Neoadjuvant therapy of rectal carcinoma with UFT–leucovorin plus radiotherapy

J. Feliu1,+, J. Calvillo2, A. Escribano3, J. de Castro1, M. E. Sánchez3, A. Mata2, E. Espinosa1, A. García Grande3, A. Mateo2 and M. González Barón1

1Department of Medical Oncology, 2Department of General Surgery and 3Department of Radiotherapy, Hospital La Paz, Madrid, Spain

Received 5 July 2001; revised 30 October 2001; accepted 15 November 2001.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background

The object of this phase II study was to assess the impact of preoperative external radiation therapy combined with UFT and leucovorin on tumor response, sphincter preservation and tumor control in patients with rectal carcinoma.

Patients and methods

Forty-one patients with resectable extraperitoneal rectal adenocarcinoma received radiation therapy and two courses of chemotherapy. Chemotherapy consisted of a 2-h infusion of 6S-steroisomer of leucovorin (6SLV) 250 mg/m2 on day 1, oral 6SLV 7.5 mg every 12 h on days 2–14, and UFT either 350 or 300 mg/m2 on days 1 to 14 every 28 days. Six additional courses of chemotherapy were given after surgery.

Results

Seven of 16 patients (43%) who received 350 mg/m2/day of UFT had grade 3–4 diarrhea and two other patients (12%) had grade 3–4 dermatitis. The next 25 patients received 300 mg/m2/day of UFT and only 14% of them had grade 3–4 diarrhea. Surgery consisted of low-anterior resection in 26 patients (63%) and abdominal-perineal amputation in 15 (37%). There were six histological complete responses (15%). Downstaging occurred in 25 patients (63%). The overall survival at 3 years was 90% and the pelvic disease-free survival 92%.

Conclusions

Preoperative therapy with radiotherapy and UFT–6SLV downstaged 63% of tumors and allowed a sphincter-preserving procedure in some patients. Toxicity was moderate. This scheme is convenient because of the oral administration of chemotherapy.

Key words: leucovorin, neoadjuvant, preoperative, radiotherapy, rectal carcinoma, UFT


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Rectal adenocarcinoma has a very high rate of local relapse with surgery alone. Mesorectal excision may reduce this rate, but so far its safety and reproducibility has not been clearly demonstrated [1], so the use of this surgical procedure remains limited. Some studies have demonstrated that adjuvant chemotherapy (CT) and radiotherapy (RT) reduce the rate of local relapse and prolong survival in patients whose tumors extend into the perirectal fat (T3) or who have involvement of mesorectal or pelvic lymph nodes (N1–3) [2].

However, preoperative CT plus RT offers some theoretical advantages over adjuvant therapy for patients with a tumor of the middle to lower rectum: (i) micrometastases are treated early in the course of the disease; (ii) the risk of tumor seeding during surgery is reduced; (iii) RT toxicity is also reduced; (iv) the efficacy of CT and RT is higher in a tumor with an intact vasculature; (v) if the tumor shrinks, a sphincter-preserving procedure can be performed. This treatment also has some drawbacks: (i) definitive therapy is delayed, which may allow the growth and dissemination of the tumor; (ii) as preoperative staging is not very precise, patients with early stages (T1–2N0) of the disease, who do not need this therapy because of their very low risk of relapse, would be overtreated.

Phase II trials have confirmed the safety of neoadjuvant therapy for rectal adenocarcinoma with encouraging preliminary results [3]. Although different schedules have been used, authors agree that this strategy may avoid abdominal-perineal amputation in selected cases [46]. For this reason, treatment before surgery has been recommended for patients with clinical stage T3 disease who would not initially undergo sphincter-preserving surgery [7].

Chemotherapy is usually based on 5-fluorouracil (5-FU), either as a continuous infusion or modulated by leucovorin (LV). The superiority of one way of administration over the other has not been demonstrated. However, these regimens require repeated administrations at hospital or the use of infusion pumps. For this reason, oral chemotherapy may represent a convenient and more acceptable treatment modality. Such a therapy may save money and avoid the problems associated with central venous lines. Besides, some studies indicate that patients prefer oral rather than intravenous therapy, provided that efficacy remains the same [8, 9].

