Int J Clin Oncol DOI 10.1007/s10147-013-0636-4
ORIGINAL ARTICLE
Preoperative versus postoperative chemoradiotherapy in stage T3, N0 rectal cancer ¨ zcan Yıldız • Deniz Tural • Fatih Selcukbiricik • O Olgun Elcin • Sibel Erdamar • Sabri Gu¨ney • Fuat Demireli • Evin Bu¨yu¨ku¨nal • Su¨heyla Serdengec¸ti
Received: 18 May 2013 / Accepted: 23 October 2013 Ó Japan Society of Clinical Oncology 2013
Abstract Background The study populations of previous preoperative chemoradiotherapy (pre-CRT) studies have consisted of mixed clinical stages, such as cT3-cT4 and/or cN positive. For this reason, it has not been possible to demonstrate whether pre-CRT is of benefit for individual subgroups. Methods The medical records of 137 rectal cancer patients with clinical stage T3, N0 disease who received either pre-CRT or postoperative chemoradiotherapy (postCRT) between 2002 and 2011 were retrospectively analyzed. The regimen of pre-CRT consisted of slow fluorouracil (5FU) infusion and that of post-CRT consisted of bolus 5FU and leucovorin concurrent with radiation. Results Following pre-CRT, significant downstaging was achieved. However, administration of pre-CRT did not influence the type of surgical resection in tumours B5 cm distant from the anal verge (p = 0.14). Pathological
complete response was achieved in 16 % of the patients in the pre-CRT group. The local recurrence rate (LRR) at 5 years was 5.7 % in the pre-CRT and 11.1 % in the postCRT groups (p = 0.04). The distant recurrence rate (DRR) at 5 years was 76 % and 77 % in the pre-CRT and postCRT groups, respectively (p = 0.1). Overall survival was similar in two groups (74.8 % vs. 75.3 %, p = 0.3). Conclusions The treatment of stage T3, N0 rectal cancer patients with pre-CRT followed by surgery decreased LRR, but did not improve DRR or OS as compared with surgery followed by post-CRT in our patient cohort. Keywords Preoperative chemoradiotherapy Postoperative chemoradiotherapy Stage T3 N0 rectal adenocarcinoma Outcome Introduction Following the 1990 National Institutes of Health Consensus Conference, adjuvant chemoradiation for all pT3 and/or
D. Tural (&) Division of Medical Oncology, Department of Internal Medicine, Medical Faculty, Akdeniz University, 7058 Antalya, Turkey e-mail: [email protected] F. Selcukbiricik Department of Medical Oncology, Sisli Education and Research Hospital, Istanbul, Turkey ¨ . Yıldız O Division of Medical Oncology, Department of Internal Medicine, Medical Faculty, Medipol University, Istanbul, Turkey
S. Erdamar Department of Pathology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey S. Gu¨ney Department of Surgery, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey F. Demireli E. Bu¨yu¨ku¨nal S. Serdengec¸ti Division of Medical Oncology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
O. Elcin Department of Radiation Oncology, Medical Faculty, Istanbul University Cerrahpasa, Istanbul, Turkey
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pN rectal adenocarcinomas has become the standard of care [1]. However, several studies prior to 1990 had demonstrated that patients undergoing sharp mesorectal resection of pT3, N0, M0 stage rectal cancer with favorable pathological features experience a low recurrence rate after surgery alone and it has been suggested that these patients may not significantly benefit from postoperative chemoradiotherapy (post-CRT) [2–5]. This is why it is not possible to demonstrate whether preoperative chemoradiotherapy (pre-CRT) is of benefit to every subgroup of patients. Gunderson et al. [6] identified patients with pT3, N0, M0 stage rectal cancer as a prognostic subgroup at intermediate risk, suggesting that post-CRT may be excessive for some patients in this subset. Park et al. [7] reported retrospective analysis data demonstrating that adjuvant radiotherapy did not seem to provide additional benefits in terms of decreased recurrence rate in T3, N0 (stage IIA) rectal cancer, and suggested that the role of radiotherapy needs to be carefully evaluated in selected patients with stage IIA rectal cancer. The German Rectal Cancer Study Group compared preCRT with post-CRT for the treatment of clinical stage T3, T4 and/or N-positive rectal cancer. The results of this study indicated that pre-CRT was associated with a significant reduction in local recurrence and treatment-associated toxicity compared with patients who received post-CRT [8]. On the other hand, a European Organisation for Research and Treatment of Cancer (EORTC) trial demonstrated that patients who received preoperative radiotherapy and either concurrent or postoperative chemotherapy had significantly lower rates of local recurrence than patients who received preoperative radiotherapy alone [9]. One possible drawback of pre-CRT is overtreatment of early lesions which would not require adjuvant therapy [8, 10]. Based on those trials, pre-CRT is recommended as a standard treatment modality for locally advanced rectal cancer [8, 9]. However, the role of pre-CRT is not clear in clinical (c) stages T3 and NO. The study population of pre-CRT studies has consisted of different clinical stages, such as cT3-cT4 and/or cN positive. In our study, we aimed to evaluate retrospectively local and distant recurrence rates and overall survival in patients undergoing pre-CRT and post-CRT in stage T3, N0, M0 rectal adenocarcinoma. Early and late complications and treatment toxicity were also evaluated.
