Annals of Oncology Advance Access published online on April 1, 2008
Annals of Oncology, doi:10.1093/annonc/mdn067
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UFT (tegafur–uracil) in rectal cancer
1 Department of Medical Oncology, Hospital Infanta Sofía, Madrid, Spain
2 Department of Oncology, Odense University Hospital, Odense, Denmark
3 Department of Medical Oncology, Hospital Universitario La Paz, Madrid, Spain
* Correspondence to: Dr E. Casado, Department of Medical Oncology, Hospital Infanta Sofía, Paseo de Europa, 34, 28702 San Sebastián de los Reyes, Madrid, Spain. Tel: +34-647420771; Fax: +34-917277118; E-mail: enriquecasado{at}hotmail.com
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Abstract |
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 Top Abstract introductionthe case for UFT...preoperative UFT-based...UFT in the postoperative...tolerabilitydiscussionthe future for rectal...AcknowledgementsReferences |
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Background: Major achievements in the treatment of localised rectal cancer include the development of total mesorectal excision and the perioperative administration of radiotherapy in combination with continuous infusion (CI) 5-fluorouracil (5-FU). This multimodal approach has resulted in extended survival and lower local relapse rates, with the potential for sphincter-preserving procedures. However, CI 5-FU is inconvenient for patients and is costly. Oral fluoropyrimidines like UFT (tegafur–uracil) offer a number of advantages over 5-FU.
Methods: We undertook a review of published articles and abstracts relating to clinical studies of UFT in the treatment of locally advanced rectal cancer (LARC). Pre- and postoperative studies carried out in patients with newly diagnosed or recurrent disease were included.
Results: The combination of UFT and radiotherapy was effective and well tolerated in the preoperative setting, while adjuvant UFT improved survival and reduced distant relapse compared with surgery alone. The efficacy of UFT appears comparable with that of 5-FU and capecitabine and its side-effect profile is favourable.
Conclusion: Clinical experience to date suggests that UFT is a valuable treatment option for the perioperative treatment of LARC. Further improvements in patient outcomes may result from the combination of UFT with targeted agents.
Chemoradiotherapy, oral fluoropyrimidines, rectal cancer, tegafur-uracil, UFT
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introduction |
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TopAbstractintroductionthe case for UFT...preoperative UFT-based...UFT in the postoperative...tolerabilitydiscussionthe future for rectal...AcknowledgementsReferences |
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Colorectal cancer is one of the most common cancers in the developed world, accounting for 13% of cancers and 12% of cancer deaths [1]. Approximately one-third of these tumours arise in the rectum [2]. In Europe, the incidence of rectal cancer is
13 per 100 000/year in 45- to 54-year olds, increasing to 38, 73 and 107 per 100 000/year for those aged 55–64 years, 65–74 and 
75 years of age, respectively [3]. Over 41 000 new rectal cancer cases were predicted to arise in the United States in 2007 [4]. For tumours confined to the rectal wall (including T1 and some T2 tumours), local excision can result in good local control while preserving the anal sphincter. However, most tumours are more advanced at diagnosis. Treatment of locally advanced, stage II (T3–4 N0, M0) and III disease (any T, N1–2, M0) includes a combination of surgery—the mainstay of therapy—radiotherapy and chemotherapy. Locally advanced rectal cancer (LARC), a term used inconsistently, is usually defined as a tumour that cannot be resected without leaving microscopic or gross residual disease at the local site because of tumour adherence to that site. Regardless of the disease stage, the major goals of therapy are (i) long-term survival, (ii) local control, (iii) preservation of the anal sphincter and (iv) maintenance of quality of life (QoL). Preoperative treatment with radiotherapy plus protracted or continuous infusion (CI) 5-fluorouracil (5-FU) has become the standard of care in Europe and the United States for patients with LARC [2, 5–7]. Although the benefits of 5-FU-based chemotherapy and concurrent radiotherapy are widely accepted, the short half-life of i.v. 5-FU presents some difficulties. The radiosensitising effect of 5-FU depends on prolonged tumour exposure to 5-FU; therefore, CIs are needed to maintain adequate drug levels following irradiation and to minimise side-effects [8]. CI regimens require repeated administration in the clinic or the use of portable infusion pumps, which are inconvenient for patients and can result in catheter-related complications, such as infection and thrombosis [9, 10].
