- Email: [email protected]
leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 67, No. 2, pp. 378 –384, 2007 Copyright © 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter
doi:10.1016/j.ijrobp.2006.08.063
CLINICAL INVESTIGATION
Rectum
COMPARISON OF 5-FLUOROURACIL/LEUCOVORIN AND CAPECITABINE IN PREOPERATIVE CHEMORADIOTHERAPY FOR LOCALLY ADVANCED RECTAL CANCER DAE YONG KIM, M.D.,* KYUNG HAE JUNG, M.D.,* TAE HYUN KIM, M.D.,* DUCK-WOO KIM, M.D.,* HEE JIN CHANG, M.D.,* JUN YONG JEONG, M.D.,* YOUNG HOON KIM, M.D.,† SEOK-HYUN SON, M.D.,‡ TAK YUN, M.D.,* CHANG WON HONG, M.D.,* DAE KYUNG SOHN, M.D.,* SEOK-BYUNG LIM, M.D.,* HYO SEONG CHOI, M.D.,* SEUNG-YONG JEONG, M.D.,* AND JAE-GAHB PARK, M.D.* *Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea; †Department of Radiology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; ‡Department of Radiation Oncology, Kangnam St. Mary’s Hospital, Seoul, Republic of Korea Purpose: To describe our experience with a bolus injection of 5-fluorouracil and leucovorin (FL) vs. capecitabine in terms of radiologic and pathologic findings in preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. Methods: The study enrolled 278 patients scheduled for preoperative CRT using two protocols with different chemotherapeutic regimens. Pelvic radiotherapy (50.4 Gy) was delivered concurrently with FL (n ⴝ 145) or capecitabine (n ⴝ 133). Surgery was performed 6 weeks after CRT completion. Tumor responses to CRT were measured using both radiologic and pathologic examination. Magnetic resonance volumetry was performed at the initial workup and just before surgery after completion of preoperative CRT. Post-CRT pathology tests were used to determine tumor stage and regression. Results: Radiologic examination showed that tumor volume decreased by 68.2% ⴞ 20.5% in the FL group and 68.3% ⴞ 22.3% in the capecitabine group (p ⴝ 0.970). Postoperative pathologic T stage determination showed that downstaging occurred in 44.3% of FL and 49.9% of capecitabine patients (p ⴝ 0.571). The tumor regression grades after CRT were Grade 1 (minimal response) in 22.6% and 21.0%, Grade 2 (moderate response) in 53.2% and 50.0%, Grade 3 (near-complete response) in 12.9% and 12.9%, and Grade 4 (complete response) in 11.3% and 16.1% of the FL and capecitabine groups, respectively (p ⴝ 0.758). Conclusion: In the present study, the radiologic and pathologic findings did not reveal significant differences in short-term tumor responses between preoperative FL and capecitabine CRT for locally advanced rectal cancer. Long-term results and a prospective randomized trial are needed. © 2007 Elsevier Inc. Rectal cancer, Preoperative chemoradiotherapy, 5-Fluorouracil, Capecitabine.
INTRODUCTION
istration. Capecitabine is highly selective toward tumor tissue, because thymidine phosphorylase, essential for capecitabine activation, is more active in tumor than in normal tissue (2), and radiation upregulates thymidine phosphorylase in tumor, but not normal, tissue (3). Although some studies have found that preoperative CRT using capecitabine achieved encouraging rates of tumor downstaging and sphincter preservation with a low toxicity profile, those studies did not directly compare preexisting 5-fluorouracil (5-FU) and capecitabine treatment in preoperative CRT for rectal cancer (4, 5).
A recent prospective randomized rectal cancer study with a large sample size and long-term follow-up reported that preoperative chemoradiotherapy (CRT) was superior to postoperative CRT in terms of local control, feasibility, and toxicity (1). Moreover, preoperative CRT allows for primary tumor response evaluation within the relatively short period of approximately 3 months. In contrast, several years are required in the postoperative CRT setting. Many regimens have been used in preoperative CRT, and capecitabine has become popular because of its oral admin-
Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea. Conflict of interest: none. Received April 25, 2006, and in revised form Aug 27, 2006. Accepted for publication Aug 29, 2006.
Reprint requests to: Kyung Hae Jung, M.D., Center for Colorectal Cancer, National Cancer Center, 809 Madu-1-dong, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769 Republic of Korea. Tel: (⫹82) 31-920-1611; Fax: (⫹82) 31-920-1520; E-mail: [email protected] Supported by Grant No. 0412-CR01-0704-0001 of the Korea 378
Comparison of FL and capecitabine for rectal cancer
Two randomized studies have compared the outcomes after protracted infusion or bolus injection of 5-FU in postoperative CRT for rectal cancer (6, 7). O’Connell and colleagues (6) reported that protracted 5-FU infusion with concurrent radiotherapy (RT) resulted in an increased interval to relapse and improved survival compared with conventional 5-FU bolus injections. In contrast, Smalley and associates (Intergroup 0144) (7) reported no such superiority using protracted 5-FU infusion. Oral capecitabine administration is gradually replacing protracted 5-FU infusion, because it avoids invasive procedures such as central line insertion and inconvenient complexity. The present study was based on the assumption that the pharmacokinetic action of capecitabine mimics that of protracted venous 5-FU infusion (8, 9). We report our experience with a bolus injection of 5-FU and leucovorin (FL) vs. capecitabine in terms of the radiologic and pathologic findings after preoperative CRT for locally advanced rectal cancer when the chemotherapeutic agents were administered in conjunction with preoperative RT. METHODS AND MATERIALS Patients Between October 2001 and March 2005, 278 patients with primary rectal cancer underwent preoperative CRT under two protocols that had the same eligibility criteria but different chemotherapeutic regimens at the National Cancer Center (Goyang, Korea). The eligibility criteria were (1) adenocarcinoma confirmed histologically by endoscopic biopsy; (2) tumor located within 8 cm of the anal verge; (3) locally advanced and curatively resectable tumor (cT3-T4 classification) evaluated using magnetic resonance imaging (MRI) with or without transrectal ultrasonography; (4) patient age ⬎18 years; (5) Eastern Cooperative Oncology Group performance status of 0 or 1; (6) adequate bone marrow function (white blood cell count ⱖ3,000/mm3, hemoglobin ⱖ10 g/dL, platelet count ⱖ100,000/mm3); (7) adequate liver function (serum bilirubin ⱕ1.5 mg/dL, serum transaminase ⱕ2.5 times the upper normal limit); and (8) adequate renal function (serum creatinine ⱕ1.5 mg/dL). The exclusion criteria were (1) distant metastasis in staging workup; (2) previous or concurrent malignancy; (3) pregnant or breast-feeding women; and (4) impending rectal obstruction. The FL protocol was executed between October 2001 and March 2005 and capecitabine protocol between April 2003 and March 2005. In overlapping period, the protocol undertaken was determined according to patient preference. The study was performed in accordance with the guidelines of our institutional review board, and all patients provided written informed consent before preoperative CRT. Of the 278 patients, 14 refused surgery and 7 were treated with transanal local excision because their co-morbidities made general endotracheal anesthesia and radical proctectomy impossible (2 patients had a longstanding heart problem) or they strongly disagreed with anal ablation (5 patients). In addition, 9 patients were transferred to other hospitals closer to their residence. Table 1 shows the compliance with each protocol.
