Continuous Infusion Of 5-fluorouracil Research Articles

Dose-Dense Regimen of Cisplatin and Infusional Fluorouracil in Advanced Gastric Cancer—A Single Institution Experience

Chemotherapy with continuous infusion of 5-fluorouracil and cisplatin in a monthly schedule is one of the most common regimens in the treatment of advanced gastric cancer. In this study, we evaluated the efficacy and safety of a dosedense administration of this regimen in this patient population. Sixty-six consecutive patients with previously untreated histologically confirmed unresectable or metastatic gastric adenocarcinoma were treated with a 2-hour infusion of cisplatin 100 mg/m2 followed by continuous infusion of 5-fluorouracil 1000 mg/m2/day for 5 days, every 21 days. The most common grade ≥3 toxicities were fatigue (42%), nausea/vomiting (30%) and leucopenia (12%). Four patients (6%) died from treatment-related toxicity. The response rate was 35%, the median progression-free survival was 4.3 months and the median survival was 5.9 months. In light of these results, the dose-dense approach seems to offer little, if any, benefit compared with the standard regimens.

Peri-operative Chemotherapy in Patients with Oesophageal and Gastro-oesophageal Junction Cancer – Three Years of Experience

Peri-operative chemotherapy has been found to benefit patients with oesophageal and gastro-oesophageal junction adenocarcinoma. This study's aim was to evaluate the efficacy and tolerance of this treatment. The study included patients with carcinoma of the lower oesophagus and gastro-oesophageal junction in whom the disease was evaluated as potentially operable. Chemotherapy (CHT) consisted of three preoperative and three postoperative cycles of intravenous epirubicin and cisplatin on day 1 plus a continuous infusion of fluorouracil for 21 days (ECF) or oral capecitabine for 14 days (ECCap). Postoperative radio-chemotherapy (CRT) with fluorouracil or capecitabine after CHT was indicated in patients with two and more positive lymph nodes. Sixty-three patients started the treatment. Median follow-up was 32 months. Preoperative CHT was completed by 62 patients, 52 had surgery, 46 had radical resection, 25 patients had pN0 and 21 patient pN plus findings. Postoperative CHT was started in 39 (62%) patients and completed in 32 (51%). Ten (16%) patients had postoperative CRT. Adverse events of grade 3 and 4 were: neutropenia 17%, vomiting 8%, fatigue 5%, diarrhoea 3%. Reasons for omitting surgery in 11 (17%) patients were: progression in 7 patients, medically unfit in 3 patients, other in 1 patient. In the reporting period there were recurrences in 39 of all patients, in 7 locoregional only, in 10 distant plus locoregional, and in 19 distant metastases. Median survival was 24.1 months and 3-year survival rate was 42%. Peri-operative chemotherapy ECF/ECCap was feasible and well tolerated. Radical resection was performed in most patients.

DeCIDE and PARADIGM: nails in the coffin of induction chemotherapy in head and neck squamous cell carcinoma?

