwent surgery at least 9 weeks after the last dose of bevacizumab. Results: Nineteen patients were enrolled in the study: 1 withdrew early because of insurance issues and was non-evaluable. The clinical stage was T3N0 in 3, T3N1 in 13, T3N2 in 1 and T4N0 in 1 patient. No patient had grade 4-5 acute toxicity; 1 patient had grade 3 acute toxicity (hypertension, DL 2) during or within 4 weeks after RT. The MTD was not reached; the probability of dose limiting toxicity at DL 4 was 0.15. All 18 evaluable patients underwent surgery, with low anterior resection in 7 (39%), proctectomy with coloanal anastomosis in 5 (28%), and abdominoperineal resection in 6 (33%) patients. Eight patients (44%) had pCR, and an additional 8 (44%) had ≤ 10% viable tumor in the surgical specimen. Fifteen patients (83%) had T downstaging. Three patients developed grade 3 post-operative complications (ileus, small bowel obstruction and infection). After a median follow-up of 21 months (range 9-39 months), no patient had local recurrence, but 1 patient developed distant metastasis. Conclusions: The combination of preoperative RT with concurrent capecitabine, bevacizumab and erlotinib was well tolerated. The pCR rate of 44% is promising and warrants further investigation. [Table: see text]
The role of partial splenic embolization (PSE) in the management of chemotherapy-induced thrombocytopenia.
Authors: Ohinata Aki , Wallace Michael J. , Overman Michael J. , Phillips Jonathan , Wolff Robert A. , Eng Cathy 
Published: February 2017

569 Background: Chemotherapy-induced splenomegaly is a relatively known treatment complication, where the clinical sequale of hypersplenism is persistent thrombocytopenia due to splenic sequestration. For cancer patients (pts) undergoing chemotherapy, thrombocytopenia may result in a dose delay or dose reduction, thus reducing dose intensity. The impact of refinement in technique with limited volume embolization (50-70%) of the spleen upon morbidity and mortality has not been well studied. Methods: A retrospective review of gastrointestinal cancer pts undergoing PSE for thrombocytopenia to facilitate the initiation or resumption of systemic chemotherapy between Jan. 2008 and March 2011 was completed. Pre- and post-PSE platelet (plt) counts within 30 days were evaluated for benefit of treatment. Objectives included the re-initiation of systemic therapy and post-PSE plt count >150 (< 30 days). Periprocedural laboratory values and adverse events were recorded. Results: PSE was performed in 79 pts. Median prior chemotherapy regimens = 2 (range 1-3). The median follow-up was 12M (range: 7-31). The mean plt count prior to PSE was 80 K/ UL (3-196). Post-PSE platelet count of > 150 was achieved in 52 (66%) pts with a mean peak plt count of 219 K/UL. Six (8%) pts underwent repeat PSE due to recurrent thrombocytopenia after initiation of systemic therapy. Re-initiation of chemotherapy was achieved in 59 (79%) pts. The median duration of chemotherapy following PSE was 8M (95% CI: 4.2-14.2); median overall survival was 33M (95% CI: 10-47). Post-procedure fever developed in 7 (9%) pts and pleural effusion, atelectasis, or consolidation was reported in 8 (10%) pts. Seventeen (21%) pts developed reversible grade 1 hyperbilirubinemia. Median length of hospital stay was 3 days (interquartile range 1-5 days). 60-day mortality rate was 9% (7 of 79). Conclusions: Partial splenic embolization (PSE) is a safe and effective method of managing thrombocytopenia secondary to chemotherapy-induced hypersplenism to facilitate re-initiation of systemic therapy in cancer patients. PSE may be considered as a potential option in patients with good performance status to facilitate further systemic chemotherapy.
Reasons for and outcomes of adjuvant chemotherapy choices in elderly patients with resected stage III colon cancer.
Authors: Ko Jenny , Kennecke Hagen F. , Lim Howard John , Gill Sharlene , Woods Ryan , Speers Caroline , Cheung Winson Y. 
Published: February 2017

