Phase I Trial of Neoadjuvant Preoperative Chemotherapy With S-1 and Irinotecan Plus Radiation in Patients With Locally Advanced Rectal Cancer

Int. J. Radiation Oncology Biol. Phys., Vol. 69, No. 5, pp. 1442–1447, 2007 Copyright Ó 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter

doi:10.1016/j.ijrobp.2007.05.081

CLINICAL INVESTIGATION

Rectum

PHASE I TRIAL OF NEOADJUVANT PREOPERATIVE CHEMOTHERAPY WITH S-1 AND IRINOTECAN PLUS RADIATION IN PATIENTS WITH LOCALLY ADVANCED RECTAL CANCER TAKEO SATO, M.D.,* YUKIHITO KOKUBA, PH.D.,* WASABURO KOIZUMI, PH.D.,y KAZUSHIGE HAYAKAWA, PH.D.,z ISAO OKAYASU, PH.D.,x AND MASAHIKO WATANABE, PH.D.* Departments of *Surgery, y Internal Medicine, z Radiology, and x Pathology, Kitasato University School of Medicine, Kanagawa, Japan Purpose: To determine the maximum tolerated dose (MTD) and recommended dose (RD) of irinotecan combined with preoperative chemoradiotherapy with S-1 in patients with locally advanced rectal cancer. Patients and Methods: We gave preoperative radiotherapy (total dose, 45 Gy) to 23 patients with locally advanced (T3/T4) rectal cancer. Concurrently, S-1 was given orally at a fixed dose of 80 mg/m2/day on Days 1–5, 8–12, 22–26, and 29–33, and irinotecan was given as a 90-min continuous i.v. infusion on Days 1, 8, 22, and 29. The dose of irinotecan was initially 40 mg/m2/day and gradually increased to determine the MTD and RD of this regimen. Results: Among the 4 patients who received 90 mg/m2 irinotecan, 2 had Grade 4 neutropenia and 1 had Grade 3 diarrhea. Because dose-limiting toxicity (DLT) occurred in 3 of the 4 patients, 90 mg/m2 irinotecan was designated as the MTD. Consequently, 80 mg/m2 irinotecan was given to 7 additional patients, with no DLT, and this was considered the RD. Of the patients who received irinotecan at the RD or lower doses, 6 (31.6%) had a complete pathologic response (Grade 3) and 9 (47.4%) underwent sphincter-preserving surgery. Conclusions: With our new regimen, the MTD of irinotecan was 90 mg/m2, and the RD of irinotecan for Phase II studies was 80 mg/m2. Although our results are preliminary, this new neoadjuvant chemoradiotherapy was considered safe and active, meriting further investigation in Phase II studies. Ó 2007 Elsevier Inc. Neoadjuvant chemoradiotherapy, S-1, Irinotecan, Rectal cancer.

cases. The German Intergroup trial (3) comparing preoperative with postoperative chemoradiotherapy recently reported that the former does not improve overall survival but enhances local control and reduces toxicity. Furthermore, because preoperative chemoradiotherapy may increase the rate of anal sphincter preservation, this approach continues to be actively studied, mainly in Europe and North America. Because it was believed that the rate of local recurrence after surgery alone is lower in Japan than in Western countries, large Japanese clinical trials of regimens including adjuvant radiotherapy are scarce. On the other hand, improvements in local control and survival beyond current levels are unlikely to be achieved with surgery and postoperative adjuvant chemotherapy alone. We, therefore, believe that studies of preoperative chemoradiotherapy are needed. S-1 is a novel oral fluoropyrimidine, combining tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate at a molar ratio of 1:0.4:1. Tegafur is a prodrug of 5fluorouracil (5-FU) that acts as an effector. 5-Chloro-2,

