bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic markers in stage II/III rectal cancer after neoadjuvant 5-fluorouracil-based chemoradiotherapy
Authors: Pinto C. , Di Fabio F. , Longobardi C. , Ceccarelli C. , Cuicchi D. , Iacopino B. , Ugolini G. , Minni F. , Cola B. , Martoni A. A.
Published: March 2020

14514

Background: The aim of this study was to evaluate the prognostic value of histologic tumor regression grade (TRG) and pathological biomarkers after neoadjuvant chemoradiotherapy (CT/RT) in rectal cancer pts. Methods: Pts entering the study had rectal adenocarcinoma and stage uT3-T4 N-/+ with location <12 cm from the anal margin. CT consisted of 5-fluorouracil (5FU) 225 mg/m2/die continuous infusion IV d1–38 with/without oxaliplatin (OXA) 60 mg/m2 weekly infusion IV for 6 times. RT was delivered up to a dose of 50.4 Gy in daily fractions of 1.8 Gy. Rectal surgery with TME was performed 6–8 weeks after neoadjuvant therapy. Eight courses of adjuvant CT (LV5FU2) were given after surgery. Immunohistochemical determination of Ki67, p53, bcl2, TS, EGFR, MLH1, MSH2 was performed in pre-treatment biopsy and operative specimen; TRG (Dworak) response (0=none, 1=low, 2–3= intermediate, 4=complete) and circumferential resection margin (CRM) were evaluated on surgical specimens. Results: Between March 2002 and December 2006, 56 pts had completed the integrated treatment. Pt characteristics were: 39M/17F; stage uT3N- 32(57.1%), uT3N+ 15(26.8%), uT3Nx 4(7.1%), uT4N+ 4(7.1%), uT4Nx 1(1.8%). CT was 5FU in 15(26.8%) pts, 5FU/OXA in 41(73.2%) pts. Pathological downstaging was achieved in 31(55.4%) pts, including 9(16.1%) pCR. After a median follow-up of 28.5(6–58) months, 7(12.5%) pts had disease recurrence. TRG evaluation was: no TRG0, 9(16.1%) TRG1, 21(37.5%) TRG2, 17(30.4%) TRG3, 9(16.1%) TRG4. CRM was negative in 91% of pts. By means of univariate analysis, TRG was found to be significantly correlated with DFS (estimated median DFS was 23 months in TRG1 pts, not achieved in TRG2–4 pts; p<0.0001). Other factors correlating significantly with a better DFS by univariate analysis included ypT0–2 (p=0.013) and pN- (p=0.002) categories, CRM- (p=0.024) and lower Ki67 expression post-CT/RT (p=0.012). Using multivariate analysis, we found that TRG2–4 was the strongest DFS prognostic factor (HR=0.0312; 95% CI: 0.003–0.40, p=0.008). Conclusions: In this analysis complete (TRG4) and intermediate (TRG2+3) pathological response produced improved DFS. Significant favorable prognostic factors were the ypT0–2/pN- categories, CRM- status and lower Ki67 expression after CT/RT.

No significant financial relationships to disclose.
Prognostic significance of pathological biomarkers in patients with stage II-III colorectal cancer
Authors: Funaioli C. , Pinto C. , Ceccarelli C. , Di Fabio F. , Cuicchi D. , Rojas Llimpe F. L. , Lombardi R. , Longobardi C. , Bottazzi M. , Martoni A. A.
Published: March 2020

14518

Background: Biopathological colorectal cancer (CRC) studies have provided information on pathogenesis, but it is unclear how important biomarkers actually are in predicting prognosis. The aim of our study was to define the prognostic significance of biomarkers and a biopathological profile that could predict an increase in the disease relapse risk in stage II-III CRC patients (pts). Methods: The primary tumor of the CRC pts treated with surgery was immunohistochemically evaluated on the Ki67, p53, bcl-2, TS, EGFR, MLH1 and MSH2 expressions. All 7 markers were measured using standard immunohistochemical techniques. The biomarker evaluations were scored by just one pathologist. Results: Between March 2001 and October 2006 the primary tumor of 242 consecutive pts was investigated. Pt characteristics were: males 141(58.3%), females 101(41.7%); median age 68.5 (24–88); primary tumor site: right colon 94(38.8%), left colon 148(61.2%); stage II 102(42.1%), stage III 81(33.5%), stage IV 59(24.4%). 5-fluorouracil based adjuvant chemotherapy was performed in 121 (66.1%) pts. After a median follow up of 30 months (1–80), 34 pts (10 pts stage II, 24 pts stage III) of 183 stage II-III pts (18.6%) had a disease recurrence. In a univariate analysis of stage II-III pts, a higher expression of Ki67 (= 50% positive cells) was significantly associated with an improved DFS (p= 0.014) and overall survival (OS) (p=0.010). Expression of p53, bcl-2, TS, EGFR, MLH1 and MSH2 were not significantly associated with DFS and OS. In a multivariate analysis adjusted for the impact of the disease stage and adjuvant chemotherapy, a higher expression of Ki67 was significantly associated with diminished risk of recurrence (HR: 0.395; 95% CI: 0.183–0.855, p=0.018) and death (HR: 0.179; 95% CI: 0.046–0.696, p=0.013). The evaluation of DNA mismatch repair status (MLH1, MSH2) demonstrated that the lack of MLH1 is more frequent in non-relapsed II-III stage pts than in IV stage pts (p= 0.024). Conclusions: This analysis showed a significant correlation between higher Ki67 expression and better DFS and OS in pts with stage II-III CRC. An higher frequency of MLH1 deficiency was observed in non-relapsed pts with stage II-III than in advanced disease.