571 Background: Research suggests that elderly cancer patients are commonly undertreated, but the precise reasons for this are unclear. Robust clinical data on the optimal adjuvant chemotherapy regimen for elderly colon cancer patients are also lacking. Our aims were to: 1) evaluate the impact of advanced age on choice of adjuvant chemotherapy (none vs. capecitabine vs. FOLFOX) for curatively resected colon cancer; b) determine the reasons for selecting a particular regimen; and 3) examine whether treatment effect on outcomes is modified by age. Methods: All patients diagnosed with stage III colon cancer between 2006 and 2008, and referred to any 1 of 5 regional cancer centers in British Columbia, Canada were identified. Descriptive statistics were used to summarize treatment patterns among young patients (YPs) aged <70 years vs. elderly patients (EPs) aged >/=70 years. Multivariate logistic regression models were constructed to evaluate the association between adjuvant chemotherapy and cancer-specific survival (CSS) in YPs and EPs. Results: In total, 810 patients were identified: 51% were male, 52% YPs and 48% EPs, and 74% received adjuvant chemotherapy. When compared to YPs, EPs had worse ECOG and more comorbidities (both p<0.001). EPs were less likely than YPs to receive adjuvant chemotherapy (57% vs. 91%, p<0.001). Frequent reasons for no treatment included age, comorbidities, and small perceived benefit from adjuvant therapy. Among treated pts, EPs were less likely to receive FOLFOX (32% vs. 74%, p<0.0001) in favor of capecitabine due to patient preference, age, and comorbidities. In multivariate analyses, receipt of either FOLFOX or capecitabine was correlated with improved CSS compared to surgery alone. The effect of adjuvant chemotherapy on CSS was not modified by age (interaction p for capecitabine and age = 0.26; interaction p for FOLFOX and age = 0.40). Conclusions: EPs with stage III colon cancer frequently received either no adjuvant treatment or capecitabine monotherapy due to advanced age and co-morbidities. The treatment effect of adjuvant therapy on CSS is similar among EPs and YPs. Adjuvant chemotherapy should not be withheld from colon cancer patients based on advanced age alone.
BSA dosing and suboptimal 5-FU exposure among colorectal cancer patients of varying gender and age.
Authors: Haregewoin Abebe , Hamilton Stephanie A. , Grier Charles E. , Kaldate Rajesh R. 
Published: February 2017

579 Background: 5-Fluorouracil (5-FU) remains the cornerstone of colorectal cancer (CRC) therapy and its dosing is based on body surface area (BSA). Although convenient, BSA dosing disregards factors that impact 5-FU PK such as genotype, age, gender, etc. Thus, patients receiving the same BSA based dose show a wide range of 5-FU plasma levels (measured as AUC in mg·h/L), resulting in ineffective or toxic doses affecting therapy outcome. An optimal therapeutic AUC target range of 20-30 mg·h/L has been proposed. Methods: Plasma samples from the initial treatment cycle of 927 CRC patients who received 2400 mg/m2 continuous infusion of 5-FU over 44-48 hours, with or without bevacizumab, were tested for 5-FU exposure using an immune-based assay (OnDose). AUC results were analyzed to evaluate gender and age effects. Results: There are 391 (42.2%) female and 536 (57.8%) male patients with age ranging from 17-93 years (mean/SD: 58.5/11.8). These analyses indicate that in comparison to the proposed optimal AUC target range of 20-30 mg·h/L, females receive supra-optimal doses compared to males (p=0.0083). Age also affects the 5-FU AUC (p=0.0002), with younger patients more likely to receive sub-optimal doses than older patients. Conclusions: BSA dosing is an unreliable indicator of exposure and may lead to under dosing in males and younger patients, and overdosing in females and older patients, potentially resulting in corresponding diminished efficacy or increased toxicity. Data suggest that therapy could be optimized by 5-FU dose adjustment in subsequent cycles based on PK monitoring so that AUC values will converge towards the target range irrespective of gender or age. A large clinical trial is in progress to validate these findings.
Pathologic complete response rates after neoadjuvant chemoradiation (CRT) for rectal cancer: Do novel agents have a role?
Authors: Beg Muhammad Shaalan , Meyer Jeffrey , Balch Glen C. , Xie Xian-Jin , Singal Amit G 
Published: February 2017

