bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of innate responses elicited by neoadjuvant radio-chemotherapy for rectal cancer
Authors: Castiglioni A. , Bencardino K. , Tamburini A. M. , Monno A. , Albarello L. , Staudacher C. , Ronzoni M. , Doglioni C. , Rovere-Querini P. , Manfredi A.
Published: August 2020

e15044

Background: The neoadjuvant chemo-radiotherapy (CT-RT) has improved the treatment of locally advanced rectal cancer reducing the local recurrence. However a survival benefit has not been reached yet. In order to increase the rate of pathological complete remissions in our Institution we intensified both the CT schedule adding oxaliplatin to 5-FU and the RT program with tomotherapy. The aim of this study was to verify: whether the pattern of innate response elicited by the neoadjuvant CT-RT is heterogeneous among pts and whether this information can be used to identify which pts will benefit from the treatment. Methods: We collected samples of T3N+M0 rectal cancer pts before, during and after neoadjuvant CT-RT (3 cycles of oxaliplatin + 5-FU; 45 Gy). At each time point we characterized circulating monocytes by flow cytometry, infiltrating macrophages by immunoistochemistry (IHC) and selected inflammatatory molecules by ELISA.Results: We recruited so far 25 pts, of whom 10 have reached the surgery with three pathological complete remission and four down staging. No substantial changes were detectable in the number of circulating monocytes. In contrast we observed a clear expansion of CD14/CD86 and CD14/CD163 double positive subsets. This event was transient and apparently causally related to the treatment since it abated at the later time point. Moreover, it correlated with sensitivity to the treatment: 5/7 pts who underwent disease regression had an early and transitory increase of the number of CD14/CD86 and CD14/CD163 positive cells, which was absent or negligible in non responder pts. The IHC study revealed a massive tumoral infiltration by macrophages which displayed clear features of alternative M2 polarization as assessed by expression of the CD163 and 206 scavenger receptors. A subset of pts had elevated PTX3 and low CRP concentration at the onset of treatment. PTX3 concentration abated after the first CT cycle. Conclusions: These data suggest that neoadjuvant CT-RT modulates the cellular components of innate immune responses, that could represent valuable predictive factors.

No significant financial relationships to disclose.
Adjuvant chemotherapy for stage II and stage III colon cancer—What is happening in routine practice?
Authors: Ananda S. , Kosmider S. , Lim L. , Barnett F. , Desai J. , Gibbs P.
Published: August 2020

e15046

Background: Randomised studies have defined adjuvant chemotherapy as standard treatment for stage III colon cancer (SIIICC), with multiple options available. For stage II (SII) disease, the selection of patients for adjuvant treatment remains controversial. There remains limited data on clinician decision making regarding adjuvant chemotherapy in routine clinical practice. Methods: A review of patients treated with SII & IIICC at 4 hospitals, utilising data from BioGrid Australia, where clinician choice and rationale were prospectively documented. Results: 372 patients (37%) with SII and 307 (30%) with SIIICC were identified from 1015 CC patients treated from January 2003 till November 2008. Median age was 68 years, 51% were male; 49% female. 66 (25%) of patients with SIIICC were not offered chemotherapy, predominantly due to advanced age or co-morbidity. Since oxaliplatin and capecitabine became widely available in 2005, 66% of treated patients have received oxaliplatin based therapy, 15% bolus 5-FU alone and 19% capecitabine. For SII disease, overall 81 (26%) pts received adjuvant chemotherapy. Age was the dominant influence on treatment choice with 41% aged 70 (p<0.001) receiving treatment. Patients with high risk features were also more likely to receive adjuvant therapy. (p= 0.006 for those with lymphovascular invasion and p= 0.0068 for those with T4 tumours). Dose reductions and completion rates were similar for SII and III disease, and for older and younger patients. Conclusions: Over 25% of patients with SIIICC do not receive adjuvant chemotherapy in routine practice, with physicians basing non-treatment recommendations predominantly on patient age and co-morbidity. Where treatment is used, oxaliplatin-based therapy is the dominant regimen, except in older patients. In SIICC, adjuvant chemotherapy is used in one in four patients, more frequently in younger patients and those with high risk features.

No significant financial relationships to disclose.
Long-term overall survival (os) and prognostic factors of patients (pts) with surgery of liver metastases from colorectal cancer origin (lm/crc): Retrospective analysis of a Spanish single institution
Authors: Quispe I. R. , Ramos F. J. , Bilbao I. , Macarulla T. , Cedres S. , Charco R. , Lázaro J. , Moreiras M. , Moreiras M. , Tabernero J.
Published: August 2020

e15052

Background: Hepatectomy is the only potentially curative treatment for LM/CRC. Long-term survival following liver resection (LR) has improved. The aim of this study was to analyze prognostic factors and OS after LR Methods: A retrospective review of the medical records of pts who underwent LR for LM/CRC from 1997 to 2007 was conducted. Multiple potential prognostic factors for survival were analyzed: synchronic vs. metachronic, post-op chemotherapy (CT) vs. no, lymph node (LN) status of primary tumor, R0 vs. R1–2 resection, gender, location of primary tumor, number and size of metastases, and unilobar vs. bilobar disease. Results: 190 pts (colon 130, rectum 60) underwent LR. Pts’ characteristics: 123 male, 67 female; median age 63 yrs (32–85); 95 pts synchronic, 95 metachronic; 145 pts (76%) received post-op CT; LN status was pN0 in 61 (32%) pts, pN1 in 74 (39%) and pN2 in 52 (27%). A R0 resection was performed in 164 (86%) and R1 in 25 (13%). Post-op mortality was 2.6%.Median OS was 68 months with 5- and 10-year OS of 52% and 31%, and 5- and 10-year disease free survival of 36% and 18%. 5-year OS differed between metachronic and synchronic (64% vs. 39%; p<0.001); LN-status (73% for pN0 vs. 41% for pN1–2; p<0.001); R0/R1–2 surgery (58% for R0 vs. 21% for R1- 2; p=0.002). With a median follow-up of 70 months, 71 (37%) pts remained free of disease, 60 (32%) had new metachronic LM/CRC, 18 (9.5%) had LM/CRC and extrahepatic disease and 36 (19%) had extrahepatic disease alone. Non-significant factors for prognosis were gender, location of primary tumor, number and size of metastases, bilobar disease and adjuvant CT. Conclusions: Pts with LM/CRC who undergo liver resection can achieve long-term OS, our data identifying as prognostic factors: LN status, synchronic/metachronic disease and Type of resection (R0).