Induction chemotherapy was first used in squamous cell carcinoma of the head and neck (SCCHN) in the 1970s. High overall response rates were observed in previously untreated tumours [1] and a correlation between response to induction chemotherapy and favourable outcome following radiotherapy was noted [2]. Numerous subsequent randomised studies and meta-analyses nonetheless failed to demonstrate a significant survival advantage with the use of induction chemotherapy compared with locoregional treatment alone [3]. A marginally significant 5 % absolute improvement in 5 year survival was seen when analysis was restricted to studies using a platin and 5-fluorouracil (PF) as the induction regimen. This was however overshadowed by the larger survival benefit observed with concurrent chemoradiation (CRT). As a result, CRT became widely accepted as the standard of care in the nonsurgical management of patients with locoregionally advanced SCCHN. Recent years have witnessed a renewed interest in the use of induction chemotherapy in SCCHN. Increased locoregional tumour control and survival with CRT have resulted in a shift in the pattern of treatment failure, with a higher incidence of distant relapse compared with locoregional recurrence, especially in patients with advanced nodal disease at presentation [4]. Although induction chemotherapy has a limited impact on locoregional control, it is more effective than concurrent chemotherapy at reducing distant disease relapse [3]. By adding multi-agent induction chemotherapy to CRT, in a treatment paradigm known as sequential chemoradiotherapy (SCRT), survival of patients with advanced SCCHN can potentially be maximised with CRT providing optimal locoregional control and induction chemotherapy reducing distant disease relapse [5]. Such a paradigm also allows treatment selection based on the magnitude of response to induction chemotherapy. These potential roles of induction chemotherapy were tested against CRT in two key randomised controlled trials: DeCIDE and PARADIGM [6, 7]. Preliminary results from both studies were presented at the 2012 annual meeting of the American Society of Clinical Oncology and we await their full publication. DeCIDE is a multicentre randomised phase III study designed to assess whether the addition of 2 cycles of induction docetaxel, cisplatin and 5-fluorouracil (TPF) chemotherapy to CRT (docetaxel 25 mg/m day 1, continuous infusion 5-fluorouracil 600 mg/m days 0–4 and oral hydroxyurea 500 mg twice daily days 0–4 with hyperfractionated twice daily radiotherapy at 1.5 Gy per fraction days 1–5 every 14 days for 5 cycles) reduces the distant failure rate and improves overall survival in patients with previously untreated SCCHN and advanced nodal disease (N2/N3 M0) at presentation [6]. Target accrual was initially 400 patients, which would have provided 88 % power to detect an improvement in the 3 year survival rate of 50 % assumed with CRT to 65 % with SCRT. This was reduced to 280 patients as a result of slow accrual, with 80 % power to detect a hazard ratio of 0.5 for the primary endpoint of overall survival at 3 years. One hundred and forty-two patients were randomised to the induction chemotherapy arm of the study, while 138 were randomised to CRT. The majority presented with N2 disease and 55 % had primary tumours in the oropharynx. Of those randomised to induction chemotherapy, 91 % received 2 cycles of TPF with 9 % achieving a complete response and 55 % a partial response to treatment. Eighty-seven percent proceeded to CRT following induction chemotherapy. S. W. Loo (&) K. Geropantas T. W. Roques Department of Oncology, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK e-mail: suatloo@doctors.org.uk

A triplet combination with irinotecan (CPT-11), oxaliplatin (LOHP), continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in KRAS wt, metastatic colorectal cancer: a pilot phase II trial

Background:We conducted an open-label, pilot phase II trial to evaluate the efficacy and safety of FOLFOXIRI plus cetuximab as first-line treatment of patients with metastatic colorectal cancer (mCRC).Methods:Thirty patients with KRAS wild-type mCRC, <70 years and with performance status 0–1 were included in the trial.Results:Complete and partial responses were observed in 4 (13.3%) and 17 (56.7%) patients, respectively (overall response rate (ORR)=70% 95% confidence interval (CI): 53.6%-86.4%); 8 patients (26.7%) had stable disease and 1 had progressive disease. The median time to tumour progression was 10.2 months (95% CI: 7.1–13.4) and the overall median survival time was 30.3 months (95% CI: 18.8–41.9). Secondary R0 resection was performed in 11 (37%) patients. Grade 3 or 4 diarrhoea and neutropenia were observed in 16 (53%) and 7 (23.3%) patients, respectively, and febrile neutropenia observed in 2 (6.6%) patients. Neurotoxicity grade 2 or 3 was reported in 7 (23.3%) and in 2 (6.7%) patients, respectively, and grade 3 rush was reported in 1 patient.Conclusion:The FOLFOXIRI/cetuximab combination presented increased activity in terms of response rate and R0 secondary liver metastases resection, and merits further investigation, especially in patients with initially unresectable disease confined to the liver.

Neoadjuvant therapy with weekly docetaxel and cisplatin, 5‐fluorouracil continuous infusion, and concurrent radiotherapy in patients with locally advanced esophageal cancer produced a high percentage of long‐lasting pathological complete response

This phase 2 study was aimed at defining the pathological response rate of a neoadjuvant schedule including weekly docetaxel and cisplatin, continuous infusion (c.i.) of 5-fluorouracil (5-FU) and concomitant radiotherapy (RT) in untreated stage II-III adenocarcinoma and squamous cell carcinoma of mid-distal thoracic esophagus. The schedule consisted of a first phase of chemotherapy alone and of a second phase of concurrent chemoradiation. Doses were as follows: docetaxel 35 mg/m(2) and cisplatin 25 mg/m(2) on days 1, 8, 15, 29, 36, 43, 50, and 57 plus 5-FU c.i. (180 mg/m(2) on days 1-21 and 150 mg/m(2) on days 29-63); RT (50 Gy) started at day 29. Surgery was planned 6 to 8 weeks after the completion of chemoradiation. A total of 74 patients were enrolled; pathological complete remission (pCR) was found in 47% (35 of 74) and near pCR (microfoci of tumor cells on the primary tumor without lymph nodal metastases) (pnCR) in 15% of the patients (11 of 74). Grade 3-4 neutropenia, nonhematological toxicity, and toxic deaths occurred in 13.5%, 32.4%, and 4% of the patients, respectively. Median follow-up was 55 months (range, 3-108 months). Median survival of all 74 patients was 55 months, whereas it was not reached in the pCR subset. The 3- and 5-year survival rates were, respectively, 83% and 77% for pCR, 73% and 44% for pnCR, and 21% and 14% for Residual Tumor subsets (P < .001). This study shows that 1) this intensive weekly schedule produced a high pathological response rate, 2) responders had high and long-term durable survival rates.

