Fluoropyrimidine-based Regimens Research Articles

The Role of Capecitabine in Locally Advanced Rectal Cancer Treatment

Preoperative infusional 5-fluorouracil (5-FU) and concurrent radiation therapy (RT) followed by total mesorectal surgery is the current standard of care for locally advanced rectal cancer (LAR). When compared with postoperative 5-FU-based chemoradiation, this strategy is associated with significantly lower rates of local relapse, lower toxicity and better compliance. Capecitabine is a rationally designed oral prodrug that is converted into 5-FU by intracellular thymidine phosphorylase. Substitution of infusional 5-FU with capecitabine is an attractive option that provides a more convenient administration schedule and, possibly, increased efficacy. Indeed, incorporation of capecitabine in combined modality neoadjuvant therapy for LAR has been under intense investigation during the last 10 years. Phase I and II clinical trials showed that a regimen consisting of capecitabine 825mg/m(2) twice daily for 7 days/week continuous oral administration in combination with RT is an active and well tolerated regimen, thereby being the preferred concurrent regimen. The definitive demonstration that efficacy of capecitabine/RT is similar to 5-FU/RT has been provided by the NSABP-R-04 and the German Margit trials. One approach to improve outcomes in rectal cancer is to deliver a second RT-sensitizing drug with effective systemic activity. Oxaliplatin and irinotecan are therefore good candidates. However, two phase III trials demonstrated that incorporation of oxaliplatin to capecitabine with RT did not improve early outcomes and, by contrast, increased toxicity. Capecitabine has also been combined with irinotecan. This regimen showed encouraging results in phase I and II clinical trials, which led to an ongoing phase III clinical trial. New strategies with induction chemotherapy with or without chemoradiation prior to surgery are currently under investigation. Whether or not capecitabine has a role in this setting is being investigated in ongoing trials. Incorporation of agents directed towards new targets, such as anti-epidermal growth factor receptor (EGFR) antibodies or antiangiogenic agents, in combination preoperative regimens, is being hampered by results of early trials in which efficacy outcomes with cetuximab were poor and an excessive rate of surgical complications with bevacizumab was observed. The lack of improvements in efficacy with the addition of cetuximab or bevacizumab in the adjuvant treatment of colon cancer led to concerns about further development of these agents in rectal cancer. The role of capecitabine in the postoperative adjuvant setting is the aim of the ongoing Dutch SCRIPT trial. The prediction of response associated with capecitabine has been based on expression of thymidylate synthase and dihydropyrimidine dehydrogenase, as well as on gene expression arrays. All these procedures require further validation and should be considered as investigational. In conclusion, capecitabine can safely and effectively replace intravenous continuous infusion of 5-FU in the preoperative chemoradiation setting for rectal cancer management. The addition of other new antineoplastic agents to a fluoropyrimidine-based regimen remains investigational.

Gemcitabine (G) and nab-paclitaxel (nab-P) in patients with refractory advanced pancreatic cancer (PC).

373 Background: There is no standard chemotherapy regimen for PC patients who have progressed on G and fluoropyrimidine-based therapy. Single agent nab-P had limited activity on a second-line phase II trial in PC. Synergistic preclinical studies with G and taxanes have been reported. Nab-P targets stromal cells and leads to improved delivery of chemotherapy to PC cells. The combination of G + nab-P might be an effective approach in pretreated PC. Methods: A retrospective analysis of advanced refractory PC patients treated from Sep 2010 to Aug 2011 with the combination of G + nab-P was performed at the Sylvester Comprehensive Cancer Center. Patients received G 1000mg/m2 and nab-P 100mg/m2 on D1, 8 and 15 of a 28 day cycle. Treatment response was assessed by review of imaging studies using the RECIST criteria, CA19-9 response and symptomatic improvement. The progression-free survival (PFS) and overall survival (OS) were calculated from time of commencement of G + nab-P until documented progression or death respectively. Results: 10 patients were treated with G + nab-P; 60%, 30% and 10% of patients had received 3, 2 and 1 prior chemotherapy regimen. 90% and 80% received prior G or fluoropyrimidine-based regimen respectively. Therapy was discontinued in one patient following only one dose of G + nab-P (Cycle 1, day 1) due to grade 2 thrombocytopenia. The remaining 9 patients received a median of 4 cycles. Two (22.2%) patients had confirmed PR, 3(33.3%) patients had confirmed stable disease while 4 (44.4%) patients progressed on therapy. The median PFS was 13.7 weeks. The median PFS was 20 weeks in patients with PR or SD and 9.9 weeks in patients with PD. Recurrent malignant ascitis resolved in a patient with peritoneal carcinomatosis. Treatment was well tolerated; grade 3-4 hematologic toxicity included anemia, thrombocytopenia and neutropenia in 2, 1 and 2 patients respectively. 70% of patients required G-CSF support. Non hematologic Grade 3-4 toxicities included fatigue, peripheral neuropathy; nausea and vomiting in 3, 2 and 1 patient respectively. Conclusions: G + nab-P resulted in clinical benefit in half of this group of advanced PC patients who had previously progressed on G and fluoropyrimidine-based regimens.

