⅐ N U M B E R 3 1 ⅐ N O V E M B E R 1 2 0 0 9
Preoperative Multimodality Therapy Improves Disease-FreeSurvival in Patients With Carcinoma of the Rectum:NSABP R-03Mark S. Roh, Linda H. Colangelo, Michael J. O’Connell, Greg Yothers, Melvin Deutsch, Carmen J. Allegra,Morton S. Kahlenberg, Luis Baez-Diaz, Carol S. Ursiny, Nicholas J. Petrelli, and Norman WolmarkPurpose Although chemoradiotherapy plus resection is considered standard treatment for operable rectal
carcinoma, the optimal time to administer this therapy is not clear. The NSABP R-03 (National
Surgical Adjuvant Breast and Bowel Project R-03) trial compared neoadjuvant versus adjuvant
chemoradiotherapy in the treatment of locally advanced rectal carcinoma. Patients and Methods
Patients with clinical T3 or T4 or node-positive rectal cancer were randomly assigned to
preoperative or postoperative chemoradiotherapy. Chemotherapy consisted of fluorouracil and
leucovorin with 45 Gy in 25 fractions with a 5.40-Gy boost within the original margins of treatment.
In the preoperative group, surgery was performed within 8 weeks after completion of radiother-
apy. In the postoperative group, chemotherapy began after recovery from surgery but no later than
4 weeks after surgery. The primary end points were disease-free survival (DFS) and overall
From August 1993 to June 1999, 267 patients were randomly assigned to NSABP R-03. The
Supported by Public Health Service Grants
intended sample size was 900 patients. Excluding 11 ineligible and two eligible patients without
follow-up data, the analysis used data on 123 patients randomly assigned to preoperative and 131
to postoperative chemoradiotherapy. Surviving patients were observed for a median of 8.4 years.
The 5-year DFS for preoperative patients was 64.7% v 53.4% for postoperative patients
(P ϭ .011). The 5-year OS for preoperative patients was 74.5% v 65.6% for postoperative
patients (P ϭ .065). A complete pathologic response was achieved in 15% of preoperative
patients. No preoperative patient with a complete pathologic response has had a recurrence. Conclusion
Preoperative chemoradiotherapy, compared with postoperative chemoradiotherapy, significantly
Clinical Trials repository link available on
improved DFS and showed a trend toward improved OS. J Clin Oncol 27:5124-5130. 2009 by American Society of Clinical Oncology
locoregional tumor recurrence at 2 years from 8.2%
INTRODUCTION
in the surgery-only arm to 2.4%.5 The addition of
Radiotherapy and surgical resection are standard
radiotherapy did not prolong survival compared
components of therapy for patients with stage
with surgery alone. The European Organisation for
II/III carcinoma of the rectum.1,2 Numerous ran-
Research and Treatment of Cancer (EORTC) eval-
uated the value of preoperative chemoradiotherapy
domized trials have investigated the impact ofdose modifications and preoperative/postopera-
or preoperative radiotherapy alone and postopera-
tive administration in an effort to improve safety
tive chemotherapy versus preoperative radiotherapyand surgery alone. The addition of fluorouracil
without compromising effectiveness, reduce theincidence of local recurrence, and significantly pro-
and leucovorin to the preoperative administra-
tion of 45 Gy during 5 weeks reduced locoregional
The Dutch Colorectal Cancer Group adminis-
recurrence from 17.1% to 8.5%; the 5-year overall
tered 25 Gy during 5 days followed by immediate
survival (OS) did not improve with the addition of
total mesorectal resection and significantly reduced
chemotherapy.6,7 A similar study conducted by the
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Preoperative Therapy Improves DFS in Rectal Carcinoma
Fe´de´ration Francophone de Cance´rologie Digestive in France (FFCD)
there is a difference in disease-free survival (DFS) and OS when the
compared the combination of preoperative chemotherapy (fluorou-
radiation therapy and chemotherapy are administered preoperatively
racil and leucovorin) and radiotherapy versus preoperative radiother-
compared with all therapy being administered postoperatively. Addi-
apy alone, with all patients receiving postoperative chemotherapy.8 The
tional aims were to determine if preoperative therapy results in im-
administration of postoperative chemotherapy reduced local recurrence
provement in local recurrence rates compared with postoperative
compared with radiotherapy alone; 5-year survival did not differ between
therapy, compare the proportion of patients receiving sphincter-
the two groups. The German Rectal Cancer Study Group trial compared
saving surgery (SSS) in the two treatment arms, and correlate the
preoperative to postoperative chemoradiotherapy in patients with
response to preoperative therapy with DFS and OS.
