SEARCH

SEARCH BY CITATION

Keywords:

  • rectal cancer;
  • preoperative chemoradiotherapy;
  • postoperative chemoradiotherapy;
  • capecitabine;
  • randomized controlled trial

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

BACKGROUND:

Although many trials have shown the efficacy of preoperative chemoradiotherapy (CRT) or postoperative CRT compared with surgery alone, the optimal sequence of radiotherapy and surgery is unclear. The authors reported the final results of this single institution prospective randomized phase 3 trial comparing preoperative CRT with postoperative CRT using capecitabine in survival, local control, sphincter preservation, and toxicity for the treatment of locally advanced rectal cancer.

METHODS:

Patients with locally advanced rectal cancer (cT3, potentially resectable cT4 or N+) were randomly assigned to receive preoperative or postoperative CRT. CRT consisted of 50 Gy/25 fractions and concurrent capecitabine (1,650 mg/m2/day). Total mesorectal excision was performed.

RESULTS:

From March 2004 to April 2006, 240 patients were enrolled. Clinical characteristics were well balanced between both arms, except for more low-lying (<5 cm from anal verge) tumors in the preoperative CRT arm (60% vs 46%, P = .041). After a median follow-up time of 52 months, the 3- and 5-year disease-free survival, overall survival, and cumulative incidence of local recurrence were similar between both arms. However, for the patients with low-lying tumors, the preoperative CRT arm had a higher rate of sphincter preservation (68% vs 42%, P = .008). Acute and late complication rates were similar between both arms.

CONCLUSIONS:

Although significant benefit of preoperative CRT in local control and survival was not demonstrated, the data showed that increased rate of sphincter preservation was possible in low-lying tumors without jeopardizing local control and surgical complication by preoperative CRT. Cancer 2011;. © 2011 American Cancer Society.

In locally advanced rectal cancer, adjuvant chemoradiotherapy (CRT) improves local control and survival.1 Although radical surgery followed by adjuvant CRT had been the standard treatment, there was a recent change from postoperative CRT to preoperative CRT based on several studies.2, 3 These trials showed the superiority of preoperative CRT over postoperative CRT, but there were several differences in the results between the trials.2, 3 The German trial demonstrated significant improvement in local control, sphincter preservation rate, and treatment-related toxicities in the preoperative CRT arm but not in disease-free survival (DFS) or overall survival (OS).2 However, the NSABP R-03 trial showed improved DFS and a trend toward improved OS in the preoperative CRT arm but not in local control, sphincter preservation, and treatment-related toxicities.3 In previous randomized trials that compared preoperative CRT with radiotherapy (RT) alone for the treatment of locally advanced rectal cancer, preoperative CRT improved local control.4, 5

In those randomized controlled trials for preoperative CRT, bolus injection or continuous infusion of 5-fluorouracil (5-FU) was used.2-5 Although CRT with protracted 5-FU infusion has proven to be superior to conventional bolus injection,6 protracted infusion is an inconvenient and invasive procedure, requires an ambulatory infusion pump, and is associated with increased risk of infection and thrombosis. Several studies have examined the use of new oral chemotherapeutic agents in the CRT protocol for treatment of rectal cancer with many biologic and clinical advantages including mimicking protracted infusion of 5-FU.7-10 In a prospective phase 2 trial of preoperative CRT with capecitabine, we reported encouraging rates of tumor down-staging, sphincter preservation, and low toxicity.11

With such encouraging outcomes, we designed a prospective, single institution phase 3 trial that compared preoperative CRT and postoperative CRT in survival, local control, sphincter preservation, and treatment-related toxicity for treatment of locally advanced rectal cancer. We hypothesized that the superiority of preoperative CRT over postoperative CRT could be effectively evaluated by a single institution study of a high-volume center for better quality assurance in surgery and RT with the potential advantages of the modern approach of CRT using capecitabine. We present the final results of our trial with a median follow-up time of 52 months.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Eligibility and Randomization

The Institutional Review Board of Asan Medical Center approved this protocol. Patients were enrolled from March 2004 to April 2006. Patients with locally advanced rectal cancer (cT3 or potentially resectable cT4 or positive regional lymph node) on endorectal ultrasonography (EUS) and abdominopelvic computed tomography (CT) scan qualified for this study. Further eligibility criteria were similar to our previous phase 2 trial (Table 1).11 After written informed consent was obtained, all patients were randomly assigned to the preoperative CRT arm or the postoperative CRT arm (Fig. 1A). The treatment allocation was performed in a randomized permuted block method using random number tables and included stratification by gender.