Laryngeal preservation in advanced piriform sinus squamous cell carcinomas using superselective intra-arterial chemoradiation therapy with three agents

Conclusion: Superselective intra-arterial chemotherapy, which enables local control and laryngeal preservation, is a safe and useful therapy for preservation of nutrition, speech, and swallowing functions. Objective: To improve the laryngeal preservation rate in patients with hypopharyngeal piriform sinus squamous cell carcinoma by superselective intra-arterial chemotherapy. Methods: Fifty-seven patients received anterograde intra-arterial administration of docetaxel and cisplatin, and two courses of intravenous continuous infusion of 5-fluorouracil as a neoadjuvant chemotherapy over 120 h starting on day 2. Concurrent chemoradiotherapy was administered from the third course to control the primary cancer. Remaining neck lymph node metastases were treated in principle by neck dissection. Results: The 5- and 10-year survival rates were 68.5% and 58.9%, respectively. The 5-year rates by the T classification were 96.0% (10-year rate, 88.6%) in T3, 48.1% in T4a, and 16.7% in T4b. The 5- and 10-year laryngeal preservation rates were 65.2% and 62.4%, respectively. The 5-year rates by the T classification were 92.4% (10-year rate, 87.6%) in T3, 36.2% in T4a, and 16.7% in T4b. No irreversible side effects, complications, or sequelae were reported. Superselective intra-arterial chemotherapy showed superior laryngeal preservation as well as high survival rates, particularly in T3, and was considered a useful therapy.

再発消化器癌に対するLow dose CDDP/5-FU併用化学療法

再発消化器癌に対するLow dose CDDP/5-FU併用化学療法

Superselective intra-arterial chemotherapy for laryngeal preservation in carcinoma of the anterior oropharyngeal wall

Conclusion: Superselective intra-arterial chemotherapy, which can provide local control and laryngeal preservation, is safe and useful for preserving pharyngeal and laryngeal functions. Objective: To evaluate superselective intra-arterial chemotherapy in terms of the contribution to survival and laryngeal preservation in squamous cell carcinoma (SCC) of the anterior oropharyngeal wall. Methods: A total of 51 patients with SCC of the anterior oropharyngeal wall received intra-arterial administration of docetaxel at 60 mg/m2 and cisplatin at 60 mg/m2 anterogradely, followed by intravenous continuous infusion of 5-fluorouracil at 750 mg/m2/day over 120 h starting on day 2. Neck lymph node metastases were treated by neck dissection. Results: The 5- and 10-year survival rates of the 51 patients were 72.8% and 66.4%, respectively. The 5-year survival rates of patients with T2, T3, T4a, and T4b cancer were 100%, 88.7%, 41.9%, and 33.3%, respectively. The 5- and 10-year laryngeal preservation rates of the 51 patients were 63.4% and 30.0%, respectively. The 5-year laryngeal preservation rates of patients with T2, T3, T4a, and T4b cancer were 100%, 75.2%, 23.6%, and 33.3%, respectively. No irreversible side effects, complications, or sequelae were reported.