Final results from study 181: Randomized phase III study of FOLFIRI with or without panitumumab (pmab) for the treatment of second-line metastatic colorectal cancer (mCRC).

387 Background: In the primary analysis of study 181, pmab+FOLFIRI significantly improved progression-free survival (PFS) vs FOLFIRI as second-line therapy in patients (pts) with wild-type (WT) KRAS mCRC. Here, we report the results of a prespecified final descriptive analysis planned for 30 months (mos) after the last pt was enrolled. Methods: Pts were randomised 1:1 to pmab 6.0 mg/kg Q2W+FOLFIRI (Arm 1) vs FOLFIRI alone (Arm 2). Pts had one prior fluoropyrimidine-based chemotherapy regimen for mCRC and ECOG 0-2. The co-primary endpoints were PFS (central assessment) and OS, and were independently tested. Secondary endpoints included objective response rate (ORR), and safety. KRAS status was determined by a blinded central lab. Results: 1,186 pts were randomised and received treatment (tx): 591 in Arm 1, 595 In Arm 2. 1,083/1,186 pts (91%) had KRAS results. Adverse event rates were consistent with the primary analysis. Results are shown in the table . Conclusions: In Arm 1, PFS (standard and on-treatment definition) and ORR were improved, and there was a trend toward improved OS in pts with WT KRAS mCRC. The large proportion of pts receiving post-progression anti-EGFR therapy may have affected the ability to observe a difference in OS between the tx arms. In pts with MT KRAS there was no difference in efficacy. KRAS testing is critical to select appropriate pts for tx with pmab. [Table: see text]

Treatment of locally advanced rectal cancer: Controversies and questions

Rectal cancers extending through the rectal wall, or involving locoregional lymph nodes (T3/4 or N1/2), have been more difficult to cure. The confines of the bony pelvis and the necessity of preserving the autonomic nerves makes surgical extirpation challenging, which accounts for the high rates of local and distant relapse in this setting. Combined multimodality treatment for rectal cancer stage II and III was recommended from National Institute of Health consensus. Neoadjuvant chemoradiation using fluoropyrimidine-based regimen prior to surgical resection has emerged as the standard of care in the United States. Optimal time of surgery after neoadjuvant treatment remained unclear and prospective randomized controlled trial is ongoing. Traditionally, 6-8 wk waiting period was commonly used. The accuracy of studies attempting to determine tumor complete response remains problematic. Currently, surgery remains the standard of care for rectal cancer patients following neoadjuvant chemoradiation, whereas observational management is still investigational. In this article, we outline trends and controversies associated with optimal pre-treatment staging, neoadjuvant therapies, surgery, and adjuvant therapy.

DNA Copy Number Profiles Correlate with Outcome in Colorectal Cancer Patients Treated with Fluoropyrimidine/Antifolate-based Regimens