The oral fluoropyrimidines UFT (tegafur–uracil) and capecitabine were developed to overcome these difficulties and are widely used instead of 5-FU in rectal cancer treatment regimens. The purpose of this report is to provide an overview of the efficacy and tolerability of UFT in the pre- and postoperative treatment of patients with LARC, detailing the progress made to date and remaining challenges. We undertook a review of articles and abstracts relating to clinical studies of UFT in the treatment of LARC published between 1990 and the present day. Pre- and postoperative studies carried out in patients with newly diagnosed or recurrent disease were included.
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the case for UFT in rectal cancer |
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TopAbstractintroductionthe case for UFT...preoperative UFT-based...UFT in the postoperative...tolerabilitydiscussionthe future for rectal...AcknowledgementsReferences |
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UFT is a combination of tegafur, a readily absorbed 5-FU prodrug, and uracil, a biomodulator, in a 1: 4 ratio. Following intestinal absorption, tegafur is metabolised into 5-FU by the hepatic mitochondrial system, while uracil competitively inhibits dihydropyrimidine dehydrogenase, the enzyme primarily responsible for 5-FU catabolism. A comparison of pharmacokinetics in patients receiving protracted 5-FU and UFT showed higher 5-FU peak plasma concentrations (Cpmax) with UFT and comparable areas under the concentration–time curves (AUCs) [11]. UFT with leucovorin (LV, also known as calcium folinate) has comparable clinical efficacy to bolus 5-FU/LV in patients with metastatic colorectal cancer [12, 13].
The combination of UFT and radiotherapy has several advantages over CI 5-FU and capecitabine. UFT-based chemoradiotherapy is effective in solid tumours, including head and neck cancer [14], non-small-cell lung cancer [15] and pancreatic cancer [16]. UFT has a better tolerability profile than either i.v. 5-FU or capecitabine. Hand–foot syndrome, any grade of which is rare in patients treated with UFT, occurs in around half of all patients treated with capecitabine [17] or CI 5-FU [18]. Other important considerations are patient preference and QoL. Generally, patients tend to prefer oral treatments, providing efficacy is not compromised [19]. In a crossover study, Borner et al. [20] reported that >80% of patients preferred oral UFT to i.v. bolus 5-FU. The major reasons for preferring oral therapy were that medication was taken at home and that it did not cause painful mouth sores. In contrast, however, 61% of patients in a similarly designed study preferred the Nordic 5-FU regimen to capecitabine because of its more favourable toxicity profile, and only 39% of patients expressed a preference for capecitabine [21]. Furthermore, in a randomised comparison of UFT with LV versus 5-FU/LV, QoL was maintained throughout a treatment cycle in patients treated with UFT with LV, whereas QoL deteriorated during treatment in the 5-FU/LV arm [22].
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resectable rectal cancer
phase I studies
In the study by Hoff et al. [23], 15 patients with resectable stage II/III rectal cancer were treated with escalating doses of UFT (250–400 mg/m2/day) together with a fixed dose of LV (90 mg/day). UFT was taken in three equal doses per day, 5 days/week for the duration of a 5-week course of preoperative radiotherapy (1.8 Gy/day administered to the pelvis; 45 Gy total). The maximum tolerated dose (MTD) was UFT 350 mg/m2/day and the most common side-effects were diarrhoea—the only dose-limiting side-effect—anorexia and vomiting. Twelve of 14 patients who underwent surgery had sphincter-preserving procedures. Three patients (21%) had a pathologic complete response (pCR) and a further 10 patients (67%) had a partial response.
A lower MTD for UFT of 240 mg/m2/day was defined in the study by Pfeffer et al. [24]. UFT was taken with LV 30 mg/day for 4 weeks and radiotherapy (1.8 Gy/day, 5 days/week for 5 weeks; 45 Gy in total) was delivered using a three-field technique. Four of 15 assessable patients achieved a pCR (27%) and the tumour downstaging rate was 60%. A single grade 4 adverse event (diarrhoea with neutropenic fever) was reported at the highest dose level (270 mg/m2/day). This may have been an idiosyncratic response since higher cumulative doses have been administered without significant side-effects in other trials.
phase II studies
Subsequent studies have attempted to improve on the regimens used in the dose-finding studies. These are summarised in Table 1.