Table 1. Eligibility Criteria
Inclusion Criteria
1. Histologically confirmed rectal adenocarcinoma
2. Tumor located below 10 cm from the anal verge
3. Clinical T3 or potentially resectable T4 stage or positive regional node on endorectal ultrasonography (EUS) and computed tomography (CT)
4. Patients must be >18 years and <76 years
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
6. Adequate bone marrow reserve (white blood cell count ≥4,000/mm3, absolute neutrophil count ≥1,500/mm3, platelet count ≥100,000/mm3, hemoglobin ≥10 g/dL)
7. Adequate renal function (serum creatinine level ≤1.5 mg/dL, calculated creatinine clearance ≥50 mg/min)
8. Adequate liver function (liver transaminase levels ≤3 times the upper normal limits, serum bilirubin ≤1.5 mg/dL).
9. Signed informed consent prior to randomization
Exclusion Criteria
1. Evidence of distant metastasis
2. Previous history of chemotherapy or radiotherapy
3. History of malignancy during recent 5 years other than skin cancer
4. Pregnant or lactating woman
5. Family history of colorectal cancer
thumbnail image

Figure 1. (A) A schematic diagram shows the trial design (apotentially resectable clinical T4 was included). (B) A CONSORT diagram shows patient distribution.

Download figure to PowerPoint

Treatment

The radiation dose for preoperative treatment was 46 Gy in 23 fractions to the whole pelvis followed by a boost dose of 4 Gy in 2 fractions. The radiation dose for postoperative RT was 50 Gy in 25 fractions to the whole pelvis. Detailed information on RT has been described previously.11

Capecitabine (825 mg/m2 twice per day, without weekend breaks) was initiated on the first day of RT and was delivered concurrently with RT. Adjuvant chemotherapy was initiated 4 weeks after surgery in the preoperative CRT arm and at 4 weeks after completion of CRT in the postoperative CRT arm. Adjuvant chemotherapy consisted of 4 cycles of capecitabine (2,500 mg/m2/day for 14 days, followed by a 1-week break) or 4 cycles of bolus 5-FU/leucovorin (375 mg 5-FU/m2/day and 20 mg leucovorin/m2/day for 5 days every 4 weeks), which was chosen based on patient economic status, because capecitabine is not covered by the medical insurance system of Korea. Patients were instructed to take capecitabine twice per day at 12-hour intervals, and to take one of the doses 1 hour before RT to maximize the radiosensitization effect based on our previous study.12

Total mesorectal excision (TME) was performed as the standard procedure, and the particular type of surgery was determined at the time of resection. All operations were carried out by specialist colorectal surgeons who had performed more than 200 TMEs each year for the past 5 years. Surgery was performed 4 to 6 weeks after completion of CRT.

Evaluation

Pretreatment evaluation included complete blood counts (CBC) and biochemical profiles, serum carcinoembryonic antigen, colonoscopy with biopsy, abdominopelvic CT scan, EUS, and chest CT scan. Clinical staging was based on abdominopelvic CT and EUS findings and the American Joint Committee on Cancer (AJCC) staging system.13

Treatment-related toxicity was evaluated according to National Cancer Institute Common Toxicity Criteria version 2.0.14 During CRT, patients were examined weekly. After completion of treatment, patients were scheduled for follow-up every 3 months for first 2 years, then every 6 months thereafter. Complete history and physical examination, complete blood count (CBC), biochemical profile, serum carcinoembryonic antigen (CEA), and chest radiography were performed at each follow-up. Abdominopelvic CT scan was performed every 6 months for first 2 years, then annually thereafter. Colonoscopic evaluation was performed annually.

After surgery and tumor fixation, the largest diameter of the tumor was recorded. Then tumor was examined by slicing it into 3- to 5-mm sections and stained with hematoxylin and eosin. If tumor cells were not found in initial examination, thinner slices were taken for further inspection. Complete lymph node dissection from perirectal fat tissue and microscopic examination were also performed. Pathologic stage was determined using the TNM classification system, as recommended by the AJCC.

