bluuebunny/crossref_metadata_2025 huggingface dataset:
Systemic chemotherapy (CT) as salvage treatment for locally advanced rectal cancer (LARC) patients (pts) who fail to respond to neoadjuvant chemoradiotherapy (CRT).
Authors: Sclafani Francesco , Brown Gina , Cunningham David , Rao Sheela , Tekkis Paris P , Tait Diana M. , Morano Federica , Baratelli Chiara , Kalaitzaki Eleftheria , Rasheed Shahnawaz , Watkins David J. , Starling Naureen , Wotherspoon Andrew , Chau Ian
Published: March 2017

709

Background: International guidelines suggest that RT dose escalation, intraoperative RT or brachytherapy could be considered for LARC pts with positive resection margins, pT4 or unresectable tumours after standard neoadjuvant CRT. However, data to support these approaches are scarce. The potential of systemic CT as salvage treatment after failure of neoadjuvant CRT for LARC has never been explored. We conducted a single-centre, retrospective analysis to address this question. Methods: Pts with newly diagnosed rectal adenocarcinoma who were deemed inoperable or candidates for extensive (i.e. beyond total mesorectal excision, TME) surgery after completion of long-course RT and received salvage systemic CT were included. The primary objective was to estimate the proportion of pts who became potentially suitable for TME after CT. Secondary objectives included the proportion of pts who ultimately underwent TME and survival outcomes. Results: 45 pts (2001-2015) met the study inclusion criteria (39 candidates for extensive surgery and 6 with unresectable tumours). Previous RT was given concurrently with CT in 43 cases (median dose: 54.0 Gy; range: 34.0-55.8). Salvage oxaliplatin-based and irinotecan-based CT was administered in 40 (88.9%) and 5 (11.1%) cases, respectively. 8 pts (17.8%) became suitable for TME based on the MRI after CT, 10 (22.2%) ultimately underwent TME with clear margins and 2 (4.4%) were managed with a watch & wait approach following radiological clinical complete response. Additionally, 13 pts had a beyond-TME surgery with curative intent. 3-year progression-free survival and 5-year overall survival in the entire population were 30.0% (95% CI: 15.0-46.0) and 44.0% (95% CI: 26.0-61.0), respectively. For the curatively resected and watch & wait pts these figures were 52.0% (95% CI: 27.0-73.0) and 67.0% (95% CI: 40.0-84.0), respectively. Conclusions: Systemic CT may be an effective salvage strategy for LARC pts who fail to respond to long-course CRT and are inoperable or candidates for beyond-TME surgery. According to our study, 1 out of 4 pts may become resectable or being spared from an extensive surgery after systemic CT.
Primary tumor location as a prognostic and predictive factor in metastatic colorectal cancer (mCRC) treated with chemotherapy plus cetuximab: A retrospective analysis.
Authors: Sagawa Tamotsu , Hamaguchi Kyoko , Sakurada Akira , Tamura Fumito , Hayashi Tsuyoshi , Fujikawa Koshi , Takahashi Yasuo , Sato Yasushi
Published: March 2017

711

Background: Left- and right-sided colon cancers are significantly different in epidemiologic, clinicopathological and molecular characteristics. However, the impact of primary tumor location in mCRC treated biological targeted agent in combination with chemotherapy is unclear. We therefore investigated the prognostic and predictive impact of primary tumor location in mCRC. Methods: Single-institution, retrospective, case-control study was reviewed. A total of 96 patients with mCRC were enrolled between January 2011 and December 2015. We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy plus cetuximab or bevacizumab. The impact of primary tumor location for cetuximab and bevacizumab groups was analyzed, respectively. Left-sided primary tumors were defined as tumors from rectum to splenic flexure, while right-sided primary tumors were defined as tumors from cecum to the distal part of the transverse colon. Results: 68 patients presented left-sided tumors and 28 patients right-sided primary tumors. In the cetuximab group, left-sided tumors were significantly superior to right-sided tumors in terms of the progression-free survival (PFS) and Overall survival (OS) (PFS, left vs right, 18.3 vs 6.8 M, p = 0.0415; OS, 50.6 vs10.5 M, p = 0.0004). Likewise, in the bevacizumab group, OS showed differences between the left- and right-sided tumors (PFS, left vs right, 11.6 vs 7.3 M, p = 0.1904; OS, 25.7 vs 16.2 M, p = 0.0389). In left-sided tumors, cetuximab group were significantly superior to bevacizumab group in terms of the OS (PFS, cetuximab vs bevacizumab, 18.0 vs 11.6 M, p = 0.1088; OS, 50.6 vs 25.7 m p = 0.0354). Conversely, in right-sided, the survival times showed no differences between cetuximab- and bevacizumab group (PFS, cetuximab vs bevacizumab, 6.8 vs 7.3 M, p = 0.7816; OS, 10.5 vs 16.2 M, p = 0.1088). Conclusions: Our study demonstrates that primary tumor location is an important prognostic factor in previously untreated mCRC. Furthermore, left-sided primary tumor location might be a strong predictor of PFS and OS in cetuximab therapy.
Effect of number of prior lines versus prior regimens in pts receiving trifluridine/tipiracil (TAS-102).
Authors: Van Cutsem Eric , Ohtsu Atsushi , Leger Catherine , Amellal Nadia , Poirot Camille , Fougeray Ronan , Mayer Robert J.
Published: March 2017