clinical stage T3 or T4 or node-positive disease.9 The 5-year locore-gional recurrence rate decreased from 13% in the postoperativegroup to 6%. Survival was not different between the two groups. PATIENTS AND METHODS
The NSABP R-03 (National Surgical Adjuvant Breast and Bowel
Project R-03) trial was designed to determine the best time to admin-
Patients
ister multimodality therapy to patients with stage II/III carcinoma of
These studies were approved by institutional review committees, with
the rectum. The primary aim of this study was to determine whether
assurances approved by the Department of Health and Human Services, and
Fig 1. (A) CONSORT diagram showing
stage of National Surgical Adjuvant Breastand Bowel Project R-03 trial. (B) Diagramof chemotherapy and radiotherapy treat-
Preoperative workup to determine eligibility
ment regimens. (*) Forty-five Gy in 25fractions with a 5.4 Gy boost within theoriginal margins of treatment. FU, fluorou-
racil; LV, leucovorin; APR, anterior-posteriorresection; RTX, radiation therapy.
LV 20 mg/m2 for 5 days(1st and 5th week of RTX)
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Table 1. NSABP R-03 Trial Patient Eligibility and Ineligibility Criteria Table 1. NSABP R-03 Trial Patient Eligibility and Ineligibility Criteria (continued)
14. Patients having nonmalignant systemic disease (cardiovascular,
1. The patient must consent to be in the study. The informed consent
renal, hepatic, etc.), which would preclude their being subjected to
form conforming to federal and institutional guidelines must be
the treatment (surgery, chemotherapy, and radiotherapy).
signed, witnessed, and dated prior to random assignment.
15. Patients with active inflammatory bowel disease.
2. Patients in whom the diagnosis of invasive rectal cancer has been
16. Patients who are pregnant at the time of random assignment.
obtained by incisional (surgical or endoscopic) biopsy so that the
17. Patients with psychiatric or addictive disorders that would preclude
majority of the tumor has not been removed are eligible.
3. Patients must be able to begin protocol therapy (surgery or chemo-
18. Patients who have multiple primary tumors involving both the colon
therapy) within 49 days from initial histologic diagnosis.
and rectum that would preclude them from being classified as
4. Patients must have a life expectancy of at least 10 years, excluding
19. Patients who are found, by endoluminal ultrasonography, to have a
5. The tumor should be either palpable by clinical rectal examination or
be accessible via a proctoscope or sigmoidoscope, and its distalborder should be located no more than 15 cm from the anal verge.
Abbreviations: NSABP R-03, National Surgical Adjuvant Breast and Bowel
Project R-03; CT, computed tomography.
6. The tumor should be movable on clinical examination without
ءEligible patients having histologic diagnosis by proctoscopic incisional
evidence of fixation to the pelvis or to surrounding organs (vagina,
biopsy of invasive rectal adenocarcinoma will be considered for entry in
prostate, bladder) beyond the limits of resection via exenteration.
7. The patient must have no radiologic evidence of metastatic spread.
†Performance status key: 0, normal activity; 1, symptoms but ambulatory; 2,
The patient must have a CT scan of the abdomen and pelvis prior to
in bed Յ 50% of the time; 3, in bed Ͼ 50% of the time; 4, 100% bedridden.
random assignment. Any suspicious findings (ie, liver nodule,retroperitoneal adenopathy) will render the patient ineligible unlessmalignancy is ruled out by further tissue documentation (CT- orultrasound-guided biopsy, laparoscopic biopsy, or open biopsy) priorto random assignment.
are in accordance with the Helsinki Declaration. Informed consent was re-
8. Evidence by CT scan of enlarged perirectal or pelvic lymph nodes is
quired for participation. Patients were randomly assigned to preoperative
not a condition of ineligibility unless they appear to preclude
(group 1) or postoperative (group 2) administration of adjuvant chemother-
apy with radiotherapy, as indicated in the CONSORT diagram (Fig 1A).