Concurrent Chemo-Proton Therapy Using 5-fluorouracil and Cisplatin for Esophageal Cancer

Concurrent Chemo-Proton Therapy Using 5-fluorouracil and Cisplatin for Esophageal Cancer

ACR Appropriateness Criteria® Resectable Rectal Cancer

The management of resectable rectal cancer continues to be guided by clinical trials and advances in technique. Although surgical advances including total mesorectal excision continue to decrease rates of local recurrence, the management of locally advanced disease (T3-T4 or N+) benefits from a multimodality approach including neoadjuvant concomitant chemotherapy and radiation. Circumferential resection margin, which can be determined preoperatively via MRI, is prognostic. Toxicity associated with radiation therapy is decreased by placing the patient in the prone position on a belly board, however for patients who cannot tolerate prone positioning, IMRT decreases the volume of normal tissue irradiated. The use of IMRT requires knowledge of the patterns of spreads and anatomy. Clinical trials demonstrate high variability in target delineation without specific guidance demonstrating the need for peer review and the use of a consensus atlas. Concomitant with radiation, fluorouracil based chemotherapy remains the standard, and although toxicity is decreased with continuous infusion fluorouracil, oral capecitabine is non-inferior to the continuous infusion regimen. Additional chemotherapeutic agents, including oxaliplatin, continue to be investigated, however currently should only be utilized on clinical trials as increased toxicity and no definitive benefit has been demonstrated in clinical trials.The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Safety and preliminary results of perioperative chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) for high-risk gastric cancer patients

BackgroundGastric cancer relapse occurs in about 30% of the patients treated with gastrectomy and D2-lymphadenectomy, mainly as distant or peritoneal metastases. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been associated with an improvement in survival and lower peritoneal recurrence, albeit with increased morbidity. The aim of this study is to report the preliminary results of the association of perioperative chemotherapy, radical surgery and HIPEC in high-risk gastric patients in a single institution.MethodsTreatment protocol was started in 2007 and included patients younger than 65 years old, with good performance status and gastric adenocarcinoma with serosa involvement and lymph node metastases, located in the body or antrum. Patients should receive three preoperative cycles of DCF (Docetaxel 75 mg/m2, Cisplatin 75 mg/m2 and continuous intravenous infusion of 5-Fluorouracil 750 mg/m2 for 5 days), followed by gastric resection with D2-lymphadenectomy, hyperthermic intraperitoneal chemotherapy with Mytomicin C 34 mg/m2 and three more postoperative cycles of DCF.ResultsTen patients were included between 2007 and 2011. Their median age was 47 years old and six were male. Nine were staged with cT4 cN + tumors and one as cT3 cN+. Nine patients completed all three preoperative chemotherapy cycles. Eight individuals were treated with a total gastrectomy and the other two had a distal gastrectomy, all having HIPEC. Postoperative morbidity was 50%, with no deaths. Regarding postoperative chemotherapy, only 5 patients completed three cycles. With a median follow-up of 25 months, three relapses were identified and 7 patients remain disease-free, two with more than 4 years of follow-up.ConclusionThe association of perioperative systemic and intraperitoneal chemotherapy plus radical surgery is a feasible multimodality treatment, with acceptable morbidity. With a longer follow-up and a larger group of patients, we hope to be able to determine if it also influences survival outcomes and patterns of recurrence.Mini-The association of perioperative chemotherapy, gastric resection and D2-lymphadenectomy and hyperthermic intraperitoneal chemotherapy proved to be associated with acceptable morbidity. For survival analysis, a longer follow-up is needed.

Cisplatin and 5‐fluorouracil in inoperable, stage IV squamous cell carcinoma of the penis

What's known on the subject? and What does the study add? Metastatic or locally advanced squamous cell carcinoma of the penis (SCCP) is generally incurable, but it can be palliated with systemic chemotherapy. Two retrospective studies, involving <10 patients each, showed that cisplatin plus continuous infusion of 5-fluorouracil (5-FU) may be effective and well tolerated. Cisplatin, methotrexate and bleomycin, cisplatin and irinotecan and taxanes can also play an important role for patients with locally advanced/metastatic SCCP. Finally, anti-EGFR therapy may also be effective in advanced SCCP. Although cisplatin plus continuous infusion of 5-FU is widely used in clinical practice for palliation of SCCP, toxicity and efficacy data regarding this schedule include a total of 14 patients with SCCP, treated more than two decades ago. In our retrospective study, cisplatin plus continuous infusion of 5-FU was used for palliative purposes in a homogenous sample of 25 patients with SCCP. Partial responses and stable disease were observed in 8 (32%) and 10 (40%) patients, respectively, with a median progression-free survival of 20 weeks. Neutropenia was the most important grade 3-4 side effect observed, occurring in 20% of patients. These data provide confirmation that such a combination regimen is moderately effective and well tolerated in patients with SCCP. • To investigate the activity and toxicity of 5-fluorouracil (5-FU) as a first-line treatment in metastatic squamous cell carcinoma of the penis (SCCP). • The medical records of 78 patients with SCCP treated between January 2000 and June 2011 at the four participating centres were reviewed. • Data regarding patients treated with first-line 5-FU were extracted. • Patients were included in the study if radiological reports were available for determination of response and progression-free survival (PFS) according to response evaluation criteria in solid tumours (RECIST) 1.1. • Between January 2000 and June 2011, 25 patients were treated with i.v. cisplatin on day 1 followed by 5-FU as a continuous 24-h infusion for 4 days every 3 weeks until disease progression or unacceptable toxicity. Partial responses and stable disease were observed in eight (32%) and 10 (40%) patients, respectively, with a disease control rate of 72%. • Severe neutropenia was the most important grade 3-4 side effect observed, occurring in 20% of patients. • The median (interquartile range [IQR]) PFS was 20 (11-20) weeks and the median (IQR) overall survival (OS) was 8 (7-12) months. • 5-FU is associated with a moderate response rate and is well tolerated in patients with metastatic SCCP.