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Wang et al. [25] combined a dose-intense radiotherapy schedule (45 Gy in 4 weeks) with two courses of UFT at lower doses 200 mg/m2/day on days 1–28 in cycle 1 and 250 mg/m2/day in cycle 2 (postradiotherapy) with LV in an attempt to minimise side-effects and maintain systemic treatment during the postradiation period. This approach was effective, with high rates of downstaging (75%), pCR (25%) and sphincter preservation (55%); overall survival (OS) and disease-free survival (DFS) rates at 3 years (92% and 76%, respectively) were excellent. Transient grade 3/4 adverse events were rare. Results from a phase II study in which a similar approach was taken resulted in a similar pCR rate (25%) [26].
In a large phase II study by Fernández-Martos et al. [27], 94 patients with T3–4 tumours received a higher dose of UFT (400 mg/m2/day) without LV, together with radiotherapy 5 days/week for 5 weeks (total dose 45 Gy; 1.8 Gy/day). After surgery, four cycles of adjuvant 5-FU (Mayo regimen) were administered to most patients (76%). In addition to pCR, which occurred in 15% of patients, microscopic foci were observed in a further 23%. Sphincter-conserving surgery was possible in 11 of 43 patients with a tumour located 2–5 cm from the pectineal line who were initially allocated to abdominoperineal resection. Treatment was well tolerated, with few preoperative grade 3 side-effects.
A different regimen was evaluated by Feliu et al. [28], in which UFT was modulated with an initial dose of i.v. LV (250 mg/m2) followed by 15 mg/day p.o. of the S-enantiomer of LV (S-LV; two daily doses) >14 days. Two cycles of chemotherapy (UFT 350 mg/m2/day on days 1–14 of a 28-day cycle) were started on the first day of radiotherapy (45 Gy >5 weeks plus a 5.4 Gy boost in three fractions) and six additional courses of chemotherapy were administered after surgery. Although the UFT dose had been determined in earlier studies [29], 7 of 16 patients treated with 350 mg/m2/day in the study experienced grade 3/4 diarrhoea and two had grade 3 dermatitis but no hand–foot syndrome; the UFT dose was thus reduced to 300 mg/m2/day in subsequent patients. A total of 25 patients received this reduced dose, which was well tolerated and very effective, with downstaging in 63% of patients and a 3-year OS of 90%.
A similar tolerability profile but slightly reduced efficacy was reported by Kundel et al. [30]. Patients (n = 32) had pelvic irradiation (45 Gy in fractions of 1.8 Gy) plus UFT (240 mg/m2/day) with LV (30 mg/day) given during the first 28 days of radiotherapy. The regimen was well tolerated and adverse events, which were predominantly gastrointestinal in nature, were generally mild. Downstaging occurred in 13 patients (42%) and three patients (10%) had a pCR. Sphincter preservation was possible in 71% of patients undergoing surgery.
phase III study
UFT has been compared with bolus 5-FU in preoperative chemoradiotherapy for LARC [31]. In an open-label phase III study of 155 patients, the pCR rate was 13% in patients treated with either UFT with LV or 5-FU/LV, although more patients in the UFT group had tumour downstaging (59% versus 43% for 5-FU/LV; P = 0.04). Although the study was not powered to exclude clinically significant differences between the groups, outcomes in the UFT group did not differ from those in the 5-FU group. Most notable, however, was the difference in the tolerability profiles of the two regimens. Severe haematological toxic effects were common in the 5-FU/LV group, and significantly more patients in the 5-FU/LV group had severe leucopenia compared with the UFT group.
UFT-based combination regimens
Preclinical studies have shown that oxaliplatin is a potent radiosensitiser [32], making it a natural partner for use with UFT in combined-modality regimens. Patients in a phase I/II study by Aschele et al. [33] received weekly oxaliplatin (60 mg/m2/day), escalating doses of UFT (200–350 mg/m2/day, 5 days/week) and LV (90 mg/day, fixed dose) during radiotherapy (total dose 50.4 Gy). Although the MTD had not been reached at UFT 300 mg/m2/day, two pCRs had been observed in 11 assessable patients (18%) and three patients had tumour downstaging (27%). Preliminary results from a phase II study by Fernández-Martos et al. [34] demonstrated that UFT 400 mg/m2/day, taken 5 days/week for 5 weeks and oxaliplatin 85 mg/m2 on days 1, 15 and 29 can be administered safely with radiotherapy (50 Gy total) to patients with LARC. A pCR rate of 15% was observed in 13 assessable patients, with microscopic foci in an additional 23% of patients; all patients underwent R0 resection.