9. The WBC count must be Ն 4,000/L and the platelet count must be
Patients were eligible if they had a histologic diagnosis of rectal adenocarci-
10. There must be evidence at random assignment of adequate hepatic
noma, as defined by the distal border of the tumor being no more than 15 cm
and renal function (bilirubin and AST or ALT; creatinine must be
from the anal verge as measured using a rigid proctoscope or sigmoidoscope.
Յ 1.5ϫ the upper limit of normal for the performing laboratory).
Patients must have been able to begin treatment (surgery or chemotherapy)
11. Patients with more than one synchronous rectal lesion are eligible.
within 49 days from the histologic diagnosis. Other eligibility criteria included
12. Patients with a performance status of 0, 1, or 2 are eligible.†
no radiologic evidence of metastatic disease on abdominal and pelvic com-
puted tomography (CT) scans, an Eastern Cooperative Oncology Group
1. Patients with malignant rectal tumors other than adenocarcinoma
(ECOG) performance status Յ 2, adequate blood counts, and adequate he-
(eg, sarcoma, lymphoma, carcinoid, squamous cell carcinoma, or
patic and renal function. Endoscopic ultrasound was optional as a staging
technique. Table 1 lists criteria for patient eligibility or ineligibility.
2. Patients who have life expectancy of Ͻ 10 years, excluding their
Treatment
3. Patients who demonstrate, prior to random assignment, evidence of
Patients were stratified according to sex and age (Յ 60 or Ͼ 60 years).
free perforation, as manifested by free air or free fluid in theabdomen. Patients with walled-off perforations are eligible.
Table 2 lists patient characteristics. The prescribed amount of chemotherapy
4. Patients with a previous or concomitant malignancy, regardless of
site, except patients with squamous or basal cell carcinoma of theskin, or carcinoma in situ of the cervix that has been adequatelytreated. Table 2. Characteristics of Eligible Patients in NSABP R-03 Trial
5. Patients who have received surgical treatment for rectal cancer,
other than preliminary decompressing colostomy or diagnostic
laparoscopy or laparotomy without any resection of primary tumor.
6. Patients who have received any other therapy (radiation, chemother-
apy) for rectal cancer prior to random assignment.
7. Patients in whom rectal cancer was diagnosed by excisional biopsy
(removal of polyp with adenocarcinoma, removal of villous adenoma
8. Patients who are unable to begin protocol therapy within 49 days
9. Patients with a tumor whose distal border is located more than 15
10. Patients whose tumor is fixed by clinical examination to surrounding
structures, precluding the possibility of adequate surgical resection
11. Patients who show radiologic evidence of advanced disease
(inoperable locoregional disease, or metastatic disease). Evidence of
biopsy-proven retroperitoneal lymph node involvement will deem a
12. Patients who demonstrate involvement of perirectal or pelvic lymph
nodes with evidence of fixation to the pelvic side wall.
13. Patients with a performance status of 3 or 4.†
Abbreviations: NSABP R-03, National Surgical Adjuvant Breast and Bowel
Project R-03; SSS, sphincter-saving surgery.
ءExcludes patients with multiple tumors.
