Published Ahead of Print on April 21, 2014 as 10.1200/JCO.2013.54.3769 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.54.3769
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
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Tumor Regression Grading After Preoperative Chemoradiotherapy for Locally Advanced Rectal Carcinoma Revisited: Updated Results of the CAO/ARO/AIO-94 Trial Emmanouil Fokas, Torsten Liersch, Rainer Fietkau, Werner Hohenberger, Tim Beissbarth, Clemens Hess, Heinz Becker, Michael Ghadimi, Karl Mrak, Susanne Merkel, Hans-Rudolf Raab, Rolf Sauer, Christian Wittekind, and Claus Ro¨del See accompanying editorial doi: 10.1200/JCO.2014.55.4766 Emmanouil Fokas and Claus Ro¨del, University of Frankfurt, Frankfurt; Torsten Liersch, Tim Beissbarth, Clemens Hess, Heinz Becker, and Michael Ghadimi, University Medical Center Go¨ttingen, Go¨ttingen; Rainer Fietkau, Werner Hohenberger, Susanne Merkel, and Rolf Sauer, University of Erlangen, Erlangen; Hans-Rudolf Raab, Oldenburg Hospital, Oldenburg; Christian Wittekind, University Hospital Leipzig, Leipzig, Germany; and Karl Mrak, Krankenhaus der Barmherzigen Bru¨der, St Veit, Austria. Published online ahead of print at www.jco.org on April 21, 2014. Supported by Grant No. 70-578 from German Cancer Aid (Deutsche Krebshilfe). Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Emmanouil Fokas, MD, DPhil, Department of Radiotherapy and Oncology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; e-mail: [email protected]. © 2014 by American Society of Clinical Oncology 0732-183X/14/3299-1/$20.00 DOI: 10.1200/JCO.2013.54.3769.
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Purpose We previously described the prognostic impact of tumor regression grading (TRG) on the outcome of patients with rectal carcinoma treated with preoperative chemoradiotherapy (CRT) in the CAO/ARO/AIO-94 trial. Here we report long-term results after a median follow-up of 132 months. Patients and Methods TRG after preoperative CRT was determined in 386 surgical specimens by the amount of viable tumor cells versus fibrosis, ranging from TRG 4 (no viable tumor cells) to TRG 0 (no signs of regression). Clinicopathologic parameters and TRG were correlated to the cumulative incidence of local recurrence, distant metastasis, and disease-free survival (DFS). Results Ten-year cumulative incidence of distant metastasis and DFS were 10.5% and 89.5% for patients with TRG 4 (complete regression), 29.3% and 73.6% for TRG 2 and 3 (intermediate regression), and 39.6% and 63% for TRG 0 and 1 (poor regression), respectively (P ⫽ .005 and P ⫽ .008, respectively). On multivariable analysis, residual lymph node metastasis (ypN⫹) and TRG were the only independent prognostic factors for cumulative incidence of distant metastasis (P ⬍ .001 and P ⫽ .035, respectively) and DFS (P ⬍ .001 and P ⫽ .039, respectively), whereas local recurrence was significantly affected by ypN status (P ⬍ .001) and lymphatic invasion (P ⫽ .026). Conclusion Complete and intermediate tumor regressions were associated with improved long-term outcome in patients with rectal carcinoma after preoperative CRT independent of clinicopathologic parameters. This classification system needs to be prospectively tested in multiple data sets to validate its reproducibility in a wider setting. J Clin Oncol 32. © 2014 by American Society of Clinical Oncology
INTRODUCTION
Rectal carcinoma accounts for approximately 28% of all colorectal malignancies.1,2 The treatment of choice in patients with locally advanced rectal carcinoma is preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) surgery.1,3 The CAO/ARO/AIO-94 (Working Group of Surgical Oncology/Radiation Oncology/Medical Oncology of the German Cancer Society) trial demonstrated the superiority of preoperative over postoperative CRT with regard to local control, treatment compliance, and toxicity profile.3 Ten-year follow-up outcomes confirmed the original findings.4,5 An important clinicopathologic observation derived from the general adoption of preoperative
CRT was the broad variety in tumor response, ranging from pathologic complete response (pCR; ypT0N0), with no viable tumor cells left (currently 10% to 25% of patients), to less than pCR to virtually no tumor regression at all or even tumor progression during therapy.6,7 Although the clinical significance of histopathologically determined tumor regression grading (TRG) is still under investigation, several studies have suggested that the degree of tumor regression may be of high clinical relevance because it could be used as a treatment monitoring and prognostic parameter.8-22 However, a majority of the reports were retrospective and included patients with heterogeneous tumor stages and CRT regimens and were characterized by relatively short follow-up periods, making interpretation of these © 2014 by American Society of Clinical Oncology
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Fokas et al
findings challenging. Moreover, the clinical significance of less than complete tumor regression (ie, intermediate or poor TRG) remains to be determined. To prospectively evaluate TRG after preoperative CRT in patients treated in the CAO/ARO/AIO-94 trial, a standardized 5-point TRG system was used based on the work of Dworak et al.10,23 In that context, we previously reported the prognostic value of TRG in patients with rectal adenocarcinoma after preoperative CRT, after a median follow-up of 41 months.10 In the present study, we provide long-term results regarding the prognostic role of TRG after a median follow-up of 132 months.
PATIENTS AND METHODS The CAO/ARO/AIO-94 trial constituted a multicenter, open-label, randomized phase III study.3 The design of the clinical trial, eligibility and exclusion criteria, treatment plan and long-term oncologic results have been reported in detail elsewhere.3,4 Pathologic Examination and TRG Pathologic examination details were reported previously.10 In brief, all resection specimens were examined by local pathologists, blinded to patients’ clinical outcome, from 26 participating hospitals according to a standardized protocol that included International Union Against Cancer TNM category (y prefix indicates classification after neoadjuvant treatment), stage grouping, numbers of examined and involved lymph nodes, and presence or absence of lymphatic and venous invasions.24 Completeness of resection was scored as R0 for negative margins (regardless of distance between tumor and resection margins), R1 for microscopic involvement of margins, and R2 for gross residual tumor. To avoid possible inconsistencies, the reference pathologist (C.W.) developed a standardized case report form for the documentation of all pathologic data. The latter was tested for plausibility in each case by the reference pathologist. For analysis of TRG, fixation of the resected specimen was performed in 4% formaldehyde overnight. After opening of the resected specimen, the latter was examined and described macroscopically. In the presence of macroscopic residual tumor, a minimum of four paraffin blocks were prepared for further analysis. In the absence of macroscopic residual tumor, the whole area consisting mainly of fibrotic tissue was sliced in one specimen per 5 mm and embedded in paraffin. From those blocks 5 m thick, serial slices were prepared. Median and mean numbers of blocks examined were five and 6.43, respectively (range, one to 60). Pathologic grading of primary tumor regression was performed semiquantitatively by determining the amount of viable tumor versus fibrotic tissue that ranged from the lack of tumor regression to complete response with no viable tumor identified, according to Dworak et al.10,23 The five groups of TRG classification were as follows: grade 0, no regression; grade 1, minor regression (dominant tumor mass with obvious fibrosis in ⱕ 25% of tumor mass); grade 2, moderate regression (dominant tumor mass with obvious fibrosis in 26% to 50% of tumor mass); grade 3, good regression (dominant fibrosis outgrowing tumor mass [ie, ⬎ 50% tumor regression]); and grade 4, total regression (no viable tumor cells; fibrotic mass only). According to our previous report,10 the 5-point TRG system was separated into three groups to avoid small categories. These included complete regression (TRG 4), intermediate regression (TRG 2 and 3), and poor regression (TRG 0 and 1). Follow-Up Protocol-specified follow-up was performed as described elsewhere at 3-month intervals during the first 2 years and then at 6-month intervals to a total of 5 years after completion of treatment.4 Follow-up procedures beyond 5 years were not explicitly specified in the original study protocol. Long-term data were obtained by collecting additional information from all participating hospitals and clinical centers, from general practitioners, and finally from German registry offices. 2
© 2014 by American Society of Clinical Oncology
Enrollment (N = 823) Excluded (n = 24) Did not meet (n = 15) inclusion criteria Refused to participate (n = 9)
Randomly allocated to preoperative chemoradiotherapy (n = 404)
Randomly allocated to postoperative chemoradiotherapy (n = 395)
Requested change of arm or erroneously received other treatment arm (n = 18)
Requested change of arm or erroneously received other treatment arm (n = 20)
Allocated to preoperative chemoradiotherapy (n = 406)
Allocated to postoperative chemoradiotherapy (n = 393)
Received preoperative chemoradiotherapy (n = 406) Underwent surgery No surgery
(n = 402) (n = 4)
TRG available TRG 0 TRG 1 TRG 2 TRG 3 TRG 4
(n = 386) (n = 32) (n = 58) (n = 53) (n = 203) (n = 40)
Median follow-up: 132 months (range, 90 to 184 months) Life status known (n = 404) Life status unknown (n = 2) Tumor status known (n = 398) Tumor status unknown (n = 8) Fig 1. CONSORT diagram illustrating treatment flow of CAO/ARO/AIO-94 (Working Group of Surgical Oncology/Radiation Oncology/Medical Oncology of the German Cancer Society) trial. Relevant to tumor regression grading (TRG), only preoperative arm is shown.