No significant financial relationships to disclose.
Phase II study of biweekly XELOX (capecitabine and oxaliplatin) as first line chemotherapy in elderly patients with metastatic colorectal cancer
Authors: Grande C. , Quintero G. , Mel J. R. , Huidobro G. , Campos B. , Candamio S. , Méndez J. C. , Salgado M. , Álvarez E. , Casal J.
Published: August 2020

e15053

Background: Analysis of efficacy and toxicity of biweekly XELOX as first line monotherapy in elderly patients (pts) with metastatic colorectal cancer (MCRC), based in results of W. Scheithauer (J Clin Oncol 2003; 21: 1307). Methods: From March/06 to November/08, 28 chemonaïve elderly pts (>75 years old) with MCRC, PS: 0–2, and adequate renal, hepatic and bone marrow functions, were included in a phase II study of: oxaliplatin 85 mg/ m2/ day 1 plus capecitabine 2000/ m2/ in 2 divided doses/ days 1–7 every 2 weeks. Treatment was continued until 12 cycles, tumour progression or innaceptable toxicity. Response evaluation every 6 cycles and toxicity every cycle was performed. At present 28 pts for toxicity and 24 pts for response are evaluable. Results: Median age: 78.2 years (range: 73.5–79.5). Male/Female: 14/14. Rectal/Colon: 9/19. Metastatic sites 1/2/>2: 15/6/6. Liver 78.6%, Lung 32.1%, Local tumour 7.1%, Retroperitoneum 14.2%, Peritoneum 10.7%. and Bones 7.1 %. Previous adjuvant with 5-FU regimens to 4 pts. Comorbidity grade by Charlson index 0–1/2/>2: 60.8%/ 28.6% / 10.7%, respectively. Median number of cycles for oxaliplatin and capecitabine were 8 (5.25–12) and 8 (5.25–11.75). Response rate: 2 pts complete response (8.3%), 8 pts partial response (33.3%),10 pts stable disease (41.7 %) and 4 pts progression (16.7%). The main CTC toxicity was Asthenia G2+3 in 6 (21.5%), Nausea and emesis G2 in 7 (25%), Diarrhea G2+3 in 7 (25%) and Hand-foot syndrome G1+2 in 5 pts (17.8%). No G4 toxicity or toxic deaths were observed. Median time to progression was 8.6 months.Median overall survival will be given updated at the congress. Conclusions: Preliminary results suggest that bi-weekly XELOX is an effective first line treatment for MCRC in elderly pts with an acceptable toxicity profile (especial surveillance of diarrhea is necessary) and protocol cumpliment. Combination with bevacizumab should be considered.

No significant financial relationships to disclose.
Extent of resection for curable colorectal cancer in young patients: A 27-year experience at a tertiary care centre
Authors: Al-sukhni E. , Ridgway P. F. , O’Connor B. , McLeod R. S. , Swallow C. J.
Published: August 2020

e15059

Background: Patients diagnosed with colorectal cancer (CRC) under the age of 50 have an increased lifetime risk of developing metachronous primary tumours. Some familial GI cancer experts have recommended that younger patients with curable CRC undergo definitive subtotal colectomy at initial presentation. We sought to determine the compliance with these recommendations at our institution, the factors predictive of subtotal/total colectomy, and the influence of resection extent on survival. Methods: A case- control study utilised a prospective CRC database at Mount Sinai Hospital, Toronto. All patients under 50 who underwent initial resection of CRC with curative intent from 1979–2007 were included. Patients 50 or over were identified as controls. Type of resection was classified as complete (total/subtotal colectomy, proctocolectomy) or segmental. Results: From the database of over 1400 CRC cases, 201 patients were under age 50. 1182 controls were identified. The young patients had significantly higher rates of identifiable risk factors for CRC (IBD, FAP/HNPCC, family history of cancer) and were significantly more likely to undergo complete resection (23.38% vs 6.01%, OR 4.78). Interestingly, rectum was the primary site in 54.73% of young patients. Factors contributing to complete resection were site of disease (colon), IBD, and family history of CRC (Table). Four patients (2.6%) who underwent segmental resection developed metachronous disease at a median of 66.38 months post resection. No significant change in practice was noted over time. Conclusions: The majority of young patients with curable CRC underwent segmental resection only. Factors predictive of a complete resection included IBD, family history of CRC, and colonic primary site. Overall survival was not influenced by extent of resection. The authors support this pragmatic approach while more sophisticated estimates of tumor biology are being developed to guide the decision for more extensive prophylactic resection.

