bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative chemoradiation with nimotuzumab and capecitabine in patients with locally advanced rectal cancer: A phase II study.
Authors: Zhu Yuan , Liu Luying , Luo Jialing , Li Dechuan , Zhu Yuping
Published: March 2020

e14049

Background: To evaluate the efficacy and safety of preoperative chemoradiation with Nimotuzumab(a humanized monoclonal antibody that targets and binds to the epidermal growth factor receptor)and capecitabine in the patients with locally advanced rectal cancer. Methods: Twelve patients with locally advanced, nonmetastatic, and mid- to lower rectal cancer were enrolled. Radiotherapy was delivered at a dose of 50 Gy/25 fractions. Concurrent therapy consisted of Nimotuzumab 400 mg/m2,1 week before radiotherapy, and then Nimotuzumab 400 mg/m2/week for 5 weeks, and capecitabine 1,650 mg/m2/day for 5 days a week (weekdays only) from the first day during radiotherapy. Three weeks after the end of chemoradiation, 1 cycle chemotherapy with oxaliplatin and capecitabine(XELOX) was performed. Oxaliplatin 130mg/m2, Day1 and capecitabine 1000 mg/m2, bid, from Day 1 to Day 14. Postoperative chemotherapy after surgery followed by preoperative CRT was in all patients, The same dosage of XELOX was started within 3 to 4 weeks after surgery, repeated every 3 weeks for 6 cycles. Total mesorectal excision was performed within 6 ~ 8 weeks. The pathologic response was evaluated as study endpoint, and an additional KRAS mutation analysis was performed. Results: In total, 9 patients completed their planned preoperative chemoradiation and underwent R0 resection. The pathologic complete response rate was 33.3% (3/9), and 3 patients (33.3%) showed near total regression of tumor. Grade 3 toxicities was diarrhea (2/12, 16.7 %), No grade 4 toxicity was observed. KRAS mutations were found in 2 of 12 patients (16.7%) who had available tissue for testing. Clinical outcomes were not significantly correlated with KRAS mutation status. Conclusions: Preoperative chemoradiation with Nimotuzumab and capecitabine was active and well tolerated. KRAS mutation status was not a predictive factor for pathologic response in this study.
Colorectal cancer in young population: Yangon, Myanmar.
Authors: Nwe Khin Khin
Published: March 2020

e14055

Background: CRC is the tenth most common cause of cancer in 2006 Myanmar Cancer Statistic. Recently, increased incidence of CRC among young age has been seen in our population. Methods: Demographic data of CRC pts registered in medical oncology unit, YGH from January 2009 to September, 2011 were studied. Age under 40 yrs was considered as a young patient. Stage distribution were analyzed to study about young onset CRC pattern. Results: Among 351 CRC patients registered, 120pts (34.19%) were under 40 yrs old. In young age group, age range from 12 to 40 yrs (median 29.5 yrs). Male to female ration was 1:1.26. Left-sided cancer (splenic flexure to rectum) in 93 patients (77.5%) and right sided (caecum to transverse colon) cancer in 27 pts (22.5%). Six pts (5%) were stage I, 41 people (34.17%) with stage II. Forty-four patients (36.67%) were node positive Stage III and 29 people (24.17%) with distant metastasis, Stage IV. Conclusions: Three percent of colorectal cancers occur in patients younger than 40 years of age in World Cancer Data. However, one third of CRC pts registered within 3 yrs in our unit were under age 40.The commonest stage seen in those pts were stage III at initial diagnosed. According to this data, younger onset of CRC in Myanmar is increasing although it doesn’t reflect the whole population. Further larger study is required to prove it. [Table: see text]
Adverse events (AE) following diagnosis (Dx) in older metastatic colorectal cancer (mCRC) patients (Pts).
Authors: Shankaran Veena , Mummy David G , Blough David K , Koepl Lisel , Yim Yeun Mi , Yu Elaine , Ramsey Scott David
Published: March 2020

e14068

Background: The relative safety of newer drugs in older pts with mCRC is understudied. The objective of this analysis is to determine factors associated with AEs in a population-based sample of older mCRC pts treated in real-world clinical settings. Methods: Pts ≥ age 65 Dx with mCRC in 2004-2007 were identified from SEER-Medicare, and excluded if they were enrolled in a Medicare HMO or lacked Medicare parts A and B. Pts who received 1st line (1L) chemotherapy (CTx) within 3 mo of Dx were dichotomized as 1L CTx alone and 1L CTx + bevacizumab (BV). Preexisting conditions (PCs) identified from claims in the 12 mo prior to start of 1L CTx were grouped into 5 categories (cardiovascular (CV), cerebrovascular (CNS), gastrointestinal (GI), tissue integrity (TI), and pulmonary (Pulm)). Claims for any of these same conditions between start of 1L CTx and end of follow-up were identified as AEs. Crude AE incidence rates were determined. Logistic regression was used to examine factors associated with BV use. Factors associated with time to 1st AE were identified in a Cox model. Results: 4,514 pts (median age 77) met inclusion, of whom 1,139 (25%) received 1L CTx only and 669 (15%) received 1L CTx + BV. BV use was less likely among pts age ≥ 75 (OR 0.35, p<0.001), non-whites (OR 0.75, p=0.002), and women (OR 0.8, p=0.001). Bev use was as likely in pts with CV, Pulm, or CNS PCs, and more likely in pts with GI (OR 1.67, p <0.001) and TI (OR 2.75, p=0.001) PCs. In a Cox model of time to 1st AE with death as a competing risk, increased risk of AE was associated with age ≥ 75 (HR 1.13, p=0.02), CNS PC (HR 1.35, p=0.02), and CV PC (HR 1.13, p=0.05). Relative to 1L CTx alone, pts receiving 1L CTx + BV did not have a higher AE risk (HR 0.89, 95% CI 0.80-0.99). AE incidence was higher in pts receiving 1L CTx alone (without subsequent biologic) (185 events / 100,000 person-days (P-D) compared with pts receiving 1L CTx + BV (139 events / 100,000 P-D). Conclusions: In this cohort, pts who received 1L CTx + BV had neither increased AE incidence nor increased risk of 1st AE compared to pts who received 1L CTx alone. PCs were not associated with decreased BV use. These data suggests BV utilization may not increase AE risk among elderly mCRC pts tx in the community.
Molecular predictors of treatment response in colon and gastric cancer.
Authors: Shen John P. , Roeland Eric , Hwang Michael , Shimabukuro Kelly Anne , Sicklick Jason Keith , Ramamoorthy Sonia , McLemore Elisabeth C. , Reid Tony R. , Lowy Andrew M. , Fanta Paul Timothy
Published: March 2020

