TTD Group Research Articles

Phoenixin-14 may ameliorate testicular damage caused by torsion-detorsion by reducing oxidative stress and inflammation in prepubertal rats

The present study aimed to investigate the effects of Phoenixin-14 (PNX-14) on oxidative damage, inflammatory response, histopathological variations, and serum testosterone levels in testicular tissues. Forty-eight Wistar albino prepubertal male rats were divided into 4 groups (Sham, TTD, TT+PNX+TD, TTD+PNX) (n=12). The torsion period was 2 hours and the detorsion period was 24 hours in the testicular torsion/detorsion (TD) groups. A single PNX-14 (50 µg/kg) dose was injected into the rats in the TT+PNX TD group on the 90th minute of torsion, and it was injected into the rats in the TTD+PNX group at the beginning of detorsion. Oxidative damage in testicular tissues was determined based on superoxide dismutase (SOD), malondialdehyde (MDA), total antioxidant status (TAS) and total oxidant status (TOS), and inflammatory damage was determined based on TNF-α and IL-6 levels. Histopathological variations were investigated with the Periodic Acid Schiff (PAS) staining method in testicular tissues and analyzed based on Johnsen scores. Spermatogonia cells were examined immunohistochemically. Serum testosterone levels were determined with the enzyme-linked immunosorbent assay (ELISA). A significant increase in oxidative stress and inflammation parameters was determined in the TTD group when compared to the other groups (p<0.05). PNX-14 treatment led to a statistically significant decrease in these parameters and significantly repaired the TD damage in testicular tissue (p<0.05). Johnsen scoring revealed significant improvement in PNX-14 groups and an increase in spermatogonia count, supporting the biochemical findings (p<0.05). PNX-14 could be a potential therapeutic agent in testicular TD damage and further studies should be conducted to elucidate the present study findings.

Upfront primary tumour resection and survival in synchronous metastatic colorectal cancer according to primary tumour location and RAS status: Pooled analysis of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)

IntroductionRetrospective studies and meta-analyses suggest that upfront primary tumour resection (UPTR) confers a survival benefit in patients with asymptomatic unresectable metastatic colorectal cancer (mCRC) undergoing chemotherapy, however a consensus of its role in routine clinical practice in the current era of targeted therapies is lacking. This retrospective study aimed to analyse the survival benefit of UPTR in terms of tumour location and mutational status, in patients with synchronous mCRC receiving chemotherapy and targeted therapy. Patients and methodsSurvival was analysed in a pooled cohort of synchronous mCRC patients treated with a first-line anti-VEGF or anti-EGFR inhibitor in seven trials of the Spanish TTD group, according to UPTR, tumour-sidedness and mutational profiling. ResultsOf 1334 eligible patients, 642 (48%) had undergone UPTR. UPTR was associated with significantly longer overall survival (OS; 25.0 vs 20.3 months; HR 1.30, 95%CI 1.15–1.48; p < 0.0001). UPTR was associated with significant OS benefit in both left-sided (HR 1.38, 95%CI 1.13–1.69; p = 0.002) and right-sided (HR 1.39, 95%CI 1.00–1.94; p = 0.049) tumours, RASwt (HR 1.29, 95%CI 1.05–1.60; p = 0.016) and BRAFwt (HR 1.49, 95%CI 1.21–1.84; p = 0.0002) tumours, and treatment with anti-EGFRs (HR 1.47, 95%CI 1.13–1.92; p = 0.004) and anti-VEGFs (HR 1.25, 95%CI 1.08–1.44; p = 0.003). Multivariate analysis identified number of metastatic sites, RAS status, primary tumour location and UPTR as independent prognostic factors for OS. ConclusionConsidering the selection bias inherent to this study, our results support UPTR before first-line anti-EGFR or anti-VEGF targeted therapy in right and left-sided asymptomatic unresectable synchronous mCRC patients. RAS/BRAF mutational status may also influence UPTR function.