Treatment Chemotherapy. Preoperative chemotherapy was delivered concurrently with pelvic RT, with 145 patients receiving FL and 133
●
D. Y. KIM et al.
379
Table 1. Compliance with protocol Variable
FL
Capecitabine
Enrolled patients No radical surgery Surgery refused Local excision only Transferred to other hospitals Incomplete RT Incomplete chemotherapy
145 21 (14.5) 11 3 7
133 9 (6.2) 3 4 2
3 (2.1) 1 (0.7)
0 (0) 1 (0.7)
p* 0.052
0.249 1.000
Abbreviations: FL ⫽ 5-fluorouracil and leucovorin; RT ⫽ radiotherapy. Data in parentheses are percentages. * Two-tailed Fisher’s exact test. patients receiving capecitabine. The FL group received two cycles of an i.v. bolus injection of 5-FU (400 mg/m2/d) and leucovorin (20 mg/m2/d) for 3 days in the first and fifth weeks of RT (6, 10). The capecitabine group received an oral 825 mg/m2 dose twice daily for the duration of RT (4, 11). Because capecitabine is supplied as 150- and 500-mg tablets, the administered dose was rounded up. Radiotherapy. Preoperative RT (45 Gy in 25 fractions) was delivered to the pelvis, followed by a boost of 5.4 Gy in 3 fractions to the primary tumor within 5.5 weeks. All patients underwent computed tomography (CT) simulation for three-dimensional conformal RT, and had their targets defined in accordance with the International Commission on Radiation Units and Measurements Report 50 as follows. The gross tumor volume encompassed the primary rectal mural tumor and lymph nodes ⬎1.5 cm of smallest diameter observed on CT and MRI. The clinical target volume included the gross tumor volume, mesorectum, presacral space, whole of the sacral hollow, and regional lymphatics, including the perirectal, internal iliac, presacral, and distal common iliac lymphatics. The planning target volume included the clinical target volume plus a 15-mm margin. The superior border was placed at L5-S1, and the inferior border ⬎3 cm caudal to the gross tumor. The boost planning target volume included the gross tumor volume and mesorectum plus a ⬎2-cm margin in all directions. All patients underwent three-dimensional treatment planning, and the dose distribution was computed without heterogeneity corrections for bone, muscle, fat, or gas-filled cavities. The prescription dose was specified at the isocenter. A three-field treatment plan comprised a 6-MV photon PA field and 15-MV photon opposed lateral fields with wedges of 45°. The beam weights of the three-field plan were optimized to minimize the maximal dose within the target volume. Surgery. A total of 248 patients underwent open radical proctectomy, including high ligation of the inferior mesenteric vessels and total mesorectal excision 4 – 8 weeks (median 6) after preoperative CRT completion. Anastomosis was performed using either the double-stapled or hand-sewn technique.
Evaluation Before preoperative CRT, all patients were evaluated with staging workups, including digital rectal examination, complete blood count, liver function test, determination of carcinoembryonic antigen level, colon videoscopy, chest radiography, CT of the abdomen and pelvis, and MRI with or without transrectal ultrasonography. CT was initiated 60 s after an i.v. injection of
380
I. J. Radiation Oncology
●
Biology
●
Physics
140 cm3 of contrast material at the rate of 2.5 cm3/s, and a single-phased image was obtained. To identify the small bowel, an oral contrast solution (450 cm3) was given 1 h before CT, but rectal contrast administration was not done. The scanning parameters included 140 KVp, 200 mA, 3.75-mm slice thickness, and 32-cm field of view. The MRI protocol has been described in a previous report (12). The imaging protocol was the same for all patients. The primary T stage was determined using MRI. Stage T3 lesions on MRI were defined as those for which the tumor signal intensity extended through the muscle layer into the perirectal fat, with obliteration of the interface between the muscle and perirectal fat. Stage T4 lesions on MRI were defined as those for which the tumor signal intensity extended into an adjacent structure or viscus. To measure the tumor response quantitatively, magnetic resonance (MR) volumetry was performed on two occasions with the same protocol, at the initial workup and 2– 4 days before surgery. The cross-sectional areas of the lesions were measured using axial T2-weighted images by tracing the lesion boundary. On T2weighted images, the cross-sectional lesion areas were defined as intermediate-signal intensity areas that differed from the normal adjacent rectal wall in terms of signal intensity and contour. The MRI-based tumor volume was calculated for each MRI scan to determine the volume reduction rate. The volume reduction rate was determined using the equation R (%) ⫽ (VpreCRT ⫺ VpostCRT) ⫻ 100/VpreCRT, where R is the tumor volume reduction rate, VpreCRT is the pre-CRT tumor volume, and VpostCRT is the postCRT tumor volume. Clinical response was defined as a volume reduction rate of ⱖ65% (13). After surgery, the pathologic tumor stage was determined according to the TNM classification system recommended by International Union Against Cancer and American Joint Committee on Cancer. Downstaging was applied only for the T stage and was defined as Stage ypT2 or better (“yp” prefix indicates final staging after CRT [y] and postoperative pathologic examination [p]). All resected specimens underwent pathologic testing to assess the preoperative CRT response. In each case, the entire tumor, plus the mesorectal fat, was serially sliced into 4-mm-thick sections and embedded in paraffin. We carefully inspected the circumferential resection margin under the definition of a positive margin as tumor within ⱕ1 mm of the circumferential margin (14). The tumor regression grade was microscopically evaluated using the scale proposed by Dworak et al. (15). Tumor regression was graded as follows: Grade 0, no regression; Grade 1, dominant tumor mass with obvious fibrosis and/or vasculopathy (minimal response); Grade 2, dominant fibrotic changes with some obvious tumor cells or groups of cells (moderate response); Grade 3, fibrotic tissue with or without mucous substance that contained tumor cells that were very few in number and were difficult to detect microscopically (near-complete response); and Grade 4, fibrotic mass or acellular mucin pools only, without detectable tumor cells (complete response).
Statistical analysis This study was designed to retrospectively compare the efficacy of two protocols in terms of the radiologic and pathologic findings. The radiologic findings were analyzed to determine the mean volume reduction rate and clinical response rate (volume reduction rate ⱖ65%). The pathologic findings were used to determine the pathologic stage (ypT, ypN, and post-CRT stage) and tumor regression grade. Gender (male vs. female), cT stage (cT3 vs. cT4), clinical tumor
Volume 67, Number 2, 2007
Table 2. Patient characteristics Characteristic Gender Male Female Age (y) Mean Median Range Distance from anal verge (cm) Mean Median Range cT stage cT3 cT4 cN stage cN0 cN⫹ Histologic type Adenocarcinoma Mucinous Signet ring cell Histologic grade Low High
FL (n ⫽ 145)
Capecitabine (n ⫽ 133)
103 (71.0) 42 (29.0)
84 (63.2) 49 (36.8)
58.2 ⫾ 10.8 60 27–76
56.3 ⫾ 11.7 56 31–82
p 0.201* 0.157†
0.131† 4.4 ⫾ 2.2 4.0 0–8
5.1 ⫾ 2.1 5.0 0.5–8
139 (95.9) 6 (4.1)
130 (97.7) 3 (2.3)
27 (18.6) 118 (81.4)
27 (20.3) 106 (79.7)
143 (98.6) 1 (0.7) 1 (0.7)
131 (98.4) 1 (0.8) 1 (0.8)
138 (95.2) 7 (4.8)
128 (96.2) 5 (3.8)
0.504* 0.763* 1.000*
0.772*
Abbreviation: FL ⫽ 5-fluorouracil and leucovorin. Data in parentheses are percentages. * Two-tailed Fisher’s exact tests. † Two-tailed t test.
response (tumor volume reduction rate ⱖ65% vs. ⬍65%) and Grade 3 or worse toxicity (yes vs. no) were considered as binary variables. The ypT, ypN, and post-CRT stage and tumor regression grade were considered as categorical variables. Patient age, distance from anal verge, pre-CRT tumor volume, post-CRT tumor volume, and tumor volume reduction rate were analyzed as continuous variables. The t test and Fisher’s exact test were used to compare various parameters between the chemotherapy groups (FL vs. capecitabine). All statistical tests were two-sided and were performed using Statistical Analysis Systems software, version 8.2 (SAS Institute, Cary, NC). A p value of ⬍0.05 was considered to indicate statistical significance.