Other agents have also been combined with UFT-based chemoradiotherapy. Gemici et al. [35] combined UFT (300 mg/m2/day, 5 days/week) and mitomycin C (10 mg/m2 on day 1) with radiotherapy (total dose 46 Gy) in this setting, with respectable pCR (11%) and nodal sterilisation rates (69%), despite >60% of the patients having T4 node-positive disease. However, preliminary results from a Japanese phase I trial in which UFT (300 mg/m2/day, 5 days/week) was combined with concurrent weekly irinotecan (starting at 30 mg/m2) and radiotherapy (2 Gy/day, 40–50 Gy total) resulted in an excess of grade 3 diarrhoea [36].
unresectable or recurrent rectal cancer
The prognosis for patients with nonresectable locally advanced or recurrent rectal cancer is very poor, with a median survival of only 9–18 months [37]. As a result, treatment has evolved to include multimodal strategies. The efficacy of UFT in the preoperative treatment of patients with advanced or recurrent rectal cancer has been assessed in several phase I and II studies (Table 2).
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UFT monotherapy
In a study of 56 patients with progressive, unresectable disease, Sanchiz and Milla [38] observed partial responses in 40% of assessable patients following treatment with UFT 600 mg/m2/day plus LV 90 mg/m2/day for 14 days. Response to chemotherapy and time to disease progression were highest in previously untreated patients, with a response rate of 70% versus 22% in previously treated patients; time to progression was 19.6 versus 7.7 months, respectively.
UFT with concomitant radiotherapy
phase I studies
Schiebe et al. [39]examined escalating doses of UFT with LV (90 mg/day) taken 5 days/week with concomitant radiotherapy in 19 patients with recurrent rectal cancer. The MTD was UFT 400 mg/m2/day, with dose-limiting diarrhoea and emesis; the recommended UFT dose was established at 350 mg/m2/day. Complete responses were observed in two patients, with partial responses in a further three patients (36% overall response rate). It is noteworthy that a higher MTD was established in this study than in the phase I study by Hoff et al. [23], despite the fact that patients had recurrent disease and were receiving a higher dose of radiotherapy.
A second phase I study was conducted by Pfeiffer [40] in 18 patients with unresectable LARC. UFT was given 5 days/week for 6 weeks, with increasing doses from 150 to 300 mg/m2/day, together with S-LV 22.5 mg/day and radiotherapy (60 Gy in 30 fractions). This regimen was well tolerated and effective; 11 patients achieved an R0 resection (61%), two patients had a pCR and 10 patients were alive after a median follow-up of 49 months (range 46–62 months). All patients received the planned dose of radiotherapy and only one patient had grade 3 diarrhoea. There were no early postoperative complications with this high-dose radiotherapy, possibly as a result of the five-field technique used.
phase II studies
In an extension to the phase I study by Pfeiffer et al., Qvortrup et al. [41] reported a 10% pCR rate and R0 resections in 60% of 50 patients with primary and recurrent LARC patients. Only three patients experienced grade 3 side-effects (diarrhoea and/or nausea/vomiting). After a median follow-up of 22 months, 36 patients were still alive.
In a phase II study by de la Torre et al. [42], patients received UFT 300 mg/m2/day and low-dose LV (30 mg/day) daily for 28 days (days 8–35). Radiotherapy (45 Gy total) was delivered over >5 weeks. Seventeen of the 22 patients with unresectable disease underwent surgery, with R0 resections in 88%. Three patients (18%) had a pCR. Two-year DFS and OS were 54% and 61%, respectively, for patients with unresectable tumours and 27% and 55%, respectively, for those with recurrent disease. The only meaningful side-effect was grade 3 diarrhoea, which was observed in eight patients (23%).
