bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of totally implantable venous access port systems (TIVAPS) related adverse events (AEs) in metastatic colorectal cancer (mCRC) patients treated with and without bevacizumab.
Authors: Tsushima Takahiro , Mori Keita , Yamazaki Kentaro , Hikosaka Tomomi , Funakoshi Taro , Tabuse Hiroyuki , Hamauchi Satoshi , Todaka Akiko , Yokota Tomoya , Machida Nozomu , Fukutomi Akira , Onozawa Yusuke , Boku Narikazu , Yasui Hirofumi
Published: March 2020

e14623

Background: TIVAPS are widely used for cancer chemotherapy. Bevacizumab, a key drug for mCRC, associates with AEs such as thromboembolism, bleeding, and impaired wound healing. Bevacizumab may complicit in increasing incidence of TIVAPS related AEs. To assess the incidence of TIVAPS related AEs in mCRC patients who received chemotherapy with and without bevacizumab. Methods: We retrospectively reviewed the medical records of consecutive patients whose TIVAPS were placed at our institution between Apr. 2004 and Apr. 2009. Major selection criteria were histologically proven colorectal adenocarcinoma, metastatic disease, and receiving chemotherapy after TIVAPS placement. We assessed the incidence of AEs occurred from the first administration of chemotherapy via TIVAPS to TIVAPS removal, death, or the last follow-up. We compared the incidence of TIVAPS related AEs in the cases bevacizumab was administered (group A) with that in the cases without bevacizumab administration (group B). Results: TIVAPS was placed 549 times for 505 patients, and 544 TIVAPS placements for 501 patients were analyzed. Bevacizumb was administered in 174 patients (32%), and median duration of bevacizumab therapy was 9.2 months. Characteristics of the cases in the group A and B were: male (60% and 59%); primary site colon (60% and 57%); catheterized in left subclavian vein (85% and 81%); history of prior chemotherapy (53% and 60%); median time from TIVAPS placement to administration of chemotherapy (1 day and 1 day). Incidence of common AEs in the group A and B were: infection (7.5% and 6.8%); venous thromboembolism (3.4% and 1.4%); TIVAPS occlusion (2.3% and 1.9%); delay of wound healing (1.1% and 0.5%); hematoma (0.6% vs 0%). Median time to AE in the group A and B was 21 months and 9 months. There was no significant difference in the incidence of TIVAPS related AEs between group A and B. During median observation period of 40.5 months, no arterial thrombotic event or AE resulted in death occurred. Conclusions: Addition of bevacizumab did not increase TIVAPS related AEs during chemotherapy for mCRC.
A central review of resectability of optimally unresectable colorectal liver metastases following neoadjuvant chemotherapy (KSCC0802).
Authors: Takatsuki Mitsuhisa , Eguchi Susumu , Tokunaga Shoji , Emi Yasunori , Oki Eiji , Uchida Shinji , Sakoda Masahiko , Kakeji Yoshihiro , Shirabe Ken , Akagi Yoshito , Beppu Toru , Baba Hideo , Ueno Shinichi , Natsugoe Shoji , Ogata Yutaka , Maehara Yoshihiko ,   Kyushu Study Group of Clinical Cancer
Published: March 2020

e14633

Background: Kyushu Study group of Clinical Cancer (KSCC) conducted the phase II study that evaluated the neoadjuvant chemotherapy for optimally-unresectable colorectal liver-limited metastases (KSCC0802, Samura et al, J Clin Oncol 30:4s, 2012). We carried out a central review for the purpose of obtaining an objective assessment of how resectability changed during treatment. Methods: We reviewed the CT or MRI images before and after protocol treatment, according to the method of CELIM study. A surgical review was done by five independent hepatobiliary special surgeons from five different centers. A resectability was reviewed based on radiological images only. Individual surgeons were blinded to the time when the CT scan was taken. The surgeons voted for (1) curative resection, (2) exploratory laparotomy with aim of resection (3) borderline resectable with chemotherapy preferred first, (4) unresectable, (5) non-evaluable. Patients were considered resectable if 50% (non-evaluable is excluded) or more of surgeons voted for categories (1) and (2), and images were considered evaluable if more than three surgeons voted with categories (1)–(4). Results: In KSCC0802 study, of the 40 pts. enrolled from Sept. 9 2008 to Aug. 10 2010. The number of cases to intent operation after chemotherapy was 17 (42.5%), and the actual liver resectability was 16/40 (40.0 %). The number of R0 cases was 10 pts. . In total, 77 images were presented for this central review. Only three follow-up scans were not available. Following review, 17 (42.5%) of 40 patients were judged to be resectable after chemotherapy, compared with 14 (35.0%) patients at baseline. Of 36 cases in which both imaging studies were available to be evaluated before and after chemotherapy, 7 cases (19.4%) judged as unresectable before chemotherapy were finally determined as resectable after chemothrerapy. Conclusions: With the central review by 5 independent liver surgeons, the resectability was fairly determined before and after chemotherapy. mFOLFOX6 with Bevacizumab regimen is safe and effective for unresectable liver limited-metastases from colorectal cancer, and might be to lead the liver resectability. Clinical trial information: UMIN000001308.
Preclinical model for combined effects of metformin and vitamin D3 on colitis-associated colon neoplasia.
Authors: Li Wan , Wang Qi-Long , Li Hong-Xia , Li Chun-Yang , Berger Nathan A. , Li Li , Wu Yongjie
Published: March 2020