597 Background: Preoperative concurrent radiation with either 5-fluorouracil (5FU) or capecitabine (CAP) is considered standard of care for T3-T4 and/or node positive rectal cancers with historical pathological complete response (pCR) rates ranging from 7-29%. There is lack of randomized data on the incorporation of bevacizumab (B) and cetuximab (C) with neoadjuvant chemoradiation (CRT). The aim of our study was to quantify pCR and adverse event rates for B-CRT and C-CRT in patients with rectal cancer. Methods: A systematic literature review using the Medline database and national meeting abstracts identified trials incorporating bevacizumab and cetuximab for neoadjuvant chemoradiation between 2000 and 2011. Pooled rates of pCR and frequency of grade 3-4 adverse events per patient with 95% confidence intervals (CI) using the adjusted Wald method, were calculated. Results: Out of 24 trials identified, 15 trials with a total of 457 (range 8-61) patients incorporated B-CRT. Five studies used 5FU, ten used CAP. A third chemotherapeutic agent was also included in 7 trials of B-CRT. There were 9 trials incorporating C-CRT with a total of 332 (range 20-50) patients. Two studies used 5FU, 7 used CAP, while four studies also included a third therapeutic agent. The pooled pCR rate for B-CRT of 20.8% (95% CI 17.3-24.8), was significantly higher than the 9.6% (95%CI 6.92-13.2) pCR rate for C-CRT (p < 0.001). The rate of grade 3-4 adverse events was significantly lower for B-CRT at 0.38 per patient studied (95% CI 0.34-0.43) compared to C-CRT at 0.55 per patient (95%CI 0.49-0.60) (p<0.001). Surgery was performed in 92% of B-CRT and 94% of C-CRT patients. Conclusions: The addition of either B or C to conventional neoadjuvant CRT does not appear to yield higher pCR rates than those reported with conventional CRT alone. There is insufficient evidence to support routine use of novel agents in this treatment strategy for rectal cancer. Interestingly, although surgical rates are high in both groups, C-CRT has significantly lower rates of pathologic complete response and significantly higher rates of toxicity than B-CRT.
Effect of inhibition of nuclear protein export using a novel CRM1 inhibitor on the apoptotic response to SN38 in preclinical colon cancer models.
Authors: Chung Hye Won , Salas Fragomeni Roberto A. , Shacham Sharon , Kauffman Michael , Cusack James C. 
Published: February 2017

609 Background: Resistance to conventional chemotherapy remains a major challenge in Stage IV colon cancer. CRM1 inhibition leads to nuclear sequestration of proteins such as tumor suppressor p53, growth regulatory proteins, and chemotherapy targets such as topoisomerase I/II. We examined the effects of combination use of KPT185 (a novel CRM1 inhibitor) with SN38 (active metabolite of irinotecan) and the effect of drug administration sequence in human colon cancer cell lines to determine if CRM1 inhibition enhances the cytotoxic effect of chemotherapy. Methods: We evaluated the combination effect of KPT185 with SN-38 on both Lovo (KPT-sensitive, IC50 = ∼ 500nM) and HT29 cells (KPT-resistant, IC50 = 1000 ∼ 3000nM) by the Chou-Talalay method, an MTT-based assay that interrogates response across a spectrum of drug dosages: KPT185 (0, 1, 10, 100, 1000, 10000 nM) and SN38 (0, 100, 500, 1000 nM). Cell cycle analysis by FACS with propidium iodide (PI) staining was performed. Effects on apoptosis were determined by FACS (Annexin V/PI staining) and Cell Death Detection ELISA assay. Results: The Chou-Talalay method determined that there is a synergistic effect when KPT185 is combined with SN38 in both Lovo and HT29 cells (combination index > 1). FACS analysis demonstrated combination use of KPT185 and SN38 induced an increase in the apoptotic sub-G1 fraction and a shift toward G2/M arrest. Combination treatment also significantly increased the Annexin V/PI-positive fraction compared with SN38 alone case (P < 0.05). Treatment sequence studies demonstrated that pretreatment of SN38 followed by KPT185 (KPT-post) produced the maximum synergistic effect compared with pretreatment of KPT185 followed by SN38 (KPT-pre) or concurrent use (KPT-con); Cell Death Detection ELISA assay showed KPT-post increased apoptosis most (4.3-fold) compared with KPT-pre (4.2-fold), KPT-con (3.8-fold) and SN38 alone (1-fold). Conclusions: Our results show KPT185, a novel CRM1 inhibitor, sensitizes the response to SN38 in KPT-sensitive as well as KPT-resistant colon cancer cells. This method of sensitizing colon cancer cells warrants further evaluation in preclinical models of colon cancer.
A phase II, single-arm clinical trial involving an alternative cancer treatment psorinum therapy in patients with advanced esophageal carcinoma.
Authors: Chatterjee Aradeep , Bhattacharya Sudin , Chakraborty Amitava , Bhakta Radhe S. , Chatterjee Ashim Kumar , Biswas Jaydip 
Published: February 2017