UFT is an oral combination of uracil and tegafur in a molar ratio of 4:1. Tegafur is metabolized into 5-FU following in-testinal absorption. Uracil inhibits the catabolism of 5-FU by competitive inhibition of the enzyme uracil dehydrogenase, which maintains active drug levels for a prolonged period and thus simulates a continuous infusion of 5-FU [10].

Some years ago, we developed a therapeutic scheme to modulate UFT with LV. It consisted of the infusion of a high dose of LV, followed by the oral administration of both UFT and LV for 14 days. Theoretically, the scheme takes advantage of the biochemical modulation and the continuous infusion of 5-FU. Briefly, it consisted of intravenous LV 500 mg/m2 over 2 h followed by oral UFT and LV for 14 days. The intravenous administration of LV was based on in vitro observations suggesting that the optimal stabilization of the ternary complex and potentiation of 5-FU cytotoxicity is achieved at a total LV concentration of 20 mmol/l in the tumor tissue [11]. This may be achieved with high doses of LV, for instance 500 mg/m2 over 2 h [12]. The oral administration of LV after the intravenous dose maintains the cellular deposits of reduced folate during the administration of UFT and therefore obtains a continuous modulation.

A phase I trial determined that the maximum tolerated dose of UFT when modulated in this way was 390 mg/m2/day [13]. This regimen obtained a 39% response rate in patients with advanced colon cancer in both adults [14] and elderly patients [15]. We have used the same schedule as adjuvant therapy for colon cancer [16] and rectal cancer (in association with RT) [17]. In this study, patients with rectal carcinoma received radiotherapy (50–50.4 Gy over 6–7 weeks) and UFT 350 mg/m2/day: 21% experienced grade 3–4 toxicity, consisting of diarrhea (19%), nausea and vomiting (2%), and neutropenia (2%).

Considering the activity, low toxicity and convenience of this regimen, we decided to assess its activity as neoadjuvant therapy in combination with RT for patients with stage II–III rectal adenocarcinoma. The objective of this phase II trial was to determine the toxicity and the efficacy of this combination in terms of downstaging, local control, survival and sphincter preservation.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
From August 1995 to April 1999, 41 patients with histologically confirmed rectal adenocarcinoma were included. The entry criteria were as follows: (i) tumor location within 10 cm of the anal verge, as measured by sigmoidoscopy or colonoscopy; (ii) clinically resectable stage T3–T4 disease (vaginal or bladder involvement included) and N0–2, according to the TNM classification [18]. Patients with partially resectable metastatic disease were also included provided that the local tumor was resectable; (iii) Eastern Cooperative Oncology Group (ECOG) performance status of zero to two; (iv) absence of metastatic spread by computed tomographic scan, unless it was initially considered as resectable; (v) age <75 years.

Patients with previous CT or RT or with a previous malignant disease were excluded (except skin cancer or non-invasive cervical cancer adequately treated). Other requirements were a leukocyte count >4 x 109/l, a platelet count >100 x 109/l, bilirubin, transaminases and creatinine levels <1.5-fold the upper normal limit, and written informed consent according to directives of the local ethics committee.

Pretreatment evaluation included a complete history and physical examination, including digital examination, flexible sigmoidoscopy or colonoscopy, transrectal ultrasound, barium enema, complete blood count, liver function tests, carcinoembryonic antigen determination, chest X-ray film and abdominal/pelvic computed tomography. The primary tumor was staged by ultrasound and computed tomography. After the diagnostic work-up, patients were classified according to the initial surgical option: (i) candidate for a sphincter-saving procedure if the distance between the lower pole of the tumor and the anal verge (as measured by flexible sigmoidoscopy and digital examination) was >60 mm; (ii) probable candidate for an abdominal perineal resection otherwise. This measurement was not performed under general anesthesia.

Neoadjuvant treatment was initiated after the staging work-up. CT consisted of intravenous 6SLV 250 mg/m2 given over 2 h on day 1, followed by oral UFT 350 mg/m2 on days 1–14 (in two daily doses, before breakfast and before dinner) and oral 6SLV 7.5 mg/12 h on days 2–14. This treatment was repeated every 28 days. In the case of grade 3–4 toxicity, the dose of UFT was reduced by 25%; if a new episode of grade 3–4 toxicity appeared after this reduction, CT was withdrawn. Two courses were scheduled before surgery, although a third course was to be given if surgery was delayed.