No significant financial relationships to disclose.
Metronomic irinotecan and standard FOLFIRI regimen as first-line chemotherapy in metastatic colorectal cancer (MCRC). Final results of phase II study
Authors: Nardi M. , Azzarello D. , Del Medico P. , Giannicola R. , Falzea A. , Giuffrè C. , Maisano R. , Panuccio V. , Raffaele M. , Zavettieri M. , Avallone A.
Published: March 2020

14520

Background: Angiogenesis is necessary to sustain the growth of both the primary tumour and the development of metastases in colorectal cancer. Before the clinical use of bevacizumab, metronomic chemotherapy was the only mean to block the growth of tumor microvessel. CPT-11 showed, in preclinical model, to have antiangiogenetic properties using low doses and weekly administration. We carried out this study in order to evaluate the activity and toxicity of mixed metronomic and standard FOLFIRI regimen in MCRC. Methods: From 10/03 to 9/05 we treated 46 pts (24M 22F), median age 66 years (range 41–79), ECOG PS 0–2 with this schedule: CPT- 11 10 mg/mq days 1, 7, 10 and CPT-11 150 mg/mq day 2, l-Folinic Acid 100 mg/mq days 2 and 3, 5-FU 400 mg/mq bolus days 2 and 3 and 5- FU 600 mg/mq 44 hours c.i. days 2 and 3 every two weeks for a maximum of 12 cycles. Results: All pts have been evaluable activity and toxicity. We obtained 9 CR (20%), 12 PR (26%) with an ORR of 46% (CI 95%: ±13%) and 17 SD. After a median follow-up of 24 months we registered a median TTP of 10 months and a median OS of 22 months. As regard toxicity, the chemotherapy has been well tolerated; no toxic deaths occurred and no therapy ended for toxicity. 6 pts had 25% dose reduction (standard schedule) for diarrhea G4 after the first cycle. The main toxicities recorded on a total of 440 cycles (cy) delivered were: diarrhea G4 1.7% and G3 2.3% of the cy. Neutropenia G3 5.8% and vomiting G3 0.5% of the cy. Anemia G2 was recorded in 14 pts. All pts suffered from partial alopecia and half of the pts from mild oral mucositis. Conclusions: This mixed schedule seems to be active and well tolerated, ORR, TTP and OS are similar to Hurwitz results (NEJM 2004; 350: 2335–42) but with less adverse events. The combination of this schedule with bevacizumab deserves further studies.

No significant financial relationships to disclose.
A randomised, placebo-controlled, double-blind phase II study of raltitrexed and gefitinib vs raltitrexed alone as 2nd line chemotherapy in subjects with advanced colorectal cancer (CRC). GON group study (Grupo Oncologico del Norte)
Authors: Vieitez J. , Valladares M. , Pelaez I. , Gonzalez-de-Sande L. , García-Girón C. , García-López J. , Jimenez-Lacave A. , Reboredo M. , Bovio H. , Garcia-Foncillas J.
Published: March 2020

14523

Background: Second-line monotherapy activity in patients with metastatic CRC is low with an objective response rate of 9% in phase II-III studies (Viéitez et al, Am J Clin Oncol 2003; Rougier y cols., 1998). Gefitinib has shown activity in vitro and in animal models against colon cancer cell lines, and has shown to increase the activity of raltitrexed (Cardiello et al, Clin Cancer Res 2000). Methods: A multi-center randomized, double blind, phase II study was initiated in patients with metastatic CRC who failed prior therapy based on 5-FU LV plus OXL or/and CPT and measurable disease. Patients were randomized to received Raltitrexed, 3 mg/m2 IV q3w, (arm A) or Raltitrexed plus Gefitinib, 250 mg PO OD (arm B). Primary end-point was time to progression (TTP); Secondary end-point was objective tumour response rate (ORR) based on the RECIST criteria at six month, overall survival (OS) and safety. Results: Between Dec 2003 and Oct. 2005, 76 patients were recruited in 7 centers. Median age was 65.0 (range 75–31) and 63.5 (range 76–40) years for arm A and B respectively; demographics characteristics were well balanced between both arms including sex, race or other previous mayor conditions. Both treatment arms were well tolerated. Grade 3/4 toxicity in Arm A was: anorexia 10.5% (4), asthenia 10.5% (4), liver toxicity 10.5% (4), nausea 5.3% (2), diarrhea 5.3% (2), abdominal pain 2.6% (1), neutropenia 2.6% (1), thrombopenia 2.6% (1), renal failure 2.6% (1). Grade 3/4 toxicity in Arm B included: anemia 2.6% (1), liver toxicity 7.9% (3), diarrhea 5.3% (2), skin rash 2.6% (1), melenas/upper digestive bleeding 2.6% (1), fever 2.6% (1). ORR was 5.3% (2/38) (95%CI: 0.64–17.75) and 7.9% (3/38) (95%CI: 1.66–21.38) for arm A and B. Median TTP was 72 (95%CI: 59–132) and 63 (95%CI: 57–84) days; median OS was 291 (95%CI: 255–539) and 361 (95%CI: 283–533) days; and median duration of treatment was 74.5 (range 21–274) and 63.5 (range 12–324) days for arm A and B. Conclusions: Addition of Gefitinib to Raltitrexed in pretreated patients with advanced CRC is well tolerated, with manageable toxicity profile, but not increases Raltitrexed efficacy.