600P - Bifractionated CPT-11 with LV5FU2 Infusion (FOLFIRI-3) In Combination with Bevacizumab Followed by a Capecitabine and Bevacizumab Maintenance Therapy: A Phase II Study in First-Line Metastatic Colorectal Cancers

ABSTRACT Background Bevacizumab (Bev) with FOLFIRI or FOLFOX regimen is a standard of care in first-line metastatic colorectal cancers (mCRC). As second-line regimen after FOLFOX, FOLFIRI-3 has shown a significantly better PFS in comparison with other irinotecan-based regimen. We therefore evaluated the safety, efficacy and possible predictive factors for FOLFIRI-3 in combination with Bev as initial treatment for mCRC. Since fully validated biomarkers in mCRC are still lacking, we decided to assess the prognostic value of Angiopoietin-2 (Ang-2). Patients and methods We conducted a three-institution phase II trial of FOLFIRI-3 regimen (irinotecan 100mg/m2 before and after a 46-hour continuous infusion of fluorouracil (2400 mg/m2) with Bev (5mg/kg day 1) repeated every 2 weeks, as first-line treatment in mCRC. Induction treatment (FOLFIRI-3 and Bev) was administrated for 6 months, followed by a maintenance treatment including Bev (7.5 mg/kg day 1) and capecitabine (1000 mg/m2 day 1 to 14), repeated every 3 weeks. Plasma VEGF and serum Ang-2 were measured at baseline. The primary endpoint was ORR. Secondary endpoints were PFS, OS, and biologic analysis of potential predictive factors of response to treatment. Results 61 patients were enrolled for treatment. The ORR was 66.7% (95% CI, 55-79). SD in 25% of patients (DCR of 91.7%). PFS was 12 months (95% CI, 9-16) and OS was 33 months (95% CI, 19-44). A total of 41 patients entered the maintenance phase of the study. Bev/capecitabine maintenance therapy appeared as an appropriate and well-tolerated option. High pre-therapeutic serum Ang-2 level was identified as a potential biomarker correlated to worse outcomes in this cohort (median progression free survival of 14.7 months vs. 7.3 months, p Conclusions As front-line regimen in mCRC, FOLFIRI-3/Bev regimen, followed by a capecitabine-based maintenance therapy, is effective and might be considered for future development particularly in patients treated by oxaliplatin in the adjuvant setting. Serum angiopoietin 2 is a promising biomarker to predict PFS and OS in mCRC patients treated with chemotherapy and bevacizumab. External validation is in course. Disclosure All authors have declared no conflicts of interest.

The efficacy and toxicity of irinotecan with leucovorin and bolus and continuous infusional 5-fluorouracil (FOLFIRI) as salvage therapy for patients with advanced gastric cancer previously treated with platinum and taxane-based chemotherapy regimens

There is no established standard salvage chemotherapy in the second-line setting for patients with advanced gastric cancer (AGC) pre-treated with platinum and taxane-based chemotherapy. Our study aims to evaluate the safety and efficacy of FOLFIRI regimen (irinotecan with leucovorin and bolus and continuous infusion with 5-fluorouracil) as a salvage chemotherapy regimen in patients with AGC. Medical records of 97 patients with AGC who received second-line FOLFIRI regimen between March 2006 and February 2011 were examined. Complete and partial responses were observed in 3 (3·1%) and 23 (23·7%) patients, respectively. The median time to progression (TTP) was 3·5 months (95% CI: 2·4–4·6) and the median overall survival (OS) was 10·5 months (95% CI: 8·8–12·2). The most common observed grade 3/4 toxicities were neutropenia (23·7%), diarrhea (6·2%), and stomatitis (5·2%). FOLFIRI regimen is safe and effective in the second-line treatment of AGC patients pre-treated with cisplatin and taxanes.