RESULTS Patient characteristics The study population had a median age of 58 years (range, 27– 82 years) and was predominantly male (187 men and 91 women). The median distance from the anal verge to the caudal edge of the tumor was 5 cm (range, 0 – 8 cm). The clinical staging workup revealed Stage cT3 in 269 patients (96.8%) and cT4 in 9 patients (3.2%). The patient characteristics were stratified by the two chemotherapeutic regimens and summarized in Table 2. Analysis revealed no differences between the FL and capecitabine groups in terms of gender, age, distance from the anal verge, cT stage, histologic type, or grade.
Comparison of FL and capecitabine for rectal cancer
●
D. Y. KIM et al.
381
Table 3. Radiologic findings for both groups Radiologic findings Pre-CRT tumor volume (cm3) Mean Median Range Post-CRT tumor volume (cm3) Mean Median Range Tumor volume reduction rate† (%) Mean Median Range Clinical response (tumor volume reduction rate ⱖ65%)
FL (n ⫽ 116)
Capecitabine (n ⫽ 121)
22.1 ⫾ 27.3 15.0 0.8–235.8
17.6 ⫾ 21.4 12.1 1.0–176.2
6.3 ⫾ 8.7 4.3 0–82.7
5.2 ⫾ 6.6 3.6 0–39
68.2 ⫾ 20.5 72.0 15.9–100 73 (62.9)
68.3 ⫾ 22.3 73.0 3.0–100 77 (63.6)
p 0.162*
0.294*
0.970*
1.000‡
Abbreviations: FL ⫽ 5-fluorouracil and leucovorin; CRT ⫽ chemoradiotherapy. * Two-tailed t test. † Tumor volume reduction rate ⫽ (pre-CRT tumor volume ⫺ post-CRT tumor volume) x 100/pre-CRT tumor volume. ‡ Two-tailed Fisher’s exact test.
Surgery A total of 248 patients underwent curative surgery, although 2 patients in each group had a positive circumferential resection margin microscopically. Distant metastasis, which was undetected in the initial staging workups, was discovered in the liver in 2 patients and the common iliac or para-aortic lymph nodes in 3 patients during surgery. Of these 5 patients, 3 were in the FL group and 2 in the capecitabine group (p ⫽ 0.875). The sphincter was preserved in 99 (79.8%) of 124 FL and 110 (88.7%) of 124 capecitabine patients (p ⫽ 0.080). Of the 62 patients whose tumors were located within 3 cm of the anal verge and were likely to require sphincter ablation according to previous data reported by our surgeons (16), the anal sphincter was preserved in 14 (40.0%) of 35 FL patients and 13 (48.1%) of 27 capecitabine patients (p ⫽ 0.521). Radiologic findings An MR volumetry assessment was undertaken for 237 patients (85.3%). The median pre-CRT tumor volume was 13.5 cm3 (range, 0.8 –235.8 cm3). The median post-CRT tumor volume for all patients was 3.9 cm3 (range, 0 – 82.7 cm3). The median tumor volume reduction rate was 72.8% (range, 3.0 –100%). Of the 237 patients, 150 (63.3%) had clinical responses in which the tumor volume reduction was ⱖ65%. The radiologic findings showed no differences between the FL and capecitabine groups in terms of pre-CRT tumor volume, post-CRT tumor volume, tumor volume reduction rate, and clinical response (Table 3). Pathologic findings A pathologic assessment was undertaken for 248 patients (89.2%). The pathologic T stage of the surgical specimens was Stage ypT0 in 36 patients (14.5%), ypTis in 3 (1.2%), ypT1 in 11 (4.4%), ypT2 in 67 (27.0%), ypT3 in 123 (49.6%), and ypT4 in 8 (3.2%) patients. The pathologic N
stage of the surgical specimens was Stage ypN0 in 165 patients (66.5%), ypN1 in 58 (23.4%), and ypN2 in 25 (10.1%) patients. One patient in each group who achieved Stage ypT0 also had Stage ypN1 disease. The pathologic staging of surgical specimens showed Stage 0 in 37 patients (14.9%), Stage I in 67 (27.0%), Stage II in 60 (24.2%), Stage III in 79 (31.9%), and Stage IV in 5 (2.0%) patients. Downstaging to Stage ypT2 or less occurred in 44.3% of FL patients and 49.9% of capecitabine patients (p ⫽ 0.571). These pathologic findings showed no differences between the FL and capecitabine groups in terms of ypT, ypN, or post-CRT stage. The tumor regression grade after pre-CRT was Grade 1 in 54 patients (21.8%), Grade 2 in 128 (51.6%), Grade 3 in 32 (12.9%), and Grade 4 in 34 patients (13.7%). The pathologic finding subgroup analysis showed no differences between the FL and capecitabine groups in terms of tumor regression grade (Table 4). Toxicity Thirty-three patients had Grade 3 or worse acute toxicity. Of these, 14 had Grade 3 or 4 hematologic toxicity, 12 had nonhematologic toxicity, and 9 had postoperative complications (Table 5). No significant differences were found between the FL and capecitabine groups in terms of hematologic and nonhematologic toxicity or postoperative complications. DISCUSSION Protracted 5-FU infusion prolongs the exposure of noncycling tumor cells to 5-FU, and constant exposure of tumor cells to 5-FU after irradiation enhances the cytotoxic effect of combined RT plus 5-FU treatment (17). Although protracted 5-FU infusion is effective during RT to the pelvis, debate remains as to whether it is more effective than a bolus 5-FU injection with concurrent RT in rectal cancer
382
I. J. Radiation Oncology
●
Biology
●
Physics
Table 4. Pathologic findings for both groups Pathologic findings ypT stage ypT0 ypTis ypT1 ypT2 ypT3 ypT4 ypN stage ypN0 ypN1 ypN2 Post-CRT stage 0 I II III IV Tumor regression grade 1 2 3 4
FL (n ⫽ 124)
Capecitabine (n ⫽ 124)
15 (12.1) 2 (1.6) 7 (5.6) 31 (25.0) 66 (53.2) 3 (2.4)
21 (16.9) 1 (0.8) 4 (3.2) 36 (29.0) 57 (46.0) 5 (4.0)
89 (71.8) 23 (18.5) 12 (9.7)
76 (61.3) 35 (28.2) 13 (10.5)
16 (12.9) 33 (26.6) 39 (31.5) 33 (26.6) 3 (2.4)
21 (16.9) 34 (27.4) 21 (16.9) 46 (37.1) 2 (1.6)
28 (22.6) 66 (53.2) 16 (12.9) 14 (11.3)
26 (21.0) 62 (50.0) 16 (12.9) 20 (16.1)
p* 0.571
0.188
0.069
0.758
Data in parentheses are percentages. * Two-tailed Fisher’s exact test.