No significant financial relationships to disclose.
Prognostic importance of primary tumor resection in patients with advanced colorectal cancer (CRC): A Canadian province’s experience
Authors: Ahmed S. , Shahid R. , Ahmad I. , Alvi R. , Yadav S. , Sami A. , Arnold F. , Popkin D. , Haider K.
Published: March 2020

14529

Background: Surgical resection (SR) of primary tumor in patients with newly diagnosed advanced CRC remains controversial. Limited data is available regarding potential benefit of resection in these patients. We performed a population-based study to determine the prognostic value of SR of primary tumor in patients with metastatic CRC. Methods: Medical records of patients with metastatic CRC diagnosed between 1991–2000 in the province of Saskatchewan were reviewed. Patients with unresectable T4M0 disease were excluded. A multivariate analysis was performed using Cox regression model and various clinicopathologic variables were tested for their prognostic significance. Kaplan-Meier curves were used to determine survival. A preliminary analysis of data of 212 eligible patients diagnosed between 1998–2000 is presented here. Results: Patients median age was 71 yrs (33–94) and M:F was 1:0.77. One hundrad thirty one (62%) patients underwent SR for the primary tumor. Among 131 patients, 76 (58%) were operated for tumor related symptoms (36% obstruction, 14% perforation, and 9% bleeding). Six percent patients died of postoperative complications. Of 212 patients, 36% received 5FU-based chemotherapy (46% patients with SR) and 17% received a second line therapy. Median overall survival (OS) of all patients was 6.7 months. Patients who underwent SR of primary tumor had a significantly better median OS of 11 months compared with 3 months in patients who did not have surgery (HR 0.47; 95% CI 0.29–0.76). Patients who underwent SR and had received chemotherapy had a median OS of 14.8 months compared with median OS of 6 months if they did not receive chemotherapy (HR, 0.29; 95% CI 0.15–0.55). In addition to 5FU-based chemotherapy and SR of primary tumor; metastectomy, age >65 yrs, elevated alkaline phosphatase level and thrombocytosis were other important variables that were correlated with survival in patients with advanced CRC. Conclusions: SR of primary tumor has been associated with significant improvement in survival independent of systemic chemotherapy in patients with advanced CRC. Further analysis of data in patients diagnosed between 1991–2000 is planned to confirm these findings in a larger group of patients.

No significant financial relationships to disclose.
Effect of hyperthermia on the pharmacokinetic profile of oxaliplatin administered by intraperitoneal route in rats
Authors: Piche N. , Leblond F. , Sideris L. , Leblanc G. , Leclerc Y. E. , Pichet V. , Dube P.
Published: March 2020

14535

Background: Whereas in vitro studies have demonstrated that hyperthermia enhances the cytotoxicity and tissue penetration of oxaliplatin, in vivo studies conducted so far have failed to document clearly such effect in the context of heated intraperitoneal chemotherapy. The purpose of this study is to assess the effect of heat on the pharmacokinetic profile of oxaliplatin administered intraperitonealy in rats. Methods: Under general anesthesia, 25 Sprague-Dawly rats of 258 g (235–440 g) were submitted to 3 different doses of intraperitoneal oxaliplatin (460, 920 and 1840 mg/m2) at 3 different temperatures of perfusion (37, 40 and 43Â°C) during 25 minutes. At the end of perfusion, samples in different compartments were harvested for dosage of oxaliplatin concentration: 2 ml of perfusate, 1 ml of portal blood, 1 ml of systemic blood, 100 mm3 of parietal peritoneum and 100 mm3 of mesentery. Dosage of oxaliplatin was performed by high performance liquid chromatography. Results: We observed a linear and proportional correlation between the concentration of oxaliplatin in the perfusate and the concentration of oxaliplatin for all compartments (R2 : 0.9833 for systemic blood, 0.9874 for portal blood, 0.9053 for parietal peritoneum and 0.9999 for mesentery). Regarding the effect of temperature, we observed a linear and proportional correlation of heat on the concentration of oxaliplatin in parietal peritoneum (R2 : 0.8543), no effect on mesentery (R2: 0.1371) and a tendency of heat to limit concentration of oxaliplatin in portal and systemic blood (R2 = 0.0994 and 0.5854 respectively). Conclusion: Heat improves the absorption of oxaliplatin into the peritoneal cells and seems to limit the systemic absorption of oxaliplatin, the latter observation suggesting a decrease in systemic toxicity. These are two strong arguments supporting the use of oxaliplatin by intraperitoneal route, as it is currently done in the human treatment of peritoneal carcinomatosis from colorectal origin.

No significant financial relationships to disclose.
Autoimmunity predicts prolonged survival in colon cancer patients undergoing GOLFIG biochemotherapy
Authors: Correale P. , Tagliaferri P. , Montagnani F. , Remondo C. , Intrivici C. , Fulfaro F. , Tsang K. Y. , Tassone P. , Rotundo M. S. , Venuta S. , Francini G.
Published: March 2020

14542

Background: A multi-center phase II trial has been designed to evaluate toxicity, anti-tumour and immune-biological activity of the bio-chemotherapy GOLFIG regimen in advanced colorectal cancer (A-CRC). Methods: The trial involved 46 patients (34/46 2nd line or more). The biweekly GOLFIG regimen consisted of gemcitabine (1,000 mg/m2, day 1), oxaliplatin (85 mg/m2, day 2), levofolinic acid (100 mg /m2, day 1,2) and 5-FU (400 mg/m2 as a bolus, and 800 mg/m2 as 24 hour infusion, days 1,2) followed by sc GM-CSF (100 μg, days 3 to 8) and sc IL-2 (0.5 X 106 IUs twice a day, days 9 to 14). Results: GOLFIG regimen was well tolerated and resulted very active (ORR = 56.5%; disease control = 91.3%), fulfilling the pre-selected (40–60%) target of activity, with a promising TTP [12.26 months, 95% CI; 9.2–15.2 mo.] and OS [18.76 months, 95% CI; 15.2–22.3 mo.]. We detected a significant rise in lymphocyte number and colon cancer-specific cytotoxic T cells (CTLs) paralleled by a reduction in suppressive T-regulatory CD4+CD25+ FoxP3+ lymphocytes -Treg. Self-limiting autoimmunity (AI) occurred in 6 (14%) patients. 1 patient developed cutaneous lesions, with pathological diagnosis of Discoid Lupus Erythematosus (DLE), while 5 other presented a mono / oligoarticular arthritis mainly localized at the knees, elbows, shoulders and fingers with signs of synovitis (pain and swelling) paralleled by a significant increase of inflammatory markers (ESR, C-RP and rheumatoid factor). Subgroup analysis disclosed a mean time to progression of 23.8 months (95% CI; 12.1–35.56 mo.) and an overall survival of 31.83 months (95% CI; 19.9–43.7 mo.) in the 6 AI patients, significantly longer than in patients who did not develop AI [TTP and OS respectively 10.52 (95% CI; 7.7–13.3) and 16.8 months (95% CI; 13.3–20.2)], P ≤ 0.0039 and 0.0080. 5/6 AI patients are still alive and 3 have so far achieved a survival of 37, 41 and 50 months. Conclusions: The GOLFIG regimen exerts immunological and anti-tumour activity and has manageable toxicity in A-CRC. The occurrence of AI is predictive of a favourable outcome. These results provided the rationale for a presently ongoing phase III trial aimed to compare the efficacy of GOLFIG vs. FOLFOX-4 regimen as first line treatment in A- CRC patients.