Statistical Analysis Local recurrence analyses were performed for all eligible patients who underwent a macroscopically complete local resection after preoperative CRT (patients with R1 resection of primary tumor or with distant metastasis found at time of surgery were included, whereas patients who did not undergo surgery or with macroscopically incomplete local resection [R2] were excluded). Distant recurrence analyses were performed for all eligible patients, and any occurrence of distant metastasis during preoperative CRT, at surgery, or during follow-up was calculated as an event. Disease-free survival (DFS) was calculated for patients with macroscopically complete local resection (R0/1) and no evidence of distant metastasis at the time of surgery (M0). All time-toevent end points were measured from date of random assignment. In accordance with previous reports of this trial, data from patients who were alive and free of recurrence or who died without having had a recurrence were censored in the analyses of recurrence and DFS. We did not use any statistical methods to account for variability in patient follow-up. Statistical analysis was performed using SPSS software (version 16; SPSS, Chicago, IL) and R software (version 3.0.1; http://www.r-project.org). DFS was calculated using the Kaplan-Meier method. Analyses for recurrence were JOURNAL OF CLINICAL ONCOLOGY
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Prognostic Significance of TRG in Rectal Carcinoma
Table 1. Influence of Different Covariables on 10-Year Cumulative Incidence of Local Recurrence, Cumulative Incidence of Distant Metastases, and DFS After Neoadjuvant Chemoradiotherapy
Variable Overall Median age, years ⱕ 61 ⬎ 61 Sex Male Female Distance from anal verge, cm ⬍5 5-10 ⬎ 10 Unknown Preoperative T category cT2 cT3 cT4 Unknown Preoperative N category cN0 cN⫹ Unknown ypT category ypT0 ypT1 ypT2 ypT3 ypT4 Unknown ypN category ypN0 ypN1 ypN2 Unknown Local resection status R0 R1 R2/no resection Unknown Lymphatic invasion L0 L1 Unknown Venous invasion V0 V1 Unknown TRG 0-1 2-3 4 Unknown
No. at Risk
10-Year Cumulative Incidence of Local Recurrence (%)
391
6.9
P
No. at Risk
10-Year Cumulative Incidence of Distant Metastasis (%)
406
30.2
.669 205 186
6.9 7.1
283 108
6.7 7.5
113 182 83 13
10.4 4.9 4.3
16 271 23 81
6.2 5.0 17.4
161 213 17
7.7 6.9
40 22 116 200 13 0
2.6 0 3.4 9.6 28.6
271 70 50 0
4.0 11.4 21.3
387 4 0 0
6.7 25.0
298 82 11
4.2 15.6
366 18 0
6.3 9.1
87 253 40 11
3.6 8.0 2.6
P
No. at Risk
10-Year DFS (%)
361
73
190 171
75.3 70.5
258 103
73.2 72.7
102 169 77 13
67.2 78.4 79.9
15 253 20 73
66.7 75.9 68.7
152 193 16
71.6 74.7
40 21 113 177 10 0
89.5 95.2 77.9 65.7 40
261 60 40 0
83.5 59.4 27.5
357 4 0 0
73.3 50
281 70 10
77.4 55
342 14 5
74.5 42.9
80 232 40 9
63 73.6 89.5
.435 209 197
28.6 32.1
293 113
30.5 29.4
117 189 85 15
36.3 25.0 31.8
16 279 24 87
37.5 26.5 38.9
169 220 17
31.2 28.9
40 23 117 203 15 8
10.5 8.7 21 38.9 61.9
275 73 50 8
17.7 45.8 72.8
387 4 8 7
29.5 50.0 57.1
302 84 20
24.3 50.8
371 19 16
28 57.9
90 256 40 20
39.6 29.3 10.5
.596
.328
.902
.036
.791
.103
.045
.110
.684
.508
.987
.612
< .001
.425
< .001
< .001
< .001
< .001
.006
< .001
.011
< .001
.079
< .001
.785
< .001
.002
.410
P
.002
.005
.008
NOTE. Bold font indicates significance. Abbreviations: DFS, disease-free survival; TRG, tumor regression grade.
reported as cumulative incidences. Differences were evaluated with the logrank test. Multivariable models were computed using the Cox proportional hazards model. All variables that were significant in the corresponding univariable analysis were included in multivariable Cox regression models in a www.jco.org
forward-step procedure. The variables were entered in a predefined order according to clinical relevance into the regression models with increasing complexity, and significance was assessed using analysis of variance analysis. For this purpose, the functions “coxph” and “anova” from the R © 2014 by American Society of Clinical Oncology
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Fokas et al
0.6
A TRG 0 + 1 TRG 2 + 3 TRG 4
Cumulative Incidence of Local Recurrence
Cumulative Incidence of Local Recurrence
A
P = .410
0.4
0.2
0
30
60
90
120
150
180
0.6
ypT4 ypT3 ypT0-2 P < .001
0.4
0.2
0
30
60
Time (months)
Cumulative Incidence of Distant Metastases
B
0.6
73 216 37
58 190 37
50 168 34
39 108 21
18 41 6
3 3 0
B TRG 0 + 1 TRG 2 + 3 TRG 4 P = .005
0.4
0.2
0
30
60
90
120
150
1.0
0.8
54 171 35
50 157 34
37 104 21
156 132 5
144 112 4
90 79 2
35 29 1
3 2 0
60
90
120
150
180
ypT4 ypT3 ypT0-2
0.4
0.2
30
Time (months) 17 39 6
3 3 0
C
1.0
0.8
0.6 0.4
0.2
TRG 0 + 1 TRG 2 + 3 TRG 4
30
159 142 9
147 117 5
139 114 5
86 77 2
34 27 1
1 2 1
60
90
120
150
180
33 27 1
3 0 0
1.0
0.8
0.6 0.4
0.2
P = .008
0
ypT4 ypT3 ypT0-2 P < .001
60
90
120
150
180
0
30
Time (months) No. at risk TRG 0 + 1 80 TRG 2 + 3 232 TRG 4 40
57 193 36
50 166 35
46 153 34
35 101 21
Time (months) 15 38 6
3 3 0
Fig 2. Long-term prognostic significance of tumor regression grading (TRG) after preoperative chemoradiotherapy and total mesorectal excision surgery in rectal carcinoma; 10-year cumulative incidences of (A) local recurrence and (B) distant metastasis and (C) 10-year disease-free survival, according to TRG.
4
180
0.6
No. at risk ypT0-2 180 ypT3 203 ypT4 15
Disease-Free Survival (probability)
Disease-Free Survival (probability)
C
63 201 36
150
P < .001
0
180
166 162 9
Time (months) No. at risk TRG 0 + 1 90 TRG 2 + 3 256 TRG 4 40
120
Time (months) No. at risk ypT0-2 178 ypT3 200 ypT4 13
Cumulative Incidence of Distant Metastases
No. at risk TRG 0 + 1 87 TRG 2 + 3 253 TRG 4 40
90
© 2014 by American Society of Clinical Oncology
No. at risk ypT0-2 174 ypT3 177 ypT4 10
156 134 5
143 112 4
135 102 4
85 73 2
Fig 3. Long-term prognostic significance of ypT categories after preoperative chemoradiotherapy and total mesorectal excision surgery in rectal carcinoma; 10-year cumulative incidences of (A) local recurrence and (B) distant metastasis and (C) 10-year disease-free survival, according to ypT category.
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Prognostic Significance of TRG in Rectal Carcinoma
Patient Characteristics and Association of TRG With Clinicopathologic Factors In total, 823 patients participated in the randomized trial (Fig 1). Of those, 24 patients were excluded from the study because of protocol violation. Of the remaining 799 patients, 404 and 395 patients were randomly assigned to preoperative and postoperative treatment, respectively. Furthermore, change in treatment arm or therapy using the schedule of the opposite arm occurred in 18 and 20 patients, respectively. Hence, 406 patients received preoperative CRT, and 393 patients received postoperative CRT. From the 406 patients, life and tumor statuses were unknown in two and eight patients at the last follow-up examination, respectively. TRG was available in 386 patients treated in the preoperative CRT arm (TRG 0, 32 patients [8.3%]; TRG 1, 58 patients [15.0%]; TRG 2, 53 patients [13.7%]; TRG 3, 203 patients [52.6%]; TRG 4, 40 patients [10.4%]). The association of TRG with various pretreatment clinical and postoperative histopathologic factors is provided in the original work.10 In brief, none of the pretreatment factors, including cT and cN categories, predicted TRG. After preoperative CRT and TME surgery, TRG was significantly associated with ypN1-2 (TRG 0 and 1, 40.7%; TRG 2 and 3, 31.9%; TRG 4, 10%; P ⫽ .001). Moreover, ypT3-4 tumors (P ⫽ .03) and venous invasion (V1; P ⫽ .03) were noted more frequently in the poor response group (TRG 0 and 1) as compared with the intermediate TRG 2 and 3 group.
Cumulative Incidence of Local Recurrence
RESULTS
A
0.6
P < .001
0.2
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30
60
90
120
150
180
Time (months) No. at risk ypN2 50 ypN1 70 ypN0 271
B
1.0
0.8
33 56 248
19 45 229
15 39 206
7 22 141
4 10 51
0 0 6
60
90
120
150
180
ypN2 ypN1 ypN0 P < .001
0.6 0.4
0.2
0
30
Time (months) No. at risk ypN2 50 ypN1 73 ypN0 275
C Disease-Free Survival (probability)
TRG As Prognostic Factor for Clinical Outcome In total, 234 surviving patients in the preoperative treatment group underwent follow-up, for a median of 132 months (range, 90 to 184 months). Local recurrence after preoperative CRT and R0/1 local tumor resection was encountered in 22 patients. Six had local recurrence alone, and 16 also had synchronous distant metastasis. Five (23%) of 22 local recurrences occurred beyond 5 years of follow-up. Ten-year cumulative incidence of local recurrence in 391 eligible patients was 6.8%. Of the 406 patients assessed for metastatic disease, distant metastasis was observed in 119 patients. Ten-year cumulative incidence of distant metastasis was 30.2%. For patients with R0/1 local tumor resection and no evidence of distant metastasis at surgery (M0), disease recurrence (local, distant, or both) occurred in 94 patients. DFS at 10 years was 73%. We performed a univariable analysis to assess the prognostic impact of TRG on the cumulative incidence of local recurrence after R0/1 local resection, on the cumulative incidence of distant metastasis, and on DFS after curative surgery (R0/1; M0; Table 1; Fig 2A). TRG was not prognostic for cumulative incidence of local recurrence. A slight trend toward less local recurrence was observed for TRG 4, with a cumulative incidence of 2.6% versus 8.0% (TRG 2 and 3) and 3.6% (TRG 0 and 1). The relatively low number of local recurrences in the TRG 0 and 1 group could have resulted from the limited number of patients in this group. In contrast, TRG was significantly associated with the cumulative incidence of distant metastasis and DFS (Figs 2B and 2C). Indeed, the cumulative incidence of distant metastasis was 10.5%, 29.3%, and 39.6% in patients with TRG 4, TRG 2 and 3 and
ypN2 ypN1 ypN0
0.4
0
Cumulative Incidence of Distant Metastases
package survival were used. A two-sided P value less than .05 was considered significant.