RT was begun on the same day as CT. It was delivered using a four-field box technique (anterior and posterior plus right and left lateral). At simulation, patients were placed in the prone position after contrast enhancement of the small bowel, with the bladder full, to remove the ileon from the pelvis and to optimize small bowel protection. Initial radiation fields encompassed the pelvis to treat the primary tumor, presacral area and internal iliac lymph nodes. Cephaled field borders were at the L5–S1 inter-space and inferiorly 5 cm distal to the tumor or including the perineum for tumors in the distal 5 cm of the rectum. The lateral limits were placed 1.5 cm outside the true bony pelvis. The upper and lower limits of the lateral fields coincided with the front fields, with the anterior limit located behind the symphysis pubis (except in the case of urinary bladder involvement, in which the anterior limit was placed in front of the symphysis pubis to include both the urinary and external iliac lymph nodes). The posterior limit encompassed the sacral concavity and coccyx and the anterior limit the femoral head, to include the obturator nodes. The anterior border was adjusted to include the external iliac lymph nodes in patients with involvement of structures draining to this chain. A dose of 45 Gy in 25 fractions over 5 weeks was applied to the isocenter of the four fields. Forty-five degree wedges were used over the lateral fields. A boost of 5.4 Gy in three fractions was delivered using either a posterior–anterior or two lateral fields, or just lateral fields to treat the tumor with a 3 cm margin in all dimensions. All fields were treated daily with megavoltage equipment. Treatment was given 5 days/week, single dose 1.8 Gy.

During RT, toxicity was recorded every week according to World Health Organization (WHO) [19] and Radiation Therapy Oncology Group (RTOG) [20] criteria for CT and RT, respectively. After the completion of RT, toxicity was registered after each course of CT. Patients may experience gastric pain related to UFT and this side effect is not included in the WHO classification: we considered that grade 3–4 gastric pain was intense enough to require the withdrawal of UFT despite treatment with an H2-blocker (grade 1–2 otherwise) [14]. If the patient experienced grade 3 toxicity (RTOG scale), RT was stopped until complete recovery.

Computed tomography scan, colonoscopy and transrectal ultrasound examinations were repeated once the neoadjuvant treatment had been completed. WHO criteria were used to evaluate the response [19], which had to be agreed by all investigators after a review of the staging procedures. Surgery was performed 4–6 weeks after the end of chemoradiation. However, this period was prolonged up to 8 weeks if doubts persisted about the chances of performing a sphincter-conserving procedure, so that a third course of CT was given. The surgeon decided the surgical procedure: abdominal perineal resection or low anterior resection. It was strongly recommended that the entire mesorectum was removed and that a distal rectal margin of at least 2 cm was obtained for sphincter preservation. Rich’s criteria were used to evaluate the histological response [21]: (i) macroscopic or microscopic tumors are seen in all layers of the bowel wall, including perirectal fat; (ii) microscopical tumor is confined to the bowel wall; (iii) isolated foci of microscopic tumor (usually less than three); (iv) no evidence of tumor.

After surgery, patients received six courses of adjuvant UFT–6SLV, but in this case, the dose of UFT was 390 mg/m2.

Dose intensity was calculated by dividing the total amount of the drug given in the first two courses (mg/m2) by the number of weeks elapsed from the first dose to the beginning of the third course. Sphincter function was scored according to the Memorial Sloan Kettering Cancer Center scale [22]: (i) excellent, 1–2 daily movements without soiling (minimal leakage of mucous or liquid stools only occasionally); (ii) good, 3–4 daily movements or mild soiling (1–2 weekly episodes of minimal leakage of mucous or liquid stool); (iii) fair, more than four daily movements, occasional or moderate soiling (more than two weekly episodes of minimal leakage of mucous or liquid stool). (iv) poor, incontinence. Sphincter function was recorded on the date of the last follow-up.

After the completion of all therapy, follow-up visits included physical examination, complete blood count, serum biochemistry and computed tomography scan of the abdomen and pelvis, and were performed every 3 months for 2 years and every 6 months thereafter.

