Adjuvant chemotherapy for colorectal cancer

In Western countries, efficacy of 5-fluorouracil (5-FU)+leucovorin (LV) as adjuvant chemotherapy for colorectal cancer has been already established. Recently, large multicenter randomized controlled trials evaluating value of new regimens such as oxaliplatin+5-FU+LV, capecitabine, and uracil-tegafur (UFT)+LV, as compared with 5- FU+LV, have been conducted. Such trials are yielding evidence for, and are establishing new standard adjuvant chemotherapy. In Japan,we have a long history of oral prodrugs of 5-FU. We are also recently observing efficacy of oral regimen including UFT and carmofur in each trials or meta-analysis. Accordingly, we have become to have, and to report our own evidence. Although further integration of targeted compounds including cetuximab and bevacizumab into adjuvant therapy may be promising, cost issues may also emerge.     

Novel chemotherapy agents for colorectal cancer: Oral fluoropyrimidines, oxaliplatin, and raltitrexed

Agents now under investigation for treatment of advanced colorectal cancer (CRC) include the oral fluoropyrimidines, oxaliplatin, and raltitrexed. Research efforts directed at finding agents that conveniently and effectively deliver 5-fluorouracil (5-FU) in a protracted fashion have led to the development of several oral fluoropyrimidines. These agents, which include capecitabine; tegafur and uracil plus leucovorin (UFT/LV); eniluracil plus oral 5-FU; and S-1, are convenient and less toxic than intravenous bolus 5-FU. Oxaliplatin has a uniquely different mechanism of action compared with that of 5-FU and has demonstrated activity not only in the first-line treatment setting but also in patients whose disease has progressed during or following 5-FU treatment. In the first-line setting, when oxaliplatin is combined with 5-FU plus LV, response rates and time to disease progression are remarkably improved compared with 5-FU/LV alone. Raltitrexed, a unique thymidylate synthase inhibitor, has undergone extensive phase III evaluation in CRC. The advent of these novel agents has led to development of combined chemotherapy regimens now being introduced into the adjuvant setting.     

New options for outpatient chemotherapy--the role of oral fluoropyrimidines.

For several decades fluoropyrimidines, especially 5-fluorouracil (5-FU), have played a role in standard chemotherapy regimens for a range of solid tumours, including breast and colorectal cancers. In recent years, schedule modification and biomodulation have achieved improved efficacy and tolerability. However, the complications arising from infused intravenous administration are well-recognized and there is an unmet medical need for oral agents with improved efficacy and tolerability, offering more convenient outpatient therapy.Several oral fluoropyrimidines are in development, including capecitabine, UFT (uracil plus tegafur), S-1 and eniluracil. As yet, only UFT/leucovorin and capecitabine have been evaluated in randomized phase III clinical trials in metastatic colorectal cancer. Both have demonstrated safety benefits and equivalent survival compared with the Mayo Clinic regimen, and capecitabine has demonstrated a significantly superior response rate. Time to disease progression was equivalent to the Mayo Clinic regimen with capecitabine, but inferior with UFT/leucovorin. Capecitabine is also effective in patients with taxoid-pretreated metastatic breast cancer, a population which previously had no established treatment options.Both capecitabine and UFT/leucovorin are being evaluated in combination with irinotecan and oxaliplatin in colorectal cancer, and vinorelbine and docetaxel/paclitaxel in breast cancer. In the future, these more convenient, oral fluoropyrimidines may replace intravenous 5-FU in the treatment of breast and colorectal cancer.     

