AIO Regimen Research Articles

Prospective, multi-center study of 5-fluorouracil (5-FU) therapeutic drug management (TDM) in metastatic colorectal cancer (mCRC) patients treated in routine clinical practice.

650 Background: Studies have demonstrated that body surface area (BSA)-based dosing of chemotherapy drugs leads to significant individual exposure variability with a substantial risk of under- or overdosing. This study was initiated to validate use of TDM to personalize 5-FU dosing in mCRC patients treated in routine clinical practice. Methods: 75 mCRC patients from 8 German medical centers received up to 6 administrations of infusional 5-FU according to either the AIO (n = 16), FOLFOX6 (n = 26) or FUFOX (n = 33) regimen. Initial infusional 5-FU dosing for all patients was based on BSA. Individual 5-FU exposure (AUC) was measured by an immunoassay using a blood sample drawn during each infusion. To achieve target AUC of 20 to 30 mg•h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle 5-FU AUC. Tumor markers CEA and CA19-9 were also measured before, during and after treatment. Primary objective was to confirm TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the 4th versus the 1st administration. Secondary objective was to determine whether 5-FU TDM reduced treatment-related toxicities compared to historical data. Results: Average 5-FU AUC at 1st administration was 18 + 6 mg•h/L, with 64%, 33% and 3% of the patients below, within or above target AUC range, respectively. By the 4th administration average 5-FU AUC was 25 + 7 mg•h/L (p < 0.001), with 54% patients within the target 5-FU AUC range (p = 0.0294). Compared to baseline levels, CEA and CA19-9 remained stable or decreased at the end of treatment in 82% and 84% of the patients, respectively. 5-FU-related grade 3-4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%) and mucositis (0.2%) were reduced compared to historical data inspite of 55% of patients having their doses increased. Conclusions: Personalization of 5-FU dosing via TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested lower 5-FU-related toxicities. Clinical trial information: 2011-003553-26.

Prospective, Multicenter Study of 5-Fluorouracil Therapeutic Drug Monitoring in Metastatic Colorectal Cancer Treated in Routine Clinical Practice

BackgroundStudies have demonstrated that body surface area-based dosing of chemotherapy drugs leads to significant individual exposure variability, with a substantial risk of under- or overdosing. The present study was initiated to validate the use of therapeutic drug management (TDM) to personalize 5-fluorouracil (5-FU) dosing in patients with metastatic colorectal cancer treated in routine clinical practice. Patients and MethodsA total of 75 patients with metastatic colorectal cancer from 8 German medical centers received ≤ 6 administrations of infusional 5-FU according to the AIO (folinate, 5-FU; n = 16), FOLFOX6 (leucovorin calcium [folinic acid], 5-FU, and oxaliplatin; n = 26), or FUFOX (oxaliplatin plus 5-FU/folinic acid; n = 33) regimen. Initial infusional 5-FU dosing for all patients was determined by the BSA. Individual 5-FU exposure (area under the curve [AUC]) was measured using an immunoassay of a blood sample taken during each infusion. To achieve a target AUC of 20 to 30 mg × h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle's 5-FU AUC. The primary objective was to confirm that TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the fourth versus the first administration. The secondary objective was to determine whether 5-FU TDM reduced the treatment-related toxicities compared with the historical data. ResultsThe average 5-FU AUC at the first administration was 18 ± 6 mg × h/L, with 64%, 33%, and 3% of the patients below, within, or above the target AUC range, respectively. By the fourth administration, the average 5-FU AUC was 25 ± 7 mg × h/L (P < .001), with 54% of patients within the target 5-FU AUC range (P = .0294). The incidence of 5-FU–related grade 3 and 4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%), and mucositis (0.2%) was reduced compared with the historical data, despite 55% of the patients receiving increased doses. ConclusionPersonalization of 5-FU dosing using TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested a lower incidence of 5-FU–related toxicities.

A multinational, randomized, phase III trial of XELIRI (+bevacizumab) versus FOLFIRI (+bevacizumab) as the second-line chemotherapy for metastatic colorectal cancer: Asian XELIRI project (AXEPT).

TPS780 Background: Life-prolonging systemic therapy such as chemotherapy (FOLFOX, XELOX, FOLFIRI, 5-FU/LV) with / without molecular targeted agents (bevacizumab, afilibercept, cetuximab, panitumumab) are important treatment for metastatic colorectal cancer (mCRC). On the other hand, it is required to establish an evidence of convenient therapy including oral anticancer agent which is expected lower risk of safety. XELIRI was already examined by various doses in this decade, and result of AIO 0604 was regarded as one of the most appropriate regimen. The BIX phase II study showed the tolerability and promising efficacy of the AIO regimen for Japanese mCRC patients (Hamamoto Y, et al. Oncologist 2014). Methods: Asian XELIRI Project (AXEPT) is an East Asian collaborated, open label, randomized phase III clinical trial designed to demonstrate the non-inferiority of XELIRI (+bevacizumab) to the standard of care FOLFIRI (+bevacizumab) as the second-line chemotherapy in patients with mCRC. The primary endpoint is median overall survival. The secondary endpoints are progression-free survival, time to treatment failure, overall response rate, disease control rate, relative dose intensity, safety, correlation between UGT1A1 polymorphisms (*28, *6) and safety. Eligible patients were 20 years of age and older, had histologically proven CRC, ECOG performance status 0-2, adequate organ function, progression or difficult to continue after first line regimen. Patients were randomized 1:1 to standard FOLFIRI (+bevacizuamb 5mg/kg day1), repeated every 14 days (Group A) or XELIRI, Irinotecan 200mg/m2 day1, and capecitabine 1600mg/m2 day 1-14 (+bevacizumab 7.5mg/kg day1), repeated every 21 days (Group B). A Total of 464 events were needed to show non-inferiority with a two-sided α of 0·05 and a power of 80%, a target sample size of 600 patients was required. (The 95% CI upper limit of the hazard ratio was pre-specified as less than 1.3.). Enrollment has started in December 2013. As of August 2015, 98 centers in the Japan, South Korea and China are participating in this trial. Clinical trial information: NCT01996306. UMIN000012263. Clinical trial information: NCT01996306.