patients. O’Connell and associates (6) reported that protracted 5-FU infusion during RT increased the time to relapse and improved survival compared with conventional bolus 5-FU administration. The 328 patients who received protracted venous infusion of 5-FU had lower overall rates of tumor relapse (47% vs. 37%, p ⫽ 0.01) and distant metastasis (40 vs. 31%, p ⫽ 0.03) compared with the 332 patients who received a bolus injection of 5-FU during RT. In contrast, the Intergroup 0144 study found that protracted 5-FU infusion was not superior (7). That study compared three 5-FU– based regimens (bolus injection before and after protracted infusion of 5-FU plus RT vs. protracted infusion of 5-FU before, during, and after RT vs. biochemically modulated bolus 5-FU and RT) added to RT in the postoperative setting and concluded that protracted infusion and bolus injection of 5-FU resulted in similar relapse-free survival and overall survival. Although prolonged exposure of tumor cells to 5-FU might theoretically result in enhanced cytotoxicity (18), the method resulting in the best clinical outcome remains unclear. Protracted infusion of 5-FU requires central venous access and an ambulatory infusion pump, which increases the complexity and cost of therapy. Recently, it has been demonstrated that capecitabine is a tumor-selective fluoropyrimidine carbamate that is converted to active 5-FU by thymidine phosphorylase. Thymidine phosphorylase is more concentrated in tumor than normal tissue (2) and is upregulated by RT in tumor, but not normal, tissue (3). Capecitabine can achieve a greater intratumoral 5-FU level and lower systemic 5-FU level compared with i.v. infusion of 5-FU (8). Theoretically, oral capecitabine could replace
Volume 67, Number 2, 2007
protracted infusion of 5-FU and avoid complicated procedures. Two randomized Phase III trials found that capecitabine use resulted in a superior overall response rate and safety profile compared with a bolus injection of FL for metastatic colorectal cancer (19, 20). On the basis of those results, the present study compared the outcomes of patients receiving either capecitabine or a bolus injection of FL for locally advanced rectal cancer. We found no significant differences between the two chemotherapeutic regimens in terms of short-term tumor responses according to the radiologic and pathologic findings. The groups did not differ in terms of sphincter preservation rate, MR volumetry, or pathologic results, including the complete response rate, downstaging, tumor regression grade, and toxicity. Although the study endpoints differed, the present results are consistent with those of the Intergroup 0144 study. However additional study is needed to confirm this result. This study examined the T stage and chose to exclude nodal status. Accurate preoperative staging is essential to plan optimal therapy for patients with rectal cancer. Transrectal ultrasonography and MRI are reliable methods of the assessment of the T stage, with accuracies as great as 80 –100% (21–24). However, lymph node evaluation can have a poor correlation between the pathologic and radiologic nodal status (25, 26). Morphologic criteria, such as the size and shape of the node, is difficult to distinguish between reactive and metastatic nodes, and micrometastasis in normal-size nodes occurs at a high frequency in rectal cancer compared with other pelvic tumors (27, 28). Thus, the present study did not consider nodal status when ana-
Table 5. Toxic effects (Grade 3 or worse*) of 5-fluorouracil/ leucovorin and capecitabine Type of toxic effect Hematologic toxicity Leukopenia Neutropenia Anemia Thrombocytopenia Nonhematologic toxicity Hand-foot syndrome Anorexia Vomiting Diarrhea Stomatitis Postoperative complications Ileus Voiding problem Wound problem Fever
FL (n ⫽ 145)
Capecitabine (n ⫽ 133)
5 2 3 2 0 8 0 3 0 4 1 4
9 3 4 5 0 4 0 1 1 2 1 5
1 2 1 0
1 2 1 1
p Value† 0.274
0.230
0.741
Abbreviation: FL ⫽ 5-fluorouracil and leucovorin. Some patients had more than one toxic effect. * National Cancer Institute Common Terminology Criteria for Adverse Events, version 2.0. † Two-tailed Fisher’s exact test.
Comparison of FL and capecitabine for rectal cancer
lyzing the downstaging effect of the two chemotherapeutic regimens. The present study had some limitations. First, the endpoints were limited to the short-term and locoregional effects. A more comprehensive comparison between the two chemotherapy regimens awaits analysis of long-term relapse-free and overall survival data. Second, this was a retrospective comparison study of two protocols using different chemotherapeutic regimens, not a randomized study. The initial attempts at a randomized protocol were thwarted by national insurance conditions and individual preferences, which were largely based on patients’ personal economic status. The data were analyzed with the assumption that the economic status would have no significant influence on tumor response. Third, the study populations of two groups
●
D. Y. KIM et al.
383
were not evenly distributed in terms of gender, age, and distance from anal verge. Although the differences between the two groups were not statistically significant, those could have had some influence on the rates of sphincter preservation, ypT0, and ypN0. Fourth, MR volumetry was obtained by two radiologists because of one leaving. Although image acquisition and tumor volume delineation were performed under the same protocol, interpersonal variation should be taken into consideration for interpretation of this study. Using the radiologic and pathologic findings, the present study, examining short-term tumor responses, could not find any significant differences between capecitabine and a bolus injection of FL for preoperative CRT for locally advanced rectal cancer. Long-term results and a prospective randomized trial are needed.
REFERENCES 1. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731–1740. 2. Miwa M, Ura M, Nishida M, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998;34: 1274 –1281. 3. Sawada N, Ishikawa T, Sekiguchi F, et al. X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts. Clin Cancer Res 1999;5:2948 –2953. 4. Kim JC, Kim TW, Kim JH, et al. Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2005;63:346 –353. 5. Kim JS, Kim JS, Cho MJ, et al. Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2002;54:403– 408. 6. O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protractedinfusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502–507. 7. Smalley SR, Benedetti JK, Williamson SK, et al. Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 2006;24:3542–3547. 8. Schuller J, Cassidy J, Dumont E, et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000;45:291–297. 9. Judson IR, Beale PJ, Trigo JM, et al. A human capecitabine excretion balance and pharmacokinetic study after administration of a single dose of 14C-labelled drug. Invest New Drugs 1999;17:49 –56. 10. Wolmark N, Wieand H, Hyams D, et al. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 2000;92:388 –396. 11. Dunst J, Reese T, Sutter T, et al. Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol 2002;20:3983–3991. 12. Kim YH, Kim DY, Kim TH, et al. Usefulness of magnetic resonance volumetric evaluation in predicting response to preoperative concurrent chemoradiotherapy in patients with
13.
14. 15. 16.
17.
18. 19.
20.
21. 22. 23. 24. 25.
resectable rectal cancer. Int J Radiat Oncol Biol Phys 2005;62:761–768. Therasse P, Arbuck SG, Eisenhauer EA, et al., for the European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000; 92:205–216. Adam IJ, Mohamdee MO, Martin IG, et al. Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet 1994;344:707–711. Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 1997;12:19 –23. Kim DW, Lim SB, Kim DY, et al. Preoperative chemoradiotherapy improves the sphincter preservation rate in patients with rectal cancer located within 3 cm of the anal verge. Eur J Surg Oncol 2006;32:162–167. Byfield JE, Calabro-Jones P, Klisak I, et al. Pharmacologic requirements for obtaining sensitization of human tumor cells in vitro to combined 5-fluorouracil or ftorafur and X rays. Int J Radiat Oncol Biol Phys 1982;8:1923–1933. Hansen RM, Quebbeman E, Anderson T. 5-Fluorouracil by protracted venous infusion: A review of current progress. Oncology 1989;46:245–250. Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 2001;19:4097– 4106. Hoff PM, Ansari R, Batist G, et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 2001;19:2282–2292. Rifkin MD, Ehrlich SM, Marks G. Staging of rectal carcinoma: Prospective comparison of endorectal US and CT. Radiology 1989;170:319 –322. Heriot AG, Grundy A, Kumar D. Preoperative staging of rectal carcinoma. Br J Surg 1999;86:17–28. Brown G, Richards CJ, Newcombe RG, et al. Rectal carcinoma: Thin-section MR imaging for staging in 28 patients. Radiology 1999;211:215–222. Laghi A, Ferri M, Catalano C, et al. Local staging of rectal cancer with MRI using a phased array body coil. Abdom Imaging 2002;27:425– 431. Nielsen MB, Qvitzau S, Pedersen JF. Detection of pericolonic
384
I. J. Radiation Oncology
●
Biology
●
Physics
lymph nodes in patients with colorectal cancer: An in vitro and in vivo study of the efficacy of endosonography. AJR Am J Roentgenol 1993;161:57– 60. 26. Zerhouni EA, Rutter C, Hamilton SR, et al. CT and MR imaging in the staging of colorectal carcinoma: report of the Radiology Diagnostic Oncology Group II. Radiology 1996;200:443– 451.