21 51 238
10 39 220
9 37 204
6 21 138
2 10 50
0 0 6
60
90
120
150
180
2 9 48
0 0 6
1.0
0.8
0.6 0.4
0.2
ypN2 ypN1 ypN0 P < .001
0
30
Time (months) No. at risk ypN2 40 ypN1 60 ypN0 261
17 45 233
9 36 214
8 35 198
5 20 135
Fig 4. Long-term prognostic significance of ypN categories after preoperative chemoradiotherapy and total mesorectal excision surgery in rectal carcinoma; 10-year cumulative incidences of (A) local recurrence and (B) distant metastasis and (C) 10-year disease-free survival, according to ypN category.
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Fokas et al
TRG 0 and 1, respectively (P ⫽ .005). Similarly, DFS was 89.5%, 73.6%, and 63% in patients with TRG 4, TRG 2 and 3, and TRG 0 and 1, respectively (P ⫽ .008). We also examined the prognostic significance of various clinicopathologic factors (Table 1). The cumulative incidence of local recurrence was correlated with the distance of the aboral tumor border to the anocutaneous verge (P ⫽ .036); cT (P ⫽ .045), ypT (P ⬍ .001), and ypN categories (P ⬍ .001); resection status (P ⫽ .006); and lymphatic invasion (P ⬍ .001; Figs 3A and 4A). In addition, ypT (P ⬍ .001) and ypN categories (P ⬍ .001), resection status (P ⫽ .011), venous invasion (P ⫽ .002), and lymphatic invasion (P ⬍ .001) were significantly associated with the cumulative incidence of distant metastasis (Figs 3B and 4B). Similar results were obtained for DFS, with the exception of R status, which lacked prognostic significance (P ⫽ .079; Figs 3C and 4C). All factors that showed significance in univariable analysis were included in the multivariable analyses (Table 2). Hazard ratios (HRs) are reported, along with 95% CIs, from the multivariable Cox models. P values are derived from comparisons of models with increasing complexity (ie, from top to bottom). Lymph node metastasis after preoperative CRT (ypN1-2) constituted the strongest prognostic factor for the cumulative incidence of local recurrence (HR, 2.07; 95% CI, 1.04 to 4.10; P ⬍ .001), distant metastasis (HR, 2.44; 95% CI, 1.92 to 3.10; P ⬍ .001), and DFS (HR, 2.5; 95% CI, 1.95 to 3.22; P ⬍ .001). Lymphatic invasion was associated with increased cumulative incidence of local recurrence (HR, 4.00; 95% CI, 1.16 to 13.82; P ⫽ .026). In multivariable analysis, TRG after preoperative CRT was an independent prognostic factor for ypN and ypT, with regard to cumulative incidence of distant metastasis (HR, 0.74; 95% CI, 0.52 to 1.06; P ⫽ .035) and DFS (HR, 0.76; 95% CI, 0.52 to 1.11; P ⫽ .039). None of the other analyzed factors significantly added prognostic information in multivariable models already containing ypN and TRG.
preoperative CRT and surgery, and combination with chemotherapy.25-28 In this study, we analyzed the prognostic impact of TRG in a large patient cohort after homogenous treatment with preoperative CRT in the CAO/ARO/AIO-94 trial after a median follow-up of 132 months. We showed that a simplified three-tier TRG, as established in our previous analysis,10 constituted an independent prognostic factor for 10-year cumulative incidence of distant metastasis and DFS. Importantly, clinicopathologic parameters, including ypN category, did not affect the prognostic significance of TRG in multivariable analysis. In line with our observations, several studies have demonstrated better outcome in patients with complete tumor regression (pCR) compared with noncomplete tumor regression.8-22 Although the pooled analysis by Maas et al29 involved a large number of patients (N ⫽ 3,105), median follow-up was only 48 months, and a majority of patients were treated outside clinical trials, with treatment characterized by heterogeneous strategies and lack of a uniform TRG evaluation method. In contrast, our study reports the prognostic significance of a three-tier TRG system in a patient group treated homogeneously in a phase III trial after long follow-up. A pooled analysis of the EORTC (European Organisation for Research and Treatment of Cancer) 22921 and FFCD (Fe´de´ration Francophone de Cance´rologie Digestive) 9203 trials, comparing preoperative fluorouracil-based CRT (n ⫽ 886) with radiotherapy alone (n ⫽ 881), showed that pCR and local control rates were significantly improved by preoperative CRT; however, these effects did not translate into improved progression-free or overall survival.30 Of note, this pooled analysis did not compare different degrees of pathologic response, as in our study, but rather the effect of different regimens on outcome. We agree that pCR is not a reliable end point for phase III trials comparing the efficacy of different treatment regimens on longterm end points. However, here we show that TRG may identify different prognostic groups when treated homogeneously. We consider the most striking finding of this study to be the significant association of TRG—which is an assessment of local treatment efficacy regarding the primary tumor in the rectal wall—with the risk of distant metastasis and DFS in both univariable and multivariable analyses. Thus, an important yet unresolved issue has been raised
DISCUSSION
Tumor regression varies among patients with rectal carcinoma after preoperative CRT. Some tumors demonstrate pCR, whereas others show either intermediate regression or even complete lack of response.6,7 Various factors seem to determine pathologic tumor regression, including radiotherapy dose and schedule, time between
Table 2. Multivariable Analysis of Different Covariables on 10-Year Cumulative Incidence of Local Recurrence, Cumulative Incidence of Distant Metastasis, and DFS After Neoadjuvant Chemoradiotherapy 10-Year Cumulative Incidence of Local Recurrence
Variable Significant in Univariable Analysis
HR
ypN category Preoperative T category ypT category TRG Distance from anal verge Lymphatic invasion Venous invasion Local resection
2.07 2.13 0.78 — 0.50 4.00 — 0.00
95% CI 1.04 to 4.1 0.61 to 7.41 0.48 to 1.27
P
10-Year Cumulative Incidence of Distant Metastasis ⴱ
< .001 .091 .132
0.23 to 1.10 1.16 to 13.82
.057 .026
0.00 to infinity
.648
ⴱ
10-Year DFS
HR
95% CI
P
HR
95% CI
Pⴱ
2.44 — 0.90 0.74 — 1.29 1.52 1.25
1.92 to 3.10
< .001
1.95 to 3.22
< .001
0.79 to 1.03 0.52 to 1.06
.129 .035
0.81 to 1.08 0.52 to 1.11
.391 .039
0.83 to 2.00 0.76 to 3.03 0.57 to 2.75
.121 .216 .595
2.50 — 0.93 0.76 — 1.29 1.89 —
0.81 to 2.05 0.93 to 3.82
.115 .093
NOTE. Bold font indicates significance. Abbreviations: DFS, disease-free survival; HR, hazard ratio; TRG, tumor regression grade. ⴱ Analysis of variance.