On the basis of these studies, some observations can be made regarding the use of UFT in the treatment of LARC. While these results indicate that the prognosis for patients with unresectable or recurrent LARC is improved by treatment with UFT-based multimodal therapy, it is important to note that a range of doses and schedules have been evaluated in these studies, likely on the basis of the personal experience of the investigators, without a consensus being reached on which is optimal. Nonetheless, efficacy appears to be consistent across these studies, with a 3-year local recurrence rate of 8% and DFS of 72%–83%. Further research is required to clearly define the most effective dose and schedule and to increase the applicability of the combination of preoperative UFT concomitant with radiotherapy.
Variations in pCR rates are likely to be attributable to differences in the quality of the examination of surgical specimens, as new procedures are not universally adopted. The inclusion of patients with different tumour stages and with tumours at a varying distance from the anal verge also influences rates of pCR, downstaging and sphincter-preserving operations. Notwithstanding these confounding factors, low anterior resections were carried out in the majority of patients in these studies. The use of local recurrence rate in measuring the efficacy of preoperative treatment may be misleading, as many factors, including performance status and tumour stage at diagnosis, radiotherapy dose and the quality of the surgical procedure, have a profound impact on clinical outcome in rectal cancer. Nonetheless, results from the studies described above are generally consistent in suggesting a benefit for preoperative UFT-based chemoradiotherapy in LARC.
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UFT in the postoperative treatment of rectal cancer |
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TopAbstractintroductionthe case for UFT...preoperative UFT-based...UFT in the postoperative...tolerabilitydiscussionthe future for rectal...AcknowledgementsReferences |
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Adjuvant chemotherapy is currently recommended in US guidelines for patients with stage II/III rectal cancer [7, 43] and in combination with radiotherapy for patients who did not receive preoperative radiotherapy. Postoperative 5-FU-based chemoradiotherapy improves local control, DFS and, in some studies, OS compared with surgery alone or surgery followed by radiotherapy [44–46]. In addition, while a meta-analysis by the Colorectal Cancer Collaborative Group confirmed that postoperative radiotherapy significantly reduced local recurrence, no significant effect on OS was observed [47]. As a result, radiotherapy is less commonly used in the postoperative setting than before surgery. UFT with LV has been used both with and without radiotherapy in the postoperative treatment of rectal cancer (Table 3).
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postoperative chemotherapy alone
The effect of UFT on survival compared with surgery alone has been investigated in several adjuvant studies. In a recent study by Akasu et al. [48], 276 patients with stage III rectal cancer who had undergone successful excision of the primary tumour were randomised to either postoperative therapy with UFT for 1 year or no postoperative chemotherapy. OS at 3 years was significantly better in the UFT group (91% versus 81%; P = 0.0048); postoperative UFT also reduced the rate of distant metastasis compared with surgery alone (18% versus 32%, respectively).
In a large randomised study comparing postoperative treatment with a low dose of UFT (400 mg/day) plus mitomycin C (20 mg sprinkled into the abdominal cavity during surgery then 6 mg/m2 i.v. on day 7 and monthly thereafter for 6 months) (n = 416) versus a control group who received surgery alone (n = 418), the 5-year DFS rate was significantly higher in the chemotherapy group (69% versus 59% in the control group; P = 0.005), although there was no difference in OS at 5 years [49].
A meta-analysis of data from >2000 patients in five Japanese trials demonstrated a significant benefit for postoperative UFT versus surgery alone in terms of OS, DFS and local relapse [50]. In this pooled analysis, UFT had a significant advantage over surgery alone in OS (hazard ratio, 0.82; 95% confidence interval 0.70–0.97; P = 0.02) and DFS (hazard ratio, 0.73; 95% confidence interval, 0.63–0.84; P < 0.0001), thus supporting the role of UFT monotherapy in the adjuvant setting.
While these data are promising, the studies described above were carried out in Asian populations and, as a result, their relevance to Western patients may be questioned. For example, race was a significant predictor of response in a study of Caucasian and Asian patients with non-small-cell lung cancer who were treated with docetaxel–carboplatin [51]. In contrast, however, Shirao et al. [52] demonstrated similar response rates in 44 Japanese and 44 American patients with advanced colorectal cancer who were treated with UFT with LV. The incidence of grade 3/4 diarrhoea was higher in American patients in this study (22% versus 9% in Japanese patients; P = 0.006) while grade 3/4 stomatitis/mucositis was more common in Japanese patients (34% versus 5% in American patients). Pharmacokinetic parameters were similar in both populations, although AUC and Cpmax were slightly higher in Japanese patients.