62 Background: We prospectively studied the clinical efficacy of an alternative cancer treatment “psorinum therapy” in treating advanced esophageal carcinoma (ECA). Methods: Our study was phase- II, open level, single arm and single stage. Participants’ eligibility criteria included (1) histopathology confirmation of ECA (2) inoperable tumor (3) no prior conventional cancer treatments (4) karnofsky performance status between 40 -70%. The primary outcome measures of the study were (1) to assess the radiological tumor response rate (using CT scanning procedure and following the RECIST criteria); (2) to assess how many participants survived at least 1 yr, 2 yrs, 3 yrs, 4 yrs and finally, after 5 yrs of the study. The secondary outcome measure was to assess the side effects of the investigational anti- cancer drug (psorinum) if any. Psorinum (an alcoholic extract of scabies slough and pus cells) was administered orally at a dose of 0.02ml / kg body weight / day as a single dose on an empty stomach for a complete course duration of 2 yrs to all the participants along with allopathic and homeopathic supportive cares. Results: 65 participants included in the final analysis at the end of the study. According to the RECIST criteria, complete response occurred in 11 (16.92%) case and partial response occurred in 20 (30.77%) cases. 44 (67.69%) of them survived at least 1 yr, 32 (49.23%) survived at least 2 yrs, 24 (36.92%) survived at least 3 yrs, 21 (32.31%) survived at least 4 yrs and 17 (26.15%) of them survived at least 5 yrs. These participants didn’t receive conventional or any other investigational cancer treatments. According to AJCC TNM staging system, 31 (47.69%) participants diagnosed at stage IV. Among them complete response observed in 4 (12.90%) cases, partial response observed in 8 (25.81%) cases and 5 (16.13%) of them survived at least 5 yrs. Conclusions: The results of the study show clinical efficacy of psorinum therapy in treating patients with advanced ECA. The investigational drug psorinum is non- toxic. Randomized controlled clinical trial should be conducted for further investigation of this alternative cancer treatment in treating esophageal cancer.
Genetic polymorphisms and ethnic difference in outcome of adjuvant FOLFOX chemotherapy in Korean patients with colon cancer.
Authors: Lee Kyung-Hun , Chang Hye Jung , Han Sae-Won , Oh Do-Youn , Im Seock-Ah , Bang Yung-Jue , Kim Sun Young , Lee Keun-Wook , Kim Jee Hyun , Hong Yong Sang , Kim Tae Won , Park Young Suk , Kang Won Ki , Shin Sang Joon , Ahn Joong Bae , Kang Gyeong Hoon , Jeong Seung-Yong , Park Kyu Joo , Park Jae-Gahb , Kim Tae-You 
Published: February 2017

623 Background: Ethnic diversity of genetic polymorphism can result in individual differences in the efficacy and toxicity of cancer chemotherapy. Methods: A total of 292 Korean patients (183 men and 109 women) from six hospitals in Korea were prospectively enrolled. Patients had resected stage III or high-risk stage II colon cancer and were treated with 12 cycles of adjuvant oxaliplatin plus leucovorin plus 5-fluorouracil (FOLFOX) chemotherapy. 20 germline polymorphisms in 10 genes (TS, MTHFR, ERCC1, XPD, XRCC1, ABCC2, AGXT, GSTP1, GSTT1 and GSTM1) were analyzed from peripheral blood. TS genotype in 5’UTR was classified as ‘high’ (2R/3G, 3C/3G, and 3G/3G) or ‘low’ (2R/2R, 2R/3C, and 3C/3C). Results: Most patients (86.3%) received 12 complete cycles of FOLFOX chemotherapy. In contrast to previous studies in Caucasians, neutropenia (grade 3–4, 60.5%) was frequently observed in our Korean patients, whereas only 16.4% experienced grade 2 or more sensory neuropathy. Neutropenia was more frequent in MTHFR 677TT [adjusted odds ratio (OR) 2.32, 95% confidence interval (CI) 1.19–4.55] and ERCC1 19007TT (adjusted OR 4.58, 95% CI 1.20–17.40) genotypes. Patients harboring XRCC1 23885GG had lower risk of neuropathy (adjusted hazard ratio 0.56, 95% CI 0.32-0.99) and longer time to the onset of grade 2-4 neuropathy. MTHFR 677TT and XRCC1 23885GG genotype was also more prevalent in Koreans compared to Caucasians, and the difference of genotypic frequency could partly explain the ethnically different toxicity profile. After median 49.4 months of follow-up, there were 58 (19.9%) relapses and 19 (6.5%) deaths. TS ‘low’ genotype [adjusted hazard ratio (OR) 1.83, 95% CI 1.003–3.34] was significantly related to shorter disease-free survival. Overall survival was not significantly different according to the polymorphisms. Conclusions: Polymorphisms in MTHFR, XRCC1 and TS are related to toxicities and disease-free survival in patients with colon cancer. These polymorphisms may explain the ethnic difference in toxicity profile following adjuvant FOLFOX chemotherapy.