e14634

Background: Metformin and vitamin D each has been shown to have anti-colon carcinogenic effects in pre-clinical and epidemiologic studies. We tested the potential synergistic effects of Metformin and vitamin D3 against colorectal neoplasia in a DMH-DSS induced colitis-associated colon neoplasia mouse model. Methods: We randomized 182 5-week old ICR male mice into 7 groups: 1) normal controls; 2) DMH controls; 3) DSS controls; 4) DMH + DSS controls; 5) vitamin D3 (3 dosage groups), 6) metformin (3 dosage groups), and 7) vitamin D3 + metformin (3 dosage combinations). After 20 weeks of treatment, the mice were sacrificed and colon tissues were harvested and examined for multiplicity of adenoma/cancer, volume of each tumor, number and score of aberrant crypt foci (ACF). Results: Compared to the DMH + DDS controls, combination of vitamin D3 (200 IU/kg/day) and metformin (240 mg/kg/day) statistically significantly reduced the average number of adenoma/cancer per mouse formed (6.20 ± 3.68 vs. 2.20 ± 2.12, p<0.01), volume (mm3 ) of tumor (115.46 ± 107.32 vs. 31.05 ± 38.26, p< 0.05), number of ACF (0.46 ± 0.88 vs. 2.58 ± 1.93, p <0.01), and ACF score (5.00 ± 3.26 vs. 1.23 ± 2.04, p <0.01). Western blot and IHC show that vitamin D3 potentiates metformin in activating AMPK (phos-AMPK: 0.53 ± 0.01 vs. 0.70 ± 0.03, p < 0.01), inhibiting AKT (phos-AKT: 0.39 ± 0.10 vs. 0.15 ± 0.04, p < 0.01), S6P (phos-S6P: 0.36 ± 0.03 vs. 0.14 ± 0.04, p <0.01), cyclin D1 (0.24 ± 0.02 vs. 0.06 ± 0.02, p <0.01), ?-catenin (0.808 ± 0.142 vs. 0.010 ± 0.001, p < 0.01), and VDR (0.182 ± 0.045 vs. 0.488 ± 0.081). Combination treatment also statistically significantly increases serum levels of IGFBP-3, with little effect on IGF-1, IGFBP-1 or IL-1?. Conclusions: Metformin and vitamin D3 synergistically inhibit the development of colorectal neoplasia in a colitis-associated mouse colon carcinogenesis model. Further study of the underlying mechanisms is warranted.
Downstaging after preoperative chemoradiation as a prognostic marker for recurrence after curative surgery in locally advanced rectal cancer.
Authors: Lee Jieun , Lee Myung Ah , Kim Sang Woo , Kim Jun Ki , Oh Seong Taek , Kang Won Kyung , Jang HongSeok
Published: March 2020

e14650

Background: 5-fluorouracil (5-FU) based preoperative concurrent chemoradiation (CCRT) with surgery is the standard treatment for resectable rectal cancer. Chemotherapy after surgery improves local control, but there are some debates for the role in 5-FU based adjuvant chemotherapy. This study was aimed to analyze the tumor recurrence pattern in locally advanced rectal cancer, and the relationship between clinicopathologic factors with tumor recurrence. Methods: One hundred forty-nine patients with locally advanced rectal cancer, receiving preoperative 5-FU based CCRT (radiation dose: 5040 cGy) with total mesorectal excision (TME), followed by adjuvant 5-FU based chemotherapy were enrolled. Sex ratio was 95:54. Median age was 61 (range 37~83). Medical records were reviewed retrospectively. Clinicopathologic factors, oncologic outcomes (tumor recurrence, disease free survival (DFS)) were assessed. Results: Median follow-up duration was 25.3 months (range 5.2~66.2). Median DFS was 19.3 months (range 0~63.4). Thirty-five (23%) patients showed recurrence after surgery. Among tumor recurrence, 86% of patients were presented with distant metastases. Absence of T or N downstaging after 5-FU CCRT was significantly correlated with tumor recurrence (P=0.032 and P=0.011 by Fisher’s exact test, respectively) and longer DFS (P=0.003 and P<.001 by Kaplan-Meier survival curve, respectively). Lymphatic invasion, neural invasion after 5-FU CCRT showed correlation with recurrence (HR=6.37, 95% CI; 2.74-14.84, P<.001; HR=4.9, 95% CI; 1.85-12.97, P=0.002, respectively). In contrast, vascular invasion was not associated with tumor relapse after 5-FU CCRT followed by surgery. Conclusions: The absence of T or N downstaging, the presence of lymphatic or perineural invasion in pathology was associated with tumor recurrence. In spite of 5-FU based adjuvant chemotherapy, distant metastases were more prevalent. In patients with the possibility of distant metastases, more aggressive adjuvant chemotherapy-including platinum agents-should be considered.
Serum iron levels potential biomarker in FOLFOX/FOLFIRI with or without molecularly targeted drug therapy.
Authors: Ochiai Takumi , Nishimura Kazuhiko , Watanabe Tomoo , Kitajima Masayuki , Nakatani Akinori , Sato Tsuyoshi , Kishine Kennji , Okubo Satoshi , Futagawa Shunji , Nagaoka Isao
Published: March 2020

e14651

Background: We reported an increase in serum iron levels during therapy with FOLFOX or FOLFIRI ± molecularly targeted drugs and a correlation between prognosis and transition of those levels in advanced colorectal cancer (CRC) patients (ASCO; 2009: #e15110, 2011: #e14141, 2012: #e14004). The aims of this prospective cohort study were to establish serum iron levels as a new biomarker in advanced CRC patients undergoing therapy based on this correlation and investigate the mechanism of this increase in serum iron levels. Methods: Eighty-one advanced CRC patients were treated; all died between Dec. 2005 and Nov. 2012; none received radiotherapy; 9 of these patients were undergoing treatment between Sep. 2012 and Nov. 2012. Serum iron levels were measured at before and 48 hr after treatment. Taking the median rate of increase in serum iron levels as the cut-off value in each therapy, the patients were categorized into cohort I (increase rate over cut-off value in at least one therapy) or cohort II (increase rate under cut-off value in all therapies). Prognosis was evaluated between the two. Hepcidin (Hepc), Interleukin-6 (IL-6) and soluble transferrin receptor (sTfR) were measured at before and 48 hr after treatment. Results: No significant bias in patient characteristics (including in frequency or type of regimen) was observed between the two cohorts. Serum iron levels transiently increased after treatment (p<0.001), then returning to baseline within 2 weeks. Median survival time (MST) in cohort I (n: 50) and cohort II (n: 31) was 437 and 378 days, respectively, with MST significantly better in cohort I (p=0.0417). Multivariate analysis identified Dukes’ stage, recurrence type, and serum iron level as independent risk factors for overall survival (OS). Hepc significantly increased after treatment (p<0.001), with no significant change in IL-6 or sTfR. Conclusions: Serum iron levels offer potential as an extremely useful and convenient biomarker for OS in CRC patients. While Hepc significantly increased, no significant decrease was observed in sTfR after treatment. This suggests that serum iron levels increased as a result of a treatment-induced reduction in iron consumption by bone marrow.
Benefit-risk evaluation of ziv-aflibercept in combination with irinotecan-fluoropyrimidine-based chemotherapy (FOLFIRI) from the VELOUR trial using multicriteria decision analysis (MCDA).
Authors: Macarulla Teresa , Wu Jasmanda , Phillips Larry , Iqbal Sheikh Usman , Kripas Chris , Gu Zheng , Freedman Amy , Bhargava Pankaj , Van Cutsem Eric
Published: March 2020

