Download Prognosis Factors for Recurrence in Patients With Locally Advanced

ORIGINAL CONTRIBUTION
Prognosis Factors for Recurrence in Patients
With Locally Advanced Rectal Cancer
Preoperatively Treated With Chemoradiotherapy
and Adjuvant Chemotherapy
Jorge Arredondo, M.D.1 • Jorge Baixauli, Ph.D.1 • Carmen Beorlegui, Ph.D.2
Leire Arbea, Ph.D.3 • Javier Rodríguez, M.D.4 • Jesús Javier Sola, Ph.D.5
Ana Chopitea, M.D.4 • José Luís Hernández-Lizoáin, Ph.D.1
1 Department of General Surgery, Clínica Universidad de Navarra, Pamplona, Spain
2 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain
3 Department of Radiation Oncology, Clínica Universidad de Navarra, Pamplona, Spain
4 Department of Medical Oncology, Clínica Universidad de Navarra, Pamplona, Spain
5 Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain
BACKGROUND: Neoadjuvant chemoradiotherapy
followed by total mesorectal excision has improved the
outcome of locally advanced rectal carcinoma.
OBJECTIVE: The aim of this study was to identify
independent prognosis factors of disease recurrence in a
group of patients treated with this approach.
DESIGN AND PATIENTS: This study was retrospective in
design. Data from patients with locally advanced rectal
cancer who had completed treatment from 2000 to 2010
were reviewed.
SETTINGS: The analysis was performed in a tertiary
referral center.
MAIN OUTCOME MEASURES: The primary outcomes
measured were the recurrence risk factors.
RESULTS: The cohort consisted of 228 patients; 69.3%
of them were men, and median age was 59 years. Stage
III rectal cancer was found in 64.9% of patients. The
most frequently administered therapy was concurrent
capecitabine, oxaliplatin, and 7-field radiotherapy,
followed by 3-field radiotherapy and fluoropyrimidines.
After a median follow-up of 49 months, 23.7% of the
patients experienced disease recurrence: 2.6% had local
Financial Disclosures: None reported.
Correspondence: Jorge Arredondo, M.D., Department of General
­Surgery, Clínica Universidad de Navarra, 36 Pio XII Ave, Pamplona
31008, Navarra, Spain. E-mail: [email protected].
Dis Colon Rectum 2013; 56: 416–421
DOI: 10.1097/DCR.0b013e318274d9c6
© The ASCRS 2013
416
recurrence, 21.1% had distant metastases, and 0.5% had
both. Factors significantly correlated with recurrence risk
in multivariate logistic regression were y-pathological
stage (III vs I/II: OR = 2.51), tumor regression grade (1/2
vs 3+/4: OR = 3.34; 3 vs 3+/4: OR = 1.20), and low rectal
location (OR = 2.36). The only independent prognosis
factor for liver metastases was tumor regression grade
(1/2 vs 3+/4: OR = 4.67; 3 vs 3+/4: OR = 1.41), whereas
tumor regression grade (1–2 vs 3+/4: OR = 5.5; 3 vs
3+/4: OR = 1.84), low rectal location (OR = 3.23),
and previous liver metastasis (OR = 7.73) predicted
lung recurrence.
LIMITATIONS: This is a single institutional experience,
neoadjuvant combined therapy is not homogeneous,
and the analysis has been performed in a retrospective
manner.
CONCLUSIONS: Patients with low third locally advanced
rectal cancer with a poor response to neoadjuvant
chemoradiotherapy (high y-pathological stage or low
tumor regression grade) are at high risk of recurrence.
Intense surveillance and the design of alternative
therapeutic approaches aimed to lower the distant failure
rate seem warranted.
KEY WORDS: Locally advanced rectal cancer;
Neoadjuvant combined therapy.