For decades 5-fluorouracil (5-FU) has remained the treatment of choice in the adjuvant and palliative setting of colorectal cancer (CRC). The combinations of 5-FU or its oral prodrug capecitabine with irinotecan/oxaliplatin and the novel agents bevacizumab/cetuximab increased responses. However, the overall prognosis is poor, and predictive biomarkers of cytotoxic drugs activity are missing. Pharmacogenetic studies focused on candidate determinants of drug activity/metabolism, such as thymidylate synthase or dihydropyrimidine dehydrogenase, but reported controversial results. Given the heterogeneous and complex nature of CRC, it is likely that many aberrations underlying its progression can also affect therapeutic response. Therefore, high-throughput arrays for genome-wide-DNA aberrations play a pivotal role for new markers discovery by moving from hypothesis-driven, targeted-research to unbiased screening of the whole genetic spectrum. Chromosomal aberrations are critical events in tumorigenesis, and genomic regions harbouring DNA gains/losses have been identified in 85% of CRC patients. These aberrations change the expression of many genes, which might explain the differential effects of specific chemotherapeutic agents. In particular, recent studies reported correlations between DNA copy-number profiles and response to fluoropyrimidine-based regimens, such as leucovorin-modulated-5-FU+irinotecan (FOLFIRI), capecitabine+irinotecan (CAPIRI) and pemetrexed+irinotecan (ALIRI). Genome-wide profiling by oligonucleotide-based array-comparative-genomic-hybridization (aCGH) revealed genomic loci, of which the copy-number status may serve as marker for outcome after FOLFIRI and CAPIRI. Larger randomized and prospective trials of these aCGH platforms in CRC patients treated with fluoropyrimidine-based regimens are ongoing, and will ultimately demonstrate whether these findings can be of actual value to predict clinical outcome and direct the choice of therapy.

Is There a Future for Bevacizumab in the Adjuvant Setting After the C-08 and AVANT Trials?

Fluoropyrimidine-based regimens have become the standard adjuvant treatment for stage III colorectal cancer (CRC). Despite the superior outcomes with adjuvant 5-FU/leucovorin/oxaliplatin schedules, nearly one third of node-positive CRC patients still recur. Bevacizumab is a recombinant humanized monoclonal antibody to vascular endothelial growth factor, which has demonstrated efficacy in terms of progression-free survival, and overall survival for patients with metastatic CRC. These positive results formed the basis to explore its role in the adjuvant setting. To answer the question of whether bevacizumab would add on overall and/or disease-free survival, two large randomized phase 3 trials (NSABP C-08 and AVANT) tested the addition of bevacizumab to standard oxaliplatin-based adjuvant chemotherapy in early-stage CRC patients. However, the addition of anti-angiogenic therapy to adjuvant scenario failed to improve disease-free survival and overall survival. This article aimed to explain the reasons why bevacizumab had no impact on the outcomes of adjuvant treatment of colorectal cancer.

Antiemetic control of palonosetron in patients with gastrointestinal cancer receiving a fluoropyrimidine-based regimen containing either irinotecan or oxaliplatin.

9079 Background: In moderately emetogenic regimens, palonosetron provides complete control of chemotherapy-induced nausea/vomiting (CINV) in 69.3% of patients [Grall, et al. Ann Oncol.14:2003, 1570-77]. Given this promising outcome, we hypothesized that adding palonosetron to our first-line prevention anti-emetic regimen will significantly increase complete control rate of CINV. Methods: Beginning August 2009, all patients starting a fluoropyrimidine-based regimen containing irinotecan (FOLFIRI or XELIRI) or oxaliplatin (FOLFOX or XELOX) received palonosetron at 0.25 mg and dexamethasone 12 mg prior to chemotherapy on day #1. Prior to August 2009, our standard consisted of ondansetron 16 mg and dexamethasone 12 mg prior to chemotherapy on day#1. Failure was defined as grade ≥ 1 vomiting or grade ≥ 2 nausea on days 1 to 5 post chemotherapy. In the event of failure, patients received Aprepitant (125 mg on day 1 and 80 mg on days 2 and 3) plus dexamethasone at 8 mg on days 2 through 4. In this retrospective ...

Evaluating the relationship between progression-free survival (PFS) and overall survival (OS) in clinical trials of patients (pts) with metastatic colorectal cancer (mCRC).

3617 Background: Analyses of combined data from clinical trials of chemotherapy (CT) regimens in mCRC have shown that PFS is strongly positively correlated with OS. (Buyse M, et al. J Clin Oncol. 2007;25:5218–5224; Tang P, et al. J Clin Oncol. 2007;25:4562-4568.) Here, we examine this relationship further by including data from published trials of targeted agents plus CT in the first- and second-line setting. Methods: A MEDLINE search was conducted using the keywords “neoplasm metastasis” and “colorectal neoplasm.” The search limited to “randomized controlled trial,” “clinical trial phase II or III” and a publication date between “2000 and present.” Published trials of fluoropyrimidine-based regimens enrolling at least 100 pts, and reporting mature PFS and OS data were included. A manual search (matching the MEDLINE search criteria) was performed for bibliographies of published overviews and conference abstracts. The correlation (R2) between log(PFS) and log(OS) was estimated using a linear regression model. The analysis uses OS and PFS as defined in the publication. Results: In total 22 trials (∼17,000 patients) were included. The R2 value between log(PFS) and log(OS) was: 0.74 for all trials; 0.78 among 11 trials of targeted agents in combination with oxaliplatin or irinotecan-based CT; and 0.79 among 8 first-line phase III trials of targeted agents, including 4 in which epidermal growth factor receptor (EGFR)-targeted agents were used in patients with wild-type KRAS tumors. Conclusions: In this analysis of clinical trials of CT and targeted agents plus CT in the first or second-line treatment of pts with mCRC, improvements in PFS were highly correlated with improvements in OS. These results are consistent with those previously reported for trials of CT alone.