[Table: see text]

No significant financial relationships to disclose.
Regulation of expression of cd133, a colon cancer stem cell marker and other stemness genes/pathways, by celecoxib: Clues from clinical observations
Authors: Deng Y. , Wang L. , Tian Q. , Miller C. , Lin T. , Chien A. J. , Ulrich C. M. , Grady W. M. , Blau C. A. , Lin E. H.
Published: August 2020

e15065

Background: CD133 identifies intestinal stem cells and colon CSC, the putative culprit of cancer initiation, progression and resistance. Elevated CD133 levels at protein & mRNA levels predict poor outcomes in patients (pts) with colon cancer. Given that celecoxib reduces colon polyp and only maintenance capecitabine plus celecoxib lead to paradoxically high complete remission (CR) in colon cancer pts who had no resection or positive margin resection of metastases (ASCO 2007), we hypothesized that celecoxib could modulate CD133 and other stemness genes/signaling pathways. Methods: we studied the effects of celecoxib versus 5-FU on CD133, Wnt and other stemness genes/pathways using flow cytometry, immunoflurorescence, real time RT-PCR, western blot, TOP-Flash for Wnt, limiting dilution assay, and Affymetrix in colon cancer cell lines and primary colon cancer spheres. Results: Celecoxib or 5FU inhibited the growth of COX-2+ HT29 or COX-2- DLD1 that express CD133 at 80% and 30% respectively. Only celecoxib down-regulated CD133 expression at the mRNA, and protein levels in a dose and time dependent manner. This effect could not be rescued with PGE2 and may be due to Wnt inhibition. Microarray showed 4 folds down-regulation of CD133 and other stemness genes e.g. CD24, ABC transporters, and LGR4/5, findings of colon cancer sphere under differentiation. Celecoxib affected several key stem cells signaling pathway, restored RB and promote cell cycle progression (P < 0.05). In contrast, 5FU affected G2M transition but had no effects on stemness genes/pathways (p < 0.05). Celecoxib resulted in 6–10 folds reduction in colony size and number with 5.6–36 folds down-regulation of CD133 mRNA in primary colon cancer spheres. Pts with confirmed radiographic CR who had received >6 months of maintenance capecitabine and celecoxib reached 5-year survival > 90% comparable to pts who achieved pathological CR (12/19). Conclusions: Targeting colon CSC with capecitabine and celecoxib may lead to durable CR and survival and deserves further investigation.

No significant financial relationships to disclose.
Safety of bevacizumab when given perioperatively for colorectal cancer with liver metastases: McGill University pilot study
Authors: Kavan P. , Bouganim N. , Eid M. , Metrakos P. , Chaudhury P. , Batist G.
Published: August 2020

e15083

Background: Bevacizumab (BV) increases responses and survival rates when used with chemotherapy in metastatic colorectal cancer (CRC). Current practice is to give peri-operative chemotherapy for resectable CRC liver metasases (LM). The safety and efficacy of chemo-BV in this setting is unknown. Post-operative complications have been reported in patients (pts) who underwent surgery while receiving BV. The goals were to determine safety of perioperative BV. Methods: In a prospective pilot study, patients with resectable LM from October 2005 to 2008 that received BV perioperatively along with chemotherapy. Of a total of 60 pts, 34 had oxaliplatin-based CTX, 22 CPT-11 (FOLFIRI) and 4 IROX. All but seven pts received BV pre and postoperatively. The average age was 55 years. All patients underwent liver surgery 6–8weeks post last dose of BV. Univariate Cox regression models were used to evaluate the association of patient and tumour characteristics, therapy and postoperative complications. Results: Postoperative complications developed in a total of 24 pts (40%). 12 pts (35%) who received Oxaliplatin CTX + BV, 9 pts (40%) with CPT 11 CTX + BV and 3 pts (75%) with Oxaliplatin + CPT-11 CTX +BV. The average time from BV discontinuation to surgery was 49 days. No significant associations were identified between BV and CTX regimen or timing and postoperative complications. Wound healing complication were most frequent with 8 pts (13%), DVT diagnosed in 6 pts (10%), protracted pancytopenia 4 pts (7%), sepsis 1pt, infections 2pts, MI 1pt, acute cardiomyopathy 1pt, and billiary leak 1pt. No bowel perforations or sudden deaths were reported. These side effects apart from thromboembolic events are comparable to previously reported post-operative complications. Conclusions: Neither the use of BV with CTX nor timing of BV administration were associated with a non acceptable increase in complication rates as compared to previously published by EORTC intergroup. Our data confirm that the combination of BV with neoadjuvant chemotherapy is feasible and safe in patients CRC LM. A higher incidence of thromboembolic events was seen. To determine the optimal timing and drug combination prospective randomized trials are urgently required.

[Table: see text]
Systematic review of histamine type 2 receptor antagonists as an adjunct to curative surgical resection in gastrointestinal malignancies
Authors: Deva S. , Jameson M. B.
Published: August 2020

e15085

Background: H2RAs have induced regression in a number of malignancies. The mechanisms that may contribute to this effect include inhibition of T-suppressor lymphocytes, increased tumor infiltrating lymphocytes and blockade of histamine-induced tumor proliferation and angiogenesis. Unique to cimetidine is its ability to inhibit vascular endothelial expression of the cell adhesion molecule E-selectin, to which many GI tumor cells adhere via carbohydrate antigen ligands. The optimal use of H2RAs in cancer patients could therefore be as adjuvant therapy rather than for metastatic disease. Methods: This systematic review examines the impact of H2RAs on the overall survival of patients when used as an adjunct to curative surgical resection for a GI malignancy. Using a sensitive search strategy, randomized controlled trials were identified in relevant databases. Criteria for study selection included: patients with colorectal or gastric cancer surgically resected with curative intent; H2RAs used i) at any dose, ii) for any length of time, iii) with any other treatment modality and iv) in the pre-, peri- or post-operative period. The results were stratified for both the type of malignancy and the H2RA used and analyzed by meta-analysis using Cochrane Collaboration software. Results: Of 350 trials identified, 8 were eligible for inclusion and had sufficient data for analysis, including a total of 1461 patients. Meta-analysis revealed a risk ratio for mortality of 0.86 (95% CI 0.76–0.99, p = 0.03) for patients randomised to H2RAs. Trials of colorectal cancer patients where cimetidine was the H2RA being evaluated demonstrated a significant survival advantage, risk ratio 0.53 (95% CI 0.33–0.84, p = 0.007). All other subgroups demonstrated a non-significant trend favouring H2RAs. Conclusions: H2RAs, and cimetidine in particular, appear to confer a survival benefit when given as an adjunct to curative surgical resection of GI cancers. The trial designs were heterogeneous and further large studies are warranted.