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Preoperative Therapy Improves DFS in Rectal Carcinoma
according to the protocol consisted of seven cycles; the duration of cycle 1 and
1 was assessed with proctosigmoidoscopy after patients completed the first
cycles 4 to 7 was 8 weeks including rest periods. Chemotherapy administered
cycle of chemotherapy (within 2 weeks of the beginning of radiotherapy) and
during radiotherapy was considered cycles 2 and 3. A schematic of chemother-
on completion of radiotherapy (no sooner than 2 weeks after completion of
apy and radiation therapy regimens is provided in Figure 1B. The pelvis was
radiotherapy, but before tumor removal).
treated with 45 Gy in 25 fractions to the isocenter using a four-field box
The diagnosis of recurrence was made on the basis of imaging and, if
technique with a 5.4-Gy boost in three fractions to a restricted volume. All
possible, cytologic analysis or biopsy. An elevated carcinoembyronic antigen as
simulation portal films and dosimetry data were centrally reviewed.
a solitary finding was not acceptable evidence of treatment failure.
The treating physician determined the type of surgical procedure for
each patient. Acceptable procedures included an abdominoperineal resection,
Statistical Methods
low anterior resection (including coloanal), and local excision. Group 1 pa-
Patients were randomly assigned to either pre- or postoperative chemo-
tients who were found after surgery to have a stage I tumor were to continue
therapy and radiation and were stratified by age (Յ 60 years or Ͼ 60 years), sex,
protocol therapy because it was not evident in which patients this was a true
and randomizing institution using a biased coin minimization algorithm.10
stage I tumor and in which this was a result of the downstaging effect of
The protocol-specified primary end points were DFS and OS. Data on all
chemotherapy/radiotherapy. Group 2 patients who were found after surgery
patients who were eligible and had follow-up were used in the primary analy-
to have a stage I tumor were treated at the discretion of the investigator.
ses, and patients were analyzed according to their randomly assigned therapy
Group 1 patients who developed progressive inoperable disease (ad-
regardless of therapy actually received. DFS was defined as the time from
vanced locoregional or distant) while receiving chemotherapy or radiotherapy
random assignment to recurrence, second primary cancer (excluding basal cell
before surgery were considered to have experienced treatment failures and
carcinomas of the skin and carcinoma in situ of the cervix), or death without
were treated at the discretion of the investigator. Patients who developed
evidence of recurrence or second primary cancer. OS was defined as the time
progressive operable disease while receiving radiotherapy and chemotherapy
from random assignment to death as a result of all causes. These analyses were
(cycles 2 and 3) had interruption of therapy and were offered immediate
supplemented by analyses of time to locoregional recurrence (after the com-
surgery. Postoperatively, the patients received the remaining four cycles of
pletion of therapy, including surgery, evidence of tumor in the pelvis, includ-
chemotherapy. Group 2 patients who were found at surgery to have inoperable
ing the presacrum, pelvic sidewalls, base of the bladder and the perineum, or at
or metastatic disease were classified as having experienced treatment failures
the anastomotic site) and time to recurrence (time to locoregional or distant
(representing protocol diagnostic failures) and were treated at the discretion of
recurrence of rectal cancer) as a first event. Patients who had inoperable
the investigator. Adverse effects were graded according to National Cancer
disease, gross residual disease, or involved surgical margins were also consid-
Institute Common Toxicity Criteria, version 1.
ered to have locoregional recurrence. Patients diagnosed concurrently with
Follow-Up
both locoregional and distant recurrence were considered to have locore-
Patients were assessed before being randomly assigned, every week be-
fore chemotherapy during radiotherapy, during chemotherapy every 8 weeks
The Kaplan-Meier method was used to construct OS and DFS curves.
before the next cycle, and post-therapy every 3 months during the first and
Plots showing the incidence of recurrence and locoregional recurrence by time
second year; during years 3 to 5, they were assessed every 6 months, and after 5
were generated by using a cause-specific incidence approach as defined by
years, every 12 months. The baseline assessment included a history and phys-
Gaynor et al.11 Although plots show data through 7 years, all follow-up data
ical examination, tumor measurements, performance status, measurement of
were used in the statistical calculations. The log-rank test was used to compare
carcinoembyronic antigen level, hematologic studies, serum chemistries, chest
distributions, stratifying by age and sex. Cox proportional hazards models
radiography, CT of abdomen and pelvis, and barium enema and/or full
were used to compute relative risks and 95% CIs. Analyses were stratified by
colonoscopic examination. Clinical response to preoperative therapy in group
age and sex. Because of the small number of events, local recurrence models
Table 3. Worst Grade of Toxicity per Patient by Arm in NSABP R-03 Trial According to National Cancer Institute Common Toxicity Criteria, Version 1.0
NOTE. In National Cancer Institute Common Toxicity Criteria, Version 1.0, grade 3 diarrhea was defined as an increase of seven to nine stools over baseline every
24 hours (severe). Grade 4 diarrhea was defined as having 10 or more stools per day, grossly bloody diarrhea, or need for parenteral support.