A phase II study of biweekly mitomycin C and irinotecan combination therapy in patients with fluoropyrimidine-resistant advanced gastric cancer: a report from the Gastrointestinal Oncology Group of the Japan Clinical Oncology Group (JCOG0109-DI Trial)

Preclinical studies have shown that mitomycin C (MMC) acts synergistically with irinotecan (CPT-11). In this phase II study, we evaluated the efficacy and toxicity of MMC/CPT-11 therapy as second-line chemotherapy for patients with fluoropyrimidine-resistant advanced gastric cancer. Eligible patients had evidence of tumor progression despite prior treatment with fluoropyrimidine-based regimens or had relapsed within 6 months after completion of therapy with adjuvant fluoropyrimidines. Treatment consisted of MMC (5 mg/m(2)) and CPT-11 (150 mg/m(2)) administered i.v. every 2 weeks. The primary endpoint was the response rate (RR). Our hypothesis was that this combination therapy was efficacious when the lower boundary of the 95% confidence interval (CI) of the RR exceeded 20% of the threshold RR. Between April 2002 and July 2003, 45 eligible patients were registered and analyzed. Among the 45 patients, 40 (89%) had previously received chemotherapy for metastasis and 24 (53%) had a performance status (PS) of 0. Thirteen partial responses were obtained among the 45 patients, resulting in an overall RR of 29% (95% CI, 16-42%). The median time to progression was 4.1 months, and the median survival time was 10 months, with a 1-year survival rate of 36%. Grade 4 neutropenia was observed in 29% of the patients, whereas febrile neutropenia occurred in 9%. The incidence rates of grade 3 nausea and diarrhea were 13 and 2%, respectively. Although this study did not achieve the per-protocol definition of activity, the progression-free survival and overall survival appeared to be promising, with acceptable tolerability. Thus, MMC/CPT-11 therapy as second-line chemotherapy for fluoropyrimidine-resistant advanced gastric cancer presents a potential treatment option in patients with a good PS.

A retrospective study of first-line combination chemotherapy in advanced colorectal cancer: A Korean single-center experience.

623 Background: Fluoropyrimidine-based combination chemotherapy, in combination with either oxaliplatin or irinotecan, have demonstrated efficacy and tolerability against advanced colorectal cancer (ACC). Methods: Between Jan 2006 and Dec 2007, 478 ACC patients were treated with combination chemotherapy in first-line setting: 5-fluorouracil, folinic acid plus oxaliplatin (FOLFOX, n=172), 5-fluorouracil, folinic acid plus irinotecan (FOLFIRI, n=95), capecitabine plus oxaliplatin (XELOX, n=155), and capecitabine plus irinotecan (XELIRI, n=56). FOLFOX and FOLFIRI were repeated every 2 weeks, whereas XELOX and XELIRI were repeated every 3 weeks until disease progression or unacceptable toxicity occurred or until a patient chose to discontinue treatment. Results: The median age was 58 years (range, 19-84 years) and the median chemotherapy duration for FOLFOX, FOLFIRI, XELOX and XELIRI were 4.9, 4.5, 5.7 and 5.4 months, respectively. Combination chemotherapy regimens were generally well tolerated. The estimated median PFS for all patients was 6.8 months (95% confidence interval, 6.3-7.3 months). No statistically significant difference in PFS was found each regimen used as first-line chemotherapy. Sixty-percent (n=290) of patients received second or further lines of therapy after failure. Conclusions: Fluoropyrimidine-based combination chemotherapy regimens appear to be equally active and tolerable as first-line therapy for ACC. No significant financial relationships to disclose.

Irinotecan monotherapy offers advantage over combination therapy with irinotecan plus cisplatin in second-line setting for treatment of advanced gastric cancer following failure of fluoropyrimidine-based regimens.