P-0145 Anal Canal Carcinoma – Radiotherapy and Combined Chemotherapy with Mitomycin-C and 5-Fluorouracil Continuous Infusion – A Single Portuguese Institution Experience

ABSTRACT Introduction Anal canal squamous cell carcinoma is an uncommon malignancy, accounting for a small percentage (4%) of all cancers of the lower intestinal tract. Concurrent chemoradiation with 5-fluorouracil (5-FU) and mitomycin-C (MMC) is the standard of care. Due to acute and long term treatment related toxicities, a split radiotherapy course was the norm. Developments in radiation technique with three-dimensional planning and conformal treatment decreased toxicity, allowing for a shortened 6 weeks treatment time with no planned treatment break. The concurrent use of chemotherapy is also responsible for treatment toxicity. The best way to combine chemotherapy with the shortened radiotherapy is still subject to debate. Along with MMC, a continuous infusion of 5-FU for the hole duration of radiotherapy could reduce the toxicity, maintaining the effectiveness of the treatment. We aim to describe a single institution experience in advanced anal carcinoma combined treatment with radiation and MMC with continuous infusion of 5-FU. Methods Retrospective analysis of all anal cancer patients treated at our institution with the chemoradiation regimen of MMC (10mg/m2 in the beginning of the first and the last week of radiotherapy) and 5-FU (200mg/m2/day continuously for the whole duration). Radiotherapy doses were 45 Gy plus a 9 Gy boost. Endpoints were response, toxicity, colostomy-free rate, relapse and survival. Results From 2007-2011, 29 patients (pts) were included (20 women and 9 men), median age 67 years (35-82) and median follow-up time 25 months (1-58). Tumor location: canal – 28, margin – 1. Histology: squamous cell carcinoma – 25, basaloid carcinoma – 4. Stage groups: I – 4, II – 13, IIIA – 1, IIIB – 11. Median duration of chemoradiotherapy (CMT) was 57 days. Tumor response: complete response – 23, partial response – 1, progression – 5. Among 28 pts who completed CMT, 14 pts (50%) presented with recurrence (local – 5, distant – 9) at a median time of 7 months after CMT ending. Local relapse was treated with salvage surgery in 3 cases and palliative colostomy in 2. Distant metastasis locations were bone – 3, lung, liver and lymph node – 2 each, skin – 1. Four pts received chemotherapy and 1 had a local resection of a single lesion. 6 pts died (related to cancer – 5, AIDS – 1) at a median time of 15 months. Acute grade III/IV toxicities were present in 12 pts (perineal skin reaction – 10, haematological – 4, diarrhoea – 1, mucositis – 1) and 3 pts had severe late toxicity (vaginal and canal anal stenosis). Conclusion In our results continuous infusion of 5-FU during radiotherapy in the treatment of anal carcinoma was associated with complete remission in 82.1% of patients with acceptable toxicity (42.8% of acute and 10.7% of late severe events). The response data is comparable to our previous experience, but there is a high rate of early recurrence that warrants further analysis and suggests that continuous infusion might not be the best 5-FU regimen to combine with radiation in anal canal cancer.

Randomized Prospective Phase II Study to Compare the Combination Chemotherapy Regimen Epirubicin, Cisplatin, and 5-Fluorouracil With Epirubicin, Cisplatin, and Capecitabine in Patients With Advanced or Metastatic Gastric Cancer

The aim of this study was to compare the efficacy and safety of the epirubicin, cisplatin, and continuous infusion of 5-fluorouracil (ECF) regimen with that of the epirubicin, cisplatin, and capecitabine (ECX) regimen in patients with advanced or metastatic gastric cancer. Patients were randomized to receive either the ECF or ECX regimen. The primary end point was the response rate. The secondary end points were time to progression (TTP), overall survival (OS), and safety. Eighty-five patients were enrolled in the study from January 2003 to March 2007. Forty-five patients received the ECF regimen and 40 patients received the ECX regimen. The objective response rate was 31% [9% complete response (CR) and 22% partial response (PR)] for ECF and 30% (10% CR and 20% PR) for ECX. The disease control rate was 51% and 73%, respectively (P<0.05). Median OS and TTP were 6.8 and 5.5 months, respectively, in the ECF group and 8.3 and 6.0 months, respectively, in the ECX group. The majority of adverse events were grade 1/2. The most frequent grade 3/4 adverse events in both groups were fatigue (ECF 15%, ECX 21%), neutropenia (ECF 16%, ECX 16%), vomiting (ECF 11%, ECX 8%), nausea (ECF 9%, ECX 3%), and anemia (ECF 7%, ECX 5%). The ECX regimen was at least as effective as the ECF regimen with a similar tolerability profile, and could therefore replace the ECF regimen for the first-line treatment of patients with advanced gastric cancer.