R
ectal cancer is a frequent disease with an annual
incidence of 39,670 cases in the United States.1
Preoperative radiotherapy (RT) decreases local
­recurrence rates in comparison with surgery alone,2,3 and
Diseases of the Colon & Rectum Volume 56: 4 (2013)
417
Diseases of the Colon & Rectum Volume 56: 4 (2013)
the widespread performance of total mesorectal excision (TME) has improved survival rates.2,4 Preoperative
chemoradiotherapy (CRT), in comparison with postoperative combined modality therapy, improves local control,
treatment compliance, sphincter preservation, and toxicity profile.5–12 On this basis, for locally advanced ­rectal
cancer (LARC), neoadjuvant CRT followed by surgery is
currently the preferred treatment option.5,13–15 Adjuvant
chemotherapy (ChT) is usually recommended, although
controversy exists in patients who have been rendered
node negative by preoperative treatment.15,16
The multidisciplinary management of LARC has
translated into a decrease in the rate of local failure.
­However the incidence of distant metastases remains in
the range of 25% to 30%. In this setting, strategies aimed to
reduce the burden of metastases are a priority of research.
The aim of this study was to identify prognosis factors
correlated with the risk of recurrence in LARC ­patients
treated with a multidisciplinary approach based on
­neoadjuvant CRT, TME, and adjuvant ChT.
MATERIAL AND METHODS
Medical records of LARC patients who completed
­preoperative CRT and surgery in Clínica Universidad de
Navarra (Spain) between January 2000 and December
2010 were retrospectively reviewed.
The cohort consisted of 235 consecutive patients with
biopsy-proven resectable rectal adenocarcinoma with the
inferior margin within 15 cm from the anal verge. Tumors
were classified by location in the lower (0–5 cm), middle
(5.1–10 cm), or upper rectum (10.1–15 cm) by flexible
endoscopy.
Eligibility criteria included clinical stage II or III
rectal cancer by physical examination, endorectal ultrasound and CT of the chest, abdomen, and pelvis. Tumors
were staged according to the American Joint Committee
on Cancer Cancer Staging Manual.17 All patients had a
World Health Organization performance status of 0 or 1.
Patients were excluded in cases of previous cancer aside
from nonmelanoma skin cancer, previous therapy with
ChT or RT to the pelvis, or medical contraindications to
receive CRT. This retrospective analysis was approved by
the ­institutional review board.
Two different protocols of neoadjuvant ChT were
used: 5-fluorouracil (5-FU) alone (225 mg/m2 on days
1–4 and 24–28); or capecitabine (825 mg/m2 twice daily Monday to Friday) in combination with oxaliplatin
­administered at a dose of 60 mg/m2 on days 1, 8, and 15.18
Concomitant preoperative external beam irradiation was
delivered either by using a 3- or 4-field technique, or by
7-field intensity-modulated technique. The results of the
former approach have been reported elsewhere.19 Surgery
was scheduled 5 to 6 weeks after the completion of CRT.
Patients underwent TME according to a standardized
technique, and sphincter preservation was preferable if
this was both technically and oncologically feasible.
Pathological analyses were performed by a specialized
GI pathologist (J.S.). Staging was performed according to
TNM classification.17 Tumor regression grade (TRG) was
obtained based on a modification of the 5-point scale proposed by Ruo et al.7 This classification takes into ­account
the percentage of tumor cells that remain visible in the
surgical specimen: grade 0 (no response to treatment),
grade 1 (response <33%), grade 2 (response between 33
% and 66%), grade 3 (response between 66% and 94%),
grade 3+ (95%–99% response, focus or microscopic residual), and grade 4 (no viable tumor identified, pathological
complete response (pCR)). In the present study, a 3-point
TRG scale was used by grouping grades 0-1-2, grade 3, and
grades 3+ and 4. In addition, distal resection margins and
lymphovascular or perineural invasion were documented.
Circumferential radial margins were not available in most
patients of this historical study; thus, this variable was not
included in the analysis.
The relationship of age, sex, clinical (tumor location,
tumor volume, clinical N, clinical T, clinical stage, type
of surgery, neoadjuvant ChT, RT, and adjuvant ChT) and
pathological variables (total number of lymph nodes,
­lymphovascular invasion, perineural invasion, distal resection margin, ypT, ypN, yp stage, TRG) with the risk
of distant relapse was analyzed by univariate logistic
regression.
Patients were followed-up every 3 months for 2 years,
every 6 months for the next 3 years, and afterward annually, according to National Comprehensive Cancer Network
guidelines.20 Local recurrence was defined as clinical or radiologic tumor regrowth within the previous pelvic treatment field. Distant recurrence was considered as tumor
growth in any other area. Diagnosis of relapse was based
on 2 consecutive CT within 4 to 6 weeks. Histopathological verification was performed when feasible.