No significant financial relationships to disclose.
Phase II comparative study of capecitabine combined with oxaliplatin (XELOX) and CPT-11 (XELIRI) for advanced colorectal cancer patients (p) previously treated with 5-FU-based chemotherapy
Authors: Manzano J. L. , Díaz N. , Rolfo C. , Juez I. , Gracía-Bueno J. M. , González M. L. , Queralt B. , Losa F. , Martín C. , Abad A.
Published: March 2020

14544

Background: Based on the results obtained with Capecitabine (XEL), Oxaliplatin (OX), and CPT-11 (IRI), we proposed this exploratory study to asses the efficacy of XELIRI and XELOX, for advanced colorectal cancer, after a first line treatment with 5 FU plus OX (FOLFOX) or IRI (FOLFIRI). Methods: P aged = 18 with histological diagnosis of metastatic colorectal adenocarcinoma, were assigned to XELOX arm (XEL, 1000 mg/m2 BID during 14 d; OX, 130 mg/m2 d1; q3w) or XELIRI arm (XEL 1000 mg/m2 BID during 14 d; IRI 240 mg/m2 d1; q3w), depending on previous treatment (FOLFIRI or FOLFOX, respectively). Although sample size was calculated for 115 p, recruitment was premature closed due to the low inclusion rate related with cetuximab + IRI approval for second line treatment. Results: Forty three p (25 p, XELOX; 18 p, XELIRI) were enrolled: median age 63.2 years; M/F, 40.5%/59.5%; ECOG PS 0–1, 79.1%. All p have been previously treated for metastatic disease and 65.1% had stage IV. Main sites of metastatic disease were liver (71.8%), lymph nodes (7.7%), pelvis (7.7 %) and lung (5.1%). XELOX/XELIRI treatment data: total number of administered cycles was 94/85 and median relative dose intensity 100%(XEL)/99%(OX) and 96%(XEL)/94%(IRI); disease control rate (PR+SD) was 28%/33.3%, median TTP 3.4/4.1 months, median OS 10.3/11.2 months and 1-year survival, 39.1%/44.3%, respectively. Twenty p (46.5%) received further antitumoral treatment. Most frequent G3–4 toxicities per p are detailed in table 1 . Conclusions: Capecitabine based combinations show an excellent toxicity profile and good efficacy results, in terms of disease control and survival rates, for advanced colorectal cancer patients previously treated with 5-FU schedules.

[Table: see text]

No significant financial relationships to disclose.
A study for establishment of individualized chemotherapy for colorectal cancer based on the individual 50% inhibitory area under the concentration curve (AUCIR50) using the collagen gel droplet embedded culture-drug sensitivity test (CD- DST)
Authors: Ochiai T. , Nishimura K. , Watanabe T. , Kitajima M. , Konishi N. , Sato G. , Futagawa S. , Nagaoka I.
Published: March 2020

14553

Background: The drug sensitivity of tumor cells is one of the key issues to explore in individualized 5-fluorouracil (5-FU) based chemotherapy for colorectal cancer patients. We reported that growth inhibition rate (IR) and area under the concentration curve (AUC) approximated to a logarithmic curve using the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) in ASCO 2003 (#1283). We also reported that the individual 50% inhibitory area under the concentration curve (AUC IR50) could be obtained using the individual AUC-IR curve in ASCO 2006 (#13560). The aim of this study was to evaluate the achievement of the individual AUCIR50 in 5-FU based adjuvant chemotherapy for the establishment of individualized chemotherapy. Methods: Surgical specimen was obtained from resectable 33 CRC patients without any preoperative chemotherapy during 2001 to 2005. 5-FU based adjuvant chemotherapy was administered in all patients. CD-DST was performed under 6–9 different conditions. The individual AUCIR50 was obtained from the individual AUC-IR curve. The patients were divided into 2 groups, the achieved group and the non-achieved group. In the achieved group, total administered AUC was more than the individual AUCIR50 and in non-achieved group, the total administered AUC was less than the individual AUCIR50. Recurrence rates were evaluated from the 2 groups. Results: In all patients, the recurrence rates were 6.7% (1/15) in the achieved group and 27.8% (5/18) in the non-achieved group. In the colon cancer patients, the recurrence rates were 8.3% (1/12) in the achieved group and 10.0% (1/10) in the non-achieved group. In the rectal cancer patients, the recurrence rates were 0% (0/3) in the achieved group and 50.0% (4/8) in the non-achieved group. Conclusions: The recurrence rate of the achieved group was lower than that of the non-achieved group. Therefore, this study demonstrated that the achievement of the individual AUCIR50 could be a prerequisite of individualized 5-FU based adjuvant chemotherapy.