Patients and methods Patients The medical records of 137 patients with clinical stage T3, N0, M0 rectal cancer who received either pre-CRT or post-
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CRT between 2002 and 2011 were analyzed retrospectively. Patients with a histological diagnosis of rectal adenocarcinoma were included in the study, provided that the tumour was located in the distal 15 cm from the anal verge. Preoperative staging was performed with thoracic and abdominal computed tomography (CT) or abdominal and pelvic magnetic resonance imaging (MRI) and endoscopic rectal ultrasonography (ERUS). The distances from the inferior aspect of the tumour to the anal verge were determined by rigid proctoscopy and colonoscopy. The clinical stage was determined based on the findings of MRI, CT, and ERUS by the same medical team. MRI and ERUS were performed to assess the depth of local tumour invasion. Written informed consent was obtained prior to the study from the patients or their next of kin. ERUS Ultrasound T stage was determined according to the fivelayer model proposed by Hildebrandt and Feifel [11]. Circular hypoechoic structures of at least 3 mm diameter were classified as malignant lymph nodes (LN). Nodes less than 3 mm in diameter or nodes with central hyperechogenicity were considered benign. MRI Images were made using a 1.5 T MR device with an endorectal and pelvic phased-array coil, as well as a spinal coil activated at the same time. An MRI diagnosis of T3 lesions was based on the presence of a tumor signal intensity extending through the muscle layers into the perirectal fat. LN with either heterogeneous signal intensity or an irregular border, regardless of node size, were considered suggestive of metastatic disease [12]. Treatment The chemotherapy regimen used concurrently with preoperative radiotherapy (RT) in all patients receiving pre-CRT was slow 5-fluorouracil (5FU) infusion (225 mg/m2/day). These patients received post-surgery, as indicated, 4 cycles of adjuvant bolus 5FU (425 mg/m2/day) and leucovorin (20 mg/m2/day), as in the Mayo regimen, on days 1–5 every 28 days. Bolus 5FU and leucovorin were administered on days 1–4, respectively, every 28 days concurrently with postoperative RT in the 3rd and 4th cycles of the planned 6 cycles of adjuvant chemotherapy. Eighty-nine percent of the patients received 50.4 Gy RT and 11 % received 45 Gy RT in 5 weeks. The total RT dose was delivered in 28 fractions of 1.8 Gy per day; a three- or four-box field technique was used. Then, a boost of 3 fractions of 5.4 Gy was given using four reduced fields
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including tumor with a 2-cm margin if indicated based on tumor site. Surgical resection was suggested 6–8 weeks after completion of preoperative CRT. Abdominoperineal resection (APR) or sphincter-saving surgery was performed based on the surgeon’s preference. Surgical resection was performed based on principles of total mesorectal excision. The 6th edition of the American Joint Committee on Cancer TNM system was used for staging [13]. If there was no viable tumor cell in the resected specimen, this was considered a complete response.
Table 1 Clinical characteristics of the patients
Follow-up
Tumour location
Patients were followed up every 3 months for 2 years, every 6 months between 2 and 5 years, and annually thereafter. Evaluation included clinical examination, complete blood count, serum chemistry, serum carcinoembryonic antigen (CEA) level, thoracic and abdominal CT and colonoscopy, as indicated. Adverse events were defined using the WHO criteria. Recurrence was diagnosed on the basis of imaging findings and/or elevated CEA levels. Pathological confirmation was obtained in selected cases.
Pre-CRT [n = 58 (42 %)]
Post-CRT [n = 79 (58 %)]
p value
58 (26–75)
58 (30–75)
0.2
30 (52) 28 (48)
41 (52) 38 (48)
LAR
36 (62)
47 (60)
APR
22 (38)
32 (40)
\5 cm
32 (56)
21 (27)
5–10 cm
21 (37)
36 (46)
[10 cm
4 (7)
Age (years) (median, range) Sex Male Female
0.6
Type of surgery
0.14
0.001
20 (26)
Unknown
1 (1)
Clinical stage imaging
0.3
MR ? CT MR ? ERUS
28 (48) 16 (28)
40 (51) 20 (25)
CT ? ERUS
14 (24)
19 (24)
LAR low anterior resection, APR abdominoperineal resection, MRI magnetic resonance imaging, CT: computed tomography, ERUS endoscopic rectal ultrasonography
Statistical methods Categorical and continuous variables were compared using chi-squared and Mann–Whitney U tests, respectively. Local recurrence-free survival (LRFS) and distant recurrence-free survival (DRFS) were defined as the time from diagnosis to the detection of any local or distant recurrence, respectively. Overall survival (OS) was defined as the time from diagnosis to death by any cause. LRFS, DRFS, and OS were estimated using the Kaplan– Meier method. The log-rank test was used to evaluate differences between groups. All analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 15.0 (SPSS Inc., Chicago, SA,USA) software. The statistical level of significance was defined as p \ 0.05.
Table 2 Post-surgical histopathological characteristics Pre-CRT [n (%)]
Post-CRT [n (%)]
p value
pT1
7 (12)
2 (3)
pT2
12 (21)
8 (10)
pT3
30 (51)
65 (82)
0.001
pT4
0
4 (5)
0.6
pCR
9 (16)
NA
NA
pN?
13 (23)
30 (38)
0.01
10 3–27
13 1–40
Histopathological findings
Number of lymph nodes harvested Median Range
0.02
0.02
NA not applicable
Results Patients The data from a total of 137 patients (84 females, 53 males) were analyzed. The median age was 58 years (range 26–76). Fifty-eight (42 %) patients received pre-CRT and 79 (58 %) received post-CRT. The median distance of the tumour from the anal verge was 5 cm (range 0–12) and 7 cm (range 0–15) in the pre-CRT and post-CRT arms
respectively, with a statistically significant difference between the two groups [p = 0.001, mean difference = 2.6 cm, 95 % confidence interval (CI) 1.3–4.2]. The interval between CRT and surgery ranged from 4 to 12 weeks, with a median of 7 weeks. Pre-CRT did not have any effect on the final surgery type in any of the patients (p = 0.4). There were no differences between clinical staging modality in the pre-CRT and post-CRT groups (p = 0.3).