Statistical Analysis

The primary end point was 3-year DFS. This study was designed to have 85% statistical power to detect an increase in DFS of 15% at 3 years in the preoperative CRT group, with a 2-sided significance level of 0.05. This required a sample size of 216 patients per treatment arm. The secondary end points were OS, local or distant relapse, sphincter preservation, and treatment-related toxicities.

All statistical analysis was performed using SPSS (version 14.0, SPSS Inc, Chicago, IL). Chi-square tests or Fisher exact tests were used to compare patient characteristics between both arms for categorical variables, and Student t tests were used to compare quantitative variables. All eligible patients were included in the evaluation of OS, DFS, and the cumulative incidence of local and distant recurrences based on intent-to-treat analysis. All events were determined from the first day of RT in the preoperative CRT arm and from the date of surgery in the postoperative CRT arm. Pathologic confirmation of recurrent disease was encouraged. If histologic evidence was not available, a clear demonstration of recurrent lesions or serial enlargement of the lesions based on radiology was accepted as the evidence of treatment failure. Elevated CEA alone was not considered as evidence of recurrence. Local recurrence was defined as tumor recurrence within radiation field in pelvic cavity, and distant metastasis was defined as any recurrence outside of pelvic cavity. All survival curves were estimated using the Kaplan-Meier method and were compared using the log-rank test. Two-tailed probability (P) values less than .05 were considered to indicate a significant difference.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Accrual of the Patients and Patient Characteristics

Between March 2004 and April 2006, 240 patients were randomly assigned to receive preoperative or postoperative CRT. We could not enroll the planned number of patients because patient accrual decreased after publication of the study by Sauer et al.2 In addition, randomization could have been affected by investigator preference for preoperative treatment for low-lying tumors; hence, we closed this protocol earlier than initially planned.

Among the 240 patients initially enrolled, 20 were determined to be ineligible for the following reasons: 10 patients withdrew consent, 5 had distant metastases that were detected after enrollment, 3 had early stage disease (cT2N0) on additional staging work-ups, 1 had a history of pelvic irradiation for uterine cervical cancer, and 1 had recurrent rectal cancer. Most of the characteristics of the 220 eligible patients were relatively well balanced between both arms (Table 2). However, there were significantly more patients with low-lying tumors (<5 cm from the anal verge) in the preoperative treatment arm (Table 2).

Table 2. Demographic and Clinical Characteristics of Enrolled Patients
VariablesPreoperative CRT Arm (n=107)Postoperative CRT Arm (n=113)P
  • CRT indicates chemoradiotherapy; CEA, carcinoembryonic antigen.

  • a

    The distance from the distal margin of tumor to anal verge.

  • Data presented as numbers, with percentages in parentheses.

Age, y  .185
 Median5456 
 Range29-7333-75 
Sex  .974
 Male67 (63)71 (63) 
 Female40 (37)42 (37) 
CEA level  .358
 Normal88 (82)98 (87) 
 Increased19 (18)15 (13) 
Tumor locationa  .041
 Low (<5 cm)64 (60)52 (46) 
 Middle (5-10 cm)43 (40)61 (54) 
Grade (n=203)  .095
 Well differentiated17 (18)9 (8) 
 Moderately differentiated71 (76)93 (85) 
 Poorly differentiated5 (6)8 (7) 
Clinical stages  .883
 T3N035 (32)36 (32) 
 T4N00 (0)1 (1) 
 T2N+1 (1)3 (2) 
 T3N+70 (66)72 (64) 
 T4N+1 (1)1 (1) 

Treatment

A total of 107 patients were randomly assigned to the preoperative CRT arm and 113 patients to the postoperative CRT arm. CRT was not administered to 16 patients assigned to the postoperative CRT arm (Fig. 1B). Two patients in the preoperative CRT arm did not have surgical resection after preoperative CRT, and there were protocol violations in 11 patients, including 10 patients in the postoperative CRT arm who were transferred to regional hospitals and received nonprotocol-based treatment (Fig. 1B).