INTRODUCTION Colorectal cancer is the fourth leading cause of cancer-related deaths worldwide (1). In Japan, the incidence of colorectal cancer is rising year by year. Approximately 92,000 colorectal cancer patients were diagnosed in Japan in 2000, following gastric cancer, according to the estimates of the Japan Cancer Surveillance Research Group (2). The prevention, early diagnosis, and development of new therapies for colorectal cancer have thus become an important international concern. Postoperative adjuvant chemotherapy is recognized as a standard treatment for colon cancer. In locally advanced rectal cancer, however, standard therapy remains to be established. Treatments for advanced rectal cancer that can control local recurrence and improve overall survival are urgently needed. Total mesorectectomy reduces the rate of local recurrence and is internationally considered as a potential standard treatment. The addition of preoperative radiation to total mesorectectomy has further enhanced local control in resectable

Acknowledgment—The authors thank Prof. J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript. Received March 29, 2007, and in revised form May 7, 2007. Accepted for publication May 8, 2007.

Reprint requests to: Masahiko Watanabe, M.D., Ph.D., Department of Surgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan. Tel: (+81) 42778-8735; Fax: (+81) 42-778-8735; E-mail: [email protected] Conflict of interest: none. 1442

Radiation with S-1 and irinotecan in rectal cancer d T. SATO et al.

4-dihydroxypyridine reversibly inhibits the degradation of 5-FU by dihydropyrimidine dehydrogenase, resulting in prolonged high concentrations of 5-FU in blood, thereby enhancing the antitumor activity of tegafur. Japanese pharmacokinetic studies have shown that the area under the time-plasma-concentration curve for 5-FU in patients orally given 80 mg/m2/day of S-1 is 1.9-fold greater than that in patients given 250 mg/m2/day of 5-FU by protracted venous infusion (4). Potassium oxonate is selectively distributed to the gastrointestinal tract, where high concentrations inhibit orotate phosphoribosyltransferase, which phosphorylates 5-FU to an active metabolite in humans. Inhibition of this enzyme reduces gastrointestinal toxicity. Two recent Phase II studies of S-1 in Japanese patients with metastatic colorectal carcinoma showed high response rates of 35% and 39.5%, respectively (5, 6). Irinotecan (CPT-11) in combination with a bolus or infusional fluoropyrimidine derivative has become a standard first-line treatment for metastatic colorectal cancer (7, 8). Several trials have evaluated a combination of irinotecan and infusional 5-FU plus radiotherapy in patients with rectal cancer (9–12). Promising pathologic complete remission rates of 21% to 37% were reported. We have developed a new regimen for neoadjuvant chemoradiotherapy that combines the oral fluoropyrimidine derivative S-1 with irinotecan and irradiation. This clinical Phase I trial was conducted to determine the maximum tolerated dose (MTD) and recommended dose (RD) of irinotecan in combination with S-1 and radiation. We also evaluated pathologic response rates. PATIENTS AND METHODS This study was performed according to the guidelines of the Declaration of Helsinki, as amended in Edinburgh, Scotland in October 2000. The protocol was approved by the Institutional Review Board of Kitasato University Hospital. All patients gave written informed consent before study entry.

Eligibility criteria Eligible patients had previously untreated T3 or T4 and N0–N3 and M0 locally advanced rectal cancer, histopathologically confirmed before surgery, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Other eligibility criteria were as follows: age 20–80 years (completed years) at enrollment; no severe disturbance of main organ functions (including bone marrow, heart, lung, liver, and kidney) or blood biochemistry (leukocyte count, 4000–12,000/mm3; neutrophil count, $2000/mm3; platelet count, $100  103/mL; hemoglobin concentration, $9.0 g/dL; total bilirubin concentration, #1.5 mg/dL; serum aspartate aminotransferase and alanine aminotransferase levels, less than twice the upper limit of normal at our hospital; serum creatinine concentration, less than the upper limit of the normal at the hospital; and normal electrocardiographic findings); and the ability to ingest solid foods and drugs orally.

Treatment Radiotherapy was administered in fractions of 1.8 Gy/day, given 5 days per week for 5 weeks. The total dose of radiation was 45 Gy.