Volume 67, Number 2, 2007
27. Williams AD, Cousins C, Soutter WP, et al. Detection of pelvic lymph node metastases in gynecologic malignancy: A comparison of CT, MR imaging, and positron emission tomography. AJR Am J Roentgenol 2001;177:343–348. 28. Beets-Tan RG, Beets GL. Rectal cancer: Review with emphasis on MR imaging. Radiology 2004;232:335–346.
doi:10.1016/j.ijrobp.2006.08.063
CLINICAL INVESTIGATION
Rectum
COMPARISON OF 5-FLUOROURACIL/LEUCOVORIN AND CAPECITABINE IN PREOPERATIVE CHEMORADIOTHERAPY FOR LOCALLY ADVANCED RECTAL CANCER DAE YONG KIM, M.D.,* KYUNG HAE JUNG, M.D.,* TAE HYUN KIM, M.D.,* DUCK-WOO KIM, M.D.,* HEE JIN CHANG, M.D.,* JUN YONG JEONG, M.D.,* YOUNG HOON KIM, M.D.,† SEOK-HYUN SON, M.D.,‡ TAK YUN, M.D.,* CHANG WON HONG, M.D.,* DAE KYUNG SOHN, M.D.,* SEOK-BYUNG LIM, M.D.,* HYO SEONG CHOI, M.D.,* SEUNG-YONG JEONG, M.D.,* AND JAE-GAHB PARK, M.D.* *Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea; †Department of Radiology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; ‡Department of Radiation Oncology, Kangnam St. Mary’s Hospital, Seoul, Republic of Korea Purpose: To describe our experience with a bolus injection of 5-fluorouracil and leucovorin (FL) vs. capecitabine in terms of radiologic and pathologic findings in preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. Methods: The study enrolled 278 patients scheduled for preoperative CRT using two protocols with different chemotherapeutic regimens. Pelvic radiotherapy (50.4 Gy) was delivered concurrently with FL (n ⴝ 145) or capecitabine (n ⴝ 133). Surgery was performed 6 weeks after CRT completion. Tumor responses to CRT were measured using both radiologic and pathologic examination. Magnetic resonance volumetry was performed at the initial workup and just before surgery after completion of preoperative CRT. Post-CRT pathology tests were used to determine tumor stage and regression. Results: Radiologic examination showed that tumor volume decreased by 68.2% ⴞ 20.5% in the FL group and 68.3% ⴞ 22.3% in the capecitabine group (p ⴝ 0.970). Postoperative pathologic T stage determination showed that downstaging occurred in 44.3% of FL and 49.9% of capecitabine patients (p ⴝ 0.571). The tumor regression grades after CRT were Grade 1 (minimal response) in 22.6% and 21.0%, Grade 2 (moderate response) in 53.2% and 50.0%, Grade 3 (near-complete response) in 12.9% and 12.9%, and Grade 4 (complete response) in 11.3% and 16.1% of the FL and capecitabine groups, respectively (p ⴝ 0.758). Conclusion: In the present study, the radiologic and pathologic findings did not reveal significant differences in short-term tumor responses between preoperative FL and capecitabine CRT for locally advanced rectal cancer. Long-term results and a prospective randomized trial are needed. © 2007 Elsevier Inc. Rectal cancer, Preoperative chemoradiotherapy, 5-Fluorouracil, Capecitabine.
INTRODUCTION
istration. Capecitabine is highly selective toward tumor tissue, because thymidine phosphorylase, essential for capecitabine activation, is more active in tumor than in normal tissue (2), and radiation upregulates thymidine phosphorylase in tumor, but not normal, tissue (3). Although some studies have found that preoperative CRT using capecitabine achieved encouraging rates of tumor downstaging and sphincter preservation with a low toxicity profile, those studies did not directly compare preexisting 5-fluorouracil (5-FU) and capecitabine treatment in preoperative CRT for rectal cancer (4, 5).
A recent prospective randomized rectal cancer study with a large sample size and long-term follow-up reported that preoperative chemoradiotherapy (CRT) was superior to postoperative CRT in terms of local control, feasibility, and toxicity (1). Moreover, preoperative CRT allows for primary tumor response evaluation within the relatively short period of approximately 3 months. In contrast, several years are required in the postoperative CRT setting. Many regimens have been used in preoperative CRT, and capecitabine has become popular because of its oral admin-
Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea. Conflict of interest: none. Received April 25, 2006, and in revised form Aug 27, 2006. Accepted for publication Aug 29, 2006.
Reprint requests to: Kyung Hae Jung, M.D., Center for Colorectal Cancer, National Cancer Center, 809 Madu-1-dong, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769 Republic of Korea. Tel: (⫹82) 31-920-1611; Fax: (⫹82) 31-920-1520; E-mail: [email protected] Supported by Grant No. 0412-CR01-0704-0001 of the Korea 378
Comparison of FL and capecitabine for rectal cancer
Two randomized studies have compared the outcomes after protracted infusion or bolus injection of 5-FU in postoperative CRT for rectal cancer (6, 7). O’Connell and colleagues (6) reported that protracted 5-FU infusion with concurrent radiotherapy (RT) resulted in an increased interval to relapse and improved survival compared with conventional 5-FU bolus injections. In contrast, Smalley and associates (Intergroup 0144) (7) reported no such superiority using protracted 5-FU infusion. Oral capecitabine administration is gradually replacing protracted 5-FU infusion, because it avoids invasive procedures such as central line insertion and inconvenient complexity. The present study was based on the assumption that the pharmacokinetic action of capecitabine mimics that of protracted venous 5-FU infusion (8, 9). We report our experience with a bolus injection of 5-FU and leucovorin (FL) vs. capecitabine in terms of the radiologic and pathologic findings after preoperative CRT for locally advanced rectal cancer when the chemotherapeutic agents were administered in conjunction with preoperative RT. METHODS AND MATERIALS Patients Between October 2001 and March 2005, 278 patients with primary rectal cancer underwent preoperative CRT under two protocols that had the same eligibility criteria but different chemotherapeutic regimens at the National Cancer Center (Goyang, Korea). The eligibility criteria were (1) adenocarcinoma confirmed histologically by endoscopic biopsy; (2) tumor located within 8 cm of the anal verge; (3) locally advanced and curatively resectable tumor (cT3-T4 classification) evaluated using magnetic resonance imaging (MRI) with or without transrectal ultrasonography; (4) patient age ⬎18 years; (5) Eastern Cooperative Oncology Group performance status of 0 or 1; (6) adequate bone marrow function (white blood cell count ⱖ3,000/mm3, hemoglobin ⱖ10 g/dL, platelet count ⱖ100,000/mm3); (7) adequate liver function (serum bilirubin ⱕ1.5 mg/dL, serum transaminase ⱕ2.5 times the upper normal limit); and (8) adequate renal function (serum creatinine ⱕ1.5 mg/dL). The exclusion criteria were (1) distant metastasis in staging workup; (2) previous or concurrent malignancy; (3) pregnant or breast-feeding women; and (4) impending rectal obstruction. The FL protocol was executed between October 2001 and March 2005 and capecitabine protocol between April 2003 and March 2005. In overlapping period, the protocol undertaken was determined according to patient preference. The study was performed in accordance with the guidelines of our institutional review board, and all patients provided written informed consent before preoperative CRT. Of the 278 patients, 14 refused surgery and 7 were treated with transanal local excision because their co-morbidities made general endotracheal anesthesia and radical proctectomy impossible (2 patients had a longstanding heart problem) or they strongly disagreed with anal ablation (5 patients). In addition, 9 patients were transferred to other hospitals closer to their residence. Table 1 shows the compliance with each protocol.