Metastatic Adenocarcinomas of the Stomach or Esophagogastric Junction (UICC Stage IV) Are Not Always a Palliative Situation: A Retrospective Analysis

Gastric cancer is one of the most common cancers. Unfortunately, it is often diagnosed at the advanced stage International Union Against Cancer stage IV. This induced us to carry out an interdisciplinary analysis of this patient group with the Department of Internal Medicine 1. Our aim was to discuss cancers classified initially as unresectable in a meeting of the interdisciplinary tumor board after palliative chemotherapy, and to refer selected patients for surgery after establishing resectability. The outcome of the chemotherapy, operation method, complication rate, and long-term survival were analyzed. From 1999 to 2008, 76 patients with metastatic gastric cancer or carcinoma of the esophagogastric junction were discussed by the interdisciplinary tumor board of the University of Erlangen and classified initially as unresectable. The patients then received palliative chemotherapy according to the AIO regimen (weekly high-dose 5-fluorouracil/folinic acid [FU/FA] in a 24 h infusion), plus irinotecan. If the tumor was subsequently classified as resectable, the patient underwent either gastric resection or gastrectomy with DII-III dissection. Metastases were resected depending on their location (liver). Peritoneal carcinomatosis was treated additionally by HIPEC. Statistical analysis was with SPSSS version 20. Surgical and general complications and hospital mortality were acceptable. There were no cases of anastomotic leak, but one patient died of fulminant pneumonia. The R0 resection rate was 69 %, and four patients had long-term survival of more than 60 months. There were significant survival advantages. Metastatic gastric cancer or carcinoma of the esophagogastric junction can become resectable after downsizing the tumor with palliative chemotherapy. Long-term survival is achieved in some cases. Therefore, every patient with this type of cancer should be discussed by the interdisciplinary tumour board after palliative chemotherapy to provide him with a chance of cure after re-evaluation.

Efficacy and toxicity of second-line AIO plus irinotecan (IRI) after pretreatment with AIO plus oxaliplatin (L-OHP) in the sequential therapy of metastatic colorectal cancer (CRC).

3561 Background: The FOLFIRI followed by FOLFOX6 (or vice versa) schedule has been considered as the gold standard of sequential treatment in CRC (Tournigand C. JCO 2004). In contrast to those bi-weekly schedules, the wide-spread weekly chemotherapy administration (e.g. AIO regimen), has not been investigated as yet for second-line treatment. The AIO + IRI schedule has provided promising results in the first-line treatment of CRC (Köhne C.-H. JCO 2005). Therefore, we now investigated the efficacy and toxicity of this schedule in second-line treatment in a phase II study. Methods: From 5/02 to 6/10, 60 palliative patients (pts.) with histologically proven CRC were enrolled in an oligocentric phase II study based on the following regimen: weekly IRI (80 mg/m2 i.v.) as 1h-infusion (inf.): d1, 8, 15, 22, 29, 36, qd 57 followed by 5-FU (2000 mg/m2 i.v.) combined with sodium folinic acid (500 mg/m2, d1, 8, 15, 22, 29, 36, qd 57) as a 24h-inf. via port-a-cath. This study focused on the efficacy and toxicity of second-line treatment with AIO + IRI. Results: Last date of evaluation: November 30, 2012; evaluable for efficacy: n = 58 pts., evaluable for toxicity: n = 59 pts.; men/women: 28/72%; median age: 65y; primary tumor location: rectum/colon: 45/55%.; toxicity data: higher grade toxicity (grade 3-4): leukocytopenia: 5.1%; thrombocytopenia: 1.7%; vomiting: 3.4%; diarrhea: 13.5%; hand-foot-syndrome: 1.7%; alopecia (grade 2) 3.4%; efficacy data: PFS: 4.2 m; median OS 14.2 m, RR: 10%; AIO + IRI following AIO + L-OHP achieved a median OS of 25.0 months. Conclusions: In the field of second-linetreatment of CRC the AIO plus IRI regimen offers both a favorable toxicity profile and promising results in terms of efficacy compared with the FOLFIRI regimen.

Palliative first-line therapy with weekly high-dose 5-fluorouracil and sodium folinic acid as a 24-hour infusion (AIO regimen) combined with weekly irinotecan in patients with metastatic adenocarcinoma of the stomach or esophagogastric junction followed by secondary metastatic resection after downsizing