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Int J Clin Oncol Table 3 Grade 3 or 4 toxic effects and long-term toxicity of chemoradiotherapy
Survival
Grade 3–4 toxicity
Median follow-up times for patients who underwent preCRT and post-CRT were 44.2 months (range 12–92) and 48.6 months (range 9–96), respectively. Of the 58 patients who received pre-CRT, local and distant recurrences developed in 1 and 9 patients, respectively. Of the 79 patients who received post-CRT, local and distant recurrences developed in 9 and 16, respectively. The cumulative incidence of local recurrence at five years was 5.7 % in the preoperative group and 11.1 % in the postoperative group (p = 0.04) (Fig. 1). The incidence of distant recurrence was not different between pre-CRT and post-CRT groups. DRR at 5 years was 76 % in pre-CRT and 77 % in post-CRT groups (p = 0.1) (Fig. 2). In the full analyses of all patients, 10 of the 58 patients (17 %) who received pre-CRT had a relapse and 9 (16 %) died. Among the 79 patients who received post-CRT, 26 (32 %) had a relapse and 15 (19 %) died. The OS rate was similar in pre-CRT and post-CRT patients. Five-year OS rates were 74.8 % in pre-CRT patients versus 75.3 % in post-CRT patients (p = 0.3) (Fig. 3).
Pre-CRT [n (%)]
Post-CRT [n (%)]
Hematological
2 (3)
6 (8)
Diarrhea
2 (3)
7 (8)
Nausea and vomiting Mucositis and dermatitis
1 (1) 6 (10)
4 (5) 8 (10)
Other
3 (6)
6 (8)
Total
14 (24.1)
31 (39.2)
p value
0.03
Long-term surgical toxicities Anastomotic site stenosis
2 (3)
5 (6)
Anastomosis leakage
1 (2)
2 (2)
Pelvic abscess
3 (5)
3 (3)
Fistula formation
1 (2)
4 (4)
Herniation
0
2 (2)
Total
7 (12)
16 (20)
0.01
Patient characteristics are summarized in Table 1. Accuracy of preoperative CRT imaging Among the 79 patients who did not receive pre-CRT , the overall accuracy of pretreatment clinical stage modality in evaluating the depth of tumour invasion and lymph node involvement were 82 % (65/79) and 62 % (49/79), respectively. Details are shown in Table 2. Efficacy of pre-CRT Among the 58 patients who had pre-CRT followed by radical surgery, 9 patients had no residual tumour detected in the resected specimen. Pathological CR was achieved in 16 % (9/58). Following pre-CRT, significant downstaging was achieved; downstaging rates were 41 % based on the T stage. Thirteen patients (23 %, 13/58) were node positive and these patients received pre-CRT after the surgical specimen had been evaluated. The pre-CRT arm had a smaller number of LN harvested (p = 0.02). Detailed histopathological characteristics are summarized in Table 2. Toxicity of CRT and surgery Overall grade 3/4 acute toxicities of pre-CRT and postCRT were 24.1 and 39.2 %, respectively (p = 0.03). Overall long-term and surgical complications of pre-CRT and post-CRT were 10 and 18 %, respectively (p = 0.01). Details of acute CRT and long-term surgical complications are presented in Table 3.
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Discussion Patients with local advanced rectal cancer (LARC) have a higher incidence of local recurrences following surgery alone. Several studies confirmed the efficacy of a short course of radiation (25 Gy over 5 days) for the treatment of rectal cancer [14–16]. The Swedish Rectal Cancer Trial showed a survival advantage and a decreased LRR in patients receiving a short course of preoperative RT. Other studies showed a decreased rate of LRR but no survival advantage. However, short-course preoperative RT increased postoperative complications [14]. Several randomized studies demonstrated the effectiveness of CRT compared with RT alone [17, 18]. However, the EORTC 22921 trial showed that, compared with RT alone, pre-CRT was associated with significantly higher pCR, lower pN stage, and less frequent lymphatic, venous and perineural invasion [18]. However, this trial showed no significant effect on survival despite significantly reduced local recurrence [9]. Bujko et al. [19] demonstrated that shortcourse preoperative radiotherapy had a lower rate of early toxicity and similar late toxicity when compared with patients who received preoperative conventional radiotherapy with chemotherapy. Moreover, the study failed to demonstrate any significant difference in terms of LRR and OS. The Fe´de´ration Francophone de la Cance´rologie Digestive (FFCD) 9203 trial comparing preoperative RT with CRT showed higher grade 3/4 acute toxicity and pCR
Int J Clin Oncol Fig. 1 Local recurrence-free survival in patients with preoperative chemoradiation vs. postoperative chemoradiation in stage T3, N0, M0 rectal adenocarcinoma
Fig. 2 Distant recurrence-free survival in patients with preoperative chemoradiation vs. postoperative chemoradiation in stage T3, N0, M0 rectal adenocarcinoma
rates with CRT [20]. There was no difference in sphincter preservation rates. Although LRR was lower in the pre-CRT group, OS was similar [20]. In a meta-analysis of 4 studies, pre-CRT was shown to enhance pCR and decrease LRR in stage II/III rectal cancer compared with preoperative RT
alone with no advantage in disease-free survival (DFS) or OS. Moreover, pre-CRT increased acute toxicity [21]. A large prospective, randomized trial from The German Rectal Cancer Study Group compared pre-CRT versus post-CRT in 823 patients with clinical T3, T4 or N-positive
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Int J Clin Oncol Fig. 3 Overall survival in patients with preoperative chemoradiation vs. postoperative chemoradiation in stage T3, N0, M0 rectal adenocarcinoma