The sample size was calculated to reject a probability of T downstaging <20%. The expected downstaging rate was 40%, with an alpha error of 5% and a predictive power of 80%. According to the Fleming method [23], 19 patients were first included. As pT downstaging was >21% in these first patients, the sample was increased to 35 plus 10% to allow for loses, which gives a total of 38 patients evaluable. Fisher’s exact test was used to compare qualitative variables. Relapse-free and overall survival were calculated with the Kaplan–Meier method from the time of diagnosis.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
There were 41 patients of which 23 were male and 15 female. Clinical staging before surgery was as follows: T3N0M0 in 17 patients (41%), T4N0M0 in two (5%), T3N1–2M0 in 16 (39%), T4N1–2M0 in four (10%) and T3N1M1 in two (5%). Two patients were upstaged after the computed tomography scan showed lymph nodes that had not been detected by transrectal ultrasound. Two patients with stage IV disease had resectable liver metastases. On digital examination, the tumor was mobile in 14 patients (34%) and tethered in 27. The tumor covered 100% of the lumen in 11 patients (27%), 75% in 10 (24%), 50% in 14 (34%) and 25% in six (15%). The tumor was located in the distal rectum (1–6 cm from the pectineal line) in 23 patients (56%) and in the medium third (between 7 and 10 cm) in 18. The mean length of the tumor along the longitudinal axis was 40 mm (range 20–80 mm). Table 1 shows the patients’ characteristics. Sixteen patients (39%) were eligible for a sphincter-preserving procedure at diagnosis.


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Table 1. Patient characteristics
 
A total of 111 courses of CT were given preoperatively, with an average of 2.7 per patient (12 patients received two courses and 29 patients three). The first 16 patients received UFT 350 mg/m2/day and the remaining 25 received 300 mg/m2/day. The median dose intensity was 1090 mg/m2/week in the first group (89% of the scheduled dose) and 1029 mg/m2/week in the second group (98% of the scheduled dose).

The median time elapsed from inclusion to surgery was 15 weeks (range 12–20), whereas it was 6 weeks from the end of RT to surgery (range 4–9 weeks). Surgery consisted of low anterior resection in 26 patients (63%) and an abdominal perineal resection in 15 (37%). Low anterior resection was performed in eight out of 23 patients (35%) with a tumor located within 6 cm from the anal margin, and in all 18 patients with a tumor located beyond that distance. Two patients (5%) had an incomplete resection (affected surgical margins). Two patients had liver metastases at diagnosis: one had four lesions in the right lobe, which were resected along with the primary tumor. The other patient had involvement of both hepatic lobules and surgery was limited to the primary tumor.

Histological study revealed six pathological complete remissions (15%), microscopic foci in 15 cases (37%), tumor confined to the bowel wall in 17 cases (41%) and infiltration in all layers, including the perirectal fat in three cases (7%). Post-surgical stage was stage pCR in six patients (15%), pT1N0 in 12 (29%), pT2N0 in six (15%), pT3N0 in five (12%), pT4N0 in three (7%), pT3N1-2 in four (10%), pT4N1-2 in three (7%) and pT3NiMi in two (5%).

Tumor downstaging was determined by comparing pretreatment TN stage (as defined by clinical, radiographic and ultrasound staging) and the pathological stage. Tumor downstaging was observed in 25 patients (61%; 95% CI 45% to 76%). In three patients the tumor shrank but the N stage remained the same. Table 2 shows the stage at diagnosis and after surgery. One of the patients with liver involvement at diagnosis had a radiological complete response that was not confirmed at surgery; the other patient with liver disease had stable disease.


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Table 2. Stage evolution after neoadjuvant therapy
 
The first 16 patients received UFT 350 mg/m2/day and toxicity was as follows: grade 3 diarrhea in six patients (37%), grade 4 diarrhea plus grade 3 nausea/vomiting in one (6%), grade 3 dermatitis in two (12%), grade 1–2 dermatitis in six (36%), grade 1–2 cystitis in five (31%) and grade 1–2 proctitis in two (12%) (Table 3). After the dose was reduced to 300 mg/m2, the incidence of diarrhea dropped to 14%. RT was stopped more than once in three patients (7%), all of which were in the UFT 350 mg/m2/day group. As a whole, 93% of patients received full doses of RT.


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Table 3. Toxicity by patients, preoperative treatment
 
Due to the high incidence of gastrointestinal toxicity, the dose of UFT was reduced to 300 mg/m2/day in the next 25 patients. In this group, three patients (12%) experienced grade 3 diarrhea. Other grade 1–2 side effects in this second group were diarrhea in four patients (16%), nausea/vomiting in two (8%), stomatitis in one (4%), thrombocytopenia in two (8%), anemia in one (4%), cystitis in three (12%), dermatitis in four (16%) and proctitis in one (4%).