postoperative chemoradiotherapy
Hsieh et al. [53] compared postoperative concurrent radiotherapy (total dose 50.4 Gy) plus UFT 250–300 mg/m2/day with LV 30–45 mg/m2/day versus weekly i.v. bolus 5-FU 400–450 mg/m2 plus LV 80–100 mg/m2 in a nonrandomised study in 30 patients with stage II or III rectal cancer. After chemoradiotherapy, patients received UFT plus LV for at least 1 year or until treatment failure or 5-FU/LV for 42 weeks or until treatment failure. OS and DFS were similar in both groups; however, treatment with UFT resulted in fewer grade 3 toxic effects and greater compliance, leading the authors to conclude that UFT with LV was a suitable alternative to weekly i.v. bolus 5-FU treatment in the adjuvant setting.
Similar results were seen in a Turkish study in which UFT 300 mg/m2/day plus LV 30 mg/day was administered during radiotherapy (1.8 Gy/day; total dose 50.4 Gy) on days 1–28 every 35 days), with four additional courses after radiotherapy [54]. The most common adverse event during chemoradiotherapy was diarrhoea, with grade 3 reported by 19% of patients. Two-year DFS was 72% and 2-year OS was 83%.
While the advantages of UFT-based multimodality treatment regimens are apparent in patients who have undergone curative surgery, the role of UFT in combination with postoperative radiotherapy is less clear. However, results from the Colorectal Cancer Collaborative Group meta-analysis are likely to have signalled the change from post- to preoperative radiotherapy for LARC [47].
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tolerability |
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TopAbstractintroductionthe case for UFT...preoperative UFT-based...UFT in the postoperative...tolerabilitydiscussionthe future for rectal...AcknowledgementsReferences |
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Gastrointestinal events are the most common side-effects of treatment with UFT, with grade 3/4 symptoms in 7%–25% of patients in the phase I and II studies of preoperative UFT-based chemoradiotherapy described above and nausea/vomiting in 3%–7% of patients. Grade 3/4 haematological side-effects are uncommon, although grade 3/4 leucopenia was observed in 3% of patients in the study by Wang et al. [25] and in 1% of patients in the study by Fernandez-Martos et al. [27]. UFT monotherapy was also well tolerated; Sanchiz and Milla [33] reported no grade 3/4 side-effects in their study of UFT in patients with recurrent rectal cancer [38], as did Aschele et al., who combined UFT with LV and oxaliplatin in LARC. In the adjuvant setting, Atasoy et al. [54] observed grade 3 diarrhoea and nausea/vomiting in 25% and 6% of patients, respectively, during a period of chemotherapy alone after postoperative chemoradiotherapy. Diarrhoea was less common in the larger study by Akasu et al. [48], occurring at grade 3 in only 1% of patients. This difference may arise from patients receiving chemotherapy alone, rather than chemoradiotherapy. Increases in liver enzymes were also observed in this study. Compliance with the 1-year treatment regimen was good (80%). Hand–foot syndrome is a common side-effect of treatment with capecitabine, with 3%–11% of patients in capecitabine studies experiencing severe grade symptoms [55]. Hand–foot syndrome is also common in patients receiving 5-FU, in particular when administered by CI. A meta-analysis of data from randomised trials comparing bolus and CI 5-FU demonstrated that hand–foot syndrome was significantly more common with CI than bolus 5-FU (34% versus 13%, respectively; P < 0.0001) [56]. In a more recent retrospective analysis, Saif et al. [57] reported that grade III hand–foot syndrome was more common in patients treated with combination of capecitabine plus radiotherapy than in those treated with CI 5-FU plus radiotherapy. In contrast, hand–foot syndrome is rare in patients treated with UFT (<0.01% [58]), although the mechanisms underlying this difference have not been clearly elucidated. One possible explanation is the presence of the DPD inhibitor, uracil, in UFT, as DPD inhibitors have been shown to reduce the incidence of HFS [59].