The effect of taxifolin on experimental testicular ischaemia reperfusion injury in rats. A biochemical and histopathological analysis

ObjectivesThe aim of the study is to investigate the protective effect of taxifolin (3,5,7,3,4-pentahydroxy flavanone), a strong antioxidant, against testicular I/R injury in rats biochemically and histopathologically. Materials and methods50mg/kg taxifolin was administered to taxifolin+testicular torsion–detorsion (TTTD, n-10) group of Albino Wistar male rats by oral gavage. Distilled water .5ml as a solvent was administered to testicular torsion–detorsion (TTD, n-10) and Healthy Control (SG, n-10) groups using the same method. An hour after the administration of taxifolin and distilled water, anaesthesia (ketamine 60mg/kg) was administered to all animal groups. TTD and TTTD group animals were subjected to testicular torsion at 720 degrees for four hours during anaesthesia. At the end of this period, testicular detorsion was applied and perfusion was allowed for four hours. Sham operation was applied to SG group. ResultsOur biochemical experiment results showed that the amount of malondialdehyde (MDA) in testicular tissue of TTD group presented a significant increase compared to SG and TTTD groups whereas total glutathione (tGSH) and superoxide dismutase (SOD) levels decreased. In addition, while TTD group presented severe histopathological damage in germinal epithelium cell and seminiferous tubule, mild damage was observed in TTTD group. ConclusionsThe results of our experiment indicate that taxifolin could be useful in the treatment of testicular I/R damage.

583P - Impact of tumor location on the efficacy of first-line anti-EGFR monoclonal antibody plus chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC): Retrospective analyses of the randomized MACRO-2 and PLANET trials from TTD Group

Background: mCRC is a group of heterogeneous diseases rather than a homogeneous one, resulting in clinical and molecular characteristics between right- and left-sided tumors driving to different prognosis. Methods: Pts with KRAS Wild-Type (WT) mCRC treated in 1st-line with EGFR monoclonal antibody inhibitors (EGFRI) plus either FOLFOX or FOLFIRI from two randomized phase II trials (MACRO-2/PLANET) were included in the analysis. Pts were classified according to their primary tumor location as right-sided or left-sided. The main objective was to analyze the effect of primary tumor location on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Differential responses in RAS WT pts according to tumor location were also evaluated. Results: Pts with KRAS WT left-sided primary tumors (N = 209) versus right-sided primary tumors (N = 52) were analyzed. RAS was retrospectively determined in 69% of pts. Both KRAS and RAS WT left-sided had significantly superior ORR, median PFS and median OS compared with right-sided (Table).Table583PKRAS WTRAS WTRight-sided (N = 52)Left-sided (N = 209)Right-sided (N = 33)Left-sided (N = 148)ORR (confirmed)Rate, %25.046.933.352.7OR (95% CI)0.38 (0.19 – 0.75)0.45 (0.20 – 0.99)P-value0.0040.044PFSMedian, m (95% CI)7.209.866.5410.09(4.21 – 11.14)(9.13 – 11.73)(3.91 – 12.58)(9.43 – 12.06)HR (95% CI)0.64 (0.44 – 0.92)0.63 (0.40 – 0.99)P-value0.0160.044OSMedian, m (95% CI)13.5727.7313.5732.79(8.44 – 26.02)(24.97 – 36.17)(8.41 – 34.23)(26.45 – 39.85)HR (95% CI)0.47 (0.33 – 0.67)0.44 (0.28 – 0.68)P-value<0.00010.0002CI: confidence intervals; HR: hazard ratio; m: months; OR: odds ratio; ORR: objective response rate; OS: overall survival; PFS: progression-free survival WT: wild-type. Open table in a new tab CI: confidence intervals; HR: hazard ratio; m: months; OR: odds ratio; ORR: objective response rate; OS: overall survival; PFS: progression-free survival WT: wild-type. Conclusions: Pts with Left-sided primary tumors KRAS or RAS WT mCRC treated with first-line EGFRI plus chemotherapy have significantly improved efficacy outcomes as compared with pts with right-sided primary tumors KRAS or RAS WT mCRC Clinical trial identification: MACRO-2 trial: NCT01161316, PLANET trial: NCT00885885 Legal entity responsible for the study: Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD) Funding: Amgen SA (PLANET), Merck. S. L. (MACRO-2) Disclosure: C. Guillen-Ponce: Consultant or advisory role, travel and accommodation: Roche Pharma, Merck Serono. E. Diaz Rubio: Consultant or advisory role, research funding: Bayer, Amgen and Merck. E. Aranda Aguilar: Advisory role: Amgen, Bayer, Celgene, Merck, Roche, Sanofi. All other authors have declared no conflicts of interest.