The optimal regimen of chemotherapy for gastric cancer in a second-line setting remains to be clarified. The aim of this retrospective study was to evaluate the efficacy and safety of second-line irinotecan treatment. A total of 134 patients with gastric cancer who had received prior chemotherapy with fluoropyrimidine-based regimens were treated with irinotecan (150 mg/m(2) on days 1 and 15) alone every 4 weeks (Arm I) or irinotecan (70 mg/m(2) on days 1 and 15) plus cisplatin (80 mg/m(2) on day 1) every 4 weeks (Arm IP) between April, 2004 and March, 2009. Patient characteristics, response rate, progression-free survival, overall survival and safety were investigated. Of 134 patients with recurrent or unresectable gastric cancer, 92 were treated in Arm I and 42 patients in Arm IP. Overall response rate in Arm I was 8.1%, compared with 20.0% in Arm IP (P=0.65). Median progression-free survival (Arm I vs. IP; 2.6 vs. 2.7 months, P=0.73) and median overall survival (Arm I vs. IP; 9.8 vs. 8.0 months, P=0.67) did not differ between the two treatment groups. Neutropenia, leukopenia and anorexia were the most common grade 3/4 adverse events, occurring significantly more frequently in Arm IP than in Arm I (P<0.05). Irinotecan may be a key agent, and serial irinotecan monotherapy is more beneficial as compared to irinotecan plus cisplatin in the treatment of advanced gastric cancer in second-line settings. Irinotecan monotherapy is beneficial compared to irinotecan plus cisplatin in second-line settings for the treatment of advanced gastric cancer refractory to fluoropyrimidine-based regimens.

Availability of irinotecan in a second-line setting confers survival benefit to patients with advanced gastric cancer refractory to fluoropyrimidine-based regimens.

Optimal second-line chemotherapy may contribute to favorable survival in patients who receive first-line treatment for advanced gastric cancer. The aim of this retrospective study was to compare a second-line setting using irinotecan with paclitaxel in terms of survival benefit and safety. A total of 179 patients with recurrent or unresectable gastric cancer who had received prior chemotherapy with a fluoropyrimidine-based regimen were treated with irinotecan alone at 150 mg/m(2) on days 1 and 15 every 4 weeks (Cohort I) or weekly paclitaxel at 80 mg/m(2) on days 1, 8 and 15 every 4 weeks (Cohort P) between April, 2004 and March, 2009. Patient characteristics, overall response rate, disease control rate, progression-free survival, overall survival and safety were investigated. Of the 179 patients, 92 received irinotecan and 87 patients who were contraindicated for irinotecan received weekly paclitaxel. The overall response and disease control rates in Cohort I were 6.5 and 43.5%, respectively, as compared with 9.8 and 54.9%, respectively, in Cohort P. No variation was noted in median progression-free survival (Cohort I vs. P, 2.6 vs. 2.8 months; P=0.812), whereas median overall survival (Cohort I vs. P, 9.8 vs. 4.9 months; P<0.0001) differed significantly between the two cohorts. The most common grade 3/4 adverse events were neutropenia, leukopenia, anemia and anorexia, which were tolerable in each treatment cohort. Availability of irinotecan in a second-line setting confers a survival benefit to advanced gastric cancer patients in whom fluoropyrimidine-based first-line chemotherapy was unsuccessful.

A Phase II Study of Irinotecan, Continuous 5-Fluorouracil, and Leucovorin (FOLFIRI) Combination Chemotherapy for Patients With Recurrent or Metastatic Gastric Cancer Previously Treated With a Fluoropyrimidine-Based Regimen

A phase II study was carried out to assess the efficacy and toxicity of combination chemotherapy with irinotecan, 5-fluorouracil (5-FU), and leucovorin (FOLFIRI) for the treatment of patients with metastatic or recurring gastric cancer previously treated with fluoropyrimidine-based chemotherapy. Eligible patients were those who had metastatic gastric cancer previously treated with a fluoropyrimidine-based chemotherapy regimen or had disease recurrence within 6 months of completing adjuvant fluoropyrimidine-containing chemotherapy. Participants received irinotecan (150 mg/m² on day 1) and leucovorin (LV; 20 mg/m² on days 1-2) followed by continuous infusion of 5-FU (1500 mg/m² on days 1-2), every 2 weeks. Between April 2006 and March 2008, 33 patients were enrolled in the study. FOLFIRI served as a second-line treatment in 27 patients, third-line treatment in 4 patients, and fourth-line treatment in 2 patients. The patients had a median age of 60 years (range, 40-75) and underwent 132 cycles of chemotherapy, with a median of 3 cycles (range, 1-15) per patient. The response rate was 18.2%, and the disease control rate was 36%. Median overall survival was 5.1 months (95% confidence interval, 3.74-6.45), and median time to progression was 2.3 months (95% confidence interval, 1.81-2.78). The major grade 3-4 toxicity was neutropenia (45.4%). Combination chemotherapy with irinotecan, 5-FU, and LV is feasible in gastric cancer patients previously treated with fluoropyrimidine-based chemotherapy.