6
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Prognostic Significance of TRG in Rectal Carcinoma
of whether less extensive or even complete lack of local tumor regression reflects an inherently aggressive malignant biologic phenotype that is at the same time less responsive to local CRT and also exhibits higher propensity to metastasize. An important implication of this concept would be that the genetic abnormalities and biologic mechanisms responsible for resistance to CRT are closely linked or even overlap with those responsible for distant cancer cell spread and seeding. There is now ample evidence to suggest that abnormalities, such as oncogenic activation of RAS,31,32 epithelial-mesenchymal transition,33,34 antiapoptotic factors,35,36 and hypoxia,37-39 to name a few, contribute to both local resistance to CRT and increased metastasis. For example, survivin, an inhibitor of apoptosis protein frequently overexpressed in rectal carcinoma, is associated with decreased response to irradiation in cell culture and animal models and increased risk of local recurrence in patients with rectal carcinoma after preoperative CRT and TME surgery.40-42 Also, survivin constitutes an important metastasis gene in animal models and clinical series.35,40,43 Thus, it is likely that the genetic alterations that transform a cell from nonmetastatic to metastatic also result in decreased response to CRT. In line with this, our present findings provide clinical evidence that the propensity of a tumor to develop distant metastases is closely linked to (and can be unmasked by monitoring) the local treatment response of the primary tumor to preoperative CRT. Several additional biologic mechanisms could be responsible for the association of tumor regression and risk of developing distant metastases after preoperative CRT. Reduction in total tumor burden might limit the level of circulating tumor cells and malignant seeding to distant sites44; elimination of primary tumor cells with CRT will stop the release of cytokines and growth factors that modulate the stromal matrix and stimulate bone marrow– derived cells to promote angiogenesis and growth in the metastatic niche44,45 and/or activate dormant cancer cells that disseminated early during tumor formation.46 Complete or near-complete tumor regression after CRT could also reverse immunosuppression and elicit a systemic immunosurveillance response.47 The prognostic value of important clinicopathologic factors, such as ypT and ypN categories, remains unquestionable, especially with regard to ypN. Higher ypN category after preoperative CRT was the strongest prognostic factor in multivariable analysis. Our longterm finding that CRT-induced tumor regression correlates with favorable prognosis might have direct clinical relevance. There is currently an intense discussion as to whether tumor regression is an acceptable criterion for less aggressive therapy, under the prerequisite of close follow-up. Conversely, patients with poor pathologic response could be considered for treatment intensification.1,48-50 However, caution is required before adapting such a policy. The EORTC 22921 trial showed that postoperative chemotherapy only improved DFS in REFERENCES 1. Rodel C, Hofheinz R, Liersch T: Rectal cancer: State of the art in 2012. Curr Opin Oncol 24:441447, 2012 2. McCarthy K, Pearson K, Fulton R, et al: Preoperative chemoradiation for non-metastatic locally advanced rectal cancer. Cochrane Database Syst www.jco.org
patients whose tumors were downstaged to ypT0-2 but not in those with ypT3-4 tumors.51 Hence, trials with the necessary stratification should be designed to address this question. Our study has some limitations. First, at the initial design of the study, TRG was not a described clinical end point. Second, the results obtained by the current three-tier TRG classification were stronger than would have been obtained through a different grouping method. Third, although our TRG classification was based on the work of Dworak et al,23 there is no consensus for a universally approved regression classification; several regression systems have been proposed.52-54 There was no central review procedure to determine reproducibility of the TRG classification, and no measurement of inter- or intraobserver variability in TRG scoring was performed. Fourth, the number of patients who presented complete tumor regression was small compared with the entire cohort. In summary, our three-tier TRG classification was significantly related to the risk of developing distant metastases and to DFS after neoadjuvant CRT and TME surgery in multivariable analysis. This classification system needs to be prospectively tested in multiple data sets to validate its reproducibility in a wider setting. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Rainer Fietkau, Roche; Claus Ro¨del, F. Hoffmann-La Roche, sanofi-aventis Research Funding: Rainer Fietkau, Roche; Claus Ro¨del, F. Hoffmann-La Roche Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None
AUTHOR CONTRIBUTIONS Conception and design: Rainer Fietkau, Werner Hohenberger, Hans-Rudolf Raab, Rolf Sauer, Christian Wittekind, Claus Ro¨del Collection and assembly of data: Torsten Liersch, Rainer Fietkau, Werner Hohenberger, Clemens Hess, Heinz Becker, Susanne Merkel, Hans-Rudolf Raab, Rolf Sauer, Christian Wittekind, Claus Ro¨del Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors
Rev 12:CD008368, 2012 3. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004 4. Sauer R, Liersch T, Merkel S, et al: Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: Results of the German CAO/ARO/AIO-94 randomized phase III trial
after a median follow-up of 11 years. J Clin Oncol 30:1926-1933, 2012 5. Mamon HJ: Long-term follow-up of a paradigm-changing study: The paradigm still holds. J Clin Oncol 30:1901-1903, 2012 6. Chetty R, Gill P, Bateman AC, et al: Pathological grading of regression: An International Study Group perspective. J Clin Pathol 65:865866, 2012
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7. Chetty R, Gill P, Govender D, et al: International study group on rectal cancer regression grading: Interobserver variability with commonly used regression grading systems. Hum Pathol 43:19171923, 2012 8. Janjan NA, Khoo VS, Abbruzzese J, et al: Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: The M. D. Anderson Cancer Center experience Int J Radiat Oncol Biol Phys 44:10271038, 1999 9. Valentini V, Coco C, Picciocchi A, et al: Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long-term analysis of 165 patients. Int J Radiat Oncol Biol Phys 53:664-674, 2002 10. Ro¨del C, Martus P, Papadoupolos T, et al: Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23:8688-8696, 2005 11. 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 66:1378-1383, 2006 12. Kuo LJ, Liu MC, Jian JJ, et al: Is final TNM staging a predictor for survival in locally advanced rectal cancer after preoperative chemoradiation therapy? Ann Surg Oncol 14:2766-2772, 2007 13. Hughes R, Glynne-Jones R, Grainger J, et al: Can pathological complete response in the primary tumour following pre-operative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for sterilisation of pelvic lymph nodes, a low risk of local recurrence and the appropriateness of local excision? Int J Colorectal Dis 21:11-17, 2006 14. Garcı´a-Aguilar J, Hernandez de Anda E, Sirivongs P, et al: A pathologic complete response to preoperative chemoradiation is associated with lower local recurrence and improved survival in rectal cancer patients treated by mesorectal excision. Dis Colon Rectum 46:298-304, 2003 15. Sua´rez J, Vera R, Bale´n E, et al: Pathologic response assessed by Mandard grade is a better prognostic factor than down staging for disease-free survival after preoperative radiochemotherapy for advanced rectal cancer. Colorectal Dis 10:563-568, 2008 16. Park IJ, You YN, Agarwal A, et al: Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol 30:17701776, 2012 17. Shivnani AT, Small W Jr, Stryker SJ, et al: Preoperative chemoradiation for rectal cancer: Results of multimodality management and analysis of prognostic factors. Am J Surg 193:389-393, 2007; discussion 393-394 18. Goethals L, Haustermans K, Perneel C, et al: Chemo-radiotherapy versus radiotherapy alone in the pre-operative treatment of resectable rectal cancer. Eur J Surg Oncol 31:969-976, 2005 19. Mohiuddin M, Hayne M, Regine WF, et al: Prognostic significance of postchemoradiation stage following preoperative chemotherapy and radiation for advanced/recurrent rectal cancers. Int J Radiat Oncol Biol Phys 48:1075-1080, 2000 20. Quah HM, Chou JF, Gonen M, et al: Pathologic stage is most prognostic of disease-free survival in locally advanced rectal cancer patients after preoperative chemoradiation. Cancer 113:57-64, 2008
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21. Chari RS, Tyler DS, Anscher MS, et al: Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum. Ann Surg 221: 778-786, 1995; discussion 786-787 22. Stipa F, Chessin DB, Shia J, et al: A pathologic complete response of rectal cancer to preoperative combined-modality therapy results in improved oncological outcome compared with those who achieve no downstaging on the basis of preoperative endorectal ultrasonography. Ann Surg Oncol 13:1047-1053, 2006 23. Dworak O, Keilholz L, Hoffmann A: Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 12:19-23, 1997 24. Hermanek P, Sobin LH (eds): International Union Against Cancer (UICC): TNM Classification of Malignant Tumours (ed 4). Berlin, Springer-Verlag, 1987 25. Ro¨del C, Liersch T, Becker H, et al: Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: Initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol 13:679-687, 2012 26. Mohiuddin M, Regine WF, John WJ, et al: Preoperative chemoradiation in fixed distal rectal cancer: Dose time factors for pathological complete response. Int J Radiat Oncol Biol Phys 46:883-888, 2000 27. Francois Y, Nemoz CJ, Baulieux J, et al: Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: The Lyon R90-01 randomized trial. J Clin Oncol 17:2396, 1999 28. Wolthuis AM, Penninckx F, Haustermans K, et al: Impact of interval between neoadjuvant chemoradiotherapy and TME for locally advanced rectal cancer on pathologic response and oncologic outcome. Ann Surg Oncol 19:2833-2841, 2012 29. Maas M, Nelemans PJ, Valentini V, et al: Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: A pooled analysis of individual patient data. Lancet Oncol 11:835-844, 2010 30. Bonnetain F, Bosset JF, Gerard JP, et al: What is the clinical benefit of preoperative chemoradiotherapy with 5FU/leucovorin for T3-4 rectal cancer in a pooled analysis of EORTC 22921 and FFCD 9203 trials: Surrogacy in question? Eur J Cancer 48:17811790, 2012 31. Malumbres M, Barbacid M: RAS oncogenes: The first 30 years. Nat Rev Cancer 3:459465, 2003 32. McKenna WG, Muschel RJ, Gupta AK, et al: The RAS signal transduction pathway and its role in radiation sensitivity. Oncogene 22:5866-5875, 2003 33. Kurrey NK, Jalgaonkar SP, Joglekar AV, et al: Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27:2059-2068, 2009 34. Tsuji T, Ibaragi S, Hu GF: Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Res 69:7135-7139, 2009 35. Mehrotra S, Languino LR, Raskett CM, et al: IAP regulation of metastasis. Cancer Cell 17:53-64, 2010
36. Moussata D, Amara S, Siddeek B, et al: XIAP as a radioresistance factor and prognostic marker for radiotherapy in human rectal adenocarcinoma. Am J Pathol 181:1271-1278, 2012 37. Vaupel P: Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol 14:198-206, 2004 38. Bertout JA, Patel SA, Simon MC: The impact of O2 availability on human cancer. Nat Rev Cancer 8:967-975, 2008 39. Semenza GL: Oxygen sensing, homeostasis, and disease. N Engl J Med 365:537-547, 2011 40. Sprenger T, Ro¨del F, Beissbarth T, et al: Failure of downregulation of survivin following neoadjuvant radiochemotherapy in rectal cancer is associated with distant metastases and shortened survival. Clin Cancer Res 17:1623-1631, 2011 41. Ro¨del F, Hoffmann J, Distel L, et al: Survivin as a radioresistance factor, and prognostic and therapeutic target for radiotherapy in rectal cancer. Cancer Res 65:4881-4887, 2005 42. Capalbo G, Ro¨del C, Stauber RH, et al: The role of survivin for radiation therapy: Prognostic and predictive factor and therapeutic target. Strahlenther Onkol 183:593-599, 2007 43. Hehlgans S, Petraki C, Reichert S, et al: Double targeting of survivin and XIAP radiosensitizes 3D grown human colorectal tumor cells and decreases migration. Radiother Oncol 108:32-39, 2013 44. Kang Y, Pantel K: Tumor cell dissemination: Emerging biological insights from animal models and cancer patients. Cancer Cell 23:573-581, 2013 45. Comen E, Norton L, Massague´ J: Clinical implications of cancer self-seeding. Nat Rev Clin Oncol 8:369-377, 2011 46. Klein CA: Parallel progression of primary tumours and metastases. Nat Rev Cancer 9:302-312, 2009 47. Formenti SC, Demaria S: Combining radiotherapy and cancer immunotherapy: A paradigm shift. J Natl Cancer Inst 105:256-265, 2013 48. Marquardt F, Ro¨del F, Capalbo G, et al: Molecular targeted treatment and radiation therapy for rectal cancer. Strahlenther Onkol 185:371-378, 2009 49. Wadlow RC, Ryan DP: The role of targeted agents in preoperative chemoradiation for rectal cancer. Cancer 116:3537-3548, 2010 50. Petersen C: Optimal timing of surgery for rectal cancer after neoadjuvant chemoradiotherapy: Which patients would benefit from waiting? [in German]. Strahlenther Onkol 189:904-906, 2013 51. Collette L, Bosset JF, den Dulk M, et al: Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: Does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 25:4379-4386, 2007 52. Mandard AM, Dalibard F, Mandard JC, et al: Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma: Clinicopathologic correlations. Cancer 73: 2680-2686, 1994 53. Wheeler JM, Warren BF, Mortensen NJ, et al: Quantification of histologic regression of rectal cancer after irradiation: A proposal for a modified staging system. Dis Colon Rectum 45:1051-1056, 2002 54. Washington MK, Berlin J, Branton P, et al: Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. Arch Pathol Lab Med 133:1539-1551, 2009
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Prognostic Significance of TRG in Rectal Carcinoma
■ ■ ■
GLOSSARY TERMS
Less than pathologic complete response: The presence of any residual tumor cells in a histologic evaluation of a tumor specimen.