RT was completed according to protocol in 106 patients from the preoperative CRT arm and 86 patients from the postoperative CRT arm (99% vs 76%, P < .001) (Table 3). Concurrent chemotherapy was completed according to protocol in 100 patients from the preoperative CRT arm and 85 patients from the postoperative CRT arm (93% vs 75%, P < .001). Thus, 99 patients (93%) in the preoperative CRT arm and 84 patients (74%) in the postoperative CRT arm completed CRT as protocol.

Table 3. Treatment Compliance of Patients in the Preoperative and Postoperative Treatment Arms
VariablesPreoperative CRT Arm (n=107)Postoperative CRT Arm (n=113)P
  1. CRT indicates chemoradiotherapy.

  2. Data presented as numbers, with percentages in parentheses.

Radiotherapy  <.001
 50 Gy106 (99)86 (76) 
 48 Gy1 (1)1 (1) 
 No CRT0 (0)16 (14) 
Chemotherapy   
 Concurrent chemotherapy <.001
  Full dose100 (93)85 (75) 
  Dose reduction3 (3)1 (1) 
  Incompletion of the full cycle4 (4)1 (1) 
  No CRT0 (0)16 (14) 
 Adjuvant chemotherapy .002
  Capecitabine82 (77)66 (58) 
   Full dose6451 
   Dose reduction1413 
   Incompletion of the full cycle42 
  5-FU/Leucovorin13 (12)17 (15) 
   Full dose45 
   Dose reduction910 
   Incompletion of the full cycle02 
 No chemotherapy12 (11)20 (18) 
Protocol violation0 (0)10 (9).002

Among all patients, except the patients who did not received the postoperative CRT (16 patients), 16 (7%) never started adjuvant chemotherapy due to disease progression (5 patients), postoperative complication (3 patients), refusal (3 patients), toxic effects of concurrent CRT (1 patient), and other causes (4 patients). Treatment compliance with the adjuvant chemotherapy was better in the preoperative CRT arm. Adjuvant chemotherapy was administered to 95 patients in the preoperative CRT arm and 83 patients in the postoperative CRT arm (89% vs 73%, P = .002) as full dose or modified dose/cycle. The full protocol dose was administered to 68 patients in the preoperative-CRT arm and 56 patients in the postoperative CRT arm (64% vs 50%, P = .036).

Surgery and Pathologic Findings

Complete resection confirmed by pathologic examination was performed in 217 of 218 patients who had resection. In 1 patient, the tumor could not be completely resected due to extensive vaginal invasion. The sphincter-sparing rate was similar in the 2 groups; however, among patients with low-lying tumors, the preoperative CRT arm had a higher rate of sphincter-sparing surgery (Table 4).

Table 4. Type of Surgery and Rate of Sphincter-Sparing Procedures in the Preoperative and Postoperative Treatment Arms
 All PatientsPatients With Low-Lying Tumorsa
 Preoperative CRT ArmPostoperative CRT ArmPreoperative CRT ArmPostoperative CRT Arm
  • CRT indicates chemoradiotherapy; APR, abdominoperineal resection; LAR, low anterior resection.

  • a

    Distal margin of tumor located within 5 cm from anal verge.

  • Data presented as numbers, with percentages in parentheses.

APR19 (18)31 (27)18 (29)29 (56)
LAR84 (80)81 (72)42 (68)22 (42)
Others2 (2)1 (1)2 (3)1 (2)
P.248.008

Pathologic stage was lower in the preoperative CRT arm than in the postoperative CRT arm (Table 5). Complete disappearance of the primary tumor in pathology specimens (ypCR-T) occurred in 22 patients (21%), and 83 patients (79%) had no tumor cells in their lymph node specimen (ypCR-N). Four of the ypCR-T patients had residual tumor cells in lymph nodes; thus, complete tumor disappearance occurred in 18 patients (17%). The mean tumor size was significantly smaller in the preoperative CRT arm and microscopic tumor invasions such as perineural and/or lymphovascular invasion were less frequent in preoperative CRT arm (Table 5).

Table 5. Pathologic Findings for the Preoperative and Postoperative Treatment Arms
VariablesPreoperative CRT Arm (n=105)Postoperative CRT Arm (n=113)P
  1. CRT indicates chemoradiotherapy; SD, standard deviation.