720

Background: RECOURSE showed that treatment with trifluridine/tipiracil in patients (pts) with refractory metastatic colorectal cancer was associated with significantly improved overall survival (OS) versus placebo. Pts were classified in this analysis according to number of prior regimens of anticancer therapy, i.e. regardless of treatment duration or occurrence of progressive disease (PD). Classification by prior lines of treatment may provide a better appreciation of prognosis than prior regimens. Methods: We performed a post hoc analysis of the RECOURSE population to explore the effect of number of prior lines of treatment vs prior regimens on OS in metastatic disease. We analysed individual pt data (n = 800) and reclassified pts on the basis of prior lines of treatment (< 3, 3, and > 3). In our analysis, a line of treatment ended with clinical or radiological PD. Adjuvant treatments counted as a line if the pt had had PD within 6 months after the end of treatment. If there was a delay > 6 months between 2 regimens, they could still count as 1 line. Treatments stopped due to toxicity were not considered as a line (since they were not stopped due to PD). Results: When the RECOURSE population was divided by prior lines, there were 170/83 trifluridine-tipiracil/placebo pts receiving < 3 lines of treatment, 174/72 receiving 3 lines, and 190/111 receiving > 3 lines. By contrast, there were 95/45 pts receiving < 3 regimens, 119/54 receiving 3 regimens, and 320/167 receiving > 3 regimens. Conclusions: Clinically, it appears that patients with 1 or 2 prior lines of anticancer therapy (with PD between lines) are different from patients with 1 or 2 prior regimens (which may have been within the same line of treatment). Analyzing the RECOURSE results according to prior lines of treatment provides a more homogeneous classification than prior regimens (smaller CIs) with lower HRs for OS. Clinical trial information: NCT01607957. [Table: see text]
A phase II study of panitumumab with FOLFOX or FOLFIRI as first-line chemotherapy for KRAS-wild type metastatic colorectal cancer: The PaFF-J study.
Authors: Shinozaki Eiji , Ishiguro Megumi , Nakatani Eiji , Yamaguchi Tatsuro , Nakamura Masato , Miyamoto Yuji , Ojima Hitoshi , Honma Yoshitaka , Gotoh Masahiro , Ishikawa Toshiaki , Takahashi Keiichi , Shimada Yasuhiro , Yoshida Kazuhiro , Mizunuma Nobuyuki , Muro Kei , Komatsu Yoshito , Yamaguchi Kensei , Nakano Hiroshi , Koike Junki , Sugihara Kenichi ,   PaFF-J Study Group
Published: March 2017

722

Background: For the patients with unresectable metastatic colorectal cancer (mCRC), response to the1st line chemotherapy has strong impact on their prognosis. Shrinkage of tumors may result in conversion to surgical resection and, concurrently, improved their survival. We conducted a multicenter phase II trial to investigate the efficacy and safety of panitumumab (Pmab) with chemotherapy as the 1st line treatment in Japanese patients with mCRC. Methods: Patients with no prior chemotherapy for unresectable, KRAS wild type mCRC, 20-80 years, and PS 0-1 were arbitrarily received either FOLFOX + Pmab or FOLFIRI + Pmab. Patients were evaluated every 8 weeks until progression. The primary endpoint was overall response rate (ORR), the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), R0 resection rate, and safety. Results: A total of 162 patients (140 with FOLFOX + Pmab and 22 with FOLFIRI + Pmab) were analyzed. Median follow-up was 28.2 months, median age at enrollment was 64.5 years, and 17.9% of the patients was recurrent disease. Number of target organ was 1 in 35.2%, 2 in 40.7%, and ≥ 3 in 24.1% of the subjects. Median administered cycle was 7, and median treatment duration was 16 weeks. ORR was 51.2% (95%CI: 43.3-59.2), and DCR was 82.1% (95%CI: 75.3-87.7). ≥ 30% tumor shrinkage (PR-in) was observed in 115 patients (71.0%). Median time to PR-in and maximum shrinkage was 10 and 16 weeks, respectively. Surgical resection was done in 66 patients (40.7%), of which R0 was in 43 patients; R0 resection rate was 26.5% (95%CI: 19.9-34.0). Median PFS and OS was 9.2 (95%CI: 7.2-11.4) and 33.8 months (95%CI: 29.4-43.1), respectively. ≥ Grade 3 adverse events with > 5% incidence were neutropenia (31.8%), stomatitis (10.5%), rash acneiform (9.9%), paronychia (9.3%), anorexia (8.6%), and diarrhea (6.2%). Conclusions: In our study, OS was favorable with high R0 resection rate, whereas ORR, DCR, PFS and toxicities were similar to those in previously reported studies. Because the maximum tumor shrinkage was observed around 16 weeks, optimal timing for considering conversion surgery might be 16 weeks from the start of treatment. Clinical trial information: UMIN000004991.
Representation of peritoneal metastases in published clinical trials of metastatic colorectal cancer.
Authors: Tseng Jennifer , Bryan Darren S , Poli Elizabeth , Sharma Manish , Polite Blase N. , Turaga Kiran
Published: March 2017

725

Background: Peritoneal metastases occur in 6-15% of patients with metastatic colorectal cancer. Non-invasive detection of peritoneal metastases is difficult given limitations in discrimination of cross sectional imaging. We hypothesized that patients with peritoneal metastases are underrepresented in clinical trials. Methods: Randomized controlled trials of systemic chemotherapy for metastatic colorectal cancer between 2003-16 were included after a PubMed search. Articles were restricted to those published in leading oncology journals and with ≥100 patients (total). Protocol designs were hand searched to identify whether clinical trials explicitly included or reported on patients with peritoneal metastases. Results: Of 72 clinical trials identified, 7 (10%) studies specifically reported inclusion of peritoneal disease (Table 1). Of 45,783 patients enrolled in all trials, 670 patients (1.5%) specifically had peritoneal metastases. Response for peritoneal disease was measured using Response Evaluation Criteria in Solid Tumors (RECIST) criteria in 6 (of 7, 86%) and modified World Health Organization (WHO) criteria in 1 but not reported in the final manuscript or supplementary material. Peritoneal specific outcomes were not reported in any study. No studies included metastatic colorectal cancer patients with peritoneal metastases alone. Conclusions: Patients with peritoneal metastases are underrepresented in published clinical trials. Specific efforts to include patients, measure burden of disease and response to therapy and report peritoneal specific outcomes are essential to draw generalizable inferences. [Table: see text]
Utilization of primary chemoradiotherapy for anal squamous cell carcinoma in the elderly: An analysis of the NCDB.
Authors: Motz Benjamin Mitchell , Lorimer Patrick Daniel , Walsh Kendall K , Perry I'sis N , Boselli Danielle , White Richard L. , Salo Jonathan C. , Hill Joshua S.
Published: March 2017