No significant financial relationships to disclose.
Hepatic artery triplet chemotherapy for liver metastases from colorectal cancer
Authors: Levi F. , Adam R. , Innominato P. , Giacchetti S. , Castaing D. , Hauteville D. , Kunstlinger F. , Li X. M. , Machover D. , Bouchahda M.
Published: March 2020

14554

Background: Chronomodulated (Chrono) irinotecan (I), 5-fluorouracil (F), leucovorin and oxaliplatin (O) offered sustained tumor control in CRC patients (pts) failing several chemo (Gholam et al. The Oncologist 2006). The relevance of Chrono IFO as hepatic artery infusion (HAI) for long term outcome was investigated in CRC pts with liver metastases. Methods: 32 heavily pretreated non hospitalized CRC pts received 5-day (d) q21 d courses (c) with d1 I (160 mg/m2 from 2 to 8 am, peak at 5 am) and d2–5 F (600 mg/m2/d from 10 pm to 10 am, peak at 4 am) and O (20 mg/m2/d from 10 am to 10 pm, peak at 4 pm). Intravenous cetuximab was also given to 3 pts. 172 courses (c) were given (median, 5; 1–15) using a multichannel pump (Mélodie, Aguettant, F). Toxicity was assessed q21 d and response q3 c with CT scan. Results: Prior chemo lines 1/2/3/4+: 3/5/10/14 pts; WHO Performance Status 0/1/2/3: 14/11/6/1 pts; median age: 63 years (32–73); liver only: 25 pts; liver and lung: 7 pts. Treatment was withdrawn for thrombosis (7 pts, 21%) and/or Grade (G) 3 abdominal pain (4 pts ). G3–4 diarrhea occurred in 6 pts (12%). G3–4 leucopenia, anemia and thrombocytopenia were respectively found in 5, 2 and 1 pt. G3 sensory neuropathy occurred in 3 pts with similar G at baseline. 3 pts displayed alopecia. Of 29 pts with measurable lesions, disease progressed in 12 pts (exclusively outside the liver for 4 pts) and was controlled in 17 pts (58%), including 10 objective responses - 34% [95% C.L. 13.4 to 50.6]. Partial hepatectomy was performed in 4 pts with measurable disease (14%): R0 (3 PR) and R1 (1 SD). Median Progression free survival (months, m) is 5 m [1.9 to 8.0] and median survival is 18.4 m [9.9 to 26.9], with 6 pts alive at 2.9 to 63 m. Conclusions: Triplet chronoHAI is safe in heavily pretreated pts and achieves consistent activity against CRC liver metastases despite prior failure on the same 3 drugs. The combination of systemic cetuximab with triplet HAI is feasible and could prevent extra hepatic dissemination, a hypothesis to be soon tested in a prospective European trial. Supported by ARTBC, Hôpital P. Brousse, Villejuif, France.

No significant financial relationships to disclose.
Clusterin in stool: A new diagnostic marker of colorectal cancer
Authors: Pucci S. , Sesti F. , Mazzarelli P. , Bonanno E. , Spagnoli L. G.
Published: March 2020

14561

Background: Colon cancer is second only to lung cancer in men and to breast carcinoma in women, for incidence and mortality in western countries .The higher incidence per age is observed between the sixth and seventieth decade, while 60% of the patients survive up to five years. The most important reason for the low percentage of recoveries is due to the fact that when the primary tumour is removed, a high number of patients have already developed micro-metastases, principally at liver. Therefore, methods for early screening are requested. Molecular markers have emerged as an important strategy to evaluate the individual susceptibility for cancer insorgence and for clinical cancer therapy. Recent studies have demonstrated an increase in clusterin expression in breast carcinoma suggesting a possible role of this protein in tumour progression. Clusterin is an heterodimeric (a and β chains) ubiquitous glycoprotein implicated in a large number of physiological processes and in the control of cellular proliferation. Despite the original hypothesis that clusterin is a marker for programmed cell death, several experiments and clinical studies have demonstrated conflicting findings on its role in tumors. Methods: We have studied clusterin isoforms expression in tumour progression, in particular in the adenoma-carcinoma sequence of colorectal cancer. Results: the observation of 35 samples of human intestinal mucosa, such as endoscopic biopsies and surgical specimens, demonstrated that the progression towards high grade and metastatic colon carcinoma leads to a pattern shift of clusterin isoforms production, the complete loss of the proapoptotic nuclear form and an over expression of cytoplasmic secreted form correlateting to a phenotype with high metastatic potential. Moreover we observed in tumor biopsies the release of clusterin in the crypts lumen. The ELISA immuno-dosage of clusterin demonstrated that the sclusterin overexpression in tumours correlates to a significant increase of clusterin in the serum and stools of patients affected by tumoural pathologies and in particular by colorectal cancer. Conclusions: These data suggests a new role of secreted clusterin as a new diagnostic circulating marker and a potential new therapeutic target.

No significant financial relationships to disclose.
Combined treatment of colorectal cancer cell lines with aspirin and bortezomib
Authors: Voutsadakis I. , Patrikidou A. , Tsapakidis K. , Stathakis N. E. , Papandreou C. N.
Published: March 2020

14562

Background: The ubiquitin-Proteasome system (UPS) has emerged as an important proteolytic system for the regulation of a wide range of cellular functions. Key determinants of carcinogenesis, are regulated in multiple levels by UPS. Proteasome inhibition by the boronic containing molecule bortezomib is already in use for the treatment of multiple myeloma and is in various phases of investigation for other malignancies. Cox inhibitors such as NSAIDs have been shown to inhibit the growth of colorectal cancer cells in vitro and polyp formation in vivo. Methods: HT-29 and HCT116 colorectal cancer cell lines were treated with aspirin (ASA), bortezomib and their combination. MTT assay was used to evaluate the effect of treatment on cell proliferation compared to controls. Cox activity and proteasome activity were measured with colorimetric methods. The effect of drug treatments on specific proteins expression was assayed by western blotting. Results: Both cell lines are inhibited by ASA and bortezomib and their proliferation is further inhibited by the combination of the two drugs. In HT-29 cells both ASA and bortezomib inhibit proteasome and their combination has additive effect in this inhibition. In contrast in HCT116 cells ASA-mediated inhibition is accompanied by increased proteasome activity while bortezomib-mediated growth inhibition is accompanied as expected by proteasome inhibition. ASA-mediated inhibition is not Cox-mediated since no Cox activity was detected in either cell line. Cell cycle inhibitor p27 expression is induced in HCT116 cells by bortezomib while ASA fails to do so. In HT29 cells p27 is expressed at baseline and does not change significantly by treatments. Conclusion: The combination of ASA and bortezomib inhibited the proliferation of both cell lines more than either drug alone in a Cox-independent way. ASA had opposite effects on proteasome activity in the two lines. p27 induction may mediate at least partially the anti-proliferative effect of bortezomib in HCT116 cells. Further studies are in progress to determine other molecular components of the cellular processes taking place during treatment by the combination of these drugs in order to better understand their mechanism of action and thus explore their potential therapeutic use.