e14069

Background: With the exception of KRAS mutational status, there is limited use of tumor-derived biomarkers in the clinical management of GI malignancies. High ERCC1 expression is associated with inferior outcomes in platinum-exposed patients with non-small cell lung, esophageal, and head and neck cancers. Previous studies have concluded ERCC-1 gene expression levels may identify patients unlikely to benefit from oxaliplatin-based chemotherapy in metastatic colon cancer and in the adjuvant therapy of esophageal/gastric cancer. Methods: Biomarkers were obtained from formalin fixed paraffin embedded tumor samples from 69 colorectal and 22 gastric cancer subjects. Each tumor was dissected using laser-captured microdissection and analyzed mRNA expression using a quantitative RT-PCR. A retrospective chart review was performed to evaluate clinical response. The primary objective was todetermine the prevalence of select tumor biomarkers including ERCC1, TS, VEGFR2a, Her2, KRAS, BRAF, and EGFR mutation status and and correlate these with overall survival. Results: Colon: Subjects with high ERCC1 expression had significantly worse OS survival compared to those with lower ERCC1 expression (26.0 vs 71.1 mo, p=0.0077). There was a trend towards decreased OS with high TS expression, but this was not statistically significant (71 vs 56 mo, p=0.49). Subjects with the V600E BRAF mutation had significantly worse OS compared to wild-type tumors (48.5 vs 61.3 mo, p=0.03). Gastric: Median OS was not reached due to a limited number of gastric subjects and only 9 of 22 had died at time of analysis. Updated analysis is planned. Conclusions: Even in this small population it is possible to detect survival differences using biomarker analysis of biopsy and resection specimens. Virtually all tumor samples yielded sufficient material for analyses. We suspect that the decreased OS in high ERCC1 expressing tumors is a result of platinum resistance. These results suggest that the use of biomarkers may identify patients unlikely to respond to conventional therapy, and warrant further investigation in a prospective clinical trial.
Predictors of pathologic complete response (pCR) after neoadjuvant chemoradiation (Neo CRT) for rectal cancer: A multicenter population-based study.
Authors: Armstrong Dawn Elizabeth , Ali Haider , Powell Erin Diana , Price Hiller Julie A. , Tang Patricia , Bebb D. Gwyn , Dowden Scot D. , Tam Vincent Channing , Lupichuk Sasha M. , MacLean Anthony , Easaw Jacob C. , Davies Janine Marie , Heng Daniel Yick Chin , Vickers Michael M.
Published: March 2020

e14073

Background: pCR to Neo CRT for rectal cancer is associated with better outcomes and used as an early indicator of response. To assess the rate and predictors of pCR, as well as access to care, we performed a retrospective study in two Canadian provinces. Methods: Cancer registries identified consecutive patients with clinical stage I-III rectal cancer from the Tom Baker Cancer Center, Cross Cancer Institute, and Dr. H. Bliss Murphy Cancer Centre who received Neo CRT and had curative intent surgery (Sx) from 2005 to 2011. Patient, tumor and therapy characteristics were correlated with response. Results: 301 patients were included of which 59 (19.6%) had a pCR to Neo CRT. At a median follow-up of 17 months, disease free survival was 96.7% for pCR vs 82.3% for non-pCR (p=0.005). 43 (73%) patients with pCR received adjuvant chemotherapy including bolus FU 27 (63%), capecitabine 10 (23%) and oxaliplatin-based 6 (14%). Median time from diagnosis to consult was 4 weeks (wks), from consult to start of Neo CRT 3.3 wks and start of CRT to Sx 13 wks. On multivariate analysis a low pre-op CEA (p=0.0323) was a significant independent predictor of pCR while statin use at initial consult (p=0.077) and higher pre-op hemoglobin (p=0.0974) trended toward significance when adjusted for clinical stage. Conclusions: Rates of pCR in a population based setting are substantial. A lower pre-op CEA is associated with a pCR to Neo CRT. Statin use and pre-op hemoglobin require further investigation. Our access to care data provides a baseline for future comparisons. [Table: see text]
Heterogeneous prevalence of somatic mutations in KRAS, BRAF, and PIK3CA genes among patients with colorectal carcinoma: Clues from Sardinia.
Authors: Palomba Grazia , Colombino Maria , Contu Antonio Silverio , Massidda Bruno , Baldino Giovanni , Pazzola Antonio , Ionta Maria Teresa , Capelli Francesca , Trova Vittorio , Sedda Tito , Tanda Francesco , Palmieri Giuseppe , Cossu Antonio ,   Sardinian Translational Oncology Group (STOG)
Published: March 2020