  2. Data presented as numbers, with percentages in parentheses.

T stage  <.001
 T022 (21)0 (0) 
 T13 (3)1 (1) 
 T231 (29)16 (14) 
 T349 (47)92 (81) 
 T40 (0)4 (4) 
N stage  <.001
 N083 (79)36 (32) 
 N116 (15)44 (39) 
 N26 (6)33 (29) 
TNM stage  <.001
 018 (17)0 (0) 
 I26 (25)9 (8) 
 II34 (32)24 (21) 
 III26 (25)77 (68) 
 IV1 (1)3 (3) 
Tumor size  <.001
 Mean±SD (cm)1.9±1.75.5±1.5 
Perineural invasion  .045
 No94 (89)90 (80) 
 Yes11 (11)23 (20) 
Lymphovascular invasion <.001
 No96 (91)70 (62) 
 Yes9 (9)43 (38) 
Complete resection  1.000
 Complete105 (100)112 (99) 
 Incomplete0 (0)1 (1) 

Acute Toxicities and Postoperative Complications

Preoperative and postoperative CRT was relatively well tolerated in most patients, and there was no treatment-related mortality. Most acute adverse events were mild to moderate, and all of them resolved spontaneously with supportive care (Table 6). The overall incidence of acute toxicities was comparable between both arms (15% vs 16%, P = .827).

Table 6. Grade 3 or Higher Toxicities Related to Chemoradiotherapy in the Preoperative and Postoperative Treatment Arms
 Preoperative CRT Arm (n=107)Postoperative CRT Arm (n=87)
  • CRT indicates chemoradiotherapy.

  • a

    Complications within 2 months from the date of surgery.

  • b

    Complications after 2 months from the date of surgery.

  • Data presented as numbers, with percentages in parentheses.

Acute toxicities  
 Dermatitis3 (3)5 (6)
 Proctitis3 (3)4 (5)
 Hand-foot syndrome3 (3)2 (2)
 Leukopenia3 (3)4 (5)
 Anemia6 (6)1 (1)
 Thrombocytopenia1 (1)0 (0)
 Any grade 3 or higher toxicities16 (15)14 (16)
Perioperative complicationsa 
 Ileus/obstruction5 (5)5 (6)
 Anastomotic leakage2 (2)5 (6)
 Wound healing1 (1)1 (1)
 Fistula1 (1)0 (0)
 Any grade 3 or higher toxicities8 (9)10 (12)
Late complicationsb  
 Pelvic abscess2 (2)0 (0)
 Anastomotic leakage2 (2)0 (0)
 Ureteral stricture2 (2)0 (0)
 Ileus/obstruction1 (1)2 (2)
 Fistula1 (1)0 (0)
 Rectal stricture0 (0)1 (1)
 Any grade 3 or higher toxicities8 (8)3 (3)

Perioperative (within 2 months of surgery) and late complications (more than 2 months after surgery) were also similar between both arms (Table 6). All patients recovered after supportive care or surgical treatment. Among the patients with perioperative complications, 8 patients in the preoperative CRT arm and 10 patients in the postoperative CRT arm had grade 3 or 4 toxicities (9% vs 12%, P = .359). Among the patients with late complications, 8 patients in the preoperative CRT arm and 3 patients in the postoperative CRT arm had grade 3 or 4 toxicities (8% vs 3%, P = .350).

Patterns of Failure and Survival

After a median follow-up time of 52 months, 24% of patients in the preoperative CRT arm and 25% of patients in the postoperative CRT arm experienced treatment failure. Follow-up data were missing for 1 patient in the postoperative CRT arm. In the preoperative CRT arm, we observed local failure alone in 3 patients (3%), distant failure alone in 23 patients (21%), and synchronous local and distant failure in 1 patient (1%). In the postoperative CRT arm, we observed local failure alone in 2 patients (2%), distant failure alone in 22 patients (19%), and synchronous local and distant failure in 5 patients (4%).