SummaryBackgroundThe aim of this retrospective study was to evaluate the efficacy and safety of weekly high-dose 5-fluorouracil (5-FU)/folinic acid (FA) as 24-h infusion (AIO regimen) plus irinotecan in patients with histologically proven metastatic gastroesophageal adenocarcinoma (UICC stage IV).Material/MethodsFrom 08/1999 to 12/2008, 76 registered, previously untreated patients were evaluable. Treatment regimen: irinotecan (80 mg/m2) as 1-h infusion followed by 5-FU (2000 mg/m2) combined with FA (500 mg/m2) as 24-h infusion (d1, 8, 15, 22, 29, 36, qd 57).ResultsMedian age: 59 years; male/female: 74%/26%; ECOG ≤1: 83%; response: CR: 1%, PR: 16%, SD: 61%, PD: 17%, not evaluable in terms of response: 5%; tumor control: 78%; median OS: 11.2 months; median time-to-progression: 5.3 months; 1-year survival rate: 49%; 2-year survival rate: 17%; no evidence of disease: 6.6%; higher grade toxicities (grade 3/4): anemia: 7%, leucopenia: 1%, ascites: 3%, nausea: 3%, infections: 12%, vomiting: 9%, GI bleeding of the primary tumor: 4%, diarrhea: 17%, thromboembolic events: 4%; secondary metastatic resection after downsizing: 16 patients (21%), R-classification of secondary resections: R0/R1/R2: 81%/6%/13%, median survival of the 16 patients with secondary resection: 23.7 months.ConclusionsCombined 5-FU/FA as 24-h infusion plus irinotecan may be considered as an active palliative first-line treatment accompanied by tolerable toxicity; thus offering an alternative to cisplatin-based treatment regimens. Thanks to efficient interdisciplinary teamwork, secondary metastatic resections could be performed in 16 patients. In total, the patients who had undergone secondary resection had a median survival of 23.7 months, whereas the median survival of patients without secondary resection was 10.1 months (p≤0.001).

Long-term follow-up of efficacy of irinotecan-based chemotherapy in poor-risk patients suffering from metastatic colorectal cancer.

e14102 Background: Irinotecan (CPT11)-based chemotherapy has provided a significant advancement in the management of patients with metastatic colorectal cancer (MCRC). However, some previous data indicated that patients with poor PS, prior adjuvant chemotherapy and high tumor burden at diagnosis might not benefit from longer survival with CPT11-based chemotherapy. To evaluate whether CPT11-based chemotherapy could be suitable for poor-risk MCRC, we performed a retrospective analysis. Methods: Out of 197 CRC patients treated in our department between 2002-2009, 53 poor risk MCRC patients (poor-risk group was defined as ≥ 2 criteria being fulfilled, i.e. PS > 1, and/or elevated serum LDH, and/or > 1 metastatic site, and/or prior adjuvant chemotherapy) were chosen for the analysis and the results were compared (retrospectively) to respective standard risk MCRC cases. The poor-risk arm included 17 females and 36 males, age between 40- 81 (median 64.7). All the patients were treated with first-line irinotecan-based chemotherapy, according to either de Gramont or AIO regimen. Results: In the analyzed poor-risk group the confirmed RR (CR + PR) was 21.3% what was lower than in the standard-risk group (RR = 50%, p < 0.05). The poor risk group median TTP was 7.1 months, median PFS was 7.3 months, and median OS 15 months. The standard-risk group median TTP, PFS and OS were not statistically different from the poor-risk group (9.3 mts, 9.9 mts, and 16 mts respectively). All the patients received second-line chemotherapy, including biologic agents. CPT11-based chemotherapy was safe. No grade (G) 4 toxicity was observed. The most common adverse events (AE) were diarrhea (28.3% – 15 pts) and neutropenia (11.3% – 6 pts), but G3 AE were noted only in three and two persons respectively. Conclusions: Our analysis showed, that irinotecan-based chemotherapy was an effective and safe treatment option even for poor-risk patients suffering from MCRC. Although the RR was lower in comparison to standard-risk cases it did not translate into significantly shorter TTP and PFS. Subsequent lines of chemotherapy affected the overall survival. Thus, poor-risk status did not preclude irinotecan-based chemotherapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Pfizer, Roche, sanofi-aventis

Downsizing after palliative systemic chemotherapy with weekly high-dose 5-fluorouracil (5-FU) as a 24h-infusion and sodium folinic acid (AIO regimen) plus irinotecan in patients with metastatic adenocarcinomas of the stomach or the gastro-esophageal junction followed by secondary metastatic resection

e15585 Background: Due to the positive experience with combined AIO plus irinotecan (iri.) in a phase II trial (Möhler M et al, Br J Cancer 2005), this combination has been applied as first-line treatment in our department since 1999. Methods: 76 chemonaive patients (pts.) with histologically proven metastatic adenocarcinomas of the stomach or AEG tumours (tum.) (UICC IV), deemed to be non-resectable by the Interdisciplinary Tumour Board (ITB), were enrolled from 08/99 to 12/08. Chemotherapy (chemoth.) schedule: iri. (80 mg/m2 i.v. as 1h-infusion (inf.); d1, 8, 15, 22, 29, 36, qd 57) followed by 5-FU (2000 mg/m2 i.v.) with sodium folinic acid (500 mg/m2; d1, 8, 15, 22, 29, 36, qd 57) as 24h-inf. via port-a-cath. After downsizing the patients were again presented at the ITB. In 16 out of 76 pts. (21%) a secondary (sec.) metastatic resection (res.) with curative intent was taken into account. This collective is presented here evidencing the efficacy of this interdisciplinary procedure in palliative (pall.) treatment of gastric cancer. Results: Last date of evaluation: Dec/31/2008; median age: 58,7 years; men/women: n=12/4; res. of the primary tum. prior to pall. chemoth.: yes/no: n=2/14, ECOG 0/1: n=5/11; primary tum. localisation: AEG tum.: n=7; gastric carcinoma: n=9, elevated CEA yes/no: n=5/11, elevated CA19–9 yes/no: n=5/11. Number of metastatic localisations: 1/2/3: 69%/19%/12%, chemoth. application: total number:267; average value/patient:17 cycles altogether: 46, median cycles/pt.: 3, higher grade tox. (grade 3–4): anaemia 4%; diarrhea 2%, vomitus 2%, fever/infection 2%; response: PR 32%; SD 56 %; PD 6%; not evaluable 6 %; tum. control (PR, SD) 88 %; sec. res.: R0: 82 %; R1: 6 %, R2: 6 %; RX: 6%; gastrectomy with peritonectomy (R0): n=4 (25%), gastrectomy with lymph node dissection (D4,R0): n=6 (38%); HIPEC: n=4 (25%); 1-year survival:81%, 2-year survival: 44%, 3-year survival: 25%; deceased pts.: n=9 (56%), NED 19% (n=3). Conclusions: In our trial curative resections could be achieved in 82 % of the pts. During a follow-up of 20 months a NED status could be documented in 19% of the patients. No significant financial relationships to disclose.