Statistical Analysis
All the statistical analyses were done by using the SPSS/
PC v.15 for Windows statistical package (SPSS, Chicago,
IL). Results were expressed as mean or median (P25 to
P75) for continuous variables, depending on whether or
not normal distribution was followed, and proportion
for qualitative variables. Relationship between variables
and development of metastases (global and both hepatic
and pulmonary) were studied by Student t (or MannWhitney U, depending on whether or not data followed
a normal distribution) and χ2 tests. All factors with p <
0.2 were considered in the multivariate logistic regression analyses with a semimanual backward (likelihood
ratio) variable selection.
418
Arredondo et al: Prognosis Factors in Rectal Cancer
TABLE 1. Demographic and treatment characteristics
n (%)
Age
Sex
Male
Female
Rectal third location
Lower
Middle
Upper
Clinical stage
II
III
Chemotherapy regimen
Oxaliplatine-based
Fluoropyrimidine-based
Radiotherapy
3–4 fields
7 fields
Surgical procedure
LAR
APR
Hartmann
59 (24–85)
a
158 (69.3)
70 (30.7)
128 (56.1)
73 (32)
27 (11.8)
80 (35.1)
148 (64.9)
165 (72.4)
63 (27.6)
96 (42.1)
132 (57.9)
174 (76.3)
48 (21.1)
6 (2.6)
LAR = low anterior resection; APR, abdominoperineal resection.
a
Median (rank).
RESULTS
Patients Characteristics and Surgical Findings
The final cohort consisted of 228 LARC patients with a
median age of 59 years (range, 24–85), of whom 158
(69.3%) were men. At the time of diagnosis, clinical stage
II and III were found in 35.1% and 64.9%. The tumor
was located in the lower, middle, and upper rectum in
56.1%, 32.0%, and 11.8% of the patients. Concurrent fluoropyrimidines plus oxaliplatin were administered to 165
­patients (72.4%), whereas 63 patients (27.6%) received
5-FU-based CRT. The number of RT fields was 7 in 132
patients (57.9%) and 3 to 4 in the remaining 96 (42.1%).
Demographic and treatment variables are summarized in
Table 1, and pathological stage and TRG are outlined in
Table 2. A sphincter-preserving surgery was performed in
60.2% of patients with low rectal cancer. A total of 155
patients (68%) received adjuvant ChT, of whom 84.5%
completed the planned treatment.
Evolution of the Disease
The median follow-up for the entire cohort was 49
months (range, 30–73). Fifty-four (23.7%) patients had
disease ­recurrence: 6 (2.6%) local recurrence (median
time to ­relapse, 12.5 months) and 47 (20.6%) had distant metastases (median time to relapse, 15.7 months); 16
­patients developed liver metastases, 34 lung metastases,
and 8 metastases in other locations. Only 1 patient (0.5%)
had both local and distant recurrence. Fourteen of 34 lung
­metastases and 11 of 16 liver metastases were ­histologically
confirmed. Of the patients who primarily had a relapse in
the liver, 77.8% had lung metastases in the course of the
disease. The median disease-free survival was not reached.
The estimated 5- and 10-year disease-free ­survival was
75.3% and 65.0%. At the time of the final analysis, 25
­patients (11.0%) had died of disease progression. Figure 1
shows the flow of patients through the study.
Prognosis Factors for Recurrence
Results of the univariate analyses regarding the risk of
­distant metastases are presented in Table 3.
Factors significantly associated to distant recurrence
by multivariate logistic regression analysis were y-pathological stage (III vs I/II: OR = 2.51, 95% CI 1.25–5.05;
p = 0.010), TRG (1/2 vs 3+/4: OR = 3.34, 95% CI 1.24–
9.02; 3 vs 3+/4: OR = 1.20, 95% CI 0.47–3.02; p = 0.014),
and low third location (OR = 2.36, 95% CI 1.15–4.85;
p = 0.016). The inclusion of patients with local recurrence
did not change these results.