547P - ULTRA clinical trial: Prospective comparative clinical outcome analysis of three different RAS/BRAF sensitivity mutational cut-offs. A Phase II study of the Spanish TTD Group

547P - ULTRA clinical trial: Prospective comparative clinical outcome analysis of three different RAS/BRAF sensitivity mutational cut-offs. A Phase II study of the Spanish TTD Group

Systematic review with meta-analysis of studies comparing primary duct closure and T-tube drainage after laparoscopic common bile duct exploration for choledocholithiasis.

With advances in laparoscopic instrumentation and acquisition of advanced laparoscopic skills, laparoscopic common bile duct exploration (LCBDE) is technically feasible and increasingly practiced by surgeons worldwide. Traditional practice of suturing the dochotomy with T-tube drainage may be associated with T-tube-related complications. Primary duct closure (PDC) without a T-tube has been proposed as an alternative to T-tube placement (TTD) after LCBDE. The aim of this meta-analysis was to evaluate the safety and effectiveness of PDC when compared to TTD after LCBDE for choledocholithiasis. A systematic literature search was performed using PubMed, EMBASE, MEDLINE, Google Scholar, and the Cochrane Central Register of Controlled Trials databases for studies comparing primary duct closure and T-tube drainage. Studies were reviewed for the primary outcome measures: overall postoperative complications, postoperative biliary-specific complications, re-interventions, and postoperative hospital stay. Secondary outcomes assessed were: operating time, median hospital expenses, and general complications. Sixteen studies comparing PDC and TTD qualified for inclusion in our meta-analysis, with a total of 1770 patients. PDC showed significantly better results when compared to TTD in terms of postoperative biliary peritonitis (OR 0.22, 95% CI 0.06-0.76, P = 0.02), operating time (WMD, -22.27, 95% CI -33.26 to -11.28, P < 0.00001), postoperative hospital stay (WMD, -3.22; 95% CI -4.52 to -1.92, P < 0.00001), and median hospital expenses (SMD, -1.37, 95% CI -1.96 to -0.77, P < 0.00001). Postoperative hospital stay was significantly decreased in the primary duct closure with internal biliary drainage (PDC + BD) group when compared to TTD group (WMD, -2.68; 95% CI -3.23 to -2.13, P < 0.00001). This comprehensive meta-analysis demonstrates that PDC after LCBDE is feasible and associated with fewer complications than TTD. Based on these results, primary duct closure may be considered as the optimal procedure for dochotomy closure after LCBDE.

149IN - Ttd Contribution to the Precision Oncology

ABSTRACT The TTD Group is a Spanish Cooperative Group with 28 years of history investigating and developing protocols in the digestive tumor field to improve healthcare quality. In the last decade, it research has been focused on the identification of biomarkers to improve and predict treatment outcomes. The MACRO (Maintenance in Colorectal Cancer) study was a phase III study to assess maintenance therapy with single-agent bevacizumab (B) versus B plus chemotherapy (QT) in patients (p) with metastatic colorectal cancer (mCRC). A post hoc analysis of the trial investigated the prognostic value of the circulating tumor cell (CTC) count and KRAS mutation status on patient outcomes and showed that both factors were independent prognostic factors for outcomes. Based on these results, the ongoing VISNU study will screen 750 p previously untreated with mCRC according to CTC count and gene status (RAS, BRAF y PI3K). In VISNU-1 trial (NCT01640405), 350 p with ≥ 3 CTC, will be randomized to receive FOLFOX-6 + B or FOLFOXIRI + B. In VISNU-2 trial (NCT01640444), 240 p with Disclosure: E. Aranda Aguilar: Honoraria or consultation fees: Roche and Merck.