Weekly high-dose 5-fluorouracil as a 24-h infusion and sodium folinic acid (AIO regimen) plus irinotecan in patients with locally advanced nonresectable and metastatic adenocarcinoma or squamous cell carcinoma of the oesophagus: a phase II trial

In the majority of patients with oesophageal carcinoma, curative treatment proves to be impossible when diagnosis was established; therefore, most of the patients are candidates for palliative chemotherapy. The aim of this phase II study was to evaluate the efficacy and safety of 5-fluorouracil/folinic acid (AIO regimen) plus irinotecan in patients with locally advanced or metastatic carcinoma of the oesophagus. The methods used a prospective phase II trial, start: November 2002; patients: n=25; chemotherapy: irinotecan (80 mg/m2) as a 1-h infusion and 5-fluorouracil (2000 mg/m2) with sodium folinic acid (500 mg/m2) as a 24-h infusion on days 1, 8, 15, 22, 29 and 36, repeated on day 57. Last date of evaluation: 28 February 2007; n=24; adenocarcinoma: n=13, squamous cell carcinoma (SCC): n=11; UICC III/IV: 3/21; grading G1/G2/G3/G4: 0/8/12/4; median age: 58 years (range 44-75); men/women: 19/5; Eastern Cooperative Oncology Group index 0/1/2: 3/17/4; applications: 460. Higher-grade toxicity: grade 3 diarrhoea: n=2, grade 4 diarrhoea: n=1, grade 4 vomiting: n=1, grade 4 nausea: n=1, grade 3 fatigue: n=1, grade 3 hyponatraemia: n=2, grade 4 elevation of creatinine: n=1, thrombosis of the vena subclavia: n=1, ischaemic lesion of the brain stem: n=1. Three patients died after two chemotherapeutic applications because of high tumour burden. Evaluable for response: n=19. Partial response: n=8 (33%), stable disease: n=9 (38%), progressive disease: n=2 (8%), not evaluable: n=5 (21%). Time-to-progression: 6.6 months (range 1.6-24.6). Total median survival: 13.6 months (median survival of adenocarcinoma: 20.3 months, median survival of SCC: 10.0 months). Secondary resection (R0): n=3. In oesophageal carcinomas, the AIO regimen plus irinotecan is excellently manageable as an outpatient treatment and shows efficacy in adenocarcinomas and SCCs of the oesophagus.

Neoadjuvant treatment with weekly high-dose 5-fluorouracil as a 24h-infusion, folinic acid (AIO regimen) and oxaliplatin in patients with primary resectable liver metastases of colorectal cancer: Long-term results of a phase II trial

15083 Background: Only 15–20% of all patients (pts.) with colorectal liver metastases are suitable for primary surgical resection. Liver resection offers the only chance of cure for these pts. In 2003 Wein et al. (Oncology) published the first data of neoadjuvant therapy following curative resection of liver metastases after a short median follow up (23 months) within a phase II trial. Here we report on the long-term results (median follow up: 45,5 months). Methods: Prospective phase II trial; pts.: n=20; start: 1/1998; end of recruitment: 2/2000; neoadjuvant chemotherapy: oxaliplatin (Eloxatin, 85 mg/m2 i.v. as a 2h-infusion (inf.); d 1, 15, 29 qd 57) and FA (Rescuvolin, 500 mg/m2 i.v. as a 1h- to 2h-inf.; d 1, 8, 15, 22, 29, 36 qd 57) followed by 5-FU (2600 mg/m2 i.v. as a 24h-inf.; d 1, 8, 15, 22, 29, 36 qd 57). Results: Last date of evaluation: 31/5/2007; localisation of the primary tumor: colon: n=40%, rectum: n=60%; histology: adenocarcinoma: n=20; G1/G2/G3/G4: 0/17/3/0; median age: 62,5 years; men/women: 75%/25%; ECOG 0/1: 10/10; higher grade toxicity: diarrhea CTC toxicity grade 3: 30%, vomiting grade 3+4: 15%; response of the neoadjuvant chemotherapy: CR: 10%, PR: 90%; metastatic resection: R0: 80%, R2: 20%. Median survival of all pts. (n=20): 3,0 years; 5-year overall survival (n=20): 40%. Median survival of the pts. (n=16) with R0 resection: 4,8 years; 5-year overall survival of the R0 resected pts.: 50%; 5-year disease-free survival rate: 25%. Median disease-free time period: 20,9 months. Conclusions: The neoadjuvant treatment with weekly high-dose 5-FU in the form of a 24h-inf. combined with FA and Oxaliplatin has proved to be highly effective and well tolerated. Disease-free survival rates and median overall survival rates are promising. Additionally, the data of a phase III trial published by Nordlinger et al. (ASCO 2007) indicate that a perioperative chemotherapy treatment combined with a curative resection of metastases may improve the prognosis in pts. with primarily resectable liver metastases. No significant financial relationships to disclose.