rectal cancer [8]. All patients underwent total mesorectal excision (TME). This study showed that pre-CRT was associated with a significantly decreased 5-year cumulative incidence of LRR (6 vs. 13 %; p = 0.006) and treatmentassociated toxicity (27 vs. 40 %; p = 0.001) with a 46-month median follow-up. However, the pre-CRT arm did not show a 5-year OS advantage (76 vs. 74 %; p = 0.8). Moreover, complete resection and sphinctersparing surgery rates were also similar in the two treatment arms. Interestingly, among 194 patients with low-lying tumors who were preoperatively anticipated to require APR, a statistically significant increase in sphincter preservation was achieved among patients who received preCRT (39 vs. 19 % p = 0.004). A second prospective randomized trial from the National Surgical Adjuvant Breast and Bowel Project (NSABP) (R-03) comparing pre-CRT versus post-CRT in 267 LARC patients showed a 15 % pCR rate after pre-CRT [22]. The pre-CRT arm was associated with a significantly higher rate of 5-year DFS (64.7 vs. 53.4 %; p = 0.011) and a trend to better OS (74.5 vs. 65.6 %; p = 0.065). However, LRR was not different between the two treatment arms (10.7 % in both groups). There was no increase in sphincter preservation rates with pre-CRT. LRR was higher in the NSABP R-03 trial than in the German trial, possibly because of low TME rates. Kao et al. [24] compared pre-CRT with post-CRT in 136 patients with T3, T4 and N-positive disease. All patients underwent TME. The pCR rate following pre-CRT
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was 24.6 %. Moreover, pre-CRT was associated with significantly decreased 5-year LRR (5.8 vs. 19.4 %; p = 0.02) and increased OS (88.4 vs. 65.7 %; p = 0.001). However, the incidence of distant metastases was similar in the two treatment arms (26.1 vs. 40.3 %; p = 0.11). Although patients undergoing pre-CRT had a significantly higher sphincter preservation rate, there was no difference in the preserved anorectal function at the 5-year follow-up. Thus, pre-CRT has been broadly adopted as the standard of management for locally advanced rectal adenocarcinoma in most Western countries. Meanwhile, in the era of pre-CRT, the challenge continues to be the management of clinical stage T3, N0 disease. The study populations of pre-CRT consist of patients with varying clinical stages (T3, T4 and/or N positive), and it is not possible to predict whether each subgroup will benefit from pre-CRT or not. In the current study, pre-CRT was associated with significantly decreased 5-year LRR. LRR at 5 years was 5.7 % in the pre-CRT group compared with 11.1 % in the post-CRT group (p = 0.04). The incidence of distant recurrence and OS was not different between pre-CRT and post-CRT patients in our study. These results are consistent with those reported in recent studies for clinical stages T3, T4 and/or N-positive rectal adenocarcinoma. The type of surgical resection was not affected by the administration of pre-CRT in tumours B 5 cm distant from the anal verge (p = 0.14). However, we were not able to determine the percentage of patients who achieved
Int J Clin Oncol
sphincter preservation after pre-CRT in comparison with patients who were deemed to require APR in preoperative assessment. Finally, in line with previous studies, in our series, acute and late toxicities were encountered more frequently in post-CRT patients. With the increasing use of pre-CRT in patients with rectal adenocarcinoma, accurate staging is needed to avoid unnecessary treatment of early-stage tumours. Bipat et al. demonstrated this result using a meta-analysis of 90 studies that showed that ERUS and MRI have similarly high sensitivities for evaluating the depth of tumour penetration into the muscularis propria (94 %). ERUS was found be more specific than MRI in evaluation of local tumour invasion (86 % vs. 69 %) [25]. The sensitivity and specificity of the three imaging modalities were comparable for accurately evaluating lymph node metastases: CT (55 and 74), ERUS (67 and 78), MRI (66 and 76) [25]. A disadvantaged RUSG is highly operator-dependent and an advantaged MRI is able to provide accurate imaging of soft tissue structures and mesorectal fascia [25]. We demonstrated 82 % and 62 % deep tumour invasion and LN involvement, respectively, and these results are consistent with previous studies. Guillem et al. demonstrated with 188 patients that 22 % of patients staged before pre-CRT as having cT3, N0 rectal cancer on either ERUS or MRI had pathological LN metastases in this large retrospective multicenter study. Lombard et al. demonstrated with 32 patients that 28 % of patients staged before pre-CRT as having cT3, N0 rectal cancer had pathological positive LN involvement [10, 23]. We demonstrated that 23 % of patients with rectal cancer clinically staged as cT3, N0 before pre-CRT had LN involvement in the surgical specimen. These results are consistent with those reported in recent studies by Guillem et al. and Lombardi et al. It seems that currently, imaging performed before pre-CRT is likely to result in understaging and thus an undertreatment of a number of cT3, N0 rectal cancers. Therefore, in the area of preoperative evaluation of rectal cancer patients, the determination of LN involvement and depth, and tumour stage should be a major concern for the radiologist. On the other hand, a number of trials have demonstrated that patients who underwent surgical resection of stage T3, N0, M0 rectal adenocarcinoma with favourable pathological features experienced a low rate of local recurrence after surgery alone, and it has been suggested that these patients may not benefit from post-CRT [2–4]. There is no clear consensus on the management of stage T3, N0 patients with rectal cancer regarding pre-CRT and postCRT. There are no clinical trials in this area. Our study is the first to compare pre-CRT with post-CRT in terms of local recurrence, distant failure, overall survival, and toxicity. The main limitation of this study is the bias that arises
from its retrospective design. We believe that randomized trials are required in this area. In conclusion, in the treatment of stage T3, N0 patients with rectal cancer, pre-CRT followed by surgery, as compared with surgery followed by post-CRT, decreased LRR, but did not improve DRR or OS in our patient cohort. PreCRT was better tolerated with fewer acute and late toxicities. Conflict of interest interest.