No significant financial relationships to disclose.
Phase II study of biweekly cetuximab (C) and irinotecan (I) as a second-line regimen for metastatic colorectal cancer (mCRC)
Authors: Carneiro B. A. , Bahary N. , Lembersky B. , Fakih M. , Krishnamurthi S. S. , Lancaster S. , Pinkerton R. , Crandall T. , Potter D. , Ramanathan R. K.
Published: August 2020

e15088

Background: I + C is a standard second line mCRC regimen. Our study investigated the efficacy and safety of a biweekly I + C combination in patients (pts) with mCRC. Methods: mCRC pts who failed 1st line fluoropyrimidine/oxaliplatin regimens and had not received I or C, were eligible for this open label phase II trial with response rate (RR) as the primary end-point and planned sample size of 31 patients to achieve a 25% RR with 80% power. C 500 mg/m2 IV was administered on d1 followed by I 180 mg/m2 IV over 60 minutes biweekly. Results: Pt. characteristics (n=32): Male (n=17), female (n=15), Median age 59.9; ECOG PS ≤1 (31 pt), PS=2 (1). Median number of cycles 3 (range 1–21), 17pts received ≤ 3 cycles. Chemotherapy doses were reduced/delayed in 20 pts. Initial I dose was reduced to 150mg/m2 in 12 pts due to previous radiation (6 pts), age ≥ 70 years (5 pts), or PS 2 (1 pt). Grade 3 or 4 adverse events: acneiform rash (n=6), diarrhea (n=5), and neutropenia (n=4); possible grade 5 (respiratory failure). One PR was seen, 12 pts had stable and 13 pts PD; 6 pts were not evaluable for response. Median OS 11.1 mos (95% CI 6.0–15.1) and TTP 2.4 mos (95% CI 1.4-NA). Among the 23 pts tested, 9 pts had KRAS, and 2 pts BRAF mutations. There was a trend towards higher OS and TTP among pts with wild type (wt) KRAS (OS 11.9 vs 9.96mo, p=0.66; TTP 5.97 vs 3.11mo, p=0.288) and BRAF (OS 12 vs 4.6mo, p=0.17; TTP 4.56 vs 1.86mo, p=0.239). Conclusions: The lower RR than previously reported was likely caused by the small sample size and possibly those factors leading to initial I dose reductions. In addition 90% of patients had prior therapy with FOLFOX/bevacizumab. The OS and TTP are consistent with those reported previously (Martin et al Brit J Cancer 2008, Pfeiffer P et al Ann Oncol 2008), supporting biweekly I + C as a convenient second-line regimen in mCRC.

[Table: see text]
Bevacizumab plus FOLFOX7 as first line treatment in patients with advanced colorectal cancer
Authors: Oukkal M. , Kara F. , Difi S. , Bouzidi D. , Bentabak K. , Graba A. , Smail N. , Ait Kaci N. , Baba Ahmed R. , Bouzid K.
Published: August 2020

e15092

Background: Bevacizumab a monoclonal antibody against vascular endothelial growth factor (VEGF) has shown in combination with chemotherapy a significant survival improvement in pts with advanced colorectal cancer (F. Kabbinavar JCO 2005 and H. Hurwitz NEJM 2004). In this study we investigated the safety and the efficacy of the addition of bevacizumab to FOLFOX7 regimen in pts with metastatic colorectal cancer. Methods: Inclusion criteria: Histological proven colorectal carcinoma, measurable disease at time of inclusion, no prior chemotherapy (adjuvant chemotherapy allowed), no CNS metastasis, no peripheral neuropathy, no other serious concomitant illness, ECOG PS ≤ 2, Urine dipstick of proteinuria <2+, adequate renal and liver function, good bone marrow reserve and informed consent. Pts received bimonthly Oxaliplatin 130 mg/m2 D1, Folinic acid 400 mg/m2 D1, Fluorouracil 2400 mg/m2 46 hours continuous infusion and Bevacizumab 5mg/kg D3 Results: From April 2005 to June 2007, 47 pts (M/F = 28/19, colon/rectum = 28/19) were enrolled in the study. Median age is 52,7 years old (32–74). They received 452 cycles, median=7 range (1–18). All pts were evaluable for toxicity and survival and 46 for responses. Complete response (CR) was achieved in 3 pts (6.6%), partial response (PR) in 28 pts (60.8%), stable disease in 4 pts (8.7%) and progressive disease in 11 pts (24%). The overall response rate (ORR=CR+PR) is 67.3%. Severe toxicity (CTC/NCI ¾ Grade) related to chemotherapy was neuropathy 5.3%, neutropenia 8.4%, anaemia 3.3%, thrombocytopenia 1.8%, vomiting 8.2%, diarrhoea 2.9%, stomatis 4.9% and allergy 0.7%. Toxicity related to Bevacizumab was bleeding CTCNCI grade 1 and 2 in 40.8%, hypertension grade 1 qnd 2 in 3.7% qnd grqde 3 in 0.2. proteinuria grade and 2 in 13.7%. 1 case of phlebitis and 1 case of Bevacizumab allergy Conclusions: Bevacizumab and FOLFOX7 combination is a promising treatment with high efficacy and safety profile for pts with advanced colorectal cancer