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Pathologic complete response: The absence of any residual tumor cells in a histologic evaluation of a tumor specimen.
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JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
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Tumor Regression Grading After Preoperative Chemoradiotherapy for Locally Advanced Rectal Carcinoma Revisited: Updated Results of the CAO/ARO/AIO-94 Trial Emmanouil Fokas, Torsten Liersch, Rainer Fietkau, Werner Hohenberger, Tim Beissbarth, Clemens Hess, Heinz Becker, Michael Ghadimi, Karl Mrak, Susanne Merkel, Hans-Rudolf Raab, Rolf Sauer, Christian Wittekind, and Claus Ro¨del See accompanying editorial doi: 10.1200/JCO.2014.55.4766 Emmanouil Fokas and Claus Ro¨del, University of Frankfurt, Frankfurt; Torsten Liersch, Tim Beissbarth, Clemens Hess, Heinz Becker, and Michael Ghadimi, University Medical Center Go¨ttingen, Go¨ttingen; Rainer Fietkau, Werner Hohenberger, Susanne Merkel, and Rolf Sauer, University of Erlangen, Erlangen; Hans-Rudolf Raab, Oldenburg Hospital, Oldenburg; Christian Wittekind, University Hospital Leipzig, Leipzig, Germany; and Karl Mrak, Krankenhaus der Barmherzigen Bru¨der, St Veit, Austria. Published online ahead of print at www.jco.org on April 21, 2014. Supported by Grant No. 70-578 from German Cancer Aid (Deutsche Krebshilfe). Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Emmanouil Fokas, MD, DPhil, Department of Radiotherapy and Oncology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; e-mail: [email protected]. © 2014 by American Society of Clinical Oncology 0732-183X/14/3299-1/$20.00 DOI: 10.1200/JCO.2013.54.3769.
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Purpose We previously described the prognostic impact of tumor regression grading (TRG) on the outcome of patients with rectal carcinoma treated with preoperative chemoradiotherapy (CRT) in the CAO/ARO/AIO-94 trial. Here we report long-term results after a median follow-up of 132 months. Patients and Methods TRG after preoperative CRT was determined in 386 surgical specimens by the amount of viable tumor cells versus fibrosis, ranging from TRG 4 (no viable tumor cells) to TRG 0 (no signs of regression). Clinicopathologic parameters and TRG were correlated to the cumulative incidence of local recurrence, distant metastasis, and disease-free survival (DFS). Results Ten-year cumulative incidence of distant metastasis and DFS were 10.5% and 89.5% for patients with TRG 4 (complete regression), 29.3% and 73.6% for TRG 2 and 3 (intermediate regression), and 39.6% and 63% for TRG 0 and 1 (poor regression), respectively (P ⫽ .005 and P ⫽ .008, respectively). On multivariable analysis, residual lymph node metastasis (ypN⫹) and TRG were the only independent prognostic factors for cumulative incidence of distant metastasis (P ⬍ .001 and P ⫽ .035, respectively) and DFS (P ⬍ .001 and P ⫽ .039, respectively), whereas local recurrence was significantly affected by ypN status (P ⬍ .001) and lymphatic invasion (P ⫽ .026). Conclusion Complete and intermediate tumor regressions were associated with improved long-term outcome in patients with rectal carcinoma after preoperative CRT independent of clinicopathologic parameters. This classification system needs to be prospectively tested in multiple data sets to validate its reproducibility in a wider setting. J Clin Oncol 32. © 2014 by American Society of Clinical Oncology
INTRODUCTION
Rectal carcinoma accounts for approximately 28% of all colorectal malignancies.1,2 The treatment of choice in patients with locally advanced rectal carcinoma is preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) surgery.1,3 The CAO/ARO/AIO-94 (Working Group of Surgical Oncology/Radiation Oncology/Medical Oncology of the German Cancer Society) trial demonstrated the superiority of preoperative over postoperative CRT with regard to local control, treatment compliance, and toxicity profile.3 Ten-year follow-up outcomes confirmed the original findings.4,5 An important clinicopathologic observation derived from the general adoption of preoperative
CRT was the broad variety in tumor response, ranging from pathologic complete response (pCR; ypT0N0), with no viable tumor cells left (currently 10% to 25% of patients), to less than pCR to virtually no tumor regression at all or even tumor progression during therapy.6,7 Although the clinical significance of histopathologically determined tumor regression grading (TRG) is still under investigation, several studies have suggested that the degree of tumor regression may be of high clinical relevance because it could be used as a treatment monitoring and prognostic parameter.8-22 However, a majority of the reports were retrospective and included patients with heterogeneous tumor stages and CRT regimens and were characterized by relatively short follow-up periods, making interpretation of these © 2014 by American Society of Clinical Oncology
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findings challenging. Moreover, the clinical significance of less than complete tumor regression (ie, intermediate or poor TRG) remains to be determined. To prospectively evaluate TRG after preoperative CRT in patients treated in the CAO/ARO/AIO-94 trial, a standardized 5-point TRG system was used based on the work of Dworak et al.10,23 In that context, we previously reported the prognostic value of TRG in patients with rectal adenocarcinoma after preoperative CRT, after a median follow-up of 41 months.10 In the present study, we provide long-term results regarding the prognostic role of TRG after a median follow-up of 132 months.
PATIENTS AND METHODS The CAO/ARO/AIO-94 trial constituted a multicenter, open-label, randomized phase III study.3 The design of the clinical trial, eligibility and exclusion criteria, treatment plan and long-term oncologic results have been reported in detail elsewhere.3,4 Pathologic Examination and TRG Pathologic examination details were reported previously.10 In brief, all resection specimens were examined by local pathologists, blinded to patients’ clinical outcome, from 26 participating hospitals according to a standardized protocol that included International Union Against Cancer TNM category (y prefix indicates classification after neoadjuvant treatment), stage grouping, numbers of examined and involved lymph nodes, and presence or absence of lymphatic and venous invasions.24 Completeness of resection was scored as R0 for negative margins (regardless of distance between tumor and resection margins), R1 for microscopic involvement of margins, and R2 for gross residual tumor. To avoid possible inconsistencies, the reference pathologist (C.W.) developed a standardized case report form for the documentation of all pathologic data. The latter was tested for plausibility in each case by the reference pathologist. For analysis of TRG, fixation of the resected specimen was performed in 4% formaldehyde overnight. After opening of the resected specimen, the latter was examined and described macroscopically. In the presence of macroscopic residual tumor, a minimum of four paraffin blocks were prepared for further analysis. In the absence of macroscopic residual tumor, the whole area consisting mainly of fibrotic tissue was sliced in one specimen per 5 mm and embedded in paraffin. From those blocks 5 m thick, serial slices were prepared. Median and mean numbers of blocks examined were five and 6.43, respectively (range, one to 60). Pathologic grading of primary tumor regression was performed semiquantitatively by determining the amount of viable tumor versus fibrotic tissue that ranged from the lack of tumor regression to complete response with no viable tumor identified, according to Dworak et al.10,23 The five groups of TRG classification were as follows: grade 0, no regression; grade 1, minor regression (dominant tumor mass with obvious fibrosis in ⱕ 25% of tumor mass); grade 2, moderate regression (dominant tumor mass with obvious fibrosis in 26% to 50% of tumor mass); grade 3, good regression (dominant fibrosis outgrowing tumor mass [ie, ⬎ 50% tumor regression]); and grade 4, total regression (no viable tumor cells; fibrotic mass only). According to our previous report,10 the 5-point TRG system was separated into three groups to avoid small categories. These included complete regression (TRG 4), intermediate regression (TRG 2 and 3), and poor regression (TRG 0 and 1). Follow-Up Protocol-specified follow-up was performed as described elsewhere at 3-month intervals during the first 2 years and then at 6-month intervals to a total of 5 years after completion of treatment.4 Follow-up procedures beyond 5 years were not explicitly specified in the original study protocol. Long-term data were obtained by collecting additional information from all participating hospitals and clinical centers, from general practitioners, and finally from German registry offices. 2
© 2014 by American Society of Clinical Oncology
Enrollment (N = 823) Excluded (n = 24) Did not meet (n = 15) inclusion criteria Refused to participate (n = 9)
Randomly allocated to preoperative chemoradiotherapy (n = 404)
Randomly allocated to postoperative chemoradiotherapy (n = 395)
Requested change of arm or erroneously received other treatment arm (n = 18)
Requested change of arm or erroneously received other treatment arm (n = 20)
Allocated to preoperative chemoradiotherapy (n = 406)
Allocated to postoperative chemoradiotherapy (n = 393)
Received preoperative chemoradiotherapy (n = 406) Underwent surgery No surgery
(n = 402) (n = 4)
TRG available TRG 0 TRG 1 TRG 2 TRG 3 TRG 4
(n = 386) (n = 32) (n = 58) (n = 53) (n = 203) (n = 40)
Median follow-up: 132 months (range, 90 to 184 months) Life status known (n = 404) Life status unknown (n = 2) Tumor status known (n = 398) Tumor status unknown (n = 8) Fig 1. CONSORT diagram illustrating treatment flow of CAO/ARO/AIO-94 (Working Group of Surgical Oncology/Radiation Oncology/Medical Oncology of the German Cancer Society) trial. Relevant to tumor regression grading (TRG), only preoperative arm is shown.