After surgery, one patient declined to receive adjuvant CT and the others received six courses. A total of 232 courses were delivered in the adjuvant setting, a median of 5.8 per patient. Two patients (5%) had grade 3–4 nausea/vomiting and three (8%) had grade 3–4 diarrhea (Table 4).


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Table 4. Toxicity, postsurgical treatment
 
Treatment sequelae were as follows. Four patients (10%) had an anastomotic leakage and three of them needed a transitory colostomy; in the fourth patient the partial disruption of the anastomosis healed with conservative therapy. Three patients (10%) had an abscess after surgery. Finally, another patient (2%) had urinary incontinence due to chronic actinic cystitis.

Twenty-six patients were evaluable for sphincter function outcome. It was scored as excellent in 17 (65%), good in six (23%), fair in two (8%) and poor in one (4%). Two patients developed a rectal stenosis (8%).

The median follow-up was 37 months (range 10–62). Local relapse (none without distant metastases) occurred in three patients (8%) and distant relapse in two (5%). The 3-year actuarial disease-free survival was 83%. Two local relapses took place in patients with incomplete resection 5 and 6 months after surgery. The third local relapse occurred 35 months after surgery. Relapse was confirmed in all cases by computed tomography-guided cytology. Two of these patients with a local failure were re-operated by pelvic exanteration: one relapsed 8 months later and the other remains disease free at 12 months. Another patient had a second adenocarcinoma in the transverse colon, 18 months after the first diagnosis. The rate of local control was 92% [38/41]. Overall 3-year survival was 90%. Four patients have died so far, two due to disease progression after a local relapse, one due to progression of liver disease after an initial response and the other one because of a stroke 7 months after surgery.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Primary excision as the only therapy for rectal adenocarcinoma is associated with a high rate of relapse, the development of distant metastases and morbidity associated to abdominal perineal amputation. Adjuvant treatment decreases the rates of local and distant relapse in patients with rectal wall invasion or lymphatic spread. Neoadjuvant therapy should attain these objectives and decrease the number of amputations.

Because the standard schedule of preoperative radiochemotherapy for rectal cancer remains to be established, and due to the convenience of oral prodrugs of 5-FU, we evaluated the activity of UFT, LV and preoperative radiotherapy in patients with stage II–III rectal cancer.

Our results show that preoperative treatment achieves tumor downstaging in 61% of patients. The pathological remission rate (pT0) was 15%, the postoperative local failure 8%, the rate of distant failure 5% and the 3-year overall survival rate 90%. The percentage of sphincter-preserving procedures was also increased from an initial estimation of 39% to 63% after preoperative treatment. Similar results, i.e. downstaging in 60% [24] and histological complete responses in 9% to 27% of patients [6, 2428] have been reported with 5-FU given either as continuous infusion or modulated by LV. Likewise, the reported 3-year survival with these schemes ranged from 88% to 100% [6, 21, 28], whereas the local relapse rate varied from 4% to 8% [21, 27], which is similar to our results.

The reported rates of sphincter preservation in phase II trials have varied from 17% to 89% [21, 22, 25, 2732]. This difference is striking considering that the rates of tumor downstaging and histological complete response are similar among trials. However, these differences in the rate of sphincter preservation may be attributed to the inclusion of patients with early stage disease (T1–2N0), in whom the rate of complete response rises to 27% to 29% [21, 32], the proportion of patients with tumors within 6 cm of the anal margin, the variability in each surgeon’s criteria concerning whether to perform sphincter preservation and the interval between preoperative radiation therapy and surgery (a long interval, 6 to 8 weeks, increases tumor downstaging) [33]. The results of the phase III trial National Surgical Adjuvant Breast and Bowel Project (NSABP) R03, which compared preoperative versus postoperative RT and CT in 267 patients, yielded less optimistic results. It was concluded that preoperative treatment increased the rate of sphincter-preserving procedures by 10% (44% versus 34%), but at the cost of increased serious toxicity (34% versus 23%) and increased early deaths (10% versus 6%) [26]. As a consequence, this issue will remain unresolved until the results of ongoing phase III trials become available.