e14094

Background: Role of KRAS, BRAF and PIK3CA mutations in pathogenesis of colorectal cancer (CRC) has been mostly clarified. In this population-based study, we investigated the incidence rates and roles for such somatic mutations in genetically isolated population of Sardinia. Methods: From April 2009 to July 2011, formalin-fixed paraffin-embedded tissues (n=478) were prospectively collected from Sardinian CRC patients at clinics across the entire island. Genomic DNA was isolated from tissue sections and screened for mutations in KRAS, BRAF, and PIK3CA genes by automated DNA sequencing. Results: Overall, KRAS tumor mutation rate was 30% (145/478 positive cases). Distribution of mutation carriers was however different within the island: 87/204 (43%) in North Sardinia vs. 58/274 (21%) in Middle-South Sardinia (p=0.023). Among 384 CRC cases whose DNA was available, only one (0.3%) mutation in BRAF gene was observed; conversely, PIK3CA was found mutated in 158/384 (41%) patients. An inverse distribution of PIK3CA mutation rates was observed within Sardinian population: 60/181 (33%) cases from northern vs. 98/203 (48%) cases from central-southern island. This heterogeneity in frequencies of KRAS/PIK3CA somatic mutations is consistent with already-reported discrepancies in distribution of germline mutations for other malignancies within Sardinian population. Preliminary clinical evaluation of 118 KRAS wild-type patients undergoing anti-EGFR-based treatment indicated lack of role for PIK3CA in predicting response to therapy in our series. Conclusions: Our findings further support the hypothesis that patients’ origin and genetic background may contribute to even determine the incidence rate of somatic mutations in candidate cancer genes.
Activity of neoadjuvant bevacizumab at the time of surgery after 6 weeks of preoperative cessation: A translational study.
Authors: Starlinger Patrick , Alidzanovic Lejla , Schauer Dominic , Maier Thomas , Sommerfeldt Silvia , Perisanidis Beata , Tamandl Dietmar , Gruenberger Birgit , Gruenberger Thomas , Brostjan Christine
Published: March 2020

e14099

Background: The use of bevacizumab (BV), a monoclonal antibody against VEGF, together with an increase in hepatic resection has improved the outcome of colorectal cancer (CRC) patients with liver metastasis. However, despite the frequent use of BV, its accurate timing prior to liver resection to avoid surgical complications and to allow for hepatic regeneration remains discussed controversially. In this context, it is unclear to which extent VEGF is complexed by BV at the time of surgery. Methods: 42 CRC patients with liver metastases, potentially curable by resection, were included. Patients received neoadjuvant chemotherapy (CTx) either with or without concomitant biweekly BV. The last cycle of therapy did not include BV, resulting in a median 6 weeks between the last administration of BV and surgery. Plasma and wound fluid were obtained perioperatively. Immunoprecipitation was applied to determine the proportion of BV-bound VEGF. Alternative angiogenesis factors were evaluated. Results: No increased perioperative complications in BV treated patients were observed. At the time of surgery, the majority of plasma VEGF was inactivated by BV. In wound fluid, the actual site of wound healing and hepatic regeneration, VEGF was remarkably low and also complexed by BV. The anti-angiogenic protein thrombospondin-1 was reduced in BV treated patients. Conclusions: These data document that after the clinical standard cessation time of 6 weeks, BV is still fully active and binds to the majority of circulating and local (wound fluid) VEGF. Despite the potent VEGF inactivation at the time of liver resection no substantial increase in perioperative morbidity after neoadjuvant BV therapy has been documented in our study and the current literature. Compensatory mechanisms, such as thrombospondin-1 reduction during BV treatment may enable wound healing.
Neoadjuvant capecitabine and oxaliplatin (CAPOX) followed by chemoradiation (CRT) in high-risk rectal cancer: A single-institution experience.
Authors: Ahmad Saif , Parashar Deepak , Jephcott Catherine Rachel , Ford Hugo , Wilson Charles
Published: March 2020