726

Background: Definitive chemoradiotherapy (CHEMORT) is the treatment of choice for anal squamous cell carcinoma (SCC), while surgery is typically reserved for salvage therapy. Patients (pts) who are frail due to advanced age or medical comorbidities often have difficulty completing therapy. Methods: The NCDB was queried for pts with anal SCC (2004-2012). Pts < 50 years, and those with in situ or metastatic disease, or with incomplete CHEMORT treatment data were excluded. The primary outcome was completion of CHEMORT. Secondary outcome was requirement of salvage surgical therapy. Statistical analyses include Chi-square, univariate and multivariable logistic regression. Results: N = 11918. 5907 (49.5%) did not complete recommended CHEMORT. 9862 (82.8%) received CHEMO, 6011 (61.0%) of whom completed RT with dosage > 45Gy. Factors significantly associated with failure to complete therapy on multivariable analysis include: older age at diagnosis, higher Charlson-Deyo score, earlier year of diagnosis, male gender, and earlier clinical T and N stages (Table 1). 41.7% of pts who did not complete CHEMORT required salvage surgical therapy, versus 25.1% of pts completing CHEMORT (OR: 2.14 95% CI [1.97, 2.31], p < 0.01). Conclusions: Approximately half of pts older than 50 years of age with anal SCC failed to complete definitive CHEMORT. This study highlights the negative impact of frailty on the ability of pts to receive optimal therapy, resulting in more operative interventions. Medical optimization of older pts with more comorbidities in order to improve utilization of CHEMORT is one possible area of improvement in the management of anal SCC. [Table: see text]
Ten-year survival data following resection of locally recurrent rectal cancer (LRRC).
Authors: Cyr David Patrick , Zih Francis Si Wai , Swett-Cosentino Jossie , Luu Shelly , Wells Bryan J , Burkes Ronald L. , Cummings Bernard , Esmail Faryal , Smith Andrew J , Swallow Carol Jane
Published: March 2017

730

Background: The ‘Beyond TME’ Collaborative identified LRRC as a complex problem requiring multidisciplinary consultation and specialized surgical care. Aggressive en bloc resection of LRRC at specialized cancer centers is associated with 5y survival rates of 25-50%. However, skepticism persists that LRRC can be cured given the lack of published longer-term survival data. We investigated the oncologic outcomes at 10y following resection of LRRC and sought relevant clinicopathologic prognostic variables. Methods: The study cohort consists of 52 consecutive patients (31M, 21F) who underwent LRRC resection at our center between 09/1997 and 08/2005. En bloc sacrectomy was performed in 30 patients (58%) with the goal of achieving complete margin negative (R0) resection. At the time of LRRC resection, 46 of 52 patients had isolated LRRC (M0), and 6 had potentially resectable distant metastasis (M1). Patients were followed with H&P, CT-CAP q4mos X2y, q6mos X3y, then annually. Results: At last follow-up (f/u), 32 patients had died of rectal cancer, 1 died of other causes, 4 were alive with rectal cancer, and 15 (30%) were alive cancer-free. For the entire cohort of 52 patients, median f/u time was 44mos (4-162) and overall survival (OS) was 42% at 5y, 37% at 10y, median 43mos. In the group who were alive at last f/u (N = 19), median f/u time was 123mos (45-162). Prognostic variables for OS in univariate analysis included: m status, resection margin status, receipt of systemic Rx, and receipt of radiotherapy. All patients who had M1 disease at the time of LRRC resection died of recurrent cancer at a median of 21mos (4-46). In the 46 M0 patients, OS was 47% at 5y, 42% at 10y, median 50mos; furthermore, disease-free survival (DFS) was 38% at 5y, 38% at 10y, median 39mos. In patients who had R0 resection (n = 41), OS was 51% at 5y, 45% at 10y, median 72mos. Preoperative chemotherapy at the time of primary presentation (n = 26) or before resection of LRRC (n = 20) was associated with significantly improved prognosis ( p= 0.004, p= 0.03, respectively). Conclusions: Complete resection of LRRC was associated with durable survival in approximately 40% of patients, with plateauing of survival curves after 5y. Preoperative therapy of LRRC may improve survival.
Retrospective analysis of the effects of systemic chemotherapy to the ovarian metastases from colorectal cancer.
Authors: Sekine Katsutoshi , Hamaguchi Tetsuya , Shoji Hirokazu , Nakamura Shoko , Miyamoto Takahiro , Takashima Atsuo , Honma Yoshitaka , Iwasa Satoru , Kato Ken , Takahashi Kenta , Kato Tomoyasu , Kanemitsu Yukihide , Boku Narikazu
Published: March 2017