The estimated 3- and 5-year DFS (77% vs 74% and 73% vs 74%, P = .8656) and OS (91% vs 90% and 83% vs 85%, P = .6204) did not differ significantly between both arms (Figs. 2A and 2B). There was also no significant difference between both arms in the 3- and 5-year cumulative incidence of local recurrence (3% vs 6% and 5% vs 6%, P = .3925) and distant metastasis (21% vs 24% and 23% vs 24%, P = .7384) (Figs. 2C and 2D). Although tumor location was explored to investigate any influence of the treatment effect between the 2 arms on survival or local control, there was no evidence of any interactions.

thumbnail image

Figure 2. Graphs show (A) comparison of disease-free survival (DFS), (B) comparison of overall survival (OS), (C) comparison of cumulative incidence of local recurrence, and (D) comparison of cumulative incidence of distant metastasis.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Compliance and Toxicity

In the current trial, preoperative and postoperative CRT with capecitabine was well tolerated by most patients, and there was no significant difference in acute and late toxicities in both arms. Compliance rate was higher in the preoperative CRT arm. However, most of the noncompliant patients in the postoperative CRT arm were those who were transferred from distant cancer centers and travel problems led to noncompliance. Although they were regarded as a noncompliance group in our protocol, they all received one of the standard treatments recommended by National Comprehensive Cancer Network (NCCN) guidelines in regional cancer centers.

Postoperative CRT arm of our trial had a more favorable toxicity profile and compliance than those of the German or NSABR-R03 trial,2, 3 although we cannot explain. It is possible that this difference might be due to the use of different chemotherapeutic agents. The design of the current trial was similar to other phase 3 trials,2, 3 but we used oral capecitabine based on encouraging results of our previous studies.11, 12 Clearly, more data are needed to determine whether continuous infusion or bolus injection of 5-FU is more effective for treatment of rectal cancer.15 However, previous retrospective studies comparing capecitabine and 5-FU indicated that capecitabine was at least as effective as 5-FU in preoperative CRT regimen.16-19 The NSABP R-04 trial is expected to provide important information about the efficacy of oral capecitabine versus 5-FU chemotherapy.20 This trial has completed accrual and the results are pending. Surgeon factor could be another possible reason for the superior result of the current study than the German trial. Because the current trial was a single institution study of a high-volume center and our retrospective study also showed relatively low incidence of late complications in the postoperative RT group, better quality in surgery and RT could be possible reasons.21

In our current study, we used a 7-day-per-week capecitabine schedule based on our previous phase 2 trial that showed encouraging rates of tumor down-staging and sphincter preservation with a low toxicity profile.11 However, a 7-day-per-week schedule is not the golden standard of care, and a 5-day-per-week schedule used in many centers could be superior to the 7-day regimen in the view of compliance and toxicity, with similar efficacy.22 We think that further study concerning this issue will be needed for the establishment of an ideal regimen of capecitabine with preoperative RT in rectal cancer.

Sphincter Preservation

One of the rationales for preoperative CRT is the enhancement of sphincter preservation in patients with low rectal cancer. The current study showed that low-lying rectal cancer patients in the preoperative CRT arm had significantly better sphincter preservation than did patients in the postoperative CRT arm, but sphincter preservation did not produce negative effects in terms of complications and disease control in the preoperative CRT arm.

However, functional outcome after sphincter preservation was not examined in the German and the current trial.2 The ultimate goal of sphincter preservation must be improvement in quality of life and not simply preservation of the sphincter complex. We suggest that future trials use a functional end point to assess sphincter preservation.

Pathologic Response

In the current trial, even though we performed meticulous pathologic examination described previously,11 our ypCR rate or other histologic parameters were comparable with other studies that used capecitabine,16-18, 23-26 and our ypCR rate was higher than that of the German trial (17% vs 8%) in spite of more adverse factors (Table 7).2

Table 7. Summary of Phase 3 Prospective Randomized Trials That Compared Preoperative and Postoperative Chemoradiotherapy for Locally Advanced Rectal Cancer
AuthorsSauer et al2Rho et al3Current Trial
  • pCR indicates pathologic complete response; CRT, chemoradiotherapy.

  • a

    Information for node-positive disease was missing in 7% of patients.

  • b

    Information for the location of disease was missing in 9% of patients.

  • c

    Palpable tumor/nonpalpable tumor; the patients with multiple tumors were excluded.

  • d

    Preoperative CRT arm/postoperative CRT arm.

  • e

    Among patients with tumors that were determined to require abdominoperineal resection before randomization.

  • f

    Among all evaluable patients regardless of tumor location.

  • g

    Among patients with tumors located <5 cm from the anal verge.