e14656

Background: In the VELOUR trial, in metastatic colorectal cancer (mCRC) patients, ziv-aflibercept (Afl) combined with FOLFIRI demonstrated significant improvements in median overall survival (OS) by 1.44 mos and median progression-free survival (PFS) by 2.23 mos when compared with FOLFIRI + placebo. We utilized a systematic approach to evaluate the benefit/risk profile of the regimen in the target disease population. Objectives: To evaluate favorable and unfavorable effects of Afl in combination with FOLFIRI in patients with mCRC previously treated with an oxaliplatin-based regimen using the MCDA method. Methods: Data from VELOUR were used to compare the 2 treatment arms (Afl + FOLFIRI vs placebo + FOLFIRI). An 8-step process based on the MCDA was used to construct a value tree that displayed evaluation criteria for favorable and unfavorable effects, determined score, assigned weight for each criteria, and then combined weights and scores for each treatment arm to derive an overall value. Sensitivity analysis was also conducted. Results: The final value tree comparing the 2 treatment arms had 2 branches representing favorable and unfavorable effects. Favorable effects criteria included survival probability at 12, 18, and 24 mos, median OS, median PFS, and overall response rate. Unfavorable effects criteria included 11 anti-VEGF- and FOLFIRI-associated adverse events (AEs), as well as deaths and treatment discontinuation due to AEs. The survival rate at 24 mos had the highest weight (100), followed by median OS (95). For unfavorable effects, diarrhea had the highest weight (15), followed by arterial thromboembolism (ATE) (12). AEs seen with Afl + FOLFIRI were generally manageable; their clinical impact did not outweigh the benefits. The overall value combining favorable and unfavorable effects for Afl + FOLFIRI was 53 vs 40 for placebo + FOLFIRI. Conclusions: Results from this quantitative benefit-risk analysis indicate that the benefit-risk balance for ziv-aflibercept in combination with FOLFIRI is favorable compared with FOLFIRI alone in adults with mCRC previously treated with an oxaliplatin-based regimen. Clinical trial information: NCT00561470.
Leucovorin shortage: Impact on leucovorin/levoleucovorin usage and tx choices in colon cancer patients treated in the United States.
Authors: Katler Ann , Wang Zhaohui , Bergstrom Kimberly A.
Published: March 2020

e14668

Background: 5FU + leucovorin (LV) containing regimens are the most commonly used regimens for colorectal cancer (CRC). A LV shortage in the U.S. beginning Apr 2010 became critical by fall 2011. In May ’11, levoleucovorin (LLV) was approved to treat CRC in the U.S. LV replacement by LLV incurs a 34 fold cost increase. This study examines if the LV shortage impacted colon cancer (CC) regimen selection and LV/LLV usage in the adjuvant and 1st line tx. Methods: Data obtained via web-based, drug dispensing technology was used to identify 3 groups of adult CC patients starting adjuvant or first-line tx within a 6 month period: Group 1 (Q2,Q3 2009), Group 2 (Q2,Q3 2010) and Group 3 (Q4, 2011 – Q1, 2012). Regimen selection and LV usage were examined from tx onset through completion. Results: Adjuvant and first-line tx administered by 545 practices across 47 states was examined and including 2,502 pts, 2,551 pts, and 2,689 pts in Groups 1, 2, and 3 respectively. The median pt age was 66. 77% of pts in each group received FOLFOX for adjuvant tx. Approx 7% of pts in Groups 1 and 2 received capecitabine-containing regimens compared to 9.9% in Group 3. 58% of pts in Group 1, 51% in Group 2 and 56% in Group 3 received mFOLFOX6 or mFOLFIRI + bevacizumab for first-line tx. Use of 5FU + LV or LLV-containing regimens remained constant in all 3 groups. The Table summarizes LV/LLV usage in LV-containing regimens planned for ’09 - Q1 of ‘12. Lower LV dosing and relative dose intensity (RDI), fewer LV administrations and increased LLV usage are seen for the time period reviewed. Conclusions: Based on data examined from 2009-Q1 2012, while no significant impact on regimen selection was observed, the LV shortage significantly decreased LV and raised LLV usage (and cost) in the adjuvant and first-line tx for colon cancer. [Table: see text]
Six years of experience in citoreductive surgery and the application of HIPEC-oxaliplatin.
Authors: Nikolic Srdjan , Zegarac Milan , Djurisic Igor , Martinovic Aleksandar , Kocic Milan , Tomasevic Zorica
Published: March 2020