731

Background: Ovarian metastases from colorectal cancers are relatively rare. Since most ovarian metastases are also associated with other metastatic sites, the prognosis is reported to be poor. It is not fully understood whether the response to systemic chemotherapy of ovarian metastases differs from that to other metastatic sites. Methods: We retrospectively reviewed the clinical data of patients with ovarian metastases from colorectal cancer treated at our hospital between January 2006 and December 2015. Results: Among the 635 female patients with relapsed or metastatic colorectal cancer, 57 (9.0%) had ovarian metastases before the first-line treatment; 37 patients received palliative chemotherapy, and 20 patients were initially treated by surgical resection. In addition, 38 cases of ovarian metastases developed after the initiation of first-line chemotherapy. Overall, 95 patients (15.0%) with ovarian metastases were treated during this period. The objective response rate for systemic chemotherapy of ovarian metastases was lower than that for other metastatic sites (22.9 % vs 60.9 % for first-line, 3.4 % vs 13.6 % for second-line, 11.1 % vs 26.6 % for third-line, and 0% vs 18.2 % for fourth-line, respectively). After the initiation of chemotherapy, surgical resection of ovarian metastases was positively associated with a longer overall survival (26.8 months for cytoreductive surgery and 17.0 months for only systemic chemotherapy, p < 0.001), especially when the other metastatic sites had not progressed after chemotherapy. Conclusions: Ovarian metastases are less responsive to systemic chemotherapy compared to the extra-ovarian metastases. Our data also suggest that multi-disciplinary treatment strategy including systemic chemotherapy and cytoreductive surgery might improve the prognosis of ovarian metastases.
Demographic and clinical characteristics of patients with metastatic colorectal cancer (mCRC) associated with RAS testing from 129 million covered lives.
Authors: Bach Bruce A. , Christodoulopoulou Alexandra , Klink Andrew , Hechmati Guy , Mujumdar Urvi , Feinberg Bruce A. , Fakih Marwan
Published: March 2017

739

Background: Guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) recommend that all tumors be tested for RAS mutations to identify patients who will most benefit from chemotherapy regimens with biologic agents. The aim of this study was to describe characteristics of patients captured by a large national health claims database who were tested vs those who were not tested for RAS mutations and to identify potential predictors of RAS testing. Methods: Patients with mCRC diagnosed from 2012–2014 (ICD-9 codes 153.x, 154.0x, or 154.1x and 197.x–198.x) were identified from a US healthcare claims database consisting of 129 million unique covered patient lives. Patient demographics and baseline clinical characteristics were compared between patients who were and were not tested for RAS mutations (identified by CPT codes) using chi-square and t-tests. Odds ratios (ORs) were estimated for potential predictors by fitting multivariate logistic regressions to adjust for patient characteristics. Results: Of the 4,527 mCRC patients identified (mean age at diagnosis, 61.2 years; 54% male); 39% (n = 1,787) had a claim for RAS testing during the study period. Patients tested had similar mean age and comorbidity index at diagnosis compared to those not tested (60.8 vs 61.5 years, P = 0.06; 3.98 vs 3.90, P = 0.47). A greater proportion of RAS-tested patients were commercially insured compared to those not tested (37% vs 26%, P < 0.01). Adjusted for other patient characteristics, patients with commercial insurance (OR: 1.62 [95% confidence interval–CI: 1.41–1.87]), metastases to viscera (OR: 1.61 [95% CI: 1.42–1.84]), or diagnosis of colon primary site compared to rectum (OR: 1.32 [95% CI: 1.16–1.51]) had increased odds of receiving RAS testing; all P < 0.01. Conclusions: These observational data show that mCRC patients with commercial insurance, metastases to viscera, and colon cancer have a higher probability of being tested for RAS mutations. Overall, the data suggest that RAS status is underdetermined, with certain subgroups appearing to be more likely to be tested than others.
Role of systemic immune-inflammatory index, tumor infiltrating neutrophils and PD-1+ T cells to predict the postoperative recurrence after S-1 adjuvant chemotherapy for gastric cancer: A retrospective study.
Authors: Tanaka Hiroaki , Tamura Tatsuro , Hiramatsu Soichiro , Muguruma Kazuya , Miki Yuichiro , Shibutani Masatsune , Yamazoe Sadaaki , Kimura Kenjiro , Nagahara Hisashi , Toyokawa Takahiro , Amano Ryosuke , Maeda Kiyoshi , Hirakawa Kosei , Ohira Masaichi
Published: March 2017

74

Background: The adjuvant chemotherapy with S-1 is the standard treatment for Stage II/III gastric cancer in Japan. Immunological status of host is critical for treatment outcome. Several investigators showed that systemic immune-inflammaotry indexes including neutrophil lymphocyte ratio (NLR) and modified Glasgow Prognostic Score (mGPS) well reflected the tumor progression. Methods: We analyzed clinical data obtained from 170 patients with pathological stage II/III gastric cancer who underwent surgery followed by S-1 adjuvant chemotherapy at Osaka City University Hospital between 2006 and 2015. Tumor infiltrating cells were detected by immunohistochemistry. Results: We found recurrent diseases in 70 (41%) patients including 15 in stage II and 55 in stage III. In univariate analysis using Cox proportion model, 2 grade of mGPS, the increase value of post-operative CEA, CA19-9, number of lymphocytes and NLR were associated with recurrence. Post-operative elevation of CEA and NLR were identified as independent risk factors for recurrence in multivariate analysis. Increase value of pre-operative NLR and CEA was significantly associated with early recurrent within one year after surgery. Tumor infiltrating neutrophils and PD-1+ T cells had correlated with the increase of pre-operative NLR and CEA value, respectively. Patients with low PD-1+T cells and low neutrophils had better prognosis than those with high infiltration. Conclusions: Post-surgical elevation of CEA and NLR value were useful as a predictive marker for recurrence in patients treated with S-1 adjuvant chemotherapy after surgery for gastric cancer. Early recurrence had correlated with tumor infiltrating neutrophils and PD-1+T cells. Our results suggested that systemic and local immune suppression should be an important element to exacerbate prognosis after chemotherapy for resectable gastric cancer.
Overall survival of elderly metastatic colorectal cancer patients treated in second and third line by tumor site.
Authors: Luhn Patricia , Cha Edward , Hsieh Angela Fu-Chi , Taylor Michael , Grossman William
Published: March 2017