1443

Patients were treated in the prone position using a dedicated device to minimize exposure of the small bowel. A 1-cm circumference around the rectum was treated with radiation from a 10-MV linear accelerator. Two parallel opposed lateral fields were used (total, 40 mV). A computed tomography–based treatment-planning system was mandatory to define the planning target volume (clinical target volume plus >1-cm margin; Fig. 1). S-1 (80 mg/m2/day) was given orally after breakfast and dinner on Days 1–5, 8–12, 22–26, and 29– 33. Irinotecan was given as a continuous i.v. infusion for 90 min on Days 1, 8, 22, and 29. The initial dose of irinotecan was 40 mg/m2 (Level 1), given to 3 patients. The dose was increased in a stepwise fashion, and 3 other patients received the next dose level until the MTD was reached (Table 1). Radical surgery was performed at least 4–6 weeks after the completion of 5 weeks of chemoradiotherapy. Total mesorectectomy with bilateral autonomic nerve preservation was performed. Tissue samples were bilaterally obtained from the middle rectal, internal iliac, and obturator lymph nodes. For sphincter-preserving surgery, the anorectal side of the rectum was divided, leaving a margin of $2 cm from the inferior border of the tumor. Abdominoperineal resection was done if the distal margin was insufficient.

Dose-limiting toxicity Drug-related adverse events were classified according to the Common Toxicity Criteria of the National Cancer Institute, version 2 (April 30, 1999). Dose-limiting toxicity (DLT) was defined as Grade 4 hematologic toxicity, fever (body temperature $38 C) with Grade 3 neutropenia, Grade 3 or higher thrombocytopenia, or Grade 3 or higher nonhematologic toxicity. Dose-limiting toxicity was considered to have occurred if S-1 was given on less than two thirds of the days specified in the protocol (13 days or less), if irinotecan was not given on Days 8, 22, and 29, or if radiotherapy was stopped for 1 week or more. Dose-limiting toxicity was evaluated on the basis of adverse events occurring within 1 week after the completion of chemoradiotherapy.

Dose-escalation scheme The MTD was defined as the dose level that produced DLT in at least 3 of 6 patients. If DLT occurred in 1 or 2 of the first 3 patients, 3 additional patients were assigned to receive the same dose level. If none of the 3 patients initially receiving a given dose level had DLT or if 1 or 2 of 6 patients had DLT, the dose was increased to the next level. Dose escalation was not allowed in the same patient. The dose level immediately below the MTD was considered the RD for Phase II studies. Additional patients were assigned to receive the RD until a total of 10 was reached.

Patients and tumor evaluation Before enrollment in the study, we reviewed the histories of past and present disease and the general condition of all patients, assessed on the basis of interview, physical examination, and blood tests. Locally advanced rectal cancer (T3 or T4) without distant metastasis was confirmed by barium-enema examination, colonoscopic examination including histopathologic evaluation, computed tomographic scans of the chest, abdomen, and pelvis, and magnetic resonance imaging of the pelvis. Regarding pretreatment T-staging, we used magnetic resonance imaging. Because radical surgery was performed after chemoradiotherapy, the protocol did not require confirmation of the duration of response (i.e., 4 weeks) to preoperative chemoradiotherapy. The pathologic response was evaluated after surgery according to the

I. J. Radiation Oncology d Biology d Physics

1444

Volume 69, Number 5, 2007

Fig. 1. Treatment field of the radiotherapy.

Histopathological Response Criteria (Table 2) of the General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus (Japanese Society for Cancer of the Colon and Rectum). The pathologic response to preoperative chemoradiotherapy was evaluated on the basis of the degrees of tumor degeneration, necrosis, and fusion and was rated according to a 4-grade scale, ranging from Grade 0 (no response) to Grade 3 (complete response) (13). The rate of complete resection (R0) was calculated on the basis of the histopathologic evaluations.

and 1 had Grade 1 anorexia. At Level 2 (60 mg/m2 of irinotecan), 2 had Grade 2 diarrhea, which responded to conservative treatment. At Level 3 (70 mg/m2 of irinotecan), 1 patient had Grade 3 neutropenia and another had Grade 2 diarrhea. Both patients responded to conservative therapy, and Table 2. Criteria used to evaluate histopathologic response Grade

Evaluation

RESULTS

0

No response

Patient characteristics From August 2004 through August 2005, 23 patients treated at our hospital were enrolled in the study. Table 3 shows their clinical characteristics. All patients had an ECOG performance status of 0.