Treatment Chemotherapy. Preoperative chemotherapy was delivered concurrently with pelvic RT, with 145 patients receiving FL and 133
●
D. Y. KIM et al.
379
Table 1. Compliance with protocol Variable
FL
Capecitabine
Enrolled patients No radical surgery Surgery refused Local excision only Transferred to other hospitals Incomplete RT Incomplete chemotherapy
145 21 (14.5) 11 3 7
133 9 (6.2) 3 4 2
3 (2.1) 1 (0.7)
0 (0) 1 (0.7)
p* 0.052
0.249 1.000
Abbreviations: FL ⫽ 5-fluorouracil and leucovorin; RT ⫽ radiotherapy. Data in parentheses are percentages. * Two-tailed Fisher’s exact test. patients receiving capecitabine. The FL group received two cycles of an i.v. bolus injection of 5-FU (400 mg/m2/d) and leucovorin (20 mg/m2/d) for 3 days in the first and fifth weeks of RT (6, 10). The capecitabine group received an oral 825 mg/m2 dose twice daily for the duration of RT (4, 11). Because capecitabine is supplied as 150- and 500-mg tablets, the administered dose was rounded up. Radiotherapy. Preoperative RT (45 Gy in 25 fractions) was delivered to the pelvis, followed by a boost of 5.4 Gy in 3 fractions to the primary tumor within 5.5 weeks. All patients underwent computed tomography (CT) simulation for three-dimensional conformal RT, and had their targets defined in accordance with the International Commission on Radiation Units and Measurements Report 50 as follows. The gross tumor volume encompassed the primary rectal mural tumor and lymph nodes ⬎1.5 cm of smallest diameter observed on CT and MRI. The clinical target volume included the gross tumor volume, mesorectum, presacral space, whole of the sacral hollow, and regional lymphatics, including the perirectal, internal iliac, presacral, and distal common iliac lymphatics. The planning target volume included the clinical target volume plus a 15-mm margin. The superior border was placed at L5-S1, and the inferior border ⬎3 cm caudal to the gross tumor. The boost planning target volume included the gross tumor volume and mesorectum plus a ⬎2-cm margin in all directions. All patients underwent three-dimensional treatment planning, and the dose distribution was computed without heterogeneity corrections for bone, muscle, fat, or gas-filled cavities. The prescription dose was specified at the isocenter. A three-field treatment plan comprised a 6-MV photon PA field and 15-MV photon opposed lateral fields with wedges of 45°. The beam weights of the three-field plan were optimized to minimize the maximal dose within the target volume. Surgery. A total of 248 patients underwent open radical proctectomy, including high ligation of the inferior mesenteric vessels and total mesorectal excision 4 – 8 weeks (median 6) after preoperative CRT completion. Anastomosis was performed using either the double-stapled or hand-sewn technique.
Evaluation Before preoperative CRT, all patients were evaluated with staging workups, including digital rectal examination, complete blood count, liver function test, determination of carcinoembryonic antigen level, colon videoscopy, chest radiography, CT of the abdomen and pelvis, and MRI with or without transrectal ultrasonography. CT was initiated 60 s after an i.v. injection of
380
I. J. Radiation Oncology
●
Biology
●
Physics
140 cm3 of contrast material at the rate of 2.5 cm3/s, and a single-phased image was obtained. To identify the small bowel, an oral contrast solution (450 cm3) was given 1 h before CT, but rectal contrast administration was not done. The scanning parameters included 140 KVp, 200 mA, 3.75-mm slice thickness, and 32-cm field of view. The MRI protocol has been described in a previous report (12). The imaging protocol was the same for all patients. The primary T stage was determined using MRI. Stage T3 lesions on MRI were defined as those for which the tumor signal intensity extended through the muscle layer into the perirectal fat, with obliteration of the interface between the muscle and perirectal fat. Stage T4 lesions on MRI were defined as those for which the tumor signal intensity extended into an adjacent structure or viscus. To measure the tumor response quantitatively, magnetic resonance (MR) volumetry was performed on two occasions with the same protocol, at the initial workup and 2– 4 days before surgery. The cross-sectional areas of the lesions were measured using axial T2-weighted images by tracing the lesion boundary. On T2weighted images, the cross-sectional lesion areas were defined as intermediate-signal intensity areas that differed from the normal adjacent rectal wall in terms of signal intensity and contour. The MRI-based tumor volume was calculated for each MRI scan to determine the volume reduction rate. The volume reduction rate was determined using the equation R (%) ⫽ (VpreCRT ⫺ VpostCRT) ⫻ 100/VpreCRT, where R is the tumor volume reduction rate, VpreCRT is the pre-CRT tumor volume, and VpostCRT is the postCRT tumor volume. Clinical response was defined as a volume reduction rate of ⱖ65% (13). After surgery, the pathologic tumor stage was determined according to the TNM classification system recommended by International Union Against Cancer and American Joint Committee on Cancer. Downstaging was applied only for the T stage and was defined as Stage ypT2 or better (“yp” prefix indicates final staging after CRT [y] and postoperative pathologic examination [p]). All resected specimens underwent pathologic testing to assess the preoperative CRT response. In each case, the entire tumor, plus the mesorectal fat, was serially sliced into 4-mm-thick sections and embedded in paraffin. We carefully inspected the circumferential resection margin under the definition of a positive margin as tumor within ⱕ1 mm of the circumferential margin (14). The tumor regression grade was microscopically evaluated using the scale proposed by Dworak et al. (15). Tumor regression was graded as follows: Grade 0, no regression; Grade 1, dominant tumor mass with obvious fibrosis and/or vasculopathy (minimal response); Grade 2, dominant fibrotic changes with some obvious tumor cells or groups of cells (moderate response); Grade 3, fibrotic tissue with or without mucous substance that contained tumor cells that were very few in number and were difficult to detect microscopically (near-complete response); and Grade 4, fibrotic mass or acellular mucin pools only, without detectable tumor cells (complete response).
Statistical analysis This study was designed to retrospectively compare the efficacy of two protocols in terms of the radiologic and pathologic findings. The radiologic findings were analyzed to determine the mean volume reduction rate and clinical response rate (volume reduction rate ⱖ65%). The pathologic findings were used to determine the pathologic stage (ypT, ypN, and post-CRT stage) and tumor regression grade. Gender (male vs. female), cT stage (cT3 vs. cT4), clinical tumor
Volume 67, Number 2, 2007
Table 2. Patient characteristics Characteristic Gender Male Female Age (y) Mean Median Range Distance from anal verge (cm) Mean Median Range cT stage cT3 cT4 cN stage cN0 cN⫹ Histologic type Adenocarcinoma Mucinous Signet ring cell Histologic grade Low High
FL (n ⫽ 145)
Capecitabine (n ⫽ 133)
103 (71.0) 42 (29.0)
84 (63.2) 49 (36.8)
58.2 ⫾ 10.8 60 27–76
56.3 ⫾ 11.7 56 31–82
p 0.201* 0.157†
0.131† 4.4 ⫾ 2.2 4.0 0–8
5.1 ⫾ 2.1 5.0 0.5–8
139 (95.9) 6 (4.1)
130 (97.7) 3 (2.3)
27 (18.6) 118 (81.4)
27 (20.3) 106 (79.7)
143 (98.6) 1 (0.7) 1 (0.7)
131 (98.4) 1 (0.8) 1 (0.8)
138 (95.2) 7 (4.8)
128 (96.2) 5 (3.8)
0.504* 0.763* 1.000*
0.772*
Abbreviation: FL ⫽ 5-fluorouracil and leucovorin. Data in parentheses are percentages. * Two-tailed Fisher’s exact tests. † Two-tailed t test.
response (tumor volume reduction rate ⱖ65% vs. ⬍65%) and Grade 3 or worse toxicity (yes vs. no) were considered as binary variables. The ypT, ypN, and post-CRT stage and tumor regression grade were considered as categorical variables. Patient age, distance from anal verge, pre-CRT tumor volume, post-CRT tumor volume, and tumor volume reduction rate were analyzed as continuous variables. The t test and Fisher’s exact test were used to compare various parameters between the chemotherapy groups (FL vs. capecitabine). All statistical tests were two-sided and were performed using Statistical Analysis Systems software, version 8.2 (SAS Institute, Cary, NC). A p value of ⬍0.05 was considered to indicate statistical significance.