Evaluation of Spondin-1 as a predictive marker for palliative 5-FU-based chemotherapy in metastatic colorectal cancer

4112 Background: An individualized tumor tailored chemotherapy may improve survival of patients with metastatic colorectal carcinoma (CRC). Therefore, we analyzed gene expression profiles of liver metastases and primaries of patients with CRC before application of a palliative 5-Fluorouracil based chemotherapy (AIO regimen) due to find predictive markers. These potential markers had to: (1) be highly expressed in the primary (2) and in the metastases, (3) be applicable to qRT-PCR of formalin-fixed paraffin embedded (FFPE) sections, and (4) remain their predictive power in a test set cohort. Methods: The training set consisted of 30 specimen from primary CRC and metastatic liver, which were laser micro dissected, the RNA was amplified and hybridized to Affymetrix HG U-133A microarrays. Additionally, RNA was isolated from FFPE sections of the same tumors and a qRT-PCR was performed for specific gene expression analysis. After surgery of the primary tumor all patients were treated with the AIO regimen. The test set consisted of 61 metastatic CRC patients, who were treated with the AIO regimen and where FFPE sections were available. Markers who showed promising predictive power and fulfilled criteria 1–3 (cp. background) were tested in the validation cohort. Response to chemotherapy was verified by CT scans according to WHO criteria. Results: By using statistical tests we identified some markers showing promising predictive power. However, most of them did not fulfill the further criteria. Spondin-1 expressions were very predictive for response (CR, PR) with a sensitivity of 62.5% and a specifity of 87.5% in the training set. Additionally, Spondin-1 was highly expressed as well in the tumors as in the metastases of CRC. Furthermore, the Affymetrix expression values for Spondin-1 were highly comparable with the RT-PCR data using FFPE sections from the same specimen. In the FFPE test set Spondin-1 remained its predictive value with sensitivity and specifity rates of 53.3% and 70.0%, respectively. Conclusions: Spondin-1 is an attractive candidate for further evaluation of response in CRC tumors treated with a 5-FU based chemotherapy as it is predictive and robust in terms of use in FFPE material. Further research with additional predictive markers to increase accuracy is ongoing. [Table: see text]

Weekly high-dose 5-FU as a 24h-infusion and sodium folinic acid (AIO regimen) plus Irinotecan in patients with locally advanced non-resectable and metastatic adenocarcinoma or squamous epithelial carcinoma of the esophagus: Analysis of a phase II trial

15051 Background: In the majority of patients with esophageal carcinoma curative treatment proves to be impossible when establishing the diagnosis. While adenocarcinomas (ac) of the oesophago-gastric junction are increasingly treated in the same way as gastric carcinomas, the most frequently applied palliative chemotherapy regimen for both advanced squamous epithelial carcinomas (sec) of the oesophagus and gastric carcinomas is a combination of 5-FU and cisplatin. The question should be answered whether the AIO regimen plus irinotecan may achieve similarly positive results in esophageal carcinomas such as in gastric carcinomas (median survival (ms) up to 11 months). Methods: Prospective phase II trial, patients: n=25, trial start: 11/2002, chemotherapy: Irinotecan (80 mg/m2 i.v. as 1h-infusion; d 1, 8, 15, 22, 29, 36, qd 57) as well as sodium folinic acid (500 mg/m2 i.v.) together with 5-FU (2000 mg/m2 i.v.; d 1, 8, 15, 22, 29, 36, qd 57) as 24h-infusion via a miniature pump system. Results: Last date of evaluation: 31/12/2006: n=25; ac: n=13, sec: n=12; UICC III: n=3, UICC IV: n =22; grading G1/G2/G3/G4: 0/10/10/5; median age: 58 (44- 77) years; men/women: 20/5; ECOG 0/1/2/3: 3/17/4/1; chemotherapeutic applications: 429. Evaluable in terms of toxicity: n=25. Higher grade toxicity: grade (g) III diarrhea: n=2, g III hyponatremia: n=1, g III stomatitis: n=1, g III fatigue: n=1, g III vomiting: n=1, g IV nausea: n=1, g IV elevation of creatinine: n=1, thrombosis of the vena subclavia: n=1, ischemic lesion of the brain stem: n=1. 4 patients died after 2 chemotherapeutic applications due to known peritoneal carcinomatosis and high tumour burden. Evaluable in terms of response: n=25. PR: n=7 (28%), SD: n=10 (40%), PD: n=2 (8%), not evaluable: n=6 (24%). Cases of death: n=18. Total ms: 13 months (95% CI 3,9–22,1). ms of ac: 20 months (95% CI 8,6–31,4). ms of sec: 8 months (95% CI 0,0–17). Secondary resection (R0): n=2. Conclusion: In oesophageal carcinomas the AIO regimen plus irinotecan is excellently manageable on an outpatient basis and shows high efficacy in both adenocarcinomas and squamous epithelial carcinomas of the oesophagus. No significant financial relationships to disclose.