1

a. Extremely slight response b. Slight response

DLT and RD level Acute toxicities observed are listed in Table 4. At Level 1 (40 mg/m2 of irinotecan), 1 patient had Grade 2 neutropenia 2

Considerable response

3

Complete response

Table 1. Planned dose escalation schedule of irinotecan Level 1 2 3 4 5 6

Irinotecan 90 min i.v. on Days 1, 8, 22, and 29 40 mg/m2 60 mg/m2 70 mg/m2 80 mg/m2 90 mg/m2 100 mg/m2

Histopathologic findings Virtually no treatmentinduced disturbances of cancer tissue or cells, such as degeneration or necrosis Degradation or necrosis and fusion of cancer cells in approximately less than one third of tumor Degradation or necrosis and fusion of cancer cells in approximately one third to less than two thirds of tumor Marked degradation or necrosis and fusion of cancer cells in at least two thirds of tumor Necrosis of entire tumor, or replacement of tumors undergoing fusion and disappearance by granulation tissue or fibrotic tissue

Grades 1 and 2 were differentiated primarily on the basis of quantitative differences in the region showing changes.

Radiation with S-1 and irinotecan in rectal cancer d T. SATO et al.

Table 3. Patient characteristics Age (y) Median Range Gender Male Female Carcinoembryonic antigen (ng/mL) (upper limit of normal, 5.0 ng/mL) Median Range Tumor site Ra Rab Rb

1445

Pathological findings Tumor stage and grade were classified according to the tumor-node-metastasis classification of the International Union Against Cancer (Table 5). Of the 19 patients who received the RD or lower doses, 14 had stage T3 rectal cancer, 4 had T4 rectal cancer, and 12 had suspected regional lymph node metastases before the start of chemoradiotherapy. The mean number of lymph nodes examined on sphincterpreserving surgery or abdominoperineal resection was 29 (range, 12–52). Of the 19 patients given the RD or lower doses, 8 had lymph node metastases (6 pN1, 2 pN2). Of the 7 patients in whom primary lesions disappeared, 1 had regional (pN1) lymph node metastasis. Finally, 6 had a complete pathologic response, and 12 had a partial pathologic response. The response rate was 94.7%; the pathologic complete response (pCR) rate was 31.6%. The final rate of complete resection (R0) was 100%.

61 37–80 18 (78.3) 5 (21.7) 4 0.6–58.4 5 (21.7) 7 (30.4) 11 (47.8)

Abbreviations: Ra = rectum above the peritoneal reflection; Rb = rectum below the peritoneal reflection; Rab = tumor spreading on the both Ra and Rb. Values are number (percentage), unless otherwise noted.

DISCUSSION

treatment was completed according to protocol. At Level 4 (80 mg/m2 of irinotecan), Grade 1 neutropenia occurred in 1 patient but resolved spontaneously. Of the 4 patients who received Level 5 (irinotecan 90 mg/m2), 2 had Grade 4 neutropenia and 1 had Grade 3 diarrhea. Level 5 (irinotecan 90 mg/m2) was therefore designated the MTD. Seven additional patients were given Level 4 (irinotecan 80 mg/m2), considered the RD. Although 2 of these 7 patients had Grade 1 and Grade 2 diarrhea, respectively, there was no other hematologic toxicity in these 7 patients. Therefore, Level 4 (80 mg/ m2 of irinotecan) was confirmed as the RD for our regimen.