RESULTS Patient characteristics The study population had a median age of 58 years (range, 27– 82 years) and was predominantly male (187 men and 91 women). The median distance from the anal verge to the caudal edge of the tumor was 5 cm (range, 0 – 8 cm). The clinical staging workup revealed Stage cT3 in 269 patients (96.8%) and cT4 in 9 patients (3.2%). The patient characteristics were stratified by the two chemotherapeutic regimens and summarized in Table 2. Analysis revealed no differences between the FL and capecitabine groups in terms of gender, age, distance from the anal verge, cT stage, histologic type, or grade.
Comparison of FL and capecitabine for rectal cancer
●
D. Y. KIM et al.
381
Table 3. Radiologic findings for both groups Radiologic findings Pre-CRT tumor volume (cm3) Mean Median Range Post-CRT tumor volume (cm3) Mean Median Range Tumor volume reduction rate† (%) Mean Median Range Clinical response (tumor volume reduction rate ⱖ65%)
FL (n ⫽ 116)
Capecitabine (n ⫽ 121)
22.1 ⫾ 27.3 15.0 0.8–235.8
17.6 ⫾ 21.4 12.1 1.0–176.2
6.3 ⫾ 8.7 4.3 0–82.7
5.2 ⫾ 6.6 3.6 0–39
68.2 ⫾ 20.5 72.0 15.9–100 73 (62.9)
68.3 ⫾ 22.3 73.0 3.0–100 77 (63.6)
p 0.162*
0.294*
0.970*
1.000‡
Abbreviations: FL ⫽ 5-fluorouracil and leucovorin; CRT ⫽ chemoradiotherapy. * Two-tailed t test. † Tumor volume reduction rate ⫽ (pre-CRT tumor volume ⫺ post-CRT tumor volume) x 100/pre-CRT tumor volume. ‡ Two-tailed Fisher’s exact test.
Surgery A total of 248 patients underwent curative surgery, although 2 patients in each group had a positive circumferential resection margin microscopically. Distant metastasis, which was undetected in the initial staging workups, was discovered in the liver in 2 patients and the common iliac or para-aortic lymph nodes in 3 patients during surgery. Of these 5 patients, 3 were in the FL group and 2 in the capecitabine group (p ⫽ 0.875). The sphincter was preserved in 99 (79.8%) of 124 FL and 110 (88.7%) of 124 capecitabine patients (p ⫽ 0.080). Of the 62 patients whose tumors were located within 3 cm of the anal verge and were likely to require sphincter ablation according to previous data reported by our surgeons (16), the anal sphincter was preserved in 14 (40.0%) of 35 FL patients and 13 (48.1%) of 27 capecitabine patients (p ⫽ 0.521). Radiologic findings An MR volumetry assessment was undertaken for 237 patients (85.3%). The median pre-CRT tumor volume was 13.5 cm3 (range, 0.8 –235.8 cm3). The median post-CRT tumor volume for all patients was 3.9 cm3 (range, 0 – 82.7 cm3). The median tumor volume reduction rate was 72.8% (range, 3.0 –100%). Of the 237 patients, 150 (63.3%) had clinical responses in which the tumor volume reduction was ⱖ65%. The radiologic findings showed no differences between the FL and capecitabine groups in terms of pre-CRT tumor volume, post-CRT tumor volume, tumor volume reduction rate, and clinical response (Table 3). Pathologic findings A pathologic assessment was undertaken for 248 patients (89.2%). The pathologic T stage of the surgical specimens was Stage ypT0 in 36 patients (14.5%), ypTis in 3 (1.2%), ypT1 in 11 (4.4%), ypT2 in 67 (27.0%), ypT3 in 123 (49.6%), and ypT4 in 8 (3.2%) patients. The pathologic N
stage of the surgical specimens was Stage ypN0 in 165 patients (66.5%), ypN1 in 58 (23.4%), and ypN2 in 25 (10.1%) patients. One patient in each group who achieved Stage ypT0 also had Stage ypN1 disease. The pathologic staging of surgical specimens showed Stage 0 in 37 patients (14.9%), Stage I in 67 (27.0%), Stage II in 60 (24.2%), Stage III in 79 (31.9%), and Stage IV in 5 (2.0%) patients. Downstaging to Stage ypT2 or less occurred in 44.3% of FL patients and 49.9% of capecitabine patients (p ⫽ 0.571). These pathologic findings showed no differences between the FL and capecitabine groups in terms of ypT, ypN, or post-CRT stage. The tumor regression grade after pre-CRT was Grade 1 in 54 patients (21.8%), Grade 2 in 128 (51.6%), Grade 3 in 32 (12.9%), and Grade 4 in 34 patients (13.7%). The pathologic finding subgroup analysis showed no differences between the FL and capecitabine groups in terms of tumor regression grade (Table 4). Toxicity Thirty-three patients had Grade 3 or worse acute toxicity. Of these, 14 had Grade 3 or 4 hematologic toxicity, 12 had nonhematologic toxicity, and 9 had postoperative complications (Table 5). No significant differences were found between the FL and capecitabine groups in terms of hematologic and nonhematologic toxicity or postoperative complications. DISCUSSION Protracted 5-FU infusion prolongs the exposure of noncycling tumor cells to 5-FU, and constant exposure of tumor cells to 5-FU after irradiation enhances the cytotoxic effect of combined RT plus 5-FU treatment (17). Although protracted 5-FU infusion is effective during RT to the pelvis, debate remains as to whether it is more effective than a bolus 5-FU injection with concurrent RT in rectal cancer
382
I. J. Radiation Oncology
●
Biology
●
Physics
Table 4. Pathologic findings for both groups Pathologic findings ypT stage ypT0 ypTis ypT1 ypT2 ypT3 ypT4 ypN stage ypN0 ypN1 ypN2 Post-CRT stage 0 I II III IV Tumor regression grade 1 2 3 4
FL (n ⫽ 124)
Capecitabine (n ⫽ 124)
15 (12.1) 2 (1.6) 7 (5.6) 31 (25.0) 66 (53.2) 3 (2.4)
21 (16.9) 1 (0.8) 4 (3.2) 36 (29.0) 57 (46.0) 5 (4.0)
89 (71.8) 23 (18.5) 12 (9.7)
76 (61.3) 35 (28.2) 13 (10.5)
16 (12.9) 33 (26.6) 39 (31.5) 33 (26.6) 3 (2.4)
21 (16.9) 34 (27.4) 21 (16.9) 46 (37.1) 2 (1.6)
28 (22.6) 66 (53.2) 16 (12.9) 14 (11.3)
26 (21.0) 62 (50.0) 16 (12.9) 20 (16.1)
p* 0.571
0.188
0.069
0.758
Data in parentheses are percentages. * Two-tailed Fisher’s exact test.