P-0297 Predictive/Prognostic Value of TS, KI-67, Egfr, MLH-1, MSH-2 and Trg in Locally Advanced Rectal Cancer Treated with Neoadjuvant Chemoradiation (Bmg-B1-Study)

ABSTRACT Introduction Preoperative 5-fluorouracil/capecitabine based chemoradiation (CRT) is standard treatment in locally advanced rectal cancer (LARC) patients (pts). The aim of this Bologna Multidisciplinary Group (BMG-B1) study was to evaluate the predictive and prognostic value of Tumor Regression Grade (TRG) and pathological biomarkers (thymidylate synthetase/TS, epidermal growth factor receptor/EGFR, Ki-67, p53, Bcl-2, MLH1 and MSH2). Methods Between December 2001 to January 2011 we evaluated 149 pts with cT3-T4 N-/+ rectal adenocarcinoma and location ≤12 cm from the anal margin. Preoperative CRT consisted of radiotherapy 50.4 Gy in 28 daily fractions in combination with 5-fluorouracil continuous infusion or capecitabine +/- oxaliplatin. Rectal surgery with total mesorectal excision was performed 6-8 weeks after neoadjuvant treatment. Pathological examination of surgical specimens included the TRG according to Dworak (TRG0=no regression, TRG1=minor regression, TRG2=moderate regression, TRG3=good regression TRG4=complete regression). TS, EGFR, Ki-67, p53, Bcl-2, MLH1 and MSH2 were immunohistochemically determined in pretreatment biopsies and surgical specimens. Serial sections of formalin-fixed, paraffin-embedded tissues were stained with anti-TS (clone TS106/4H4B1, Zymed Lab. Inc., Invitrogen USA), anti-EGFR (clone DAK-H1-WT, DakoCytomation USA), anti-Ki-67 (clone MM1, Novocastra Lab.UK), anti-p53 (clone BP53-12, Novocastra Lab. UK), anti-Bcl-2 (clone 124, DakoCytomation. USA), anti-MLH1 (clone G168-15, Pharmingen, USA), anti-MSH2 (clone FE11, Zymed Lab. Inc., Invitrogen USA) using a biotin free ready-to-use amplification system (Dako Advance HRP, DakoCytomation DK). Results Immunohistochemistry results of 100 biopsies and 97 surgical specimens were available. After a median follow-up of 60.3 months (2-122) we observed 4.7% local recurrences, 12.7% distant recurrences, and 13.4% deaths. TRG grade 1, 2, 3, and 4 were observed respectively in 22.6%, 35.4%, 25.5%, 16.5% of patients. Patients with TRG grade 0-1 compared to patients with TRG grade 2-4 had significant worse disease free survival (DFS) (p=0.008) and overall survival (p=0.04). High TS expression in biopsy specimens is related with TRG grade 0-1 (p=0.009). High EGFR expression in surgical specimen is related with low DFS (p=0.01). The high decrease in Ki-67 expressions between biopsy and surgical specimen is related with TRG grade 3-4 (p=0.001). The others evaluated biomarkers did not showed clinical correlations. Conclusion In BMG-B1 Study TRG grade and EGFR expression in operative specimen after CRT showed a prognostic value. High TS expression in biopsy before CRT was related to worse pathological response, and high Ki-67 decrease after CRT is related to best response.