Local excision after neoadjuvant chemoradiation for rectal cancer: Is it an acceptable treatment option?

3646 Background: Neoadjuvant concurrent chemoradiation (CCRT) followed by radical surgery is standard in patients (pts) with locally advanced rectal cancer (LARC). Nevertheless, some pts undergo local excision (LE) only, for various reasons. The role of LE in this setting is currently unclear; the main concern regarding LE is the possible neglectance of involved regional lymph nodes (LNs). We therefore evaluated the correlation between pathologic T stage and LN involvement following CCRT and the outcome of pts with good histologic response, i.e. pathological complete response (pCR), undergoing LE. Methods: 340 eligible pts, who underwent neoadjuvant CCRT followed by surgery for LARC between 1/1997 and 12/2007, were included in the study. LARC was defined as T3-4Nx, TxN+ or distal (≤ 6 cm from the anus) T2N0. Radiotherapy was standard (50.4-54 Gy in fractions of 1.8 Gy) and chemotherapy consisted of several common fluoropyrimidine-based regimens. Results: The median age of the whole group was 67 years, 50% were males and 52% had distal tumors. 309 pts (91%) underwent radical surgery, 22 (6%) had LE only and 9 (3%) did not have surgery following CCRT. Of the 22 pts who had LE only, 15 had pT0, 3- microscopic residual disease (mRd), 3-pT1 and 1-pT2. With a median follow-up of 34 month, two pts died, one with mRd and one with T1. We compared the outcome of pT0 pts (n = 37) who underwent radical surgery (group I) with that of pT0 pts (n = 15) who had LE only (group II). With a median follow-up of 48 month, 4 pts in group I had a recurrence (3-local, 1-distant) and none in group II; one pt died in group I and none in group II. There was no significant difference in 5-year disease-free survival (88% vs. 100%), pelvic recurrence-free survival (92% vs. 100%) and overall survival (97% vs. 100%) between the groups. Conclusions: In this small cohort, pts who underwent LE following neoadjuvant CCRT had a relatively good outcome. In pts with pCR, radical surgery did not result in an improved outcome. Therefore, LE may be an acceptable option, at least for pts with mural pCR. No significant financial relationships to disclose.

Evolution of Capecitabine Dosing in Colorectal Cancer

Fluoropyrimidines remain the cornerstone of chemotherapy regimens in the treatment of metastatic colorectal cancer (mCRC), even with the availability of newer cytotoxic and targeted biologic agents (eg, irinotecan, oxaliplatin, bevacizumab, cetuximab, and panitumumab). Though 5-fluorouracil (5-FU) can be administered via bolus or infusional schedules, the intermittent infusional schedule has been a mainstay of fluoropyrimidine-based regimens. This strategy, however, requires the insertion of central venous catheters and infusion pumps, which represent major inconveniences for patients and are associated with an increased risk for complications. Capecitabine is an orally administered fluoropyrimidine carbamate that is absorbed intact from the gastrointestinal tract and becomes metabolically activated to 5-FU within the tumor. Orally administered chemotherapy gives patients greater flexibility and independence and, as a result, may improve compliance and lower overall healthcare costs. Several randomized phase III studies have demonstrated the efficacy and safety of capecitabine in mCRC, whether used as monotherapy or in combination with oxaliplatin. However, dosing has been the subject of considerable debate, and there is evidence that dosing differs among clinical practices in Europe, Asia, and North America. The optimal dose and dosing schedule of capecitabine might require individualization based on specific patient factors, such as presence of comorbid illnesses, renal function, use of other prescription and nonprescription drugs, herbal and/ or nutritional supplements, and the development of adverse events. Guidelines for capecitabine dose modification/ interruption have been developed, and they should be used when trying to optimize oral fluoropyrimidine therapy for patients with mCRC.