Abbreviations: NSABP R-03, National Surgical Adjuvant Breast and Bowel Project R-03; NA, not applicable.
ءDeaths within 30 days of last chemotherapy dose or random assignment occurred in 5% of preoperative patients and 3% of postoperative patients. However,
several of these deaths appeared to be unrelated to treatment. Probable or possible treatment-related mortality was 3% for preoperative and 1% for postoperativepatients. A total of nine deaths occurred within 30 days of random assignment or last dose of chemotherapy administration; four deaths did not appear to be relatedto protocol therapy. Other deaths comprised two patients with a history of severe coronary artery disease who experienced cardiac arrest with no evidence ofchemotherapy adverse effects, one patient with a dissecting thoracic aortic aneurysm, and one patient who died postoperatively of aspiration pneumonia who hadnot received any chemotherapy. The number of deaths considered possibly or probably related to protocol therapy were four (3.2%) of 126 in the preoperative group;two were due to complications from chemotherapy-induced dehydration related to diarrhea, nausea, and/or vomiting; one was due to perforated sigmoid colon ina patient with fixation of the bowel to a large rectal tumor; one was due to postoperative acute respiratory distress syndrome and peritonitis. In the postoperativegroup, the only death (one ͓1%͔ of 99) was due to dehydration related to chemotherapy-induced diarrhea, nausea, and vomiting. We believe these rates oftreatment-related fatality are within the acceptable range for combined modality adjuvant therapy of high-risk rectal cancer in clinical practice. Clinicians should beaware of the potential for severe diarrhea, nausea, and vomiting, which can lead to dehydration; should monitor patients carefully, particularly during radiationtherapy; and should treat dehydration aggressively with intravenous fluids.
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and outcomes by pathologic response status were not stratified. Hazard ratios
percentages of patients with three or fewer positive nodes were 86.7%
(HRs) compared preoperative relative to postoperative arms.
for preoperative and 69.5% for postoperative (P ϭ .004).
Analyses are based on the cohort of patients eligible with follow-up,
except where otherwise specified. All P values are two-sided. The 2 test was
SSS
used to compare proportions. The study was designed to have a power greaterthan 0.81 to detect a 33% reduction in death rate in the preoperative group.
In this study, 47.8% (55 of 115) of the preoperative patients and
The required sample size was 900 patients.
39.2% (47 of 120) of the postoperative patients had SSS (P ϭ .227). At
For the analyses of pathologic response and SSS, results are presented as
5 years after random assignment, 33.9% (39 of 115) of the preopera-
proportions. Patients with missing data who had a treatment-related death or
tive patients maintained their sphincter and were free of disease versus
recurrence/progression of disease before evaluation of a response (or within 7
24.2% (29 of 120) of the postoperative patients (P ϭ .13).
months of being randomly assigned for preoperative patients who refusedsurgery) were included as treatment failures. Patients with missing data who
Postoperative Complications
were event free or had a non–treatment-related death or a second primarycancer were not included. Ten patients who were randomly assigned to post-
Postoperative complication rates were similar in both arms. Of
operative therapy refused their assigned treatment (crossovers) and received
the preoperative patients, 25.0% had a complication compared with
preoperative therapy instead. These 10 patients were removed from the patho-
logic response and SSS analyses. One postoperative patient with squamous cellcancer was removed from the pathologic nodal status analysis. Toxicities
Toxicity data were collected for all patients who began protocol
chemotherapy for each cycle of therapy and for the 3-month period
Accrual
The first patient was entered on August 12, 1993, and accrual
continued until June 30, 1999. Two hundred sixty-seven patients were
accrued (130 to the preoperative therapy arm and 137 to the postop-
After 6 years of slower-than-anticipated accrual, the trial was
terminated short of the planned goal of 900 patients. The combination
of fewer patients but longer follow-up than originally anticipated
resulted in a reduction in the planned power of 0.81 to 0.54 for the
primary end point of OS and 0.61 for DFS.