No significant financial relationships to disclose.
Predictive value of D-dimer and LDH levels in response to chemotherapy in metastatic colorectal cancer patients
Authors: Er O. , Inanc M. , Ozkan M. , Dogu G. G. , Dikilitas M. , Ozturk A.
Published: March 2020

14568

Background: Hemostatic activation is known to occur in malignant diseases and this may be associated with tumor progression and angiogenesis. D-dimer levels are elevated in lung, uterine cervix, prostate and colorectal cancer patients. We aimed to evaluate the association and predictive value of LDH and D-Dimer levels with chemotherapy response in metastatic colorectal cancer (MCRC) patients. Patients and Methods: Twenty-five chemotherapy-naive MCRC patients were enrolled into this study. Plasma CEA, CA19–9, D-Dimer and LDH levels were measured before and after 3 cycles of capecitabine + oxaliplatin combination chemotherapy. The comparison between groups were done by Wilcoxon W and Mann-Whitney U tests. Results: Median age was 58 years in 15 female, 10 male patients. All patients received Capecitabine 2,000 mg/m2/day orally on days 1- 14 + Oxaliplatin 130 mg/m2 intravenously on day 1 every 21 days. The chemotherapy response after 3 cycles of treatment were 2 complete response, 7 partial response, 8 stable disease and progressive disease in 8 patients. Plasma CEA, CA19–9, LDH and D-Dimer levels were not significantly different between two groups before chemotherapy (table). Plasma LDH and D-Dimer levels were significantly higher in progressive disease patients than patients with complete, partial or stable response after 3 cycles of chemotherapy, but plasma CEA and CA19–9 were not significantly different between these groups (table). Conclusion: We found that D-dimer and LDH levels dropped in responders while they increased in patients with disease progression. D- Dimer and LDH plasma levels decrease or increase after response and progressive disease, respectively, and can act as a predictive factor of the clinical outcome of the disease.

[Table: see text]

No significant financial relationships to disclose.
Preventive approach to allergic reaction to oxaliplatin
Authors: Suenaga M. , Mizunuma N. , Chin K. , Kuboki Y. , Shizozaki E. , Yamaguchi T. , Muto T. , Hatake K.
Published: March 2020

14569

Background: Allergic reaction to oxaliplatin is a chronic adverse event in the treatment of cancer. Patients with colorectal cancer were given FOLFOX4, using preventive approaches composed of two steps. Methods: Step I included 40 mg famotidine, 8 mg dexamethasone from the first cycle and 50 mg of diphenhydramine after cycle 4. In step II, for the patients who had a reaction but not a severe one in step I, a 20 mg dose of dexamethasone and four-hour oxaliplatin infusion were administered. Results: Forty-eight patients (15.1%) presented with allergic reaction, divided into group A receiving step I except diphenhydramine and B undergoing all of step I. Significant delay on occurrence was observed in group B. Thirty patients underwent step II. Prevention success (well-prevented) was defined as no reaction in two or more treatments. Allergic reaction appeared again in eleven patients (not well-prevented, 36.7%), but most well-prevented patients got four months longer treatment time with no reaction than not well-prevented patients. Conclusions: In our preventive approach, administration of H-1RA was effective in delaying the occurrence of allergic reaction to oxaliplatin, and increased dose of dexamethasone 20 mg and prolongation of oxaliplatin infusion from 2 to 4 hours was succeeded in continuing the FOLFOX4.

No significant financial relationships to disclose.
Colorectal cancer nutritional and quality-of-life parameters predict patients outcomes after radiotherapy: Long-term follow-up from a prospective randomized controlled trial
Authors: Ravasco P. , Monteiro Grillo I. , Camilo M.
Published: March 2020

14570

Background: Long term data of our published randomized trial of nutritional therapy in colorectal cancer showed that nutritional counseling optimizes pts prognosis. This study aimed to search whether outcomes were affected by individual nutritional & Quality of Life (QoL) parameters after nutrition intervention and radiotherapy (RT). Methods: Data were obtained from the trial pts’ records: G1 (n=37) on individualized nutritional counseling & education (regular foods), G2 (n=37) ad lib+polymeric protein supplements & G3 (n=37) ad lib intake. After RT, current intake (diet history), nutritional status (PG-SGA) & QoL scores (EORTC) were evaluated; their ability to predict survival, disease outcome [loco regional recurrence (LRR), distant metastases] & late RT toxicity (permanent flatulence, abdominal distension, diarrhea) were analyzed after a median follow-up of 3.7 (2.0–5.8) yrs. Results: Energy/protein intakes had decreased in G3 (p<0.01) & increased in G1>G2, p=0.007; wasting only occurred in G3>G2 (p<0.05); QoL scores worsened in G3>G2 (p<0.05) yet improved in G1, p<0.01. On multivariate analyzis of coded time-dependent variables: poorer diet intake, nutritional wasting & worse QoL scores were associated with decreased survival (p<0.002), LRR (p=0.01), distant metastases (p=0.005) & late RT toxicity, p<0.003. Landmark analysis showed that pts with nutritional intake/status & QoL deterioration, had significantly lower survival (hazard ratio [HR]: 8.25; 95% CI 2.74–26.47; p<0.001), worse disease outcome (HR: 8.15; 95% CI 2.22–25.40; p<0.002) & more severe late RT toxicity (HR: 7.15; 95% CI 2.25–16.11; p<0.004). Conclusions: In colorectal cancer after RT, poor diet intake, wasting & deteriorated QoL look as if significant predictors of survival, treatment response & late RT toxicity; such patients are prone to a more aggressive clinical course.