e14100

Background: Total Mesorectal Excision (TME) is standard of care in early rectal cancer. Pre-operative CRT facilitates microscopic complete resection (R0), improving outcome in high risk disease. Recent Phase 2 studies investigated the role of neoadjuvant CAPOX chemotherapy pre-CRT with promising results. We have adopted this strategy in high risk cancers with threatened circumferential resection margin (CRM) on MRI, and report our institution’s early outcome data. Methods: Retrospective data was collected on 37 patients with high risk disease treated March 2007 to December 2011. Patients received 12 weeks oxaliplatin (130mg/m2) and capecitabine (1000mg/m2 BD for 14 days) every 3 weeks, followed by CRT (45 Gy/ 25 #) with concurrent capecitabine (800mg/m2 BD). 11/37 patients had a 5.4 Gy/ 3 # boost with CRT. 4 patients were in a clinical trial, 2 of whom had cetuximab in addition to CAPOX. Patients deemed operable on repeat MRI had TME and 4 cycles of adjuvant CAPOX. Results: Median age was 64 (33-78) and male: female ratio 2.1:1. Median follow-up was 22 months (1.9-53.7). 2 patients did not complete 4 cycles neoadjuvant CAPOX due to toxicity. Median time to surgery post CRT was 6.6 weeks (4.7-10 weeks). 1 patient had an embolic event and femoral embolectomy. 7/31 (23%) patients had no post-operative chemotherapy (4 wound; 2 previous toxicity; 1 comorbidity). Radiological response rates post CRT were 26/34 (76%). 2 patients progressed and were unable to have radical surgery. 1 further patient was found to have unsuspected metastatic disease (liver) at time of surgery. 28/35 (80%) patients had R0 resection and pathological complete response (pCR) was 6/37 (16%). 2 year DFS and OS was 89% and 91.3%. Conclusions: Our outcomes, within an unselected cohort, reflect outcomes consistent with published trial data and support routine use of pre-operative CAPOX and CRT in high risk rectal cancers. This strategy is feasible in a non-trial population, and offers the benefit of early sterilisation of micrometastases, better prediction of chemotherapy response and facilitates the incorporation of novel agents within neoadjuvant window studies.
Capecitabine in early-stage colon cancer and metastatic colorectal cancer: Results from an Austrian noninterventional trial.
Authors: Eisterer Wolfgang , Jagdt Bjoern , Haeusler Christa , Krenn Markus
Published: March 2020

e14103

Background: Capecitabine (Cap) is approved for adjuvant therapy in stage III colon cancer and for metastatic colorectal cancer (mCRC) in Austria. Methods: In this open-label, multicenter, single-arm non-interventional trial, Cap-based therapy in patients with early-stage colon cancer and mCRC was observed at 30 sites. Cap was prescribed at the physician’s discretion and according to drug labelling. 409 patients were included between 2008 and 2011. Safety of Cap in routine clinical practice was the primary study endpoint. All adverse events (AEs) were documented in an online CRF by participating investigators. Progression-free survival (PFS), defined as the time from study entry until tumour progression or death, and treatment duration were also assessed. Results: Most of the 409 patients were ≥65 years old (72.6%; n=297). 249 (60.9%) patients were male and 160 (39.1%) were female. 221 (54.0%) patients received Cap as adjuvant therapy; 111 (50.2%) of these received Cap alone, and 110 (49.8%) were treated with Cap plus oxaliplatin. 188 (46.0%) patients were treated for mCRC; 105 (55.9%) received first-line therapy, 48 (25.5%) second-line therapy and 35 (18.6%) third-line or later lines of therapy with different Cap-containing regimens. 163 mCRC patients were eligible for PFS evaluation. The median PFS was 8.1 (range 1.0–28.5) months. Patients who received Cap-based therapy for at least 8 cycles (n=97) had a profound increase in PFS to 9.4 months. The longest treatment duration with Cap was 47 cycles. The median duration of treatment for all patients was 8 cycles (range 1–47) at a median daily dose of 1944 mg/m2 (range 833–3055 mg/m²) for Cap alone and 1862 mg/m2 (range 1111–4166 mg/m²) as part of a combination regimen. The most common grade 3/4 AEs included diarrhoea (2.2%), hand-foot syndrome (2.0%), nausea (0.7%), neuropathy (0.7%), and leukopenia (0.2%). Conclusions: Cap therapy is well tolerated in routine clinical practice. The median number of 8 cycles correlates well with the suggested treatment duration. AEs included only known and previously documented safety reactions. Prolonged treatment with Cap in patients with mCRC leads to a meaningful increase in PFS.
Role of estrogen receptor-β as prognostic factor in colorectal cancer.
Authors: Alonso Lorenzo , Pérez-Ruiz Elisabeth , Perez-Villa L. , Sevilla Isabel , Torres Esperanza , de Luque V. , Alvarez Martina , Vicioso Luis , Alba E.
Published: March 2020

e14115

Background: Gender-related differences in colorectal cancer (CRC) development have been reported with a higher incidence in males than in females and several studies suggest estrogens can be protective. The role of these receptors is controversial. The aim was to elucidate the association between estrogen receptor- β (ER- β), clinicopathological variables, disease-free survival (DFS), and overall survival (OS). Methods: Protein expression was evaluated by immunohistochemistry, and antibody staining detected in the nuclear compartment was taken into account in 109 CRC patients tissue. Results: The sample characteristics are summarized in Table 1. The expression of nuclear ERβ was found to be positive in 101 cases (92.7%), and only 8 cases (7.3%) were negative. The ERβ expression was found to be associated with mucinous histology (p<0.0001), while no association was found with any of the remaining variables examined. There was a non significant association between ERβ and IIIB-IV stage. Median follow-up was 38 months and there was no correlation with the clinical outcome and ERβ status. Conclusions: In our small sample, it appears that ERβ did not influence the clinical outcome although the number of events is too small to draw conclusions. We have described an association between negative ERβ and mucinous adenocarcinoma CRC which has not been reported previously. [Table: see text]
Identification of stage I/II colorectal cancer patients at risk of recurrence: The role of elastica stains to detect venous invasion.
Authors: Roxburgh Campbell SD , Foulis Alan K , Atwan Manal , Horgan Paul G , Mcmillan Donald C.
Published: March 2020