e14676

Background: In this abstract we present six years of experience in citoreductive surgery and intraperitoneal chemotherapy (HIPEC) as treatment for patients with peritoneal carcinosis of colorectal carcinoma. Methods: In six years time 61 patient has been operated. Age distribution was from 27 to 76 and median age was 55. Male/female distribution was 18.13%/81.87%. All patients have been treated with intraperitoneal Oxaliplatin with dose of 410mg/m2 in 2 liters of perfusions. In 93.44% cases R0 resection was done and R1 in 3.28%. There was no patient with R2 resection. In 13.1% cases there was Grade I postoperative complication Adjuvant chemotherapy has been applied to 67.21% of operated patients and most had FOLFOX protocol. By the end of this research we still follow up 55,74 % of patients as 44.26% had lethal outcome. Results: Median (95% CI )overall survival(OS) was 51 month(22+ months) . Disease free survival (DFS) was 23 months (16+ months ) . One, two and six years OS was 78.6% ,58.7% and 50.5% One , two and six years DFS was 68.3%, 46.7% and 38.1%. The research has shown that factors such as patient age, sex, preoperative symptoms, synchronous and metachronous carcinosis had no statistically relevant influence on OS. There was statistic relevance in DFS for patients who developed peritoneal carcinosis within 12 months after primary tumor resection(p=0.03) Carcinosis node size has no statistical relevance on OS(p=0.24) and DFS(p=0.64). Involving of left subdiaphragmal region significantly reduces OS(p=0.0022) , but has no statistically relevant influence on DFS(p=0.49). Involving of left iliacal region was on boundary of statistical relevance on OS(p=0.05). Involving of right subdiaphragmal regions statistically significantly reduces OS(p=0.04) , and has no influence on DFS. Involving of small intestine has statistical relevance on OS(p=0.01) As the most important prognosis factor we highlight the peritoneal cancer index (PCI). Patients with PCI less then 13 have statistically better OS (p<0.01) and also statistically better DFS (p<0.05). Conclusions: Our results show that citoreductive surgery followed up by HIPEC with Oxaliplatin should always be considered for patients with colorectal cancer carcinosis.
The impact of multidisciplinary cancer conferences (MCC) on the treatment of metastatic rectal cancer (MRC) at the Ottawa Hospital Cancer Centre (TOHCC).
Authors: Di Valentin Tanya , Asmis Timothy R. , Auer Rebecca Ann C.
Published: March 2020

e14686

Background: There is significant controversy surrounding the management of surgically resectable MRC. The use and timing of neoadjuvant chemotherapy, pelvic radiation, and relative risks and benefits of a combined surgical resection are areas of debate among surgeons, medical, and radiation oncologists. The TOHCC multidisciplinary Cancer Conferences (MCC) provide an opportunity to discuss these cases and propose treatment plans for these patients. Methods: We conducted a retrospective chart review of all the cases of MRC which were discussed at MCC at the TOHCC from November 2007 until October 2009. Information collected included patient demographics, site of metastases, the treatment they received prior to their case being discussed at MCC (past surgeries, chemotherapy, radiotherapy), the treatment plan discussed at MCC, treatment actually administered post MCC discussion, and patient outcome at 6 months. Results: Forty-two patients with MRC were reviewed. The most common sites of metastases were liver (45.2%) and lung (31%). Once diagnosed with metastatic disease, prior to the MCC, patients had received the following treatments alone or in combination: chemotherapy (33.3%), radiotherapy (21.4%), surgery (19.0%), no treatment (n=57.1%). After their case was presented, 38 patients (90.5%) received the treatment recommended at the MCC , while 4 (9.5%) did not. Treatment post MCC included: chemotherapy (neoadjuvant: 38.1%; adjuvant: 23.8%; palliative: 28.6%), radiotherapy (neoadjuvant: 14.3%; adjuvant: 7.1%; palliative: 7.1%) and surgery (31.0%). Conclusions: There is no standardized approach to the management of MRC. Given its complexity, many cases are reviewed at MCC, which allow coordination for multidisciplinary care of these patients. The results of this study suggest that in a majority of cases, the recommendations brought forth at MCC are indeed acted upon. Given that these meetings have a significant impact on the treatment plan and outcome of patients with MRC, they should represent the standard of care when treating this disease.
Chemokine receptor CXCR4: What is its role in gastrointestinal cancer?
Authors: Lombardi Lucia
Published: March 2020

e14687

Background: Multiple metastasis is the predominant cause of colorectal cancer (CC) and pancreatic cancer (PC) related mortality. Chemokines receptors have been implicated in cancer metastatic process by directing the migration of tumour cells to sites of metastasis. However, their clinical relevance in gastrointestinal cancer has not been defined. The aim of our study was to evaluate the possible role of CXCR4 as prognostic factor in CC and PC. Methods: Quantitative determination of CXCR4 in serum samples were collected before and after surgery from 36 CC and 23 PC patients later treated with adjuvant (Ad) therapy or for metastatic (Meta) disease (19 Ad-and 17 Meta-CC; 15Ad-PC and 8 Meta-PC) and from 31 healthy controls (HC) enrolled as controls group, was performed by means of ELISA. Relative expression levels of CXCR4 in matched-pairs of tumour and adjacent normal tissue samples collected from the same 36 CC and 15 Ad-PC patients, were determined by means of qRT-PCR using the QuantiFast SYBR Green PCR kit. Results: Compared to HC, pre-operative CXCR4 serum levels were increased in both CC and PC patients. Post-operative serum levels were higher than those observed pre-operatively in 42% and 47% of patients with Ad- and Meta-CC, respectively. Conversely, in 53% and 50% of patients with Ad- and Meta-PC, CXCR4 serum levels decreased after surgical treatment. Furthermore, higher levels of CXCR4 were associated with advanced stages and in PC with lymph nodes involvement. In addition, CXCR4 was over-expressed in tumor compared to normal tissue in 42% and 41% of patients with Ad- and Meta-CC, and in 73% of patients with Ad-PC. In relation to clinical phenotype, all these patients had stage T3N1 disease in both disease. Conclusions: Our data showed that CXCR4 levels may be associated with tumor stage and disease progression in CC and PC patients. Further studies with larger samples size, might confirm the role for CXCR4 as prognostic factor and/or marker of patients’ response to therapy.
An overview of clinical and economic outcomes of U.S. veteran colorectal cancer patients.
Authors: Baser Onur , Fritschel Elyse , Li Lu , Zhang J , Wang Li
Published: March 2020