Adjuvant therapy for colorectal carcinoma

Adjuvant therapy for colorectal carcinoma has been developed over the last two decades. We have reviewed the history of adjuvant chemotherapy for colorectal carcinoma in the United States, Europe and Japan with regard to the rationale of the chemotherapy regimen and the survival benefit for the establishment of a standard regimen. Treatment with 5-fluorouracil (5-FU) and leucovorin (LV) for postoperative adjuvant chemotherapy had an overall survival benefit, compared with surgery alone, in randomized controlled trials in the United States and Europe for Dukes' C colon carcinoma. In contrast, the survival benefit of adjuvant chemotherapy for Dukes' B colon carcinoma and for rectal carcinoma has not yet been established. In Japan, randomized controlled trials have examined combination treatment with mitomycin (MMC) and oral fluoropyrimidines for colorectal carcinoma compared with surgery alone. A meta-analysis indicated that combination treatment with MMC and oral fluoropyrimidines had a survival benefit for colorectal carcinoma. The survival benefit of combination treatment with irinotecan (CPT-11) + 5-FU + LV or uracil + tegaful (UFT) + LV (Orzel) for adjuvant chemotherapy are currently being compared with 5-FU + LV. Meta-analysis revealed a survival benefit at 2-years in the prevention of liver metastasis following intraportal or intraarterial infusion of 5-FU. The survival benefit of preoperative radiotherapy was superior to postoperative radiotherapy for advanced rectal carcinoma in association with the prevention of local recurrence. Clinical trial data suggest that the current standard regimen of adjuvant chemotherapy is a combination of 5-FU and LV for Dukes' C colon carcinoma and that radiotherapy for local control of rectal carcinoma has a survival benefit.     

Integrating the oral fluoropyrimidines into the management of advanced colorectal cancer

In colorectal cancer, leucovorin-modulated 5-fluorouracil (5-FU) has been the mainstay of both adjuvant treatment and treatment of metastatic disease for many years. In advanced disease, response rates of 10-43% are reported; efforts to improve efficacy through schedule modification, including prolonged infusions, have led to limited success. New agents with improved efficacy, tolerability and ease of administration are required. Among the newer drugs, irinotecan and oxaliplatin are becoming established as first- and second-line treatment for advanced disease. Their novel mechanisms of action have proven to be of value in 5-FU-resistant patients. In tandem with these developments, thymidylate synthase inhibition has remained an important objective and oral fluoropyrimidines such as capecitabine and UFT (uracil plus tegafur)/leucovorin have been developed with this goal in mind. Two large, phase III studies of capecitabine in metastatic disease demonstrated objective response rates of 26.6 and 24.8%. UFT/leucovorin has also been evaluated in phase III trials, with an 11.7% response rate reported. Both agents are being evaluated in combination with oxaliplatin and irinotecan, and ultimately oral fluoropyrimidines as monotherapy or combination therapy may replace intravenous (i.v.) 5-FU as first-line treatment for metastatic colorectal cancer.     

Oxaliplatin plus oral fluoropyrimidines in colorectal cancer

The medical treatment of colorectal cancer (CRC) has rapidly evolved in recent years with the introduction of novel cytotoxic drugs into clinical practice such as irinotecan, oxaliplatin, and capecitabine. Combination regimens using infusional 5-fluorouracil (5-FU)/leucovorin (LV) plus either oxaliplatin or irinotecan have demonstrated clinically meaningful, high efficacy in advanced CRC. Based on the results of the Intergroup trial N9741, FOLFOX4, a combination of infusional plus bolus 5-FU/LV and oxaliplatin, has emerged as the standard first-line therapy in the palliative setting. However, infusional 5-FU-based regimens carry the need for use of central venous lines and implantable ports to allow treatment on an outpatient basis and are thus inconvenient and expensive. The use of oral fluoropyrimidines (capecitabine or uracil/tegafur [UFT] plus LV) as substitutes for infusional 5-FU in combination protocols with oxaliplatin offers greater convenience, at the same time conceivably maintaining the high efficacy and tolerability observed with intravenous protocols. Various phase I/II trials have recently been reported that investigated oxaliplatin in combination with either capecitabine or UFT/LV in patients with advanced CRC. This review will detail the results of these trials focused on capecitabine-based combinations.     