No significant financial relationships to disclose.
Institutional experiences with panitumumab monotherapy in metastatic colorectal cancer (mCRC) patients (pts) intolerant to cetuximab
Authors: Langerak A. D. , Mitchell E. , Cheema P. , River G. L. , Shing M.
Published: March 2020

14579

Background: Two monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor are approved for the treatment (tx) of advanced mCRC - panitumumab (Vectibix™), a fully human mAb, and cetuximab (Erbitux®), a chimeric mAb. Potential for cross-reactivity between these two mAbs with regard to infusion reactions (IR) has not been fully explored. Given the lack of sequence homology between the 2 agents and the fully human nature of panitumumab, it is hypothesized that pts intolerant to cetuximab due to IR could be tolerant to panitumumab. Methods: Single pt tx IND applications to administer panitumumab monotherapy in pts with advanced mCRC were approved by the FDA and local institutions as part of the Panitumumab Compassionate Use program. Eligibility also included previous tx with standard chemotherapy and intolerability to cetuximab, ie. CTCAE v3.0 grade 3 (severe) or grade 4 (life-threatening) IR. Results: Upon informed consent, 4 pts (2M/ 2F) were enrolled in 4 centers. Median (range) age was 62.5 (52, 64) years. 3 pts had colon cancer and 1 pt had rectal cancer. All had surgery and received prior 5-fluorouracil, leucovorin, irinotecan, oxaliplatin, bevacizumab, and cetuximab. One pt had a CTC grade 3 IR and 3 pts had a CTC grade 4 IR to cetuximab. IR symptoms included fever, wheezing, dyspnea, chest/back/abdominal pain, anxiety, hypotension, flushing, tachycardia, and tachypnea. Two IRs occurred within 10 minutes of the first cetuximab infusion. Cetuximab was discontinued and IR symptoms were treated with bronchodilators, diphenhydramine, epinephrine, methylprednisolone, oxygen, intravenous saline, and hospitalization. All pts received panitumumab. Data for pts 1, 2, and 3 are available: pt 1 received 1 infusion of panitumumab at 5 mg/kg Q2W with premedication (diphenhydramine and methylprednisolone); pts 2 and 3 received 7 and 2 panitumumab infusions, respectively, at 6 mg/kg Q2W without premedication. No pt had an IR to panitumumab. Pt 2 had stable disease; pts 1 and 3 died due to disease progression. Conclusions: Panitumumab monotherapy was tolerated without incidence of an IR in these cases of mCRC pts who are intolerant to cetuximab due to a severe or life-threatening IR. Additional data will be presented.

No significant financial relationships to disclose.
Additional variables other than AJCC staging show clinical utility for predicting survival in colon cancer
Authors: Wiseman S. M. , Leung S. , Griffith O. , Jones S. , Masoudi H. , Phang T.
Published: March 2020

14584

Background: The most important predictor of colon cancer patient outcome is disease stage at the time of surgery. However, staging does not accurately predict survival for all patients undergoing a resection with curative intent. The aim of this study was to analyze clinical and pathological characteristics of patients undergoing curative colon cancer, in order to identify characteristics, in addition to stage, predictive of disease outcome. Methods: Between 1997 and 2005 data for 114 patients undergoing curative resection for colon cancer at a tertiary care institution were collected. Clinical and pathological characteristics evaluated were: age, gender, tumor location, tumor size, scheduled vs emergent surgery, pathologic margin status, TNM stage, pathologic grade, number of positive lymph nodes, total number of lymph nodes resected, vascular and lymphatic invasion. Characteristics found to be significant in a Kaplan-Meier univariate survival analysis were included in a multivariate stepwise logistic regression analysis. Patient outcomes studied were overall survival, cancer specific survival, and disease free survival. Results: From the 114 patients examined in this cohort the mean age was 67 years, the male to female ratio was 0.8:1, and the mean follow up time was 2.61 years. Overall survival, cancer specific survival, and disease free survival were calculated to be 83.3%, 91.2% and 84.2%, respectively. Statistically significant variables by univariate analysis were: AJCC stage, number of positive lymph nodes, pathologic N stage, lymphatic and vascular invasion by the primary tumor. Further multivariate analysis revealed that lymphatic invasion was the only significant independent influence for predicting disease recurrence. Conclusions: Clinicopathologic characteristics, in addition to AJCC disease stage, may be of clinical utility in predicting outcome for patients who have undergone curative resection for colon cancer. Further evaluation of these clinicopathologic characteristics should be carried out in a larger colon cancer patient cohort.

No significant financial relationships to disclose.
Hand-assisted laparoscopic vs open colectomy in a rural healthcare center
Authors: Osarogiagbon R. U. , Ogbeide O. , George R.
Published: March 2020