e14689

Background: Colorectal cancer is the second leading cause of cancer-related death in the United States. While studies have shown that conditions such as diabetes are associated with shorter disease-free survival in colon cancer patients, fewer U.S. Department of Veterans Affairs (VA)-specific studies have been conducted focusing on colorectal cancer outcomes (Centers for Disease Control and Prevention. Colorectal (colon) cancer. www.cdc.gov/cancer/colorectal. Extermann M. Interaction between comorbidity and cancer. Cancer Control. 2007; 14(1): 13-22). This study aimed to describe the comorbidity profile and economic outcomes of colorectal cancer patients in the VA population. Methods: A retrospective study of patients diagnosed with colorectal cancer during the study period of October 1, 2005 to September 30, 2010 was conducted using the Veterans Health Administration datasets. All colorectal cancer patients were identified using International Classification of Disease 9thRevision Clinical Modification (ICD-9-CM) diagnosis codes 153.xx and 154.xx. Descriptive statistics were calculated as means ± standard deviation (SD) and percentages using SAS version 9.3 software. Results: In diagnosed colorectal cancer patients (n=62,200), common comorbidities included hypertension (n=18,309, 29.44%) and diabetes (n=10,891, 17.51%). Other minor comorbidities included hyperlipidemia and benign neoplasm of the colon. The average Fecal Occult Blood Test result (found in 12.21% of colorectal cancer veterans) was 96.37. Outpatient services were utilized by 99.71% of colorectal cancer patients, followed by pharmacy (91.94%) and inpatient visits (31.15%). Costs for outpatient ($10,637, SD=$17,125), pharmacy ($2,704, SD=$9,773), and inpatient services ($16,032, SD=$53,078) contributed to follow-up health care expenditures. Conclusions: Despite frequent outpatient utilization, inpatient costs have the greatest impact on the considerable health care cost incurred by lung cancer veterans. The presence of comorbid conditions may further complicate colorectal cancer treatment, though further characterization requires further research.
Incidence and impact of K-ras mutation in colorectal cancer (CRC) in a minority population.
Authors: Dietz Donny , Braverman Albert S. , Axiotis Constantine A , Khillan Ratesh , Sidhu Gurinder Singh
Published: March 2020

e14690

Background: K-ras mutation in CRC is known to occur in around 40% of the general population. It implies a poor prognosis, and resistance to anti- EGFR monoclonal therapy. The incidence of Kras mutation in African American (AA) patients with CRC is not known. Methods: Records of patients treated for CRC at Kings County Hospital and Downstate Hospital; in Brooklyn from 2005-12 were reviewed. Results: Of 116 patients’ records, 90 were informative for presenting stage, K-ras expression or both; all but one were AA, and 60 of 90 (67%) were male. Their ages ranged from 36 to 86 (median 64) years. The stages at presentation were known in 76; 3% were stage I, 17% stage II, 35% stage III and 45% stage IV. Follow-up periods ranged from 14 to 2381 days (median 409). K-ras mutation analysis was performed by a single commercial laboratory in 68 patients who had, or were suspected of having advanced disease. Codons 12 and 13 in K-ras exon 2 were analyzed. Of these 68 patients 31 (45%) bore K-ras mutations. K-ras mutation status was known in 9 stage I and II pts, and 6 of 9 pts (67%) bore mutations. After 233-967 days follow-up (median 474) 8 of 9 patients were alive. The 3 pts with wild type K-ras were a median of 70 years of age, 67% were female, and all were alive at median of 266 days (range 239-122-) follow up. Of the 16 stage III patients whose K-ras was analyzed, 7 (44%) were mutated. These 7 pts were a median of 66 years of age, and 86% were male. After 398 days median follow up 57% had relapsed and 45% had died. The 9 stage III pts with wild type K-ras were a median of 70 years of age and 78% were male. After a median follow up of 600 days, 2 were relapse-free, 7 had relapsed and 6 had died. Of the 34 stage IV pts, K-ras was analyzed in 29 and mutated in 12 (41%). Of the mutated patients, 83% were female and the median age 57. Their median survival was 557 days (56-1627). The 17 pts with wild type K-ras were 67% female with a median age of 59. Their median survival was 711 days (25-2040). The presenting CEA levels were similar in wild type and mutated patients. Conclusions: The prevalence of K-ras mutations, and the better prognosis of wild type K-ras in advanced CRC in AA patients, is similar to that of the general American population. The relapse rate of stage 3 AA patients seems higher in both wild type and mutated pts.
Can PET CT predict response in locally advanced rectal cancer patients treated with induction FOLFOX?
Authors: Gunduz Seyda , Coskun Hasan Senol , Goksu Sema Sezgin , Arslan Deniz , Tatli Ali Murat , Uysal Mukremin , Savas Burhan , Ozdogan Mustafa
Published: March 2020