Statistical Analysis Local recurrence analyses were performed for all eligible patients who underwent a macroscopically complete local resection after preoperative CRT (patients with R1 resection of primary tumor or with distant metastasis found at time of surgery were included, whereas patients who did not undergo surgery or with macroscopically incomplete local resection [R2] were excluded). Distant recurrence analyses were performed for all eligible patients, and any occurrence of distant metastasis during preoperative CRT, at surgery, or during follow-up was calculated as an event. Disease-free survival (DFS) was calculated for patients with macroscopically complete local resection (R0/1) and no evidence of distant metastasis at the time of surgery (M0). All time-toevent end points were measured from date of random assignment. In accordance with previous reports of this trial, data from patients who were alive and free of recurrence or who died without having had a recurrence were censored in the analyses of recurrence and DFS. We did not use any statistical methods to account for variability in patient follow-up. Statistical analysis was performed using SPSS software (version 16; SPSS, Chicago, IL) and R software (version 3.0.1; http://www.r-project.org). DFS was calculated using the Kaplan-Meier method. Analyses for recurrence were JOURNAL OF CLINICAL ONCOLOGY
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Prognostic Significance of TRG in Rectal Carcinoma
Table 1. Influence of Different Covariables on 10-Year Cumulative Incidence of Local Recurrence, Cumulative Incidence of Distant Metastases, and DFS After Neoadjuvant Chemoradiotherapy
Variable Overall Median age, years ⱕ 61 ⬎ 61 Sex Male Female Distance from anal verge, cm ⬍5 5-10 ⬎ 10 Unknown Preoperative T category cT2 cT3 cT4 Unknown Preoperative N category cN0 cN⫹ Unknown ypT category ypT0 ypT1 ypT2 ypT3 ypT4 Unknown ypN category ypN0 ypN1 ypN2 Unknown Local resection status R0 R1 R2/no resection Unknown Lymphatic invasion L0 L1 Unknown Venous invasion V0 V1 Unknown TRG 0-1 2-3 4 Unknown
No. at Risk
10-Year Cumulative Incidence of Local Recurrence (%)
391
6.9
P
No. at Risk
10-Year Cumulative Incidence of Distant Metastasis (%)
406
30.2
.669 205 186
6.9 7.1
283 108
6.7 7.5
113 182 83 13
10.4 4.9 4.3
16 271 23 81
6.2 5.0 17.4
161 213 17
7.7 6.9
40 22 116 200 13 0
2.6 0 3.4 9.6 28.6
271 70 50 0
4.0 11.4 21.3
387 4 0 0
6.7 25.0
298 82 11
4.2 15.6
366 18 0
6.3 9.1
87 253 40 11
3.6 8.0 2.6
P
No. at Risk
10-Year DFS (%)
361
73
190 171
75.3 70.5
258 103
73.2 72.7
102 169 77 13
67.2 78.4 79.9
15 253 20 73
66.7 75.9 68.7
152 193 16
71.6 74.7
40 21 113 177 10 0
89.5 95.2 77.9 65.7 40
261 60 40 0
83.5 59.4 27.5
357 4 0 0
73.3 50
281 70 10
77.4 55
342 14 5
74.5 42.9
80 232 40 9
63 73.6 89.5
.435 209 197
28.6 32.1
293 113
30.5 29.4
117 189 85 15
36.3 25.0 31.8
16 279 24 87
37.5 26.5 38.9
169 220 17
31.2 28.9
40 23 117 203 15 8
10.5 8.7 21 38.9 61.9
275 73 50 8
17.7 45.8 72.8
387 4 8 7
29.5 50.0 57.1
302 84 20
24.3 50.8
371 19 16
28 57.9
90 256 40 20
39.6 29.3 10.5
.596
.328
.902
.036
.791
.103
.045
.110
.684
.508
.987
.612
< .001
.425
< .001
< .001
< .001
< .001
.006
< .001
.011
< .001
.079
< .001
.785
< .001
.002
.410
P
.002
.005
.008
NOTE. Bold font indicates significance. Abbreviations: DFS, disease-free survival; TRG, tumor regression grade.
reported as cumulative incidences. Differences were evaluated with the logrank test. Multivariable models were computed using the Cox proportional hazards model. All variables that were significant in the corresponding univariable analysis were included in multivariable Cox regression models in a www.jco.org
forward-step procedure. The variables were entered in a predefined order according to clinical relevance into the regression models with increasing complexity, and significance was assessed using analysis of variance analysis. For this purpose, the functions “coxph” and “anova” from the R © 2014 by American Society of Clinical Oncology
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0.6
A TRG 0 + 1 TRG 2 + 3 TRG 4
Cumulative Incidence of Local Recurrence
Cumulative Incidence of Local Recurrence
A
P = .410
0.4
0.2
0
30
60
90
120
150
180
0.6
ypT4 ypT3 ypT0-2 P < .001
0.4
0.2
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30
60
Time (months)
Cumulative Incidence of Distant Metastases
B
0.6
73 216 37
58 190 37
50 168 34
39 108 21
18 41 6
3 3 0
B TRG 0 + 1 TRG 2 + 3 TRG 4 P = .005
0.4
0.2
0
30
60
90
120
150
1.0
0.8
54 171 35
50 157 34
37 104 21
156 132 5
144 112 4
90 79 2
35 29 1
3 2 0
60
90
120
150
180
ypT4 ypT3 ypT0-2
0.4
0.2
30
Time (months) 17 39 6
3 3 0
C
1.0
0.8
0.6 0.4
0.2
TRG 0 + 1 TRG 2 + 3 TRG 4
30
159 142 9
147 117 5
139 114 5
86 77 2
34 27 1
1 2 1
60
90
120
150
180
33 27 1
3 0 0
1.0
0.8
0.6 0.4
0.2
P = .008
0
ypT4 ypT3 ypT0-2 P < .001
60
90
120
150
180
0
30
Time (months) No. at risk TRG 0 + 1 80 TRG 2 + 3 232 TRG 4 40
57 193 36
50 166 35
46 153 34
35 101 21
Time (months) 15 38 6
3 3 0
Fig 2. Long-term prognostic significance of tumor regression grading (TRG) after preoperative chemoradiotherapy and total mesorectal excision surgery in rectal carcinoma; 10-year cumulative incidences of (A) local recurrence and (B) distant metastasis and (C) 10-year disease-free survival, according to TRG.
4
180
0.6
No. at risk ypT0-2 180 ypT3 203 ypT4 15
Disease-Free Survival (probability)
Disease-Free Survival (probability)
C
63 201 36
150
P < .001
0
180
166 162 9
Time (months) No. at risk TRG 0 + 1 90 TRG 2 + 3 256 TRG 4 40
120
Time (months) No. at risk ypT0-2 178 ypT3 200 ypT4 13
Cumulative Incidence of Distant Metastases
No. at risk TRG 0 + 1 87 TRG 2 + 3 253 TRG 4 40
90
© 2014 by American Society of Clinical Oncology
No. at risk ypT0-2 174 ypT3 177 ypT4 10
156 134 5
143 112 4
135 102 4
85 73 2
Fig 3. Long-term prognostic significance of ypT categories after preoperative chemoradiotherapy and total mesorectal excision surgery in rectal carcinoma; 10-year cumulative incidences of (A) local recurrence and (B) distant metastasis and (C) 10-year disease-free survival, according to ypT category.
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Prognostic Significance of TRG in Rectal Carcinoma
Patient Characteristics and Association of TRG With Clinicopathologic Factors In total, 823 patients participated in the randomized trial (Fig 1). Of those, 24 patients were excluded from the study because of protocol violation. Of the remaining 799 patients, 404 and 395 patients were randomly assigned to preoperative and postoperative treatment, respectively. Furthermore, change in treatment arm or therapy using the schedule of the opposite arm occurred in 18 and 20 patients, respectively. Hence, 406 patients received preoperative CRT, and 393 patients received postoperative CRT. From the 406 patients, life and tumor statuses were unknown in two and eight patients at the last follow-up examination, respectively. TRG was available in 386 patients treated in the preoperative CRT arm (TRG 0, 32 patients [8.3%]; TRG 1, 58 patients [15.0%]; TRG 2, 53 patients [13.7%]; TRG 3, 203 patients [52.6%]; TRG 4, 40 patients [10.4%]). The association of TRG with various pretreatment clinical and postoperative histopathologic factors is provided in the original work.10 In brief, none of the pretreatment factors, including cT and cN categories, predicted TRG. After preoperative CRT and TME surgery, TRG was significantly associated with ypN1-2 (TRG 0 and 1, 40.7%; TRG 2 and 3, 31.9%; TRG 4, 10%; P ⫽ .001). Moreover, ypT3-4 tumors (P ⫽ .03) and venous invasion (V1; P ⫽ .03) were noted more frequently in the poor response group (TRG 0 and 1) as compared with the intermediate TRG 2 and 3 group.