742

Background: The anatomical side of the colon where a tumor arises has been shown to be prognostic in patients treated with first-line therapy; patients with tumors that arise from the left side of the colon have significantly longer survival compared with patients whose tumors arise from the right side of the colon. However, there is little evidence of whether this factor is prognostic in later lines of treatment. The objective of this study was to determine the impact of tumor side on the survival of metastatic colorectal cancer patients who received second line (2L) or third line (3L) therapy. Methods: Metastatic (stage IV) colorectal cancer patients in the Surveillance, Epidemiology, and End Results (SEER) database linked to Medicare claims diagnosed 2001-2005 who received 2L (n = 921) or 3L (n = 502) therapy were included in the study. Overall survival (OS) was determined from the start of the indicated line of therapy and was estimated using the Kaplan-Meier method; statistical differences were tested using the log-rank tests. Results: The distribution of tumor sites was similar for 2L and 3L treated patients (right: 36%; left: 58%; transverse: 6%; for 2L). The median follow up time from start of therapy was 11 months (mo) for 2L and 10 mo for 3L patients. Median OS for left-sided tumors receiving 2L+ therapy was 13.6 mo (95%CI: 11.9, 14.8) compared with 8.7 mo (95%CI: 7.5, 9.9) for right-sided tumors (log-rank p < 0.001). Similar results were seen in patients receiving 3L+ therapy, although the difference was of lesser magnitude. The median OS for patients with left-sided tumors was 10.8 mo (95%CI: 9.6, 12.9) compared with 7.6 mo (95%CI: 5.7, 9.4) for right-sided tumors (log-rank p = 0.002). Conclusions: These results suggest that side of tumor origin remains a prognostic factor for colorectal cancer patients treated in later lines of therapy (2L+).
Fast track multidiscipline treatment versus conventional treatment for colorectal cancer: The results of a prospective randomized controlled study (FTMDT trial).
Authors: Ding Ke-Feng , Li Jun , Zhou Jiao-Jiao , Kong Xiang-Xing , He Jin-Jie , Yuan Ying , Yan Min , Chen Rong , Huang Xue-Feng , Chen Gang , Ying Xiao-Jiang , Dai Xiao-Yu , Li Gen-Hai , Zhang Su-Zhan , Zheng Shu
Published: March 2017

743

Background: Fast Track Multi-Discipline Treatment (FTMDT) integrates fast-track perioperative treatment (laparoscopic or open surgery) plus XELOX adjuvant chemotherapy for colorectal cancer (CRC). This study aimed to verify the effects of FTMDT model and to clarify the value of laparoscopic surgery in fast-track perioperative treatment. Methods: The study (NCT01080547) was a prospective randomized controlled multi-centers study. Group I (FTMDT) received fast-track treatment plus XELOX chemotherapy (Group Ia received laparoscopic surgery and Group Ib received open surgery). Group II (conventional treatment, CT) received conventional treatment plus mFOLFOX6 chemotherapy (Group IIa received laparoscopic surgery and Group IIb received open surgery). The primary endpoint was total hospital stays during treatment. The secondary endpoints included surgical complications, chemotherapy related adverse events, quality of life and hospitalization costs. Results: Between April 2010 and June 2014, 374 patients were enrolled and 342 patients were finally analyzed. The total hospital stays were shorter in FTMDT than CT (median 13 days vs. 23.5 days, P= 0.0001) but similar between Group Ia and Group Ib (median 13 days vs. 14 days, P= 0.1951). The postoperative hospital stays were shorter in FTMDT than CT (median 6 days vs. 9 days, P= 0.0001) but similar between Group Ia and Group Ib (median 6 days vs. 6 days, P= 0.2160). Resume of flatus and defecation was earlier in FTMDT ( P< 0.05) and Group Ia was the earliest. The in-hospital complication rate was lower in FTMDT (6.40% vs. 14.71%, P= 0.014) but similar between Group Ia and Group Ib. The surgery cost of Group Ib was the lowest ( P< 0.05). The rate of chemotherapy related adverse events was similar between FTMDT and CT( P> 0.05). The EORTC QLQ-C30 physical functioning and fatigue in one week postoperative were better in FTMDT than CT( P< 0.05). Conclusions: FTMDT model enhanced the postoperative recovery of CRC patients. On the premise of fast-track perioperative treatment, laparoscopic surgery showed minor advantage over open surgery which had economic advantages. Clinical trial information: NCT01080547.
Phase I/II trial of dose reduced capecitabine in elderly or frail patients with untreated advanced colorectal cancer.
Authors: Breadner Daniel Adam , Welch Stephen , Jonker Derek J. , Klimo Paul , Cripps M. Christine , Biagi James Joseph , Lam Wendy , Whiston Frances , Stitt Larry , Vincent Mark David
Published: March 2017

745

Background: Capecitabine (Cape) was initially assessed at a dose of 2500 mg/m2 in young or robust patients that do not represent the population in which oncologists consider Cape monotherapy in advanced colorectal cancer (aCRC). In practice Cape is frequently given to elderly or frail patients at 2000 mg/m2 but the optimal dosing remains controversial. Methods: A multi-centered phase I/II trial of reduced dose Cape 2000 mg/m2 d1–14 q21d was conducted in 221 patients in one or more of the following subsets: age65 years (167 pts), ECOG PS 1 (139 pts), elevated LDH (105 pts), prior pelvic RT (54 pts). Results: Median age was 72 years. A median 5 and mean 8 cycles were given (range 0 to 50). The phase I portion of the study determined prior pelvic radiation required dose reduction to 1500 mg/m2 for diarrhea. Grade 3/4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand-foot syndrome, 7.7% diarrhea). Dose reductions were required in 14% and dose delays in 21%. Response rate is 13.6%, with 69.7% disease control rate. Median PFS was 5.6 months. Post progression 125 patients (67%) received further chemotherapy, 56 received further Cape monotherapy with a median of 4 additional cycles. Median overall survival for all patients is 14.3 months. Median survival was significantly higher for baseline ECOG 0 vs. ≥ 1 and normal vs. elevated LDH. When comparing patients receiving 2000 compared to 1500 mg/m2 the ORR was 19% vs. 17%, and the DCR was 73% vs. 63%. Median PFS was 5.9 vs. 4.7 months, and the OS was equal at 14.3 months. Hand-foot syndrome was more common at the higher dose, 46% vs. 30%, any grade. Conclusions: This report suggests dose reduced Cape has less toxicity compared to full dose, with only a small tradeoff in efficacy seen as a lower ORR. However, its improved tolerability likely leads to an increased number of cycles of therapy, and the PFS seems consistently higher at the lower dose. This trial reduces uncertainty regarding further dose reductions to 1500 mg/m2 for frail patients, in whom quality of life may be paramount. This should be viewed as compelling evidence, in the absence of a head to head clinical trial, that 2000, or even 1500, mg/m2 is an appropriate dose in elderly or frail patients with aCRC.
Hepatic artery therapies for unresectable colorectal liver metastases: Pooled survival analysis of 968 patients from TACE, yttrium-90, and HAI studies.
Authors: Moutinho Vitor , Connell Louise Catherine , D'Angelica Michael Ian , Kemeny Nancy E.
Published: March 2017