Among all the variables related to the development
of liver metastases by univariate analysis (Table 3), only
the 3-point TRG retained its significance in logistic regression multivariate analysis (1/2 vs 3+/4: OR = 4.67, 95%
TABLE 2. Posttreatment pathological characteristics
and TRG scores
n (%)
y-pathological T
T0
T1
T2
T3
T4
y-pathological N
N0
N1
N2
Resected nodesa
Lymphovascular invasion
Perineural invasion
Distal margin status
<0.5 cm
0.5–1 cm
>1 cm
Distal margin distancea
TRG
0
1
2
3
3+
4
Final AJCC/UICC stage
0
I
II
III
26 (11.4)
15 (6.6)
76 (33.3)
108 (47.4)
3 (1.3)
158 (69.3)
58 (25.4)
12 (5.3)
9 (5–15)
35 (15.4)
43 (18.9)
6 (2.6)
22 (9.7)
200 (87.7)
6 (0.5–8)
0 (0)
5 (2.2)
47 (20.6)
96 (42.1)
49 (21.5)
26 (11.4)
52 (22.8)
96 (42.1)
75 (32.9)
26 (11.4)
70 (30.7)
62 (27.2)
70 (30.7)
TRG = tumor response grade; AJCC = American Joint Committee on Cancer;
UICC = Union for International Cancer Control.
a
Median (rank).
419
Diseases of the Colon & Rectum Volume 56: 4 (2013)
DISCUSSION
235 patient candidates for treatment
7 excluded: 3 with contraindication to CRT. 4 with previous cancer
228 patients completed neoadjuvant treatment
2 lost to 1-year follow-up
226
13 lost to 3-year follow-up
213
FIGURE 1. Flow of patients through the study. CRT = chemoradiotherapy.
CI 1.18–18.5 and 3 vs 3+/4: OR = 1.41, 95% CI 0.36–6.09;
p = 0.007).
Table 3 also highlights the risk factors associated to
lung recurrence in univariate analyses. Only the low third
location (OR = 3.23, 95% CI 1.27–8.13; p = 0.009) and the
TRG (1–2 vs 3+/4: OR = 5.5, 95% CI 1.74–17.3; 3 vs 3+/4:
OR = 1.84, 95% CI 0.66–5.67; p = 0.007) were significantly
correlated with lung relapse by multivariate analysis. Previous liver metastasis was also an independent prognostic factor for pulmonary recurrence (OR = 7.73, 95% CI
2.16–21.9; p = 0.002; data not shown in Table 3).
This study shows several clinical and pathological factors
that may be related to disease relapse in a large cohort of
LARC patients after a long-term follow-up.
By multivariate analysis, y-pathological stage, TRG,
and lower third location were found to be independently
associated with the risk of distant relapse. Although lung
metastases were related to lower third location, TRG, and
previous disease relapse in the liver, only TRG seemed
to influence the development of liver metastases. These
data should be viewed with caution, however, given the
low number of relapses seen in this cohort of patients.
The grouping that we have used for the y-pathological
stage coincides with the nodal involvement, a well-known
­prognosis factor for the development of metastases.
The lower risk of recurrence in patients with good
TRG shown in this study is in agreement with the results
reported by other groups.9,21–24 pCR was achieved in
11.4% of the patients, and none of them experienced
a relaps at any site. No patients with ypT0 had positive
lymph nodes. Previously reported pCR rates range
from 8% to 38%.21,22,25 Despite of the high percentage
TABLE 3. Univariate analyses of factors significantly related to distant recurrence
Recurrence/metastases
Distant
n (%)
y-pTNM
I,II (n = 156). N−
III (n = 66). N+
Tumor regression grade
1,2 (n = 50)
3 (n = 93)
3+,4d (n = 75)
Rectal third location
Lower (n = 124)
Middle, upper (n = 98)
Lymphovascular invasion
Yes (n = 33)
No n = (179)
Perineural invasion
Yes (n = 41)
No (n = 181)
Chemotherapy regimen
Oxaliplatin-based (n = 160)
Fluoropyrimidine-based (n = 62)
Radiotherapy
3–4 fields (n = 92)
7 fields (n = 130)
Surgical procedure
LAR (n = 171)
APR (n = 46)
Local recurrence has been excluded.