Therapeutic usefulness of postoperative adjuvant chemotherapy with Tegafur-Uracil (UFT) in patients with breast cancer: focus on the results of clinical studies in Japan.

In Japan, the history of postoperative chemotherapy for breast cancer started with 5-fluorouracil (5-FU), launched in the 1980s. Currently, oral fluoropyrimidine-based regimens indicated for the treatment of breast cancer in Japan include tegafur plus uracil (UFT); tegafur, gimeracil, and oteracil (TS-1); doxifluridine; and capecitabine. In particular, UFT represents an important option for long-term treatment because of minimal adverse events and the potential for long-term maintenance of effective plasma concentrations of 5-FU to inhibit micrometastasis after surgery. Therefore, various clinical studies of postoperative adjuvant chemotherapy with UFT have been conducted in patients with completely resected tumors. Recent studies have shown that UFT prolongs survival after tumor resection in patients with gastric cancer, colorectal cancer, and lung cancer. In patients with breast cancer, large clinical trials of UFT-based postoperative chemotherapy conducted in Japan have shown that UFT is useful for the treatment of intermediate-risk patients with no lymph node metastasis. This paper reviews the results of clinical studies of UFT conducted in Japan to assess the therapeutic usefulness of this oral 5-FU. The types of patients most likely to benefit from UFT are discussed on the basis of currently available evidence and a global consensus of treatment recommendations. The optimal timing of endocrine therapy and strategies for postoperative adjuvant chemotherapy with UFT in patients with breast cancer are also discussed.

Docetaxel combined with oral etoposide as second-line treatment for advanced gastric carcinoma after failure of platinum- and fluoropyrimidine-based regimens

Platinum, antracyline, and fluoropyrimidine combination chemotherapy has been widely used as a first-line treatment for advanced gastric cancer (AGC). In the present study, we determined the efficacy and the safety of docetaxel and oral etoposide as second-line combination chemotherapy after failure of commonly used combination regimens in AGC. Patients with histologically proven gastric cancer and measurable metastatic disease received docetaxel 75 mg/m(2) as a 1-h intravenous infusion on day 1, and oral etoposide 50 mg/m(2) once daily on days 1-5, every 3 weeks until disease progression or unacceptable toxicities. Between June 2006 and September 2008, 32 patients, of median age 60 years (range 32-77 years) were included in the study. Overall response rate was 9.4% and 31.3% of patients achieved a stable disease. Median progression-free survival was 3 months (95% CI, 2.5-3.5). Median overall survival was 6 months (95% CI, 3.8-8.2) with 16.9% 1-year survival rate. Grade 3-4 toxicities included neutropenia (28.8%), febrile neutropenia (18.8%), thrombocytopenia (3.1%), nausea and vomiting (15.6%), diarrhea (9.4%), and mucositis (6.2%). Docetaxel and oral etoposide combination was moderately effective and safe in appropriately selected AGC patients after failure of platinum- and fluoropyrimidine-based combination regimens.

Chemotherapy for small-bowel Adenocarcinoma at a single institution

Small-bowel adenocarcinoma (SBA) is rare. No standard chemotherapy for this type of cancer has yet been established. At Cancer Institute Hospital (CIH), the chemotherapy regimen used for colorectal cancer is initially used for patients with SBA, followed by that used for gastric cancer. Patients with advanced or recurrent SBA who had been treated with chemotherapy in CIH were retrospectively analyzed. The first-line treatments were fluoropyrimidines used alone or in combination with other drugs, such as 5-fluorouracil plus leucovorin (FL), UFT-E, or TS-1. The second-line treatment was irinotecan (CPT-11) monotherapy. Fluoropyrimidine-based regimens, mainly FL, were used for 10 patients. Seven patients received the second-line CPT-11 regimen. Disease control was seen in five patients (50%) with the first-line chemotherapy and in three (43%) with the second-line. The median overall survival time was 12 months (range 3-39). The treatments were generally tolerated. Gastrointestinal symptoms were the most common adverse effects. Fluoropyrimidines as the first-line and CPT-11 as the second-line chemotherapy yielded low response, although the adverse effects were mild. The FOLFOX and FOLFIRI regimens such as those used for metastatic colorectal cancer are potential alternative strategies. Extensive trials are needed to develop standard chemotherapy with new drugs.