The authors have indicated no conflicts of
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ORIGINAL ARTICLE
Preoperative versus postoperative chemoradiotherapy in stage T3, N0 rectal cancer ¨ zcan Yıldız • Deniz Tural • Fatih Selcukbiricik • O Olgun Elcin • Sibel Erdamar • Sabri Gu¨ney • Fuat Demireli • Evin Bu¨yu¨ku¨nal • Su¨heyla Serdengec¸ti
Received: 18 May 2013 / Accepted: 23 October 2013 Ó Japan Society of Clinical Oncology 2013
Abstract Background The study populations of previous preoperative chemoradiotherapy (pre-CRT) studies have consisted of mixed clinical stages, such as cT3-cT4 and/or cN positive. For this reason, it has not been possible to demonstrate whether pre-CRT is of benefit for individual subgroups. Methods The medical records of 137 rectal cancer patients with clinical stage T3, N0 disease who received either pre-CRT or postoperative chemoradiotherapy (postCRT) between 2002 and 2011 were retrospectively analyzed. The regimen of pre-CRT consisted of slow fluorouracil (5FU) infusion and that of post-CRT consisted of bolus 5FU and leucovorin concurrent with radiation. Results Following pre-CRT, significant downstaging was achieved. However, administration of pre-CRT did not influence the type of surgical resection in tumours B5 cm distant from the anal verge (p = 0.14). Pathological
complete response was achieved in 16 % of the patients in the pre-CRT group. The local recurrence rate (LRR) at 5 years was 5.7 % in the pre-CRT and 11.1 % in the postCRT groups (p = 0.04). The distant recurrence rate (DRR) at 5 years was 76 % and 77 % in the pre-CRT and postCRT groups, respectively (p = 0.1). Overall survival was similar in two groups (74.8 % vs. 75.3 %, p = 0.3). Conclusions The treatment of stage T3, N0 rectal cancer patients with pre-CRT followed by surgery decreased LRR, but did not improve DRR or OS as compared with surgery followed by post-CRT in our patient cohort. Keywords Preoperative chemoradiotherapy Postoperative chemoradiotherapy Stage T3 N0 rectal adenocarcinoma Outcome Introduction Following the 1990 National Institutes of Health Consensus Conference, adjuvant chemoradiation for all pT3 and/or
D. Tural (&) Division of Medical Oncology, Department of Internal Medicine, Medical Faculty, Akdeniz University, 7058 Antalya, Turkey e-mail: [email protected] F. Selcukbiricik Department of Medical Oncology, Sisli Education and Research Hospital, Istanbul, Turkey ¨ . Yıldız O Division of Medical Oncology, Department of Internal Medicine, Medical Faculty, Medipol University, Istanbul, Turkey
S. Erdamar Department of Pathology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey S. Gu¨ney Department of Surgery, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey F. Demireli E. Bu¨yu¨ku¨nal S. Serdengec¸ti Division of Medical Oncology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
O. Elcin Department of Radiation Oncology, Medical Faculty, Istanbul University Cerrahpasa, Istanbul, Turkey
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pN rectal adenocarcinomas has become the standard of care [1]. However, several studies prior to 1990 had demonstrated that patients undergoing sharp mesorectal resection of pT3, N0, M0 stage rectal cancer with favorable pathological features experience a low recurrence rate after surgery alone and it has been suggested that these patients may not significantly benefit from postoperative chemoradiotherapy (post-CRT) [2–5]. This is why it is not possible to demonstrate whether preoperative chemoradiotherapy (pre-CRT) is of benefit to every subgroup of patients. Gunderson et al. [6] identified patients with pT3, N0, M0 stage rectal cancer as a prognostic subgroup at intermediate risk, suggesting that post-CRT may be excessive for some patients in this subset. Park et al. [7] reported retrospective analysis data demonstrating that adjuvant radiotherapy did not seem to provide additional benefits in terms of decreased recurrence rate in T3, N0 (stage IIA) rectal cancer, and suggested that the role of radiotherapy needs to be carefully evaluated in selected patients with stage IIA rectal cancer. The German Rectal Cancer Study Group compared preCRT with post-CRT for the treatment of clinical stage T3, T4 and/or N-positive rectal cancer. The results of this study indicated that pre-CRT was associated with a significant reduction in local recurrence and treatment-associated toxicity compared with patients who received post-CRT [8]. On the other hand, a European Organisation for Research and Treatment of Cancer (EORTC) trial demonstrated that patients who received preoperative radiotherapy and either concurrent or postoperative chemotherapy had significantly lower rates of local recurrence than patients who received preoperative radiotherapy alone [9]. One possible drawback of pre-CRT is overtreatment of early lesions which would not require adjuvant therapy [8, 10]. Based on those trials, pre-CRT is recommended as a standard treatment modality for locally advanced rectal cancer [8, 9]. However, the role of pre-CRT is not clear in clinical (c) stages T3 and NO. The study population of pre-CRT studies has consisted of different clinical stages, such as cT3-cT4 and/or cN positive. In our study, we aimed to evaluate retrospectively local and distant recurrence rates and overall survival in patients undergoing pre-CRT and post-CRT in stage T3, N0, M0 rectal adenocarcinoma. Early and late complications and treatment toxicity were also evaluated.