A phase II study of modified FOLFOX as first-line chemotherapy in advanced small bowel adenocarcinoma

This study aimed at assessing the efficacy and safety of biweekly oxaliplatin in combination with continuous infusional 5-fluorouracil and leucovorin (modified FOLFOX regimen) in patients with advanced small bowel adenocarcinoma (SBA). Thirty-three eligible patients with previously untreated SBA received 85 mg/m(2) of oxaliplatin intravenously over a 2-h period on day 1, together with 400 mg/m(2) of leucovorin over 2 h, followed by a 46-h infusion of 5-FU 2600 mg/m(2) every 2 weeks. All patients were evaluable for efficacy and toxicity. A median of nine cycles (range 3-18) was administered. The objective response rate was 48.5% [95% confidence interval (95% CI): 31-67%], with one complete response, 15 partial responses, 12 stable diseases, and five progressions. The median time to progression was 7.8 months (95% CI: 6.0-9.6) and the median overall survival was 15.2 months (95% CI: 11.0-19.4). Toxicity was fairly mild. Grade 3 toxicities included neutropenia (12.1%), thrombocytopenia (3.0%), nausea (6.1%), vomiting (3.0%), diarrhea (3.0%), peripheral neuropathy (9.1%), and fatigue (3.0%), and grade 4 toxicities occurred in none of the patients. The modified FOLFOX regimen is highly active and well tolerated as first-line chemotherapy for advanced SBA patients.

Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study

Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in locally advanced rectal cancer (LARC). To evaluate in LARC patients, the feasibility and efficacy of a short intense course of induction oxaliplatin before preoperative chemoradiotherapy (CRT). Patients with T2-T4/N+ rectal adenocarcinoma were randomly assigned to arm A-preoperative CRT with 5-fluorouracil (5-FU) continuous infusion followed by surgery-or arm B-induction oxaliplatin, folinic acid and 5-FU followed by CRT and surgery. The primary end point was the rate of ypT0-1N0 stage achievement. Fifty seven patients were randomly assigned (arm A/B: 29/28) and evaluated for planned interim analysis. On an intention-to-treat basis, the ypT0-1N0 rate for arms A and B were 34.5% (95% CI: 17.2% to 51.8%) and 32.1% (95% CI: 14.8% to 49.4%), respectively, and the study therefore was closed prematurely for futility. There were no statistically significant differences in other end points including pathological complete response, tumor regression and sphincter preservation. Completion of the preoperative CRT sequence was similar in both groups. Grade 3/4 toxicity was significantly higher in arm B. Short intense induction oxaliplatin is feasible in LARC patients without compromising the preoperative CRT completion, although the current analysis does not indicate increased locoregional impact on standard therapy.

Perioperative management of patients with distal esophagus and gastroesophageal junction tumors: Three years of results.

e14631 Background: In patients with operable gastroesophageal adenocarcinoma, a perioperative regimen ECF significantly improved survival (MAGIC trial - Cunnigham 2006) and has been accepted as standard treatment option. In our study we present experience with modified MAGIC protocol in patients with lower esophagus or GE junction tumors. Methods: 67 patients (pts) (60 men, 7 women), median age 59 years (37-74), with resectable adenocarcinoma in lower esophagus or gastroesophageal junction were included in period 01 Mar 2008 – 15 Jun 2010. Fifty one (76%) pts had clinical stage nodal positive. Chemotherapy (CT) consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg/m2) and cisplatin (60 mg/m2) on day 1, and a continuous infusion of fluorouracil (200 mg/m2 per day) for 21 days or oral capecitabine 1000 mg/m2 for 14 days. Postoperative radiochemotherapy (CRT) with fluorouracil or capecitabine after the end of CT was indicated in pts with two and more positive lymphnodes in surgical specimen if feasible. Results: Preoperative CT completed 64 (94%) pts, 52 (78%) had surgery, 46 (69%) had radical resection with 3 cases of complete pathological response, 22 pts had pN0 and 21 pts pN plus finding. Postoperative CT was started in 39 (58%) pts and was completed in 32 (48%) pts. 10 (22%) pts had postoperative CRT. Adverse events grade 3-4 were: neutropenia 10%, vomiting 8%, fatigue 5%, diarrhea 3%. Reasons for omitting surgery in 15 (22%) pts were: progression in 7 pts, medically unfit in 4 pts, other in 4 pts. With a median follow-up of 31 months (17-47) there were recurrences in 35 (52%) of all pts, in 5 (7%) pts locoregional only, in 7 (11%) distal plus locoregional and in 23 (34%) pts distal metastases. Recurrence rate in radically resected pts was 39%, in patients with pN0 28% and in pN1 86%, despite adding CRT. Thirty one patients are alive with 3-year survival 46%. Conclusions: Perioperative chemotherapy ECF/ECCap in our set was feasible and well tolerated. Patients with node positive postoperative stage had poor prognosis, despite completing adjuvant treatment including postoperative CRT. This work was supported by grant NO: IGA MZ(CR) NT/12331-5/2011.