This Phase I study of our regimen for chemoradiotherapy, combining S-1 and irinotecan chemotherapy with local radiation, was safely completed. The MTD was determined to be 90 mg/m2 of irinotecan on the basis of neutropenia in 2 patients and diarrhea in 1. At the RD (80 mg/m2 irinotecan) or lower levels, there were no serious adverse events. Patients given the RD or lower levels had a pCR rate of 31.6% (6 of 19). As compared with conventional preoperative chemoradiotherapy used to treat locally advanced rectal cancer, our regimen seems to be very promising, although the efficacy was not a primary objective in this small Phase I study. Sauer et al. (3) reported that preoperative chemoradiotherapy did not contribute to improved survival but decreased the rates of toxicity and local recurrence, as compared with postoperative chemoradiotherapy. A higher pCR rate may decrease the rate of local recurrence, as well as improve survival (14). Therefore, our study suggests that our regimen has the potential to improve survival. Preoperative chemoradiotherapy may enable more patients to undergo sphincterpreserving surgery. Our regimen for chemoradiotherapy seemed to promote tumor shrinkage (‘‘downsizing’’); sphincter-preserving surgery could be performed in 9 patients (31.6%) who would have otherwise required abdominoperineal resection.

Postoperative complications The postoperative complications were wound infections in 2 (10.5%) and ileus in 2 (10.5%) of the 19 patients who received the RD or lower doses of irinotecan. There were no other serious postoperative complications. Operation Of the 19 patients given the RD or lower doses of irinotecan, sphincter-preserving surgery was performed in 9 (47.4%) and abdominoperineal resection in 10 (52.6%). A diverting ileostomy was created in all patients who underwent sphincter-preserving surgery. At the patients’ request, surgery was not performed in 2 of the patients given Level 5.

Table 4. Acute toxicity of chemoradiotherapy Dose level 1 (n = 3) Toxicity Hematologic Neutropenia Nonhematologic Anorexia Diarrhea

2 (n = 3)

3 (n = 3)

4 (n = 10)

5 (n = 4)

G1*

G2

G3

G4

G1

G2

G3

G4

G1

G2

G3

G4

G1

G2

G3

G4

G1

G2

G3

G4

0

1

0

0

0

0

0

0

0

0

1

0

1

0

0

0

0

0

0

2

1 0

0 0

0 0

0 0

0 0

0 2

0 0

0 0

0 0

0 1

0 0

0 0

0 1

0 1

0 0

0 0

0 0

0 0

0 1

0 0

* Toxicity grade (G) according to the National Cancer Institute Common Toxicity Criteria, version 2.

I. J. Radiation Oncology d Biology d Physics

1446

Volume 69, Number 5, 2007

Table 5. Response to chemoradiotherapy Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Level

CPT-11 (mg/m2)

Primary (T)*

L/N metastasis suspected*

Method

Primary tumor pathology

IMA area pN

IIA area pN

Remnant tumor (R)

1 1 1 2 2 2 3 3 3 4 4 4 4 4 4 4 4 4 4 5 5 5 5

40 40 40 60 60 60 70 70 70 80 80 80 80 80 80 80 80 80 80 90 90 90 90

3 3 3 3 4 4 3 3 3 3 3 3 3 4 4 3 3 3 3 4 3 3 3

1 0 0 0 0 1 1 1 1 0 1 1 1 1 0 0 1 1 1 0 0 0 1

APR APR APR APR SLAR APR SLAR SLAR SLAR APR APR APR SLAR SLAR APR APR SLAR SLAR SLAR APR — — SLAR

Grade 2 Grade 3 Grade 3 Grade 3 Grade 2 Grade 3 Grade 2 Grade 3 Grade 2 Grade 3 Grade 2 Grade 2 Grade 2 Grade 2 Grade 3 Grade 2 Grade 1b Grade 2 Grade 2 Grade 3 — — Grade 2

0/28 0/13 0/16 0/12 0/9 1/12 3/23 0/2 0/10 0/25 4/14 1/18 0/12 2/11 0/10 0/25 2/6 1/13 3/8 0/22 — — 0/6

0/24 0/7 0/13 0/28 0/7 0/0 0/7 0/20 0/12 0/19 1/13 0/12 0/18 0/10 0/12 0/21 0/21 0/16 2/23 0/9 — — 0/6

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 — — 0

Abbreviations: L/N = lymph node; IMA = inferior mesenteric artery; IIA = internal iliac artery; APR: abdominoperineal resection; SLAR = stapled low anterior resection. * According to the pretreatment evaluations.