LAR = low anterior resection; APR = abdominoperineal resection.
a 2
χ.
b
Fisher exact test.
c 2
χ linear trend.
d
All tumor which relapsed were 3+.
Liver
p
n (%)
0.001a
24 (15.4)
24 (36.4)
p
<0.001c
0.002c
0.042a
0.974a
6 (18.2)
10 (5.3)
<0.001a
0.085b
0.002a
0.023a
11 (26.8)
23 (12.7)
0.003b
6 (3.8)
10 (16.1)
0.001a
30 (32.6)
18 (13.8)
0.002a
11 (33.3)
23 (12.2)
6 (14.6)
10 (5.5)
26(16.3)
22(35.5)
0.024a
25 (20.2)
9 (9.2)
0.018b
<0.001a
17 (41.5)
31 (17.1)
<0.001c
16 (32)
12 (12.9)
5 (6.7)
9 (7.3)
7 (7.1)
18 (54.5)
30 (15.9)
<0.001a
16 (10.0)
18 (29)
<0.001a
14 (15.2)
2 (1.5)
<0.001a
0.009a
21 (22.8)
13 (10.0)
0.181b
9 (5.3)
5 (10.9)
p
0.005 a
17 (10.9)
15 (25.8)
8 (16)
5 (5.4)
1 (1.3)
33 (26.6)
15 (15.3)
n (%)
0.087b
8 (5.1)
8 (12.1)
21 (42.0)
17 (18.3)
8 (10.7)
26 (15.2)
20 (43.5)
Lung
0.002a
20 (11.7)
14 (30.4)
420
of patients with low rectal cancer in the present series
(56.1%), our local recurrence rate (2.6%) is lower than
that reported by most authors,5,6,9–12,21,23–25 whereas
the distant metastases rate (21.1%) is similar to other
published results.5,6,9,10,21,24,26 We have also found a
posttreatment nodal involvement (30.7%) slightly higher
than in other studies.5,8–11,14,24
Total mesorectal excision was performed by the same
­senior surgical team 5 to 6 weeks after neoadjuvant treatment.
Sphincter preservation was achieved in 51 patients (60.2%)
with low rectal cancer. These results compare f­ avorably with
other reported series. Different rates of sphincter-sparing
surgery, which range from 35% to 62%, have been presented, possibly owing to the different s­ urgeons’ criteria, variations on the interval between r­adiation and surgery, and
different stage of disease.5,7,9,11,26,27
The rate of lung metastases is 2-fold that of liver
metastases. Recently published studies are in agreement
with this finding.28–30 Different theories have been proposed to explain the pattern of metastases, although this
process seems to be multifactorial.30 The most accepted
is the one based on the nature of the venous drainage
of the rectum.31,32 However some studies have suggested
that tumors may metastasize to specific organs independently from the vascular anatomy, given the existence of
different organ-specific microenvironments.33 Moreover,
a differential sensitivity to 5-FU-based chemotherapy in
lung pattern compared with liver metastases34 has also
been described because of a different expression of thymidilate synthase.35 The chest CT scan-based follow-up
used in this study may be another reason for the higher
rate of lung metastases in comparison with other works
in which surveillance was based simply on chest x-ray.36
This attitude is in agreement with the National Comprehensive Cancer Network surveillance guidelines and
the American Society of Clinical Oncology.20,37 There is
a growing evidence suggesting that new follow-up strategies are warranted.29,30,32,38 Whether a more intensive
follow-up will translate into a survival benefit remains
to be determined.39
This study has some limitations that deserve
­consideration. This is a single institutional experience,
recorded in a retrospective way, and the neoadjuvant
CRT regimen used is not homogeneous, as a consequence
of the evolution that the chemotherapy schedules have
presented in the past decade. This is a frequent matter in
long-term retrospective analysis. On the other hand, we
had few patients who developed ­metastasis, which obligates the results of the comparisons to be handled with
caution, especially those referred to h
­ epatic metastases.
This is one of the reasons why factors predicting local recurrence could not be assessed. Therefore, ­further studies in a larger series of patients with LARC are w
­ arranted
to validate these results.