e14117

Background: Venous invasion (VI) is a high-risk characteristic in colorectal cancer (CRC) and in stage II disease guides provision of adjuvant therapy. However, reported rates vary in published studies from 10-90%. We recently reported use of elastica stains improve reproducibility of reporting, increasing rates to >50% (Roxburgh, Ann Surg, 2010). Furthermore, compared to H&E alone, elastica detected VI provided superior prediction of 3yr cancer survival in an unselected cohort of CRC patients. The present study aims to examine how the approach could be used in patients with node negative CRC. Methods: We retrieved pre-2003 tumour blocks, sectioned and stained them with elastica. Post-2003, elastica detected VI was routinely reported. A minimum of 3 blocks was required for analysis. Those who died within 30 days of surgery or had neoadjuvant therapy were excluded. Results: 244 stage I/II patients underwent surgery between 1997-2006. 65 cases pre-2003 were analyzed retrospectively. The rate of elastica detected VI was 54%. Elastica detected VI related to other high-risk pathology including T stage (p<0.001), serosal invasion (p<0.01), tumour grade (p<0.05) and low-grade lymphocytic infiltrate (P<0.05). Minimum follow-up was 5 yrs; mean follow-up 99 months (60-178), during which there were 99 deaths, 48 from cancer. Absence of VI related to improved 5-yr cancer specific survival (93% vs 66%). On multivariate analysis, VI independently related to cancer specific survival (HR=5.5,95%CI 2-13,p<0.001) with margin involvement (HR=2.4,95%CI 1-6,p=0.067) and serosal involvement (HR=2.2,95%CI1-4, p=0.015). For CRC mortality, the area under the receiver operator curve was highest for VI compared with other pathology (AUC 0.69, 95%CI 0.6-0.8, P<0.001). Absence of VI related to 5-yr survivals of 92% and 97% in colon and rectal cancer respectively. Conclusions: More objective assessment of VI with routine elastica staining provides accurate prediction of survival in stage I/II CRC. Presence of VI was associated with a 5.5 fold increased risk of cancer death at 5 yrs. Such results support routine use of elastica stains to identify patients with node negative disease at risk of recurrence.
A dose escalation study of nimotuzumab plus irinotecan as second-line treatment in metastatic colorectal cancer with wild-type K-ras.
Authors: Zhou Jun , Shen Lin , Gao Jing
Published: March 2020

e14122

Background: Nimotuzumab is a humanized monoclonal antibody of EGFR. We assessed the safety/tolerability and the efficacy of nimotuzumab combined with Irinotecan as the second-line treatment in Chinese patients with metastatic colorectal cancer (mCRC). Methods: Patients with mCRC refractory to oxaliplatin, K-ras WT, signed informed consent, target lesion(s), performance status (PS) ≤2, adequate organ functions, were eligible for this open-labelled, single-armed trial (NCT00972465). Irinotecan was given as 180mg/m2 d1, Q2w until progression or AEs or maximum 6 cycles. Nimotzumab was given as 200, 400, 600 or 800mg weekly until progression or AEs. The primary end points were objective response rate and toxicity. The second end points are PFS and OS. Results: A total of 31 patients (M/F = 22/9; median age 55; range 29-77) have been enrolled from July 2009 to Nov 2011. 4/11/12/4 patients received nimotuzumab as the dose of 200/400/600/800mg respectively. Most common grade 3/4 toxicity are leukopenia (14.8%,) and neutrocytopenia 18.5%). For all the patients, no grade 3/4 toxicity relating with Nimotuzumab was observed. 2 and 3 patients developed skin rash (grade 1) in 400 and 600mg arm respectively. 2 patients developed skin rash grade 2 in 600/800mg arm. The maximum tolerated dose has not yet been reached. Three patients (400/600mg: 2/1) quitted the trial because of personal reason. In 600mg arm, PR was 33.3% (4/12), SD was 25% (3/12); in 400mg arm, PR was 9.l%(1/11), SD was 36.4%(4/11); in 200mg arm, SD was 50%(2/4), PD was 50% (2/4); in 800mg arm, PR was 25%(1/4), PD was 75%(3/4). The follow-up of overall survival is ongoing. Conclusions: Addition of Nimotuzumab with 600mg weekly plus Irinotecan is safe and first data suggest a promising activity. The maximum tolerated dose of Nimotuzumab has not been reached yet.
FOLFIRI plus bevacizumab (B) as neoadjuvant treatment for potentially resectable colorectal cancer patients (pts) with liver metastasis: A phase II trial.
Authors: Nasti Guglielmo , Ottaiano Alessandro , Romano Carmen , Izzo Francesco , Delrio Paolo , Albino Vittorio , Giordano Pasqualina , Piccirillo Maria Carmela , Daniele Gennaro , Lastoria Secondino , Caraco Corradina , Arrichiello Cecilia , De Lutio Elisabetta , Maiolino Piera , Tatangelo Fabiana , Iaffaioli Rosario Vincenzo
Published: March 2020