Role of Kras Status in Patients with Metastatic Colorectal Cancer Receiving First-Line Chemotherapy plus Bevacizumab: A TTD Group Cooperative Study

BackgroundIn the MACRO study, patients with metastatic colorectal cancer (mCRC) were randomised to first-line treatment with 6 cycles of capecitabine and oxaliplatin (XELOX) plus bevacizumab followed by either single-agent bevacizumab or XELOX plus bevacizumab until disease progression. An additional retrospective analysis was performed to define the prognostic value of tumour KRAS status on progression-free survival (PFS), overall survival (OS) and response rates.Methodology/Principal FindingsKRAS data (tumour KRAS status and type of mutation) were collected by questionnaire from participating centres that performed KRAS analyses. These data were then cross-referenced with efficacy data for relevant patients in the MACRO study database. KRAS status was analysed in 394 of the 480 patients (82.1%) in the MACRO study. Wild-type (WT) KRAS tumours were found in 219 patients (56%) and mutant (MT) KRAS in 175 patients (44%). Median PFS was 10.9 months for patients with WT KRAS and 9.4 months for patients with MT KRAS tumours (p = 0.0038; HR: 1.40; 95% CI:1.12–1.77). The difference in OS was also significant: 26.7 months versus 18.0 months for WT versus MT KRAS, respectively (p = 0.0002; HR: 1.55; 95% CI: 1.23–1.96). Univariate and multivariate analyses showed that KRAS was an independent variable for both PFS and OS. Responses were observed in 126 patients (57.5%) with WT KRAS tumours and 76 patients (43.4%) with MT KRAS tumours (p = 0.0054; OR: 1.77; 95% CI: 1.18–2.64).Conclusions/SignificanceThis analysis of the MACRO study suggests a prognostic role for tumour KRAS status in patients with mCRC treated with XELOX plus bevacizumab. For both PFS and OS, KRAS status was an independent factor in univariate and multivariate analyses.

Hereditary pancreatic cancer: molecular bases and their application in diagnosis and clinical management. A guideline of the TTD group

Pancreatic carcinoma (PC) represents the fourth leading cause of cancer death in Spain with a death rate of 2,400 males and 2,000 females per year. Poor outcome related to its silent nature and the lack of reliable secondary prevention measures translate into advanced-stage diagnosis, 75% of deaths within the first year of diagnosis and 5-year survival rate of <5%. Family history was first recognized as a risk factor for PC. Further population-based and case-control studies subsequently found that 7.8% of patients with PC have a family history of the same tumor and individuals with a first-degree relative with PC have a 3.2-fold increased risk of developing PC. Overall, it is estimated that up to 10% of PC have a familial component. However, known genetic syndromes account for <20% of the observed familial aggregation of PC. We review the most important aspects in epidemiology, molecular biology and clinical management of familial PC.

First-Line Cetuximab Plus Capecitabine in Elderly Patients with Advanced Colorectal Cancer: Clinical Outcome and Subgroup Analysis According toKRASStatus from a Spanish TTD Group Study

Single-agent cetuximab is safe and active in elderly patients with advanced colorectal cancer (CRC). A cetuximab-capecitabine combination has not previously been tested in elderly patients with advanced CRC. Sixty-six patients with advanced CRC were treated with cetuximab as a 400 mg/m2 i.v. infusion followed by 250 mg/m2 i.v. weekly plus capecitabine at a dose of 1,250 mg/m2 every 12 hours. After the inclusion of 27 patients, the protocol was amended for safety reasons, reducing the dose of capecitabine to 1,000 mg/m2 every 12 hours. Thirty-nine additional patients were treated with the reduced dose of capecitabine. The overall response rate was 31.8%. KRAS status was determined in 58 patients (88%). Fourteen of 29 patients with wild-type KRAS tumors responded (48.3%; 95% confidence interval [CI], 29.4%-67.5%), compared with six of 29 patients with mutant KRAS tumors (20.7%; 95% CI, 8.0%-39.7%). The median progression-free survival (PFS) interval was 7.1 months. The median PFS interval for patients whose tumors were wild-type KRAS was significantly longer than for those with mutant KRAS tumors (8.4 months versus 6.0 months; p = .024). The high incidence of severe paronychia (29.6%) declined (7.7%) after capecitabine dose adjustment. Cetuximab plus capecitabine at a dose of 1,000 mg/m2 every 12 hours may be an alternative to more aggressive regimens in elderly patients with advanced wild-type KRAS CRC.