Cumulative Incidence of Local Recurrence
RESULTS
A
0.6
P < .001
0.2
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30
60
90
120
150
180
Time (months) No. at risk ypN2 50 ypN1 70 ypN0 271
B
1.0
0.8
33 56 248
19 45 229
15 39 206
7 22 141
4 10 51
0 0 6
60
90
120
150
180
ypN2 ypN1 ypN0 P < .001
0.6 0.4
0.2
0
30
Time (months) No. at risk ypN2 50 ypN1 73 ypN0 275
C Disease-Free Survival (probability)
TRG As Prognostic Factor for Clinical Outcome In total, 234 surviving patients in the preoperative treatment group underwent follow-up, for a median of 132 months (range, 90 to 184 months). Local recurrence after preoperative CRT and R0/1 local tumor resection was encountered in 22 patients. Six had local recurrence alone, and 16 also had synchronous distant metastasis. Five (23%) of 22 local recurrences occurred beyond 5 years of follow-up. Ten-year cumulative incidence of local recurrence in 391 eligible patients was 6.8%. Of the 406 patients assessed for metastatic disease, distant metastasis was observed in 119 patients. Ten-year cumulative incidence of distant metastasis was 30.2%. For patients with R0/1 local tumor resection and no evidence of distant metastasis at surgery (M0), disease recurrence (local, distant, or both) occurred in 94 patients. DFS at 10 years was 73%. We performed a univariable analysis to assess the prognostic impact of TRG on the cumulative incidence of local recurrence after R0/1 local resection, on the cumulative incidence of distant metastasis, and on DFS after curative surgery (R0/1; M0; Table 1; Fig 2A). TRG was not prognostic for cumulative incidence of local recurrence. A slight trend toward less local recurrence was observed for TRG 4, with a cumulative incidence of 2.6% versus 8.0% (TRG 2 and 3) and 3.6% (TRG 0 and 1). The relatively low number of local recurrences in the TRG 0 and 1 group could have resulted from the limited number of patients in this group. In contrast, TRG was significantly associated with the cumulative incidence of distant metastasis and DFS (Figs 2B and 2C). Indeed, the cumulative incidence of distant metastasis was 10.5%, 29.3%, and 39.6% in patients with TRG 4, TRG 2 and 3 and
ypN2 ypN1 ypN0
0.4
0
Cumulative Incidence of Distant Metastases
package survival were used. A two-sided P value less than .05 was considered significant.
21 51 238
10 39 220
9 37 204
6 21 138
2 10 50
0 0 6
60
90
120
150
180
2 9 48
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0
30
Time (months) No. at risk ypN2 40 ypN1 60 ypN0 261
17 45 233
9 36 214
8 35 198
5 20 135
Fig 4. Long-term prognostic significance of ypN categories after preoperative chemoradiotherapy and total mesorectal excision surgery in rectal carcinoma; 10-year cumulative incidences of (A) local recurrence and (B) distant metastasis and (C) 10-year disease-free survival, according to ypN category.
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5
Fokas et al
TRG 0 and 1, respectively (P ⫽ .005). Similarly, DFS was 89.5%, 73.6%, and 63% in patients with TRG 4, TRG 2 and 3, and TRG 0 and 1, respectively (P ⫽ .008). We also examined the prognostic significance of various clinicopathologic factors (Table 1). The cumulative incidence of local recurrence was correlated with the distance of the aboral tumor border to the anocutaneous verge (P ⫽ .036); cT (P ⫽ .045), ypT (P ⬍ .001), and ypN categories (P ⬍ .001); resection status (P ⫽ .006); and lymphatic invasion (P ⬍ .001; Figs 3A and 4A). In addition, ypT (P ⬍ .001) and ypN categories (P ⬍ .001), resection status (P ⫽ .011), venous invasion (P ⫽ .002), and lymphatic invasion (P ⬍ .001) were significantly associated with the cumulative incidence of distant metastasis (Figs 3B and 4B). Similar results were obtained for DFS, with the exception of R status, which lacked prognostic significance (P ⫽ .079; Figs 3C and 4C). All factors that showed significance in univariable analysis were included in the multivariable analyses (Table 2). Hazard ratios (HRs) are reported, along with 95% CIs, from the multivariable Cox models. P values are derived from comparisons of models with increasing complexity (ie, from top to bottom). Lymph node metastasis after preoperative CRT (ypN1-2) constituted the strongest prognostic factor for the cumulative incidence of local recurrence (HR, 2.07; 95% CI, 1.04 to 4.10; P ⬍ .001), distant metastasis (HR, 2.44; 95% CI, 1.92 to 3.10; P ⬍ .001), and DFS (HR, 2.5; 95% CI, 1.95 to 3.22; P ⬍ .001). Lymphatic invasion was associated with increased cumulative incidence of local recurrence (HR, 4.00; 95% CI, 1.16 to 13.82; P ⫽ .026). In multivariable analysis, TRG after preoperative CRT was an independent prognostic factor for ypN and ypT, with regard to cumulative incidence of distant metastasis (HR, 0.74; 95% CI, 0.52 to 1.06; P ⫽ .035) and DFS (HR, 0.76; 95% CI, 0.52 to 1.11; P ⫽ .039). None of the other analyzed factors significantly added prognostic information in multivariable models already containing ypN and TRG.
preoperative CRT and surgery, and combination with chemotherapy.25-28 In this study, we analyzed the prognostic impact of TRG in a large patient cohort after homogenous treatment with preoperative CRT in the CAO/ARO/AIO-94 trial after a median follow-up of 132 months. We showed that a simplified three-tier TRG, as established in our previous analysis,10 constituted an independent prognostic factor for 10-year cumulative incidence of distant metastasis and DFS. Importantly, clinicopathologic parameters, including ypN category, did not affect the prognostic significance of TRG in multivariable analysis. In line with our observations, several studies have demonstrated better outcome in patients with complete tumor regression (pCR) compared with noncomplete tumor regression.8-22 Although the pooled analysis by Maas et al29 involved a large number of patients (N ⫽ 3,105), median follow-up was only 48 months, and a majority of patients were treated outside clinical trials, with treatment characterized by heterogeneous strategies and lack of a uniform TRG evaluation method. In contrast, our study reports the prognostic significance of a three-tier TRG system in a patient group treated homogeneously in a phase III trial after long follow-up. A pooled analysis of the EORTC (European Organisation for Research and Treatment of Cancer) 22921 and FFCD (Fe´de´ration Francophone de Cance´rologie Digestive) 9203 trials, comparing preoperative fluorouracil-based CRT (n ⫽ 886) with radiotherapy alone (n ⫽ 881), showed that pCR and local control rates were significantly improved by preoperative CRT; however, these effects did not translate into improved progression-free or overall survival.30 Of note, this pooled analysis did not compare different degrees of pathologic response, as in our study, but rather the effect of different regimens on outcome. We agree that pCR is not a reliable end point for phase III trials comparing the efficacy of different treatment regimens on longterm end points. However, here we show that TRG may identify different prognostic groups when treated homogeneously. We consider the most striking finding of this study to be the significant association of TRG—which is an assessment of local treatment efficacy regarding the primary tumor in the rectal wall—with the risk of distant metastasis and DFS in both univariable and multivariable analyses. Thus, an important yet unresolved issue has been raised
DISCUSSION
Tumor regression varies among patients with rectal carcinoma after preoperative CRT. Some tumors demonstrate pCR, whereas others show either intermediate regression or even complete lack of response.6,7 Various factors seem to determine pathologic tumor regression, including radiotherapy dose and schedule, time between
Table 2. Multivariable Analysis of Different Covariables on 10-Year Cumulative Incidence of Local Recurrence, Cumulative Incidence of Distant Metastasis, and DFS After Neoadjuvant Chemoradiotherapy 10-Year Cumulative Incidence of Local Recurrence
Variable Significant in Univariable Analysis
HR
ypN category Preoperative T category ypT category TRG Distance from anal verge Lymphatic invasion Venous invasion Local resection
2.07 2.13 0.78 — 0.50 4.00 — 0.00
95% CI 1.04 to 4.1 0.61 to 7.41 0.48 to 1.27
P
10-Year Cumulative Incidence of Distant Metastasis ⴱ
< .001 .091 .132
0.23 to 1.10 1.16 to 13.82
.057 .026
0.00 to infinity
.648
ⴱ
10-Year DFS
HR
95% CI
P
HR
95% CI
Pⴱ
2.44 — 0.90 0.74 — 1.29 1.52 1.25
1.92 to 3.10
< .001
1.95 to 3.22
< .001
0.79 to 1.03 0.52 to 1.06
.129 .035
0.81 to 1.08 0.52 to 1.11
.391 .039
0.83 to 2.00 0.76 to 3.03 0.57 to 2.75
.121 .216 .595
2.50 — 0.93 0.76 — 1.29 1.89 —
0.81 to 2.05 0.93 to 3.82
.115 .093
NOTE. Bold font indicates significance. Abbreviations: DFS, disease-free survival; HR, hazard ratio; TRG, tumor regression grade. ⴱ Analysis of variance.