  • Numbers in table are percentages unless stated otherwise.

Enrollment period1995-20021993-19992004-2006
No. of eligible patients799254220
Median follow-up (y)3.88.44.3
cT1-2/T3/T4/Unknown5/67/4/24Unknown2/97/1/0
Clinical node-positive disease52aUnknown67
Distal/middle/proximal location34/42/15b81/17c53/47/0
pCR in preoperative CRT arm81517
pT1-2N0 in postoperative CRT arm18Unknown8
Sphincter preservation rated39/19e48/39f68/42g
5-year local recurrence rated6/1311/115/6
5-year disease-free survival rated68/6565/5373/74
5-year overall survival rated76/7475/6683/85
Any grade 3 or higher acute toxicitiesd27/4052/4915/16

The exact reason for these differences is not clear, but we propose the following 2 explanations. First, use of capecitabine during the whole period of RT with an optimized time interval between capecitabine intake and radiation might have enhanced the radiosensitizing effect of capecitabine relative to bolus 5-FU injection.12 Second, racial and genetic differences among the patients of East and West may account for the differences. The first explanation seems to be reasonable but not conclusive because pathologic complete response rate has been reported to be slightly higher in the capecitabine-based regimen than 5-FU.2, 3, 16-18, 20, 27 The second explanations are difficult to prove but commonly used.

Local Control and Survival

Previous German and NSABP phase 3 trials demonstrated the superiority of preoperative CRT in terms of local control and DFS (Table 7),2, 3 but we could not observe such benefits in the current study. Because the statistical power of the current trial was limited owing to premature closure, the superiority of preoperative CRT over postoperative CRT might not be excluded. However, our postoperative CRT arm had better 5-year OS and DFS rates (85% and 74%) than those reported in the German trial (74% and 65%) and NSABP-R03 trial (66% and 53%).2, 3 The 5-year cumulative incidence of local recurrence in our postoperative-CRT arm was similar to that of the preoperative CRT arm of the German trial (6%).2

One possible reason for this discordance may be that patients in the 2 studies had different distribution of cancer stage. However, we believe that this is unlikely because the proportion of clinical T4 disease was only 3% in the German trial and pathologic stage 3 disease was more prevalent in our study (68% and 40%). Moreover, the rate of overstaging in our study was 8%, which was lower than in the German trial (18%).2 Relatively high compliance rate in our study may be another possible explanation for this discordance. Pre- and postoperative CRT were both well tolerated by most patients in our study. Other trials reported very high rates of acute toxicities of grade 3 or higher (40%-49%), much higher than for the patients of our postoperative CRT arm.2, 3 Moreover, almost half of the patients in the German trial did not receive planned postoperative CRT.2 Another possible reason for our better results may be associated with a single institution study performed in a high-volume hospital. Hospital volume factor seems to play an important role in achieving high local control.28 The current trial was conducted in a high-volume tertiary referral center (with >2,500 beds), and participating surgeons were those who had performed more than 200 TMEs each year for the past 5 years. Also, the parameters for RT in a single institution study would likely be more uniform than in the multicenter trials.29 RT was performed by a single radiation oncologist who majored in gastrointestinal oncology.

Summary

One of the major strengths of the current single institution study of a high-volume center is that it allowed for better quality assurance in surgery and RT than a multicenter trial and the multidisciplinary teamwork that goes with that, so the quality of overall care was probably better and more homogeneous than the German trial. Also, the current trial included only middle and distal tumors, which had a higher risk of local recurrence than proximal tumors and which made the current trial more appropriate for evaluation of the role of RT as a local modality. This trial was closed prematurely; although the German trial that used bolus 5-FU globally accepted at that time hampered our ability to complete patient accrual, our trial provided a more modern approach in preoperative CRT for locally advanced rectal cancer with the oral fluoropyrimidine, capecitabine.