Slowly Progressing Nucleotide Excision Repair in Trichothiodystrophy Group A Patient Fibroblasts

Trichothiodystrophy (TTD) is a rare autosomal premature-ageing and neuroectodermal disease. The photohypersensitive form of TTD is caused by inherited mutations in three of the 10 subunits of the basal transcription factor TFIIH. TFIIH is an essential transcription initiation factor that is also pivotal for nucleotide excision repair (NER). Photosensitive TTD is explained by deficient NER, dedicated to removing UV-induced DNA lesions. TTD group A (TTD-A) patients carry mutations in the smallest TFIIH subunit, TTDA, which is an 8-kDa protein that dynamically interacts with TFIIH. TTD-A patients display a relatively mild TTD phenotype, and TTD-A primary fibroblasts exhibit moderate UV sensitivity despite a rather low level of UV-induced unscheduled DNA synthesis (UDS). To investigate the rationale of this seeming discrepancy, we studied the repair kinetics and the binding kinetics of TFIIH downstream NER factors to damaged sites in TTD-A cells. Our results show that TTD-A cells do repair UV lesions, although with reduced efficiency, and that the binding of downstream NER factors on damaged DNA is not completely abolished but only retarded. We conclude that in TTD-A cells repair is not fully compromised but only delayed, and we present a model that explains the relatively mild photosensitive phenotype observed in TTD-A patients.

6630 POSTER Evaluation of the Efficacy and the Safety of Lanreotide on Tumour Growth Stabilization in Patients With Progressive Neuroendocrine Tumours (NETs) Who Are Not Eligible to Be Treated With Either Surgery or Chemotherapy – TTD Group Study

6630 POSTER Evaluation of the Efficacy and the Safety of Lanreotide on Tumour Growth Stabilization in Patients With Progressive Neuroendocrine Tumours (NETs) Who Are Not Eligible to Be Treated With Either Surgery or Chemotherapy – TTD Group Study

Randomized phase III trial of the TTD Group comparing capecitabine and oxaliplatin (XELOX) vs. oxaliplatin and 5-fluorouracil in continuous infusion (FUFOX) as first line treatment in advanced or metastatic colorectal cancer (CRC)

3580 Background: OX plus CI 5-FU is one of the standard chemotherapy regimens for first-line treatment in patients (p) with advanced CRC. Phase II trials have shown XELOX as a convenient combination, with a high activity and a favourable safety profile. This study is a phase III trial comparing both schedules. Methods: Multicenter, randomized and open labeled study was designed to include p withadvanced/metastatic CRC adenocarcinoma, measurable disease, PS ≥70% and adequate bone marrow, renal and hepatic functions. Previous adjuvant chemotherapy was allowed. Primary endpoint is time to progression (TTP). The study was designed to determined non-inferiority when the median time to progression in the XELOX arm was not lower than 5.5 months (hazard ratio no larger than 1.27). A sample size of 348 p (174 per arm) was necessary (0.05 level test; 80% power). Treatment: P were randomly assigned to receive either Arm A: oral XEL 1000 mg/m2 twice daily from day 1 to day 15, plus OX 130 mg/m2, iv, 2h, day 1 (in 3-week treatment cycles) or Arm B: biweekly 85 mg/m2, OX, iv, 2h, plus weekly CI 5-FU 2250 mg/m2, in 48h (TTD schedule). Treatment was continued, until progressive disease, unacceptable toxicity or consent withdrawal. Results: 340 (170/170) p have been included in the interim analysis over 348 enrolled, (M/F, 61%/39%), median age: 65.6 years (32.3–81.6), PS 90–100%: 62%. Primary tumour sites were colon (66.4%), rectum (28.3%) and both (5.3%). Median relative dose intensity was 90% for XEL and 92% for OX in arm A and 78% for OX and 78% for 5-FU in arm B. Efficacy: overall response rate in each arm (A/B) was 37.1/43.0% (p=0.824). With a median follow up of 12.6 months, median TTP was 8.8/9.6 months (p=0.130). Main grade 3–4 toxicity per p in each arm (A/B) was: paresthesia (17.7/15.9%), asthenia (12.4/17.1%), diarrhea (14.1/23.6%), neutropenia (8.3/10.0%) and vomiting (4.1/7.6%). Mature data on TTP and OS will be presented at the meeting. Conclusions: Efficacy and safety results suggest a similar toxicity profile, response rate and TTP for both regimens. No significant financial relationships to disclose.