Efficacy and safety of irinotecan-based chemotherapy in poor risk patients suffering from metastatic colorectal cancer

14581 Background: Irinotecan (CPT11) combination chemotherapy has provided a significant advancement in the management of patients with metastatic colorectal cancer (MCRC). However, there was some data indicating that poor risk cases might not benefit from longer survival with CPT11-based chemotherapy, mainly due to higher regimen toxicity. Purpose: To evaluate the hypothesis, whether CPT-11- based chemotherapy can produce similar TTP and OS in a group of poor risk MCRC patients in comparison to standard risk MCRC cases. Patients and Methods: Out of 170 CRC patients treated in our departments between 2002 - 2006, 36 poor risk MCRC patients (poor risk group was defined as 2 or more criteria being fulfilled, i.e. PS &gt;1, and/or elevated serum LDH, and/or &gt;1 metastatic site, and/or prior adjuvant chemotherapy), were chosen for this analysis and compared retrospectively with our standard risk MCRC cases. The poor risk arm consisted of 9 females and 27 males, in age between 40–76 [median 63,5]. All the patients were treated with CPT11-based chemotherapy, according to either AIO or de Gramont regimen. Results: In the analyzed poor risk group the confirmed RR (CR+PR) after six months of the treatment was 25,0% what was much lower than in standard risk group (RR = 40%), however did not reach the statistical significance; additional 52,8% of patients achieved SD; 8 patients (22,2%) progressed during therapy. The median TTP was 9 months and the median OS was 15 months, what were not statistically different from the standard risk group; 2-year survival obtained 27,8% of patients. No grade (G) 4 toxicity was observed. The most common adverse events (AE) were diarrhea [25% - 9 pts] and neutropenia [11.1% - 4 pts], but G3 AE were noted only in 2 and 1 person respectively. Conclusions: This analysis showed, that CPT11-based chemotherapy is an effective and safe treatment option even for poor risk patients suffering from MCRC. Although the RR was lower in comparison to standard risk cases it did not translate into shorter TTP as well as OS. Similar to ours results were published in various scientific papers. To define a precise role of various optimization strategies of CPT11-based chemotherapy in MCRC, randomized prospective multicenter studies are mandatory. No significant financial relationships to disclose.

Weekly high-dose 5-FU as 24h-infusion and folinic acid (AIO regimen) plus Irinotecan in patients with advanced non-resectable adenocarcinoma or squamous epithelial carcinoma of the oesophagus: Interim analysis of a phase II trial

14109 Background: At the moment of establishing the diagnosis, in approximately 50–60% of the patients with esophageal carcinoma only palliative treatment is possible due to either a locally advanced tumour growth or due to distant metastases. While adenocarcinomas of the esophagogastric junction are increasingly treated like gastric carcinomas, no palliative standard regimen is established for advanced squamous carcinomas of the oesophagus. The question should be answered whether the AIO regimen plus Irinotecan may achieve similarly positive results in esophageal carcinomas as in gastric carcinomas. Methods: Prospective phase II trial, patients: n=20, trial start: 03/2003, chemotherapeutic regimen: Irinotecan (80 mg/m2 i.v. as 1h-infusion; d 1, 8, 15, 22, 29, 36, qd 57) as well as folinic acid (500 mg/m2 i.v.) together with 5-Fluorouracil (2000 mg/m2 i.v.; d 1, 8, 15, 22, 29, 36, qd 57) as 24h-infusion via port catheter. Results: n=16 (adenocarcinomas: n=8, squamous epithelial carcinomas: n=8); median age: 59,3 (44–72) years; men/women: 13/3; ECOG 0/1/2: 4/11/1; chemotherapeutic applications: 314. Evaluable in terms of toxicity: n=16. Higher grade toxicity: grade III diarrhea: n=2, grade III hyponatremia: n=1, thrombosis of the vena subclavia: n=1, grade III stomatitis: n=1, ischemic lesion of the brain stem: n=1. Two patients died after 2 chemotherapeutic applications with known peritoneal carcinomatosis and high tumour burden. Evaluable in terms of response: n=13. PR: n=7 (54%), SD: n=4 (31%), PD: n=2 (15%). Conclusion: The AIO regimen plus Irinotecan is excellently manageable on an outpatient basis in a multimorbid patient group and shows high efficacy in both adenocarcinomas and squamous epithelial carcinomas of the oesophagus. Final results, however, particularly in terms of median survival, still remain to be seen. No significant financial relationships to disclose.

Folinic acid modulated bolus 5-FU or infusional 5-FU for adjuvant treatment of patients of UICC stage III colon cancer: Preliminary analysis of the PETACC-2-study

3563 Background: Patients with stage III colon cancer have a high risk for recurrence. Infusional 5-FU may be more active than bolus application. Methods: From 01/1997 to 03/2004 a total of 1601 patients with UICC stage III colon cancer were randomized to receive the Mayo-Clinic regimen or infusional 5-FU either the weekly high dose AIO regimen, the bi-weekly LV5FU2 regimen or the Spanish weekly high dose TTD-regime. The major aim of this study was to demonstrate a difference of 7 % in the 5 year survival rate in favour of the infusional arm for which a total of 424 events were required. Results: After a median follow-up of 31 months 478 events have occurred. 804 patients received the standard arm and 797 the experimental arm (AIO N=331, EORTC N=92, FFCD N=211, TTD N=163). The median age was 64 years; patients were well distributed according to TNM-category (T3 73 vs. 75%, T4 17 vs. 16%, N2 31 vs. 34%), vascular and lymphatic invasion and grading. The bolus regimen induced a higher rate of grade 3 or 4 leukopenia (7.1% versus 2.0%), stomatitis grade 3 or 4 (9.8% versus 3.3%) or diarrhea grade 3 or 4 (16% vs. 15%). Hand-Foot-Syndrome was more frequent in the experimental arm (4.4% versus 0.4%). There was no difference in the recurrence free survival at 5 years (57% versus 56%; hazard ratio 1.00, 95% CI, 0.84 to 1.21; P=0.9) or overall survival at 5 years 71% versus 72%; hazard ratio 0.91, 95% CI, 0.71 to 1.16; P=0.44). Conclusions: Infusional 5-FU does not improve RFS or overall survival of stage III colon cancer compared to the Mayo regimen but is less toxic. Supported by Deutsche Krebshilfe No significant financial relationships to disclose.