e14696

Background: The aim of this study was to determine the pathological complete response rates in a group of locally advanced rectal cancer patients who underwent chemoradiotherapy after treatment with induction FOLFOX chemotherapy and the relationship between the complete response and Positron emission tomography - computed tomography (PET-CT). Methods: The files of 239 patients who were diagnosed with rectal cancer between January 2008 and January 2012 were evaluated retrospectively. Of these, there were 24 locally advanced rectal cancer patients who met the following criteria: they were administered chemoradiotherapy after receiving four courses induction oxaliplatin, folinic acid and 5-Florouracil (FOLFOX) and they underwent PET-CT for staging and for the evaluation of their response to FOLFOX treatment. Of these 24 patients, 20 operable patients were included in the study. Results: The pathological complete response was obtained in 7 patients (35%) who were operated on, and then given induction four courses FOLFOX chemotherapy and chemoradiotherapy. We determined that age, gender, clinical stage at diagnosis, and PET-CT before and after induction chemotherapy were not predictive of the pathological complete response to tumor fluorodeoxyglucose (FDG) uptake activity. Conclusions: The rates of pathological complete response were increased in locally advanced rectal cancer patients who underwent short-term induction chemotherapy. Although the PET-CT has retained its importance in predicting pathological complete response, there is still a need for studies with a larger number of patients and long-term follow-ups.
Intergroup randomized phase III study of postoperative irinotecan, 5-fluorouracil, and leucovorin versus oxaliplatin, 5-fluorouracil, and leucovorin versus 5-fluorouracil and leucovorin for patients with stage II or III rectal cancer receiving either preoperative radiation and 5-fluorouracil or postoperative radiation and 5-fluorouracil: ECOG E3201—An updated survival analysis.
Authors: Nimeiri Halla Sayed , Feng Yang , Catalano Paul J. , Meropol Neal J. , Giantonio Bruce J. , Sigurdson Elin R. , Martenson James A. , Whitehead Robert P. , Sinicrope Frank A. , Mayer Robert J. , O'Dwyer Peter J. , Benson Al Bowen ,   Eastern Cooperative Oncology Group
Published: March 2020

e14711

Background: Postoperative adjuvant chemotherapy has been historically limited to single agent 5FU in stage II/III rectal cancer pts. This phase III trial evaluated differences between pts treated with adjuvant FOLFOX versus FOLFIRI versus FU alone in stage II/III rectal cancer. Methods: Eligibility: resectable (T3-4 N0,Tany N1-3) adenocarcinoma rectum ≤12cm from anal verge. Pts had the option to receive FU with pre or postoperative XRT (50.4Gy). Preoperative FU/XRT pts were randomized to adjuvant FOLFIRI (arm A), FOLFOX (arm B), FU/LV(arm C). Postoperative FU/XRT pts were randomized to adjuvant FOLFIRI (arm D), FOLFOX (arm E), FU/LV (arm F). Pts received 8 cycles. Overall survival (OS) was the primary endpoint. Secondary endpoints included toxicity, sphincter preservation and patterns of failure. Results: 225pts out of planned 3150 were enrolled (10/03 to 10/05). Data Monitoring Committee closed E3201 when the GI Intergroup developed an alternative trial with bevacizumab (E5204). 179 pts were randomized; (A:28, B:25, C:30, D:31, E:33, F:32). There was increased grade 3/4 toxicity, mainly diarrhea,in postoperative FU/XRT arms (D:39%), (E:28%), (F:48%). Twenty-two (12%) pts did not receive adjuvant therapy. At a median follow up of 7.4yrs, the five-year recurrence free rate was 69%. Median OS was 8.3 yrs. There was no statistical difference in OS between all randomized groups. Five-year OS in arms (A:B:C:D:E:F) were (73%, 83%, 83%, 73%, 78%, 73%) respectively. Conclusions: FOLFOX can be safely administered to rectal cancer pts following chemo radiation. Given limitations of early trial closure and small sample size, there was no difference in OS between pts who received FU alone, oxaliplatin based or irinotecan based adjuvant therapy. Clinical trial information: NCT00068692.
Preoperative chemoradiotherapy (QT-RT) with capecitabine and oxaliplatin (CAPOX) or capecitabine alone (CAP) in patients (PTS) with locally advanced rectal cancer (LARC).
Authors: Marrodan Ines , Rubio Itziar , Buque Aitziber , Sancho Aintzane , Fuente Natalia , Carrera Sergio , Arruti Mikel , Mane Joan Manel , Gutierrez Eddy Isabel , Iruarrizaga Eluska , Azkona Eider , Lopez-Vivanco Guillermo
Published: March 2020

e14712

Background: Preoperative concomitant QT-RT has shown to improve sphincter preservation and local control in LARC. We analyzed two cohorts of pts diagnosed of LARC treated with QT-RT with CAP or CAPOX. Methods: Pts with LARC (T3-T4 and/or N+) were treated with pelvic radiotherapy (45Gy in 25 fractions) concomitant with oxaliplatin (50mg/m2 day 1, 8, 22 and 29) and capecitabine (1650mg/m2 on days 1 to 14 and 22 to 35) or CAP (825mg/m2 bid for 5 days/week). Surgery was scheduled 6 weeks after completion QT-RT. Main end points assessed were: toxicity of preoperative chemotherapy, rate of sphincter preservation, pathological complete response (pCR) rate, and progression-free survival (PFS). Results: From Aug 2002 to Nov 2012, 254 pts with LARC were included; 53 pts received preoperative chemotherapy with CAP (cohort A) and 201 pts with CAPOX (cohort B). Median age: 65. Pts characteristics in cohort A: ECOG 0/1/2: 13/35/5; upper/mid/distal rectum 5/25/23; stage II/III 10/43. Pts characteristics in cohort B: ECOG 0/1/2: 48/149/4; upper/mid/distal rectum 29/105/67; stage II/III 27/174. 51 pts in cohort A (96.2%) and 192 (95%) in cohort B received full dose of preoperative QT-RT. Main toxicities in cohort A were diarrhea grade 2/3: 2/3 and neutropenia grade 2/3: 1/0; in cohort B were diarrhea grade 2/3: 42/24, neutropenia grade 2/3: 2/1 and neurotoxicity grade 1/2: 94/7. Surgery: 53 pts (100%) in cohort A and 198 pts (98.5%) in cohort B. Sphincter preservation and R0 resections were achieved in 58% pts and 98% pts respectively in cohort A, and 62% pts and 91.5% pts in cohort B. pCR was achieved in 11% pts in cohort A and 17% pts in cohort B. 3-year PFS and overall survival were 62% and 82% respectively in cohort A, and 75% and 83% in cohort B. Adding oxaliplatin in pts cT4/N- or N+ does not improve PFS (p=0.73). Downstaging in cohort A and B was achieved in 69.8% pts and 65% pts respectively. Conclusions: Combination QT-RT based in CAP or CAPOX is a well tolerated regimen and achieved encouring rates of pCR, R0 resection, sphincter preservation and tumor downstaging without differences in PFS in high risk pts with LARC.
Incidence and risk of hand foot skin reaction (HFSR) in patients receiving regorafenib for cancer: A meta-analysis.
Authors: Belum Viswanath Reddy , Wu Shenhong , Lacouture Mario E.
Published: March 2020