Recent advances is surgical adjuvant chemotherapy for colorectal cancer

To evaluate the significance of surgical adjuvant chemotherapy, randomized controlled trials (RCTs) of adjuvant chemotherapy after curative resection for colorectal cancer were reviewed. Several multi-drug systemic chemotherapies (MOF, MMC/FT, 5-FU, UFT p.o.) were useful as adjuvant treatment to improve survival or disease-free survival of patients with colorectal cancer. Moreover, a worldwide meta-analysis suggested that continuous intraportal 5-FU infusion improves survival. Combination chemotherapy trials utilizing 5-FU and levamisol (LEV) demonstrated a survival advantage in patients with high risk colon cancer. Recently, many RCTs have substantiated the benefits of treatment with 5-FU/Leucovorin (LV) and this treatment is widely used as adjuvant treatment for the patients with Dukes C resected colon cancer in Europe and the U.S.A. Now, with the increasing use of oral chemotherapy drugs, new trials comparing oral UFT/LV with intravenous 5-FU/LV are being implemented to investigate these drugs in terms of QOL, toxicity and cost. Furthermore, the new drug irinotecan (CPT-11) is now under investigation to see if it brings added efficacy to 5-FU/LV. In Japan, two major groups (N-SAS-CC and TAC-CR) are comparing surgery alone and UFT alone in patients with Dukes C colon and rectal cancer. From these results, surgical adjuvant chemotherapy seems to be effective in the treatment of patients with high risk colon cancer and those with rectal cancer.     

Oral fluoropyrimidines: a closer look at their toxicities.

Patient preferences, quality of life issues, and economic considerations are driving the development of orally administered chemotherapy. Oral fluorinated pyrimidines, which have been used in Japan, are attracting increasing interest as a means to provide convenient, less toxic treatment without compromising efficacy. The oral fluoropyrimidines provide prolonged 5-fluorouracil (5-FU) exposure at lower peak concentrations than those observed with bolus intravenous administration. Moreover, depending on the dose schedule, the pharmacokinetics of the oral fluoropyrimidines may mimic the pharmacokinetics of continuous-infusion 5-FU. This review focuses on the toxicity profiles of five emerging oral fluoropyrimidine antineoplastic drugs: combined uracil and tegafur (UFT), capecitabine, eniluracil, S-1, and emitefur (BOF-A2). Different patterns of toxicities emerge from an analysis of the clinical trials of these agents relative to 5-FU administered as an intermittent intravenous bolus or as continuous infusion. The results of ongoing phase III trials comparing the oral fluoropyrimidines with conventional regimens of 5-FU plus leucovorin and 5-FU by continuous intravenous infusion are necessary before their therapeutic role in the management of colorectal carcinoma can be defined.     

Adjuvant Chemotherapy for Colon Cancer: Guidelines and Clinical Trials in Japan

In Japan, adjuvant chemotherapy for colon cancer was mainly developed using oral fluoropyrimidines. However, all Japanese studies to date have failed to demonstrate a statistically significant survival benefit of adjuvant chemotherapy with a combination of uracil and tegafur (UFT) monotherapy over surgery alone in patients with stage II or III colon cancer. The non-inferiority trials comparing different oral fluoropyrimidine monotherapies showed any fluoropyrimidine except S-1 was comparable in patients with stage III colon cancer. Japanese guideline plays an important role in the distribution of the optimal adjuvant treatment. In addition, the tolerability of oxaliplatin-based adjuvant chemotherapy was confirmed, and a multigene assay was validated in Japanese patients. A global collaboration is ongoing to test whether disease-free survival with 3 months of oxaliplatin-based adjuvant chemotherapy was non-inferior to that with 6 months of identical chemotherapy in patients with stage III or high-risk stage II colon cancer and is one of the best model task forces for the coordination of future adjuvant chemotherapy regimens in patients with colon cancer. These findings and further research will help define treatment duration and patient selection criteria for the personalization of adjuvant chemotherapy for colon cancer.     

Capecitabine

Capecitabine, an oral fluoropyrimidine carbamate, is adopted worldwide. As the treatment for metastatic colorectal cancer, capecitabine showed at least comparable efficacy with a favorable safety profile to bolus 5-FU/LV. In a large phase III trial (Xeloda Adjuvant Chemotherapy Trial: X-ACT), as the adjuvant treatment of patients with resected stage III colon cancer, capecitabine showed at least comparable disease-free survival, overall survival, and relapse-free survival with a favorable safety profile to bolus 5-FU/LV. Additionally, capecitabine-based combination regimens with oxaliplatin or irinotecan are now under evaluation. In phase II studies, capecitabine has shown the promising results in combination therapy. In Japan, capecitabine has been evaluated since 1994. In a recent phase II study, which evaluated the global dose as first-line treatment for metastatic colorectal cancer, the response rate was 35% (95% CI 23.1-48.4). The median time to disease progression was 169 days and the median overall survival was 617 days. Hand-foot syndrome (HFS), a characteristic adverse event of capecitabine, was observed in 73.3% of the patients, but the grade 3/4 was observed in 13.3% of the patients and only one patient discontinued the treatment due to HFS. An immediate approval of capecitabine in Japan is expected.     