No significant financial relationships to disclose.
Neoadjuvant chemoradiotherapy for locally advanced low-lying rectal cancer
Authors: Yu B. , Zhang M. , Wu W. , Chen L. , Peng L. , Bian G. , Fu J. , Fei C.
Published: August 2020

e15095

Objective: The aim of this trial was to explore the possibility of further improvement of efficacy in neoadjuvant chemoradiation for the treatment of locally advanced low-lying rectal cancer and the management of patients with clinical complete regression. Methods: 192 cases with locally advanced low-lying rectal cancer (T3/T4 or N+) received preoperative radiotherapy comprising 40–46 Gy/20–23 fractions and concomitant oral capecitabine 625 mg/m2 bid for 10 weeks prior to surgery. Curative resection with TME was carried out 6 weeks after the end of radiation. Results: Patients (pts) were recruited from May 2001 through August 2007. Overall, 117 pts (60.9%) experienced adverse events but only 2 suffered from grade 3 hand-foot syndrome. 17 pts (8.9%) had clinical complete tumor regression without surgery, 175 pts underwent curative resection including of 134 pts with low anterior resection (LAR), 32 pts with ultra-low anterior resection with Parks’ coloanal anastomosis and among them 6 pts with diverting temporary colostomy and 9 pts with APR. Sphincter preservation was achieved in 95.3%. Pathologically, 24 pts (12.5%) showed CR together with 17 pts with clinical CR; the overall CR rate was 21.4%. According to the pathological staging: T0N0 41 cases, T2N0 43 cases, T3N0 77 cases, T4N0 5 cases, T2N1 11 cases, T3N1 13 cases, T4N0 5 cases, and T4N1 2 cases; in semiquantitative Dworak's tumor regression grade, TRG0 8 pts,TRG1 32, TRG2 28,TRG3 83 and TRG4 41 with an overall tumor downstaging of 79.2%. There were no operative deaths, 5 pts suffered from rectovaginal fistulas and 4 anastomotic leakages with an overall anastomotic leakage rate of 5.1% (9/175) and all recovered without further events. All patients have been followed up for a median of 46 months (range 12–87). During the time, 11 pts had lung metastases, 6 liver metastases and 7 had local recurrences. The 3-year disease-free survival was 86.6% and overall survival was 92.6%. Conclusions: Neoadjuvant chemoradiotherapy has high efficacy resulting in tumor down-staging, increased resectability and sphincter preservation, and a reduction in local recurrences. Meanwhile those patients with clinical complete response can be followed up closely and safely without surgery.

No significant financial relationships to disclose.
Phase II trial comparing folinic acid, fluorouracil, and gemcitabine (FFG) and FOLFOX4 regimens with added bevacizumab (B) in metastatic colorectal cancer (mCRC)
Authors: Madajewicz S. , Waterhouse D. M. , Ritch P. , Khan M. , Higby D. , Leichman C. G. , Malik S. K. , Hentschel P. , Zhao L. , Nicol S. J.
Published: August 2020

e15098

Background: FOLFOX4 is a standard chemotherapy for mCRC. FFG has shown substantial activity in mCRC. This trial compared the safety and efficacy of FFG and FOLFOX4 regimens in patients (pts) with mCRC. B was added to each arm after FDA approval in 2004 as first-line treatment of mCRC. Methods: Pts with mCRC, chemonaïve except for adjuvant treatment, were randomized to two treatment arms: FFG given weekly for 6 weeks of an 8-week cycle; FOLFOX4 had a 2-week cycle. Pts in both groups received B at 5 mg/kg every 2 weeks. Treatment continued until disease progression. Planned enrollment was 150 pts. Primary endpoint was overall response rate (ORR); secondary endpoints included toxicity, overall survival (OS), and time to progression (TTP). Response was assessed by RECIST. Post-hoc analysis of disease control rate (DCR) was added. Results: Forty-two pts (18 pts given B) were randomized to each arm. Thirty-one cycles of FFG and 248 cycles of FOLFOX4 were delivered. FFG produced greater myelosuppression than FOLFOX4. Two cases each of MI and DVT were observed in the FOLFOX4(B) subgroup; one pt had DVT with FFG alone. The incidence of gastrointestinal hemorrhage was low and similar for FFG and FOLFOX4. Peripheral neuropathy was highest in the FOLFOX4(B) subgroup. ORR and DCR were significantly greater for FOLFOX4(B) than for FFG(B). Median TTP and OS were not statistically different for FFG and FOLFOX4 groups. The trial was stopped due to low enrollment; planned statistical power was not achieved. Conclusions: FFG and FOLFOX4 regimens were generally well tolerated, with greater neuropathy in FOLFOX4 and greater myelosuppression in FFG. ORR was greatest in the FOLFOX4(B) subgroup. TTP and OS results comparing FFG and FOLFOX4 groups were inconclusive due to low enrollment. Rapid changes in mCRC “standard of care” during this trial may have constrained pt accrual.

[Table: see text]

[Table: see text]
Long-term supportive treatment with fermented mistletoe (viscum album L.) extract in primary nonmetastatic colorectal cancer: Best time to start with for optimal effectiveness
Authors: Matthes H. , Friedel W. E. , Bock P. R.
Published: August 2020

e15099

Background: Safety and efficacy of fermented mistletoe extract (Iscador, ISC) in supportive care of post-surgical patients with primary colorectal cancer as compared to a parallel control group without ISC. Question: Is supportive ISC most effective when started before, during, or after radio- and/or chemotherapy? Methods: In a comparative, multicenter, non-interventional cohort study with parallel groups ISC was applied additionally to conventional adjuvant chemo- and/or radiotherapy (conv-th). The control group was treated with conv-th only. Unselected, standardized, anonymized data from medical records (1993–2002) meeting the eligibility criteria were followed until last visit or death. The pre-specified endpoints were the incidence of adverse drug reactions (ADR) caused by conv-th, and disease-free survival (DFS) in relation to start of ISC therapy before, during or after conv-th. All endpoints were adjusted to confounders. Results: 804 eligible patients (429 ISC and 375 control) from 26 centers were evaluated. ISC started mostly during conv-th (72.9%), and sometimes before (9.0%) or after (18.1%) conv-th. ISC dose was escalated from 0.01mg to 20mg as s.c. injection, 2–3 times weekly. The median follow-up time was 58 (ISC) vs. 51 months and median ISC duration was 52 months. The adjusted relative ADR risk was significantly lower in the ISC groups as compared to control: odds ratio, OR (95% CI) = 0.46 (0.28–0.77), p=0.003. The best results were found in patients where ISC started in parallel to conv-th. Analysis of DFS in the ISC subgroups is presently ongoing. ISC was well tolerated in all subgroups. Conclusions: The results show reliable safety and clinically relevant beneficial effects of ISC treatment, at best if applied in parallel to conv-th.