e14713

Background: Regorafenib (BAY 73-4506) is a potent oral multi-kinase inhibitor with targeted activity against (VEGFR) -1,-2, and -3, TIE-2, FGFR-1, PDGFR-α/β and ret, c-Kit, raf-1 kinases. Currently it is approved for treatment in previously treated patients with metastatic colorectal cancer (mCRC) and in locally advanced gastrointestinal stromal tumors (GIST), and is being explored in other cancers. We conducted a meta-analysis to ascertain the incidence and risk of HFSR, a commonly reported AE. Methods: Our search was performed on electronic databases (PubMed, Scopus, Web of Knowledge) and the ASCO website for presented abstracts. We searched for studies published until December 2012. Eligible Phase II-III clinical trials utilizing a 160mg dose of Regorafenib were included in the analysis. Relative risk (RR), and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Results: In these trials, regorafenib was investigated in mCRC, gastrointestinal stromal tumor (GIST), and renal cell carcinoma (RCC). A total of 1,078 patients were analyzed. The overall incidence of all-grade and high-grade HFSR was 60.5% (95% CI: 48.3–71.6%) and 20.4% (95% CI: 15.4–26.6%), respectively. The relative risks of all-grade and high-grade HFSR to regorafenib monotherapy in comparison with controls were increased for all-grade (RR=5.40, 95% CI: 3.76-7.76, p<0.001) and high-grade (RR=41.99, 95% CI: 5.88–299.93, p<0.001) HFSR. The incidence of the HFSR based on tumor type was 62.9% (95% CI: 46.9–76.5%) for mCRC, 69.5% (95% CI: 29.7–92.5%) for GIST and 46.6% (95% CI: 42.3–51.0%) for RCC, which was not very significant (p=0.08) suggesting that tumor type does not seem to influence the incidence of HFSR in patients treated with regorafenib. Conclusions: The incidence and risk of developing HFSR is highest with regorafenib, when compared to other multikinase inhibitors (e.g. sorafenib, sunitinib, pazopanib, axitinib). This toxicity warrants further investigation and evidence-based management strategies, in order to ensure adherence and most favorable clinical outcome.
Efficacy and safety of single agent (SA) or combination (CO) adjuvant chemotherapy (AC) in elderly patients with colon cancer: A Canadian Cancer Institute experience.
Authors: Kim Christina , Spratlin Jennifer L. , Ghosh Sunita , Armstrong Dawn Elizabeth , Mulder Karen E.
Published: March 2020

e14715

Background: AC for colon cancer is recommended in the fit elderly. The pattern of AC use in elderly patients (pts), the toxicity profile, and survival benefit is unclear. We sought to: 1) determine whether patients ≥65 years old with stage III colon cancer were being offered SA or CO AC; 2) evaluate the reason for selecting SA vs. CO AC; 3) evaluate the toxicity profile of SA and CO in the elderly; and 4) determine whether a survival benefit exists for elderly pts receiving CO AC. Methods: Pts ≥65 diagnosed with stage III colon cancer at the Cross Cancer Institute from 2004-2010 were identified from the provincial cancer registry. A retrospective analysis of electronic and paper patient records was performed to identify baseline characteristics, AC protocols used, toxicity, dose reductions, dose delays and survival. Results: 258 pts ≥65 years old were diagnosed and treated with AC from 2004-2010. Of these, 168 were treated with SA and 90 with CO AC. The most common reasons for choosing SA AC were patient preference (64%), comorbidities (17%), and lack of drug coverage by provincial formulary (16%). 93 pts ≥age 75 were treated with SA AC, whereas only 20 pts ≥75 were treated with CO AC. Grade 3 and 4 non-hematologic toxicity was more common with CO AC (43% vs. 27%). 20% of all pts had initial dose reductions, with most common reasons being age and comorbidities. 67%, 71% and 29% received dose delays, reductions or drug discontinuation in the SA group, respectively. 72%, 58% and 34% received dose delays, reductions or drug discontinuation in the CO group respectively. 76% of pts received ≥75% of the expected cumulative dose in the SA group, and 81% in the CO group. The 5 year overall survival (OS) of pts who received <75% of expected AC cycles was 63%, compared to 79% in those who received >75% of expected cycles. The 5 year OS was 73% in pts who received SA AC, compared to 84% in those who received CO AC. Conclusions: In elderly pts treated with AC for stage III colon cancer, SA AC is used more frequently than CO AC, based on age, comorbidities, and patient choice. Toxicity with CO AC in elderly pts is high, but may carry a potential a survival benefit for those who receive it.
A retrospective analysis of the role of gefitinib in the definitive management of esophageal/gastroesophageal junction (E/GEJ) cancer.
Authors: Sohal Davendra , Rice Thomas W. , Rybicki Lisa A. , Rodriguez Cristina P. , Videtic Gregory M. M. , Saxton Jerrold P. , Murthy Sudish C. , Mason David P. , Phillips Brooke Elizabeth , Tubbs Raymond R. , Plesec Thomas , McNamara Michael J. , Ives Denise I. , Bodmann Joanna , Adelstein David J.
Published: March 2020