On the other hand, sphincter-preserving procedures should result in adequate function of the sphincter without compromising the rates of local and distant relapse and the rate of surgical complications. In our series, 87% of evaluable patients achieved good to excellent function, similar to the 71% to 100% rates reported elsewhere [2831]. Eight percent of patients suffered a pelvic recurrence at 3 years, either alone or as a component of disseminated disease, which lies within the range of 4% to 10% found by others with preoperative therapy [21, 2729, 32] or the range of 9% to 13% obtained with surgery followed by adjuvant chemoradiation [34]. The 3-year disease-free and overall survival (83% and 90%, respectively) did not differ from other studies [6, 21, 2729]

One of the major concerns about neoadjuvant treatment is that toxicity might counterbalance the theoretical advantages [26]. The percentage of patients developing grade 3–4 side effects depends on the scheme and varies from 5% to 39% [6, 2629, 31, 32, 35]. In our series, 43% of patients receiving UFT 350 mg/m2 suffered grade 3–4 gastrointestinal toxicity. Three patients in this group (7%) required more than one interruption in their course of RT. After the dose was reduced to 300 mg/m2, the percentage of grade 3–4 toxicity dropped to 14%. We had previously used the same scheme with UFT 350 mg/m2 as adjuvant therapy along with RT, and only 21% of patients experienced grade 3–4 toxicity [17]. The reason for the greater toxicity with neoadjuvant therapy may be that an intact bowel vascularization allows the arrival of higher doses of the drug and thus increases its biological effects.

Chemotherapy not only may add toxicity, but also carries with it patient hospitalization for several days or the use of an infusion pump, depending on the schedule. In this regard, oral CT may be more convenient for the patient. Some investigators have assessed the efficacy of UFT modulated by LV in the neoadjuvant treatment of locally advanced [36, 37] or inoperable rectal cancer [38]. In these studies, the daily dose of UFT ranged from 300 to 350 mg/m2/day, but unlike our study, UFT was given from Monday through Friday for five consecutive weeks, and the initial intravenous LV was not administered. Although both studies of neoadjuvant therapy were phase I trials and included a limited number of patients, downstaging in >50% of patients was reported [36], as well as a 21% rate of pathological complete responses [37]. These preliminary results are very similar to those of our phase II study. In another study, RT with UFT alone achieved downstaging in 65% of patients and a pathological complete response in 8% [39]. Phase I studies are also evaluating capecitabine plus RT [40, 41]. In summary, there is considerable interest for oral fluoropyrimidines in the neoadjuvant treatment of rectal cancer, but results are still very limited, and the advantage of any of these compounds over others has yet to be established.

Finally, there is also some concern that preoperative treatment might increase the rate of surgical complications. In our series, 10.5% of patients had an anastomotic leakage and 8% an abscess. This is not superior to what may be expected without neoadjuvant treatment. Both the results of retrospective studies [42] and NSABP-R03 [26] show that this rate does not increase. In fact, the NSABP comparative study found surgical complications in up to one-third of patients, irrespective of whether they had received neoadjuvant treatment or not [26].

In summary, the present study suggests that preoperative RT in combination with UFT-6SLV downstages rectal carcinoma before surgery and increases the likelihood of being able to perform a sphincter-saving procedure. The scheme is moderately toxic and very convenient because of the oral administration of CT. Randomized trial are needed to compare this strategy with classical adjuvant treatment.


    Footnotes
 
+ Correspondence to: Dr J. Feliu, Servicio de Oncología Médica, Hospital La Paz, Po de la Castellana, 261-28046, Madrid, Spain. Tel/Fax: +34-91-727-71-18; E-mail: jaimefeliu@hotmail.com Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Kapiteijn E, van de Velde CJ. European trials with total mesorectal excision. Semin Surg Oncol 2000; 19: 350–357.[ISI][Medline]

2. National Institutes of Health Consensus Conference. Adjuvant therapy for patients with colon and rectal cancer. J Am Med Assoc 1990; 264: 1444–1450.[ISI][Medline]

3. Willet CG, Haller D, Steele G. Controversies in the management of localized rectal cancer. Educational Book. Am Soc Clin Oncol 1999; 212–221.