[Table: see text]
The role of contrast-enhanced ultrasound in detection of liver metastases from colorectal cancer: A prospective monocentric study
Authors: Mucciarini C. , Bellentani S. , Razzini G. , Bernardini I. , Artioli F. , Iop A. , Blanzieri S.
Published: August 2020

e15105

Background: Up to 15–25% of patients with colorectal cancer (CRC) will develop metacronous liver metastases during the follow up. The management and prognosis of these patients depend heavily on the early detection of metastases. The most effective surveillance strategy has not yet being extablished. The introduction of second generation ultrasound contrast agents have improved the ability of contrast-enhanced ultrasound (CEUS) in detecting and characterizing liver lesions, showing that its accuracy is comparable to that of spiral CT and MRI with a liver contrast agent, with a cost and a time saving. We tested the sensitivity and specificity of CEUS in detecting liver metastases compared with the standard imaging modalities used in the follow up of CRC. Methods: We conducted a prospective study considering all patients with a diagnosis of CRC in high risk stage II, stage III or with a previous metastasectomy of the liver. In order to detect possible metastases, the patients were followed with a follow-up schedule including a six-monthly ultrasonography alternated to an annual CT, and a six-monthly CEUS with SonoVue contrast agent for the first 3 years. Results: From January 1st to December 2008 we executed 60 CEUS, identifying thirteen suspected liver lesions. 10/13 were confirmed metastases by CT, MRI or TC/PET. 2/13 resulted benign lesions. 1/13 resulted negative at the CT but positive with a MRI. Another additional case was missed by CEUS but detected by CT. CEUS improve specificity and sensitivity compared with baseline ultrasonography. We had an histological confirmation in all cases except one. The study is still recruiting patients. Conclusions: The clinical value of CEUS as a reliable alternative to CT or MRI in characterizing focal liver lesions has been expressed in various documents and guidelines. Our preliminary results confirm the similar diagnostic performance and confidence of CEUS compared to these imaging modalities in the follow up of CRC. Further clinical studies are still needed to strenghten the existing data.

No significant financial relationships to disclose.
Can Kampo medicine prolong the life of metastatic colorectal cancer (MCRC) patients with chemotherapy?
Authors: Sasaki K. , Oono K. , Harada K. , Someya T. , Takada Y. , Furuhata T. , Hirata K.
Published: August 2020

e15120

Background: Many in vivo and in vitro studies have shown that Kampo medicine has various biological and immunological activities, including anti-cancer effect. However, we have little data on efficacy of survival period on MCRC patients (pts) with chemotherapy and Kampo therapy. The aim of this study was to evaluate the survival benefit on MCRC pts treated with Kampo medicine and chemotherapy. Methods: From 2002 to 2007, we treated 66 patients with MCRC. These patients were treated with chemotherapy (CPT-11 + S-1) and/or Kampo medicine (Jyuzen-Taiho-To, TJ-48) on out-patient basis. TJ-48 was given orally at a dose of 7.5g, three times daily. We randomly divided the MCRC pts following two treatment groups; chemotherapy plus Kampo medicine (Group A, n=33) and chemotherapy only (Group B, n=33). Results: Pts and tumor characteristics were much the same between the two groups at baseline. Pts treated with Kampo medicine in combination with chemotherapy (Group A) had a median survival of 20.5 months compared with 15 months for Group B (p=0.12). One and 2 years survival rates were 72% and 13%. No toxic death was reported. The overall 1, 2 and 3 years survival rate were 69, 24 and 12% respectively in Group A, 57, 0 and 0% in Group B. Adverse events did not increase in Group A. TJ-48 is low cost medicine ($1.8 / day). All patients were treated on an out-patient clinic. Conclusions: These results confirmed that the Kampo medicine is helpful and capable of prolonging the survival periods in pts with MCRC.

No significant financial relationships to disclose.
Feasibility of treatment of resectable rectal cancer with neoadjuvant treatment with pemetrexed
Authors: Carlsson G. , Bjökqvist H. , Kurlberg G. , Torbjörn S. , Casillas M. , Holmqvist M. , Stoffregen C. , Gustavsson B.
Published: August 2020

e15121

Background: Multimodality strategies of chemo- and radiotherapy (RT) in the neoadjuvant setting of resectable rectal cancer are a challenge to optimize surgery outcome. Pemetrexed (P) has shown efficacy in colorectal cancer. This phase II trial evaluated its feasibility as neo-adjuvant monotherapy for patients (pts) with resectable rectal cancer. Methods: Between June’ 06 and January’ 08, 37 pts with a histologically proven diagnosis of operable rectal adenocarcinoma were enrolled. P was dosed at 500 mg/m2 every 3 weeks, during 3 cycles with standard co-medication (vitamin B12, folic acid, and dexamethasone) on an outpatient base. If RT was given, minimum interval between start of RT and last dose of P was 2 weeks, preferably 5 consecutive days of RT occurred from day 17 to day 21 in cycle 3 or after completion of cycle 3. The feasibility hypothesis was that at least 85% of pts would be able to receive the chemotherapy as planned. Secondary endpoints were evaluation of qualitative and quantitative toxicities including rate of postoperative complications, proportion of pts with sphincter saving surgery, proportion of pts with complete tumor resection rate and pathological response rate. Results: All patients were able to receive 3 cycles of chemotherapy. 33 patients (89.2%, CI: 74.6 to 97) completed their planned dosage in time. The reason for delay was inadequate vitamin supply for 1 pt and 3 pts due to other reasons. No dose reduction or study-drug related SAE was seen. The only grade 3 and 4 toxicities (neutropenia) occurred in 7 pts (18.9%). 28 pts received RT following chemotherapy. All pts underwent R0 resection. One pathological proven complete response was evaluated. 12 out of 13 planned pts had a rectum amputation. All others received sphincter saving surgery. Postoperative complications occurred in 54% of the pts. All events were considered related to study procedure (operation) and not to study drug. Conclusions: This explorative study suggests that the administration of 3 cycles of pemetrexed is feasible and well tolerated within a multimodality treatment strategy.

