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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 Wolmark Purpose
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 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. 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) 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. 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.
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. 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.
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. 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.
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. 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 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. 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% v AUTHORS’ 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 11. Gaynor JJ, Feuer EJ, Tan CC, et al: On the use
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