Hazard ratio = 0.63; 95% CI, 0.44 to 0.90; P = .011
Pathologic Response in Preoperative Patients
Ten patients were considered to be not evaluable for pathologic
response. Two patients died before surgery as a result of a cardiac event
that was considered to be non–treatment related, one developed can-
cer of the lung and did not have surgery, five refused surgery, and two
patients were free of tumor at surgery but their nodal status was
unknown. The two latter patients had clinical responses (one com-
plete and one partial) before surgery. Seven patients who did not have
surgery because of treatment-related causes were included in the anal-ysis as failures. Of the 113 evaluable patients, 17 (15.0%) were deter-
mined to be free of disease on the basis of pathology. When we
examined tumor response only and ignored nodal status, 19 (16.5%)
of 115 patients had complete pathologic responses (cPRs). Of those
patients who had a resection and did not have an event at surgery,
there were 17 complete pathologic responders and 86 who were not
complete responders. There were no recurrences among the patho-
logic responders, but there were three deaths as a first event. The
Hazard ratio = 0.69; 95% CI, 0.47 to 1.03; P = .065
5-year OS from surgery was 87.8% for responders and 79.9% for those
who were not complete responders (P ϭ .42). Corresponding valueswere 87.8% and 70.6% (P ϭ .22) for DFS and 0% and 24.7% (P ϭ .04)
for the cumulative incidence of recurrence, respectively. Nodal Status
Nodal status was available for 105 preoperative and 118 postop-
erative patients. There was a significant benefit relative to nodal status
Fig 2. (A) Disease-free survival of 254 patients randomly assigned to preoper-
ative or postoperative chemoradiotherapy, National Surgical Adjuvant Breast and
because 66.7% of the preoperative patients had no positive lymph
Bowel Project R-03 (NSABP R-03) trial. (B) Overall survival of 254 patients randomly
nodes versus 52.5% of the postoperative patients (P ϭ .04). The
assigned to preoperative or postoperative chemoradiotherapy, NSABP R-03.
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Preoperative Therapy Improves DFS in Rectal Carcinoma
after completion of protocol therapy. All available toxicity data wereanalyzed (126 preoperative, 99 postoperative) and are listed in Table 3.
The difference in available data is largely due to those postoperative
patients who were not given protocol therapy after being diagnosed as
stage I or IV. Virtually all the patients on the study experienced some
toxicity. Toxicities were reasonably balanced between arms with the
Hazard ratio = 0.56; 95% CI, 0.36 to 0.89; P = .012
exception of diarrhea; 24% of the patients on the preoperative therapy
Postoperative 131 patients, 51 recurrencesPreoperative 123 patients, 31 recurrences
arm experienced grade 4 diarrhea versus 13% on the postoperative
therapy arm. Further analysis indicated that this difference occurred
primarily in the first three cycles of chemotherapy. During the first
chemotherapy cycle of the preoperative therapy arm, 11% of the
patients experienced grade 4 diarrhea versus 7% of those on the
postoperative arm. The corresponding percentages during the chem-otherapy plus radiation cycles were 12% v 3%, respectively. In the re-
maining chemotherapy cycles, the percentages of patients with grade 4
diarrhea were 7% and 5%, respectively. Overall, grade 5 toxicity oc-
curred in 5% of preoperative patients and 3% of postoperative patients. DFS
One hundred twenty-five patients (51 preoperative, 74 postop-
erative) had a recurrence, had a second primary cancer, or have died. The 5-year DFS for preoperative patients was 64.7% v 53.4% for
postoperative patients (Fig 2A). The HR was 0.629 (95% CI, 0.439 to
Hazard ratio = 0.86; 95% CI, 0.41 to 1.81; P = .693
0.902; P ϭ .011), indicating a benefit for preoperative therapy.