Randomized phase III trial comparing infused irinotecan/5-fluorouracil (5-FU)/folinic acid (IF) versus 5-FU/FA (F) in stage III colon cancer patients (pts). (PETACC 3)

LBA8 Background: Infused irinotecan regimens have improved survival in metastatic CRC. This international, multicenter, open-label, randomized, prospective trial of adjuvant chemotherapy with IF vs. F was designed to confirm these results in pts with stage III colon cancer. Pts were given IF (Arm A) or F (Arm B) in 4 cycles of 3 infusions every 2 weeks (de Gramont regimen) or 4 cycles of the AIO regimen. Irinotecan was given as 180 mg/m2 per dose in the de Gramont regimen, and as 80 mg/m2 in the AIO regimen. Methods: Inclusion criteria were WHO performance status <2, and stage III disease (UICC criteria). Exclusion criteria were prior treatment with chemotherapy, and rectal cancer. The primary endpoint is the comparison of 3-year disease-free survival in stage III pts who received IF vs. F in the de Gramont regimen, using the log-rank test. A total of 2014 Stage III pts were to be randomized in order to obtain the 452 events calculated to guarantee 90% power to detect an increase in 3 yr DFS from 70% to 77% in Arm A (hazard ratio 1.36). The DFS and RFS curves will also be estimated using Kaplan-Meier methodology. Cox models will be used to analyze the influence of selected variables. Secondary endpoints include relapse-free survival, overall survival, safety, and potential prognostic markers. Results: Between Jan 2000 and April 2002, 2124 pts from 28 countries were randomized and 2101 pts treated. Tumor blocks from 1500 pts were collected for translational research. The two arms were well balanced - median age 60 (19–76), 55% male, 99% WHO PS <2. Median follow-up was 31 months. Selected grade 3/4 toxicities (%) in Arms A/B respectively were: myelosuppresion (1 vs. 0.3%) diarrhea (12 vs. 6%), venous thrombosis (7 vs. 5%), infection (2 vs. 0.2%). Conclusions: The primary endpoint will be analyzed before March 25, 2005 and will be presented at the ASCO meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer, sanofi-aventis Pfizer, sanofi-aventis sanofi-aventis sanofi-aventis

Phase III trial of irinotecan plus oxaliplatin (IROX) versus irinotecan plus 5-FU/folinic acid (FOLFIRI) as first-line treatment of metastatic colorectal cancer (CRC): The FIRE-Trial

3516 Objective: This randomised cross-over study compares the 1st-line efficacy and toxicity of infusional 5-FU/FA (AIO regimen) plus irinotecan (FOLFIRI) to the combination of irinotecan plus oxaliplatin (IROX). Methods: 488 patients (pts) from 56 centres were enrolled between July 2000 and the end of study in September 2004. In the FOLFIRI arm, pts received FA 500mg/m2 plus 5-FU 2000 mg/m2 (24h) and irinotecan 80mg/m2 given weekly for 6 times. In the IROX arm pts were treated with oxaliplatin 85mg/m2 (d1, 15, 29) and irinotecan 80mg/m2 weekly times 6. Treatment cycles were repeated on day 50 in both treatment arms. Patients were stratified according to LDH, adjuvant pretreatment, and Karnofsky performance status (KPS) showing LDH >240 U/ml in 42% vs 39%, adjuvant pretreatment in 31% vs 29%, and a KPS=100% in 48% vs 47%, in the FOLFIRI- and IROX-arm respectively. The primary end-point of the trial was progression-free survival. At disease progression, pts were offered to switch to the comparator regimen. Results: At the time of analysis, treatment efficacy was evaluable in 299 pts (157 FOLFIRI, 142 IROX). The complete remission rate (CR) was 8% in both arms, the partial remission rate (PR) 38% vs 42% for an overall remission rate (CR+PR) of 46% vs 50%. Stable disease (SD) was documented in 47% vs 33% resulting in a disease control rate (CR+PR+SD) of 92% vs 83%. In the FOLFIRI- and the IROX-arm respectively, median progression-free survival was 8.7 months (95% CI, 7.3–9,6) vs 7.3 months (95% CI, 6.4–8.2) (p=0.15), while median overall survival was 21.1 months (95% CI, 18.8–27.2) vs 18.6 months (95% CI, 16.3–22.8) (p=0.23). Treatment was stopped due to toxicity in 8.5% vs 16.5%, and 60-day mortality was 5.5% and 3.4% (FOLFIRI vs IROX). Conclusions: FOLFIRI and IROX are comparably effective with regard to response, progression-free survival, and overall survival. Toxicity is similarly acceptable in both treatment arms. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Pharma Germany

Toxicity and safety of weekly high-dose 5-FU as 24-h infusion and folinic acid (AIO regimen) in adjuvant therapy of UICC stage III colon cancer. InTACT: A multicenter phase III trial