Patients and methods Patients The medical records of 137 patients with clinical stage T3, N0, M0 rectal cancer who received either pre-CRT or post-
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CRT between 2002 and 2011 were analyzed retrospectively. Patients with a histological diagnosis of rectal adenocarcinoma were included in the study, provided that the tumour was located in the distal 15 cm from the anal verge. Preoperative staging was performed with thoracic and abdominal computed tomography (CT) or abdominal and pelvic magnetic resonance imaging (MRI) and endoscopic rectal ultrasonography (ERUS). The distances from the inferior aspect of the tumour to the anal verge were determined by rigid proctoscopy and colonoscopy. The clinical stage was determined based on the findings of MRI, CT, and ERUS by the same medical team. MRI and ERUS were performed to assess the depth of local tumour invasion. Written informed consent was obtained prior to the study from the patients or their next of kin. ERUS Ultrasound T stage was determined according to the fivelayer model proposed by Hildebrandt and Feifel [11]. Circular hypoechoic structures of at least 3 mm diameter were classified as malignant lymph nodes (LN). Nodes less than 3 mm in diameter or nodes with central hyperechogenicity were considered benign. MRI Images were made using a 1.5 T MR device with an endorectal and pelvic phased-array coil, as well as a spinal coil activated at the same time. An MRI diagnosis of T3 lesions was based on the presence of a tumor signal intensity extending through the muscle layers into the perirectal fat. LN with either heterogeneous signal intensity or an irregular border, regardless of node size, were considered suggestive of metastatic disease [12]. Treatment The chemotherapy regimen used concurrently with preoperative radiotherapy (RT) in all patients receiving pre-CRT was slow 5-fluorouracil (5FU) infusion (225 mg/m2/day). These patients received post-surgery, as indicated, 4 cycles of adjuvant bolus 5FU (425 mg/m2/day) and leucovorin (20 mg/m2/day), as in the Mayo regimen, on days 1–5 every 28 days. Bolus 5FU and leucovorin were administered on days 1–4, respectively, every 28 days concurrently with postoperative RT in the 3rd and 4th cycles of the planned 6 cycles of adjuvant chemotherapy. Eighty-nine percent of the patients received 50.4 Gy RT and 11 % received 45 Gy RT in 5 weeks. The total RT dose was delivered in 28 fractions of 1.8 Gy per day; a three- or four-box field technique was used. Then, a boost of 3 fractions of 5.4 Gy was given using four reduced fields
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including tumor with a 2-cm margin if indicated based on tumor site. Surgical resection was suggested 6–8 weeks after completion of preoperative CRT. Abdominoperineal resection (APR) or sphincter-saving surgery was performed based on the surgeon’s preference. Surgical resection was performed based on principles of total mesorectal excision. The 6th edition of the American Joint Committee on Cancer TNM system was used for staging [13]. If there was no viable tumor cell in the resected specimen, this was considered a complete response.
Table 1 Clinical characteristics of the patients
Follow-up
Tumour location
Patients were followed up every 3 months for 2 years, every 6 months between 2 and 5 years, and annually thereafter. Evaluation included clinical examination, complete blood count, serum chemistry, serum carcinoembryonic antigen (CEA) level, thoracic and abdominal CT and colonoscopy, as indicated. Adverse events were defined using the WHO criteria. Recurrence was diagnosed on the basis of imaging findings and/or elevated CEA levels. Pathological confirmation was obtained in selected cases.
Pre-CRT [n = 58 (42 %)]
Post-CRT [n = 79 (58 %)]
p value
58 (26–75)
58 (30–75)
0.2
30 (52) 28 (48)
41 (52) 38 (48)
LAR
36 (62)
47 (60)
APR
22 (38)
32 (40)
\5 cm
32 (56)
21 (27)
5–10 cm
21 (37)
36 (46)
[10 cm
4 (7)
Age (years) (median, range) Sex Male Female
0.6
Type of surgery
0.14
0.001
20 (26)
Unknown
1 (1)
Clinical stage imaging
0.3
MR ? CT MR ? ERUS
28 (48) 16 (28)
40 (51) 20 (25)
CT ? ERUS
14 (24)
19 (24)
LAR low anterior resection, APR abdominoperineal resection, MRI magnetic resonance imaging, CT: computed tomography, ERUS endoscopic rectal ultrasonography
Statistical methods Categorical and continuous variables were compared using chi-squared and Mann–Whitney U tests, respectively. Local recurrence-free survival (LRFS) and distant recurrence-free survival (DRFS) were defined as the time from diagnosis to the detection of any local or distant recurrence, respectively. Overall survival (OS) was defined as the time from diagnosis to death by any cause. LRFS, DRFS, and OS were estimated using the Kaplan– Meier method. The log-rank test was used to evaluate differences between groups. All analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 15.0 (SPSS Inc., Chicago, SA,USA) software. The statistical level of significance was defined as p \ 0.05.
Table 2 Post-surgical histopathological characteristics Pre-CRT [n (%)]
Post-CRT [n (%)]
p value
pT1
7 (12)
2 (3)
pT2
12 (21)
8 (10)
pT3
30 (51)
65 (82)
0.001
pT4
0
4 (5)
0.6
pCR
9 (16)
NA
NA
pN?
13 (23)
30 (38)
0.01
10 3–27
13 1–40
Histopathological findings
Number of lymph nodes harvested Median Range
0.02
0.02
NA not applicable
Results Patients The data from a total of 137 patients (84 females, 53 males) were analyzed. The median age was 58 years (range 26–76). Fifty-eight (42 %) patients received pre-CRT and 79 (58 %) received post-CRT. The median distance of the tumour from the anal verge was 5 cm (range 0–12) and 7 cm (range 0–15) in the pre-CRT and post-CRT arms
respectively, with a statistically significant difference between the two groups [p = 0.001, mean difference = 2.6 cm, 95 % confidence interval (CI) 1.3–4.2]. The interval between CRT and surgery ranged from 4 to 12 weeks, with a median of 7 weeks. Pre-CRT did not have any effect on the final surgery type in any of the patients (p = 0.4). There were no differences between clinical staging modality in the pre-CRT and post-CRT groups (p = 0.3).