Arredondo et al: Prognosis Factors in Rectal Cancer
CONCLUSIONS
Patients with low third LARC with a poor response to
neoadjuvant CRT (advanced y-pathological stage or low
TRG) have a higher likelihood of relapse. In this subset
of patients, intensive surveillance and the design of alternative therapeutic approaches aimed to lower the distant
failure rate seem warranted.
Acknowledgment
The authors thank Isabel de Salas Tornos for helping in
­editing the manuscript.
REFERENCES
1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA
­Cancer J Clin. 2010;60:277–300.
2. van Gijn W, Marijnen CA, Nagtegaal ID, et al; Dutch Colorectal
Cancer Group. Preoperative radiotherapy combined with total
mesorectal excision for resectable rectal cancer: 12-year followup of the multicentre, randomised controlled TME trial. Lancet
Oncol. 2011;12:575–582.
3.Medical Research Council Rectal Cancer Working Party.
Randomised trial of surgery alone versus surgery followed
by radiotherapy for mobile cancer of the rectum. Lancet.
1996;348:1610–1614.
4.MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for
­rectal cancer. Lancet. 1993;341:457–460.
5. Sauer R, Becker H, Hohenberger W, et al; German Rectal ­Cancer
Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731–1740.
6. Bosset JF, Collette L, Calais G, et al; EORTC Radiotherapy
Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114–1123.
7. Ruo L, Tickoo S, Klimstra DS, et al. Long-term prognostic significance of extent of rectal cancer response to preoperative
radiation and chemotherapy. Ann Surg. 2002;236:75–81.
8. Pucciarelli S, Friso ML, Toppan P, et al. Preoperative combined
radiotherapy and chemotherapy for middle and lower rectal
cancer: preliminary results. Ann Surg Oncol. 2000;7:38–44.
9. Valentini V, Coco C, Cellini N, et al. Preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor
response, and sphincter preservation. Int J Radiat Oncol Biol
Phys. 1998;40:1067–1075.
10. Guillem JG, Chessin DB, Cohen AM, et al. Long-term ­oncologic
outcome following preoperative combined modality therapy
and total mesorectal excision of locally advanced rectal cancer.
Ann Surg. 2005;241:829–836.
11.Feliu J, Calvilio J, Escribano A, et al. Neoadjuvant therapy of
rectal carcinoma with UFT-leucovorin plus radiotherapy. Ann
Oncol. 2002;13:730–736.
12. Grann A, Feng C, Wong D, et al. Preoperative combined modality therapy for clinically resectable uT3 rectal adenocarcinoma.
Int J Radiat Oncol Biol Phys. 2001;49:987–995.
13.Scott NA, Susnerwala S, Gollins S, Myint AS, Levine E. Preoperative neo-adjuvant therapy for curable rectal cancer–­reaching a
consensus 2008. Colorectal Dis. 2009;11:245–248.
Diseases of the Colon & Rectum Volume 56: 4 (2013)
14. Jin J, Meng H, Zhou G, et al. Preoperative radiotherapy combined with capecitabine chemotherapy in Chinese ­patients
with locally advanced rectal cancer. J Gastrointest Surg.
2011;15:1858–1865.
15. Bujko K, Glynne-Jones R, Bujko M. Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients
with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised
trials. Ann Oncol. 2010;21:1743–1750.
16. Kiran RP, Kirat HT, Burgess AN, Nisar PJ, Kalady MF, Lavery IC.
Is adjuvant chemotherapy really needed after curative surgery
for rectal cancer patients who are node-negative after neoadjuvant chemoradiotherapy? Ann Surg Oncol. 2012;19:1206–1212.
17. Dalton L, Page DL. Grading breast cancer on microarray samples: comparison with Nottingham grade, and use of boosting
classification. Histopathology. 2012;61:497–508.
18. Aristu JJ, Arbea L, Rodriguez J, et al. Phase I-II trial of concurrent capecitabine and oxaliplatin with preoperative intensity-modulated radiotherapy in patients with locally advanced
rectal cancer. Int J Radiat Oncol Biol Phys. 2008;71:748–755.
19. Arbea L, Martínez-Monge R, Díaz-González JA, et al. Fourweek neoadjuvant intensity-modulated radiation therapy with
concurrent capecitabine and oxaliplatin in locally advanced
rectal cancer patients: a validation phase II trial. Int J Radiat
Oncol Biol Phys. 2012;83:587–593.