The results of the current trial suggested that preoperative or postoperative CRT with capecitabine was well tolerated by most rectal cancer patients and that treatment compliance was excellent. Perioperative and long-term late complications were not increased by use of preoperative CRT. Although we could not demonstrate significant benefit of preoperative CRT in terms of local control and survival, the rate of sphincter-sparing surgery was higher in preoperative CRT patients with low-lying rectal tumors without jeopardizing local control and surgical safety by preoperative CRT.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES
  • 1
    NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990; 264: 1444-1450.
  • 2
    Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004; 351: 1731-1740.
  • 3
    Roh MS, Colangelo LH, O'Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009; 27: 5124-5130.
  • 4
    Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006; 24: 4620-4625.
  • 5
    Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006; 355: 1114-1123.
  • 6
    O'Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med. 1994; 331: 502-507.
  • 7
    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.
  • 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
    Shimma N, Umeda I, Arasaki M, et al. The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, capecitabine. Bioorg Med Chem. 2000; 8: 1697-1706.
  • 10
    Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol. 1997; 15: 110-115.
  • 11
    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.
  • 12
    Yu CS, Kim TW, Kim JH, et al. Optimal time interval between capecitabine intake and radiotherapy in preoperative chemoradiation for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2007; 67: 1020-1026.
  • 13
    Greene F, Page D, Fleming I, Abt M. American Joint Committee on Cancer staging manual. 6th ed. New York: Springer, Inc., 2002.
  • 14
    Trotti A, Byhardt R, Stetz J, et al. Common toxicity criteria: version 2.0. an improved reference for grading the acute effects of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol Phys. 2000; 47: 13-47.
  • 15
    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.
  • 16
    Kim DY, Jung KH, Kim TH, et al. Comparison of 5-fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2007; 67: 378-384.
  • 17
    Das P, Lin EH, Bhatia S, et al. Preoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: a matched-pair analysis. Int J Radiat Oncol Biol Phys. 2006; 66: 1378-1383.
  • 18
    Yerushalmi R, Idelevich E, Dror Y, et al. Preoperative chemoradiation in rectal cancer: retrospective comparison between capecitabine and continuous infusion of 5-fluorouracil. J Surg Oncol. 2006; 93: 529-533.
  • 19
    Chan AK, Wong AO, Jenken DA. Preoperative capecitabine and pelvic radiation in locally advanced rectal cancer—is it equivalent to 5-FU infusion plus leucovorin and radiotherapy? Int J Radiat Oncol Biol Phys. 2010; 76: 1413-1419.
  • 20
    O'Connell MJ, Wolmark N, Beart R, Petrelli N. Update on design of the National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol. 2005; 23: 933-934.
  • 21
    Kim CW, Kim JH, Yu CS, et al. Complications after sphincter-saving resection in rectal cancer patients according to whether chemoradiotherapy is performed before or after surgery. Int J Radiat Oncol Biol Phys. 2010; 78: 156-163.
  • 22
    Craven I, Crellin A, Cooper R, Melcher A, Byrne P, Sebag-Montefiore D. Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer. Br J Cancer. 2007; 97: 1333-1337.
  • 23
    De Paoli A, Chiara S, Luppi G, et al. Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study. Ann Oncol. 2006; 17: 246-251.
  • 24
    Dupuis O, Vie B, Lledo G, et al. Preoperative treatment combining capecitabine with radiation therapy in rectal cancer: a GERCOR Phase II Study. Oncology. 2007; 73: 169-176.
  • 25
    Ngan SY, Michael M, Mackay J, et al. A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer. Br J Cancer. 2004; 91: 1019-1024.
  • 26
    Slampa P, Kocakova I, Sefr R, et al. Neoadjuvant treatment for locally advanced rectal adenocarcinoma with concomitant radiotherapy and oral capecitabine. J BUON. 2004; 9: 33-40.
  • 27
    Crane CH, Sargent DJ. Substitution of oral fluoropyrimidines for infusional fluorouracil with radiotherapy: how much data do we need? J Clin Oncol. 2004; 22: 2978-2981.
  • 28
    Holm T, Johansson H, Cedermark B, Ekelund G, Rutqvist LE. Influence of hospital- and surgeon-related factors on outcome after treatment of rectal cancer with or without preoperative radiotherapy. Br J Surg. 1997; 84: 657-663.
  • 29
    Kouloulias VE, Bosset JF, van Tienhoven G, Davis BJ, Pierart M, Poortmans P. Quality assurance in the EORTC 22921 trial on preoperative radiotherapy with or without chemotherapy for resectable rectal cancer: evaluation of the individual case review procedure. Eur J Cancer. 2002; 38: 1849-1856.