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Int J Clin Oncol Table 3 Grade 3 or 4 toxic effects and long-term toxicity of chemoradiotherapy
Survival
Grade 3–4 toxicity
Median follow-up times for patients who underwent preCRT and post-CRT were 44.2 months (range 12–92) and 48.6 months (range 9–96), respectively. Of the 58 patients who received pre-CRT, local and distant recurrences developed in 1 and 9 patients, respectively. Of the 79 patients who received post-CRT, local and distant recurrences developed in 9 and 16, respectively. The cumulative incidence of local recurrence at five years was 5.7 % in the preoperative group and 11.1 % in the postoperative group (p = 0.04) (Fig. 1). The incidence of distant recurrence was not different between pre-CRT and post-CRT groups. DRR at 5 years was 76 % in pre-CRT and 77 % in post-CRT groups (p = 0.1) (Fig. 2). In the full analyses of all patients, 10 of the 58 patients (17 %) who received pre-CRT had a relapse and 9 (16 %) died. Among the 79 patients who received post-CRT, 26 (32 %) had a relapse and 15 (19 %) died. The OS rate was similar in pre-CRT and post-CRT patients. Five-year OS rates were 74.8 % in pre-CRT patients versus 75.3 % in post-CRT patients (p = 0.3) (Fig. 3).
Pre-CRT [n (%)]
Post-CRT [n (%)]
Hematological
2 (3)
6 (8)
Diarrhea
2 (3)
7 (8)
Nausea and vomiting Mucositis and dermatitis
1 (1) 6 (10)
4 (5) 8 (10)
Other
3 (6)
6 (8)
Total
14 (24.1)
31 (39.2)
p value
0.03
Long-term surgical toxicities Anastomotic site stenosis
2 (3)
5 (6)
Anastomosis leakage
1 (2)
2 (2)
Pelvic abscess
3 (5)
3 (3)
Fistula formation
1 (2)
4 (4)
Herniation
0
2 (2)
Total
7 (12)
16 (20)
0.01
Patient characteristics are summarized in Table 1. Accuracy of preoperative CRT imaging Among the 79 patients who did not receive pre-CRT , the overall accuracy of pretreatment clinical stage modality in evaluating the depth of tumour invasion and lymph node involvement were 82 % (65/79) and 62 % (49/79), respectively. Details are shown in Table 2. Efficacy of pre-CRT Among the 58 patients who had pre-CRT followed by radical surgery, 9 patients had no residual tumour detected in the resected specimen. Pathological CR was achieved in 16 % (9/58). Following pre-CRT, significant downstaging was achieved; downstaging rates were 41 % based on the T stage. Thirteen patients (23 %, 13/58) were node positive and these patients received pre-CRT after the surgical specimen had been evaluated. The pre-CRT arm had a smaller number of LN harvested (p = 0.02). Detailed histopathological characteristics are summarized in Table 2. Toxicity of CRT and surgery Overall grade 3/4 acute toxicities of pre-CRT and postCRT were 24.1 and 39.2 %, respectively (p = 0.03). Overall long-term and surgical complications of pre-CRT and post-CRT were 10 and 18 %, respectively (p = 0.01). Details of acute CRT and long-term surgical complications are presented in Table 3.
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Discussion Patients with local advanced rectal cancer (LARC) have a higher incidence of local recurrences following surgery alone. Several studies confirmed the efficacy of a short course of radiation (25 Gy over 5 days) for the treatment of rectal cancer [14–16]. The Swedish Rectal Cancer Trial showed a survival advantage and a decreased LRR in patients receiving a short course of preoperative RT. Other studies showed a decreased rate of LRR but no survival advantage. However, short-course preoperative RT increased postoperative complications [14]. Several randomized studies demonstrated the effectiveness of CRT compared with RT alone [17, 18]. However, the EORTC 22921 trial showed that, compared with RT alone, pre-CRT was associated with significantly higher pCR, lower pN stage, and less frequent lymphatic, venous and perineural invasion [18]. However, this trial showed no significant effect on survival despite significantly reduced local recurrence [9]. Bujko et al. [19] demonstrated that shortcourse preoperative radiotherapy had a lower rate of early toxicity and similar late toxicity when compared with patients who received preoperative conventional radiotherapy with chemotherapy. Moreover, the study failed to demonstrate any significant difference in terms of LRR and OS. The Fe´de´ration Francophone de la Cance´rologie Digestive (FFCD) 9203 trial comparing preoperative RT with CRT showed higher grade 3/4 acute toxicity and pCR
Int J Clin Oncol Fig. 1 Local recurrence-free survival in patients with preoperative chemoradiation vs. postoperative chemoradiation in stage T3, N0, M0 rectal adenocarcinoma
Fig. 2 Distant recurrence-free survival in patients with preoperative chemoradiation vs. postoperative chemoradiation in stage T3, N0, M0 rectal adenocarcinoma
rates with CRT [20]. There was no difference in sphincter preservation rates. Although LRR was lower in the pre-CRT group, OS was similar [20]. In a meta-analysis of 4 studies, pre-CRT was shown to enhance pCR and decrease LRR in stage II/III rectal cancer compared with preoperative RT
alone with no advantage in disease-free survival (DFS) or OS. Moreover, pre-CRT increased acute toxicity [21]. A large prospective, randomized trial from The German Rectal Cancer Study Group compared pre-CRT versus post-CRT in 823 patients with clinical T3, T4 or N-positive
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Int J Clin Oncol Fig. 3 Overall survival in patients with preoperative chemoradiation vs. postoperative chemoradiation in stage T3, N0, M0 rectal adenocarcinoma