747

Background: Approximately 140,000 people are newly diagnosed with colorectal cancer (CRC) annually, while 50,000 will die from the disease. Median survival has increased with use of modern chemotherapy and biologic agents. Sixty percent of advanced CRC patients (pts) present with or develop liver metastases, with additional treatment options such as hepatic artery therapies. However, there is no strong scientific evidence to support the use of transarterial chemoembolization (TACE), Yttrium 90 (Y90) or chemotherapy infusion (HAI). Methods: Pooled survival analysis of 968 pts with unresectable colorectal liver metastases (CLRM) treated with hepatic artery therapies, including HAI, Y90 or TACE. A rigorous selection of studies was conducted to ensure exchangeability across studies and adequate comparison of groups. Kaplan Meier survival curves were reconstructed from original publications. Data was further stratified into presence or absence of extra-hepatic disease (EHD). Results: Total of 968 pts with mean age 60.5 years, 65.5% male, 64.9% ECOG 0 and 42.4% with EHD. Patient characteristics in the various studies as per Table. Initial analysis showed a significant reduction in the hazard of death comparing HAI & Y90 (HR = 0.45[0.38, 0.55]). There was a 67% reduction in the hazard of death comparing HAI to TACE (HR = 0.33[0.27, 0.41]). Median survival in pts without and with EHD was 32 &16 months for HAI, 11 & 6 months for Y90 and 11 & 8 months for TACE (p < 0.0001). Conclusions: Based on our analysis, HAI offers better survival rates when compared to TACE and Y90. This survival advantage for HAI is not only limited to CRC pts with hepatic disease only, but also is evident in those pts with unresectable CLRM in the setting of co-existent EHD. [Table: see text]
Role of cetuximab in conversion therapy in advanced KRAS WT colorectal cancer with liver limited disease: A systematic review and meta-analysis.
Authors: McMullen Michelle , Davidson Andrew , Khattak Muhammad Adnan
Published: March 2017

748

Background: Majority of advanced colorectal cancer (CRC) patients with liver limited disease (LLD) that undergo curative partial liver resection relapse within 5 years. Peri-operative chemotherapy is currently utilized, however the benefit of this is modest only. The addition of anti-EGFR therapy with cetuximab to chemotherapy has consistently demonstrated improvements in objective response rate (ORR) but its impact on potentially curative R0 resection, progression free survival (PFS) and overall survival (OS) remains debatable. The aim of this study was to evaluate the evidence for the use of cetuximab with chemotherapy, in the peri-operative setting for patients with advanced KRAS-WT CRC and unresectable LLD. Methods: Comprehensive literature search was conducted using PubMed and MEDLINE. Inclusion criteria identified studies evaluating the efficacy of chemotherapy and cetuximab vs. chemotherapy alone in advanced KRAS-WT CRC with unresectable LLD. Phase II studies evaluating chemotherapy-cetuximab without control arms were also included. Pooled data was included in meta-analysis and analysed using the Stata v.7. The primary endpoint was the R0 resection rate. Secondary endpoints were ORR, PFS and OS. Results: 5 trials, describing a total of 617 patients, were included in the analysis1–5. Patients receiving cetuximab in addition to chemotherapy were more likely to achieve R0 resection than patients receiving chemotherapy alone (OR 2.13; 95% CI 1.23-3.68, p < 0.05). Patients on cetuximab had improved ORR compared to patients not on cetuximab (OR 2.59; 95% CI 1.74-3.87, p < 0.05). Patients receiving cetuximab had a mean PFS 3.1 months higher than patients not on cetuximab (95% CI 2.76-3.45, p < 0.05). Patients on cetuximab also had a mean OS 0.67 months longer than those not on cetuximab (95% CI 0.44-0.91, p < 0.05). Conclusions: The addition of cetuximab to chemotherapy in the treatment of advanced KRAS-WT CRC with unresectable LLD leads to better outcomes compared to chemotherapy alone.
Aflibercept (Z) in combination with FOLFIRI for second-line treatment of patients (pts) with metastatic colorectal cancer (mCRC): Safety and quality of life (QoL) data from the Spanish subgroup of the Aflibercept Safety and Quality-of-Life Program (ASQoP).
Authors: Rivera Fernando , Polo Marques Eduardo , Aranda Enrique , Fernandez-Martos Carlos , La Casta Munoa Adelaida , Guillen Carmen , Lopez Rafael , Gil Silvia , Lema Laura , Aparicio Jorge , Martinez Villacampa Mercedes , Pisa Aleydis , Borrega Pablo , Lopez-Vivanco Guillermo , Garcia Alfonso Pilar
Published: March 2017