Several studies have reported outcomes of preoperative chemoradiotherapy with irinotecan and fluoropyrimidine derivatives. Mitchell et al. (10) evaluated radiotherapy plus concurrent chemotherapy with 5-FU, leucovorin, and irinotecan in patients with locally advanced or recurrent rectal cancer. That study reported a pCR rate of 26%. Mehta et al. (9) obtained a pCR rate of 37% with a similar regimen for chemoradiotherapy. These results should be confirmed in further studies. Our preliminary results suggest that the pCR rate for preoperative chemoradiotherapy with S-1 and irinotecan is similar to the rates obtained in previous studies. Experimental studies have shown that irinotecan decreases thymidylate synthase (TS) mRNA levels (15) and prolongs TS inhibition (16). Thymidylate synthase levels positively correlate with topoisomerase-1 levels, and the antitumor activity of irinotecan against gastric cancer is apparently unrelated to TS expression (17, 18). These findings suggest that 5-FU derivatives, which inhibit TS, and irinotecan, which inhibits topoisomerase-1, have completely different mechanisms of action. These distinct modes of action may underlie the high effectiveness of chemoradiotherapy with S-1 plus irinotecan. In two Phase II trials of S-1 in previously untreated Japanese patients with metastatic colorectal cancer, response rates, assessed according to site of the primary tumor, were 36.8% (7 of 19) and 33.3% (5 of 15) for colorectal cancer and 50% and 30% for lymph node metastasis, respectively (5, 6). The incidences of Grade 3 or higher diarrhea were extremely low (1.6% and 2.6%, respectively). This low inci-

dence of severe gastrointestinal toxicity is attributed to the presence of potassium oxonate in S-1 (19) in addition to the field design, which irradiates much less small bowel than traditional field designs (Fig. 1). These findings suggested that S-1 is suited for preoperative chemoradiotherapy in patients with rectal cancer. Furthermore, recent preclinical studies have shown that 5-chloro-2,4-dihydroxypyridine in S-1 inhibits dihydropyrimidine dehydrogenase and markedly increases the radiosensitivity of tumors (20). These features of S-1 may contribute to the good tolerance and high pCR rates with our regimen for chemoradiotherapy. However, our results remain preliminary and must be confirmed in further studies. Borner et al. (21) compared oral chemotherapy with tegafur, uracil, and leucovorin with i.v. chemotherapy with 5-FU and leucovorin by a crossover design. They reported that 84% of the patients preferred oral chemotherapy with tegafur, uracil, and leucovorin to i.v. treatment. These results strongly suggest that oral drugs, such as S-1, are useful for improving the quality of life of patients. In patients who receive preoperative chemoradiotherapy for locally advanced rectal cancer, such as those in our study, oral drugs also have the advantage of a lower risk of catheter-related problems, as well as greater convenience. In fact, patients who received preoperative chemoradiotherapy with our regimen, using S-1, had good compliance without compromising quality of life and were able to receive treatment according to the planned protocol. These results suggest that our regimen might enhance patients’ quality of life.

Radiation with S-1 and irinotecan in rectal cancer d T. SATO et al.

We conclude that chemotherapy with S-1 and irinotecan combined with local radiotherapy is safe and well tolerated in patients with locally advanced rectal cancer. The RD of this regimen was 80 mg/m2 of irinotecan on Days 1, 8, 22,

1447

and 29 combined with 80 mg/m2 of S-1 on days 1–5, 8–12, 22–26, and 29–33 plus concomitant radiotherapy. Phase II studies are under way to examine the efficacy and safety of our regimen in patients with locally advanced rectal cancer.