Postoperative 131 patients, 15 recurrencesPreoperative 123 patients, 13 recurrences
OS
Of 254 patients, 106 (44 preoperative, 62 postoperative) have
died. Surviving patients were observed for a median of 8.4 years
(range, 10.9 months to 12.9 years). The 5-year OS for preoperative
patients was 74.5% v 65.6% for postoperative patients (Fig 2B). TheHR comparing preoperative with postoperative patients was 0.693
(95% CI, 0.468 to 1.026; P ϭ .065), suggesting a possible survival
Recurrence-Free Interval
Thirty-one preoperative patients and 51 postoperative patients
Fig 3. (A) Cumulative incidence of recurrence in 254 patients who underwent
complete resection of rectal cancer and chemoradiotherapy, according to treat-
had a recurrence as a first event. The 5-year cumulative incidence of
ment group, National Surgical Adjuvant Breast and Bowel Project R-03 (NSABP
recurrence was 23.9% for preoperative and 27.5% for postoperative
R-03) trial. (B) Cumulative incidence of local recurrence in 254 patients who
patients (HR, 0.564; 95% CI, 0.360 to 0.885; P ϭ .0115), indicating a
underwent complete resection of rectal cancer and chemoradiotherapy, accord-ing to treatment group, NSABP R-03.
benefit for preoperative therapy (Fig 3A). Locoregional Recurrence
Thirteen preoperative patients and 15 postoperative patients had
Local recurrence in this trial for each treatment arm of 10.7% at 5
a locoregional recurrence as a first event. The 5-year cumulative inci-
years was greater than that reported in the Dutch Colorectal Cancer
dence of locoregional recurrence was 10.7% for each treatment arm
Group.5 The rate of local recurrence at 2 years was reduced from 8.2%
(HR, 0.86; 95% CI, 0.41 to 1.81; P ϭ .693; Fig 3B).
to 2.4% with the addition of preoperative radiotherapy. The differencein recurrence between the Dutch study and NSABP R-03 could be dueto the length of follow-up (2 v 5 years), dose (25 v 50.4 Gy), timing of
DISCUSSION
radiotherapy (5 days v 5 weeks), type of surgical procedure (manda-tory total mesorectal excision in the Dutch trial), and patient eligibility
The NSABP R-03 trial has shown that the preoperative administration
(inclusion of stage I patients in the Dutch study). Equivalent rates of
of radiation therapy and chemotherapy significantly prolonged DFS
local recurrence between preoperative and postoperative therapy in
compared with postoperative administration and demonstrated a
the NSABP R-03 trial are difficult to interpret because there were only
trend toward improved OS. We were not able to demonstrate any
28 locoregional events observed in this trial, and the statistical power
decrease in the local recurrence rates nor any significant increase in the
to detect a 33% reduction in local recurrence was only 18%.
proportion of patients undergoing sphincter-saving procedures in the
Differences in locoregional recurrence rates between preopera-
preoperative group, although the statistical power to detect such dif-
tive and postoperative groups were observed in the German Rectal
ferences was low because of the small number of events in our trial.
Cancer Study Group trial. The 5-year cumulative incidence of local
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recurrence was significantly reduced from 13% to 6% (P Ͻ .006) with
trial might have increased the accuracy of a complete response and
the preoperative administration of chemoradiotherapy.9 The differ-
ence could be influenced by the type of surgical procedure. Not every
The combined modality regimen used in NSABP R-03 was gen-
patient in NSABP R-03 underwent a total mesorectal excision, com-
erally well tolerated but does have the capability of causing severe
pared with 100% of the patients in the German trial.