4. Meade PG, Blatchford GJ, Thorson AG et al. Preoperative chemoradiation downstages locally advanced ultrasound-staged rectal cancer. Am J Surg 1995; 170: 609–612.[ISI][Medline]

5. Ohno S, Tomoda M, Tomisaki S et al. Improved surgical results after combining preoperative hyperthermia with chemotherapy and radiotherapy for patients with carcinoma of the rectum. Dis Colon Rectum 1997; 40: 401–406.[ISI][Medline]

6. Grann A, Minsky BD, Cohen AM et al. Preliminary results of preoperative 5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for clinically resectable T3 rectal cancer. Dis Colon Rectum 1997; 40: 515–522.[ISI][Medline]

7. Minsky BD, Coia L, Haller D et al. Treatment systems guidelines for primary rectal cancer from the 1996 patterns of care study. Int J Radiat Oncol Biol Phys 1998; 41: 21–27.[ISI][Medline]

8. Liu G, Franssen E, Fitch MI et al. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997; 15: 110–115.[Abstract]

9. Borner M, Schsffski P, de Wit R. A randomized crossover trial comparing oral UFT (uracil/tegafur) + leucovorin (LV) and intravenous fluorouracil (FU) + LV for patient preference and pharmacokinetics in advanced colorectal cancer. Proc Am Soc Clin Oncol 2000; 19: 191 (Abstr 741).

10. Ho H, Pazdur R, Covington W et al. Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2'-tetrahydrofuryl)-5-fluorouracil. Clin Cancer Res 1998; 4: 2085–2088.[Abstract]

11. Evans RM, Laskin JD, Hakala MT. Effect of excess folates and de-oxynosine on the activity and site of action of 5-fluorouracil. Cancer Res 1981; 41: 3288–3295.[ISI][Medline]

12. Trave F, Rustum YM, Petrelli NJ et al. Plasma and tumor tissue pharmacology of high-dose intravenous leucovorin in combintion with fluorouracil in patients with advanced colorectal cancer. J Clin Oncol 1988; 6: 1184–1191.[Abstract]

13. González-Barón M, Feliu J, Ordóñez A et al. Phase I study of UFT plus leucovorin in advanced colorectal cancer: a double modulation proposal. Anticancer Res 1993; 13: 759–762.[ISI][Medline]

14. González Barón M, Feliu J, de la Gándara I et al. Efficacy of oral tegafur modulation by uracil (UFT) and leucovorin in advanced colorectal cancer: a phase II study. Eur J Cancer 1995; 31: 2215–2219.

15. Feliu J, González Barón M, Espinosa E et al. Uracil and tegafur modulated with leucovorin. An effective regimen with low toxicity for the treatment of colorectal carcinoma in the elderly. Cancer 1997; 79: 1884–1889.[ISI][Medline]

16. González-Barón M, Espinosa E, Feliu J et al. UFT-LV as adjuvant therapy for Dukes’ B2-C colon cancer. GI Cancer 1999; 3: 31–37.[ISI]

17. Espinosa E, González-Barón M, Feliu J et al. Tegafur-uracilo con ácido folínico como tratamiento adyuvante del carcinoma rectal en estadios B2 y C. Neoplasia 1998; 15: 154–157.

18. International Union Against Cancer (UICC). TNM classification of malignant tumors. Hermaek P, Sobin LH (eds): 4th edition. Berlin, Heidelberg, New York, Tokyo: Springer-Verlag 1995.

19. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 42: 207–214.

20. John MJ. Grading of chemoradiation toxicity. In Yohn MJ, Flam MS, Legha S, Phillip ST (eds): Chemoradiation an Integrated Approach to Cancer Treatment. Philadelphia, PA: Lea and Febiger 1993; 601–606.

21. Rich TA, Skibber JM, Ajani JA et al. Preoperative infusional chemoradiation therapy for stage T3 rectal cancer. Int J Radiat Oncol Biol Phy 1995; 32: 1025–1029.[ISI][Medline]

22. Minsky BD, Cohen AM, Enker WE et al. Sphincter preservation with preoperative radiation therapy and coloanal anastomosis. Int J Radiat Oncol Biol Phys 1995; 31: 553–559.[ISI][Medline]

23. Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982; 38: 143–151.[ISI][Medline]

24. Janjan NA, Khoo VS, Abbruzzese J et al. Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M. D. Anderson Cancer Center experience. Int J Radiat Oncol Biol Phys 1999; 44: 1027–1038.[ISI][Medline]

25. Navarro M, Pérez F, Dotor EM et al. Preoperative chemoradiotherapy (CT-RDT) in locally advanced rectal cancer. Preliminary results. Proc Am Soc Clin Oncol 2000; 19: 313 (Abstr 1236).