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Outcome of initially unresectable advanced and metastatic colorectal cancer patients treated with first-line mFOLFOX6 followed by surgical tumor removal of metastases: Preliminary results of a phase II trial
Authors: Hasegawa J. , Yoshida Y. , Mizushima T. , Fujii M. , Mizuno H. , Tamagawa K. , Nezu R.
Published: August 2020

e15122

Objective: The aim of this study was to evaluate the efficacy and tolerability of treatment with mFOLFOX6 followed by surgical tumor removal in patients (pts) with initially unresectable liver metastases and/or extrahepatic disease from colorectal cancer (CRC). Methods: This study was a multicenter, open-label clinical trial. Eligibility criteria defined pts with advanced and metastatic CRC deemed not optimally resectable. mFOLFOX6 (oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, and fluorouracil [400 mg/m2 bolus followed by 2,400mg /m2 as a continuous 46-hour infusion]) was administered every 2 weeks for a maximum of 10 cycles. Resectability was the primary end point. Results: 26 pts (15M/11F; PS 0/1 19/7; median age: 60 years, rage 37–73) received 181cycles (median 7, range, 3–10) of mFOLFOX6. Main unresectable lesions were liver metastases in 10 pts and extrahepatic disease in 16 pts. Eleven pts (42%) had at least one grade 3 or greater adverse events. Sixteen pts (61%) achieved an objective response to mFOLFOX6 and 8 pts (31%) had a best overall response of stable disease. In 16 of these 24 pts who achieved the disease control, surgical tumor removal was performed (resectability 61%). The main reasons for initial unresectability in these 16 pts were the presence of liver metastases (6 pts), para-aortic lymph-node metastases (4 pts), carcinomatous peritonitis (4 pts), direct invasion to neighboring organ (2 pts). Four complications (25%) which were anastomotic leak, wound infection, chylous ascites, and cholangitis, were observed. At a median follow-up of 13 months (range 5 -21), 5 pts had relapsed after surgical tumor removal. The median time to progression (TTP) of the pts who underwent operation is not reached to date and those who did not undergo surgical removal is 8.6 months (log-rank p<0.05). Conclusions: Our data suggest that mFOLFOX6 has a significant antitumor activity in pts with not only liver metastases but also extrahepatic disease from CRC, allowing for successful resection of disease in a portion of pts initially not judged to be optimally resectable.

No significant financial relationships to disclose.
Phase I trial of advanced generation anti-CEA designer T cells in gastrointestinal and breast cancers
Authors: Junghans R. P. , Abedi M. , Bais A. , Gomes E. , Ma Q. , Beaudoin E. , Davol P.
Published: August 2020

e15123

Background: We created “designer T cells” by retroviral gene therapy to express chimeric immunoglobulin-T cell receptors (IgTCR) with specificity for carcinoembryonic antigen (CEA). Our previous Phase I trial with 1st generation (1st gen) designer T cells was well tolerated with proof-of-principle “biologic responses”, but of limited duration. Lab correlates showed modified T cells repeatedly kill tumor targets over 4–7 days but then undergo activation-induced cell death (AICD). We created 2nd gen designer T cells that incorporate CD28 co-stimulation into the IgTCR (IgCD28TCR), suppressing AICD and promoting T cell proliferation on tumor contact with superior tumor responses in vivo (Emtage et al. Clin Cancer Res 2008;14:8112). A Phase I clinical trial was approved under FDA BB-IND 10791. Methods: Patient T cells are modified ex vivo, expanded and then administered in a Phase Ia dose escalation, spanning doses of 10^9 to 10^11 cells. Patients are monitored for safety, pharmacokinetics and response. Results: To date, three subjects enrolled with doses prepared and two were treated. T cells were transduced with equal modification of CD4 helper and CD8 cytotoxic T cells and good ex vivo expansions of 30-fold or more. Cells were infused over 15–30 minutes. Blood clearance was rapid. Dosing was without toxicity but also without responses at this lowest T cell dose level. Results will be updated to include new patients at conference time. Conclusions: The safety of 2nd generation designer T cells is supported in two patients at the lowest T cell dose level. Higher planned doses are 10- to 100-fold more T cells, to be observed for toxicity and where responses may begin to be observed. Funding is from the Office of Orphan Products Development of the FDA.

No significant financial relationships to disclose.
Functional profiling in stage IV colorectal cancer: A phase II trial of individualized therapy
Authors: Blitzer J. B. , Shbeeb I. , Neoman A. , Azaren K. , Paulsen M. , Evans S. , Nagourney R.
Published: August 2020