751

Background: In the VELOUR trial, adding Z to FOLFIRI improves OS, PFS and RR in mCRC pts progressing after oxaliplatin ±biologic agents. The ASQoP trial (NCT01571284) was designed to gather safety and QoL data from mCRC in real-life setting. We report data collected by the Spanish investigators. Methods: ASQoP is single-arm, open-label trial evaluating safety and QoL of Z in mCRC pts as 2nd line. Eligible pts received Z (4mg/kg) q2wks on day 1/cycle, followed by FOLFIRI (dosing was at physician’s discretion) until disease progression, unacceptable toxicity, death, or investigator/pt decision. The EQ-5D was used for utility index (UI) measure and the EORTC QLQ-C30 as generic cancer instrument. QoL population consisted of pts completing the questionnaire at baseline and ≥1 assessment post-baseline and received ≥1 part of 1 dose of study treatment. Results: The safety population comprised 77 pts with ≥1 completed cycle of treatment. Grade (G)3/4 AEs were reported in 72.7% of pts (vs 83.5% in VELOUR), being G3 most commonly reported. There was no G4 hypertension, stomatitis, or proteinuria. G4 Diarrhea was found in 1.3% of pts. Mean baseline UI was 0.7 (95% CI, 0.63-0.78) in 51 pts, and remained relatively stable at cycles 3 (n=39) and 7 (n=24), with a mean (±SD) change from baseline of 0.03 (±0.26) and -0.06 (±0.35), respectively. Mean baseline global health status score was 63.1 (95% CI, 55.8-70.4) in 54 pts, and remained stable up to cycle 9 with a mean (±SD) change from baseline of 4.17 (±38). Conclusions: Thisanalysis has identified no new safety signals and suggests an acceptable toxicity profile with a relatively stable UI and QoL in Spanish mCRC pts in the real-life setting. [Table: see text]
An international patient-centered outcome measurement set for colorectal cancer.
Authors: Mamon Harvey J. , Zerillo Jessica A. , Schouwenburg Maartje Gisele , van Bommel Annelotte , Stowell Caleb , Van De Velde Cornelis J. H. , Tollenaar Rob A.E.M.
Published: March 2017

753

Background: While there are tools to measure outcomes relevant to patients with colorectal cancer, none is universally accepted and none incorporates components of long-term clinical outcomes, acute complications, and patient-reported outcomes (PROs). Methods: The International Consortium for Health Outcomes Measurement convened an international multidisciplinary working group to develop a comprehensive patient-centered outcome measurement set for patients with all stages of colorectal cancer. The working group utilized a literature review, patient focus group and their own clinical expertise to reach consensus on outcomes and case mix factors through a modified Delphi process. Measurement tools were selected by International Society of Quality of Life Research standards. The final list of PROs was validated through a patient survey. Results: The 29 members of the working group included patient representatives and palliative care, nursing, pathology, medical oncology, colorectal surgery and radiation oncology specialists from academic and nonacademic practices in Europe, Australia, Asia and the USA. The international focus group included 11 patients with colorectal cancer treated with palliative and curative intents. The working group defined four clinical outcomes applicable to all and eight specific to subgroups, such as presence of ostomy for patients with rectal cancer and hospital admission in the last 30 days of life for patients with advanced disease. An algorithm for documenting acute complications was developed. The working group defined 11 PROs applicable to all and eight specific to subgroups, such as erectile dysfunction for patients who received radiotherapy/surgery and neuropathy for those who received chemotherapy. 276 colorectal cancer patients completed the validation survey. Conclusions: Through use of extensive patient input, the international multidisciplinary group developed a patient-centered outcome measurement set incorporating clinical outcomes, acute complications and PROs for patients with colorectal cancer. This comprehensive measurement set allows for standardized international comparison on quality of care outcomes and will be revised annually.
Bevacizumab and its impact on survival for patients receiving subsequent anti-EGFR therapy: Results from the South Australian metastatic colorectal cancer registry.
Authors: Price Timothy Jay , Karapetis Christos Stelios , Roy Amitesh Chandra , Padbury Robert , Maddern Guy , Roder David , Piantadosi Cynthia , Burge Matthew E. , Townsend Amanda Rose
Published: March 2017

754

Background: Questions over the impact of 1st line bevacizumab on subsequent sensitivity to anti-EGFR therapy have been raised with authors hypothesizing that up-front anti-VEGF agent’s use influences biological changes that increase the risk of acquired resistance to subsequent EGFR inhibitors. Methods: Aretrospective cohort study was performed to compare the characteristics and survival of patients who were treated with an anti-EGFR therapy 2nd line and beyond by two groups defined by the 1st line therapy; 1. chemotherapy (chemo) plus bevacizumab (bev) and 2. chemo alone. Pearson chi test analysis was performed to determine whether receiving 1st line bev was associated with worse OS. Results: 348 mCRC patients who received chemo with or without bev and then an anti-EGFR therapy were studied. Patient characteristics are summarised in table. The significant differences between group 1. Vs. 2. were as follows; median age, lower use of single agent FU, KRAS status not tested, and where BRAF MT status was known (11%); BRAF MT rate. Median OS for the 2 groups was 34.2 mths, and 28.2 mths respectively (p = 0.12). Conclusions: Survival was not significantly different between the two groups, and the trend was towards higher OS with chemo plus bev suggesting that in our registry population, bev administration in first line therapy with chemo did not lead to a worse outcome for those patients subsequently receiving anti-EGFR therapy. [Table: see text]
Reinduction of oxaliplatin-based chemotherapy after exposure to oxaliplatin in adjuvant setting for colorectal cancer.
Authors: Beom Seung-Hoon , Ahn Joong Bae , Shin Sang Joon , Jung Minkyu
Published: March 2017