20.NCCN Clinical Practice Guidelines in Oncology. Available at:
http://www.nccn.org. Accessed April 17, 2012.
21.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. 2010;11:835–844.
22.Martin ST, Heneghan HM, Winter DC. Systematic review and
meta-analysis of outcomes following pathological complete
­response to neoadjuvant chemoradiotherapy for rectal cancer.
Br J Surg. 2012;99:918–928.
23. García-Aguilar J, Hernandez de Anda E, Sirivongs P, Lee SH,
Madoff RD, Rothenberger DA. 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. 2003;46:298–304.
24. Vecchio FM, Valentini V, Minsky BD, et al. The relationship of
pathologic tumor regression grade (TRG) and outcomes after
preoperative therapy in rectal cancer. Int J Radiat Oncol Biol
Phys. 2005;62:752–760.
25. Rödel C, Liersch T, Becker H, et al; German Rectal Cancer
Study Group. 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. 2012;13:679–687.
421
26. Burke SJ, Percarpio BA, Knight DC, Kwasnik EM. Combined
preoperative radiation and mitomycin/5-fluorouracil treatment for locally advanced rectal adenocarcinoma. J Am Coll
Surg. 1998;187:164–170.
27. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski
W, Bebenek M, Kryj M. Long-term results of a randomized
trial comparing preoperative short-course radiotherapy with
preoperative conventionally fractionated chemoradiation for
rectal cancer. Br J Surg. 2006;93:1215–1223.
28. Kobayashi H, Mochizuki H, Sugihara K, et al. Characteristics of recurrence and surveillance tools after curative
­resection for colorectal cancer: a multicenter study. Surgery.
2007;141:67–75.
29. Mitry E, Guiu B, Cosconea S, Jooste V, Faivre J, Bouvier AM.
Epidemiology, management and prognosis of colorectal cancer
with lung metastases: a 30-year population-based study. Gut.
2010;59:1383–1388.
30. Ding P, Liska D, Tang P, et al. Pulmonary recurrence predominates after combined modality therapy for rectal cancer: an
original retrospective study. Ann Surg. 2012;256:111–116.
31. Tepper JE, O’Connell M, Hollis D, Niedzwiecki D, Cooke E,
Mayer RJ; Intergroup Study 0114. Analysis of surgical salvage
after failure of primary therapy in rectal cancer: results from
Intergroup Study 0114. J Clin Oncol. 2003;21:3623–3628.
32. Watanabe K, Saito N, Sugito M, Ito M, Kobayashi A, Nishizawa Y.
Predictive factors for pulmonary metastases after curative resection of rectal cancer without preoperative c­ hemoradiotherapy.
Dis Colon Rectum. 2011;54:989–998.
33.Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and
soil’ hypothesis revisited. Nat Rev Cancer. 2003;3:453–458.
34. Assersohn L, Norman A, Cunningham D, Benepal T, Ross PJ,
Oates J. Influence of metastatic site as an additional predictor
for response and outcome in advanced colorectal carcinoma.
Br J Cancer. 1999;79:1800–1805.
35. Yamada H, Ichikawa W, Uetake H, et al. Thymidylate synthase
gene expression in primary colorectal cancer and metastatic
sites. Clin Colorectal Cancer. 2001;1:169–174.
36. Kirke R, Rajesh A, Verma R, Bankart MJ. Rectal cancer: incidence of pulmonary metastases on thoracic CT and correlation
with T staging. J Comput Assist Tomogr. 2007;31:569–571.
37. Desch CE, Benson AB 3rd, Somerfield MR, et al; American
S­ociety of Clinical Oncology. Colorectal cancer surveillance: 2005
update of an American Society of Clinical Oncology ­practice
guideline. J Clin Oncol. 2005;23:8512–8519.
38. Lee WS, Yun SH, Chun HK, et al. Pulmonary resection for
­metastases from colorectal cancer: prognostic factors and survival. Int J Colorectal Dis. 2007;22:699–704.
39.Tjandra JJ, Chan MK. Follow-up after curative resection
of colorectal cancer: a meta-analysis. Dis Colon Rectum.
2007;50:1783–1799.