Guides for adjuvant treatment of colon cancer

The choice of the most suitable chemotherapy schedule for the adjuvant treatment of colon cancer has been reviewed by the TTD group, as well as the principles of risk assessment for patients with stage II disease. In the light of data now available, oxaliplatin- based schedules (FOLFOX4 or FLOX) are recommended. Alternatives in special situations are monotherapy with capecitabine, UFT/LV, or 5- FU/LV in infusion. In patients with stage II disease, the indication of chemotherapy must be individualized and based on the patient's risk of recurrence (perforation, obstruction, peritumoral lymphovascular involvement, poorly differentiated histology, number of lymph nodes examined < or = 11, pre-surgical CEA), and comorbidities that can compromise the safety of treatment or survival of the patient.

Preliminary results of a randomized phase III trial of the TTD Group comparing capecitabine and oxaliplatin (CapeOx) vs. oxaliplatin and 5-fluorouracil in continuous infusion (5-FU CI) as first line treatment in advanced or metastatic colorectal cancer (CRC)

3524 Background: Ox plus CI 5-FU is one of the standard chemotherapy regimens for first-line treatment in patients (p) with advanced CRC. Phase II trials have shown CapeOx as a convenient combination, with a high activity and a favourable safety profile. This study is a phase III trial comparing both schedules. Methods: The study is designed to include 348 p with histological or cytological confirmation of advanced/metastatic CRC adenocarcinoma, measurable disease, PS≥70% and adequate bone marrow, renal and hepatic function. Previous adjuvant chemotherapy was allowed. Treatment: P were randomly assigned to receive either Arm A: oral Cape 1000 mg/m2 twice daily from day 1 to day 15, plus Ox 130 mg/m2, iv, 2h, on day 1 (in 3-week treatment cycles) or Arm B: biweekly 85 mg/m2, Ox, iv, 2h, plus weekly CI 5-FU 2250 mg/m2, in 48h (TTD schedule). Treatment was continued, until progressive disease, unacceptable toxicity or consent withdrawal. Results: 268 p have been included in the interim analysis over 348 enrolled, (M/F, 61%/39%), median age: 65.9 years (32.3–81.6), PS 90–100%: 62%. Primary tumour sites were colon (66.3%), rectum (27.7%) and both (6.1%). Median number of lesion sites was 1 (1 site 68.1%), located in liver (76.1%), lung (31.5%), and lymph nodes (12.0%) mainly. Previous treatment included surgery (82.0%), adjuvant chemotherapy (21.8%) and radiotherapy (12.0%). Median relative dose intensity was 94% for Cape and 95% for Ox in arm A and 83% for Ox and 81% for 5-FU in arm B. Efficacy: over 98/97 evaluable patients, overall response rate in each arm (A/B) was 46.9/53.6%, with (6.1/4.1%) CR, (40.8/49.5%) PR, (38.8/26.8%) SD and (14.3/19.6%) PD. Grade 3–4 toxicity per p in each arm (A/B) was: paresthesia (13.4/9.0%), asthenia (10.4/17.2%), diarrhea (11.2/17.1%), neutropenia (3.7/6.7%), vomiting (5.2/6.0%) and febrile neutropenia (1.5/0.7%). Conclusions: Preliminary efficacy and safety results suggest a very similar toxicity profile and response rate for both regimens. No significant financial relationships to disclose.