Chemotherapy for metastatic disease: review from JCOG trials

The Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group (GIOSG/JCOG) has conducted several clinical trials to establish standard chemotherapy for unresectable or recurrent gastric cancer. From the late 1980s to early 1990s, two phase II studies by JCOG evaluated oral fluoropyrimidines, and others introduced Western chemotherapy regimens. Thereafter, the first phase III study (JCOG9205), comparing 5-fluorouracil (5-FU), 5-FU plus ciplatin (CDDP) (FP), and uracil and tegafur (UFT) plus mitomycin (UFTM), could not show a survival benefit of either FP or UFTM over 5-FU alone. In the late 1990s, new active agents such as irinotecan (CPT-11) and S-1 (new oral fluoropyrimidine) showed promising results in their phase II trials. The latest phase III study (JCOG9912), comparing 5-FU, CPT-11 plus CDDP, and S-1, showed significant noninferiority of S-1 to 5-FU in overall survival, associated with a better response rate and progression-free survival and acceptable toxicities, and concluded that S-1 should be considered for the standard chemotherapy of unresectable or recurrent gastric cancer. Simultaneously, another Japanese phase III trial comparing S-1 with S-1 plus CDDP showed a survival benefit of S-1 plus CDDP. At present, S-1 plus CDDP is recognized as standard chemotherapy for unresectable or recurrent gastric cancer, and new treatment with molecular target agents is under development.     

Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial: overview of efficacy, safety, and cost-effectiveness

The X-ACT (Xeloda in Adjuvant Colon Cancer Therapy) trial compared the efficacy and safety of the oral fluoropyrimidine capecitabine with bolus 5-fluorouracil (5-FU)/leucovorin (LV; Mayo Clinic regimen) as adjuvant therapy for stage III colon cancer. A total of 1987 patients were enrolled at 164 centers worldwide. Disease-free survival (primary study endpoint) in the capecitabine arm was at least equivalent to that in the 5-FU/LV arm; the upper limit of the hazard ratio was significantly (P < 0.001) below the predefined margins for noninferiority. Capecitabine was also associated with significantly fewer fluoropyrimidine-related grade 3/4 adverse events (AEs; P < 0.001) and fewer AE-related hospital admissions/days than 5-FU/LV. Pharmacoeconomic analyses performed in several countries show that the savings in direct costs (drug administration and AE-related costs) associated with capecitabine versus 5-FU/LV offset the acquisition costs of the drug. Furthermore, capecitabine reduces patient travel time and costs, making it a "dominant" strategy (ie, less costly and more effective) in the adjuvant setting. In conclusion, efficacy, safety, convenience, and cost findings from the X-ACT trial show that capecitabine offers at least equivalent clinical benefit compared with bolus 5-FU/LV and can replace intravenous 5-FU/LV in the adjuvant treatment of stage III colon cancer. The X-ACT trial has not only helped to better define the role of capecitabine but has also broadened the options available to patients with early-stage disease to include a uniquely effective oral outpatient treatment.     

Adjuvant chemotherapy for colorectal cancer in Japan-current state and problem areas

Chemotherapy that targets metastatic colorectal cancer originally developed in Europe and the US, and was introduced to Japan in April, 2005, where it has since headed toward full scale clinical applications. This event created an opportunity to re-evaluate the role of postoperative adjuvant chemotherapy in Japan. In Europe and the US, adjuvant therapy has centered on the intravenous administration of leucovorin/fluorouracil, while in Japan, it has been long-term continuous administration of oral fluoropyrimidine preparations. Despite this difference in historical background,guidelines created in 2005 recommend both LV/5-FU and LV/UFT regimens and there has been increased application of evidence-based adjuvant chemotherapy. The benefits of postoperative adjuvant chemotherapy in stage II and III (high risk of recurrence) colorectal cancer patients have also come to be recognized. Examination of a new survey of 100 medical specialists on the current state of adjuvant chemotherapy for colorectal cancer in Japanese clinical settings revealed that for stage III patients, there is a tendency to choose treatment based on evidence gathered from both home and abroad. In contrast, a solid majority (60%) of stage II patients are treated exclusively with oral fluoropyrimidine despite a lack of, or limited evidence of efficacy. At the same time, half of the physicians who treated stage II patients with adjuvant chemotherapy initially attempted to identify those with a high risk of cancer recurrence and treat them accordingly; which was a breakthrough in the clinical treatment approach. While ongoing comparative Japanese clinical studies that use adjuvant chemotherapy for the treatment of colorectal cancer were noted, consideration was also given to the desired future direction clinical research should take.     

Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial.

BACKGROUND: Oral capecitabine achieves a superior response rate with an improved safety profile compared with bolus 5-fluorouracil-leucovorin (5-FU/LV) as first-line treatment for patients with metastatic colorectal cancer. We report here the results of a large phase III trial investigating adjuvant oral capecitabine compared with 5-FU/LV (Mayo Clinic regimen) in Dukes' C colon cancer. PATIENTS AND METHODS: Patients aged 18-75 years with resected Dukes' C colon carcinoma were randomized to receive 24 weeks of treatment with either oral capecitabine 1250 mg/m(2) twice daily, days 1-14 every 21 days (n = 993), or i.v. bolus 5-FU 425 mg/m(2) with i.v. leucovorin 20 mg/m(2) on days 1-5, repeated every 28 days (n = 974). RESULTS: Patients receiving capecitabine experienced significantly (P <0.001) less diarrhea, stomatitis, nausea/vomiting, alopecia and neutropenia, but more hand-foot syndrome than those receiving 5-FU/LV. Fewer patients receiving capecitabine experienced grade 3 or 4 neutropenia, febrile neutropenia/sepsis and stomatitis (P <0.001), although more experienced grade 3 hand-foot syndrome than those treated with 5-FU/LV (P <0.001). Capecitabine demonstrates a similar, favorable safety profile in patients aged <65 years or > or = 65 years old. CONCLUSIONS: Based on its improved safety profile, capecitabine has the potential to replace 5-FU/LV as standard adjuvant treatment for patients with colon cancer. Efficacy results are expected to be available in Keywords: Adjuvant treatment, capecitabine, chemotherapy, colorectal cancer     

Is XELOX Equivalent to FOLFOX or Other Continuous-Infusion 5-Fluorouracil Chemotherapy in Metastatic Colorectal Cancer?

Continuous-infusion 5-fluorouracil (5-FU)/leucovorin (LV) and oxaliplatin is a frequently used regimen in metastatic colorectal cancer. Continuous-infusion 5-FU imposes constraints on patients and institutions. Oral fluoropyrimidines that mimic continuous-infusion 5-FU are now available and can be combined with oxaliplatin. In addition, it has been shown in small randomized trials that oral fluoropyrimidines are preferred by patients. Several randomized trials have compared continuous-infusion 5-FU/oxaliplatin with the oral fluoropyrimidine capecitabine plus oxaliplatin. In all of these trials, noninferiority was demonstrated for the use of oral fluoropyrimidines on the predefined endpoints such as progression-free survival, overall survival, or response rate. In all trials, however, the hazard ratios were always in favor of the use of continuous-infusion 5-FU/LV even though noninferiority was demonstrated. This could question the need to use oral fluoropyrimidines instead of continuous-infusion 5-FU. Patient preference, quality of life, and cost of treatment could also be considered in this setting, wherein most of the patients are not in a curative situation.     