e15000

Background: The role of epidermal growth factor receptor (EGFR) inhibition in resectable E/GEJ cancer is uncertain. We update and retrospectively compare results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery; the second study differing only by the addition of gefitinib (G) to the treatment regimen. Methods: Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma (ACA), with an endoscopic ultrasound stage of at least T3, N1, or M1a (AJCC 6th). Patients (pts) in both trials received 5-FU (1000mg/m2/d) and cisplatin (20mg/m2/d) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250mg/d, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Results: Clinical characteristics were similar between the 80 pts on the G trial (2003-2006) and the 93 pts on the no-G trial (1999-2003): median age (58 vs. 59 years), male gender (91% vs. 86%), ACA (94% vs. 83%), and HER2 positivity (28% vs. 18%). Minimum follow-up for all pts was 5 years. Multivariable Cox analyses comparing the G vs. no-G pts and adjusting for statistically significant covariates demonstrated improved overall survival (HR 0.62, 95% CI 0.44-0.88, p=0.008), relapse-free survival (RFS) (HR 0.59, 95% CI 0.41-0.84, p=0.003), and distant metastatic recurrence (HR 0.64, 95% CI 0.43-0.96, p=0.03), but not locoregional recurrence. Further subgroup analyses demonstrated improved RFS with G in pts not experiencing a pathologic response (HR=0.59, 95% CI 0.38-0.92, p=0.021), with T4 or M1a disease at surgery (HR=0.33, 95% CI 0.13-0.87, p=0.024), or with HER2-negative tumors (HR=0.65, 95% CI 0.42-0.99, p=0.048). Conclusions: Although this retrospective comparison can only be considered exploratory, it suggests that gefitinib may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer. Clinical benefit may be greatest in pts with a poor response to preoperative chemoradiation, and in those with HER2-negative tumors. Clinical trial information: NCT00258323.
Pharmacokinetic (PK)/pharmacodynamic (PD) results from a phase Ib study of pegylated hyaluronidase PH20 (PEGPH20) in combination with gemcitabine (Gem) in patients with pancreatic cancer.
Authors: Harris William Proctor , Hingorani Sunil R. , Beck Joseph Thaddeus , Berdov Boris A. , Wagner Stephanie Ann , Pshevlotsky Eduard M. , Tjulandin Sergei , Gladkov Oleg , Holcombe Randall F. , Jiang Ping , Maneval Daniel C. , Zhu Joy , Devoe Craig E.
Published: March 2020

e15005

Background: Enzymatic degradation of hyaluronan (HA) is a novel strategy to target the desmoplastic stroma of pancreatic cancer. PEGPH20, a pegylated form of recombinant human hyaluronidase PH20, is an investigational drug in clinical trials. Preclinical studies demonstrate that sustained HA removal by PEGPH20 inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. Ph1 PEGPH20 monotherapy studies show increased tumor perfusion by DCE-MRI, metabolic partial responses by FDG-PET, and stromal remodeling in tumor biopsies from selected advanced cancer patients (pts). Methods: This was a dose-escalation study to find the recommended Ph2 dose of PEGPH20 in combination with Gem in pts with Stage IV previously untreated pancreatic cancer. Pts received Gem at 1000 mg/m2 IV qwk for Wks 1-7 plus PEGPH20 at 1, 1.6, or 3 μg/kg IV twice a week for Wks 1-4 and qwk for Wks 5-7. Wk 8 was a rest week. Thereafter, PEGPH20 + Gem were given qwk for 3 wks in 4-wk cycles. Serial plasma samples were collected and hyaluronidase activity measured by an ultrasensitive assay to assess PEGPH20 exposure. Plasma HA catabolites were measured by quantitative HPLC to assess PD. Results: 28 pts were enrolled. Plasma PEGPH20 concentrations were proportional to dose, and kinetics were well-characterized by a 2-compartment PK model. Estimates for clearance (0.5-2 mL/hr/kg) were consistent with long t1/2 (1-2 days) previously seen with single-dose PEGPH20 monotherapy. Wks 1 and 4 PK profiles were similar, suggesting no changes to PEGPH20 clearance mechanisms after multiple doses or effects of Gem on PEGPH20 exposure. Most pretreatment plasma HA levels were <1 μg/mL and increased in a time- and dose-dependent manner after dosing. Circulating HA concentration was >500 µg/mL in several pts given 3 μg/kg PEGPH20. Conclusions: PEGPH20 plasma levels can be predicted using a linear PK model and circulating HA catabolites can be used as a quantitative measure of PEGPH20 PD. Results are consistent with the mechanism of action of hyaluronidase and support further study of PEGPH20 with anticancer agents. Clinical trial information: NCT01453153.
Multivariate analysis of prognostic factors in cancer of unknown primary (CUP) patients treated with site-specific therapy based on the 92-gene cancer classifier.
Authors: Schnabel Catherine A. , Zhang Yi , Hainsworth John D. , Spigel David R. , Greco F Anthony , Erlander Mark G.
Published: March 2020

e15006

Background: Results from a single arm prospective study demonstrated overall survival of 12.5m in 194 patients that received first-line therapy directed by tumor classification using the 92-gene assay (JCO, 31:217-23). When the molecular assay predicted tumor types that were clinically more responsive, median survival was significantly improved when compared with predictions of more resistant tumors (13.4 v 7.6 m; p= 0.04).In this analysis, the survival benefit of assay-directed therapy was further evaluated after adjusting for pre-treatment prognostic factors. Methods: Cox proportional hazards regression was used to examine survival benefit of responsive tumor types (n=115) vs resistant tumor types (n=79) predicted by the molecular assay, after controlling for traditional prognostic factors. Results: Univariate Cox regression analysis (n=194) showed that ECOG status, responsive vs resistant tumor type, and assay probability were each significant prognostic factors. In multivariate analyses, the prognostic value of only ECOG status and the assay prediction of responsive vs resistant tumor type were maintained. Conclusions: These data demonstrate that the 92-gene assay results remained a significant independent variable affecting survival outcome in these patients after adjustment for prognostic heterogeneity, and provide further support of assay accuracy in molecular classification of CUP. Clinical trial information: NCT00737243. [Table: see text]