REFERENCES 1. Weitz J, Koch M, Debus J, et al. Colorectal cancer. Lancet 2005;365:153–165. 2. Marugame T, Kamo K, Katanoda K, et al. Cancer incidence and incidence rates in Japan in 2000: Estimates based on data from 11 population-based cancer registries. Jpn J Clin Oncol 2006; 36:668–675. 3. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731–1740. 4. Yamada Y, Hamaguchi T, Goto M, et al. Plasma concentrations of 5-fluorouracil and F-beta-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil. Br J Cancer 2003;89:816–820. 5. Ohtsu A, Baba H, Sakata Y, et al. Phase II study of S-1, a novel oral fluorophyrimidine derivative, in patients with metastatic colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study Group. Br J Cancer 2000;83:141–145. 6. Shirao K, Ohtsu A, Takada H, et al. Phase II study of oral S-1 for treatment of metastatic colorectal carcinoma. Cancer 2004;100: 2355–2361. 7. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 2000;355:1041–1047. 8. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343:905–914. 9. Mehta VK, Cho C, Ford JM, et al. Phase II trial of preoperative 3D conformal radiotherapy, protracted venous infusion 5-fluorouracil, and weekly CPT-11, followed by surgery for ultrasound-staged T3 rectal cancer. Int J Radiat Oncol Biol Phys 2003;55:132–137. 10. Mitchell EP, Winter K, Mohiuddin M, et al. Randomized phase II trial of preoperative combined modality chemoradiation for distal rectal cancer (Abstr. 3535). J Clin Oncol 2004;22:254. 11. Hofheinz RD, von Gerstenberg-Helldorf B, Wenz F, et al. Phase I trial of capecitabine and weekly irinotecan in combina-

12.

13. 14.

15. 16.

17. 18.

19.

20.

21.

tion with radiotherapy for neoadjuvant therapy of rectal cancer. J Clin Oncol 2005;23:1350–1357. Klautke G, Feyerherd P, Ludwig K, et al. Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer. Br J Cancer 2005;92:1215–1220. Japanese Society for Cancer of the Colon and Rectum. General rules for clinical and pathological studies on cancer of the colon, rectum, and anus. 6th ed. Tokyo: Kanehara & Co.; 1998. Sauer R, Roedel C, Martus P, et al. Prognostic factors after neoadjuvant radiochemotherapy for rectal cancer: Update of the CAO/ARO/AIO-94 phase III study (Abstr. 3503). J Clin Oncol 2005;23:246s. Que BG, Ardalan B, Richman S. Camptosar reduced the thymidylate synthase gene expression in 5-FU-resistant cell line (Abstr. 4763). Proc Am Assoc Cancer Res 2000;41:749. Guichard S, Hennebelle I, Bugat R, et al. Cellular interactions of 5-fluorouracil and the camptothecin analogue CPT-11 (irinotecan) in a human colorectal carcinoma cell line. Biochem Pharmacol 1998;55:667–676. Ichikawa W, Uetake H, Nihei Z, et al. Topoisomerase I expression correlates to thymidylate synthase expression in colorectal cancer (Abstr. 946). Proc Am Soc Clin Oncol 1999;17:946. Ichikawa W, Takahashi T, Suto K, et al. Thymidylate synthase predictive power is overcome by irinotecan combination therapy with S-1 for gastric cancer. Br J Cancer 2004;91: 1245–1250. Takechi T, Nakano K, Uchida J, et al. Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats. Cancer Chemother Pharmacol 1997;39:205–211. Fukushima M, Ohshimo H, Taguchi T. Combined therapy with radiation and S-1, an oral new 5-FU prodrug, is markedly effective against non-small cell lung cancer xenografts in mice. Eur J Cancer 2005;3:343. Borner MM, Schoffski P, de Wit R, et al. Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: A randomised crossover trial in advanced colorectal cancer. Eur J Cancer 2002;38:349–358.