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discussion |
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TopAbstractintroductionthe case for UFT...preoperative UFT-based...UFT in the postoperative...tolerabilitydiscussionthe future for rectal...AcknowledgementsReferences |
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Treatment for LARC has undergone major changes in recent years. Preoperative 5-FU/LV in conjunction with radiotherapy has been the preferred treatment for LARC since studies confirmed that this approach resulted in better compliance, less toxicity and a higher rate of local control compared with postoperative treatment [5]. Preoperative chemoradiotherapy remains the first-choice treatment in the United States [7]. The development of the oral fluoropyrimidines has challenged this approach, however, providing physicians with more convenient and equally effective options. However, the largest body of evidence exists for 5-FU, hence its position as the treatment of choice for LARC.
Capecitabine has undergone extensive investigation in combination with radiotherapy in recent years and, as a result, it is now recommended as an alternative to 5-FU/LV, although phase III randomised data comparing the two agents are not yet available. Results from phase II studies demonstrate that capecitabine is effective and well tolerated in combination with radiotherapy, with tumour downstaging in 50%–84% of patients and pCR achieved in 4%–31% of patients [56]. In addition, two retrospective studies suggest that capecitabine is more effective than CI or i.v. bolus 5-FU. In the retrospective analysis by Saif et al. [57], patients (n = 542) treated with the combination of capecitabine plus radiotherapy had a pCR rate of 25% compared with 13% in patients treated with CI 5-FU plus radiotherapy (P = 0.008). A similar result was observed in the study by Kim et al. [60], with a pCR rate of 22% for capecitabine compared with 11% for bolus 5-FU (n = 127; P = 0.042). In contrast, however, there was no difference in efficacy between preoperative 5-FU and capecitabine in combination with radiotherapy in a prospective study carried out in 278 patients, where similar tumour response and downstaging rates were observed [61]. Similarly, a matched-pair analysis of 89 patients treated with capecitabine plus radiotherapy and 89 control patients treated with CI 5-FU plus radiotherapy reported no differences in efficacy and similar tolerability between the two treatments [62].
While the benefits of preoperative chemoradiotherapy in patients with accurately staged rectal cancer are clear, debate continues to surround the role of postoperative chemotherapy and chemoradiotherapy in the setting of appropriate and meticulously carried out surgery. The role of adjuvant chemotherapy is to improve survival, and this approach is well established in patients with colon cancer and positive lymph nodes. The benefits of adjuvant therapy are less well established in rectal cancer, with some studies showing no improvements in survival [6, 63]. Therefore, any benefits of treatment must be weighed against the adverse events associated with postoperative treatment, in addition to the risk of poor functional and QoL outcomes. Results from the adjuvant studies described above suggest that UFT, which is well tolerated and provides survival benefits in this setting, is a promising adjuvant treatment option, although further assessment in a wider Western patient population is required.
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the future for rectal cancer treatment |
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Considerable advances have been made in the treatment of LARC. The introduction of total mesorectal excision has greatly reduced the rate of local recurrence; preoperative chemoradiotherapy has further reduced the rate of local recurrence, as well as increasing the proportion of patients undergoing sphincter-preserving procedures. In addition, adjuvant chemotherapy has extended DFS and OS. However, distant metastasis continues to pose a major challenge for this patient group.
UFT has consistent efficacy in the pre- and postoperative treatment of LARC. Preoperative UFT with radiotherapy results in sphincter preservation in 25%–87% of patients with low-seated tumours, high rates of tumour downstaging and good DFS and OS. Postoperative UFT improves survival compared with surgery alone and the combination of UFT and radiotherapy appears to be effective in this setting. UFT is generally well tolerated and, unlike CI 5-FU and capecitabine, very rarely causes severe grade hand–foot syndrome. In addition, UFT is a convenient treatment for patients because of its oral administration. This combination of efficacy, tolerability and convenience provides a high therapeutic index for UFT and suggests that this drug might represent an alternative to i.v. 5-FU for patients with LARC. Further randomised phase III studies are required, however, to establish the role of UFT in this indication.
In the short term, further improvements in rectal cancer treatment are likely to arise as a result of optimisation of chemotherapy regimens, in particular, the incorporation of mAbs that target the epidermal growth factor receptor or vascular endothelial growth factor receptor. The combination of oral agents, such as UFT, and targeted agents may provide further improvements for patients with LARC.
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The authors would like to thank Deirdre Carman, who provided medical writing support on behalf of Merck KGaA.
Received for publication August 9, 2007. Revision received February 21, 2008. Accepted for publication February 22, 2008.
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