toxicity (particularly diarrhea) in a minority of patients. Clinicians
To our knowledge, the NSABP R-03 trial is the first to dem-
should be aware of the potential for several diarrhea, nausea, and
onstrate a significant improvement in recurrence-free survival and
vomiting, which can lead to dehydration; should monitor patients
DFS with preoperative multimodality therapy compared with
carefully particularly during radiation therapy; and should treat dehy-
postoperative treatment. This observation is contrary to the results
dration aggressively with intravenous fluids.
from other phase III trials with different treatment regimens.5-9 In
In conclusion, a significant DFS benefit was achieved with
the German Rectal Cancer Study Group, the 5-year DFS was 68%
preoperative compared with postoperative chemoradiotherapy
for the preoperative and 65% for the postoperative group.9 The
and is the recommended treatment for patients with locally ad-
radiotherapy dose in the NSABP R-03 study was similar to that in
the German study, but the chemotherapy regimens were different. The NSABP R-03 5-year cumulative incidence of recurrence wassuperior to that in the German trial in the preoperative (23.9% vAUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
36%) and postoperative (27.5% v 38%) groups. However, preop-erative therapy in the NSABP R-03 trial increased the incidence of
The author(s) indicated no potential conflicts of interest.
grade 4 or 5 toxicities to 33%, compared with 23% in the postop-erative group. This may be a biased comparison, given that only thesubset of postoperative patients who had stage II or III disease were
AUTHOR CONTRIBUTIONS
to have protocol therapy. Some of the postoperative patients(stages I and IV) may not have received any chemotherapy, because
Conception and design: Melvin Deutsch
the treatment was at the discretion of the treating physician. Administrative support: Greg Yothers, Luis Baez-Diaz,
Fifteen percent of patients achieved a cPR, and no recurrence had
Norman Wolmark Provision of study materials or patients: Melvin Deutsch,
occurred at 5 years. A cPR did not significantly correlate with im-
proved OS and DFS in our study, perhaps because of the small number
Collection and assembly of data: Mark S. Roh, Greg Yothers, Melvin
of events and low statistical power to detect significant differences
between complete responders and and those who were not complete
Data analysis and interpretation: Mark S. Roh, Linda H. Colangelo,
responders. Other trials have demonstrated a significant correlation
Michael J. O’Connell, Greg Yothers, Melvin Deutsch, Carmen J. Allegra,
between tumor regression and improved DFS.12-14 An important dif-
ference between NSABP R-03 and these studies is the classification of
Manuscript writing: Mark S. Roh, Linda H. Colangelo, Michael J. O’Connell, Greg Yothers, Carmen J. Allegra, Nicholas J. Petrelli
a pathologic response. In the other studies, treatment response was
Final approval of manuscript: Mark S. Roh, Linda H. Colangelo,
assessed using a standardized 5-point grading system for tumor re-
Michael J. O’Connell, Greg Yothers, Melvin Deutsch, Carmen J. Allegra,
gression, as initially described by Dworak.15 It is not known whether
Morton S. Kahlenberg, Luis Baez-Diaz, Carol S. Ursiny, Nicholas J.
using a more rigorous tumor regression grading system in the current
sorectal excision for resectable rectal cancer. N Engl
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2009 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by CENTRE HOSP ST BRIEUC on October 30, 2009 from
Copyright 2009 by the American Society of Clinical Oncology. All rights reserved.
März 22 - 25, Stattkino am Löwenplatz 11, Luzern Einführung in den Filmabend vom 22.03.2012 - Classic Night Heute Abend haben wir für Sie zwei Perlen des Genres herausgesucht, die mit Fug und Recht als Klassi-ker des zeitgenössischen Tanzfilmes bezeichnet werden dürfen: Denn sie ebneten den Weg des zeitge-nössischen Tanzes ins Kino. Die britische Produktion Dead Dreams of Mono
Declaração Universal dos Direitos Humanos Considerando que o reconhecimento da dignidade inerente a todos os membros da família humana e dos seus direitos iguais e inalienáveis constitui o fundamento da liberdade, da justiça e da paz no mundo; Considerando que o desconhecimento e o desprezo dos direitos do Homen conduziram a actos de barbárie que revoltam a consciência da Humanidade e que