Oral capecitabine: bridging the Atlantic divide in colon cancer treatment

5-Fluorouracil (5-FU) plus leucovorin (LV) has been the mainstay of treatment for colorectal cancer (CRC), with infused schedules more widely adopted in Europe and bolus schedules preferred in North America. However, the effective, oral fluoropyrimidine capecitabine is increasingly replacing intravenous (IV) 5-FU/LV on both sides of the Atlantic. Capecitabine generates 5-FU preferentially in tumor and is a well-established, first-line treatment for metastatic CRC. In this setting, capecitabine achieves a superior response rate, at least equivalent time to disease progression (TTP) and overall survival, and favorable safety compared with bolus 5-FU/LV. The benefits of capecitabine have been transfered into the adjuvant setting. Recent data from a large, international, randomized trial (Xeloda Adjuvant Chemotherapy Trial [X-ACT]) confirm that capecitabine (Xeloda, Roche Laboratories, Nutley, NJ) achieves favorable safety versus 5-FU/LV (Mayo Clinic regimen) and is at least as effective as IV 5-FU/LV in the adjuvant treatment of patients with resected stage III colon cancer. Capecitabine is also an effective and well-tolerated combination partner for oxaliplatin (XELOX) and irinotecan (XELIRI), achieving high efficacy with a good safety profile. An extensive phase III clinical trial program is further establishing the potential of the simplified capecitabine combinations to improve outcomes and unify treatment practices in the metastatic and adjuvant settings. New combinations with novel agents such as capecitabine/oxaliplatin plus erlotinib or bevacizumab are currently under investigation. Capecitabine has also shown promising activity and good tolerability in combination with radiotherapy in rectal cancer.     

Oral fluoropyrimidine treatment of colorectal cancer

5-Fluorouracil (5-FU) has been utilized as part of standard chemotherapy for treatment of early-stage and metastatic colorectal cancer for more than 4 decades. The oral fluoropyrimidines have been studied extensively as an alternative to intravenous 5-FU. The goal of such an approach is to simplify drug administration and to improve the toxicity profile while maintaining efficacy that is at least equivalent to intravenous therapy. The goal of this article is to review the features of the main oral 5-FU prodrugs, which include capecitabine, uracil and tegafur (UFT)/leucovorin, S-1, and BOF-A2 and to describe their potential efficacy in treating colorectal cancer.     

Redefining adjuvant chemotherapy in patients with stage III colon cancer: X-ACT trial

The current standard adjuvant chemotherapy for suitable patients with stage III colon cancer is the combination of oxaliplatin and 5-fluorouracil plus folinic acid (5-FU/LV). However, until recently and for many years prior to this, the accepted standard adjuvant chemotherapy was 6-8 months of bolus 5-FU/LV. However, bolus treatment was associated with significant toxicity, namely stomatitis, diarrhea and neutropenia, in addition to multiple hospital visits for drug administration for patients. The X-ACT trial (Xeloda in Adjuvant Colon Cancer Therapy) compared traditional bolus 5-FU/LV (as per the Mayo Clinic regimen) with capecitabine, in the adjuvant treatment of 1987 stage III colon cancer patients. The main safety, efficacy and pharmacoeconomic results have all been published, and the updated 5-year efficacy results have also recently been presented. This trial demonstrated that capecitabine was at least as effective as bolus 5-FU/LV in terms of disease-free and overall survival, with trends towards superiority for both. Moreover, there was much less toxicity associated with capecitabine, apart from hand-foot syndrome which was significantly more prevalent. On the basis of the X-ACT trial, capecitabine was approved by the US FDA, the National Institute for Clinical Excellence and the Scottish Medicines Consortium as monotherapy for the adjuvant treatment of stage III colon cancer.     

Cost-effectiveness of oxaliplatin and capecitabine in the adjuvant treatment of stage III colon cancer

For many years, the standard treatment for stage III colon cancer has been surgical resection followed by 5-fluorouracil in combination with folinic acid (5-FU/LV). Ongoing clinical trial evidence suggests that capecitabine and oxaliplatin (in combination with 5-FU/LV) may improve disease-free survival and overall survival when compared against 5-FU/LV alone in the adjuvant setting. This study evaluates the cost-effectiveness profiles of these two regimens in comparison to standard chemotherapy, using evidence from two international randomised controlled trials. Survival modelling techniques were employed to extrapolate survival curves from the two trials in order to estimate the long-term benefits of alternative treatment options over the remaining lifetime of patients. The health economic analysis suggests that capecitabine is expected to produce greater health gains at a lower cost than 5-FU/LV. Oxaliplatin in combination with 5-FU/LV is estimated to cost pounds 2970 per additional QALY gained when compared to 5-FU/LV alone. Future research should attempt to elucidate uncertainties concerning the optimal roles of capecitabine and/or oxaliplatin in the adjuvant setting in order to achieve the maximum level of clinical benefit.