6
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Prognostic Significance of TRG in Rectal Carcinoma
of whether less extensive or even complete lack of local tumor regression reflects an inherently aggressive malignant biologic phenotype that is at the same time less responsive to local CRT and also exhibits higher propensity to metastasize. An important implication of this concept would be that the genetic abnormalities and biologic mechanisms responsible for resistance to CRT are closely linked or even overlap with those responsible for distant cancer cell spread and seeding. There is now ample evidence to suggest that abnormalities, such as oncogenic activation of RAS,31,32 epithelial-mesenchymal transition,33,34 antiapoptotic factors,35,36 and hypoxia,37-39 to name a few, contribute to both local resistance to CRT and increased metastasis. For example, survivin, an inhibitor of apoptosis protein frequently overexpressed in rectal carcinoma, is associated with decreased response to irradiation in cell culture and animal models and increased risk of local recurrence in patients with rectal carcinoma after preoperative CRT and TME surgery.40-42 Also, survivin constitutes an important metastasis gene in animal models and clinical series.35,40,43 Thus, it is likely that the genetic alterations that transform a cell from nonmetastatic to metastatic also result in decreased response to CRT. In line with this, our present findings provide clinical evidence that the propensity of a tumor to develop distant metastases is closely linked to (and can be unmasked by monitoring) the local treatment response of the primary tumor to preoperative CRT. Several additional biologic mechanisms could be responsible for the association of tumor regression and risk of developing distant metastases after preoperative CRT. Reduction in total tumor burden might limit the level of circulating tumor cells and malignant seeding to distant sites44; elimination of primary tumor cells with CRT will stop the release of cytokines and growth factors that modulate the stromal matrix and stimulate bone marrow– derived cells to promote angiogenesis and growth in the metastatic niche44,45 and/or activate dormant cancer cells that disseminated early during tumor formation.46 Complete or near-complete tumor regression after CRT could also reverse immunosuppression and elicit a systemic immunosurveillance response.47 The prognostic value of important clinicopathologic factors, such as ypT and ypN categories, remains unquestionable, especially with regard to ypN. Higher ypN category after preoperative CRT was the strongest prognostic factor in multivariable analysis. Our longterm finding that CRT-induced tumor regression correlates with favorable prognosis might have direct clinical relevance. There is currently an intense discussion as to whether tumor regression is an acceptable criterion for less aggressive therapy, under the prerequisite of close follow-up. Conversely, patients with poor pathologic response could be considered for treatment intensification.1,48-50 However, caution is required before adapting such a policy. The EORTC 22921 trial showed that postoperative chemotherapy only improved DFS in REFERENCES 1. Rodel C, Hofheinz R, Liersch T: Rectal cancer: State of the art in 2012. Curr Opin Oncol 24:441447, 2012 2. McCarthy K, Pearson K, Fulton R, et al: Preoperative chemoradiation for non-metastatic locally advanced rectal cancer. Cochrane Database Syst www.jco.org
patients whose tumors were downstaged to ypT0-2 but not in those with ypT3-4 tumors.51 Hence, trials with the necessary stratification should be designed to address this question. Our study has some limitations. First, at the initial design of the study, TRG was not a described clinical end point. Second, the results obtained by the current three-tier TRG classification were stronger than would have been obtained through a different grouping method. Third, although our TRG classification was based on the work of Dworak et al,23 there is no consensus for a universally approved regression classification; several regression systems have been proposed.52-54 There was no central review procedure to determine reproducibility of the TRG classification, and no measurement of inter- or intraobserver variability in TRG scoring was performed. Fourth, the number of patients who presented complete tumor regression was small compared with the entire cohort. In summary, our three-tier TRG classification was significantly related to the risk of developing distant metastases and to DFS after neoadjuvant CRT and TME surgery in multivariable analysis. This classification system needs to be prospectively tested in multiple data sets to validate its reproducibility in a wider setting. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Rainer Fietkau, Roche; Claus Ro¨del, F. Hoffmann-La Roche, sanofi-aventis Research Funding: Rainer Fietkau, Roche; Claus Ro¨del, F. Hoffmann-La Roche Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None
AUTHOR CONTRIBUTIONS Conception and design: Rainer Fietkau, Werner Hohenberger, Hans-Rudolf Raab, Rolf Sauer, Christian Wittekind, Claus Ro¨del Collection and assembly of data: Torsten Liersch, Rainer Fietkau, Werner Hohenberger, Clemens Hess, Heinz Becker, Susanne Merkel, Hans-Rudolf Raab, Rolf Sauer, Christian Wittekind, Claus Ro¨del Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors
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21. Chari RS, Tyler DS, Anscher MS, et al: Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum. Ann Surg 221: 778-786, 1995; discussion 786-787 22. Stipa F, Chessin DB, Shia J, et al: A pathologic complete response of rectal cancer to preoperative combined-modality therapy results in improved oncological outcome compared with those who achieve no downstaging on the basis of preoperative endorectal ultrasonography. Ann Surg Oncol 13:1047-1053, 2006 23. Dworak O, Keilholz L, Hoffmann A: Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 12:19-23, 1997 24. Hermanek P, Sobin LH (eds): International Union Against Cancer (UICC): TNM Classification of Malignant Tumours (ed 4). Berlin, Springer-Verlag, 1987 25. Ro¨del C, Liersch T, Becker H, et al: Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: Initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol 13:679-687, 2012 26. Mohiuddin M, Regine WF, John WJ, et al: Preoperative chemoradiation in fixed distal rectal cancer: Dose time factors for pathological complete response. Int J Radiat Oncol Biol Phys 46:883-888, 2000 27. Francois Y, Nemoz CJ, Baulieux J, et al: Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: The Lyon R90-01 randomized trial. J Clin Oncol 17:2396, 1999 28. Wolthuis AM, Penninckx F, Haustermans K, et al: Impact of interval between neoadjuvant chemoradiotherapy and TME for locally advanced rectal cancer on pathologic response and oncologic outcome. Ann Surg Oncol 19:2833-2841, 2012 29. Maas M, Nelemans PJ, Valentini V, et al: Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: A pooled analysis of individual patient data. Lancet Oncol 11:835-844, 2010 30. Bonnetain F, Bosset JF, Gerard JP, et al: What is the clinical benefit of preoperative chemoradiotherapy with 5FU/leucovorin for T3-4 rectal cancer in a pooled analysis of EORTC 22921 and FFCD 9203 trials: Surrogacy in question? Eur J Cancer 48:17811790, 2012 31. Malumbres M, Barbacid M: RAS oncogenes: The first 30 years. Nat Rev Cancer 3:459465, 2003 32. McKenna WG, Muschel RJ, Gupta AK, et al: The RAS signal transduction pathway and its role in radiation sensitivity. Oncogene 22:5866-5875, 2003 33. Kurrey NK, Jalgaonkar SP, Joglekar AV, et al: Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27:2059-2068, 2009 34. Tsuji T, Ibaragi S, Hu GF: Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Res 69:7135-7139, 2009 35. Mehrotra S, Languino LR, Raskett CM, et al: IAP regulation of metastasis. Cancer Cell 17:53-64, 2010
36. Moussata D, Amara S, Siddeek B, et al: XIAP as a radioresistance factor and prognostic marker for radiotherapy in human rectal adenocarcinoma. Am J Pathol 181:1271-1278, 2012 37. Vaupel P: Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol 14:198-206, 2004 38. Bertout JA, Patel SA, Simon MC: The impact of O2 availability on human cancer. Nat Rev Cancer 8:967-975, 2008 39. Semenza GL: Oxygen sensing, homeostasis, and disease. N Engl J Med 365:537-547, 2011 40. Sprenger T, Ro¨del F, Beissbarth T, et al: Failure of downregulation of survivin following neoadjuvant radiochemotherapy in rectal cancer is associated with distant metastases and shortened survival. Clin Cancer Res 17:1623-1631, 2011 41. Ro¨del F, Hoffmann J, Distel L, et al: Survivin as a radioresistance factor, and prognostic and therapeutic target for radiotherapy in rectal cancer. Cancer Res 65:4881-4887, 2005 42. Capalbo G, Ro¨del C, Stauber RH, et al: The role of survivin for radiation therapy: Prognostic and predictive factor and therapeutic target. Strahlenther Onkol 183:593-599, 2007 43. Hehlgans S, Petraki C, Reichert S, et al: Double targeting of survivin and XIAP radiosensitizes 3D grown human colorectal tumor cells and decreases migration. Radiother Oncol 108:32-39, 2013 44. Kang Y, Pantel K: Tumor cell dissemination: Emerging biological insights from animal models and cancer patients. Cancer Cell 23:573-581, 2013 45. Comen E, Norton L, Massague´ J: Clinical implications of cancer self-seeding. Nat Rev Clin Oncol 8:369-377, 2011 46. Klein CA: Parallel progression of primary tumours and metastases. Nat Rev Cancer 9:302-312, 2009 47. Formenti SC, Demaria S: Combining radiotherapy and cancer immunotherapy: A paradigm shift. J Natl Cancer Inst 105:256-265, 2013 48. Marquardt F, Ro¨del F, Capalbo G, et al: Molecular targeted treatment and radiation therapy for rectal cancer. Strahlenther Onkol 185:371-378, 2009 49. Wadlow RC, Ryan DP: The role of targeted agents in preoperative chemoradiation for rectal cancer. Cancer 116:3537-3548, 2010 50. Petersen C: Optimal timing of surgery for rectal cancer after neoadjuvant chemoradiotherapy: Which patients would benefit from waiting? [in German]. Strahlenther Onkol 189:904-906, 2013 51. Collette L, Bosset JF, den Dulk M, et al: Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: Does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 25:4379-4386, 2007 52. Mandard AM, Dalibard F, Mandard JC, et al: Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma: Clinicopathologic correlations. Cancer 73: 2680-2686, 1994 53. Wheeler JM, Warren BF, Mortensen NJ, et al: Quantification of histologic regression of rectal cancer after irradiation: A proposal for a modified staging system. Dis Colon Rectum 45:1051-1056, 2002 54. Washington MK, Berlin J, Branton P, et al: Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. Arch Pathol Lab Med 133:1539-1551, 2009
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Prognostic Significance of TRG in Rectal Carcinoma
■ ■ ■
GLOSSARY TERMS
Less than pathologic complete response: The presence of any residual tumor cells in a histologic evaluation of a tumor specimen.
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Pathologic complete response: The absence of any residual tumor cells in a histologic evaluation of a tumor specimen.
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UCLA on April 30, 2014 from 128.97.90.221 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
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