Prognostic factors for tumor histological response to preoperative chemoradiation in rectal cancer

4094 Background: Tumor histological response following preoperative chemoradiation for locally advanced rectal cancer (LARC) is a surrogate for patient outcome. However, predictive factors for this surrogate have not been fully defined as of yet. The aim of this study was to identify pretreatment patient and tumor factors that may predict tumor histological response. Methods: Between 1997 and 2007, 292 patients (pts) with LARC, defined as T3–4 Nx, TxN+ or distal (<6 cm from the anus) T2N0, underwent preoperative chemoradiation followed by surgery at the participating centers. The radiotherapy protocol was standard (50.4–54 Gy in 1.8 Gy fractions) while chemotherapy consisted of several common fluoropyrimidine-based regimens. Patients’ medical files were retrived and various epidemiological, clinical, pathological and treatment parameters were collected. The study cohort was divided into two: responders - pts achieving pathological complete response (pCR) or having only microscopic residual disease (mRD), and non-responders - those who did not achieve pCR or mRD. Results: The median age of the whole group was 67 years (range: 28–86) and 50% were males. Pretreatment TNM stage, available in 271 pts, was: T2N0–13%, T3–4N0–53%, T1-T2N1- 2%, and T3-T4N1–32%. Data on histological response was available for all pts: pCR was documented in 16% and mRD in 12%. With a relatively short follow-up (median: 40 months, range: 5–118), disease free (p=0.049) and overall survival (p=0.004) were significantly different for responders and non-responders. Survival rates of pts with pCR and mRD were equal (95% and 94% 5-year survival, respectively). On univariate analysis, lower pretreatment clinical stage (p=0.024), chemotherapy consisting of oral fluoropyrimidines (p=0.049), age >60 (p=0.017) and pretreatment hemoglobin (Hb) level >12 gr/dl (p=0.027) were associated with significantly higher rates of histological response. On multivariate analysis, all these factors retained statistical significance. Conclusions: Pretreatment clinical stage and Hb level, age, and the chemotherapy regimen can predict tumor histological response following preoperative chemoradiation in pts with LARC. The prognostic impact of histological response was again noted. No significant financial relationships to disclose.

Clinical and molecular determinants of survival in pancreatic cancer patients treated with second line chemotherapy: results of an Italian/Swiss multicenter survey

4622 Background: The impact on survival of palliative second-line therapy in pancreatic cancer has not been clarified and clinical/molecular predictive factors are needed in order to decide which therapeutic regimens may be effective. Methods: Clinical records of 160 Gemcitabine resistant/refractory pancreatic cancer patients (pts) treated in 11 medical oncology departments in Italy and Switzerland were reviewed. All pts received a second line regimen from June 1997 to February 2006. There were 99 males, 61 females, median age 62 years (range 34–78) and median ECOG performance status (PS): 1 (range 0–2). 16 different salvage regimens were administered consisting of monotherapy with fluoropyrimidines in 59% of cases and combinations of platinum- salts/fluoropyrimidines in 36%. Fluoropyrimidines combinations with bevacizumab, irinotecan and mitomycin C were administered in the remaining 5%. ERCC-1 expression was examined by performing immunohistochemical staining in pts treated with platinum-salts. Results: Second line chemotherapy produced partial responses (PR) in 16 (10%) and stable disease (SD) in 40 pts (25%) by RECIST criteria. The median progression free survival (PFS) was 2.65 months. Multivariate analysis revealed that the most important prognostic factor for PFS was PS at the beginning of second line therapy (Second line PFS PS=0–1 vs PS=2: 78 days vs 48 days, p&lt;0.05, log-rank test). Pts who had responded (PR) to first-line Gemcitabine were more likely to respond or attain stable disease after second-line treatment, with a PFS of 2.6 vs 1.6 months (p&lt;0.05, log-rank test). The overall survival (OS) for all evaluable pts was 11.5 months and 1-year survival was 45%. Among 57 pts treated with platinum-containing doublets, a low ERCC1 level (28/57 pts) was highly predictive of longer survival (11.9 versus 9.9 months, p&lt;0.05 log-rank test). Conclusions: These results suggest that fluoropyrimidine-based salvage regimens have marginal activity and should be considered only in pts with a good PS who have responded to first line chemotherapy. ERCC-1 expression should be further evaluated as a predictive test to select patients who may benefit from platinum/fluoropyrimidine salvage regimens. No significant financial relationships to disclose.