rectal cancer [8]. All patients underwent total mesorectal excision (TME). This study showed that pre-CRT was associated with a significantly decreased 5-year cumulative incidence of LRR (6 vs. 13 %; p = 0.006) and treatmentassociated toxicity (27 vs. 40 %; p = 0.001) with a 46-month median follow-up. However, the pre-CRT arm did not show a 5-year OS advantage (76 vs. 74 %; p = 0.8). Moreover, complete resection and sphinctersparing surgery rates were also similar in the two treatment arms. Interestingly, among 194 patients with low-lying tumors who were preoperatively anticipated to require APR, a statistically significant increase in sphincter preservation was achieved among patients who received preCRT (39 vs. 19 % p = 0.004). A second prospective randomized trial from the National Surgical Adjuvant Breast and Bowel Project (NSABP) (R-03) comparing pre-CRT versus post-CRT in 267 LARC patients showed a 15 % pCR rate after pre-CRT [22]. The pre-CRT arm was associated with a significantly higher rate of 5-year DFS (64.7 vs. 53.4 %; p = 0.011) and a trend to better OS (74.5 vs. 65.6 %; p = 0.065). However, LRR was not different between the two treatment arms (10.7 % in both groups). There was no increase in sphincter preservation rates with pre-CRT. LRR was higher in the NSABP R-03 trial than in the German trial, possibly because of low TME rates. Kao et al. [24] compared pre-CRT with post-CRT in 136 patients with T3, T4 and N-positive disease. All patients underwent TME. The pCR rate following pre-CRT
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was 24.6 %. Moreover, pre-CRT was associated with significantly decreased 5-year LRR (5.8 vs. 19.4 %; p = 0.02) and increased OS (88.4 vs. 65.7 %; p = 0.001). However, the incidence of distant metastases was similar in the two treatment arms (26.1 vs. 40.3 %; p = 0.11). Although patients undergoing pre-CRT had a significantly higher sphincter preservation rate, there was no difference in the preserved anorectal function at the 5-year follow-up. Thus, pre-CRT has been broadly adopted as the standard of management for locally advanced rectal adenocarcinoma in most Western countries. Meanwhile, in the era of pre-CRT, the challenge continues to be the management of clinical stage T3, N0 disease. The study populations of pre-CRT consist of patients with varying clinical stages (T3, T4 and/or N positive), and it is not possible to predict whether each subgroup will benefit from pre-CRT or not. In the current study, pre-CRT was associated with significantly decreased 5-year LRR. LRR at 5 years was 5.7 % in the pre-CRT group compared with 11.1 % in the post-CRT group (p = 0.04). The incidence of distant recurrence and OS was not different between pre-CRT and post-CRT patients in our study. These results are consistent with those reported in recent studies for clinical stages T3, T4 and/or N-positive rectal adenocarcinoma. The type of surgical resection was not affected by the administration of pre-CRT in tumours B 5 cm distant from the anal verge (p = 0.14). However, we were not able to determine the percentage of patients who achieved
Int J Clin Oncol
sphincter preservation after pre-CRT in comparison with patients who were deemed to require APR in preoperative assessment. Finally, in line with previous studies, in our series, acute and late toxicities were encountered more frequently in post-CRT patients. With the increasing use of pre-CRT in patients with rectal adenocarcinoma, accurate staging is needed to avoid unnecessary treatment of early-stage tumours. Bipat et al. demonstrated this result using a meta-analysis of 90 studies that showed that ERUS and MRI have similarly high sensitivities for evaluating the depth of tumour penetration into the muscularis propria (94 %). ERUS was found be more specific than MRI in evaluation of local tumour invasion (86 % vs. 69 %) [25]. The sensitivity and specificity of the three imaging modalities were comparable for accurately evaluating lymph node metastases: CT (55 and 74), ERUS (67 and 78), MRI (66 and 76) [25]. A disadvantaged RUSG is highly operator-dependent and an advantaged MRI is able to provide accurate imaging of soft tissue structures and mesorectal fascia [25]. We demonstrated 82 % and 62 % deep tumour invasion and LN involvement, respectively, and these results are consistent with previous studies. Guillem et al. demonstrated with 188 patients that 22 % of patients staged before pre-CRT as having cT3, N0 rectal cancer on either ERUS or MRI had pathological LN metastases in this large retrospective multicenter study. Lombard et al. demonstrated with 32 patients that 28 % of patients staged before pre-CRT as having cT3, N0 rectal cancer had pathological positive LN involvement [10, 23]. We demonstrated that 23 % of patients with rectal cancer clinically staged as cT3, N0 before pre-CRT had LN involvement in the surgical specimen. These results are consistent with those reported in recent studies by Guillem et al. and Lombardi et al. It seems that currently, imaging performed before pre-CRT is likely to result in understaging and thus an undertreatment of a number of cT3, N0 rectal cancers. Therefore, in the area of preoperative evaluation of rectal cancer patients, the determination of LN involvement and depth, and tumour stage should be a major concern for the radiologist. On the other hand, a number of trials have demonstrated that patients who underwent surgical resection of stage T3, N0, M0 rectal adenocarcinoma with favourable pathological features experienced a low rate of local recurrence after surgery alone, and it has been suggested that these patients may not benefit from post-CRT [2–4]. There is no clear consensus on the management of stage T3, N0 patients with rectal cancer regarding pre-CRT and postCRT. There are no clinical trials in this area. Our study is the first to compare pre-CRT with post-CRT in terms of local recurrence, distant failure, overall survival, and toxicity. The main limitation of this study is the bias that arises
from its retrospective design. We believe that randomized trials are required in this area. In conclusion, in the treatment of stage T3, N0 patients with rectal cancer, pre-CRT followed by surgery, as compared with surgery followed by post-CRT, decreased LRR, but did not improve DRR or OS in our patient cohort. PreCRT was better tolerated with fewer acute and late toxicities. Conflict of interest interest.
The authors have indicated no conflicts of
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