patients. O’Connell and associates (6) reported that protracted 5-FU infusion during RT increased the time to relapse and improved survival compared with conventional bolus 5-FU administration. The 328 patients who received protracted venous infusion of 5-FU had lower overall rates of tumor relapse (47% vs. 37%, p ⫽ 0.01) and distant metastasis (40 vs. 31%, p ⫽ 0.03) compared with the 332 patients who received a bolus injection of 5-FU during RT. In contrast, the Intergroup 0144 study found that protracted 5-FU infusion was not superior (7). That study compared three 5-FU– based regimens (bolus injection before and after protracted infusion of 5-FU plus RT vs. protracted infusion of 5-FU before, during, and after RT vs. biochemically modulated bolus 5-FU and RT) added to RT in the postoperative setting and concluded that protracted infusion and bolus injection of 5-FU resulted in similar relapse-free survival and overall survival. Although prolonged exposure of tumor cells to 5-FU might theoretically result in enhanced cytotoxicity (18), the method resulting in the best clinical outcome remains unclear. Protracted infusion of 5-FU requires central venous access and an ambulatory infusion pump, which increases the complexity and cost of therapy. Recently, it has been demonstrated that capecitabine is a tumor-selective fluoropyrimidine carbamate that is converted to active 5-FU by thymidine phosphorylase. Thymidine phosphorylase is more concentrated in tumor than normal tissue (2) and is upregulated by RT in tumor, but not normal, tissue (3). Capecitabine can achieve a greater intratumoral 5-FU level and lower systemic 5-FU level compared with i.v. infusion of 5-FU (8). Theoretically, oral capecitabine could replace
Volume 67, Number 2, 2007
protracted infusion of 5-FU and avoid complicated procedures. Two randomized Phase III trials found that capecitabine use resulted in a superior overall response rate and safety profile compared with a bolus injection of FL for metastatic colorectal cancer (19, 20). On the basis of those results, the present study compared the outcomes of patients receiving either capecitabine or a bolus injection of FL for locally advanced rectal cancer. We found no significant differences between the two chemotherapeutic regimens in terms of short-term tumor responses according to the radiologic and pathologic findings. The groups did not differ in terms of sphincter preservation rate, MR volumetry, or pathologic results, including the complete response rate, downstaging, tumor regression grade, and toxicity. Although the study endpoints differed, the present results are consistent with those of the Intergroup 0144 study. However additional study is needed to confirm this result. This study examined the T stage and chose to exclude nodal status. Accurate preoperative staging is essential to plan optimal therapy for patients with rectal cancer. Transrectal ultrasonography and MRI are reliable methods of the assessment of the T stage, with accuracies as great as 80 –100% (21–24). However, lymph node evaluation can have a poor correlation between the pathologic and radiologic nodal status (25, 26). Morphologic criteria, such as the size and shape of the node, is difficult to distinguish between reactive and metastatic nodes, and micrometastasis in normal-size nodes occurs at a high frequency in rectal cancer compared with other pelvic tumors (27, 28). Thus, the present study did not consider nodal status when ana-
Table 5. Toxic effects (Grade 3 or worse*) of 5-fluorouracil/ leucovorin and capecitabine Type of toxic effect Hematologic toxicity Leukopenia Neutropenia Anemia Thrombocytopenia Nonhematologic toxicity Hand-foot syndrome Anorexia Vomiting Diarrhea Stomatitis Postoperative complications Ileus Voiding problem Wound problem Fever
FL (n ⫽ 145)
Capecitabine (n ⫽ 133)
5 2 3 2 0 8 0 3 0 4 1 4
9 3 4 5 0 4 0 1 1 2 1 5
1 2 1 0
1 2 1 1
p Value† 0.274
0.230
0.741
Abbreviation: FL ⫽ 5-fluorouracil and leucovorin. Some patients had more than one toxic effect. * National Cancer Institute Common Terminology Criteria for Adverse Events, version 2.0. † Two-tailed Fisher’s exact test.
Comparison of FL and capecitabine for rectal cancer
lyzing the downstaging effect of the two chemotherapeutic regimens. The present study had some limitations. First, the endpoints were limited to the short-term and locoregional effects. A more comprehensive comparison between the two chemotherapy regimens awaits analysis of long-term relapse-free and overall survival data. Second, this was a retrospective comparison study of two protocols using different chemotherapeutic regimens, not a randomized study. The initial attempts at a randomized protocol were thwarted by national insurance conditions and individual preferences, which were largely based on patients’ personal economic status. The data were analyzed with the assumption that the economic status would have no significant influence on tumor response. Third, the study populations of two groups
●
D. Y. KIM et al.
383
were not evenly distributed in terms of gender, age, and distance from anal verge. Although the differences between the two groups were not statistically significant, those could have had some influence on the rates of sphincter preservation, ypT0, and ypN0. Fourth, MR volumetry was obtained by two radiologists because of one leaving. Although image acquisition and tumor volume delineation were performed under the same protocol, interpersonal variation should be taken into consideration for interpretation of this study. Using the radiologic and pathologic findings, the present study, examining short-term tumor responses, could not find any significant differences between capecitabine and a bolus injection of FL for preoperative CRT for locally advanced rectal cancer. Long-term results and a prospective randomized trial are needed.
REFERENCES 1. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731–1740. 2. Miwa M, Ura M, Nishida M, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998;34: 1274 –1281. 3. Sawada N, Ishikawa T, Sekiguchi F, et al. X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts. Clin Cancer Res 1999;5:2948 –2953. 4. Kim JC, Kim TW, Kim JH, et al. Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2005;63:346 –353. 5. Kim JS, Kim JS, Cho MJ, et al. Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2002;54:403– 408. 6. O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protractedinfusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502–507. 7. Smalley SR, Benedetti JK, Williamson SK, et al. Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 2006;24:3542–3547. 8. Schuller J, Cassidy J, Dumont E, et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000;45:291–297. 9. Judson IR, Beale PJ, Trigo JM, et al. A human capecitabine excretion balance and pharmacokinetic study after administration of a single dose of 14C-labelled drug. Invest New Drugs 1999;17:49 –56. 10. Wolmark N, Wieand H, Hyams D, et al. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 2000;92:388 –396. 11. Dunst J, Reese T, Sutter T, et al. Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol 2002;20:3983–3991. 12. Kim YH, Kim DY, Kim TH, et al. Usefulness of magnetic resonance volumetric evaluation in predicting response to preoperative concurrent chemoradiotherapy in patients with
13.
14. 15. 16.
17.
18. 19.
20.
21. 22. 23. 24. 25.
resectable rectal cancer. Int J Radiat Oncol Biol Phys 2005;62:761–768. Therasse P, Arbuck SG, Eisenhauer EA, et al., for the European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000; 92:205–216. Adam IJ, Mohamdee MO, Martin IG, et al. Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet 1994;344:707–711. Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 1997;12:19 –23. Kim DW, Lim SB, Kim DY, et al. Preoperative chemoradiotherapy improves the sphincter preservation rate in patients with rectal cancer located within 3 cm of the anal verge. Eur J Surg Oncol 2006;32:162–167. Byfield JE, Calabro-Jones P, Klisak I, et al. Pharmacologic requirements for obtaining sensitization of human tumor cells in vitro to combined 5-fluorouracil or ftorafur and X rays. Int J Radiat Oncol Biol Phys 1982;8:1923–1933. Hansen RM, Quebbeman E, Anderson T. 5-Fluorouracil by protracted venous infusion: A review of current progress. Oncology 1989;46:245–250. Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 2001;19:4097– 4106. Hoff PM, Ansari R, Batist G, et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 2001;19:2282–2292. Rifkin MD, Ehrlich SM, Marks G. Staging of rectal carcinoma: Prospective comparison of endorectal US and CT. Radiology 1989;170:319 –322. Heriot AG, Grundy A, Kumar D. Preoperative staging of rectal carcinoma. Br J Surg 1999;86:17–28. Brown G, Richards CJ, Newcombe RG, et al. Rectal carcinoma: Thin-section MR imaging for staging in 28 patients. Radiology 1999;211:215–222. Laghi A, Ferri M, Catalano C, et al. Local staging of rectal cancer with MRI using a phased array body coil. Abdom Imaging 2002;27:425– 431. Nielsen MB, Qvitzau S, Pedersen JF. Detection of pericolonic
384
I. J. Radiation Oncology
●
Biology
●
Physics
lymph nodes in patients with colorectal cancer: An in vitro and in vivo study of the efficacy of endosonography. AJR Am J Roentgenol 1993;161:57– 60. 26. Zerhouni EA, Rutter C, Hamilton SR, et al. CT and MR imaging in the staging of colorectal carcinoma: report of the Radiology Diagnostic Oncology Group II. Radiology 1996;200:443– 451.
Volume 67, Number 2, 2007
27. Williams AD, Cousins C, Soutter WP, et al. Detection of pelvic lymph node metastases in gynecologic malignancy: A comparison of CT, MR imaging, and positron emission tomography. AJR Am J Roentgenol 2001;177:343–348. 28. Beets-Tan RG, Beets GL. Rectal cancer: Review with emphasis on MR imaging. Radiology 2004;232:335–346.