3586 Background: The AIO regimen is common for palliative treatment of colorectal cancer. We report for the first time on the toxicity and safety of the AIO regimen in an adjuvant phase III trial for UICC stage III colon cancer (CC). Methods: A prospective phase III trial based on quality controlled surgery and pathology (QSCP) in UICC stage III CC (R0). Group A: QSCP vs. group B: QSCP+AIO regimen for 6 months. End of trial: 9/01 after interim analysis (Wein et al, Ann Oncol 2002). Trial monitoring: by IMEREM, Nuremberg. In group B chemotherapy was terminated in all 79 patients (pt.). The AIO regimen was administered in the form of a 500 mg / m2 application (appl.) of folinic acid (FA) as 1–2 h i.v., followed by 2000 mg/m2 5-FU as a 24-h i.v. (AIO regimen) via port-a-cath on d 1, 8, 15, 22, 29, 36, qd 57; 3 cycles (6 months). Median follow up: 45.3 months. Results: AIO regimen: n = 79 pt.; m/f: 62%/38%; age: 61 years (28–75). ECOG: 0/1: 71%/29%; Frequent concomitant diseases: arterial hypertension: n=27 (34%); DM: n=12 (15%); glaucoma: n=3 (3,8%); elevated CEA prior to surgery: yes/no/“missing”: 27%/66%/7%. Median start of treatment after surgery: d 29. Total number of 5-FU applications: 1295. The mean 5-FU appl./pt. was 16 (1–18); 18 appl: 77%; > 12 appl. 89% and the mean 5-FU total dose per pt. 32.5 g/m2 (90% of the maximum dosage). As higher grade toxicity grade 3+4 presented: diarrhea: n=7/n=1 (9% / 1.3%); nausea/vomiting: n=3/n=1 (3.8%/1.3%); stomatitis + cheilitis: n=3 /n=1 (3.8% / 1.3%); cardiac toxicity: n=1/n=1 (1.3%/1.3%); no deaths. Thrombosis due to port-a-cath complications: n=3 (3.8%). A dose reduction to 75% was carried out in 2.0% of the appl. and to 50% in 2.9% of the appl., respectively. Conclusions: The AIO regimen is well tolerated in adjuvant chemotherapy treatment of CC. It may be comfortably applied on an outpatient basis and presents a high mean 5-FU dose of 32.5 g/m2 per pt. Compared with 5-FU/FA bolus regimens the AIO regimen appears to offer a more favorable toxicity profile and a higher mean 5-FU dose. For definite conclusions the results of the EORTC (40963) phase III trial remain to be seen. No significant financial relationships to disclose.

Toxicity and safety of weekly high-dose 5-FU as 24-h infusion and folinic acid (AIO regimen) in adjuvant therapy of UICC stage III colon cancer. InTACT: A multicenter phase III trial

3586 Background: The AIO regimen is common for palliative treatment of colorectal cancer. We report for the first time on the toxicity and safety of the AIO regimen in an adjuvant phase III trial for UICC stage III colon cancer (CC). Methods: A prospective phase III trial based on quality controlled surgery and pathology (QSCP) in UICC stage III CC (R0). Group A: QSCP vs. group B: QSCP+AIO regimen for 6 months. End of trial: 9/01 after interim analysis (Wein et al, Ann Oncol 2002). Trial monitoring: by IMEREM, Nuremberg. In group B chemotherapy was terminated in all 79 patients (pt.). The AIO regimen was administered in the form of a 500 mg / m2 application (appl.) of folinic acid (FA) as 1–2 h i.v., followed by 2000 mg/m2 5-FU as a 24-h i.v. (AIO regimen) via port-a-cath on d 1, 8, 15, 22, 29, 36, qd 57; 3 cycles (6 months). Median follow up: 45.3 months. Results: AIO regimen: n = 79 pt.; m/f: 62%/38%; age: 61 years (28–75). ECOG: 0/1: 71%/29%; Frequent concomitant diseases: arterial hypertension: n=27 (...

Weekly high-dose 5-fluorouracil as 24-h infusion and folinic acid (AIO) plus irinotecan as second- and third-line treatment in patients with colorectal cancer pre-treated with AIO plus oxaliplatin.

Our objective was to evaluate the efficacy and safety of high-dose 5-fluorouracil (5-FU) as a 24-h infusion and folinic acid (FA) (AIO regimen) plus irinotecan (CPT-11) after pre-treatment with AIO plus oxaliplatin (L-OHP) in colorectal carcinoma (CRC). Twenty-six patients with non-resectable distant CRC metastases were analyzed for second- or third-line treatment with AIO plus CPT-11 after pre-treatment with AIO plus L-OHP. On an outpatient basis, the patients received a treatment regimen comprising weekly 80 mg/m2 CPT-11 in the form of a 1-h i.v. infusion and 500 mg/m2 FA as a 1- to 2-h i.v. infusion, followed by 2000 mg/m2 5-FU i.v. administered as a 24-h infusion once weekly. A single treatment cycle comprised six weekly infusions followed by 2 weeks of rest. A total of 26 patients received 344 chemotherapy applications with AIO plus CPT-11. The main symptom of toxicity was diarrhea (NCI-CTC toxicity grade 3+4) occurring in five patients (19%; 95% CI 7-39%). Nausea and vomiting presented in two patients (8%; 95% CI 1-25%). The response rate of 26 patients can be summarized as follows: partial remission: n=7 (27%; 95% CI 12-48%); stable disease: n=9 (35%; 95% CI 17-56%) and progressive disease: n=10 (38%; 95% CI 20-59%). The median progression-free survival (n=26) was 5.8 months (range 3-13), the median survival time counted from the treatment start with the AIO plus CPT-11 regimen was 10 months (range 2-24) and counted from the start of first-line treatment (n=26) was 23 months (range 10-66). We conclude that the AIO regimen plus CPT-11 is practicable in an outpatient setting and well tolerated by the patients. Tumor control was achieved in 62% of the patients. The median survival time was 10 months and the median survival time from the start of first-line treatment (n=26) was 23 months.