26. Roh MS, Petrelli N, Wieand L et al. Phase III randomized trial of preoperative versus postoperative multimodality therapy in patients with carcinoma of the rectum (NSABP R-03). Proc Am Soc Clin Oncol 2001; 20: 123 (Abstr 490).

27. Bosset JF, Magnin V, Maingon P et al. Preoperative radiochemotherapy in rectal cancer: long-term results of a phase II trial. Int J Radiat Oncol Biol Phys 2000; 46: 323–327.[ISI][Medline]

28. Grann A, Feng C, Wong D et al. Pre-OP combined modality therapy (CMT) for uT3 rectal cancer. Proc Am Soc Clin Oncol 2000; 19: 249 (Abstr 967).

29. Valentini V, Coco C, Cellini N et al. Preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation. Int J Radiat Oncol Biol Phys 1998; 40: 1067–1075.[ISI][Medline]

30. Wagman R, Minisky BD, Cohen AM et al. Sphincter preservation in rectal cancer with preoperative radiation therapy and coloanal anastomosis: long term follow-up. Int J Radiat Oncol Biol Phys 1998; 42: 51–57.[ISI][Medline]

31. Valentini V, Coco C, Cellini N et al. Preoperative chemoradiation with cisplatin and 5-fluorouracil for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, sphincter preservation. Int J Radiat Oncol Biol Phys 1999; 45: 1175–1184.[ISI][Medline]

32. Chari RS, Tyler DS, Anscher MS et al. Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum. Ann Surg 1995; 221: 778–787.[ISI][Medline]

33. Francois Y, Nemoz CJ, Baulieux J et al. Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial. J Clin Oncol 1999; 17: 2396.[Abstract/Free Full Text]

34. Tepper JE, O’Connell MJ, Petroni GR et al. Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation for rectal cancer: initial results of Intergroup 0114. J Clin Oncol 1997; 15: 2030–2039.[Abstract]

35. Stryker SJ, Kiel KD, Rademaker A et al. Preoperative ‘chemoradiation’ for stages II and III rectal carcinoma. Ann Surg 1996; 131: 514–519.

36. Pfeiffer P. Concurrent UFT/L-Leucovorin and curative intented radiotherapy (60 Gy) in patients with locally advanced rectal cancer (LARC): a phase I/II trial. Proc Am Soc Clin Oncol 2000: 255 (Abstr 992).

37. Hoff PM, Janjan N, Saad ED et al. Phase I study of preoperative oral uracil and tegafur plus leucovorin and radiation therapy in rectal cancer. J Clin Oncol 2000; 18: 3529–3534.[Abstract/Free Full Text]

38. Torre A, Ramos S, Valcárcel FJ et al. Phase II study of radiochemotherapy with UFT and low-dose oral leucovorin in patients with unresectable rectal cancer. Int J Radiat Oncol Biol Phys 1999; 45: 629–634.[ISI][Medline]

39. Fernández-Martos C, Aparicio C, Bosch D et al. Pre-operative therapy (PT) with oral uracil and tegafur (UFT) and concomitant irradiation (RT) in operable rectal cancer (RC). Preliminary results of a multicenter phase II study. Proc Am Soc Clin Oncol 2001; 20: 148 (Abstr 590).

40. Ngan S, Zalckberg J, Kell A et al. A phase I study of capecitabine combined with radiotherapy for locally advanced potentially operable rectal cancer. Proc Am Soc Clin Oncol 2001; 20: 149 (Abstr 591).

41. Dunst J, Reese T, Frings S et al. Phase I study of capecitabine with simultaneous radiotherapy rectal cancer. Proc Am Soc Clin Oncol 2001; 20: 149 (Abstr 592).

42. Pucciarelli S, Toppan P, Friso ML et al. Preoperative combined radiotherapy and chemotherapy for rectal cancer does not affect early postoperative morbidity and mortality in low anterior resection. Dis Colon Rectum 1999; 42: 1276–1284.[ISI][Medline]