14587

Background: Complete surgical resection is a key component of curative therapy for colon cancer. Accurate pathologic staging requires examination of a sufficient number of lymph nodes in the resection specimen. Open colectomy (OC) is the traditional surgical technique, newer minimally-invasive laparoscopic techniques allow equivalent-quality cancer resection while reducing post-operative morbidity, but require longer operating time. Hand-assisted laparoscopic colectomy (HALC) may yield the benefits of laparoscopic colectomy while reducing operating time. The benefits of laparoscopic surgery reported in tertiary healthcare centers may not be achievable in non-tertiary care centers. We compared the operative experience of patients undergoing HALC to those who had OC at a rural veterans Hospital. Methods: Study design: Retrospective case-control study of consecutive patients undergoing HALC for colon cancer from April 2000 to September 2004 compared to patients who had OC. Patients with rectal and stage IV colon cancer were excluded. Reported variables were compared by the non-parametric Mann-Whitney U-test, all p-values are two-tailed. Results: Data is reported as HALC vs. OC. N= 39 in HALC cohort vs. 55 in OC. Median age: 72.1 vs 70.3 yrs (p 0.46). Location of tumors: right colon 62% vs 56%, left colon 2.5 vs 11%, sigmoid colon 36% vs 33. Stage: 0, 23% vs 11%; I 23% vs 23%; II 31% vs 36%; III 23% vs 31%. Median operating room time was 139 vs 137 minutes (p 0.94). 4 of 39 (10%) HALC procedures were converted to OC. Number of lymph nodes in resection specimen 12 vs 9 (p=0.043). Duration of hospitalization: 6 days vs 10 days (p=0.007). 5% of HALC patients were transfused vs 13% of OC patients. There were 3 cases of serious post-operative infection in the HALC group vs 9 in the OC cohort, 0 cases of wound dehiscence vs 3, 0 perioperative deaths vs 3. Overall, 8% of HALC patients developed severe post-operative surgical complications vs 22% of OC patients (p<0.05). Conclusions: HALC is technically feasible in the non-tertiary care setting, with equivalent duration of surgery to OC, but significantly shorter duration of hospitalization. The quality of surgical resection, pathologic staging and rates of peri-operative morbidity and mortality are similar or slightly better with HALC.

No significant financial relationships to disclose.
Repeat hepatic resection and chemotherapy for recurrent colorectal liver metastases
Authors: Ferrari D. , Opocher E. , Santambrogio R. , Pisani A. , Barabino M. , Codecà C. , Scalzone R. , Marussi D. , Luciani A. , Foa P.
Published: March 2020

14590

Background: An aggressive surgical approach combined with chemotherapy (CHT) is the best way to prolong survival in patients with colorectal cancer and synchronous resectable metastatic disease. Reintervention followed by systemic CHT is often a safe and effective procedure for fit patients with metastatic liver recurrence. Methods: Patients with resectable metastatic liver disease who underwent at least two surgical operations were included in the study. At diagnosis they had a median number of 6 measurable liver metastases (range 1–16), and median sum of largest diameters of lesions was 35 mm (range 10–70) from CT scan. Hepatic resection was followed each time by systemic CHT. Radiofrequency (RF) was added as needed to reach a curative intent . The aim of our study was to evaluate DFS and OS combining surgery, RF and CHT in this high-risk group. Results: Between November 2003 and July 2006 13 patients (median age 52 yrs, range 36–73; PS 0) with metastatic colorectal cancer underwent surgery on primary tumour and liver metastases followed by adjuvant CHT consisting of FOLFOX4 (oxaliplatin 85 mg/m2 and LV5FU) or FOLFIRI (irinotecan 180 mg/m2 and LV5FU) for 6 months. Free margins were obtained in 12 patients (92.3%). The second relapse was treated by liver surgery and systemic CHT (either FOLFIRI or FOLFIRI + Cetuximab in EGFR expressing tumours). Eight patients were offered concomitant radiofrequency (RF) for smaller lesions. Five patients (38.5%) underwent a third operation + RF followed by third-line CHT consisting of capecitabine alone or associated to oxaliplatin. After second and third hepatectomy there was no intraoperative or early postoperative mortality. With a median follow-up of 24 months (range 6–37) 6 patients are free of disease and all patients are still alive. Two-year DFS and OS are 46.2% and 100% respectively. Conclusions: Patients with metastatic colorectal cancer should be treated aggressively by surgery and CHT. In a small group of fit patients operated at least two times we obtained excellent 2-year DFS and OS. The benefit of adding adjuvant CHT as second-line or even third-line treatment seems to be justified by good long-term results. Our promising data from a single institution prompt further evaluation for aggressive surgery associated to CHT and new target molecules.

No significant financial relationships to disclose.
XELOX causes less disabling peripheral neuropathy than FOLFOX 4 for Chinese colorectal cancer patients
Authors: Yau T. , Chan P. , Tsang J. , Liang R. , Epstein R.
Published: March 2020

14592

Background: Infusional 5-FU plus leucovorin and oxaliplatin (FOLFOX4) is an efficacious treatment for colorectal cancer patients in both the adjuvant and metastatic settings. However, around 10% of FOLFOX4 patients will develop with disabling grade 3–4 neuropathy. Recent phase II studies have demonstrated that oral capecitabine in combination with oxaliplatin (XELOX) is as least as effective as FOLFOX4 for colorectal cancer. In this study, we assessed the toxicities of XELOX in Chinese colorectal cancer patients. Methods: Patients who received XELOX at Queen Mary Hospital, Hong Kong between November 2004 and November, 2006 were analyzed. Toxicities were graded by the National Cancer Institute common toxicity system. Results: Thirty-five patients received XELOX on an outpatient basis during the study period: Twenty-four as adjuvant therapy and 11 as treatment for metastatic disease. The most common side effect was grade 1–2 peripheral neuropathy which occurred in 77% of patients. No grade 3–4 neuropathy was reported. Grade 1–2 diarrhea and palmar-plantar erythrodysesthesia (PPE) also occurred in 40 % and 37 % of patients, respectively. The commonest grade 3 toxicities was diarrhea which occurred in 17% of the patients followed by 9% of patients experienced grade 3 PPE. No grade 4 toxicities were reported in our patient’s cohort. Overall, only one (3%) patient had neutropenic sepsis and 36% of patients required 20% reduction in drug dosage. No treatment related death was reported. Conclusions: Our study suggests that XELOX is a well-tolerated and convenient treatment regime. Although mild neuropathy is common in patients receiving XELOX, it causes far less disabling neuropathy than FOLFOX4 in Chinese metastatic colorectal cancer patients.

No significant financial relationships to disclose.