e14130

Background: Irinotecan-based chemotherapy plus B was shown to be effective and safe in both first- and second-line treatment for metastatic colorectal cancer (mCRC) pts.We designed this trial to assess whether the combination of FOLFIRI + B given to untreated, potentially resectable mCRC pts was feasible and active. Methods: Phase II, single arm trial with 1-year progression-free rate (PFR) as primary end-point. A sample size of 39 pts was calculated to detect a 70% ± 12% 1-year PFR. The treatment was FOLFIRI q2w (irinotecan 180 mg/m2, leucovorin 200 mg/m2, 5FU 2400 mg/m2 iv in 46 hrs) plus B 5mg/kg q2w. Last cycle before surgery was without B. Potentially resectable, untreated mCRC pts, with liver as unique site of metastases, were eligible. Normal organ function and no contraindications to B were required. Pts were reevaluated for surgery after 6 cycles. PET-Scan were performed at baseline and at the second cycle. Results: Overall 39 pts were enrolled. Median age was 58 (range 30-75), male/female were 24/15. Twenty seven pts (69.2%; 95%CI 52.4% – 83.0%) were progression-free at 1-year. Thirty seven pts (94.9%) underwent surgery. One complete and 22 partial responses were observed (response rate 59.0%; 95% CI 42.1% – 74.4%); 5 pts had disease progression (4 resectable and 1 unresectable). Early PET-scan was assessed according PERCIST criteria [Wahl RL, J Nucl Med 2009] in 29 pts and showed metabolic response (SUV-max decrease > 30%) in 17 (58.6%; 95% CI: 38.9%- 76.5%).Severe toxicity includes grade 3 neutropenia (3 pts, 7.7%) and grade 3 diarrhea (1 pt, 2.6%). Other toxicities include grade 1-2 diarrhea (15.4%), grade 2 nausea (7.8%), grade 2 leucopenia (5.1%), grade 2 asthenia (5.1%), grade 1 anemia (2.6%), grade 2 thrombosis (2.6%). Overall, 16 pts out of 37 experienced surgical complications (43.2%; 95%CI 27.1% - 60.5%): biliary leak (11 pts, 29.7%), biliary fistula (1 pt, 2.7%), other complications (4 pts, 10.8%). All complications were reversible. No peri-operative bleeding was observed. Conclusions: The trial yielded its primary aim and shows that FOLFIRI plus B is feasible and active as neo-adjuvant treatment in patients with resectable liver metastases of CRC.
Identification of clinical predictive factors of oxaliplatin-induced chronic peripheral neuropathy in colorectal cancer patients treated with adjuvant FOLFOX IV.
Authors: Frezza Anna Maria , Schiavon Gaia , Vincenzi Bruno , Addeo Raffaele , Catalano Vincenzo , Graziano Francesco , Santini Daniele , Tonini Giuseppe
Published: March 2020

e14135

Background: Oxaliplatin-induced neuropathy is a dose-related side effect which occurs in almost 40% of patients treated with oxaliplatin. Aim of the present study was to identify reliable clinical factors predicting its development and duration. Methods: 169 completely resected CRC patients treated with adjuvant Folfox IV regimen were retrospectively included. The following pre-treatment clinical parameters were collected: hypocalcemia, hypomagnesaemia, hypoalbuminemia, anaemia, diabetes, chronic renal failure (CRF), folate deficiency, B12 deficiency, number of cycles received and habit to alcohol consumption. Incidence, grade (NCI-CTCAE v.3) and duration of neuropathy were recorded. Results: Incidence of neuropathy was found to be higher in patients with pretreatment anaemia (p=0.001), hypoalbuminemia (p=0.01) and hypomagnesemia (p=0.001) as well in those with habit to alcohol consumption (p=0.003). Neuropathy durations was conversely associated with age, being longer in younger patients (p=0.03), and again with hypoalbuminemia (p=0.04) and hypomagnesemia (p=0.002). No correlation was found with gender, hypocalcemia, diabetes and CRF. The correlation between vitamin B12 and folate levels and the development of neurotoxicity was not analysed because of the high number of missing data in the population. Conclusions: Age, anaemia, hypoalbuminemia, hypomagnesemia and alcohol consumption are reliable and easily assessable clinical factors predicting incidence and length of oxaliplatin induced neuropathy.
Year-to-year impact budget analysis of biologic therapies for first-line metastatic colorectal cancer (mCRC) therapy in Spain.
Authors: Martinez-Amores Brezo , Mezquita Laura , Ibañez de Cáceres Inmaculada , Ayuso Sacido Angel , Peña Jose Maria , Perona Rosario , Belda-Iniesta Cristobal
Published: March 2020

e14144

Background: Pharmacoeconomic studies deal with populations of patients as if they were admitted at the division of medical oncology in the same date. Real patients are treated along the entire year so that budget simulations should be adjusted to chronological patterns of oncological assistance. Deferred budget impact analysis is undergone in order to assess long-run economic implications of clinical decisions on first-line mCRC therapies in Spain. Methods: As metastatic colorectal cancer diagnosis is not affected by seasonal influences, we have created a mathematical model assuming that a single patient is diagnosed every month and this patient has a 53% possibility to harbor a native K-Ras sequence. Calculi were arranged based on median duration of therapy. For bevacizumab-based therapy, budget impact for year t+1 begins at month 5 and beyond. For patients that receive cetuximab-based therapy, budget impact for year t+1 begins at month 7. The same approach was performed for doublets without any monoclonal antibody. Prices for all drugs in Spain were assumed to represent the best-value for each drug including all possibilities to reduce pharmacy costs. For first line, median duration of therapy reported by randomized trials was used to calculate the final budget. 70kg and 1.7 m were used as reference for patient dose calculations. Results: When K-Ras status is not tested and bevacizumab-based schedules are administered to every patient, annual growth of budget increases by 55- 60%. If K-Ras status is analyzed and wild-type patients are treated with cetuximab combinations and mutated patients receive bevacizumab, yearly budget growth amounts to 39-41%. Annual budget growth is minimized (25%) when K-Ras wt patients are treated with cetuximab combinations whereas K-Ras mutated tumours received chemotherapy alone. Conclusions: Duration of therapy plays a key role on budget impact estimations from both overall and year to year perspectives. K-Ras based clinical decisions not only optimize outcomes as measured by response rates but also minimize economic implications on annual budget growths.
A phase II study of perioperative FOLFOX4 plus bevacizumab for initially unresectable advanced colorectal cancer (NAVIGATE-CRC-01): Report of interim analysis.
Authors: Suenaga Mitsukuni , Mizunuma Nobuyuki , Fujimoto Yoshiya , Ueno Masashi , Matsusaka Satoshi , Shinozaki Eiji , Fukunaga Yosuke , Nagayama Satoshi , Yamaguchi Toshiharu
Published: March 2020