755

Background: Oxaliplatin-based chemotherapy is commonly used chemotherapy in the adjuvant setting for colorectal cancer patients. In clinical practice, those patients may be retreated with oxaliplatin after relapse. The efficacy and predictive factor of oxaliplatin re-treatment are little known. Methods: We carried out a retrospective study of 53 consecutive patients who underwent surgery and adjuvant FOLFOX chemotherapy and who were re-treated oxaliplatin-based chemotherapy after relapse at Yonsei Cancer Center from April 2009 through October 2015. The main end-point was progression-free survival (PFS). Results: Among enrolled patients, 33 (62.2%) received curative resection in initially non-metastatic setting and the other 20 (37.7%) did R0 resection including metastasectomy in stage 4 at the time of previous oxaliplatin treatment. Median time from last cycle of adjuvant FOLFOX to the first cycle of palliative oxaliplatin based chemotherapy was 31.5 months. Palliative oxaliplatin was given as second and third or later in 37 (69.8%) and 16 (30.2%) patients respectively. Median PFS and overall survival (OS) were 5.1 and 17.5 months. Response rate and disease control rate to palliative oxaliplatin based treatment were 17.0 % and 66.0%. Patients with both shorter interval from first oxaliplatin exposure to recurrence (<12 months) and shorter interval from recurrence to oxaliplatin re-exposure (<18 months) experienced shorter PFS significantly compared to those who did not (2.8 vs. 7.3m, p = 0.004). It was an independent predictive factor for PFS in addition to use of targeted agent in multivaviate analysis. Conclusions: In this study, re-treatment with oxaliplatin based chemotherapy after recurrence demonstrated modest clinical efficacy. Non-use of targeted agent and both shorter interval from first oxaliplatin exposure to recurrence and shorter interval from recurrence to oxaliplatin re-exposure are poor predictive factors for PFS.
Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictive and prognostic markers in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation.
Authors: Dudani Shaan , Marginean Horia , Tang Patricia A. , Monzon Jose Gerard , Raissouni Soundouss , Asmis Timothy R. , Goodwin Rachel Anne , Gotfrit Joanna , Cheung Winson Y. , Vickers Michael M.
Published: March 2017

758

Background: A standard therapy for locally advanced rectal cancer (LARC) includes fluoropyrimidine (FP)-based neoadjuvant chemoradiation (nCRT). Previous studies have inconsistently demonstrated that baseline neutrophil- and platelet-to-lymphocyte ratios (NLR and PLR) are predictive of response to nCRT or prognostic of outcomes in LARC. Methods: We performed a review of patients with LARC undergoing nCRT followed by surgery with curative intent from 2005-2013 in 3 academic cancer centers from 2 Canadian provinces. Data regarding demographics, staging, baseline hematologic variables (<4 weeks prior/up to 2 weeks after initiating nCRT) and treatment details were collected. Outcome measures of interest were pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Logistic regression and Cox proportional hazard models were used to assess for an association between baseline hematologic variables and outcomes. Results: Of 1081 identified patients, 845 were included in the DFS/OS analysis. Median age was 61 (range 23-87), 70% male, 85% performance status (PS) 0-1. 31% and 67% had clinical stage II and III disease, respectively. 25% had elevated NLR (≥ 4), and 64% had elevated PLR (≥ 150). 98% of patients received FP-based nCRT, with 96% receiving ≥ 44 Gy (median 50 Gy [range 20-74]). 80% completed neoadjuvant chemotherapy and 94% completed neoadjuvant radiotherapy, with a pCR rate of 23%. After a median follow up time of 64 months, 6% developed local recurrence, 20% developed distant recurrence and 19% have died. 5-year OS and DFS were 78% (95% CI 74-81%) and 76% (95% CI 73-79%), respectively. In multivariate analyses, elevated baseline NLR and PLR were not prognostic for OS or DFS. Elevated NLR was a negative predictor of pCR (OR 0.61, p=0.037, 95% CI 0.38-0.97); there was no association with elevated PLR. Conclusions: Elevated NLR was a negative predictor of pCR, but not prognostic for DFS and OS. PLR was neither predictive nor prognostic.
Chemotherapy for metastatic colon cancer: Effect on survival when the dose is reduced due to side effects.
Authors: Munker Stefan , Gerken Michael , Fest Petra , Ott Claudia , Schnoy Elisabeth , Fichtner-Feigl Stefan , Wiggermann Philipp , Vogelhuber Martin , Herr Wolfgang , Stroszczynski Chrisitan , Schlitt Hans J. , Evert Matthias , Reng Michael , Klinikhammer-Schalke Monika , Teufel Andreas
Published: March 2017

761

Background: 5-Fluorouracil (5FU), Folinic acid (FA), and Oxaliplatin (FOLFOX) or 5FU, FA, and Irinotecan (FOLFIRI) are standard regimens for palliative chemotherapy of metastatic colon cancer. Since data showing the influence of dose reduction in palliative treatment are rare, the objective of this single center, retrospective study was to further characterize the influence of dose reduction on efficacy of these therapeutic regimens. Methods: 109 patients, diagnosed with stage IV colon cancer between 2004 and 2012 and receiving palliative first-line chemotherapy with either FOLFOX or FOLFIRI regimens in our outpatient clinic were analyzed for treatment efficacy. Patients who received dose reductions due to side effects usually received doses of 80% or lower of per protocol dose. Survival data were obtained from the Regensburg Tumor Registry. Survival analysis was performed using Kaplan-Meier statistical analysis. Results: Dose reduction was independent of age. Major reasons for dose reduction were neutropenia (30%) followed by polyneuropathy (16%) and diarrhea (14%). Dosage was more often reduced in patients receiving FOLFOX based therapy. Two-year survival of FOLFOX and FOLFIRI treated patients was comparable (35%). We observed no significant (p = 0.323) difference on two-year survival in patients receiving a reduction of chemotherapy with dose reduction (48%) compared to standard dose (31%). Further subgroup analysis did not reveal any subgroup of patients suffering from side effects with significantly worse outcome upon dose reduction. In contrast, patients who underwent dose reduction received more cycles of chemotherapy (13.7 vs. 10.8 cycles) and cumulative dosage was similar in both groups. Conclusions: A moderate reduction of chemotherapy due to side effects has no measurable effect on survival in patients with palliative colorectal cancer. This may be partially due to a longer treatment of patients with reduced chemotherapy dosage if side effects are present.