e15124

Background: The introduction of new classes of agents has improved survival in colorectal cancer (CRC) yet the accurate selection of candidates for these often costly & toxic drugs remains a challenge. Genomic platforms have identified several prognostic & predictive factors e.g. ERCC1, TS, kRas mutations but the comparatively small number of known cellular analytes has limited their broad application. Methods: To address the complexity and redundancy of cell-death signaling pathways, we applied Ex Vivo Analysis of Programmed Cell Death (EVA/PCD) (Nagourney, R. Curr Treat Options in Oncol. 2006) to select therapies for chemo-naïve pts with metastatic CRC. This functional platform uses morphologic and metabolic endpoints to gauge cellular response to drugs & signal transduction inhibitors in human tumor microspheroids isolated from surgical biopsies. Modified Z-scores & synergy analyses (median-effect) were used to identify the ex vivo best regimen (EVBR) for each pt. from FDA-approved CRC drugs. All pts signed informed consent. Results: 12/13 (92%) pts are evaluable. Of the 12 there was 1/12 (8%) CR; 7/12 (58%) PR; 3/12 (25%) SD & 1/12 (8%) PD for an ORR = 8/12 (66%) & CBR = 11/12 (92%). 1st line EVBR were FOLFOX 3/12 (25%); FOLFIRI 2/12 (16%); FOLFOX/Erbitux 2/12(16%); FOLFOX/Avastin 1/12 (8%); FOLFOX/Avastin/Erbitux 1/12(8%); Irinotecan/Avastin/Erbitux 2/12(16%); IROX/Avastin 1/12(8%). Three of 12 inoperable pts (25%) converted to surgical candidates. There was 1 treatment-related death. Accrual continues with current TTP ranges from 1.2–17.3 months and OS from 2.5 to 30 months. Conclusions: EVA/PCD ORR in Stage IV CRC of 66%, many durable, compares favorably with reports in this population. By examining drug-induced cell death events in native-state microspheroids, this platform has the unique capacity to capture stromal, vascular and inflammatory cell interactions with tumor cells, now known to be crucial for clinical response prediction. EVA/PCD analysis warrants further evaluation in CRC. Supported by the Memorial Medical Center Foundation of Long Beach.

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Retrospective analysis of resected primary colorectal cancer revealed
Authors: Khan K. H.
Published: August 2020

e15137

Background: Lymphadenectomy in colorectal cancer is believed to be a critical component concerning prognosis and survival of patients.. The aim of this study was to analyze the relationship between the number of lymph nodes harvested (LNH) and the number of lymph nodes involved (LNI), at the histological examination of the specimens of resected primary colorectal cancer (CRC) at our unit. Results: Over the five-year study period, 142 resections for primary CRC were performed on 141 patients (one metachronous). Mean number of resections per annum was 28. There were 86 (60.5%) colonic and 56 (39.5%) rectal cancers (Fig 1). There were 70 (49.3%) anterior resections (Fig 2). M:F ratio was 0.97:1. Median age was 71years for colonic and 69.5years for rectal cancers. Eighty eight percent of resections were elective (OR=2.2 RR=1.14 p=0.003 compared to the national audit)1. Adenocarcinoma NOS constituted 94% of all histology results (5% mucinous and 1% signet ring). Median CRM was 7.5mm (mean=8.8mm) (fig 3). The CRM involvement was 12.7% for all CRC and 16% for rectal cancers. The LRM involvement was 1.5%. Median overall LNH was 12, (mean=13 p=0.08 when compared to the recommended LNH of 12) (Fig 5). Median LNH for rectal cancers=11 and for colonic cancer=13. There were 11 (14%) APRs compared to 70 (86%) sphincter-saving operations from a total of 83 rectal resections. 84%of resections were R0. The 30-day all-cause mortality was 4.3%. Actuarial survival curve demonstrated 17.6% chance of metastasis at presentation, all-stage 3-year disease-free survival (DFS) of 67% and of 82% for stages I-III (Tany Nany M0). CEA relapse as a marker of disease recurrence (available for n=125) revealed 3-year DFS=71%.When correlation was determined between LNH and lymph node involvement, it revealed a low correlation (r=0.159 p=0.06) which was statistically insignificant. When the national audit calculated the same relationship among its much larger sample the results were the same (r=0.152 p=0.001)3 and had achieved statistical significance. Conclusions: LNI as a function of tumour and host behaviour is of prognostic significance whereas LNH may be a marker of ‘pathologist's diligence’ at the histological examination and therefore a quality assurance (QA) tool.

No significant financial relationships to disclose.
DWIBS (diffusion weighted whole body imaging with background signal suppression) scan for colorectal cancer and its evaluation: Comparison with CT or PET scans
Authors: Sasatomi T. , Ogata Y.
Published: August 2020

e15140

Background: The most important clinical point for the colorectal cancer patients after surgery is to find out local recurrence and distant metastasis to liver or lungs in early state. Recently, DWIBS (diffusion weighted whole body imaging with background body signal suppression) scan, one of the diffusion weighted MRI imaging methods, was developed, and it has been become used for diagnosis of lung cancer and bladder cancer instead of PET scan. In this report, we examined whether it was more useful method for the diagnosis of recurrence or distant metastasis of the colorectal cancer after surgery than PET/CT scan or not. Methods: All the 12 primary colorectal carcinomas were resected at the surgical division, Kumamoto Central Hospital, Fukuoka Saisekai Ohmuta Hospital and Kurume University Medical Center from 2000 to 2008. (Table 1) After surgery, 14 recurrent regions (seven liver metastasis, two lung metastasis and five local recurrence) were diagnosed by CT and MRI scans. Then all the cases were performed by DWIBS scan. And also the seven out of 12 cases (three liver metastasis, two lung metastasis and four local recurrence) were performed by PET scan. Conditions set before DWIBS scan were six hours of fasting with no restriction on drinking water and normal oral administration of regularly used drugs. No bowel preparation was carried out in any of the patients. Informed consent was obtained from each patient before DWIBS scan. Results: All the 14 metastatic and recurrent regions (seven liver metastasis, two lung metastasis and five local recurrence ) of 12 recurrent patients were performed by DWIBS, MRI and CT scans. Within the seven out of 12 recurrent patients (three liver metastasis, two lung metastasis and five local recurrence), performed by PET scan, all the liver and lung metastatic regions were detected, on the other hand, three out of four local recurrent regions were diagnosed but the other one was not diagnosed by PET scan. Conclusions: DWIBS is not only useful diagnostic method for local recurrence of colorectal cancer after surgery, but also less invasive method than PET scan.

No significant financial relationships to disclose.