e14145

Background: Perioperative chemotherapy combined with surgery for liver metastases is regarded as active strategy in metastatic colorectal cancer (mCRC). However, its impact on initially unresectable or potentially resectable previously untreated advanced CRC (ACRC), regardless of concurrent metastases, remains to be clarified. Methods: A phase II study to evaluate safety and efficacy of perioperative FOLFOX4 plus bevacizumab (BEV) for initially unresectable ACRC was conducted at a single institute in Japan. Previously untreated advanced colon or rectal (Rs-Ra) cancer and initially considered as unresectable ACRC (TNM: Stage IIIb, IIIc or IV) indicating potentially resectable after neoadjuvant chemotherapy (NAC) were eligible for this study. All patients provided their written informed consent. Patients received neoadjuvant FOLFOX4 plus BEV for six cycles. The sixth cycle did not include BEV. Duration between the last administration of BEV and surgery needed at least five weeks. Adjuvant FOLFOX4 plus BEV for six cycles were given after surgery. Completion rate of NAC and possibility of curative surgery were primary end point. Interim analysis of completion rate of NAC was planned at the end of NAC in the twelfth patient. Results: Characteristics of patients were as follows: gender, 8 male and 4 female: location, Sigmoid in 3, Ascending in 1 and Ra in 8: Stage, III in 8 and IV in 4 (liver or lymph node). All patients completed six cycles of NAC. No tumor-related severe adverse events or death were observed. Median duration between last administration of BEV, FOLFOX4 and surgery were 51 days and 34 days, respectively. Objective response to NAC was achieved in nine patients (75%), and no disease progression was observed. Eleven patients underwent curative tumor resection including metastatic lesion. Conclusions: The interim analysis met primary end point and suggests that neoadjuvant FOLFOX4 plus BEV is well tolerated and promise high response rate leading to curative surgery. These data indicate potential survival benefits from perioperative addition of BEV to the FOLFOX4 for initially unresectable ACRC if concurrent metastatic lesion.
Panitumumab as a single agent in 269 metastatic colorectal cancer patients in the real practice: A post EMA approval study.
Authors: Grude Francoise , Ramée Jean François , Guivarch Laurent , Rochard Sophie , Dupuis Olivier , Grollier Chrystelle , Guerin-Meyer Veronique , Leynia Pierre , Porneuf Marc , Peguet Elodie , Boucher Eveline , Bertrand Claude , Deguiral Philippe , Derenne Laurent , Achour Nacredine , Person Bernadette , Lebot Marie-Annick , Riche Christian , Metges Jean Philippe , Douillard Jean Yves
Published: March 2020

e14148

Background: Metastatic colorectal cancer (mCRC) management has been improved by targeted therapies. The evaluation of the use of panitumumab (PANI), after approval, in the real life is strategic to assess health politics. Clinical trials concern usually patients younger and with better health status. Little is known about elderly people (over 70 years old). The observatory of Cancer Bretagne - Pays de Loire is a network of private and public cancer centers. Methods: Patients with wild-type KRAS, EGFR-expressing, mCRC progressing after fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy , received PANI,6 mg/kg biweekly. Sex, age, primary tumor, line of treatment, toxicity, reason of discontinuation, response, progression free survival (PFS) and overall survival (OS) were collected. Results: 269 patients (183 men and 86 women) treated between second half of 2008 and end of 2010 have been included. Median age: 67 years [36-90] (Amado et al, 2008 : 62.5 years [29-82]). Primary tumor was : colon (74%), rectum (24%) and double site (2%). PANI was used mostly at line 2 (19%), 3 (31%) or 4 (29%). Discontinuation of treatment was due to disease progression: 53%, death: 12% and toxicities: 5% (skin toxicities 3.5%). Clinical response was evaluated for the first 201 patients: partial response (PR): 20%, stable disease (SD): 19% and progression (P): 60% (Amado et al, 2008 PR : 17%, SD : 34%, P : 49%). Median duration of treatment was 2.3 months [0.26-17.52]. Median of OS was 6.71 months which is lower than previously described (Amado : 8.1 months). Median duration between end of treatment and death when death is the cause of end of treatment was 17 days [4-57] (n=24). From our data of 269 patients, a comparison between 123 patients over 70 and 146 patients under 69 will be shown at the meeting. Conclusions: Analysis of patients treated with PANI for a mCRC allows assessing the proper, per label use, in the real life. Complete results on clinical response, PFS, OS and safety as well as previously published data will be shown at the meeting.
Renaissance of contact radiotherapy with RT 50 Papillon machine: A revival of new treatment option for early low rectal cancer?
Authors: Sun Myint Arthur ,   International Contact Radiotherapy Society
Published: March 2020

e14149

Background: Local contact radiotherapy for early rectal cancer is an accepted treatment in most centers but still controversial in some centres. However, the old Philips machine is obsolete and many centers are unable to continue treating patients using this technique. A new RT 50 Papillon machine is now commercially available and there is a new hope for elderly patients and others who whish to avoid major surgery or permanent stoma. Methods: Although contact radiotherapy has been in clinical use for the past 80 years it is still not regarded as standard treatment in many centers around the world. This is due to the fact that there were no large randomized trials to prove its efficacy against standard surgical treatment. ICONE group has launched CONTEM trials, which are observational trials that combine Contact RT with TEMS for various stages of malignant rectal polyps. Results: ICONE group meets annually and organized courses for contact radiotherapy. So far, 10 centers in Europe have now been trained. We hope to start the CONTEM trials later this year. The data from these trials will be collected centrally in Nice and updated annually. The results will be published later. Conclusions: At present approximately 30-50% of patients with early (T1N0) low rectal cancer (<6cm) are being over treated with APR. Revival of contact radiotherapy allows multimodality treatment for selected patients to avoid major surgery and permanent stoma. We hope the CONTEM trials will provide some evidence in this approach for suitable patients with early rectal cancer. [Table: see text]
Clinical significance and prognostic impact of CD133 expression in rectal cancer treated with preoperative radiochemotherapy.
Authors: Sprenger Thilo , Conradi Lena-Christin , Beissbarth Tim , Homayounfar Kia , Rüschoff Josef , Rödel Claus , Ghadimi B. Michael , Becker Heinz , Rödel Franz , Liersch Torsten
Published: March 2020

e14161

Background: CD133 has been described as a potential stem cell marker in colorectal cancer and to be associated with higher tumorigenic potential and resistance to radiochemotherapy (RCT). In this study the expression of CD133 was evaluated in pre-RCT tumor biopsies and the corresponding post-RCT surgical specimens of locally advanced rectal cancer patients and correlated to histopathological features and clinical follow-up. Methods: 127 patients with UICC (Union contre le Cancer) II/III rectal cancer treated with preoperative 5-FU based RCT within the German Rectal Cancer Trials were investigated. Pre- and post-RCT CD133 expression levels were determined using immunhistochemistry and correlated with histopathologic parameters, tumor regression grade, cancer recurrence and survival. Results: As compared to pre-RCT biopsies we observed a significantly higher CD133 expression in tumor specimens (p=0.01). There was, however, no correlation for both biopsies and tumor specimens between CD133 expression levels, histopathological features and survival. In matched analyses of corresponding biopsy/tumor pairs, patients with a decreased fraction of CD133+ cells after preoperative RCT showed significantly lower residual tumor stages (p=0.03) and higher histopathological tumor regression (p<0.01). Moreover, these patients had a significantly improved disease-free (DFS) and cancer-specific overall survival (CSS) in uni- (p<0.001) and multivariate analyses (p=0.001), respective. Conclusions: Enrichment of CD133+ cancer cells during preoperative RCT is correlated with minor local tumor response, distant cancer recurrence and survival. Up-regulation of intratumoral CD133 expression – more than pre- and post-RCT CD133 levels – plays an important role in therapy resistance, tumor progression and metastasis in rectal cancers undergoing neoadjuvant RCT.
A qPCR gene expression module test to predict resistance to cetuximab in colorectal cancers independent of KRAS mutation status.
Authors: Rhodes Dan , Eddy Sean , Williams Paul , Tomilo Mark , Sadis Seth , Wyngaard Peter , Vo Lien , Oades Kahuku , Kim Hyunsoo , Wang Yipeng , Lee Byung-In , Monforte Joseph
Published: March 2020

e14164

Background: While KRAS mutation predicts resistance to anti-EGFR therapy in colorectal cancer, not all KRAS wild-type patients benefit from such therapy, suggesting that complementary biomarkers capable of identifying additional non-responsive patients would have clinical utility. Methods: To search for such a biomarker, we studied the relationship of cetuximab response with twelve gene expression modules, derived from an unsupervised analysis of 20 independent microarray datasets comprising more than 2,000 colorectal cancer patients. Each module represents a set of highly co-expressed genes related to an important aspect of colorectal cancer variability. Two cetuximab-treated cohorts were studied. The first was a Phase II clinical trial (Khambata-Ford et al, J Clin Oncol, 2007) with accompanying microarray data from pre-treatment biopsies. The second was a single-institution study of cetuximab response from which formalin-fixed paraffin-embedded primary tumor specimens were available. Results: In the first study, module scores were computed by averaging co-expressed module genes in the microarray data. In the second study, module scores were generated from a qPCR gene expression module test, OncoScore Colon, which quantifies modules by averaging three representative module genes relative to housekeeping controls. Notably, in both studies, the mesenchymal module was significantly associated with cetuximab resistance, with module positive patients tending to progress on cetuximab within 10 weeks. Additionally, the status of this module was independent of KRAS mutation status—KRAS mutations occurred in both module-positive and -negative patients. Future clinical studies will continue to test the predictive capacity of the module in regards to cetuximab resistance and other mechanisms. Conclusions: In summary, this study demonstrates the value of a gene expression module-based qPCR panel for stratifying colorectal cancer patients for treatment response, and suggests that our approach may have immediate utility for cetuximab treatment response prediction.
Pathological complete response rates after neoadjuvant chemoradiation (CRT) for rectal cancer: Do novel agents have a role?
Authors: Beg Muhammad Shaalan , Meyer Jeffrey John , Xie Xian-Jin , Balch Glen C. , Singal Amit G
Published: March 2020

e14165

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